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Atrophic vaginitis Other namesVulvovaginal atrophy,[1] vaginal atrophy,[1] genitourinary syndrome of menopause,[1] estrogen deficient vaginitis[2] Normal vaginal mucosa (left) versus vaginal atrophy (right) SpecialtyGynecology SymptomsPain with sex, vaginal itchiness or dryness, an urge to urinate[1] ComplicationsUrinary tract infections[1] DurationLong term[1] CausesLack of estrogen[1] Risk factorsMenopause, breastfeeding, certain medications[1] Diagnostic methodBased on symptoms[1] Differential diagnosisInfectious vaginitis, vulvar cancer, contact dermatitis[2] TreatmentVaginal estrogen[1] FrequencyHalf of women (after menopause)[1] Atrophic vaginitis is inflammation of the vagina as a result of tissue thinning due to not enough estrogen.[2] Symptoms may include pain with sex, vaginal itchiness or dryness, and an urge to urinate or burning with urination.[1][3] It generally does not resolve without ongoing treatment.[1] Complications may include urinary tract infections.[1] The lack of estrogen typically occurs following menopause.[1] Other causes may include when breastfeeding or as a result of specific medications.[1] Risk factors include smoking.[2] Diagnosis is typically based on symptoms.[1] Treatment is generally with estrogen cream applied to the vagina.[1] Other measures that may help include vaginal lubricants.[1] It is recommended that soaps and other irritants are avoided.[2] About half of postmenopausal women are affected.[1] Many however are not being treated.[2] Women often report reduced enjoyment in sex as well as life generally.[1] ## Contents * 1 Signs and symptoms * 2 Diagnosis * 3 Treatment * 4 Epidemiology * 5 Terminology * 6 Research * 7 References * 8 External links ## Signs and symptoms[edit] After menopause the vaginal epithelium changes and becomes a few layers thick.[4] Many of the signs and symptoms that accompany menopause occur in atrophic vaginitis.[5] Genitourinary symptoms include * dryness[3][6] * pain[3][6] * itching[3][1] * burning[3][6] * soreness * pressure * white discharge * malodorous discharge due to infection * painful sexual intercourse * bleeding after intercourse[7] * painful urination[3] * blood in the urine * increased urinary frequency[3][6] * incontinence * increased susceptibility to infections[3] * decreased vaginal lubrication[6] * urinary tract infections[1][6] * painful urination[6] * difficulty sitting[1] * difficulty wiping[1] ## Diagnosis[edit] Since women can have signs and symptoms that could be attributed to other causes, diagnosis is based upon the symptoms that cannot be better accounted for by another diagnosis.[6] Lab tests usually do not provide information that will aid in diagnosing. A visual exam is useful. The observations of the following may indicate lower estrogen levels: little pubic hair, loss of the labial fat pad, thinning and resorption of the labia minora, and the narrowing of the vaginal opening. An internal exam will reveal the presence of low vaginal muscle tone, the lining of the vagina appears smooth, shiny, pale with loss of folds. The cervical fornices may have disappeared and the cervix can appear flush with the top of the vagina. Inflammation is apparent when the vaginal lining bleeds easily and appears swollen.[1] The vaginal pH will be measured at 4.5 and higher.[8] ## Treatment[edit] Symptoms of genitourinary syndrome of menopause (GSM) will unlikely be resolved without treatment.[1] Women may have many or a few symptoms so treatment is provided that best suits each woman. If other health problems are also present, these can be taken into account when determining the best course of treatment. For those who have symptoms related to sexual activities, a lubricant may be sufficient.[1][9] If both urinary and genital symptoms exist, local, low-dose estrogen therapy can be effective. Those women who are survivors of hormone-sensitive cancer may need to be treated more cautiously.[1] Some women can have symptoms that are widespread and may be at risk for osteoporosis. Estrogen and adjuvants may be best.[9] Topical treatment with estrogen is effective when the symptoms are severe and relieves the disruption in pH to restore the microbiome of the vagina. When symptoms include those related to the urinary system, systematic treatment can be used. Recommendations for the use of the lowest effective dose for the shortest duration help to prevent adverse endometrial effects.[9] Some treatments have been developed more recently. These include selective estrogen receptor modulators, vaginal dehydroepiandrosterone, and laser therapy. Other treatments are available without a prescription such as vaginal lubricants and moisturizers. Vaginal dilators may be helpful. Since GSM may also cause urinary problems related to pelvic floor dysfunction, a woman may benefit from pelvic floor strengthening exercises. Women and their partners have reported that estrogen therapy resulted in less painful sex, more satisfaction with sex, and an improvement in their sex life.[1] ## Epidemiology[edit] Up to 50% of postmenopausal women have at least some degree of vaginal atrophy. It is likely to be underdiagnosed and undertreated.[1] ## Terminology[edit] Vulvovaginal atrophy, and atrophic vaginitis have been the preferred terms for this condition and cluster of symptoms until recently. These terms are now regarded as inaccurate in describing changes to the entire genitourinary system occurring after menopause. The term atrophic vaginitis suggests that the vagina is inflamed or infected. Though this may be true, inflammation and infection are not the major components of postmenopausal changes to the vagina. The former terms do not describe the negative effects on the lower urinary tract which can be the most troubling symptoms of menopause for women.[3] Genitourinary syndrome of menopause (GSM) was determined to be more accurate than vulvovaginal atrophy by two professional societies.[1][6][10] The term atrophic vaginitis does not reflect the related changes of the labia, clitoris, vestibule, urethra and bladder.[6] ## Research[edit] The FDA has approved the use of lasers in the treatment of many disorders. The treatment of GSM is not specifically mentioned in the list of disorders by the United States' Food and Drug Administration (FDA) but laser treatments have had success. Larger studies are still needed. The laser treatment works by resurfacing the vaginal epithelium and activating growth factors that increases blood flow, deposition of collage and the thickness of the vaginal lining. Women treated with laser therapy reported diminished symptoms of dryness, burning, itching, pain during sexual intercourse, and painful urination. Few adverse effects were noted.[1] In 2018, the FDA issued a warning that lasers and other high energy devices were not approved for this application and it had received multiple reports of injuries.[11] ## References[edit] 1. ^ a b c d e f g h i j k l m n o p q r s t u v w x y z aa ab ac ad ae af ag Faubion, SS; Sood, R; Kapoor, E (December 2017). "Genitourinary Syndrome of Menopause: Management Strategies for the Clinician". Mayo Clinic Proceedings. 92 (12): 1842–1849. doi:10.1016/j.mayocp.2017.08.019. PMID 29202940. 2. ^ a b c d e f Ferri, Fred F. (2016). Ferri's Clinical Advisor 2017 E-Book: 5 Books in 1. Elsevier Health Sciences. p. 1331. ISBN 9780323448383. 3. ^ a b c d e f g h i Kim, HK; Kang, SY; Chung, YJ; Kim, JH; Kim, MR (August 2015). "The Recent Review of the Genitourinary Syndrome of Menopause". Journal of Menopausal Medicine. 21 (2): 65–71. doi:10.6118/jmm.2015.21.2.65. PMC 4561742. PMID 26357643. 4. ^ Karl Knörr, Henriette Knörr-Gärtner, Fritz K. Beller, Christian Lauritzen (2013), Geburtshilfe und Gynäkologie: Physiologie und Pathologie der Reproduktion (in German) (3. ed.), Berlin: Springer, pp. 24–25, ISBN 978-3-642-95584-6CS1 maint: multiple names: authors list (link) 5. ^ Kim, Hyun-Kyung; Kang, So-Yeon; Chung, Youn-Jee; Kim, Jang-Heub; Kim, Mee-Ran (2015). "The Recent Review of the Genitourinary Syndrome of Menopause". Journal of Menopausal Medicine. 21 (2): 65–71. doi:10.6118/jmm.2015.21.2.65. ISSN 2288-6478. PMC 4561742. PMID 26357643. 6. ^ a b c d e f g h i j Portman, D.J.; Gass, M.L.S. (November 2014). "Genitourinary syndrome of menopause: New terminology for vulvovaginal atrophy from the International Society for the Study of Women's Sexual Health and The North American Menopause Society". Maturitas. 79 (3): 349–354. doi:10.1016/j.maturitas.2014.07.013. PMID 25179577. 7. ^ Choices, N. H. S. (2018). "What causes a woman to bleed after sex? - Health questions - NHS Choices". Retrieved 2018-02-07. 8. ^ "Vaginal Wet Mount". WebMD. Retrieved 2018-02-10. 9. ^ a b c "The Best Treatments for Genitourinary Syndrome of Menopause". www.medscape.com. Retrieved 2018-02-07. 10. ^ International Society for the Study of Women's Sexual Health and the Board of Trustees of The North American Menopause Society 11. ^ "FDA warning shines light on vaginal rejuvenation". www.mdedge.com. Retrieved 21 October 2019. ## External links[edit] Classification D * ICD-10: N95.2 * ICD-9-CM: 627.3 * MeSH: D059268 * DiseasesDB: 32516 * SNOMED CT: 52441000 External resources * MedlinePlus: 000892 * v * t * e Female diseases of the pelvis and genitals Internal Adnexa Ovary * Endometriosis of ovary * Female infertility * Anovulation * Poor ovarian reserve * Mittelschmerz * Oophoritis * Ovarian apoplexy * Ovarian cyst * Corpus luteum cyst * Follicular cyst of ovary * Theca lutein cyst * Ovarian hyperstimulation syndrome * Ovarian torsion Fallopian tube * Female infertility * Fallopian tube obstruction * Hematosalpinx * Hydrosalpinx * Salpingitis Uterus Endometrium * Asherman's syndrome * Dysfunctional uterine bleeding * Endometrial hyperplasia * Endometrial polyp * Endometriosis * Endometritis Menstruation * Flow * Amenorrhoea * Hypomenorrhea * Oligomenorrhea * Pain * Dysmenorrhea * PMS * Timing * Menometrorrhagia * Menorrhagia * Metrorrhagia * Female infertility * Recurrent miscarriage Myometrium * Adenomyosis Parametrium * Parametritis Cervix * Cervical dysplasia * Cervical incompetence * Cervical polyp * Cervicitis * Female infertility * Cervical stenosis * Nabothian cyst General * Hematometra / Pyometra * Retroverted uterus Vagina * Hematocolpos / Hydrocolpos * Leukorrhea / Vaginal discharge * Vaginitis * Atrophic vaginitis * Bacterial vaginosis * Candidal vulvovaginitis * Hydrocolpos Sexual dysfunction * Dyspareunia * Hypoactive sexual desire disorder * Sexual arousal disorder * Vaginismus * Urogenital fistulas * Ureterovaginal * Vesicovaginal * Obstetric fistula * Rectovaginal fistula * Prolapse * Cystocele * Enterocele * Rectocele * Sigmoidocele * Urethrocele * Vaginal bleeding * Postcoital bleeding Other / general * Pelvic congestion syndrome * Pelvic inflammatory disease External Vulva * Bartholin's cyst * Kraurosis vulvae * Vestibular papillomatosis * Vulvitis * Vulvodynia Clitoral hood or clitoris * Persistent genital arousal disorder [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA [kDa]: kilodalton [EPC]: Early Prostate Cancer [LAPC]: locally advanced prostate cancer [NSAAs]: nonsteroidal antiandrogens [NSAA]: nonsteroidal antiandrogen [GnRH]: gonadotropin-releasing hormone [ADT]: androgen deprivation therapy [LH]: luteinizing hormone [AR]: androgen receptor [CAB]: combined androgen blockade [LPC]: localized prostate cancer [CPA]: cyproterone acetate [U.S.]: United States [FDA]: Food and Drug Administration	Atrophic vaginitis	c0156409	7,800	wikipedia	https://en.wikipedia.org/wiki/Atrophic_vaginitis	2021-01-18T18:32:54	{"mesh": ["D059268"], "umls": ["C0156409"], "wikidata": ["Q4007235"]}
## Description Reticular dystrophy is a disorder of protean manifestations occurring in the retinal pigment epithelium (RPE) with little or no involvement of the neurosensory retina. The disorder may be detected at an early age and may be slowly progressive, but the prognosis for visual acuity is good. Abnormalities of dark adaptation and nyctalopia may develop with time. Electrophysiologic testing may show a normal electroretinogram (ERG), subnormal electrooculogram (EOG), and subnormal results of dark adaptation studies (summary by Kingham et al., 1978). Clinical Features Hsieh et al. (1977) reported 2 sibs and their mother with patterned dystrophies of the RPE: the 21-year-old sister exhibited butterfly-shaped pigment dystrophy, her 23-year-old brother showed macroreticular dystrophy, and their 51-year-old mother had 'probable' reticular dystrophy. The authors noted that this family linked together several entities that had been considered separate phenotypes. Kingham et al. (1978) described 4 affected individuals over 3 generations of a family with reticular dystrophy of the RPE. The proband was a 24-year-old woman who presented with 'eye strain' and normal visual acuity. Fundus examination revealed a reticular pattern of pigment clumping in the RPE, like a 'fishnet with knots,' that was most pronounced around the macula but extended around the optic disc and was present nasal to the disc as well. ERG findings were normal, but dark adaptation showed decreased rod and cone amplitudes, and EOG showed reduced light peak/dark trough values. The proband's 20-year-old sister had no ocular complaints, but examination showed a similar fishnet-with-knots pattern, and the sister's 2-year-old daughter had macular pigment stippling. The sisters' 51-year-old father, who had decreased visual acuity and difficulty with night vision, showed irregular patchy loss of pigmentation in the macula and posterior pole of both eyes; fluorescein angiography revealed loss of underlying choriocapillaris as well, and remnants of a reticular pattern were seen in the midperiphery. The father's brother had no ocular complaints and normal examination except for reduced cone and rod amplitudes on dark adaptation testing. McGimpsey and Rankin (2007) reported an 11-year-old girl who was asymptomatic but had an unusual fundus appearance involving a dark clump of pigment at each fovea, with a bilateral symmetric reticular pattern of RPE pigment clumping like a 'fishnet with knots.' ERGs were within normal limits. Inheritance Kingham et al. (1978) reviewed published reports of reticular dystrophy and concluded that it is an autosomal dominant disease. Recessive inheritance has been suggested by others (see 267800). INHERITANCE \- Autosomal dominant HEAD & NECK Eyes \- Good visual acuity \- Abnormal dark adaptation \- Nyctalopia (in some patients) \- Reticular 'fishnet-with-knots' dystrophy of retinal pigment epithelium (RPE) \- Posterior pattern of retinal pigment clumping \- Loss of RPE on fluorescein angiography \- Loss of underlying choriocapillaris (in older patients) \- Decreased rod and cone amplitudes on electroretinography \- Reduced light peak/dark trough values on electrooculography MISCELLANEOUS \- Intrafamilial and even intrapatient variability has been observed in patterned retinal dystrophy ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA [kDa]: kilodalton [EPC]: Early Prostate Cancer [LAPC]: locally advanced prostate cancer [NSAAs]: nonsteroidal antiandrogens [NSAA]: nonsteroidal antiandrogen [GnRH]: gonadotropin-releasing hormone [ADT]: androgen deprivation therapy [LH]: luteinizing hormone [AR]: androgen receptor [CAB]: combined androgen blockade [LPC]: localized prostate cancer [CPA]: cyproterone acetate [U.S.]: United States [FDA]: Food and Drug Administration	RETICULAR DYSTROPHY OF RETINAL PIGMENT EPITHELIUM	c1867332	7,801	omim	https://www.omim.org/entry/179840	2019-09-22T16:35:18	{"mesh": ["C566721"], "omim": ["179840"], "orphanet": ["99002"]}
## Summary ### Clinical characteristics. 6q24-related transient neonatal diabetes mellitus (6q24-TNDM) is defined as transient neonatal diabetes mellitus caused by genetic aberrations of the imprinted locus at 6q24. The cardinal features are: severe intrauterine growth retardation, hyperglycemia that begins in the neonatal period in a term infant and resolves by age 18 months, dehydration, and absence of ketoacidosis. Macroglossia and umbilical hernia may be present. 6q24-TNDM associated with a multilocus imprinting disturbance (MLID) can be associated with marked hypotonia, congenital heart disease, deafness, neurologic features including epilepsy, and renal malformations. Diabetes mellitus usually starts within the first week of life and lasts on average three months but can last longer than a year. Although insulin is usually required initially, the need for insulin gradually declines over time. Intermittent episodes of hyperglycemia may occur in childhood, particularly during intercurrent illnesses. Diabetes mellitus may recur in adolescence or later in adulthood. Women who have had 6q24-TNDM are at risk for relapse during pregnancy. ### Diagnosis/testing. The diagnosis of 6q24-TNDM is established in a proband with transient neonatal diabetes mellitus and DNA methylation analysis demonstrating relative hypomethylation within the 6q24 differentially methylated region (DMR). 6q24-TNDM is caused by overexpression of the imprinted genes at 6q24 (PLAGL1 and HYMAI). The DMR (i.e., PLAGL1 TSS alt-DMR) is present within the shared promoter of these genes. Normally, expression of the maternal alleles of PLAGL1 and HYMAI is silenced by DMR methylation and only the paternal alleles of PLAGL1 and HYMAI are expressed. Additional molecular genetic testing can establish the underlying genetic mechanism, which is required for genetic counseling. Three different genetic mechanisms resulting in twice the normal dosage of PLAGL1 and HYMAI (and thus causing 6q24-TNDM) are (1) paternal uniparental disomy of chromosome 6, (2) duplication of 6q24 on the paternal allele, and (3) hypomethylation of the maternal PLAGL1 TSS alt-DMR, resulting in inappropriate expression of the maternal PLAGL1 and HYMAI alleles. Maternal PLAGL1 TSS alt-DMR hypomethylation may result from an isolated imprinting variant or as part of MLID. Biallelic ZFP57 pathogenic variants account for almost half of TNDM-MLID. ### Management. Treatment of manifestations: Rehydration and IV insulin are usually required at the time of diagnosis; subcutaneous insulin is introduced as soon as possible and used until blood glucose levels stabilize. Later recurrence of diabetes may require diet modifications alone, oral agents, or insulin. Prevention of secondary complications: Prompt treatment of dehydration to avoid sequelae. Surveillance: Periodic glucose tolerance tests (abnormalities suggest future recurrence); monitoring of growth and development. Agents/circumstances to avoid: Factors that predispose to late-onset diabetes or risk factors for cardiovascular disease. Evaluation of relatives at risk: Screening for diabetes mellitus in relatives who have inherited a paternal 6q24 duplication or who are at risk of having inherited two ZFP57 pathogenic variants. ### Genetic counseling. The risk to sibs and offspring of a proband of having 6q24-TNDM or of developing diabetes later in life depends on the genetic mechanism in the family. Recurrence risk counseling by a genetics professional is strongly recommended. 6q24-TNDM caused by paternal UPD6 is typically a de novo, non-recurrent event. 6q24-TNDM caused by paternal duplication of 6q24 can occur de novo, be inherited in an autosomal dominant manner, or be inherited as part of a complex chromosome rearrangement; TNDM caused by inherited duplication of 6q24 may recur in sibs and offspring of a proband if the duplication is inherited from the father. Prenatal diagnosis of paternal duplication of 6q24 is possible in pregnancies at risk for a structural chromosome abnormality. TNDM caused by hypomethylation of the PLAGL1 TSS alt-DMR is a de novo non-recurrent event in the majority of individuals, particularly if hypomethylation is restricted to this DMR and does not affect other imprinted loci. However, TNDM as part of a multilocus imprinting disturbance (TNDM-MLID) has a significant genetic component. TNDM-MLID is inherited in an autosomal recessive manner when caused by pathogenic variants in ZFP57; however, the phenotype of homozygous or compound heterozygous sibs is variable and cannot be predicted by molecular genetic testing. Pathogenic variants in additional genes are suspected of causing TNDM-MLID but are currently unknown. Therefore, caution should be exercised when counseling the heritability of TNDM associated with imprinting disturbance at the PLAGL1 TSS alt-DMR. ## Diagnosis ### Suggestive Findings Diagnosis of 6q24-related transient neonatal diabetes mellitus (6q24-TNDM) should be suspected in individuals with the following clinical features: * Severe intrauterine growth restriction * Diabetes mellitus that commences in the first six weeks of life in a term infant and resolves by age 18 months. Presentation includes the following: * Hyperglycemia * Dehydration * Plasma insulin concentrations that are low in the presence of high serum glucose concentrations * Absence of ketoacidosis. Ketones are usually not present in the urine. * Absence of islet cell antibodies * Presence of a pancreas ### Establishing the Diagnosis The diagnosis of 6q24-TNDM is established in a proband with one of the following: * Transient neonatal diabetes mellitus and DNA methylation analysis demonstrating relative hypomethylation within the PLAGL1 TSS alt-DMR, through one of the following mechanisms: * Partial or complete paternal uniparental disomy of chromosome 6 * Paternal duplication of 6q24 * Hypomethylation of the maternal PLAGL1 TSS alt-DMR * Biallelic pathogenic variants in ZFP57 identified on molecular genetic testing The maternal alleles of PLAGL1 and HYMAI are silenced by methylation of the PLAGL1 TSS alt-DMR, and only the paternal alleles of PLAGL1 and HYMAI are expressed. In 6q24-TNDM, PLAGL1 and HYMAI alleles are overexpressed through one of three genetic mechanisms (see Figure 1): #### Figure 1. Three different genetic mechanisms cause 6q24-TNDM: paternal uniparental disomy of chromosome 6 (UPD6) (41%); duplication of 6q24 on the paternal allele (29%); and hypomethylation of the maternally inherited PLAGL1 TSS alt-DMR (30%). Hypomethylation of (more...) * Hypomethylation of the PLAGL1 TSS alt-DMR, either: * As an isolated imprinting defect of the PLAGL1 TSS alt-DMR; or * As part of a more generalized multilocus imprinting disturbance (MLID) caused by biallelic (homozygous or compound heterozygous) pathogenic variants in ZFP57 or by as-yet-unknown mechanisms. * Partial or complete paternal uniparental disomy of chromosome 6 (UPD6) that includes the PLAGL1 and HYMAI loci * Paternal duplication of 6q24. Usually a submicroscopic duplication results in the presence of two copies of PLAGL1 and HYMAI on one paternal chromosome 6. Note: In individuals with 6q24 duplication of the paternal allele, the presence of two unmethylated alleles and one methylated allele of the PLAGL1 TSS alt-DMR causes apparent partial hypomethylation of the PLAGL1 TSS alt-DMR. ### Table 1. Molecular Genetic Mechanisms for 6q24-Related Transient Neonatal Diabetes Mellitus View in own window LocusGenes of InterestImprintParental Origin of ImprintDisease Mechanism 6q24PLAGL1, HYMA1Methylated 1MaternalHypomethylation, paternal UPD, or paternal duplication 1\. In unaffected individuals, the maternally derived methylated copy is not expressed. Molecular genetic testing approaches can include DNA methylation studies, chromosomal microarray analysis (CMA), uniparental disomy studies, targeted duplication analysis, and single-gene testing. #### Tier 1 Testing DNA methylation studies can detect hypomethylation within the 6q24 DMR region regardless of the underlying genetic mechanism, thus establishing the diagnosis of 6q24-TNDM. Note: DNA methylation analysis is the only technique that will diagnose 6q24-TNDM caused by any genetic mechanism, but it cannot establish the specific mechanism. #### Tier 2 Testing Tier 2 testing is necessary to differentiate the two different genetic mechanisms that cause expression of an extra copy of the paternal alleles of PLAGL1 and HYMAI (see Table 1). * Chromosomal microarray analysis (CMA) using oligonucleotide arrays or SNP genotyping arrays can detect a duplication of 6q24. Note that paternal disomy 6 commonly occurs by postzygotic somatic recombination resulting in isodisomy and can normally, therefore, be identified by proband-only SNP array analysis. * Uniparental disomy (UPD) studies can detect partial or complete paternal UPD6. * Targeted duplication analysis of 6q24. A variety of methods may be used for deletion/duplication analysis (copy number analysis) to identify an additional paternal copy of PLAGL1 and HYMAI (see Table 2, footnote 4). #### Tier 3 Testing Tier 3 testing is necessary if tier 2 testing does not identify the genetic mechanism for 6q24 hypomethylation. Single-gene testing. Sequence analysis of ZFP57 is performed first and followed by gene-targeted deletion/duplication analysis if no pathogenic variant is found. #### Parallel or Additional Testing Options A multigene panel that includes ZFP57 and other genes of interest (see Differential Diagnosis) may also be considered. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview; thus, clinicians need to determine which multigene panel is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. (3) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests (e.g., methylation studies). For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here. ### Table 2. Molecular Genetic Testing Used in 6q24-Related Transient Neonatal Diabetes Mellitus (TNDM) View in own window MethodPathogenic Variants/Alterations DetectedProportion of 6q24-TNDM Alterations Detected Methylation analysis 1Hypomethylation within the 6q24 DMR region including imprinting center defects100% 2 Microarray (SNP based)Duplication of 6q24, UPD6 3~70% UPD studies 4UPD6~41% Targeted duplication analysis 5Duplication of 6q24~29% 6 Single-gene testingSequence analysis 7ZFP57 pathogenic variants 89% 9 Gene-targeted deletion/duplication analysis 5ZFP57 intragenic deletion or duplicationNone reported DMR = differentially methylated region; UPD = uniparental disomy 1\. Can establish diagnosis, but will not distinguish genetic mechanism; can be done by Southern blot, methylation-specific multiple ligation-mediated PCR analysis (MS-MLPA), or methylation-specific PCR. 2\. Note: Only methylation analysis will detect an imprinting center defect, which is causative in ~30% of individuals. 3\. Paternal disomy occurs by postzygotic somatic recombination resulting in isodisomy and can therefore be identified by proband-only SNP array analysis. 4\. Use of genetic markers (usually short tandem repeats) to determine parental identity (maternal or paternal) of a chromosome or chromosomal segment in a proband. Note: This testing requires a DNA sample from the proband, mother, and father. 5\. Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include: quantitative PCR, long-range PCR, methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. 6\. Reported duplications range in size from 200 kb to several megabases [Docherty et al 2010]. A small minority of individuals have a cytogenetically visible duplication of 6q24 [Temple et al 1996, Arthur et al 1997]. If conventional karyotype analysis identifies a visible chromosome translocation or duplication of 6q24, parental studies are required to determine if the abnormality is paternal in origin. 7\. Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here. 8\. See Table A. Genes and Databases for chromosome locus and protein. See Molecular Genetics for information on allelic variants detected in this gene. 9\. Docherty et al [2013] ## Clinical Characteristics ### Clinical Description Intrauterine growth retardation may be noted in the third trimester. The mean birth weight in a study of 30 infants was 1,930 g at 39 weeks' gestation [Temple et al 2000]; this finding is in keeping with other studies [Metz et al 2002, Diatloff-Zito et al 2007]. Because the plasma concentration of insulin is low at the time of diagnosis, it is assumed that low birth weight is a result of low in utero levels of insulin, an important prenatal growth factor. Diabetes mellitus tends to develop in the first week of life, although it may not be recognized until later. Hyperglycemia may be identified by chance during routine investigations in the newborn period for a sick dehydrated infant. Infants rapidly become dehydrated and usually require insulin. The diabetes may be resistant to treatment initially. Occasionally insulin is not required and neonates are treated with rehydration alone. Diabetes mellitus lasts on average three months but has been reported to last longer than a year [Temple et al 2000]. The need for insulin gradually declines. This is often accompanied by a significant weight gain and catch-up growth, and some infants become overweight in the first year [Metz et al 2002]. Intermittent episodes of hyperglycemia may occur in childhood, particularly during intercurrent illnesses. Few studies have been performed during this period and so the extent of these episodes is not known. Shield et al [2004] studied seven children during this period and found low insulin secretion in four and normal insulin secretion in three. Diabetes may recur in very early childhood. The average age of recurrence in the series of Temple et al [2000] was 14 years, coinciding with puberty. Some individuals require insulin; others are treated with oral drugs or diet alone. In a series from France, five of seven individuals developed diabetes again after age eight years [Metz et al 2002]. Women are at risk for relapse during pregnancy and may present with gestational diabetes mellitus. Permanent diabetes mellitus can occur in up to 50% in some series [Temple et al 2000], although this figure may overestimate the actual risk because of the bias of identifying affected individuals. There is usually some residual endogenous insulin production; however, insulin therapy may be needed. Studies have not been performed to assess the level of diabetes-related complications that can occur in this disorder. One individual with poor compliance with treatment had persistent hyperglycemia from ages 14 to 28 years. He did not develop ketoacidosis but did develop evidence of microangiopathy [Valerio et al 2004]. Other. Macroglossia and umbilical hernia are sometimes observed. No other dysmorphic features are consistently associated with this condition. Screening for congenital hypothyroidism is prudent. 6q24-TNDM caused by generalized multilocus imprinting disturbance (MLID) can be associated with marked hypotonia, congenital heart disease, deafness, neurologic features including epilepsy, and renal malformations. Intelligence and growth are usually normal in this condition except in individuals with loss of methylation at multiple loci, who may have developmental delay. However, the long-term outcomes for most individuals are still not known. ### Genotype-Phenotype Correlations Diabetes mellitus. No difference in the severity, duration, or relapse rate of diabetes has been detected between the 6q24-TNDM etiologic subgroups [Temple et al 2000]. Non-diabetes manifestations vary by causative genetic mechanism. Congenital anomalies were significantly more frequent in individuals with paternal uniparental disomy of chromosome 6 (UPD6) or MLID than in those with 6q24 duplication or isolated hypomethylation defects [Docherty et al 2013]. * UPD6. The majority of UPD6 is isodisomic; i.e., two copies of chromosome 6 are identical and therefore the affected individual is at increased risk for rare autosomal recessive disorders that may be unmasked by this unusual inheritance pattern. The most common is HFE-associated hereditary hemochromatosis, for which testing can be performed in adulthood. Methylmalonic acidemia and congenital adrenal hyperplasia caused by 21-hydroxylase deficiency have also been described as occurring through this mechanism. * 6q duplication. Cytogenetically visible duplication of 6q can also be associated with learning difficulties related to other genes within the duplicated region. Note: Individuals with a submicroscopic 6q24 duplication are usually of normal intelligence. * Hypomethylation of the maternal PLAGL1 TSS alt-DMR. An imprinted differentially methylated region overlaps an alternative transcriptional start-site of PLAGL1, and hypomethylation of this PLAGL1 TSS-alt DMR is associated with TNDM. Non-diabetes manifestations are more likely in the subgroup with a more generalized hypomethylation at imprinted loci (i.e., MLID) and can include significant learning difficulties [Boonen et al 2008, Mackay et al 2008]. No correlation has been observed between clinical severity and either the degree of hypomethylation or the range of loci involved. For example, the features seen in individuals with 6q24-TNDM caused by homozygous or compound heterozygous ZFP57 pathogenic variants can vary from severe intellectual disability and early infant death to a normal phenotype. It is therefore difficult to predict the phenotype in individuals with MLID, possibly because of the inability to interrogate all imprinted loci. ### Penetrance Reduced penetrance of the 6q24-TNDM has rarely been described, but has been noted in sibs of affected individuals. The sibs reported did not have a history of neonatal diabetes mellitus but were found to have either a paternal duplication of 6q24 or biallelic ZFP57 pathogenic variants [Valerio et al 2004, Boonen et al 2013]. ### Prevalence The incidence of neonatal diabetes is reported to be 1:215,000 to 1:400,000 [Polak & Shield 2004, Stanik et al 2007, Wiedemann et al 2010]; 50% of neonatal diabetes mellitus is transient rather than permanent (see Permanent Neonatal Diabetes Mellitus). ## Differential Diagnosis Transient neonatal diabetes mellitus (TNDM) was found to account for approximately 50% of diabetes mellitus presenting in the neonatal period [Cavé et al 2000, Metz et al 2002, Polak & Cavé 2007]. Flanagan et al [2007] showed that 70% of TNDM was caused by 6q24 aberrations. Other genetic causes of transient neonatal diabetes mellitus include pathogenic variants in KCNJ11 and ABCC8, which usually cause permanent neonatal diabetes (see Permanent Neonatal Diabetes Mellitus). Metz et al [2002] failed to demonstrate clear clinical indicators to differentiate 6q24-TNDM from other causes in a large cohort of 50 individuals presenting with neonatal diabetes. Other genetic causes of neonatal diabetes mellitus (isolated and syndromic, transient and permanent): * KCNJ11\- and ABCC8-related neonatal diabetes mellitus (see Permanent Neonatal Diabetes Mellitus). Affected infants present with low birth weight and hyperglycemia. Compared to 6q24-TNDM, infants with KCNJ11\- and ABCC8-related neonatal diabetes mellitus usually present slightly later, birth weight is higher, remission usually takes longer, and ketoacidosis is often present at diagnosis. Some of the children have epilepsy, hypotonia, and developmental delay in addition to diabetes mellitus (DEND syndrome). KCNJ11-related neonatal diabetes mellitus is inherited in an autosomal dominant manner, while ABCC8-related neonatal diabetes may be inherited in either an autosomal dominant or autosomal recessive manner. * INS-related neonatal diabetes mellitus (see Permanent Neonatal Diabetes Mellitus). Although the median age of diagnosis is 11 weeks, the range of the age of onset overlaps with neonatal diabetes; therefore, pathogenic variants in INS should be considered in the differential diagnosis of 6q24-TNDM. Presentation includes ketoacidosis in half of infants. Clinical findings can vary among family members. In at least one family in the series neonatal diabetes was transient, becoming permanent diabetes at age two years. INS-related neonatal diabetes mellitus may be inherited in either an autosomal dominant or autosomal recessive manner. * Glucokinase-related neonatal diabetes mellitus. Homozygous missense loss-of-function variants within GCK, the gene encoding glucokinase, have been reported as a rare cause of permanent neonatal diabetes mellitus. This condition should be considered, particularly in consanguineous families. Glucokinase-related neonatal diabetes mellitus is inherited in an autosomal recessive manner. * PDX1-related neonatal diabetes mellitus is associated with pancreatic hypoplasia and results in a more severe insulin deficiency, lower birth weight, and younger age at diagnosis than is seen in infants with other causes of permanent neonatal diabetes mellitus. Imaging of the pancreas may help identify infants with PDX1-related neonatal diabetes mellitus. PDX1-related neonatal diabetes mellitus is inherited in an autosomal recessive manner. * Renal cysts and diabetes syndrome (OMIM 137920). The diabetes phenotype in individuals heterozygous for an HNF1B pathogenic variant manifests more frequently later in life. The neonatal presentation due to biallelic pathogenic variants in HNF1B is characterized by evidence of severe insulin deficiency (low birth weight, diabetes ketoacidosis) and pancreatic exocrine insufficiency due to hypoplastic pancreas. Other manifestations include genital tract malformations, hyperuricemia, and gout, as well as abnormal liver function. The inheritance is autosomal recessive, but penetrance is incomplete. * Wolcott-Rallison syndrome (OMIM 226980), caused by biallelic pathogenic variants in EIF2AK3, is characterized by infantile-onset (often within the neonatal period) diabetes mellitus and spondyloepiphyseal dysplasia, which may develop after the neonatal period. Wolcott-Rallison syndrome is inherited in an autosomal recessive manner. * IPEX syndrome (immune dysregulation, polyendocrinopathy, enteropathy, X-linked) can be caused by pathogenic variants in FOXP3 and is characterized by the development of overwhelming systemic autoimmunity in the first year of life resulting in the commonly observed triad of watery diarrhea, eczematous dermatitis, and endocrinopathy, most often insulin-dependent diabetes mellitus. Most infants have other autoimmune phenomena including Coombs-positive anemia, autoimmune thrombocytopenia, autoimmune neutropenia, and tubular nephropathy. Without aggressive immunosuppression or bone marrow transplantation, the majority of affected males die within the first year of life of either metabolic derangements or sepsis; a few with a milder phenotype have survived into the second and third decade. IPEX syndrome is inherited in an X-linked manner. * Neonatal diabetes mellitus and cerebellar agenesis (OMIM 609069) is caused by biallelic pathogenic variants in PTF1A. The disorder is characterized by the combination of cerebellar agenesis and neonatal diabetes mellitus. Infants usually die within a few months of birth. Neonatal diabetes mellitus and cerebellar agenesis is inherited in an autosomal recessive manner. * Neonatal diabetes mellitus, annular pancreas, intestinal atresias, and gallbladder agenesis (OMIM 615710) is caused by biallelic pathogenic variants in RFX6. A small number of affected individuals have been reported with various combinations of pancreatic hypoplasia, agenesis, and neonatal diabetes without clear evidence of abnormal pancreatic anatomy in association with gut atresias and gallbladder hypoplasia/atresia. The majority have died in the first year of life; however, some individuals are still living with normal development, although the follow up has not been long. This condition is inherited in an autosomal recessive manner. * Neonatal diabetes mellitus and congenital hypothyroidism caused by pathogenic variants in GLIS3 (OMIM 610199). This rare condition is characterized by the combination of neonatal diabetes mellitus, congenital hypothyroidism, glaucoma, polycystic kidneys, cholestasis, and hepatic fibrosis. However, the findings can be variable and not all the features are reported in all cases. Some individuals have survived infancy; mild intellectual disability has been reported. This condition is inherited in an autosomal recessive manner. * Neonatal diabetes mellitus and congenital heart disease caused by pathogenic variants in GATA6 (OMIM 600001). The combination of congenital heart disease (ventricular septal defect) and pancreatic hypoplasia was first reported by Gürson et al [1970]. Yorifuji et al [1994] reported a second Japanese family in which individuals in two generations had pancreatic hypoplasia, neonatal diabetes mellitus, and congenital heart disease. This condition is inherited in an autosomal dominant manner. ## Management ### Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with 6q24-related transient neonatal diabetes mellitus (6q24-TNDM), the following evaluations are recommended if they have not already been completed: * Birth weight, length, and head circumference and any subsequent growth parameters * General dysmorphology examination, preferably by a clinical geneticist, including evaluation of tongue size and umbilicus * Neurologic examination and developmental assessment * Investigation of the anatomy of the pancreas by ultrasound examination or MRI * Echocardiogram and ultrasound examination of the liver and kidneys to help identify those infants likely to have 6q24-TNDM caused by ZFP57 pathogenic variants * Brain MRI examination if evidence of developmental delay or hypotonia * Serum glucose concentration * C peptide measurement * Pancreatic beta cell autoantibody measurements * Liver function and thyroid function tests * Consultation with a pediatric endocrinologist for follow up of diabetes * Consultation with a clinical geneticist and/or genetic counselor Individuals with multilocus imprinting disturbance (MLID) should be evaluated for hypotonia and other neurologic features including epilepsy, congenital heart disease, deafness, renal malformations, and pseudohypoparathyroidism with measurement of serum concentrations of calcium and phosphate and parathyroid hormone testing. ### Treatment of Manifestations Rehydration and IV insulin on a sliding scale are usually required. Some infants produce some insulin and can be treated by rehydration alone. Subcutaneous injection of insulin is introduced as soon as possible, often within two weeks. Continuous insulin pump therapy (as opposed to intermittent insulin injections) has been used successfully in a number of cases in the UK and France [JP Shield, personal communication]. Successful treatment with subcutaneous insulin glargine has also been reported [Barone et al 2011]. Blood glucose concentration should be monitored and insulin doses changed accordingly as in the standard treatment for diabetes mellitus. Insulin can be discontinued when blood glucose concentrations stabilize. Once diabetes mellitus is in remission, parents need to be alerted to the possibility of recurrence of the diabetes mellitus, particularly during periods of illness. Symptoms such as excessive thirst, polyuria, and repeated bacterial infections should prompt measurement of blood glucose concentration. If diabetes mellitus recurs, treatment may require diet alone, oral agents, or insulin, although the doses of insulin needed tend to be less than those required in type 1 diabetes mellitus (i.e., some residual endogenous insulin remains). It should be noted that insulin is not always required even in the neonatal period. In several individuals, sulphonylureas or diet alone was adequate to treat relapses [Valerio et al 2004]. Note: Macroglossia could potentially cause airway obstruction; macroglossia severe enough to require treatment has not been reported. ### Prevention of Secondary Complications The main concerns are related to failure to make the diagnosis soon enough. Dehydration secondary to hyperglycemia can cause serious long-term sequelae if not treated promptly. Therefore, rehydration is most important in the early stages of the disease. ### Surveillance Periodic glucose tolerance tests can be used to assess insulin secretion. Most children with transient neonatal diabetes mellitus in remission have no evidence of beta cell dysfunction or insulin resistance in the fasting state. Insulin response to intravenous glucose loading is often normal but suggests future recurrence if abnormal [Shield et al 2004]. Measure growth (height, weight, head circumference) at regular intervals (i.e., at least every 6 months). Developmental assessment to identify any special educational needs is appropriate. Children with MLID need to be monitored for developmental delay and special educational needs. ### Agents/Circumstances to Avoid General factors that predispose to late-onset diabetes (e.g., excessive weight gain) or risk factors for cardiovascular disorders should be avoided. ### Evaluation of Relatives at Risk It is appropriate to test apparently asymptomatic at-risk relatives for the 6q24-TNDM genetic mechanism identified in the proband in order to identify family members who would benefit from follow up. (Hyperglycemia may be asymptomatic.) Recommendations for follow up vary by underlying genetic mechanism: * 6q24 duplication. Individuals with a 6q24 duplication may not present with diabetes as neonates. However, such individuals are at risk of developing diabetes later in life. Knowing this risk may facilitate prompt evaluation and treatment if they develop symptoms of diabetes. These individuals can also be counseled regarding risks to their offspring. Screening for diabetes mellitus is appropriate for those infants who have inherited the paternal 6q24 duplication. * Biallelic ZFP57 pathogenic variants. Sibs who inherit biallelic variants are at risk for the same condition (although the clinical findings can be variable) and should undergo screening for diabetes mellitus. * Hypomethylation at PLAGL1 TSS alt-DMR. Although individuals with 6q24-TNDM as the result of hypomethylation at PLAGL1 TSS alt-DMR generally represent simplex cases (i.e., a single occurrence in a family), it is not clear if all cases are de novo, and there have been relatively few families reported in the literature to determine recurrence risk (see also Genetic Counseling).Screening the mother and sibs of these individuals for hypomethylation may therefore be appropriate. See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes. ### Pregnancy Management There are no specific guidelines on pregnancy management for women with a history of 6q24-TNDM. However, it is important to inform health professionals during the pregnancy of a susceptibility to diabetes. Rarely, some affected women with classic 6q24-TNDM genetic aberrations (e.g., duplication of 6q24, paternal uniparental disomy of chromosome 6, methylation defects) will develop gestational diabetes; therefore, pregnancy is thought to be a risk factor for recurrence of diabetes. If prenatal diagnosis identifies an affected fetus, fetal growth is anticipated to lag during the third trimester. See MotherToBaby for further information on medication use during pregnancy. ### Therapies Under Investigation Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA [kDa]: kilodalton [EPC]: Early Prostate Cancer [LAPC]: locally advanced prostate cancer [NSAAs]: nonsteroidal antiandrogens [NSAA]: nonsteroidal antiandrogen [GnRH]: gonadotropin-releasing hormone [ADT]: androgen deprivation therapy [LH]: luteinizing hormone [AR]: androgen receptor [CAB]: combined androgen blockade [LPC]: localized prostate cancer [CPA]: cyproterone acetate [U.S.]: United States [FDA]: Food and Drug Administration	Diabetes Mellitus, 6q24-Related Transient Neonatal	c3711391	7,802	gene_reviews	https://www.ncbi.nlm.nih.gov/books/NBK1534/	2021-01-18T21:30:57	{"mesh": ["C579872"], "synonyms": ["6q24-TNDM"]}
Lupus panniculitis Other namesLupus erythematosus profundus,[1] Lupus panniculitis,[2] "Lupus profundus",[2] and Subcutaneous lupus erythematosus[2] SpecialtyDermatology Not to be confused with Subacute cutaneous lupus erythematosus or Lupus erythematosus. Lupus erythematosus panniculitis presents with subcutaneous nodules that are commonly firm, sharply defined and nontender.[1] ## Contents * 1 See also * 2 References * 3 External links * 4 External links ## See also[edit] * Lupus erythematosus * List of cutaneous conditions ## References[edit] 1. ^ a b William D. James; Timothy G. Berger; Dirk M. Elston (2015). Andrews' Diseases of the Skin: Clinical Dermatology (12th ed.). Elsevier. p. 156. ISBN 978-0-323-31967-6. 2. ^ a b c Rapini, Ronald P.; Bolognia, Jean L.; Jorizzo, Joseph L. (2007). Dermatology: 2-Volume Set. St. Louis: Mosby. ISBN 978-1-4160-2999-1. ## External links[edit] Classification D * ICD-10: L93.2 (ILDS L93.270) * MeSH: D015435 External resources * Orphanet: 90285 ## External links[edit] * v * t * e Disorders of subcutaneous fat Panniculitis Lobular * without vasculitis * Cold * Cytophagic histiocytic * Factitial * Gouty * Pancreatic * Traumatic * needle-shaped clefts * Subcutaneous fat necrosis of the newborn * Sclerema neonatorum * Post-steroid panniculitis * Lipodermatosclerosis * Weber–Christian disease * Lupus erythematosus panniculitis * Sclerosing lipogranuloma * with vasculitis: Nodular vasculitis/Erythema induratum Septal * without vasculitis: Alpha-1 antitrypsin deficiency panniculitis * Erythema nodosum * Acute * Chronic * with vasculitis: Superficial thrombophlebitis Lipodystrophy Acquired * generalized: Acquired generalized lipodystrophy * partial: Acquired partial lipodystrophy * Centrifugal abdominal lipodystrophy * HIV-associated lipodystrophy * Lipoatrophia annularis * localized: Localized lipodystrophy Congenital * Congenital generalized lipodystrophy * Familial partial lipodystrophy * Marfanoid–progeroid–lipodystrophy syndrome * Poland syndrome This cutaneous condition article is a stub. You can help Wikipedia by expanding it. * v * t * e [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA [kDa]: kilodalton [EPC]: Early Prostate Cancer [LAPC]: locally advanced prostate cancer [NSAAs]: nonsteroidal antiandrogens [NSAA]: nonsteroidal antiandrogen [GnRH]: gonadotropin-releasing hormone [ADT]: androgen deprivation therapy [LH]: luteinizing hormone [AR]: androgen receptor [CAB]: combined androgen blockade [LPC]: localized prostate cancer [CPA]: cyproterone acetate [U.S.]: United States [FDA]: Food and Drug Administration	Lupus erythematosus panniculitis	c0030327	7,803	wikipedia	https://en.wikipedia.org/wiki/Lupus_erythematosus_panniculitis	2021-01-18T19:08:40	{"mesh": ["D015435"], "umls": ["C0030327"], "icd-10": ["L93.2"], "orphanet": ["90285"], "wikidata": ["Q6704853"]}
Curly hair-acral keratoderma-caries syndrome is an extremely rare ectodermal dysplasia syndrome characterized by premature loss of curly, brittle, dry hair, premature loss of teeth due to caries, nail dystrophy with thickening of the finger- and toe-nails, acral keratoderma and hypohidrosis. Additionally, sparse eyebrows and eyelashes, receding frontal hairline and flattened malar region are associated. The severity of features appears to increase with age. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA [kDa]: kilodalton [EPC]: Early Prostate Cancer [LAPC]: locally advanced prostate cancer [NSAAs]: nonsteroidal antiandrogens [NSAA]: nonsteroidal antiandrogen [GnRH]: gonadotropin-releasing hormone [ADT]: androgen deprivation therapy [LH]: luteinizing hormone [AR]: androgen receptor [CAB]: combined androgen blockade [LPC]: localized prostate cancer [CPA]: cyproterone acetate [U.S.]: United States [FDA]: Food and Drug Administration	Curly hair-acral keratoderma-caries syndrome	c1843291	7,804	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=307766	2021-01-23T18:12:28	{"gard": ["10163"], "mesh": ["C536220"], "omim": ["607656"], "umls": ["C1843291"], "icd-10": ["Q82.8"], "synonyms": ["CHAC syndrome", "CHACS"]}
Poliomyelitis is a viral infection caused by any of three serotypes of human poliovirus, which is part of the family of enteroviruses. ## Epidemiology Progress in global poliomyelitis eradication, since its beginning in 1988, has been remarkable. In 1988, 125 countries were endemic for poliomyelitis and an estimated 1000 children were being paralyzed every day by wild poliovirus. By the end of 2003, six polio-endemic countries remained (Afghanistan, Egypt, India, Niger, Nigeria, Pakistan), and less than 3 children per day were being paralyzed by the poliovirus. The Global Poliomyelitis Eradication Initiative is ongoing. There remain only 4 endemic countries (Pakistan, Afghanistan, India, and Nigeria) and just 2000 reported cases globally in 2006. ## Clinical description It primarily affects children under the age of 5. Generally the infection is limited to the grastrointestinal tract and nasopharynx and is often asymptomatic. The central nervous system, primarily the spinal cord, may be affected, leading to rapidly progressive paralysis. Motor neurons are mainly affected. Encephalitis may also occur. ## Etiology Transmission is mainly person-to-person, principally through the fecal-oral route. The virus replicates in the nervous system and particularly affects motor neurons in the anterior horn of the spinal cord (`polio' means `gray'). ## Differential diagnosis Poliomyelitis must be distinguished from other paralytic conditions by isolation of virus from stool. ## Management and treatment Prevention is the only cure for paralytic poliomyelitis. Two vaccines against poliomyelitis are available: an inactive injectable vaccine and a live attenuated vaccine that is taken orally. Europe was certified as polio-free in June 2002 and immunization and disease surveillance continue to ensure the region remains polio-free [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA [kDa]: kilodalton [EPC]: Early Prostate Cancer [LAPC]: locally advanced prostate cancer [NSAAs]: nonsteroidal antiandrogens [NSAA]: nonsteroidal antiandrogen [GnRH]: gonadotropin-releasing hormone [ADT]: androgen deprivation therapy [LH]: luteinizing hormone [AR]: androgen receptor [CAB]: combined androgen blockade [LPC]: localized prostate cancer [CPA]: cyproterone acetate [U.S.]: United States [FDA]: Food and Drug Administration	Poliomyelitis	c0032371	7,805	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=2912	2021-01-23T17:05:08	{"gard": ["7413"], "mesh": ["D011051"], "umls": ["C0032371"], "icd-10": ["A80.0", "A80.1", "A80.2", "A80.3", "A80.4", "A80.9"]}
A rare genetic neurodevelopmental disorder characterized by early-onset drug-resistant seizures and severe neurodevelopmental impairment with major motor development delay. ## Epidemiology CDKL5-related epileptic encephalopathy has an estimated birth prevalence of 1/42,400 in the UK (Scotland). It affects predominantly females with a sex ratio of 12:1 ## Clinical description Presentation is of severe seizures with onset in the first six months of life (often within the first 3 months or even the first few weeks after birth), hypotonia, poor eye contact and poor neurocognitive development. Severe hypotonia can be present before seizure onset, as well as irritability, excessive crying, drowsiness, and poor sucking. Seizures are usually difficult and include epileptic spasms, myoclonic seizures, tonic seizures and tonic-clonic seizures. At the beginning EEG might not reveal significant epileptiform abnormalities, however over time abundant and multifocal epileptiform discharges are evident. During the disease course a seizure free period might be observed, this is also reported as ''honey-moon period''. The neurological outcome is poor as most affected individuals cannot walk and many are confined to a wheelchair. Communication strategies are restricted to elementary non-verbal communication. Patients do not develop autonomy to feed themselves. Subtle dysmorphic facial features include a prominent/broad forehead, deep-set eyes, a well-defined philtrum, and everted lower lip, possibly associated with tapered fingers and hallux valgus. Stereotypies are common. Some may have scoliosis, visual impairment, gastrointestinal difficulties, and sleep problems. Epilepsy is drug-resistant and most of patients continue with active epilepsy. ## Etiology The disorder is caused by mutations or deletions in the cyclin-dependent kinase-like 5 (CDKL5, Xp22.13) gene situated in the X chromosome. CDKL5 is a kinase predominantly expressed in the brain. Deficiency in CDKL5 leads to neurodevelopmental alterations. ## Diagnostic methods Diagnosis is suspected in patients with early onset epilepsy with a severe developmental delay and with a poor response to anti-epileptic drugs. Genetic identification of CDKL5 alterations confirms diagnosis. ## Differential diagnosis Differential diagnosis includes developmental epileptic encephalopathies (DEE) with early onset seizures and West syndrome. Molecular testing of the CDKL5 gene should be considered in cases DEE, West syndrome. ## Genetic counseling The pattern of inheritance is X-linked. The risk of recurrence in affected families is low since the pathogenic mutations occur de novo in most cases; however, some cases of parental mosaicism have been reported. ## Management and treatment There is no medication currently approved for the specific treatment of this disorder. Management is symptom-based and requires a multidisciplinary approach. Anticonvulsant medications and ketogenic diet is used for the management of seizures. Non-pharmacological management includes physical, occupational, visual and speech therapy. ## Prognosis Life expectancy is unknown due to underdiagnosis in adults, but adult patients are known. Prognosis is poor with severe psychomotor deficits and intractable seizures remaining into adulthood. Autonomy is never reached. * European Reference Network [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA [kDa]: kilodalton [EPC]: Early Prostate Cancer [LAPC]: locally advanced prostate cancer [NSAAs]: nonsteroidal antiandrogens [NSAA]: nonsteroidal antiandrogen [GnRH]: gonadotropin-releasing hormone [ADT]: androgen deprivation therapy [LH]: luteinizing hormone [AR]: androgen receptor [CAB]: combined androgen blockade [LPC]: localized prostate cancer [CPA]: cyproterone acetate [U.S.]: United States [FDA]: Food and Drug Administration	CDKL5-related epileptic encephalopathy	c1839333	7,806	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=505652	2021-01-23T18:27:09	{"mesh": ["C564064"], "omim": ["300672"], "icd-10": ["G40.4"], "synonyms": ["CDKL5 deficiency disorder"]}
Lower respiratory tract disease that affects the airways leading into the lungs Bronchospasm Inflamed airways and bronchoconstriction in asthma. Airways narrowed as a result of the inflammatory response cause wheezing. SpecialtyPulmonology Bronchospasm or a bronchial spasm is a sudden constriction of the muscles in the walls of the bronchioles. It is caused by the release (degranulation) of substances from mast cells or basophils under the influence of anaphylatoxins. It causes difficulty in breathing which ranges from mild to severe. Bronchospasms occur in asthma, chronic bronchitis and anaphylaxis. Bronchospasms are a possible side effect of some drugs: pilocarpine, beta blockers (used to treat hypertension), a paradoxical result of using LABA drugs (to treat COPD), and other drugs. Bronchospasms can present as a sign of giardiasis. Bronchospasms are one of several conditions associated with cold housing.[1] Some of the things that can cause bronchospasms are: consuming foods, taking medicines, allergic responses to insects, and fluctuating hormone levels, particularly in women.[2][3] A few of the more common allergens are foods such as eggs, milk, peanuts, walnuts, tree and other nuts, fish, especially shellfish, soy and wheat; insect bites and stings, especially bee stings; and other medicines, especially penicillin and its derivatives. The overactivity of the bronchioles' muscle is a result of exposure to a stimulus which under normal circumstances would cause little or no response. The resulting constriction and inflammation causes a narrowing of the airways and an increase in mucus production; this reduces the amount of oxygen that is available to the individual causing breathlessness, coughing and hypoxia. Bronchospasms are a serious potential complication of placing a breathing tube during general anesthesia. When the airways spasm or constrict in response to the irritating stimulus of the breathing tube, it is difficult to maintain the airway and the patient can become apneic. During general anesthesia, signs of bronchospasm include wheezing, high peak inspiratory pressures, increased intrinsic PEEP, decreased expiratory tidal volumes, and an upsloping capnograph (obstructive pattern). In severe cases, there may be complete inability to ventilate and loss of ETCO2 as well as hypoxia and desaturation. ## Contents * 1 Cause * 2 Diagnosis * 3 Treatment * 3.1 Beta 2 agonists * 3.2 Muscarinic Acetylcholine receptor antagonist * 4 See also * 5 References * 6 External links ## Cause[edit] Bronchospasm are caused by a number of reasons. Lower respiratory tract conditions such as asthma, chronic obstructive pulmonary disease (COPD), and emphysema can result in contraction of the airways. Other causes are side effects of topical decongestants such as oxymetazoline and phenylephrine. Both of these medications activate alpha-1 adrenergic receptors that result in smooth muscle constriction. Non-selective beta blockers are known to facilitate bronchospasm as well. Beta blockers bind into the β2 receptors and block the action of epinephrine and norepinephrine from binding to its receptors, causing shortness of breath.[citation needed] Additionally, the pediatric population is more susceptible to disease and complications from bronchospasm due to their airway diameter being smaller; applying Poiseuille’s Law to the airways it is clear that airflow resistance through a tube is inversely related to the radius of the tube to the fourth power, therefore, decreases in airway results in significant flow impediments.[4] ## Diagnosis[edit] Signs and symptoms: * Wheezing * Diminished breath sounds * Prolonged expiration * Increase airway pressures (in ventilated patients) ## Treatment[edit] ### Beta 2 agonists[edit] Beta2-adrenergic agonists are recommended for bronchospasm. * Short acting (SABA) * Terbutaline * Salbutamol * Levosalbutamol * Long acting (LABA) * Formoterol * Salmeterol * Others * Dopamine * Norepinephrine * Epinephrine \- titrate to effect (e.g. 10-50 mcg IV), especially in setting of hemodynamic compromise * increasing anesthetic depth * IV magnesium * Increase FiO2 to 100% and consider manual ventilation ### Muscarinic Acetylcholine receptor antagonist[edit] See also: Parasympathetic nervous system and Sympathetic nervous system The neurotransmitter acetylcholine is known to decrease sympathetic response by slowing the heart rate and constricting the smooth muscle tissue. Ongoing research and successful clinical trials have shown that agents such as diphenhydramine, atropine and Ipratropium bromide (all of which act as receptor antagonists of muscarinic acetylcholine receptors) are effective for treating asthma and COPD-related symptoms.[citation needed] ## See also[edit] * Bronchoconstriction * Bronchodilation * Wheezing ## References[edit] 1. ^ Marsh, Alex; Gordon, David; Heslop, Pauline; Pantazis, Christina (2000). "Housing Deprivation and Health: A Longitudinal Analysis". Housing Studies. 15 (3): 411. doi:10.1080/02673030050009258. S2CID 154051241. 2. ^ Haggerty, Catherine L.; Ness, Roberta B.; Kelsey, Sheryl; Waterer, Grant W. (2003). "The impact of estrogen and progesterone on asthma". Annals of Allergy, Asthma & Immunology. 90 (3): 284–91, quiz 291–3, 347. doi:10.1016/S1081-1206(10)61794-2. PMID 12669890. 3. ^ Hatfield. "Asthma in Women". 4. ^ Edwards, Lauren; Borger, Judith (June 26, 2020). "Pediatric Bronchospasm". statPearls. Retrieved November 22, 2020. ## External links[edit] Classification D * ICD-9-CM: 519.11 * MeSH: D001986 * DiseasesDB: 1715 [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA [kDa]: kilodalton [EPC]: Early Prostate Cancer [LAPC]: locally advanced prostate cancer [NSAAs]: nonsteroidal antiandrogens [NSAA]: nonsteroidal antiandrogen [GnRH]: gonadotropin-releasing hormone [ADT]: androgen deprivation therapy [LH]: luteinizing hormone [AR]: androgen receptor [CAB]: combined androgen blockade [LPC]: localized prostate cancer [CPA]: cyproterone acetate [U.S.]: United States [FDA]: Food and Drug Administration	Bronchospasm	c0006261	7,807	wikipedia	https://en.wikipedia.org/wiki/Bronchospasm	2021-01-18T19:01:41	{"mesh": ["D001982", "D001986"], "umls": ["C0006261"], "icd-9": ["519.11"], "wikidata": ["Q279330"]}
Mantle cell lymphoma (MCL) belongs to a group of diseases known as non-Hodgkin’s lymphomas (NHL). NHL's are cancers that affect the the lymphatic system (part of the immune system). In MCL, there are cancerous B-cells (a type of immune system cell). The cancerous B-cells are within a region of the lymph node known as the mantle zone. Although MCLs are slow-growing cancers, the cancer is usually widespread by the time it is diagnosed. In these situations, treatment must be intensive since MCL can become life threatening within a short period of time. MCL accounts for 6% of all NHL's and is mostly found in males during their early 60s. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA [kDa]: kilodalton [EPC]: Early Prostate Cancer [LAPC]: locally advanced prostate cancer [NSAAs]: nonsteroidal antiandrogens [NSAA]: nonsteroidal antiandrogen [GnRH]: gonadotropin-releasing hormone [ADT]: androgen deprivation therapy [LH]: luteinizing hormone [AR]: androgen receptor [CAB]: combined androgen blockade [LPC]: localized prostate cancer [CPA]: cyproterone acetate [U.S.]: United States [FDA]: Food and Drug Administration	Mantle cell lymphoma	c0334634	7,808	gard	https://rarediseases.info.nih.gov/diseases/6969/mantle-cell-lymphoma	2021-01-18T17:59:14	{"mesh": ["D020522"], "umls": ["C0334634"], "orphanet": ["52416"], "synonyms": ["Lymphoma, mantle cell"]}
A number sign (#) is used with this entry because Donohue syndrome is caused by homozygous or compound heterozygous mutation in the insulin receptor gene (INSR; 147670) on chromosome 19p13. Clinical Features Among the children of second cousins once removed, Donohue and Uchida (1954) observed 2 sisters with the following features: apparent cessation of growth at about the seventh month of gestation, peculiar facies creating a gnomelike appearance and leading to the designation, and severe endocrine disturbance indicated by emaciation, enlargement of breasts and clitoris, and histologic changes in the ovaries, pancreas and breasts. Three abortions (1 child at 4 months, the others earlier) had been experienced by this mother. The patients died at 46 and 66 days of age, respectively. Two affected sisters were reported by Lakatos et al. (1963). Salmon and Webb (1963) observed a patient with consanguineous parents. Dekaban (1965) found normal chromosomes. Der Kaloustian et al. (1971) described 2 unrelated patients born of consanguineous parents. Schilling et al. (1979) found a defect in insulin receptors in a Canadian Indian infant, the son of first cousins once removed. Emaciation, absence of subcutaneous fat, decreased muscle mass, hirsutism, and low-set, poorly developed ears were features. Sudden death occurred at age 47 days. Profound hyperinsulinemia and insulin receptor function in cultured fibroblasts. At autopsy, marked hypertrophy of pancreatic beta cells was noted. Epidermal growth factor, although chemically related to insulin, showed normal binding. Bier et al. (1980) concluded that hypoglycemia in leprechaunism is due to an accelerated fasting state. Elfin facial appearance, growth retardation, severely diminished subcutaneous adipose tissue stores, decreased muscle mass, hypertrichosis, pachyderma, and acanthosis nigricans were cited as notable clinical features. See Seip syndrome (269700). Elsas et al. (1985) stated that 31 patients with leprechaunism had been reported since the original description by Donohue (1948). They summarized the phenotype as follows: severe intrauterine growth retardation; small, elfin-like face with protuberant ears; distended abdomen; relatively large hands, feet, and genitalia; and abnormal skin with hypertrichosis, acanthosis nigricans, and decreased subcutaneous fat. At autopsy, patients have shown cystic changes in membranes of gonads and hyperplasia of pancreatic islet cells. Taylor et al. (1981) studied cultured lymphocytes from a patient with leprechaunism and extreme insulin resistance previously attributed to a postreceptor defect (Kobayashi et al., 1978). They found that in fact the patient had an inborn error affecting insulin receptor function. Receptor binding was abnormal in having decreased sensitivity to alterations in temperature and pH. However, the level of insulin binding to cells from the patient was within normal limits. Thus, insulin resistance probably resulted from a decreased ability of the receptor to couple insulin binding to insulin action. From studies of an infant with leprechaunism and the parents, Elsas et al. (1985) concluded that the family had 2 different recessive mutations that impair high-affinity insulin-receptor binding and that the proband was a genetic compound. The 2 mutations produced structural changes in the receptor that altered subunit interaction and resulted in loss of high-affinity binding and cellular responsiveness. After oral glucose, the proband showed marked hyperinsulinism, the father showed mild hyperinsulinism, and the mother had a normal response. The proband's fibroblasts had no high-affinity binding of insulin but normal low-affinity binding. Cells from the mother had 60% and those from the father 20% of high-affinity binding and normal low-affinity binding. The patient studied by Elsas et al. (1985), a black female, was 8 years old at the time of report. Most patients have died by the age of 10 months. The same patient, designated 'Arkansas I,' was studied by Kobayashi et al. (1978), Taylor et al. (1981), and others. In studies of probands and parents from 3 unrelated families, Endo et al. (1987) demonstrated heterogeneity of a defect in insulin receptor. One of the 3, 'Arkansas I,' showed defective alpha-subunit interaction. Geffner et al. (1987) studied a female patient with very high levels of insulin. There was evidence of residual insulin activity in the form of cystic ovarian enlargement with gonadotropin-independent steroid secretion and persistent, severe myocardial hypertrophy. Geffner et al. (1987) concluded that the response to supraphysiologic concentrations of insulin was mediated via the insulin-like growth factor receptor mechanism which remained intact. Cantani et al. (1987) reviewed 49 published cases. Reddy et al. (1988) studied insulin receptor function in cultured skin fibroblasts from 3 patients with leprechaunism. The cell lines in all 3 patients showed insulin binding less than 15% of control values. In 1 cell line this was primarily due to reduced affinity of the receptor; in the other 2, it was due to a reduced number of receptors. When expressed as a fraction of total insulin bound, the percentage of cell-associated insulin internalized and degraded did not differ between the patient cell lines and the controls. Reddy et al. (1989) characterized a second family of leprechaunism (Ark-2) and found defects of insulin receptor phosphorylation in the phenotypically normal parents. Reddy and Kahn (1989) demonstrated a functional abnormality of the epidermal growth factor receptor (131550), as well as of the insulin receptor, in 3 unrelated patients with leprechaunism. The abnormality was due to a decrease in receptor affinity in 2 of the cases and to a decrease in receptor number in the third. In all 3 cell lines studied, EGF-stimulated receptor autophosphorylation was also decreased, whereas EGF internalization and degradation were normal. The type A syndrome of insulin resistance and acanthosis nigricans showed no abnormality of EGF receptor. Reddy and Kahn (1989) proposed that 'a more fundamental defect beyond the insulin receptor alone is the probable cause of leprechaunism.' Psiachou et al. (1993) reported a female infant with leprechaunism who was homozygous for a mutation in the INSR gene. Both parents, who were first cousins, were heterozygous for the mutant allele and phenotypically and clinically normal. The patient, who died at 4 months of age, had grossly retarded bone age, with the distal femoral epiphysis not being evident at 3 months of age. She had high fasting growth hormone (GH) values without a rise in IGF-I concentrations as well as an inadequate response to exogenously administered GH, implying growth hormone resistance. Psiachou et al. (1993) suggested that this resistance was a secondary effect caused by downregulation of GH receptor activity in the presence of high concentrations of insulin proximal to the cell membrane, with consequent limitation of IGF-I formation and cellular growth. Thus, although the primary defect in leprechaunism is in the insulin receptor gene, a secondary defect is probably responsible for an impaired response to endogenous GH and growth failure. In a Yemeni family, Al-Gazali et al. (1993) observed what they considered to be a mild form of leprechaunism in 4 males and 1 female out of 8 offspring of second-cousin parents. The patients had insulin resistance with paradoxical hypoglycemia and acanthosis nigricans. However, unlike infants with classic leprechaunism who die in the first year of life, all the children were alive, the oldest being 11 years of age; furthermore, all had normal subcutaneous tissue and some showed a normal growth pattern. Ultrasound studies showed thickened myocardium and enlarged kidneys, and the female had ovarian enlargement. Molecular Genetics Psiachou et al. (1993) reported a female infant with leprechaunism who was homozygous by descent for a null allele of the insulin receptor gene. The mutation involved replacement of a 13-bp sequence in exon 13 by an unrelated 5-bp sequence. The net deletion of 8 bp shifted the reading frame and introduced a premature chain termination downstream. Both parents, who were first cousins, were heterozygous for the mutant allele and phenotypically and clinically normal. In affected members of a Yemeni family segregating Donahue syndrome, Hone et al. (1994) identified homozygosity for a substitution of methionine for isoleucine at codon 119 (exon 2) in the INSR gene. The mutation was homozygous in all patients. Nomenclature Fernhoff (2004) noted that Donohue syndrome is a more appropriate designation for this disorder because 'leprechaunism' may be viewed as pejorative by families. History Patterson and Watkins (1962) described a probable case in a male. The 4 previously described cases had been female. Follow-up observations (Patterson, 1969) suggest that this may have been a different disorder. There were clinical signs of Cushing disease and at autopsy the adrenals were found to be much enlarged. Before the patient died at the age of almost 8 years, severe changes in the bones, of an unusual type, had developed. Serum alkaline phosphatase was always low, but no phosphoethanolamine was demonstrated in the urine. INHERITANCE \- Autosomal recessive GROWTH Other \- Prenatal growth retardation \- Postnatal growth retardation \- Severe failure to thrive HEAD & NECK Face \- Elfin facies \- Small face Ears \- Large ears \- Low-set ears Eyes \- Prominent eyes Nose \- Wide nostrils Mouth \- Thick lips \- Gingival hyperplasia \- Large mouth CHEST Breasts \- Breast hyperplasia (female) \- Prominent nipples ABDOMEN External Features \- Abdominal distention Liver \- Cholestasis \- Hepatic fibrosis Pancreas \- Islets of Langerhans hyperplasia GENITOURINARY External Genitalia (Male) \- Large penis External Genitalia (Female) \- Large clitoris Internal Genitalia (Male) \- Leydig cell hyperplasia Internal Genitalia (Female) \- Cystic ovaries SKELETAL \- Delayed bone age Hands \- Large hands Feet \- Large feet SKIN, NAILS, & HAIR Skin \- Acanthosis nigricans \- Pachyderma \- Hyperkeratosis Nails \- Dysplastic nails Hair \- Hypertrichosis (body, face) MUSCLE, SOFT TISSUES \- Marked lack of adipose tissue \- Muscle wasting ENDOCRINE FEATURES \- Hyperinsulinemia \- Precocious puberty IMMUNOLOGY \- Frequent infections \- Decreased lymphatic tissue (tonsil, thymus, mesenteric nodes, Peyer patches) NEOPLASIA \- Juvenile ovarian granulosa cell tumor LABORATORY ABNORMALITIES \- Elevated plasma insulin \- Absent anti-insulin receptor antibodies \- Postprandial hyperglycemia \- Fasting hypoglycemia MISCELLANEOUS \- Death often in early infancy MOLECULAR BASIS \- Caused by mutation in the insulin receptor gene (INSR, 147670.0002 ) ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA [kDa]: kilodalton [EPC]: Early Prostate Cancer [LAPC]: locally advanced prostate cancer [NSAAs]: nonsteroidal antiandrogens [NSAA]: nonsteroidal antiandrogen [GnRH]: gonadotropin-releasing hormone [ADT]: androgen deprivation therapy [LH]: luteinizing hormone [AR]: androgen receptor [CAB]: combined androgen blockade [LPC]: localized prostate cancer [CPA]: cyproterone acetate [U.S.]: United States [FDA]: Food and Drug Administration	DONOHUE SYNDROME	c0265344	7,809	omim	https://www.omim.org/entry/246200	2019-09-22T16:26:00	{"doid": ["0050470"], "mesh": ["D056731"], "omim": ["246200"], "orphanet": ["508"], "synonyms": ["Alternative titles", "LEPRECHAUNISM"], "genereviews": ["NBK476444"]}
Sandhoff disease is an inherited lipid storage disorder that progressively destroys nerve cells (neurons) in the brain and spinal cord. The most common and severe form of Sandhoff disease becomes apparent in infancy. Infants with this disorder typically appear normal until the age of 3 to 6 months when their development slows and muscles used for movement weaken. Other forms of Sandhoff disease have been described where much milder signs and symptoms begin in childhood, adolescence, or adulthood. These forms are very rare. Sandhoff disease is caused by mutations in the HEXB gene. These mutations cause a deficiency of the enzyme beta-hexosaminidase, which results in the accumulation of certain fats (lipids) in the brain and other organs of the body. Sandhoff disease is inherited in an autosomal recessive manner. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA [kDa]: kilodalton [EPC]: Early Prostate Cancer [LAPC]: locally advanced prostate cancer [NSAAs]: nonsteroidal antiandrogens [NSAA]: nonsteroidal antiandrogen [GnRH]: gonadotropin-releasing hormone [ADT]: androgen deprivation therapy [LH]: luteinizing hormone [AR]: androgen receptor [CAB]: combined androgen blockade [LPC]: localized prostate cancer [CPA]: cyproterone acetate [U.S.]: United States [FDA]: Food and Drug Administration	Sandhoff disease	c0036161	7,810	gard	https://rarediseases.info.nih.gov/diseases/7604/sandhoff-disease	2021-01-18T17:57:50	{"mesh": ["D012497"], "omim": ["268800"], "orphanet": ["796"], "synonyms": ["Beta-hexosaminidase-beta-subunit deficiency", "GM2 gangliosidosis, type 2", "Total hexosaminidase deficiency", "Hexosaminidase A and B deficiency Disease", "Sandhoff-Jatzkewitz-Pilz disease"]}
Breast hematoma Breast hematoma is a collection of blood within the breast. It arises from internal bleeding (hemorrhage) and may arise due to trauma (breast injury or surgery) or due to a non-traumatic cause. ## Contents * 1 Symptoms * 2 Causes * 3 Pathophysiology * 4 Diagnosis * 5 Treatment * 6 References * 7 External links ## Symptoms[edit] Symptoms may include visible discoloring (ecchymosis), breast pain, and swelling. The symptoms may be similar to those of fibrocystic breast changes. ## Causes[edit] A breast hematoma may appear due to direct trauma to the breast, for example from a sports injury or a road accident, for example a vehicle collision in which a seat belt injury occurs. Hematoma can also be a consequence of breast surgery, usually due to post-operative bleeding. Bleeding may occur shortly after the intervention or a number of days later and can occur for cosmetic surgery (for example breast reduction or breast enhancement) and for non-cosmetic surgery (for example lymph node removal, lumpectomy, or mastectomy). More rarely, hematoma can result from breast biopsy. Rarely, a breast hematoma can also occur spontaneously due to a rupture of blood vessels in the breast, especially in persons with coagulopathy[1][2] or after long-term use of blood-thinning drugs such as aspirin or ibuprofen.[3] ## Pathophysiology[edit] Small breast hematomas often resolve on their own within several days or weeks by means of reabsorption of the blood. Larger hematomas are more likely to lead to inflammation or fibrosis. Breast hematomas can sometimes lead to skin discoloration, inflammation, or fever. When a hematoma resolves, it may become fibrotic, leaving behind scar tissue. A resolving hematoma may liquify to form a seroma. Post-surgical breast hematomas can also impede wound healing and therefore impact the cosmetic outcome. Hematomas are furthermore one of the risk factors for breast surgical site infections.[4] There is preliminary evidence that, after breast implant surgery, the presence of hematoma increases the risk of developing capsular contracture.[5] In mammography screening, scar tissue resulting from a breast hematoma can easily be confused with tumor tissue,[6] especially in the first years following surgery. Ultimately, fat necrosis may occur in the concerned region of the breast.[1] ## Diagnosis[edit] When there is post-operative swelling after breast surgery or core needle biopsy, a breast ultrasound examination may be indicated in order to differentiate between a hematoma and other possible post-surgical complications such as abscess or seroma,[7] A recent hematoma is usually visible in a mammogram.[1] and it also shows typical signal intensities on MR imaging.[8] If a differentiation from breast cancer is necessary, a hematoma biopsy may be indicated. A careful consideration of the case history is important for the diagnosis of a breast hematoma. ## Treatment[edit] Small breast hematomas that cause no discomfort often require merely clinical observation, with ultrasound being used to monitor the resolution of the hematoma. Large breast hematomas, or those that are not becoming smaller or that are causing discomfort, usually require drainage. Also hematomas that occur after surgery for excision of a malignant tumor are drained, because a hematoma to which irradiation is applied is unlikely to ever resolve.[9] A recent hematoma can be drained by means of needle aspiration or (rarely) open surgical drainage. ## References[edit] 1. ^ a b c "Breast hematoma". radiopaedia.org. Retrieved 18 November 2014. 2. ^ Salemis NS (2012). "Breast hematoma complicating anticoagulant therapy: management and literature review". Breast Disease (review). 34 (1): 25–8. doi:10.3233/BD-130344. PMID 23507668. 3. ^ Michael S. Sabel (23 April 2009). Essentials of Breast Surgery: A Volume in the Surgical Foundations Series. Elsevier Health Sciences. p. 177. ISBN 0-323-07464-2. 4. ^ Xue, D.Q.; Qian, C.; Yang, L.; Wang, X.F. (2012). "Risk factors for surgical site infections after breast surgery: A systematic review and meta-analysis". European Journal of Surgical Oncology (review). 38 (5): 375–381. doi:10.1016/j.ejso.2012.02.179. ISSN 0748-7983. PMID 22421530. 5. ^ Handel, Neal; Cordray, Tracy; Gutierrez, Jaime; Jensen, J Arthur (2006). "A Long-Term Study of Outcomes, Complications, and Patient Satisfaction with Breast Implants". Plastic and Reconstructive Surgery. 117 (3): 757–767. doi:10.1097/01.prs.0000201457.00772.1d. ISSN 0032-1052. PMID 16525261., see sections "Results" and "Conclusions" 6. ^ Beverly Hashimoto; Donald Bauermeister (1 January 2011). Breast Imaging: A Correlative Atlas. Thieme. p. 69. ISBN 978-1-60406-445-2. 7. ^ Christof Sohn; Jens-U. Blohmer; Ulrike Hamper (1999). Breast Ultrasound: A Systematic Approach to Technique and Image Interpretation. Thieme. p. 98. ISBN 978-3-13-111531-7. 8. ^ Ulrich Brinck (January 2004). Practical MR Mammography. Thieme. p. 99. ISBN 978-3-13-132031-5. 9. ^ W. G. Cance (1 January 2001). Breast Surgery. IOS Press. p. 96. ISBN 978-1-58603-159-6. ## External links[edit] Classification D * ICD-10: N64.8 * ICD-9-CM: 611.89 * v * t * e Breast disease Inflammation * Mastitis * Nonpuerperal mastitis * Subareolar abscess * Granulomatous mastitis Physiological changes and conditions * Benign mammary dysplasia * Duct ectasia of breast * Chronic cystic mastitis * Mammoplasia * Gynecomastia * Adipomastia (lipomastia, pseudogynecomastia) * Breast hypertrophy * Breast atrophy * Micromastia * Amastia * Anisomastia * Breast engorgement Nipple * Nipple discharge * Galactorrhea * Inverted nipple * Cracked nipples * Nipple pigmentation Masses * Galactocele * Breast cyst * Breast hematoma * Breast lump * Pseudoangiomatous stromal hyperplasia Other * Pain * Tension * Ptosis * Fat necrosis * Amazia [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA [kDa]: kilodalton [EPC]: Early Prostate Cancer [LAPC]: locally advanced prostate cancer [NSAAs]: nonsteroidal antiandrogens [NSAA]: nonsteroidal antiandrogen [GnRH]: gonadotropin-releasing hormone [ADT]: androgen deprivation therapy [LH]: luteinizing hormone [AR]: androgen receptor [CAB]: combined androgen blockade [LPC]: localized prostate cancer [CPA]: cyproterone acetate [U.S.]: United States [FDA]: Food and Drug Administration	Breast hematoma	c0342095	7,811	wikipedia	https://en.wikipedia.org/wiki/Breast_hematoma	2021-01-18T18:37:10	{"wikidata": ["Q25091292"]}
Syndrome of shellfish poisoning Karenia brevis, the primary dinoflagellate organism responsible for brevetoxin production. Red Tide caused by dinoflagellates. Picture taken off the coast of San Diego, California. Neurotoxic shellfish poisoning (NSP) is a term used to describe the disease caused by consumption of brevetoxins, which are marine toxins produced by the dinoflagellate Karenia brevis (among several others). These toxins can produce a series of gastrointestinal and neurological effects. Outbreaks of NSP commonly take place following harmful algal bloom (HAB) events, commonly referred to as “Florida red tide” (given that blooms are more commonplace along the coasts of Florida and Texas, especially during late summer and early fall). Algal blooms are a naturally-occurring phenomenon, however their frequency has been increasing in recent decades at least in-part due to human activities, climate changes, and the eutrophication (over-abundance of plant nutrients as a result of agricultural runoff, deforestation, river bed erosion, etc.) of marine waters.[1][2][3][4] HABs have been occurring for all of documented history, evidenced by the Native Americans' understanding of the dangers of shellfish consumption during periods of marine bioluminescence (a phenomenon observed during algal blooms).[5] Blooms have been noted to occur as far north as North Carolina and are commonly seen alongside the widespread death of fish and sea birds.[4] In addition to the effects on human health, the economic impact of HAB-associated shellfish toxin outbreaks can have significant economic implications as well due to not only the associated healthcare costs, but the adverse impact on the commercial shellfish industry.[3] ## Contents * 1 Causes * 2 Biochemistry/Toxicology * 3 Presentation and Diagnosis * 4 Management and Treatment * 5 See also * 6 References ## Causes[edit] Filter-feeding mollusks, such as oysters, concentrate dinoflagellates and their toxins in their flesh due to the way they feed. When the shellfish are then eaten by humans, high doses of the toxins may be consumed. Humans are typically exposed to these potent natural toxins via filter-feeding mollusks (i.e., shellfish), because shellfish accumulate biotoxins in their flesh due to the way that they feed.[1] Human exposure seems to be most common via consumption of commonly harvested shellfish such as clams, oysters, and mussels, although it has been proposed that exposure to lower levels of brevetoxins can take place following the consumption of certain planktivorous fish.[4] Toxins will typically be found in the flesh of shellfish for up to 2–8 weeks following a HAB event, however there have been reports of toxin retention for nearly one year post-bloom.[4] Notably, brevetoxins are tasteless and odorless and cannot be eradicated by rinsing, cleaning, cooking, freezing, or application of acid.[4][6] To date, there is no reasonable means of preventing the uptake of toxins by shellfish, nor of removing the toxins from shellfish after harvest.[5] ## Biochemistry/Toxicology[edit] Brevetoxin A, a group of neurotoxins isolated from the marine dinoflagellate Karenia brevis (formerly Gymnodinium breve). Basic schematic of sodium channel function. Brevetoxins bind to the voltage-gated sodium channel and induce a channel-mediated sodium ion influx. This results in neuroexcitation, membrane depolarization, and spontaneous nerve firing. Brevetoxins are a group of greater than ten lipid-soluble cyclic polyethers that bind to a specific site on the voltage-gated sodium channel (VGSC), leading to an influx of sodium ions into the cell. This results in activation of nerves and spontaneous nerve cell membrane depolarization and firing.[6][4] Due to their lipid-solubility, brevetoxins are able to pass through cell membranes and cross the blood-brain barrier.[4] They are metabolized primarily by the liver and are excreted in the bile, although it is thought that urinary excretion plays a role in toxin clearance as well.[4] Additionally, brevetoxins can bind a separate site on VGSCs, causing release of neurotransmitters (such as acetylcholine), resulting in tracheal smooth muscle contraction and widespread mast cell degranulation.[6] ## Presentation and Diagnosis[edit] Diagnosis of NSP is made based on clinical presentation as well as history findings including recent consumption of shellfish. On average, symptoms begin 3-4 hours after consumption, but can begin anywhere from several minutes to 18 hours afterward.[4] Symptoms typically include neurologic and gastrointestinal issues including:[4][6] * nausea * vomiting * diarrhea * numbness and tingling in the lips, mouth, face, and extremities The latter has been described as “nerves being on fire” or “ants crawling and biting all over”.[4] Other less common symptoms can include:[4] * ataxia * loss of coordination * limb paralysis * reversal of hot and cold sensations * slurred speech * headache * pupil dilation * generalized fatigue Patients may be thought to be disoriented or intoxicated. Rarely, patients may experience respiratory distress requiring ventilatory support. Despite this seemingly severe constellation of symptoms, there have been no documented deaths due to NSP. NSP can present similar to other disorders such as:[4] * common food poisoning * seafood allergy * paralytic shellfish poisoning * ciguatera fish poisoning * pesticide poisoning * alcohol intoxication * certain psychiatric disorders. Due to the extensive list of disorders with similar symptoms, a detailed food history is necessary to make the diagnosis.[4] ## Management and Treatment[edit] Treatment for NSP is mostly supportive with monitoring and symptom management. Intravenous fluids and observation of respiratory function are the mainstay of treatment along with pain control. Activated charcoal can be given if the patient presents within four hours of consumption to decontaminate the gastrointestinal tract. Currently, there is no specific antidote for brevetoxins, however there may be a role for mannitol (the primary treatment for ciguatoxin, a dinoflagellate-produced toxin found in some species of fish) or brevatal, a natural antagonist of brevetoxin produced by K. brevis.[4] Though public health policy differs by state, measures are taken to prevent shellfish poisoning outbreaks. The Florida Department of Health has added NSP to their list of reportable diseases. Additionally, since the mid-1970's the Florida Department of Environmental Protection has conducted monitoring of dinoflagellate levels and restricted the harvest of shellfish from nearby shellfish beds when levels are dangerously elevated. Shellfish beds are subsequently opened after two weeks with confirmation of safety by mouse bioassay testing (mouse bioassay testing involves the injection of mice with shellfish extract with subsequent observation for mouse death[4]).[7] Neurotoxic shellfish poisoning Other namesNSP ## See also[edit] * Amnesic shellfish poisoning * Diarrheal shellfish poisoning * Paralytic shellfish poisoning * Ciguatera fish poisoning ## References[edit] 1. ^ a b Zhang, Fan; Xu, Xunxun; Li, Tingting; Liu, Zhonghua (2013-11-28). "Shellfish Toxins Targeting Voltage-Gated Sodium Channels". Marine Drugs. 11 (12): 4698–4723. doi:10.3390/md11124698. ISSN 1660-3397. PMC 3877881. PMID 24287955. 2. ^ Yang, Xiao-e; Wu, Xiang; Hao, Hu-lin; He, Zhen-li (March 2008). "Mechanisms and assessment of water eutrophication". Journal of Zhejiang University Science B. 9 (3): 197–209. doi:10.1631/jzus.B0710626. ISSN 1673-1581. PMC 2266883. PMID 18357622. 3. ^ a b Farabegoli, Federica; Blanco, Lucía; Rodríguez, Laura; Vieites, Juan; Cabado, Ana (2018-05-29). "Phycotoxins in Marine Shellfish: Origin, Occurrence and Effects on Humans". Marine Drugs. 16 (6): 188. doi:10.3390/md16060188. ISSN 1660-3397. PMC 6025170. PMID 29844286. 4. ^ a b c d e f g h i j k l m n o p Watkins, Sharon M. (September 2008). "Neurotoxic Shellfish Poisoning" (PDF). Marine Drugs. 6 (3): 430–455. doi:10.3390/md20080021. PMC 2579735. PMID 19005578. 5. ^ a b Munday, Rex; Reeve, John (2013-11-11). "Risk Assessment of Shellfish Toxins". Toxins. 5 (11): 2109–2137. doi:10.3390/toxins5112109. ISSN 2072-6651. PMC 3847717. PMID 24226039. 6. ^ a b c d Wang, Da-Zhi (2008-06-11). "Neurotoxins from Marine Dinoflagellates: A Brief Review". Marine Drugs. 6 (2): 349–371. doi:10.3390/md6020349. ISSN 1660-3397. PMC 2525493. PMID 18728731. 7. ^ "Neurotoxic Shellfish Poisoning". www.whoi.edu. Retrieved 2020-12-13. * v * t * e * Poisoning * Toxicity * Overdose History of poison Inorganic Metals Toxic metals * Beryllium * Cadmium * Lead * Mercury * Nickel * Silver * Thallium * Tin Dietary minerals * Chromium * Cobalt * Copper * Iron * Manganese * Zinc Metalloids * Arsenic Nonmetals * Sulfuric acid * Selenium * Chlorine * Fluoride Organic Phosphorus * Pesticides * Aluminium phosphide * Organophosphates Nitrogen * Cyanide * Nicotine * Nitrogen dioxide poisoning CHO * alcohol * Ethanol * Ethylene glycol * Methanol * Carbon monoxide * Oxygen * Toluene Pharmaceutical Drug overdoses Nervous * Anticholinesterase * Aspirin * Barbiturates * Benzodiazepines * Cocaine * Lithium * Opioids * Paracetamol * Tricyclic antidepressants Cardiovascular * Digoxin * Dipyridamole Vitamin poisoning * Vitamin A * Vitamin D * Vitamin E * Megavitamin-B6 syndrome Biological1 Fish / seafood * Ciguatera * Haff disease * Ichthyoallyeinotoxism * Scombroid * Shellfish poisoning * Amnesic * Diarrhetic * Neurotoxic * Paralytic Other vertebrates * amphibian venom * Batrachotoxin * Bombesin * Bufotenin * Physalaemin * birds / quail * Coturnism * snake venom * Alpha-Bungarotoxin * Ancrod * Batroxobin Arthropods * Arthropod bites and stings * bee sting / bee venom * Apamin * Melittin * scorpion venom * Charybdotoxin * spider venom * Latrotoxin / Latrodectism * Loxoscelism * tick paralysis Plants / fungi * Cinchonism * Ergotism * Lathyrism * Locoism * Mushrooms * Strychnine 1 including venoms, toxins, foodborne illnesses. * Category * Commons * WikiProject [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA [kDa]: kilodalton [EPC]: Early Prostate Cancer [LAPC]: locally advanced prostate cancer [NSAAs]: nonsteroidal antiandrogens [NSAA]: nonsteroidal antiandrogen [GnRH]: gonadotropin-releasing hormone [ADT]: androgen deprivation therapy [LH]: luteinizing hormone [AR]: androgen receptor [CAB]: combined androgen blockade [LPC]: localized prostate cancer [CPA]: cyproterone acetate [U.S.]: United States [FDA]: Food and Drug Administration	Neurotoxic shellfish poisoning	c0275147	7,812	wikipedia	https://en.wikipedia.org/wiki/Neurotoxic_shellfish_poisoning	2021-01-18T18:36:52	{"mesh": ["D057096"], "wikidata": ["Q16978219"]}
A number sign (#) is used with this entry because of evidence that spastic paraplegia-30 (SPG30) can be caused by homozygous mutation in the KIF1A gene (601255) on chromosome 2q37. Mutation in the KIF1A gene can also cause hereditary sensory neuropathy type IIC (HSN2C; 614213). For a general discussion of genetic heterogeneity of autosomal recessive spastic paraplegia, see SPG5A (270800). Description SPG30 is an autosomal recessive form of slowly progressive spastic paraplegia characterized by onset in the first or second decades of unsteady spastic gait and hyperreflexia of the lower limbs. Mildly impaired sensation and cerebellar involvement has been reported in 1 putatively affected family (summary by Erlich et al., 2011). Clinical Features Klebe et al. (2006) reported a consanguineous family of Algerian origin in which 4 sibs had hereditary spastic paraplegia. Mean age at onset of stiff legs and unsteady spastic gait was 17.5 years (range 12 to 21). Other clinical features included hyperreflexia of the lower limbs and extensor plantar responses. Two sibs had distal sensory loss, primarily pinprick sensation, and 2 had saccadic ocular movements. Three sibs had subtle cerebellar signs, including ataxia, and subsequent brain imaging of 1 of them showed mild diffuse cerebellar atrophy. Disease progression was slow; all patients remained ambulatory for up to 15 years after disease onset. Klebe et al. (2006) concluded that the disorder in this family was a form of complicated SPG with cerebellar involvement and peripheral neuropathy. Klebe et al. (2012) provided follow-up of the family reported by Klebe et al. (2006). The disorder showed slow progression and all patients were able still able to walk after disease duration of 9 to 22 years, although maximal walking distance was reduced. Erlich et al. (2011) reported 3 Palestinian sibs with early childhood onset of slowly progressive spastic paraplegia. They were examined at ages 20, 15, and 14 years, respectively. Although they could participate in sports in childhood, symptoms became more severe between ages 10 and 13 years, and the patients could no longer play, run, or walk long distances. Physical examination showed scissoring gait, lower limb spasticity, hyperreflexia, and extensor plantar responses, most severe in the oldest patient. None had weakness, distal sensory loss, or cognitive dysfunction. Klebe et al. (2012) reported a consanguineous Palestinian family with genetically confirmed SPG30. Age at onset was available for 3 patients only, and occurred at ages 10, 11, and 39 years. All patients had spasticity with hyperreflexia and extensor plantar responses. Most had distal muscle wasting and weakness as well as impaired pinprick and vibration sense. Two patients tested had an axonal sensorimotor peripheral neuropathy, and brain imaging of these 2 patients was normal. None had saccadic ocular pursuit or sphincter disturbances. Inheritance The transmission patterns in the families reported by Klebe et al. (2006) and Erlich et al. (2011) were consistent with autosomal recessive inheritance. Mapping In an Algerian family with autosomal recessive spastic paraplegia, Klebe et al. (2006) found linkage to a 5.1-cM interval, termed SPG30, on chromosome 2q37.3 (maximum multipoint lod score of 3.8 between markers D2S2338 and D2S2585). Direct sequencing excluded mutations in the coding regions of the STK25 gene (602255). Molecular Genetics By homozygosity mapping, exome sequencing, and examination of candidate genes, Erlich et al. (2011) identified a homozygous mutation in the KIF1A gene (A255V; 601255.0001) in 3 Palestinian sibs with pure hereditary spastic paraplegia. Klebe et al. (2012) identified a homozygous mutation in the KIF1A gene (R350G; 601255.0005) in affected members of a consanguineous Algerian family with SPG30 originally reported by Klebe et al. (2006). Another Palestinian family with the disorder was found to be homozygous for the A255V mutation. INHERITANCE \- Autosomal recessive HEAD & NECK Eyes \- Saccadic ocular pursuit (in 1 of 3 families) GENITOURINARY Bladder \- Sphincter disturbances, mild (in 1 of 3 families) MUSCLE, SOFT TISSUES \- Lower limb muscle atrophy (in 2 of 3 families) \- Lower limb muscle weakness (in 2 of 3 families) NEUROLOGIC Central Nervous System \- Lower limb spasticity \- Spastic gait \- Hyperreflexia \- Extensor plantar responses \- Ankle clonus \- Cerebellar signs, mild (in 1 of 3 families) \- Dysmetria (in 1 of 3 families) \- Cerebellar ataxia (in 1 of 3 families) \- Cerebellar atrophy, mild (in 1 of 3 families) Peripheral Nervous System \- Peripheral sensory loss, distal, mild (in 2 of 3 families) \- Axonal neuropathy (in 2 of 3 families) MISCELLANEOUS \- Three families have been reported (last curated August 2012) \- Onset in first or second decade \- Slow progression MOLECULAR BASIS \- Caused by mutation in the kinesin family member 1A gene (KIF1A, 601255.0001 ) ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA [kDa]: kilodalton [EPC]: Early Prostate Cancer [LAPC]: locally advanced prostate cancer [NSAAs]: nonsteroidal antiandrogens [NSAA]: nonsteroidal antiandrogen [GnRH]: gonadotropin-releasing hormone [ADT]: androgen deprivation therapy [LH]: luteinizing hormone [AR]: androgen receptor [CAB]: combined androgen blockade [LPC]: localized prostate cancer [CPA]: cyproterone acetate [U.S.]: United States [FDA]: Food and Drug Administration	SPASTIC PARAPLEGIA 30, AUTOSOMAL RECESSIVE	c1835896	7,813	omim	https://www.omim.org/entry/610357	2019-09-22T16:04:41	{"doid": ["0110781"], "mesh": ["C563677"], "omim": ["610357"], "orphanet": ["101010"]}
## Clinical Features Garcia-Cruz et al. (1990) reported 3 sisters, born of nonconsanguineous parents, with congenital glaucoma, distinctive facies (large eyes, wide forehead, thin nasal bridge, and broad nose with large tip), large ears, short neck, wide thorax, umbilicated nipples, cubitus valgus, and short big toes. Radiologic examination revealed mild skeletal anomalies characterized by slender long bones with wide metaphyses and thin cortices, cuboid-shaped vertebral bodies, enlarged transverse apophysis of the seventh vertebral body, narrowed vertebral canal and decreased interpedicular distance at the lumbar segments, and generalized osteopenia. Ophthalmologic examination was suggestive of iridogoniodysgenesis, but presurgical gonioscopic data were not available. There was no family history of glaucoma or any other ophthalmologic disorder. Garcia-Cruz et al. (1990) suggested that the disorder represented a newly recognized congenital glaucoma syndrome with possible autosomal recessive inheritance. Rodriguez-Rojas et al. (2004) described a sister and 2 brothers with congenital glaucoma, skeletal anomalies, and a peculiar facial appearance whose clinical and radiologic features were identical to those of the 3 sisters reported by Garcia-Cruz et al. (1990), except for the absence of large ears and cubitus valgus, and the presence of undeveloped frontal sinuses. Ophthalmologic examination in the proposita revealed megalocornea, wide anterior chambers, concave iris with stromal atrophy, and nasal corectopia in both eyes with no evidence of posterior embryotoxon, associated with congenital glaucoma. Radiologic and ophthalmologic examination including gonioscopy in the healthy, nonconsanguineous parents and 2 unaffected sibs were normal. There was no family history of glaucoma or other ophthalmologic anomalies. Rodriguez-Rojas et al. (2004) concluded that these 2 families had a distinct iridogoniodysgenesis syndrome with probable autosomal recessive inheritance. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA [kDa]: kilodalton [EPC]: Early Prostate Cancer [LAPC]: locally advanced prostate cancer [NSAAs]: nonsteroidal antiandrogens [NSAA]: nonsteroidal antiandrogen [GnRH]: gonadotropin-releasing hormone [ADT]: androgen deprivation therapy [LH]: luteinizing hormone [AR]: androgen receptor [CAB]: combined androgen blockade [LPC]: localized prostate cancer [CPA]: cyproterone acetate [U.S.]: United States [FDA]: Food and Drug Administration	IRIDOGONIODYSGENESIS AND SKELETAL ANOMALIES	c1836074	7,814	omim	https://www.omim.org/entry/609515	2019-09-22T16:05:59	{"mesh": ["C535534"], "omim": ["609515"]}
Pityriasis rotunda Other namesPityriasis circinata,[1] Tinea circinata[2] Pityriasis rotunda is a disorder of keratisation of the skin that manifests as a perfectly circular, scaly patches on the torso and proximal portions of the extremities.[1] It may be associated with diseases like hepatocellular carcinoma in racially predisposed groups.[3] ## See also[edit] * Skin lesion * List of cutaneous conditions ## References[edit] 1. ^ a b James, William; Berger, Timothy; Elston, Dirk (2005). Andrews' Diseases of the Skin: Clinical Dermatology. (10th ed.). Saunders. ISBN 0-7216-2921-0.:566 2. ^ Rapini, Ronald P.; Bolognia, Jean L.; Jorizzo, Joseph L. (2007). Dermatology: 2-Volume Set. St. Louis: Mosby. pp. Chapter 10. ISBN 978-1-4160-2999-1. 3. ^ Medscape. "Pityriasis rotunda". WebMed LLC. Retrieved 6 July 2012. ## External links[edit] Classification D * DiseasesDB: 32814 External resources * eMedicine: article/1107624 * v * t * e Papulosquamous disorders Psoriasis Pustular * Generalized pustular psoriasis (Impetigo herpetiformis) * Acropustulosis/Pustulosis palmaris et plantaris (Pustular bacterid) * Annular pustular psoriasis * Localized pustular psoriasis Other * Guttate psoriasis * Psoriatic arthritis * Psoriatic erythroderma * Drug-induced psoriasis * Inverse psoriasis * Napkin psoriasis * Seborrheic-like psoriasis Parapsoriasis * Pityriasis lichenoides (Pityriasis lichenoides et varioliformis acuta, Pityriasis lichenoides chronica) * Lymphomatoid papulosis * Small plaque parapsoriasis (Digitate dermatosis, Xanthoerythrodermia perstans) * Large plaque parapsoriasis (Retiform parapsoriasis) Other pityriasis * Pityriasis rosea * Pityriasis rubra pilaris * Pityriasis rotunda * Pityriasis amiantacea Other lichenoid Lichen planus * configuration * Annular * Linear * morphology * Hypertrophic * Atrophic * Bullous * Ulcerative * Actinic * Pigmented * site * Mucosal * Nails * Peno-ginival * Vulvovaginal * overlap synromes * with lichen sclerosus * with lupus erythematosis * other: * Hepatitis-associated lichen planus * Lichen planus pemphigoides Other * Lichen nitidus * Lichen striatus * Lichen ruber moniliformis * Gianotti–Crosti syndrome * Erythema dyschromicum perstans * Idiopathic eruptive macular pigmentation * Keratosis lichenoides chronica * Kraurosis vulvae * Lichen sclerosus * Lichenoid dermatitis * Lichenoid reaction of graft-versus-host disease This Genodermatoses article is a stub. You can help Wikipedia by expanding it. * v * t * e [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA [kDa]: kilodalton [EPC]: Early Prostate Cancer [LAPC]: locally advanced prostate cancer [NSAAs]: nonsteroidal antiandrogens [NSAA]: nonsteroidal antiandrogen [GnRH]: gonadotropin-releasing hormone [ADT]: androgen deprivation therapy [LH]: luteinizing hormone [AR]: androgen receptor [CAB]: combined androgen blockade [LPC]: localized prostate cancer [CPA]: cyproterone acetate [U.S.]: United States [FDA]: Food and Drug Administration	Pityriasis rotunda	c0343060	7,815	wikipedia	https://en.wikipedia.org/wiki/Pityriasis_rotunda	2021-01-18T18:59:19	{"gard": ["10904"], "umls": ["C0343060"], "wikidata": ["Q7199564"]}
A number sign (#) is used with this entry because of evidence that the Megarbane-Dagher-Melki type of spondylometaphyseal dysplasia (SMDMDM) is caused by homozygous mutation in the MAGMAS (PAM16; 614336) gene on chromosome 16p13. Clinical Features Megarbane et al. (2008) described a consanguineous Lebanese family in which a sister and a brother had chondrodysplasia, developmental delay, severe pre- and postnatal short stature, dysmorphic facial appearance, narrow chest, prominent abdomen, and short limbs. Neonatal radiographs disclosed a bell-shaped thorax, short ribs (some with a cupped end), severe platyspondyly, square iliac bones, horizontal acetabula with medial and lateral spurs, hypoplastic ischia, short long bones, slight widening of the distal femoral metaphyses, and absence of epiphyseal ossification of the knees. The sister died at age 9 months as a result of respiratory insufficiency. A clinical and radiologic follow-up of the boy at age 18 months showed that the axial hypotonia, minor anomalies, and short stature were still present, whereas the bone abnormalities had improved. Megarbane et al. (2014) reported a second, unrelated consanguineous Lebanese family in which 2 sibs had pre- and postnatal growth retardation, developmental delay, large anterior fontanel, prominent forehead, low-set ears, depressed nasal bridge, short nose, anteverted nares, increased nasal width, prominent abdomen, and short limbs. Radiographs disclosed the presence of wormian bones, platyspondyly, decreased interpedicular distance at the lumbar vertebrae, square iliac bones, horizontal acetabula, trident acetabula, hypoplastic ischia, partial agenesis of the sacrum, ribs with cupped ends, short long bones with abnormal modeling, slight widening of the distal femoral metaphyses, and delayed epiphyseal ossification. Both sibs had severe cardiomegaly and died at around 2 years of age from heart failure. Moosa et al. (2016) reported a 5-year-old boy, born to distantly related parents of central European descent, with a milder phenotype of SMDMDM. At birth, his weight was -4 SD, length was -5 SD, and head circumference was at the 90th centile. He was referred at age 5 months for assessment of disproportionate short stature (-6 SD). His craniofacial dysmorphic features included macrocephaly, sparse and thin hair, broad forehead with frontal bossing, depressed nasal bridge, short nose with anteverted and wide nostrils, deep philtrum, open mouth with a prominent tongue, and a short neck. His chest was narrow and his abdomen prominent. All limbs were shortened. There was a limitation of movement at the large joints, and he was markedly hypotonic. During the first 2 years of life, he experienced several episodes of respiratory distress and otitis media. At age 2 years, he had delayed development with poor speech and was markedly hypotonic with no head control. Brain and spine imaging showed a narrowed cervical canal and a narrow cord but no intramedullary signal abnormalities. Motor and sensory nerve conduction studies showed bilateral posterior cord compromise in the L5-S1 region. Audiologic examination showed bilateral conductive hearing loss. Cardiac examination was normal, with no evidence of cardiomyopathy. Skeletal radiographs showed significant platyspondyly, narrow chest, abnormal pelvis, and shortened extremities with metaphyseal abnormalities, resembling odontochondrodysplasia (ODCD; 184260). However, skeletal radiographs at age 4 years, showed marked improvement, with no residual evidence of platyspondyly. Inheritance Megarbane et al. (2008) suggested autosomal recessive inheritance of this disorder based on its occurrence in affected sibs of healthy, consanguineous parents. Mehawej et al. (2014) confirmed autosomal recessive inheritance. Molecular Genetics In 4 patients from 2 unrelated Lebanese families with a rare lethal spondylometaphyseal dysplasia, previously described by Megarbane et al. (2008), Mehawej et al. (2014) identified a homozygous missense mutation (N76D; 614336.0001) in the MAGMAS gene. No homozygous variants in the MAGMAS gene were identified by exome sequencing in 14 unaffected Lebanese individuals, and the N76D mutation was not found in 550 Lebanese control chromosomes or in the dbSNP (build 137) database. By reconstructing haplotypes from each exome and performing STR genotyping of data from 1 affected patient in each family, Mehawej et al. (2014) identified a minimal common ancestral homozygous haplotype near the MAGMAS gene, spanning 1.9 Mb on chromosome 16p13.3, which suggested a founder mutation. By whole-exome sequencing in a 5-year-old boy, born of distantly related parents of central European descent, with a milder form of SMDMDM, Moosa et al. (2016) identified a homozygous missense mutation in the PAM16 gene (Q74P; 614336.0002). The parents were heterozygous for the mutation, which was not present in the ExAC database. INHERITANCE \- Autosomal recessive GROWTH Height \- Short stature, pre- and postnatal Weight \- Low birth weight HEAD & NECK Head \- Large fontanelles \- Prominent forehead \- Macrocephaly \- Frontal bossing Face \- Round face Ears \- Small ears \- Low-set ears \- Hearing loss, conductive (in one patient) Nose \- Depressed nasal bridge \- Short nose \- Wide nostrils \- Anteverted nares \- Increased nasal width Mouth \- Deep philtrum \- Prominent tongue Neck \- Short neck CARDIOVASCULAR Heart \- Cardiomegaly \- Global left ventricular hypokinesia \- Right atrium dilatation \- Pulmonary hypertension RESPIRATORY \- Tachypnea CHEST External Features \- Narrow chest \- Bell-shaped thorax Ribs Sternum Clavicles & Scapulae \- Short ribs \- Cupped end ribs ABDOMEN External Features \- Prominent abdomen SKELETAL \- Delayed bone age Skull \- Wormian bones Spine \- Severe platyspondyly \- Slightly ovoid vertebrae \- Partial sacral agenesis \- Decrease in interpedicular distance in the lumbar vertebrae Pelvis \- Square iliac bones \- Horizontal acetabula with medial and lateral spurs \- Hypoplastic ischia \- Lacy appearance of iliac crest \- Trident acetabula Limbs \- Short limbs \- Short long bones \- Slight widening of the distal femoral metaphyses \- Absence of epiphyseal ossification of the knees \- Abnormal modeling of the long bones \- Bowed femora \- Metaphyseal cupping NEUROLOGIC Central Nervous System \- Developmental delay \- Global developmental delay \- Poor speech development \- Axial hypotonia MISCELLANEOUS \- Bone abnormalities improve with age \- Reduced longevity \- One 5-year-old boy with a milder phenotype did not have cardiomyopathy MOLECULAR BASIS \- Caused by mutation in the presequence translocase-associated motor 16 gene (PAM16, 614336.0001 ) ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA [kDa]: kilodalton [EPC]: Early Prostate Cancer [LAPC]: locally advanced prostate cancer [NSAAs]: nonsteroidal antiandrogens [NSAA]: nonsteroidal antiandrogen [GnRH]: gonadotropin-releasing hormone [ADT]: androgen deprivation therapy [LH]: luteinizing hormone [AR]: androgen receptor [CAB]: combined androgen blockade [LPC]: localized prostate cancer [CPA]: cyproterone acetate [U.S.]: United States [FDA]: Food and Drug Administration	SPONDYLOMETAPHYSEAL DYSPLASIA, MEGARBANE-DAGHER-MELKI TYPE	c2750075	7,816	omim	https://www.omim.org/entry/613320	2019-09-22T15:59:01	{"mesh": ["C567644"], "omim": ["613320"], "orphanet": ["401979"], "synonyms": ["Alternative titles", "CHONDRODYSPLASIA, MEGARBANE-DAGHER-MELKI TYPE"]}
Sofer et al. (1983) described father and son with bilateral absence of the thumb and radius, short stature, mild external ear malformation, and renal anomaly (in the father, absent right renal kidney; in the son, crossed renal ectopia of the left kidney). The son showed a high frequency of chromosome breaks in lymphocytes. The father had 5 unaffected sibs; his parents were normal, including intravenous pyelography. The father was not blood-related to his wife; both were of Jewish-Moroccan origin. Siegler et al. (1980) described radial ray defect and renal disease in 2 sibs. Limbs \- Bilateral absent thumb and radius Inheritance \- Autosomal dominant GU \- Renal anomaly \- Absent kidney \- Crossed renal ectopia Lab \- High frequency of chromosome breaks in lymphocytes Growth \- Short stature Ears \- External ear malformation ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA [kDa]: kilodalton [EPC]: Early Prostate Cancer [LAPC]: locally advanced prostate cancer [NSAAs]: nonsteroidal antiandrogens [NSAA]: nonsteroidal antiandrogen [GnRH]: gonadotropin-releasing hormone [ADT]: androgen deprivation therapy [LH]: luteinizing hormone [AR]: androgen receptor [CAB]: combined androgen blockade [LPC]: localized prostate cancer [CPA]: cyproterone acetate [U.S.]: United States [FDA]: Food and Drug Administration	RADIAL-RENAL SYNDROME	c2931146	7,817	omim	https://www.omim.org/entry/179280	2019-09-22T16:35:20	{"mesh": ["C536267"], "omim": ["179280"], "orphanet": ["3015"]}
A rare partial autosomal monosomy characterized by global developmental delay, intellectual disability, multiple cartilaginous exostoses, and craniofacial anomalies (such as brachycephaly, biparietal foramina, large fontanels, craniosynostosis, ptosis, epicanthic folds, prominent nasal bridge with broad, depressed nasal tip, hypoplastic nares, short philtrum, downturned upper lip, and micrognathia). Additional reported features include behavioral abnormalities, myopia, strabismus, and sensorineural hearing loss, among others. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA [kDa]: kilodalton [EPC]: Early Prostate Cancer [LAPC]: locally advanced prostate cancer [NSAAs]: nonsteroidal antiandrogens [NSAA]: nonsteroidal antiandrogen [GnRH]: gonadotropin-releasing hormone [ADT]: androgen deprivation therapy [LH]: luteinizing hormone [AR]: androgen receptor [CAB]: combined androgen blockade [LPC]: localized prostate cancer [CPA]: cyproterone acetate [U.S.]: United States [FDA]: Food and Drug Administration	Potocki-Shaffer syndrome	c1832588	7,818	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=52022	2021-01-23T19:10:36	{"gard": ["9762"], "mesh": ["C538356"], "omim": ["601224"], "umls": ["C1832588"], "icd-10": ["Q93.5"], "synonyms": ["11p11.2 deletion", "Proximal 11p deletion syndrome"]}
Pyrrolizidine alkaloidosis is a disease caused by chronic poisoning found in humans and other animals caused by ingesting poisonous plants which contain the natural chemical compounds known as pyrrolizidine alkaloids.[1] Pyrrolizidine alkaloidosis can result in damage to the liver, kidneys, heart, brain, smooth muscles, lungs, DNA, lesions all over the body, and could be a potential cause of cancer.[1][2] Pyrrolizidine alkaloidosis is known by many other names such as "Pictou Disease" in Canada[3] and "Winton Disease" in New Zealand.[4] Cereal crops and forage crops can sometimes become polluted with pyrrolizidine-containing seeds, resulting in the alkaloids contaminating flour and other foods, including milk from cows feeding on these plants.[5][6] ## Contents * 1 Plant types and causes * 2 Frequency and exposure * 2.1 Humans * 3 Mechanism of Action * 4 Prevention * 5 References * 6 External links ## Plant types and causes[edit] Yellow tarweed (Amsinckia intermedia); a plant which causes pyrrolizidine alkaloidosis when eaten by animals. Pyrrolizidine alkaloidosis is caused by the consumption of one or more of the 200 known plant species containing the toxic pyrrolizine alkaloids found all over the world today.[4] Established as the most common source of this illness are plants such as ragwort (Senecio jacobaea), woolly groundsels (Senecio redellii, Senecio longilobus), rattleweed (Crotalaria retusa), and seeds of yellow tarweed (Amsinckia intermedia).[1] There are 30 known pyrrolizidine alkaloids that are hepatotoxic, meaning they cause injury to the liver.[2] Although animals innately know to give these toxic plants a wide berth while grazing, in extreme drought conditions animals have been known to ingest them as a source of minimal protein. Animals can also be poisoned if the toxic plant material is in pellets, or harvested with grain.[1][7] Echites umbellatus, belonging to the dogbane family Apocynaceae and having the English common name Devil's potato, has recently been found to contain lycopsamine-type pyrrolizidine alkaloids.[8] ## Frequency and exposure[edit] ### Humans[edit] Pyrrolizidine alkaloidosis poisoning in the United States has remained moderately rare among humans. The most common reports are the outcome of the misuse of medicinal home remedies, or the alkaloids are present in food and drink substances such as milk and honey when the animal carriers were exposed to the toxins. In other countries, mass human poisonings have occurred when cereal crops used were infected with seeds containing pyrrolizidine alkaloids.[5][9][10][11] Infants and young children are most likely to acquire pyrrolizidine alkaloidosis because of their intrinsic nature to put everything they find into their mouths. However, anyone who consumes one of the mentioned toxic plants is susceptible to the disease.[9] The typical case of pyrrolizidine alkaloidosis toxicity ends in liver damage that ranges from severe to moderate, as well as damage to other organs. The longevity of the disease is wide ranging from 2 weeks to 2 years subsequent to when the poison was ingested. The patient's recovery results may be as diverse as the permanence. Some have recovered as if they were never affected by pyrrolizidine alkaloidosis poisoning if the damage to the liver was not too severe, and others have died from it.[5] The severity of pyrrolizidine alkaloidosis depends on how much of the poisonous plant was consumed in a height, age, and weight to the amount of substance ingested ratio. The only difference in the symptoms will be how prominent they are depending on the above ratio. Symptoms include:[2][5][9][12] * Dull dragging ache in the right upper abdomen * Nausea * Vomiting * Diarrhea * Liver problems * Acute upper gastric pain * Prominent dilated veins on the abdominal wall * Fever * Jaundice * Pulmonary edema * Pleural effusions * Lung damage * Lesions all over the body * Hypertrophy of the right ventricle of the heart * Damage to the kidneys To stop the spread and severity of pyrrolizidine alkaloidosis the first step is to remove the poisonous plant from the source. Once the plant has been removed, the alkaloids can be extracted with chloroform. However, ethyl acetate is a handy and less toxic substitute.[2] Depending on the severity of the toxicity and how long the person has been exposed to the disease, there may be no means of treatment and fatality may occur. ## Mechanism of Action[edit] After oral ingestion, pyrrolizidine alkaloids are absorbed from the gastrointestinal tract. When they reach the liver, they are metabolized via three pathways: N-oxidation, oxidation, and ester hydrolysis. N-oxidation and hydrolysis are detoxification pathways, and the products of these reactions are conjugated and excreted by the kidneys. However, the N-oxide may be converted back into the pyrrolizidine by cytochrome P-450 (CYP450) monooxygenases. Oxidation of the pyrrolizidine to its respective dehydropyrrolizidine is responsible for the toxic effects. In the toxic pathway, the 2-pyrroline in the core is desaturated via an oxidation reaction to form a pyrrolic ester. This metabolite can still subsequently be eliminated if it is conjugated to glutathione. However, this metabolite is toxic because it can act as an electrophile. It may be attacked by either DNA base pairs or by amino acid residues in liver proteins, resulting in the formation of toxic adducts, including cross-linked adducts between DNA base pairs, liver proteins, or both. These adducts can damage DNA, leading to genotoxicity and carcinogenesis, and liver enzymes and hepatocytes, leading to hepatotoxicity. Metabolism and mechanism of action of pyrrolizidine toxicity. Nuc=nucleophilic protein residue or DNA base[13] ## Prevention[edit] The only known technique of prevention is to avoid ingesting the poisonous alkaloids. Some methods of control have been defoliation in areas in both Oregon and California. Also mass relocation efforts of moths, flea beetles and seed flies have been made in hopes that they will eat the toxic plants and help control the population of the plants. This manner of alkaloid control has been met with variable success. Because sheep and goats have such a high immunity to the toxicity of the alkaloids they are commonly used to graze on the plants to control them. However, this method has its risks unless sheep meant for early slaughter are used. Before hay cutting in the spring is the optimal time frame for annual herbicide applications which have also enhanced the destruction of the alkaloids.[1][9][14] ## References[edit] 1. ^ a b c d e The Merck Veterinary Manual. Pyrrolizidine Alkaloidosis: Introduction (Seneciosis, Senecio poisoning, Ragwort toxicity). Merck & Co., Inc., 2008. Web. 15 November 2. ^ a b c d Rizk, Abdel-Fattah M., Naturally Occurring Pyrrolizidine Alkaloids. Doah: CRC Press, 1990 3. ^ "Pictou disease". TheFreeDictionary.com. Retrieved 2019-03-27. 4. ^ a b Hirono, I. Naturally Occurring Carcinogens of Plant Origin. Toyoake: Elsevier, 1987 5. ^ a b c d Bad Bug Book. Pyrrolizidine Alkaloids. U.S. Food & Drug Administration, 17 Sep, 1998. Web. 3 November 6. ^ Dharmananda, Ubhuti. Safety Issues Concerning Herbs: Pyrrolizidine Alkaloids. Institute for Traditional Medicine, 2007. Web. 5 November 7. ^ Talcott P: Pyrrolizidine Alkaloid Poisoning. In: Robinson NE (ed): Current Therapy in Equine Medicine, 5th Edition. Philadelphia, W.B. Saunders Co., 2003, pp. 788-790 8. ^ Burzynski, Elizabeth A., Minbiole, Kevin P.C. and Livshultz, Tatyana, "New sources of lycopsamine-type pyrrolizidine alkaloids and their distribution in Apocynaceae" March 2015 Biochemical Systematics and Ecology 59:331-339 9. ^ a b c d World Health Organization, Environmental Health Criteria 80. Geneva: World Health Organization, 1988 10. ^ Culvenor, C.C., Edgar J.A. Smith L.W., "Pubmed." Pyrrolizidine Alkaloids in honey from Echium Plantagineum L. USA.gov, 2009. Web. 17 September 11. ^ Magnuson, Bernadene. "ExtoxNet FAQs" Pyrrolizidine Alkaloids. EXTOXNET FAQ Team, 1997. Web. 20 October 12. ^ Plant poisoning - Pyrrolizidine alkaloids, wrongdiagnosis.com 13. ^ Moreira, R; Pereira, DM; Valentão, P; Andrade, PB (5 June 2018). "Pyrrolizidine Alkaloids: Chemistry, Pharmacology, Toxicology and Food Safety". International Journal of Molecular Sciences. 19 (6): 1668. doi:10.3390/ijms19061668. PMC 6032134. PMID 29874826. 14. ^ Cheeke, P.R. Symposium on Pyrrolizidine (Senecio) Alkaloids: Toxicity, Metabolism, and Poisonous Plant Control Measures ## External links[edit] * https://web.archive.org/web/20080517051843/http://www.seafoodhaccp.com/SeafoodData/BadBugBook/CHAP42.HTML * http://www.itmonline.org/arts/pas.htm * http://www.merckvetmanual.com/mvm/index.jsp?cfile=htm/bc/212800.htm * http://www.vet.uga.edu/VPP/clerk/elliott/index.php [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA [kDa]: kilodalton [EPC]: Early Prostate Cancer [LAPC]: locally advanced prostate cancer [NSAAs]: nonsteroidal antiandrogens [NSAA]: nonsteroidal antiandrogen [GnRH]: gonadotropin-releasing hormone [ADT]: androgen deprivation therapy [LH]: luteinizing hormone [AR]: androgen receptor [CAB]: combined androgen blockade [LPC]: localized prostate cancer [CPA]: cyproterone acetate [U.S.]: United States [FDA]: Food and Drug Administration	Pyrrolizidine alkaloidosis	None	7,819	wikipedia	https://en.wikipedia.org/wiki/Pyrrolizidine_alkaloidosis	2021-01-18T19:05:02	{"wikidata": ["Q17148765"]}
Normophosphatemic familial tumoral calcinosis SpecialtyDermatology Normophosphatemic familial tumoral calcinosis is a cutaneous disorder characterized by cutaneous calcification or ossification.[1] ## See also[edit] * Progressive systemic sclerosis * List of cutaneous conditions * List of genes mutated in cutaneous conditions ## References[edit] 1. ^ Rapini, Ronald P.; Bolognia, Jean L.; Jorizzo, Joseph L. (2007). Dermatology: 2-Volume Set. St. Louis: Mosby. ISBN 978-1-4160-2999-1. This dermatology article is a stub. You can help Wikipedia by expanding it. * v * t * e [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA [kDa]: kilodalton [EPC]: Early Prostate Cancer [LAPC]: locally advanced prostate cancer [NSAAs]: nonsteroidal antiandrogens [NSAA]: nonsteroidal antiandrogen [GnRH]: gonadotropin-releasing hormone [ADT]: androgen deprivation therapy [LH]: luteinizing hormone [AR]: androgen receptor [CAB]: combined androgen blockade [LPC]: localized prostate cancer [CPA]: cyproterone acetate [U.S.]: United States [FDA]: Food and Drug Administration	Normophosphatemic familial tumoral calcinosis	c1864861	7,820	wikipedia	https://en.wikipedia.org/wiki/Normophosphatemic_familial_tumoral_calcinosis	2021-01-18T18:48:49	{"gard": ["10878"], "mesh": ["C566473"], "umls": ["C1864861"], "orphanet": ["306658", "53715"], "wikidata": ["Q7053148"]}
In a Dutch family with no known consanguinity, van Engelen et al. (1992) identified a sister and 2 brothers out of a sibship of 4 who had adult-onset, predominantly distal, muscle weakness. The female proband also had epilepsy and a progressive spastic ataxic gait. Although the 2 younger brothers showed no signs of involvement of the nervous system, further studies demonstrated evidence of leukoencephalopathy in all 3 when studied by computed tomography and MRI. No abnormality was found on MRI in the asymptomatic sister or in the parents. Muscle biopsy showed no changes suggesting mitochondrial abnormality, including no defect in oxidative metabolism on biochemical study. An association between muscular dystrophy and leukoencephalopathy has been described in congenital muscular dystrophy of the Fukuyama type (253800). The relationship of this adult-onset form of muscular dystrophy with leukoencephalopathy is unclear. Radiology \- Leukoencephalopathy by CT and MRI Muscle \- Adult-onset, predominantly distal, muscle weakness Neuro \- Seizures \- Progressive spastic ataxic gait Inheritance \- Autosomal recessive ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA [kDa]: kilodalton [EPC]: Early Prostate Cancer [LAPC]: locally advanced prostate cancer [NSAAs]: nonsteroidal antiandrogens [NSAA]: nonsteroidal antiandrogen [GnRH]: gonadotropin-releasing hormone [ADT]: androgen deprivation therapy [LH]: luteinizing hormone [AR]: androgen receptor [CAB]: combined androgen blockade [LPC]: localized prostate cancer [CPA]: cyproterone acetate [U.S.]: United States [FDA]: Food and Drug Administration	MUSCULAR DYSTROPHY, ADULT-ONSET, WITH LEUKOENCEPHALOPATHY	c1854646	7,821	omim	https://www.omim.org/entry/253590	2019-09-22T16:24:56	{"mesh": ["C565361"], "omim": ["253590"]}
A number sign (#) is used with this entry because of evidence that Diamond-Blackfan anemia-15 with mandibulofacial dysostosis (DBA15) is caused by heterozygous mutation in the RPS28 gene (603685) on chromosome 19p13. For a discussion of genetic heterogeneity of Diamond-Blackfan anemia, see DBA1 (105650). Clinical Features Gripp et al. (2014) reported 2 unrelated girls (patients 4 and 5) with Diamond-Blackfan anemia associated with mandibulofacial dysostosis. Both girls were noted at birth to micrognathia, downslanting palpebral fissures, submucosal cleft palate or bifid uvula, and malar hypoplasia. One child (patient 4) had absence of the eyelashes on the medial aspects of the lower lids, resulting in a clinical diagnosis of Treacher Collins syndrome (TCS; 154500), but sequencing of the TCOF1 gene (606847) was negative. This child also had unilateral mixed hearing loss, diaphragmatic hernia, persistent respiratory and feeding problems resulting in poor overall growth, inability to bend the thumbs at the interphalangeal joints, and delayed psychomotor development with mild intellectual disability. Macrocytic anemia due to DBA was diagnosed in the first year of life; she also had intermittent granulocytopenia. Her health was stable at age 22 years. In addition to dysmorphic facial features, the other child had severe sensorineural hearing loss, posteriorly rotated ears, sparse eyebrows, and epicanthal folds; eyelashes were intact. Small external ear canals were noted. She also had bifid uvula and mildly webbed neck. Steroid-responsive DBA was diagnosed in infancy. She had mildly delayed development and was in good heath at age 14 years. Both girls had short stature. Molecular Genetics In 2 unrelated girls with DBA and mandibulofacial dysostosis, Gripp et al. (2014) identified the same de novo heterozygous mutation affecting the translation initiation codon of the RPS28 gene (c.1A-G; 603685.0001), predicted to result in haploinsufficiency. The mutation was found by exome sequencing and confirmed by Sanger sequencing. Functional studies of the variant were not performed, but Gripp et al. (2014) noted that RPS28 interacts with other RPS proteins to generate ribosomes, and that the mutation may be comparable to the loss of RPS19 (603474), which is mutated in DBA1. One of the patients had loss of the mutant allele and SNPs on 19p in peripheral blood cells, but not in buccal DNA, whereas the other patient had loss of the mutant allele and SNPs on 19p in buccal DNA only. It was not known whether this tissue-specific allelic imbalance contributed to the clinical presentation. History Hasan and Inoue (1993) described a female born with bilateral microtia, slightly downslanting palpebral fissures, cleft palate, and micrognathia, who presented at the age of 3.5 months with Diamond-Blackfan anemia. The report noted sparse eyelashes on the lower lid. Although the patient had features in common with those of TCS, she did not have the lower lid coloboma characteristic of that disorder. Subsequent analysis of the TCOF1 gene, as reported by Gripp et al. (2001), showed no mutations therein. INHERITANCE \- Autosomal dominant GROWTH Height \- Short stature Other \- Poor overall growth (patient A) HEAD & NECK Face \- Micrognathia \- Midface hypoplasia Ears \- Microtia \- Small or atretic external auditory canals \- Mixed hearing loss (patient A) \- Posteriorly rotated ears (patient B) \- Sensorineural hearing loss (patient B) Eyes \- Downslanting palpebral fissures \- Sparse eyebrows (patient B) \- Epicanthal folds (patient B) \- Absence of eyelashes on the medial aspects of the lower lids (patient A) Mouth \- Submucosal cleft palate (patient A) Bifid uvula (patient B) Neck \- Wide neck (patient B) RESPIRATORY \- Respiratory difficulties (patient A) CHEST Diaphragm \- Diaphragmatic hernia (patient A) ABDOMEN Gastrointestinal \- Feeding difficulties (patient A) SKELETAL Hands \- Immobile thumbs at the interphalangeal joint (patient A) NEUROLOGIC Central Nervous System \- Delayed psychomotor development HEMATOLOGY \- Macrocytic anemia \- Increased fetal hemoglobin \- Increased erythrocyte adenosine deaminase activity \- Granulocytopenia, intermittent (patient A) MISCELLANEOUS \- Onset in infancy \- Two unrelated patients have been reported \- Both mutations occurred de novo MOLECULAR BASIS \- Caused by mutation in the ribosomal protein S28 gene (RPS28, 603685.0001 ) ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA [kDa]: kilodalton [EPC]: Early Prostate Cancer [LAPC]: locally advanced prostate cancer [NSAAs]: nonsteroidal antiandrogens [NSAA]: nonsteroidal antiandrogen [GnRH]: gonadotropin-releasing hormone [ADT]: androgen deprivation therapy [LH]: luteinizing hormone [AR]: androgen receptor [CAB]: combined androgen blockade [LPC]: localized prostate cancer [CPA]: cyproterone acetate [U.S.]: United States [FDA]: Food and Drug Administration	DIAMOND-BLACKFAN ANEMIA 15 WITH MANDIBULOFACIAL DYSOSTOSIS	c1260899	7,822	omim	https://www.omim.org/entry/606164	2019-09-22T16:10:37	{"mesh": ["D029503"], "omim": ["606164"], "orphanet": ["124"]}
A number sign (#) is used with this entry because of evidence that optic atrophy-5 (OPA5) is caused by heterozygous mutation in the DNM1L gene (603850) on chromosome 12p11. Description OPA5 is an autosomal dominant form of nonsyndromic optic atrophy, manifest as slowly progressive visual loss with variable onset from the first to third decades. Additional ocular abnormalities may include central scotoma and color vision defects. The pathogenesis is related to defective mitochondrial fission (summary by Gerber et al., 2017). For a discussion of genetic heterogeneity of optic atrophy, see OPA1 (165500). Clinical Features Barbet et al. (2005) described 2 unrelated 3-generation French families (families A and B) with autosomal dominant optic atrophy. Although the age of onset was in the first decade in one family and in the third decade in the other, the phenotype was similar in both families and resembled that of patients with mutations in the OPA1 gene. All of the examined patients had optic nerve pallor. Visual acuity decreased slowly, perhaps related to a central scotoma. Color vision was moderately impaired, varying from normal to blue-yellow dyschromatopsia; after several years of evolution, patients showed a severe dyschromatopsia without axis. Electroretinogram recordings were normal, but visual evoked potential recordings were moderately altered in the early stages and severely impaired in the later stages. Gerber et al. (2017) reported a large multigenerational French family (family 1) in which 8 individuals, 5 of whom were still living, had nonsyndromic optic atrophy. Four patients from 2 generations were examined; they were 10, 14, 40, and 49 years of age. The youngest patient was asymptomatic, the 14 year-old had moderate photophobia, and the older patients had decreased visual acuity beginning at 35 and 45 years, respectively. However, all had abnormalities on detailed eye studies, including narrowing of the visual fields. Three patients had central scotoma, and 2 had moderate color vision defects. All had temporal pallor of the optic discs, and a reduction of retinal nerve fiber layer thickness around the optic nerve head. Visual evoked potentials were moderately to severely impaired. One individual had moderate hearing loss, but otherwise, none had additional neurologic findings. Gerber et al. (2017) reported follow-up of the families reported by Barbet et al. (2005): family A was referred to as family 2, and family B was referred to as family 3. The phenotype of these patients had not changed significantly from the original report. Inheritance The transmission pattern of OPA5 in the families reported by Gerber et al. (2017) was consistent with autosomal dominant inheritance. Molecular Genetics In affected members from 3 unrelated French families with OPA5, Gerber et al. (2017) identified 2 different heterozygous missense mutations in the DNM1L gene (E2A, 603850.0009 and A192E, 603850.0010). The mutations in the first 2 families were found by exome sequencing and confirmed by Sanger sequencing; the mutation in the third family was found by direct sequencing of the DNM1L gene. The mutations segregated with the disorder in all 3 families. Patient fibroblasts showed that the mutant proteins were expressed, were able to dimerize with wildtype DNM1L, and formed aggregates in both the cytoplasm and on the mitochondrial network. Mitochondria in mutant cells showed a highly elongated, hyperfilamentous, and tubulated network with a decrease in the number of mitochondrial extremities, suggesting an impairment of mitochondrial fission. In addition, DNM1L clusters were not associated with mitochondrial constriction sites in mutant fibroblasts. The findings were consistent with a dominant-negative effect. There were no structural differences of the peroxisomal network, nor alteration of the respiratory machinery. Heterozygous knockdown of the Dnm1l gene in mice (Dnm1l +/-) resulted in the elongation of the mitochondrial network of retinal ganglion cells, but no axonal degeneration in the optic nerve. Two of the families had previously been reported by Barbet et al. (2005). Gerber et al. (2017) noted that OPA1, which has a similar phenotype, results from impaired mitochondrial fusion, suggesting that retinal ganglion cells are particularly sensitive to mitochondrial membrane dynamics. History Barbet et al. (2005) performed genomewide mapping in a 3-generation French family with autosomal dominant OPA and found that all 8 affected individuals shared a common haplotype on chromosome 22q12.1-q13.1. Obligatory recombination events defined a 10.4-cM critical interval between D22S1148 and D22S283. Haplotype analysis of a second 3-generation French family with autosomal dominant optic atrophy also showed linkage to the region of interest on chromosome 22q. Analyzing the 2 families together, Barbet et al. (2005) obtained a maximum lod score of 3.75 (theta = 0.0) at D22S1176, with penetrance set at 100% (all 12 individuals with the disease haplotype were affected with optic atrophy). Screening of 3 candidate genes, OSBP2 (606729), HSC20 (608142), and HSPC051, in these families failed to identify any disease-causing alterations. In the families reported by Barbet et al. (2005), Gerber et al. (2017) identified mutations in the DNM1L gene on chromosome 12p11, thus denying the existence of a 'OPA5' locus on chromosome 22q and redefining it on 12p11. INHERITANCE \- Autosomal dominant HEAD & NECK Eyes \- Optic nerve atrophy \- Slow decrease in visual acuity \- Dyschromatopsia, blue-yellow \- Central scotoma MISCELLANEOUS \- Onset in 1st to 3rd decade of life \- Slowly progressive \- Three unrelated French families have been reported (last curated November 2017) MOLECULAR BASIS \- Caused by mutation in the dynamin 1-like gene (DNM1L, 603850.0009 ) ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA [kDa]: kilodalton [EPC]: Early Prostate Cancer [LAPC]: locally advanced prostate cancer [NSAAs]: nonsteroidal antiandrogens [NSAA]: nonsteroidal antiandrogen [GnRH]: gonadotropin-releasing hormone [ADT]: androgen deprivation therapy [LH]: luteinizing hormone [AR]: androgen receptor [CAB]: combined androgen blockade [LPC]: localized prostate cancer [CPA]: cyproterone acetate [U.S.]: United States [FDA]: Food and Drug Administration	OPTIC ATROPHY 5	c0338508	7,823	omim	https://www.omim.org/entry/610708	2019-09-22T16:04:11	{"doid": ["5723"], "mesh": ["D029241"], "omim": ["165500", "610708"], "orphanet": ["98673"], "synonyms": ["Autosomal dominant optic atrophy, Kjer type", "Kjer optic atrophy", "Optic atrophy type 1"]}
This article does not cite any sources. Please help improve this article by adding citations to reliable sources. Unsourced material may be challenged and removed. Find sources: "Pulmonary-to-systemic shunt" – news · newspapers · books · scholar · JSTOR (December 2009) (Learn how and when to remove this template message) Pulmonary-to-systemic shunt Specialtyvascular medicine [edit on Wikidata] A pulmonary-to-systemic shunt is a cardiac shunt which allows, or is designed to cause, blood to flow from the pulmonary circulation to the systemic circulation. This occurs when: 1. there is a passage between two or more of the great vessels; and, 2. pulmonic pressure is higher than systemic pressure and/or the shunt has a one-way valvular opening. A pulmonary-to-systemic shunt functions as follows: 1. right-to-left in the absence of arterioventricular discordance. 2. left-to-right if the great vessels are transposed. ## References[edit] This article about a medical condition affecting the circulatory system is a stub. You can help Wikipedia by expanding it. * v * t * e This surgery article is a stub. You can help Wikipedia by expanding it. * v * t * e [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA [kDa]: kilodalton [EPC]: Early Prostate Cancer [LAPC]: locally advanced prostate cancer [NSAAs]: nonsteroidal antiandrogens [NSAA]: nonsteroidal antiandrogen [GnRH]: gonadotropin-releasing hormone [ADT]: androgen deprivation therapy [LH]: luteinizing hormone [AR]: androgen receptor [CAB]: combined androgen blockade [LPC]: localized prostate cancer [CPA]: cyproterone acetate [U.S.]: United States [FDA]: Food and Drug Administration	Pulmonary-to-systemic shunt	None	7,824	wikipedia	https://en.wikipedia.org/wiki/Pulmonary-to-systemic_shunt	2021-01-18T18:41:04	{"wikidata": ["Q7259515"]}
Gigantomastia is a rare condition characterized by excessive breast growth. It may occur spontaneously, during puberty or pregnancy, or while taking certain medications. There is no universally accepted definition of gigantomastia, but the majority of medical articles refer to a particular weight of excess breast tissue. Symptoms of gigantomastic may include mastalgia (breast pain), ulceration/infection, posture problems, back pain and chronic traction injury to 4th/5th/6th intercostal nerves with resultant loss of nipple sensation. It is also associated with decreased fetal growth, if it occurs during pregnancy. The exact cause of gigantomastia is not known; however, hormonal and hereditary factors may be involved. Additionally, gigantomastia has been noted as a side effect of treatment with certain medications, such as like D-penicillamine. Treatment may include breast reduction, mastectomy with or without reconstruction, hormonal treatment, or a combination of treatments. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA [kDa]: kilodalton [EPC]: Early Prostate Cancer [LAPC]: locally advanced prostate cancer [NSAAs]: nonsteroidal antiandrogens [NSAA]: nonsteroidal antiandrogen [GnRH]: gonadotropin-releasing hormone [ADT]: androgen deprivation therapy [LH]: luteinizing hormone [AR]: androgen receptor [CAB]: combined androgen blockade [LPC]: localized prostate cancer [CPA]: cyproterone acetate [U.S.]: United States [FDA]: Food and Drug Administration	Gigantomastia	c0405471	7,825	gard	https://rarediseases.info.nih.gov/diseases/9450/gigantomastia	2021-01-18T18:00:20	{"mesh": ["C536821"], "omim": ["113670"], "orphanet": ["180176"], "synonyms": ["Juvenile gigantomastia (subtype)", "Familial juvenile gigantomastia", "Puberty-induced gigantomastia (subtype)", "Pregnancy-induced gigantomastia (subtype)", "Idiopathic gigantomastia (subtype)", "Virginal breast hypertrophy", "Macromastia", "Drug-induced gigantomastia (subtype)", "Medication-induced gigantomastia (subtype)", "Gestational gigantomastia (subtype)"]}
Hypertrichosis cubiti SpecialtyDermatology Hypertrichosis cubiti (also known as "hairy elbow syndrome"[1]) is a cutaneous condition characterized by multiple terminal hairs on both elbows in children.[1] ## Contents * 1 Causes * 2 Diagnosis * 3 See also * 4 References ## Causes[edit] One known cause of hypertrichosis cubiti is Wiedemann-Steiner syndrome.[2][3] ## Diagnosis[edit] This section is empty. You can help by adding to it. (July 2018) ## See also[edit] * Hook nail * List of cutaneous conditions ## References[edit] 1. ^ a b Rapini, Ronald P.; Bolognia, Jean L.; Jorizzo, Joseph L. (2007). Dermatology: 2-Volume Set. St. Louis: Mosby. ISBN 1-4160-2999-0. 2. ^ Jones WD, Dafou D, McEntagart M, Woollard WJ, Elmslie FV, Holder-Espinasse M, Irving M, Saggar AK, Smithson S, Trembath RC, Deshpande C, Simpson MA (2012). "De Novo Mutations in MLL Cause Wiedemann-Steiner Syndrome". Am J Hum Genet. 91: 358–64. doi:10.1016/j.ajhg.2012.06.008. PMC 3415539. PMID 22795537. 3. ^ Jones, Wendy (2012). "De Novo Mutations in MLL Cause Wiedemann-Steiner Syndrome". American Journal of Human Genetics. 91 (2): 358–364. doi:10.1016/j.ajhg.2012.06.008. PMC 3415539. PMID 22795537. This dermatology article is a stub. You can help Wikipedia by expanding it. * v * t * e [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA [kDa]: kilodalton [EPC]: Early Prostate Cancer [LAPC]: locally advanced prostate cancer [NSAAs]: nonsteroidal antiandrogens [NSAA]: nonsteroidal antiandrogen [GnRH]: gonadotropin-releasing hormone [ADT]: androgen deprivation therapy [LH]: luteinizing hormone [AR]: androgen receptor [CAB]: combined androgen blockade [LPC]: localized prostate cancer [CPA]: cyproterone acetate [U.S.]: United States [FDA]: Food and Drug Administration	Hypertrichosis cubiti	c4025295	7,826	wikipedia	https://en.wikipedia.org/wiki/Hypertrichosis_cubiti	2021-01-18T18:37:43	{"gard": ["143"], "mesh": ["C535618"], "wikidata": ["Q16908675"]}
Not to be confused with Muscardin or Muscadine. A cockroach with muscardine caused by M. anisopliae. Muscardine is a disease of insects. It is caused by many species of entomopathogenic fungus. Many muscardines are known for affecting silkworms.[1] Muscardine may also be called calcino.[2] While studying muscardine in silkworms in the 19th century, Agostino Bassi found that the causal agent was a fungus. This was the first demonstration of the germ theory of disease, the first time a microorganism was recognized as an animal pathogen.[3] There are many types of muscardine. They are often named for the color of the conidial layer each fungus leaves on its host.[1] ## Contents * 1 Black muscardine * 2 Brown muscardine * 3 Grassy muscardine * 4 Gray muscardine * 5 Green muscardine * 6 Orange muscardine * 7 Penicillosis * 8 Red muscardine * 9 White muscardine * 10 Yellow muscardine * 11 Yellow red muscardine * 12 Control * 13 References ## Black muscardine[edit] Black muscardine is caused by Beauveria brongniartti and Metarhizium anisopliae.[1] Metarhizium species such as M. anisopliae can cause fatal disease in over 200 species of insect.[4] ## Brown muscardine[edit] Aspergillosis of insects can be called brown muscardine. Over 10 Aspergillus species can cause the disease, such as A. flavus and A. tamari. The conidial layer may be brownish or greenish yellow.[1] ## Grassy muscardine[edit] Grassy muscardine is caused by Hirsutella necatrix.[5] This fungus produces an enzyme that breaks down the chitin in its host's body.[6] ## Gray muscardine[edit] Gray muscardine is caused by Isaria javanica.[5] ## Green muscardine[edit] Green muscardine is caused by Nomuraea rileyi as well as Metarhizium species. Keepers of silkworms recognize symptoms such as dark brownish lesions with lighter centers on the sides and back of the larva. At death the larva turns white and within a few days it is covered in a bright green fungal coating.[2] ## Orange muscardine[edit] Orange muscardine is caused by Sterigmatocystis japonica.[1] ## Penicillosis[edit] Penicillosis of insects is considered a type of muscardine, particularly when caused by Penicillum citrinum and P. granulatum.[1] ## Red muscardine[edit] Red muscardine is caused by Sporosporella uvella[1] and Isaria fumosoroseus.[5] ## White muscardine[edit] One of the best known forms is white muscardine, which is caused by Beauveria bassiana.[7] When suffering from white muscardine, an insect larva may become inactive and stop eating. The elasticity of its cuticle is lost and it may experience vomiting and diarrhea. As it dies it hardens.[1] The fungus leaves the body of its host covered in powdery white conidia.[7] The fungal layer is tough due to oxalate crystals, and this slows the decay of the body.[1] When a pupa is infected, it often mummifies. It shrinks and wrinkles before growing a fungal coating. In an adult moth, the body hardens and the wings drop off.[2] Spotted in St. Tammany Parish, Louisiana a Golden silk orb-weaver dead from white muscardine disease with white mold emerging from the cadaver's joints and pores. During infection, the fungus absorbs water and nutrients from the host. The hemolymph of the insect crystallizes and thickens. The fungus usually produces toxins, as well. After it kills the host, the fungus continues to absorb water from the body, causing it to harden further.[2] Other insects prone to white muscardine include the brown planthopper[7] and the diaprepes root weevil.[8] ## Yellow muscardine[edit] Yellow muscardine is caused by Isaria farinosa.[1][5] ## Yellow red muscardine[edit] Yellow red muscardine is caused by Isaria fumosoroseus. It can produce reddish patches on the external body and powdery masses of spores internally.[1] ## Control[edit] Fungicidal agents such as azadirachtin and phytoallexin have been used against some muscardine pathogens.[9] Silkworm breeders dust their cages with slaked lime to discourage fungal growth.[10] In India a dust of chaff soaked in formalin is applied to the larvae.[11] ## References[edit] 1. ^ a b c d e f g h i j k Singh, T. Principles And Techniques Of Silkworm Seed Production. Discovery Publishing House. 2004. pg. 277. 2. ^ a b c d Lu, Y. Silkworm Diseases. FAO. 1991. pg. 37. 3. ^ Mahr, S. Know Your Friends: The Entomopathogen Beauveria bassiana. Midwest Biological Control News October, 1997. Volume IV, Number 10. 4. ^ Wang, C. and Y. Xia. Cover photo. PLoS Genetics, January, 2011. 5. ^ a b c d Vega, F. E. and H. K. Kaya. Insect Pathology. Academic Press. 2012. pg. 433. 6. ^ Chernin, L., et al. (1997). Chitinolytic activity of the acaropathogenic fungi Hirsutella thompsonii and Hirsutella necatrix. Canadian Journal of Microbiology 43(5) 440-46. 7. ^ a b c White Muscardine Fungus. Archived 2013-07-04 at Archive.today Rice Knowledge Bank. International Rice Research Institute (IRRI). 2009. 8. ^ Beavers, J. B., et al. (1972). Two Muscardine fungi pathogenic to Diaprepes abbreviatus. The Florida Entomologist 55(2) 117-120. 9. ^ Vyas, R. V., et al. (1992). Effect of some natural pesticides on entomogenous muscardine fungi. Indian J Exp Biol. 30(5) 435-6. 10. ^ Ravikumar, J., et al. Muscardine: a menace to silkworm in winter. The Hindu. January 7, 2010. 11. ^ Veeranna, G., et al. (1985). Muscardine Disease – Precautionary Measures and Its Control. Karnataka State Sericulture Research and Development Institute, Bangalore, Karnataka. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA [kDa]: kilodalton [EPC]: Early Prostate Cancer [LAPC]: locally advanced prostate cancer [NSAAs]: nonsteroidal antiandrogens [NSAA]: nonsteroidal antiandrogen [GnRH]: gonadotropin-releasing hormone [ADT]: androgen deprivation therapy [LH]: luteinizing hormone [AR]: androgen receptor [CAB]: combined androgen blockade [LPC]: localized prostate cancer [CPA]: cyproterone acetate [U.S.]: United States [FDA]: Food and Drug Administration	Muscardine	None	7,827	wikipedia	https://en.wikipedia.org/wiki/Muscardine	2021-01-18T19:08:23	{"wikidata": ["Q3328294"]}
A number sign (#) is used with this entry because the antigens of the Kidd blood group system are encoded by the SLC14A1 gene (613868) on chromosome 18q12.3. Description The Kidd blood group locus encodes a urea transporter (SLC14A1) that is expressed on human red cells and in the kidney. The Kidd blood group system (Jk) is defined by 2 alleles, Jk(a) and Jk(b), whose products were first identified with alloantibodies responsible for haemolytic disease of the newborn or transfusion reactions (summary by Olives et al., 1997). Clinical Features Although Jk-null red blood cells have reduced urea permeability, the Jk deficiency is not associated with any obvious clinical syndrome except for a urine concentration defect (Sands et al., 1992) that probably results from the absence of the Jk protein expressed on endothelial cells of the vasa recta of kidney (Xu et al., 1997; Promeneur et al., 1996). Persons with the Jk-null phenotype are detected because antibody against Jk3 can develop after immunization by transfusion or pregnancy, and this antibody may cause immediate and delayed hemolytic transfusion reactions (Lucien et al. (2002)). Mapping HGM9 concluded provisionally that the Jk locus is at 18q11-q12 (Geitvik et al., 1987). The L2.7 probe used in the assignment to chromosome 18 was thought to lie on the short arm, close to the centromere. The maximum lod score was 8.53 at recombination fraction of 0.03 (upper probability limit 0.11). Geitvik et al. (1987) quoted deletion data excluding Jk from a considerable part of chromosome 18 and contributing to the assignment of 18q11-q12. The Kidd blood group had been assigned to 18p by linkage to a polymorphic anonymous DNA probe, L2.7 (Gedde-Dahl, 1986). Leppert et al. (1987) also found linkage of blood group Kidd to 2 DNA markers on chromosome 18; the maximum lod scores were 3.61 at theta = 0.168 and 4.18 at theta = 0.218. Gross (2016) mapped the SLC14A1 gene, which encodes the antigens of the Kidd blood group system, to chromosome 18q12.3 based on an alignment of the SLC14A1 sequence (GenBank BC050539) with the genomic sequence (GRCh38). Molecular Genetics Olives et al. (1997) determined the genetic basis for the Kidd blood group polymorphism by sequencing reverse-transcribed reticulocyte RNAs from Jk(a+b-) and Jk(a-b+) donors. They found that the difference between Jk(a) and Jk(b) was a G-to-A transition at nucleotide 838, resulting in an asp280-to-asn amino acid substitution (613868.0001) and an MnlI RFLP. History On the basis of studies of a patient with deletion of part of the long arm of chromosome 7, Shokeir et al. (1973) proposed that the Kidd blood group is on the deleted segment. The parents were homozygous Jk(a) and Jk(b) and all 9 sibs of the proband were heterozygous as one would expect. The proband herself was Jk(a). Hulten et al. (1966) previously suggested that the Kidd locus is on either chromosome 2 or a C group chromosome, but banding techniques were not then available. Mace and Robson (1974) found a hint of linkage between 'red-cell' acid phosphatase (171500), which is coded by chromosome 2, and Kidd blood group. Mohr and Eiberg (1977) found a lod score of plus 2.57 for the linkage of Kidd and Colton. Each had been tentatively assigned to chromosome 7. Under 3 different genetic models for IDDM, Hodge et al. (1981) found evidence for linkage with 2 different sets of marker loci: HLA (see 142800), properdin factor B (138470), and glyoxalase-1 (138750) on chromosome 6, and Kidd blood group on chromosome 2. The 71 families studied apparently did not fall into 2 groups, one exhibiting linkage to HLA and the other to Kidd. Thus, they concluded that at least 2 distinct disease-susceptibility loci may be involved in IDDM, a situation also postulated for Graves disease (275000). (The Jk blood group is encoded by a solute carrier gene on chromosome 18q11-q12; an IDDM locus, IDDM6 (601941), maps to 18q21.) Field et al. (1985) and Sherman and Simpson (1985) provided evidence for linkage of IGK (147200) and Jk and, therefore, assignment to chromosome 2. This suggested that the Colton blood group locus (110450) may also be on chromosome 2. Sherman and Simpson (1985) published a collated maximum lod score of 3.14 at theta 0.31 for Jk:IGK. Pausch and Mayr (1987) presented additional data supporting linkage of Jk and IGK. Together with the data of Field et al. (1985), the maximum lod score reached 3.0 for theta = 0.32. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA [kDa]: kilodalton [EPC]: Early Prostate Cancer [LAPC]: locally advanced prostate cancer [NSAAs]: nonsteroidal antiandrogens [NSAA]: nonsteroidal antiandrogen [GnRH]: gonadotropin-releasing hormone [ADT]: androgen deprivation therapy [LH]: luteinizing hormone [AR]: androgen receptor [CAB]: combined androgen blockade [LPC]: localized prostate cancer [CPA]: cyproterone acetate [U.S.]: United States [FDA]: Food and Drug Administration	BLOOD GROUP, KIDD SYSTEM	None	7,828	omim	https://www.omim.org/entry/111000	2019-09-22T16:44:23	{"omim": ["111000"], "synonyms": ["Alternative titles", "KIDD BLOOD GROUP SYSTEM"]}
An autosomal dominant cerebellar ataxia type I that is characterized by very slowly progressive or non-progressive ataxia, dysarthria, oculomotor abnormalities and intellectual disability. ## Epidemiology Spinocerebellar ataxia type 29 (SCA29) prevalence is unknown. More than 50 cases have been reported in the literature to date. ## Clinical description SCA29 presents at birth, or shortly after, with manifestations including very slowly progressive or non-progressive gait and limb ataxia causing delayed walking and frequent falling in children. Mild developmental delay, learning difficulties, and language dysfunction are frequently reported. Other manifestations include nystagmus, dysarthria, dysmetria, and dysdiadochokinesia. Affected patients occasionally present with intention tremor, dystonia, and migraine headaches. Although the disease course is not well established, it appears to range from non-progressive or very slowly progressive ataxia (that does not affect ambulation) to progressively disabling ataxia. A slight improvement in cerebellar signs has been reported in some cases over time. ## Etiology SCA29 is due to mutations in the ITPR1 gene (3p26.1), which is also the causal gene of SCA15. ## Diagnostic methods Diagnosis is based on the characteristic clinical findings and molecular genetic testing. As the manifestations of SCA29 are not specific, diagnosis is only confirmed with the finding of a mutation in the ITPR1 gene. ## Differential diagnosis Differential diagnosis includes other types of autosomal dominant cerebellar ataxia. ## Antenatal diagnosis Antenatal diagnosis is possible in families with a known mutation. ## Genetic counseling SCA29 is inherited autosomal dominantly, occasionally autosomal recessively, and genetic counseling is possible. ## Management and treatment There is no cure for SCA29 and treatment is supportive. Annual neurological examinations are recommended to monitor disease progression. ## Prognosis Disease progression is very slow, but precise prognosis is unknown. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA [kDa]: kilodalton [EPC]: Early Prostate Cancer [LAPC]: locally advanced prostate cancer [NSAAs]: nonsteroidal antiandrogens [NSAA]: nonsteroidal antiandrogen [GnRH]: gonadotropin-releasing hormone [ADT]: androgen deprivation therapy [LH]: luteinizing hormone [AR]: androgen receptor [CAB]: combined androgen blockade [LPC]: localized prostate cancer [CPA]: cyproterone acetate [U.S.]: United States [FDA]: Food and Drug Administration	Spinocerebellar ataxia type 29	c1861732	7,829	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=208513	2021-01-23T17:28:55	{"gard": ["10480"], "mesh": ["C537206"], "omim": ["117360"], "umls": ["C1861732"], "icd-10": ["G11.0"], "synonyms": ["Congenital nonprogressive spinocerebellar ataxia", "SCA29"]}
Mixed connective tissue disease (MCTD) is a rare autoimmune disorder that is characterized by features commonly seen in three different connective tissue disorders: systemic lupus erythematosus, scleroderma, and polymyositis. Some affected people may also have symptoms of rheumatoid arthritis. Although MCTD can affect people of all ages, it appears to be most common in women under age 30. Signs and symptoms vary but may include Raynaud's phenomenon; arthritis; heart, lung and skin abnormalities; kidney disease; muscle weakness, and dysfunction of the esophagus. The cause of MCTD is currently unknown. Treatment may include medications such as nonsteroidal anti-inflammatory drugs (NSAIDs), corticosteroids and immune-suppressing drugs to help manage symptoms. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA [kDa]: kilodalton [EPC]: Early Prostate Cancer [LAPC]: locally advanced prostate cancer [NSAAs]: nonsteroidal antiandrogens [NSAA]: nonsteroidal antiandrogen [GnRH]: gonadotropin-releasing hormone [ADT]: androgen deprivation therapy [LH]: luteinizing hormone [AR]: androgen receptor [CAB]: combined androgen blockade [LPC]: localized prostate cancer [CPA]: cyproterone acetate [U.S.]: United States [FDA]: Food and Drug Administration	Mixed connective tissue disease	c0026272	7,830	gard	https://rarediseases.info.nih.gov/diseases/7051/mixed-connective-tissue-disease	2021-01-18T17:59:01	{"mesh": ["D008947"], "umls": ["C0026272"], "orphanet": ["809"], "synonyms": ["MCTD", "Sharp syndrome"]}
A number sign (#) is used with this entry because of evidence that nonphotosensitive trichothiodystrophy-5 (TTD5) is caused by mutation in the RNF113A gene (300951) on chromosome Xq24. One such family has been reported. For a general phenotypic description and a discussion of genetic heterogeneity of trichothiodystrophy, see TTD1 (601675). Clinical Features Corbett et al. (2015) described 2 male cousins, born of 2 sisters, who had intrauterine growth restriction, progressive microcephaly with profound intellectual disability, genital anomalies that included absent or rudimentary testes and microphallus, and severe linear growth failure despite normal growth hormone (GH1; 139250) production. On MRI, they both exhibited partial absence of the posterior portion of the corpus callosum, cerebellar hypoplasia, and a Dandy-Walker malformation. Both were social and engaging, but their expressive vocabulary consisted of only a few words in the second decade of life. Shared physical features included minimal muscle mass, reduced subcutaneous fatty tissue with an aged facial appearance, high forehead, broad mouth with widely spaced primary teeth, prominent chin, and very ataxic broad-based gait. Both had minimal body hair, with no evidence of pubertal change, as well as sparse, brittle, and slow-growing scalp hair and eyebrows. Polarizing light microscopy revealed a characteristic tiger-tail pattern, and hair amino acid content analysis showed sulfur deficiency, diagnostic of trichothiodystrophy. One cousin also had major structural anomalies, including a very short esophagus with thoracic stomach as well as ureteric obstruction, both requiring surgical correction. Both cousins had recurrent infections, and 1 showed evidence of an IgG1 subclass deficiency; the latter patient also had panhypopituitarism. In addition, ophthalmic examination in this patient at age 14 years revealed bilateral retinal dystrophy, optic nerve hypoplasia, and photosensitivity. Experiments with patient lymphoblasts showed no evidence of nucleotide excision repair (NER) deficiency. All 3 obligate carrier females in the family had 100% skewed X chromosome inactivation, and all exhibited short stature. One carrier female had delayed walking and speech as well as learning difficulties. She also had slow-growing hair with some patchiness, although no tiger-banding was observed. Mapping By linkage analysis in a family in which 2 male cousins had nonphotosensitive trichothiodystrophy, Corbett et al. (2015) obtained a peak lod score of 1.02 between markers DXS8055 and DXS1212, spanning a 7.85-Mb region on Xq23-q25 (chrX:114,654,888-122,487,070, GRCh37). Molecular Genetics In 2 male cousins with nonphotosensitive trichothiodystrophy mapping to chromosome Xq23-q25, who were negative for mutation in 4 known TTD-associated genes, Corbett et al. (2015) confirmed the presence of a nonsense mutation in the RNF113A gene (Q301X; 300951.0001), which was previously detected in the proband (family 581) as part of the IGOLD sequencing project (Tarpey et al., 2009). The mutation, which segregated with disease in the family, was not found in 1,391 control X chromosomes, in 1,122 unrelated probands with X-linked mental retardation, or in the dbSNP (build 137), Exome Aggregation Consortium, or 1000 Genomes Project databases. Analysis of the RNF113A gene in 12 additional male patients with NER-proficient TTD, who were also negative for mutation in known TTD-associated genes, revealed no mutations. INHERITANCE \- X-linked dominant GROWTH Height \- Short stature \- Severe linear growth failure Other \- Intrauterine growth restriction (IUGR) HEAD & NECK Head \- Microcephaly, progressive Face \- Aged facial appearance \- High forehead \- Prominent chin Ears \- Extra auricular crus Eyes \- Absent outer eyebrows \- Retinal dystrophy (in patient A) \- Optic nerve hypoplasia (in patient A) \- Photosensitivity (in patient A) Mouth \- Large mouth Teeth \- Widely spaced primary teeth ABDOMEN Gastrointestinal \- Short esophagus (in patient A) \- Thoracic stomach (in patient A) \- Chronic diarrhea (in patient A) GENITOURINARY External Genitalia (Male) \- Micropenis Internal Genitalia (Male) \- Absent or rudimentary testes Ureters \- Ureteric obstruction (in patient A) SKELETAL Skull \- Microcephaly, progressive SKIN, NAILS, & HAIR Skin \- Cutis marmorata Hair \- Sparse hair \- Brittle hair \- Slow-growing hair \- Tiger-tail pattern seen on polarizing light microscopy \- Sulfur deficiency seen on amino acid analysis MUSCLE, SOFT TISSUES \- Minimal muscle mass \- Reduced subcutaneous fatty tissue NEUROLOGIC Central Nervous System \- Mental retardation, profound \- Ataxic broad-based gait \- Partial absence of posterior portion of corpus callosum \- Cerebellar hypoplasia \- Dandy-Walker malformation \- Generalized cerebral atrophy Behavioral Psychiatric Manifestations \- Social and engaging personality ENDOCRINE FEATURES \- Normal growth hormone (GH) levels \- High thyroid-stimulating hormone (TSH) levels \- Low anti-diuretic hormone (ADH) levels (in patient A) \- Low cortisol levels IMMUNOLOGY \- Recurrent infections \- Hypogammaglobulinemia MISCELLANEOUS \- Female carriers exhibit short stature \- Based on a report of 2 affected male cousins (last curated June 2015) MOLECULAR BASIS \- Caused by mutation in the ring finger protein 113A gene (RNF113A, 300951.0001 ) ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA [kDa]: kilodalton [EPC]: Early Prostate Cancer [LAPC]: locally advanced prostate cancer [NSAAs]: nonsteroidal antiandrogens [NSAA]: nonsteroidal antiandrogen [GnRH]: gonadotropin-releasing hormone [ADT]: androgen deprivation therapy [LH]: luteinizing hormone [AR]: androgen receptor [CAB]: combined androgen blockade [LPC]: localized prostate cancer [CPA]: cyproterone acetate [U.S.]: United States [FDA]: Food and Drug Administration	TRICHOTHIODYSTROPHY 5, NONPHOTOSENSITIVE	c1955934	7,831	omim	https://www.omim.org/entry/300953	2019-09-22T16:19:14	{"mesh": ["D054463"], "omim": ["300953"], "orphanet": ["33364"]}
Legionellosis that is characterized by severe form of infection producing pneumonia Legionnaires' disease Other namesLegionellosis,[1] legion fever Chest X-ray of a severe case of legionellosis upon admission to the emergency department. SpecialtyInfectious disease, pulmonology SymptomsCough, shortness of breath, fever, muscle pains, headaches[2] Usual onset2–10 days after exposure[2] CausesBacteria of the Legionella type (spread by contaminated mist)[3][4] Risk factorsOlder age, history of smoking, chronic lung disease, poor immune function[5] Diagnostic methodUrinary antigen test, sputum culture[6] PreventionGood maintenance of water systems[7] TreatmentAntibiotics[8] Prognosis10% risk of death[8] Frequency~13,000 severe cases a year (US)[9] Legionnaires' disease is a form of atypical pneumonia caused by any species of Legionella bacteria,[3] quite often Legionella pneumophila. Signs and symptoms include cough, shortness of breath, high fever, muscle pains, and headaches.[2] Nausea, vomiting, and diarrhea may also occur.[1] This often begins 2–10 days after exposure.[2] A legionellosis is any disease caused by Legionella, including Legionnaires' disease (a pneumonia), Pontiac fever (a non-pneumonia illness), and Pittsburgh pneumonia, but Legionnaires' disease is the most common, so mentions of legionellosis often refer to Legionnaires' disease. The bacterium is found naturally in fresh water.[4] It can contaminate hot water tanks, hot tubs, and cooling towers of large air conditioners.[4] It is usually spread by breathing in mist that contains the bacteria.[4] It can also occur when contaminated water is aspirated.[4] It typically does not spread directly between people, and most people who are exposed do not become infected.[4] Risk factors for infection include older age, a history of smoking, chronic lung disease, and poor immune function.[5][10] Those with severe pneumonia and those with pneumonia and a recent travel history should be tested for the disease.[11] Diagnosis is by a urinary antigen test and sputum culture.[6] No vaccine is available.[7] Prevention depends on good maintenance of water systems.[7] Treatment of Legionnaires' disease is with antibiotics.[8] Recommended agents include fluoroquinolones, azithromycin, or doxycycline.[12] Hospitalization is often required.[11] The fatality rate is around 10% for healthy persons and 25% for those with underlying conditions.[8] The number of cases that occur globally is not known.[1] Legionnaires' disease is the cause of an estimated 2–9% of pneumonia cases that are acquired outside of a hospital.[1] An estimated 8,000–18,000 cases a year in the United States require hospitalization.[9] Outbreaks of disease account for a minority of cases.[1][13] While it can occur any time of the year, it is more common in the summer and fall.[9] The disease is named after the outbreak where it was first identified, at a 1976 American Legion convention in Philadelphia.[14] ## Contents * 1 Signs and symptoms * 2 Cause * 2.1 Transmission * 2.2 Reservoirs * 3 Mechanism * 4 Diagnosis * 5 Prevention * 6 Treatment * 7 Prognosis * 8 Epidemiology * 8.1 Outbreaks * 9 Name * 10 References * 11 External links ## Signs and symptoms[edit] The length of time between exposure to the bacteria and the appearance of symptoms (incubation period) is generally 2–10 days, but can more rarely extend to as long as 20 days.[15] For the general population, among those exposed, between 0.1 and 5.0% develop the disease, while among those in hospital, between 0.4 and 14% develop the disease.[15] Those with Legionnaires' disease usually have fever, chills, and a cough, which may be dry or may produce sputum. Almost all experience fever, while around half have cough with sputum, and one-third cough up blood or bloody sputum. Some also have muscle aches, headache, tiredness, loss of appetite, loss of coordination (ataxia), chest pain, or diarrhea and vomiting.[1] Up to half of those with Legionnaires' disease have gastrointestinal symptoms, and almost half have neurological symptoms,[15] including confusion and impaired cognition.[16][17] "Relative bradycardia" may also be present, which is low to normal heart rate despite the presence of a fever.[18] Laboratory tests may show that kidney functions, liver functions, and electrolyte levels are abnormal, which may include low sodium in the blood. Chest X-rays often show pneumonia with consolidation in the bottom portion of both lungs. Distinguishing Legionnaires' disease from other types of pneumonia by symptoms or radiologic findings alone is difficult; other tests are required for definitive diagnosis.[medical citation needed] People with Pontiac fever, a much milder illness caused by the same bacterium, experience fever and muscle aches without pneumonia. They generally recover in 2–5 days without treatment. For Pontiac fever, the time between exposure and symptoms is generally a few hours to two days.[medical citation needed] ## Cause[edit] Transmission electron microscopy image of L. pneumophila, responsible for over 90% of Legionnaires' disease cases[19] Over 90% of cases of Legionnaires' disease are caused by Legionella pneumophila. Other types include L. longbeachae, L. feeleii, L. micdadei, and L. anisa. ### Transmission[edit] Legionnaires' disease is usually spread by the breathing in of aerosolized water or soil contaminated with the Legionella bacteria.[1] Experts have stated that Legionnaires' disease is not transmitted from person to person.[20] In 2014, one case of possible spread from someone sick to the caregiver occurred.[21] Rarely, it has been transmitted by direct contact between contaminated water and surgical wounds.[1] The bacteria grow best at warm temperatures[4] and thrive at water temperatures between 25 and 45 °C (77 and 113 °F), with an optimum temperature of 35 °C (95 °F).[22] Temperatures above 60 °C (140 °F) kill the bacteria.[23] Sources where temperatures allow the bacteria to thrive include hot water tanks, cooling towers, and evaporative condensers of large air conditioning systems, such as those commonly found in hotels and large office buildings.[24] Though the first known outbreak was in Philadelphia, cases of legionellosis have occurred throughout the world.[15] ### Reservoirs[edit] L. pneumophila thrives in aquatic systems, where it is established within amoebae in a symbiotic relationship.[25] Legionella bacteria survive in water as intracellular parasites of water-dwelling protozoa, such as amoebae. Amoebae are often part of biofilms, and once Legionella and infected amoebae are protected within a biofilm, they are particularly difficult to destroy.[1] In the built environment, central air conditioning systems in office buildings, hotels, and hospitals are sources of contaminated water.[22] Other places the bacteria can dwell include cooling towers used in industrial cooling systems, evaporative coolers, nebulizers, humidifiers, whirlpool spas, hot water systems, showers, windshield washers, fountains, room-air humidifiers, ice-making machines, and misting systems typically found in grocery-store produce sections.[1][26] The bacteria may also be transmitted from contaminated aerosols generated in hot tubs if the disinfection and maintenance programs are not followed rigorously.[27] Freshwater ponds, creeks, and ornamental fountains are potential sources of Legionella.[28] The disease is particularly associated with hotels, fountains, cruise ships, and hospitals with complex potable water systems and cooling systems. Respiratory-care devices such as humidifiers and nebulizers used with contaminated tap water may contain Legionella species, so using sterile water is very important.[29]Other sources include exposure to potting mix and compost.[30] ## Mechanism[edit] Legionella spp. enter the lungs either by aspiration of contaminated water or inhalation of aerosolized contaminated water or soil. In the lung, the bacteria are consumed by macrophages, a type of white blood cell, inside of which the Legionella bacteria multiply, causing the death of the macrophage. Once the macrophage dies, the bacteria are released from the dead cell to infect other macrophages. Virulent strains of Legionella kill macrophages by blocking the fusion of phagosomes with lysosomes inside the host cell; normally, the bacteria are contained inside the phagosome, which merges with a lysosome, allowing enzymes and other chemicals to break down the invading bacteria.[15] ## Diagnosis[edit] Various stages of the disease: Chest radiograph (A) and high-resolution computed tomography (B) at hospital admission, repeat high-resolution computerized tomography of the chest a week after hospital admission (C, D), shown in a 42-year-old male with severe pneumonia caused by L. pneumophila serogroup 11a People of any age may suffer from Legionnaires' disease, but the illness most often affects middle-aged and older people, particularly those who smoke cigarettes or have chronic lung disease. Immunocompromised people are also at higher risk. Pontiac fever most commonly occurs in those who are otherwise healthy.[citation needed] The most useful diagnostic tests detect the bacteria in coughed-up mucus, find Legionella antigens in urine samples, or allow comparison of Legionella antibody levels in two blood samples taken 3–6 weeks apart. A urine antigen test is simple, quick, and very reliable, but only detects L. pneumophila serogroup 1, which accounts for 70% of disease caused by L. pneumophila, which means use of the urine antigen test alone may miss as many as 30% of cases.[22] This test was developed by Richard Kohler in 1982.[31] When dealing with L. pneumophila serogroup 1, the urine antigen test is useful for early detection of Legionnaire's disease and initiation of treatment, and has been helpful in early detection of outbreaks. However, it does not identify the specific subtypes, so it cannot be used to match the person with the environmental source of infection. The Legionella bacteria can be cultured from sputum or other respiratory samples. Legionella spp. stain poorly with Gram stain, stains positive with silver, and is cultured on charcoal yeast extract with iron and cysteine (CYE agar). A significant under-reporting problem occurs with legionellosis. Even in countries with effective health services and readily available diagnostic testing, about 90% of cases of Legionnaires' disease are missed. This is partly due to the disease being a relatively rare form of pneumonia, which many clinicians may not have encountered before, thus may misdiagnose. A further issue is that people with legionellosis can present with a wide range of symptoms, some of which (such as diarrhea) may distract clinicians from making a correct diagnosis.[32] ## Prevention[edit] Although the risk of Legionnaires' disease being spread by large-scale water systems cannot be eliminated, it can be greatly reduced by writing and enforcing a highly detailed, systematic water safety plan appropriate for the specific facility involved (office building, hospital, hotel, spa, cruise ship, etc.)[15] Some of the elements that such a plan may include are: * Keep water temperature either above or below the 20–50 °C (68–122 °F) range in which the Legionella bacterium thrives. * Prevent stagnation, for example, by removing from a network of pipes any sections that have no outlet (dead ends). Where stagnation is unavoidable, as when a wing of a hotel is closed for the off-season, systems must be thoroughly disinfected just prior to resuming normal operation. * Prevent the buildup of biofilm, for example, by not using (or by replacing) construction materials that encourage its development, and by reducing the quantity of nutrients for bacterial growth that enter the system. * Periodically disinfect the system, by high heat or a chemical biocide, and use chlorination where appropriate. Treatment of water with copper-silver ionization or ultraviolet light may also be effective.[33] * System design (or renovation) can reduce the production of aerosols and reduce human exposure to them, by directing them well away from building air intakes. An effective water safety plan also covers such matters as training, record-keeping, communication among staff, contingency plans, and management responsibilities. The format and content of the plan may be prescribed by public health laws or regulations.[15] To inform the water safety plan, the undertaking of a site specific legionella risk assessment is often recommended in the first instance.[34] The legionella risk assessment identifies the hazards, the level of risk they pose and provides recommendations of control measures to put place within the overarching water safety plan. ## Treatment[edit] Effective antibiotics include most macrolides, tetracyclines, ketolides, and quinolones.[1] Legionella spp. multiply within the cell, so any effective treatment must have excellent intracellular penetration. Current treatments of choice are the respiratory tract quinolones (levofloxacin, moxifloxacin, gemifloxacin) or newer macrolides (azithromycin, clarithromycin, roxithromycin). The antibiotics used most frequently have been levofloxacin, doxycycline, and azithromycin. Macrolides (azithromycin) are used in all age groups, while tetracyclines (doxycycline) are prescribed for children above the age of 12 and quinolones (levofloxacin) above the age of 18. Rifampicin can be used in combination with a quinolone or macrolide. Whether rifampicin is an effective antibiotic to take for treatment is uncertain. The Infectious Diseases Society of America does not recommend the use of rifampicin with added regimens. Tetracyclines and erythromycin led to improved outcomes compared to other antibiotics in the original American Legion outbreak. These antibiotics are effective because they have excellent intracellular penetration in Legionella-infected cells. The recommended treatment is 5–10 days of levofloxacin or 3–5 days of azithromycin, but in people who are immunocompromised, have severe disease, or other pre-existing health conditions, longer antibiotic use may be necessary.[1] During outbreaks, prophylactic antibiotics have been used to prevent Legionnaires' disease in high-risk individuals who have possibly been exposed.[1] The mortality at the original American Legion convention in 1976 was high (29 deaths in 182 infected individuals[35]) because the antibiotics used (including penicillins, cephalosporins, and aminoglycosides) had poor intracellular penetration. Mortality has plunged to less than 5% if therapy is started quickly. Delay in giving the appropriate antibiotic leads to higher mortality.[medical citation needed] ## Prognosis[edit] The fatality rate of Legionnaires' disease has ranged from 5–30% during various outbreaks and approaches 50% for nosocomial infections, especially when treatment with antibiotics is delayed.[36] Hospital-acquired Legionella pneumonia has a fatality rate of 28%, and the principal source of infection in such cases is the drinking-water distribution system.[37] ## Epidemiology[edit] See also: 1976 Philadelphia Legionnaires' disease outbreak and List of Legionnaires' disease outbreaks Legionnaires' disease acquired its name in July 1976, when an outbreak of pneumonia occurred among people attending a convention of the American Legion at the Bellevue-Stratford Hotel in Philadelphia. Of the 182 reported cases, mostly men, 29 died.[38] On 18 January 1977, the causative agent was identified as a previously unknown strain of bacteria, subsequently named Legionella, and the species that caused the outbreak was named Legionella pneumophila.[39][40][41] Outbreaks of Legionnaires' disease receive significant media attention, but this disease usually occurs in single, isolated cases not associated with any recognized outbreak. When outbreaks do occur, they are usually in the summer and early autumn, though cases may occur at any time of year. Most infections occur in those who are middle-aged or older.[36] National surveillance systems and research studies were established early, and in recent years,[when?] improved ascertainment and changes in clinical methods of diagnosis have contributed to an upsurge in reported cases in many countries. Environmental studies continue to identify novel sources of infection, leading to regular revisions of guidelines and regulations. About 8,000–18,000 cases of Legionnaires' disease occur each year in the United States, according to the Bureau of Communicable Disease Control.[42] Between 1995 and 2005, over 32,000 cases of Legionnaires' disease and more than 600 outbreaks were reported to the European Working Group for Legionella Infections. The data on Legionella are limited in developing countries and Legionella-related illnesses likely are underdiagnosed worldwide.[15] Improvements in diagnosis and surveillance in developing countries would be expected to reveal far higher levels of morbidity and mortality than are currently recognised. Similarly, improved diagnosis of human illness related to Legionella species and serogroups other than Legionella pneumophila would improve knowledge about their incidence and spread.[citation needed] A 2011 study successfully used modeling to predict the likely number of cases during Legionnaires' outbreaks based on symptom onset dates from past outbreaks. In this way, the eventual likely size of an outbreak can be predicted, enabling efficient and effective use of public health resources in managing an outbreak.[43] ### Outbreaks[edit] See also: List of Legionnaires' disease outbreaks An outbreak is defined as two or more cases where the onset of illness is closely linked in time (weeks rather than months) and in space, where there is suspicion of, or evidence of, a common source of infection, with or without microbiological support (i.e. common spatial location of cases from travel history).[44] The first recognized cases of Legionnaires' disease occurred in 1976 in Philadelphia; among more than 2,000 attendees of an American Legion convention held at the Bellevue-Stratford Hotel, 182 attendees contracted the disease and 29 of them died.[1] In April 1985, 175 people in Stafford, England, were admitted to the District or Kingsmead Stafford Hospitals with chest infection or pneumonia. A total of 28 people died. Medical diagnosis showed that Legionnaires' disease was responsible and the immediate epidemiological investigation traced the source of the infection to the air-conditioning cooling tower on the roof of Stafford District Hospital.[45] In March 1999, a large outbreak in the Netherlands occurred during the Westfriese Flora flower exhibition in Bovenkarspel; 318 people became ill and at least 32 people died. This was the second-deadliest outbreak since the 1976 outbreak and possibly the deadliest, as several people were buried before Legionnaires' disease had been diagnosed.[46] The world's largest outbreak of Legionnaires' disease happened in July 2001, with people appearing at the hospital on 7 July, in Murcia, Spain. More than 800 suspected cases were recorded by the time the last case was treated on 22 July; 636–696 of these cases were estimated and 449 confirmed (so, at least 16,000 people were exposed to the bacterium) and 6 died, a case-fatality rate around 1%.[47] In September 2005, 127 residents of a nursing home in Canada became ill with L. pneumophila. Within a week, 21 of the residents had died. Culture results at first were negative, which is not unusual, as L. pneumophila is a "fastidious" bacterium, meaning it requires specific nutrients, living conditions or both to grow. The source of the outbreak was traced to the air-conditioning cooling towers on the nursing home's roof.[citation needed] 180 people were affected with 13 resulting death in an outbreak in lower Quebec City, Canada due to contaminated water in a cooling tower.[48] In November 2014, 302 people were hospitalized following an outbreak of Legionella in Portugal and seven related deaths were reported. All cases emerged in three civil parishes from the municipality of Vila Franca de Xira in the northern outskirts of Lisbon, Portugal, and were treated in hospitals of the Greater Lisbon area. The source is suspected to be located in the cooling towers of the fertilizer plant Fertibéria.[49] Twelve people were diagnosed with the disease in an outbreak in the Bronx, New York, in December 2014; the source was traced to contaminated cooling towers at a housing development.[50] In July and August 2015, another, unrelated outbreak in the Bronx killed 12 people and made about 120 people sick; the cases arose from a cooling tower on top of a hotel. At the end of September, another person died of the disease and 13 were sickened in yet another unrelated outbreak in the Bronx.[51] The cooling towers from which the people were infected in the latter outbreak had been cleaned during the summer outbreak, raising concerns about how well the bacteria could be controlled.[52] On 28 August 2015, an outbreak of Legionnaire's disease was detected at San Quentin State Prison in Northern California; 81 people were sickened and the cause was sludge that had built up in cooling towers.[53] Between June 2015, and January 2016, 87 cases of Legionnaires' disease were reported by the Michigan Department of Health and Human Services for the city of Flint, Michigan, and surrounding areas. The outbreak may have been linked to the Flint water crisis, in which the city's water source was changed to a cheaper and inadequately treated source. Ten of those cases were fatal.[54][55] In November 2017, an outbreak was detected at Hospital de São Francisco Xavier, Lisbon, Portugal, with up to 53 people being diagnosed with the disease and five of them dying from it.[56] In Quincy, Illinois, at the Illinois Veterans home, a 2015 outbreak of the disease killed 12 people and sickened more than 50 others. It was believed to be caused by infected water supply. Three more cases were identified by November 2017.[57] In the autumn of 2017, 22 cases were reported in a Legionnaires' disease outbreak in Anaheim, CA's Disneyland theme park. It was believed to have been caused by a cooling tower that releases mist for the comfort of visitors. The contaminated droplets likely spread to the people in and beyond the park.[58] In July 2019, eleven former guests of the Sheraton Atlanta hotel were diagnosed with the disease, with 55 additional probable cases.[59] In September 2019, 141 visitors to the Western North Carolina Mountain State Fair were diagnosed with Legionnaires' disease, with four reported deaths, after a hot tub exhibit is suspected to have developed and spread the bacteria. At least one additional exposure apparently occurred during the Asheville Quilt Show that took place a couple weeks after the fair in the same building where the hot tub exhibit was held. The building had been sanitized after the outbreak.[60][61][62][63] In December 2019, the Government of Western Australia's Department of Health was notified of 4 cases of Legionnaires' disease. Those exposed had recently visited near Bali's Ramayana Resort and Spa in central Kuta.[64][65] ## Name[edit] The disease is named after the outbreak where it was first identified, at a 1976 American Legion convention in Philadelphia.[14] Journalists Paul Carpenter and Bob Dvorchak were responsible for coining the term 'Legionnaires disease'. Carpenter broke the original Legionnaires' disease story in 1976, and Dvorchak, who was the editor on the Associated Press desk who handled Carpenter's story, first came up with the name.[66] ## References[edit] 1. ^ a b c d e f g h i j k l m n Cunha BA, Burillo A, Bouza E (23 January 2016). "Legionnaires' disease". Lancet. 387 (10016): 376–385. doi:10.1016/s0140-6736(15)60078-2. PMID 26231463. S2CID 28047369. 2. ^ a b c d "Legionella (Legionnaires' Disease and Pontiac Fever) Signs and Symptoms". Centers for Disease Control and Prevention (CDC). 26 January 2016. Archived from the original on 12 March 2016. 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"Gambling is good, except for the 'toxic' Internet type that offends Sheldon Adelson". The Morning Call. Retrieved 11 September 2019. ## External links[edit] * Media related to Legionnaires' disease at Wikimedia Commons * Legionnaires' disease at Curlie * "Legionnaires' Disease". MedlinePlus. U.S. National Library of Medicine. Classification D * ICD-10: A48.1, A48.2 * ICD-9-CM: 482.84 * MeSH: D007876 * DiseasesDB: 7366 External resources * MedlinePlus: 000616 * eMedicine: med/1273 * Orphanet: 549 * v * t * e Proteobacteria-associated Gram-negative bacterial infections α Rickettsiales Rickettsiaceae/ (Rickettsioses) Typhus * Rickettsia typhi * Murine typhus * Rickettsia prowazekii * Epidemic typhus, Brill–Zinsser disease, Flying squirrel typhus Spotted fever Tick-borne * Rickettsia rickettsii * Rocky Mountain spotted fever * Rickettsia conorii * Boutonneuse fever * Rickettsia japonica * Japanese spotted fever * Rickettsia sibirica * North Asian tick typhus * Rickettsia australis * Queensland tick typhus * Rickettsia honei * Flinders Island spotted fever * Rickettsia africae * African tick bite fever * Rickettsia parkeri * American tick bite fever * Rickettsia aeschlimannii * Rickettsia aeschlimannii infection Mite-borne * Rickettsia akari * Rickettsialpox * Orientia tsutsugamushi * Scrub typhus Flea-borne * Rickettsia felis * Flea-borne spotted fever Anaplasmataceae * Ehrlichiosis: Anaplasma phagocytophilum * Human granulocytic anaplasmosis, Anaplasmosis * Ehrlichia chaffeensis * Human monocytotropic ehrlichiosis * Ehrlichia ewingii * Ehrlichiosis ewingii infection Rhizobiales Brucellaceae * Brucella abortus * Brucellosis Bartonellaceae * Bartonellosis: Bartonella henselae * Cat-scratch disease * Bartonella quintana * Trench fever * Either B. henselae or B. quintana * Bacillary angiomatosis * Bartonella bacilliformis * Carrion's disease, Verruga peruana β Neisseriales M+ * Neisseria meningitidis/meningococcus * Meningococcal disease, Waterhouse–Friderichsen syndrome, Meningococcal septicaemia M− * Neisseria gonorrhoeae/gonococcus * Gonorrhea ungrouped: * Eikenella corrodens/Kingella kingae * HACEK * Chromobacterium violaceum * Chromobacteriosis infection Burkholderiales * Burkholderia pseudomallei * Melioidosis * Burkholderia mallei * Glanders * Burkholderia cepacia complex * Bordetella pertussis/Bordetella parapertussis * Pertussis γ Enterobacteriales (OX−) Lac+ * Klebsiella pneumoniae * Rhinoscleroma, Pneumonia * Klebsiella granulomatis * Granuloma inguinale * Klebsiella oxytoca * Escherichia coli: Enterotoxigenic * Enteroinvasive * Enterohemorrhagic * O157:H7 * O104:H4 * Hemolytic-uremic syndrome * Enterobacter aerogenes/Enterobacter cloacae Slow/weak * Serratia marcescens * Serratia infection * Citrobacter koseri/Citrobacter freundii Lac− H2S+ * Salmonella enterica * Typhoid fever, Paratyphoid fever, Salmonellosis H2S− * Shigella dysenteriae/sonnei/flexneri/boydii * Shigellosis, Bacillary dysentery * Proteus mirabilis/Proteus vulgaris * Yersinia pestis * Plague/Bubonic plague * Yersinia enterocolitica * Yersiniosis * Yersinia pseudotuberculosis * Far East scarlet-like fever Pasteurellales Haemophilus: * H. influenzae * Haemophilus meningitis * Brazilian purpuric fever * H. ducreyi * Chancroid * H. parainfluenzae * HACEK Pasteurella multocida * Pasteurellosis * Actinobacillus * Actinobacillosis Aggregatibacter actinomycetemcomitans * HACEK Legionellales * Legionella pneumophila/Legionella longbeachae * Legionnaires' disease * Coxiella burnetii * Q fever Thiotrichales * Francisella tularensis * Tularemia Vibrionaceae * Vibrio cholerae * Cholera * Vibrio vulnificus * Vibrio parahaemolyticus * Vibrio alginolyticus * Plesiomonas shigelloides Pseudomonadales * Pseudomonas aeruginosa * Pseudomonas infection * Moraxella catarrhalis * Acinetobacter baumannii Xanthomonadaceae * Stenotrophomonas maltophilia Cardiobacteriaceae * Cardiobacterium hominis * HACEK Aeromonadales * Aeromonas hydrophila/Aeromonas veronii * Aeromonas infection ε Campylobacterales * Campylobacter jejuni * Campylobacteriosis, Guillain–Barré syndrome * Helicobacter pylori * Peptic ulcer, MALT lymphoma, Gastric cancer * Helicobacter cinaedi * Helicobacter cellulitis * v * t * e Legionnaires' disease List of outbreaks * 1976 Philadelphia Legionnaires' disease outbreak * 1999 Bovenkarspel legionellosis outbreak * 2002 Barrow-in-Furness legionellosis outbreak * 2014 Portugal legionellosis outbreak * 2015 Bronx Legionnaires' disease outbreaks Related * Pontiac fever * v * t * e Diseases of the respiratory system Upper RT (including URTIs, common cold) Head sinuses Sinusitis nose Rhinitis Vasomotor rhinitis Atrophic rhinitis Hay fever Nasal polyp Rhinorrhea nasal septum Nasal septum deviation Nasal septum perforation Nasal septal hematoma tonsil Tonsillitis Adenoid hypertrophy Peritonsillar abscess Neck pharynx Pharyngitis Strep throat Laryngopharyngeal reflux (LPR) Retropharyngeal abscess larynx Croup Laryngomalacia Laryngeal cyst Laryngitis Laryngopharyngeal reflux (LPR) Laryngospasm vocal cords Laryngopharyngeal reflux (LPR) Vocal fold nodule Vocal fold paresis Vocal cord dysfunction epiglottis Epiglottitis trachea Tracheitis Laryngotracheal stenosis Lower RT/lung disease (including LRTIs) Bronchial/ obstructive acute Acute bronchitis chronic COPD Chronic bronchitis Acute exacerbation of COPD) Asthma (Status asthmaticus Aspirin-induced Exercise-induced Bronchiectasis Cystic fibrosis unspecified Bronchitis Bronchiolitis Bronchiolitis obliterans Diffuse panbronchiolitis Interstitial/ restrictive (fibrosis) External agents/ occupational lung disease Pneumoconiosis Aluminosis Asbestosis Baritosis Bauxite fibrosis Berylliosis Caplan's syndrome Chalicosis Coalworker's pneumoconiosis Siderosis Silicosis Talcosis Byssinosis Hypersensitivity pneumonitis Bagassosis Bird fancier's lung Farmer's lung Lycoperdonosis Other * ARDS * Combined pulmonary fibrosis and emphysema * Pulmonary edema * Löffler's syndrome/Eosinophilic pneumonia * Respiratory hypersensitivity * Allergic bronchopulmonary aspergillosis * Hamman-Rich syndrome * Idiopathic pulmonary fibrosis * Sarcoidosis * Vaping-associated pulmonary injury Obstructive / Restrictive Pneumonia/ pneumonitis By pathogen * Viral * Bacterial * Pneumococcal * Klebsiella * Atypical bacterial * Mycoplasma * Legionnaires' disease * Chlamydiae * Fungal * Pneumocystis * Parasitic * noninfectious * Chemical/Mendelson's syndrome * Aspiration/Lipid By vector/route * Community-acquired * Healthcare-associated * Hospital-acquired By distribution * Broncho- * Lobar IIP * UIP * DIP * BOOP-COP * NSIP * RB Other * Atelectasis * circulatory * Pulmonary hypertension * Pulmonary embolism * Lung abscess Pleural cavity/ mediastinum Pleural disease * Pleuritis/pleurisy * Pneumothorax/Hemopneumothorax Pleural effusion Hemothorax Hydrothorax Chylothorax Empyema/pyothorax Malignant Fibrothorax Mediastinal disease * Mediastinitis * Mediastinal emphysema Other/general * Respiratory failure * Influenza * Common cold * SARS * Coronavirus disease 2019 * Idiopathic pulmonary haemosiderosis * Pulmonary alveolar proteinosis * v * t * e Biological warfare and bioterrorism Modern incidents * 1984 Rajneeshee bioterror attack * 1989 California medfly attack * 2001 anthrax attacks * Wood Green ricin plot * 2003 ricin letters * 2013 ricin letters Prevention and response * Australia Group * Caribbean Public Health Agency * Center for Health Security * Centers for Disease Control and Prevention * Chinese Center for Disease Control and Prevention * Council of Europe Convention on the Prevention of Terrorism * Defense Advanced Research Projects Agency * Defense Threat Reduction Agency * European Centre for Disease Prevention and Control * Global Health Security Initiative * Health Threat Unit * Laboratory Response Network * India's Ministry of Health and Family Welfare * National Biodefense Analysis and Countermeasures Center * National Science Advisory Board for Biosecurity * United Nations Office for Disarmament Affairs * United States Army Medical Research Institute of Infectious Diseases Biological agents * Anthrax * Avian influenza * Botulinum toxin * Brucellosis * Burkholderia pseudomallei * Chlamydophila psittaci * Coxiella burnetii * Ebola * Equine encephalitis (Eastern * Western * Venezuelan) * Foodborne illness * Fungi * Glanders * Hantavirus * Henipavirus * Legionnaires' disease * Marburg virus * Mold * Plague * Ricin * Salmonella enterica * Salmonellosis * Salmonella typhi * Smallpox * Staphylococcus * Tularemia * Typhus * Viral hemorrhagic fever Related concepts * Agro-terrorism * Anthrax hoaxes * Psychochemical weapons * Bacteria * Biocontainment * Biological hazard * Biological warfare in popular culture * Ethnic bioweapon * Decontamination * Entomological warfare * Infectious disease * Virus * Toxin * Terrorism * War portal * Wiktionary definition * Wikimedia Commons * Wikisource * Medicine portal [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA [kDa]: kilodalton [EPC]: Early Prostate Cancer [LAPC]: locally advanced prostate cancer [NSAAs]: nonsteroidal antiandrogens [NSAA]: nonsteroidal antiandrogen [GnRH]: gonadotropin-releasing hormone [ADT]: androgen deprivation therapy [LH]: luteinizing hormone [AR]: androgen receptor [CAB]: combined androgen blockade [LPC]: localized prostate cancer [CPA]: cyproterone acetate [U.S.]: United States [FDA]: Food and Drug Administration	Legionnaires' disease	c0023241	7,832	wikipedia	https://en.wikipedia.org/wiki/Legionnaires%27_disease	2021-01-18T18:57:19	{"gard": ["6876"], "mesh": ["D007877"], "umls": ["C0023241"], "orphanet": ["549"], "wikidata": ["Q154882"]}
A number sign (#) is used with this entry because hypogonadotropic hypogonadism-7 with or without anosmia (HH7) is caused by homozygous or compound heterozygous mutation in the GNRHR gene (138850) on chromosome 4q13, sometimes in association with mutation in another gene, e.g., FGFR1 (136350). Description Congenital idiopathic hypogonadotropic hypogonadism (IHH) is a disorder characterized by absent or incomplete sexual maturation by the age of 18 years, in conjunction with low levels of circulating gonadotropins and testosterone and no other abnormalities of the hypothalamic-pituitary axis. Idiopathic hypogonadotropic hypogonadism can be caused by an isolated defect in gonadotropin-releasing hormone (GNRH; 152760) release, action, or both. Other associated nonreproductive phenotypes, such as anosmia, cleft palate, and sensorineural hearing loss, occur with variable frequency. In the presence of anosmia, idiopathic hypogonadotropic hypogonadism has been called 'Kallmann syndrome (KS),' whereas in the presence of a normal sense of smell, it has been termed 'normosmic idiopathic hypogonadotropic hypogonadism (nIHH)' (summary by Raivio et al., 2007). Because families have been found to segregate both KS and nIHH, the disorder is here referred to as 'hypogonadotropic hypogonadism with or without anosmia (HH).' For a discussion of genetic heterogeneity of hypogonadotropic hypogonadism with or without anosmia, see 147950. Clinical Features De Roux et al. (1997) studied a brother and sister with normosmic hypogonadotropic hypogonadism. The 22-year-old propositus was referred because of hypogonadism and impaired libido, who had undergone puberty at age 16. His height was 180 cm and his arm span 186 cm. Physical examination revealed absence of facial hair, sparse pubic hair (Tanner stage 3), and a penis of 6 cm. He had scrotal testes, and the volume of each was 8 ml (normal, 15 to 25 ml). There was no gynecomastia. He had a normal sense of smell and no mirror movements of the upper limbs, no abnormal eye movements, no colorblindness, and no renal or craniofacial abnormalities. The karyotype was 46,XY. The patient's 37-year-old sister had a history of primary amenorrhea and infertility. Spontaneous thelarche had occurred at age 14 years. She had a single episode of uterine bleeding at age 18, and afterward received combined oral contraceptive treatment. This treatment was interrupted when she desired children. However, amenorrhea and absence of pregnancy led to ovulation-inducing treatment, which resulted in 2 normal pregnancies and the births of a girl and a boy, 4 and 7 years old at the time of report. After each pregnancy, she had persistent amenorrhea, and oral contraceptive treatment was resumed. Her height was 165 cm. Pubic hair development was at Tanner stage 5, and her breasts and external genitalia were those of a normal woman. Both parents and a sister were clinically and endocrinologically normal. Caron et al. (1999) studied 3 sibs with mutations in GNRHR from a kindred with isolated hypogonadotropic hypogonadism. The 2 brothers, who were referred for lack of puberty, had microphallus and bilateral cryptorchidism; their sister had primary amenorrhea and a complete lack of puberty. The authors concluded that these hypogonadal patients were partially resistant to pulsatile GNRH administration, suggesting that they should instead be treated with gonadotropins to induce spermatogenesis or ovulation. Pitteloud et al. (2001) reported a 26-year-old male with a mild form of hypogonadotropic hypogonadism, which they called a 'fertile eunuch variant' of HH. The proband had hypogonadal testosterone levels, detectable but apulsatile gonadotropin secretion, and a normal adult male testicular size of 17 mL at baseline. After only 4 months of treatment with chorionic gonadotropin (CG; see 118860) alone, he developed sperm in his ejaculate, and his wife conceived. Following cessation of CG therapy, the patient demonstrated reversal of his hypogonadotropism as evidenced by normal adult male testosterone levels and the appearance of pulsatile luteinizing hormone (LH; see 152780) secretion. The authors concluded that this case expanded the clinical spectrum of GNRHR mutations, providing the first genetic basis for the fertile eunuch variant of hypogonadotropic hypogonadism and documenting the occurrence of reversible hypogonadotropic hypogonadism in a patient with a GNRHR mutation. ### Clinical Variability De Roux et al. (1999) performed detailed endocrinologic studies in 3 affected members of a family with hypogonadotropic hypogonadism who had mutations in GNRHR (see MOLECULAR GENETICS). The proband, a 30-year-old male, had complete HH with extremely low plasma levels of gonadotropins, absence of pulsatility of endogenous LH and alpha subunit (see 152780), absence of response to GNRH (152760) and GNRH agonist (triptorelin), and absence of effect of pulsatile administration of GNRH. His affected 18- and 24-year-old sisters had only partial hypogonadotropic hypogonadism. They both had primary amenorrhea and normal breast development, but the younger sister had retarded bone maturation and uterus development. Gonadotropin concentrations were normal or low, but in both cases were restored to normal levels by a single injection of GNRH. In both sisters, there were no spontaneous pulses of LH, but pulsatile administration of GNRH provoked pulsatile secretion of LH in the younger one. The authors concluded that the same GNRHR mutations may exhibit varying degrees of alteration of gonadotropin function in affected members of the same family. Pathogenesis Janovick et al. (2002) showed pharmacologic rescue, assessed by ligand binding and restoration of receptor coupling to effector, of 5 naturally occurring GNRHR mutants identified from patients with hypogonadotropic hypogonadism, as well as rescue of other defective receptors manufactured with internal or terminal deletions or substitutions at sites expected to be involved in establishment of tertiary receptor structure. The pharmacologic agent used was a small, membrane-permeant molecule, originally designed as an orally active, nonpeptide receptor antagonist, but is believed to function as a folding template, capable of correcting the structural defects caused by the mutations and thereby restoring function. The rescued receptor, stabilized in the plasma membrane, coupled ligand binding to activation of the appropriate effector system. Janovick et al. (2002) concluded that mutant GNRHRs frequently have not lost intrinsic functionality and are subject to rescue by techniques that enhance membrane expression, and that the findings demonstrated the efficacy of an approach based on pharmacologic rescue and suggested the basis of new approaches for intervention in this and similar disorders. Molecular Genetics In a brother and sister with normosmic hypogonadotropic hypogonadism, de Roux et al. (1997) identified compound heterozygosity for 2 missense mutations in the GNRHR gene (Q106R, 138850.0001 and R262Q, 138850.0002). Layman et al. (1998) screened 46 unrelated patients with normosmic idiopathic HH for GNRHR mutations, including 32 males at least 18 years of age and 14 females at least 17 years of age, and identified compound heterozygosity for the R262Q mutation and another missense mutation (Y284C; 138850.0003) in 1 family with 4 affected sibs. At least 1 of the affected females ovulated in response to exogenous gonadotropins. In 3 sibs from a kindred with isolated HH, Caron et al. (1999) identified compound heterozygosity for the R262Q mutation and another missense mutation in GNRHR (A129D; 138850.0004). Kottler et al. (1999) analyzed in detail the GNRHR mutations in 7 independent familial and sporadic cases of idiopathic hypogonadotropic hypogonadism reported to that time. The Q106R and R262Q mutations were frequent in patients from all geographic areas (North and South America and Europe). In a brother and 2 sisters with HH, de Roux et al. (1999) identified compound heterozygosity for 3 missense mutations in the GNRHR gene, with R262Q on 1 allele, and Q106R and S217R (138850.0005) on the other allele. Endocrinologic analysis demonstrated varying degrees of alteration of gonadotropin function in the 3 sibs, although they all carried the same mutations. In a male patient with complete HH, who presented with primary failure of pulsatile GNRH (152760) therapy but responded to exogenous gonadotropin administration, Pralong et al. (1999) identified homozygosity for a missense mutation in the GNRHR gene (S168R; 138850.0006). In a woman with complete HH, Kottler et al. (2000) identified compound heterozygosity for Q106R and a nonsense mutation (L314X; 138850.0007) in the GNRHR gene. In a 26-year-old male with a mild form of hypogonadotropic hypogonadism, Pitteloud et al. (2001) identified homozygosity for the R262Q mutation in the GNRHR gene. Costa et al. (2001) investigated 17 Brazilian patients, 10 males and 7 females, from 14 different families with normosmic hypogonadotropic hypogonadism. The diagnosis of HH was based on absent or incomplete sexual development after 17 years of age associated with low or normal levels of LH in both sexes and low levels of testosterone in males and of estradiol in females. All patients presented with a normal sense of smell in an olfactory-specific test. In 1 female patient with complete HH, who had undetectable serum basal LH and FSH levels that failed to respond to GNRH stimulation, Costa et al. (2001) identified homozygosity for a missense mutation in the GNRHR gene (R139H; 138850.0008). In 4 sibs with partial HH, who had low serum basal LH levels that were responsive to GNRH stimulation, they identified compound heterozygosity for the Q106R mutation and another missense mutation in GNRHR (N10K; 138850.0009). In a woman with primary amenorrhea and absent thelarche and pubarche, Silveira et al. (2002) identified homozygosity for a splice site mutation (138850.0011). The patient had no spontaneous gonadotropin pulsatility and did not respond to either exogenous pulsatile or acute GNRH administration, but exogenous gonadotropin administration resulted in a normal pregnancy. Meysing et al. (2004) reported a normosmic female patient with congenital idiopathic HH in whom treatment with pulsatile GNRH resulted in an unusual response: she not only required an increased dose of pulsatile GNRH for ovarian follicular development, but LH secretion did not increase appropriately, estradiol levels remained low, and she did not ovulate spontaneously. Analysis of the GNRHR coding sequence revealed compound heterozygous GNRHR mutations (138850.0013 and 138850.0014). In 2 brothers with HH, Lin et al. (2006) reported homozygosity for the R262Q mutation in GNRHR. The proband presented at 15 years of age with delayed puberty. After a short course of testosterone, he seemed to be progressing through puberty appropriately and was discharged from follow-up. His younger brother was also referred with delayed puberty but showed little progress after treatment. Lin et al. (2006) concluded that homozygous partial loss-of-function mutations in GNRHR such as R262Q can present with variable phenotypes, including apparent delayed puberty. ### Oligogenic Inheritance In 2 sisters with primary amenorrhea and no breast development at 25 and 18 years of age, respectively, Seminara et al. (2000) identified compound heterozygosity for the Q106R and R262Q mutations in the GNRHR gene. The apparently unaffected parents were heterozygous for the mutations. Pitteloud et al. (2007) reexamined the family studied by Seminara et al. (2000) and identified heterozygosity for an additional missense mutation in the FGFR1 gene (136350.0016) in the 2 sisters and in their father, who had a history of delayed puberty. Mutation analysis of the children of the younger sister revealed that her unaffected daughter, who had undergone normal puberty, was heterozygous for the mutation in FGFR1 but had no mutations in the GNRHR gene, and that her prepubertal 10-year-old twin sons, born without cryptorchidism or microphallus, were each heterozygous for 1 of the mutations in GNRHR but did not have any mutations in the FGFR1 gene. Pitteloud et al. (2007) concluded that defects in 2 different genes can synergize to produce a more severe phenotype in families with hypogonadotropic hypogonadism than either alone, and that this digenic model may account for some of the phenotypic heterogeneity seen in GnRH deficiency. ### Possible Association with Functional Hypothalamic Amenorrhea in Carrier Females Caronia et al. (2011) studied 55 women with functional hypothalamic amenorrhea, who had all completed puberty spontaneously and had a history of secondary amenorrhea for 6 months or more, with low or normal gonadotropin levels and low serum estradiol levels. All had 1 or more predisposing factors, including excessive exercise, loss of more than 15% of body weight, and/or a subclinical eating disorder, and all had normal results on neuroimaging. The authors screened 7 HH-associated genes in the 55 affected women and identified 7 patients from 6 families who carried heterozygous mutations, including 1 in KAL1, 2 in FGFR1, 2 in PROKR2 (607123), and 1 in the GNRHR gene. Since these women with mutations resumed regular menses after discontinuing hormone-replacement therapy, Caronia et al. (2011) concluded that the genetic component of hypothalamic amenorrhea predisposes patients to, but is not sufficient to cause, GnRH deficiency. Population Genetics To determine the frequency and distribution of GNRHR mutations in a heterogeneous population of patients with idiopathic hypogonadotropic hypogonadism, Beranova et al. (2001) screened 108 probands with idiopathic hypogonadotropic hypogonadism for mutations in the coding sequence of GNRHR. Forty-eight of the 108 patients had a normal sense of smell, whereas the remaining 60 had anosmia or hyposmia (Kallmann syndrome). Five unrelated probands (3 men and 2 women), all normosmic, were documented to have changes in the coding sequence of the GNRHR gene. Two of these probands were from a subgroup of 5 kindreds consistent with a recessive mode of inheritance, establishing a GNRHR mutation frequency of 2 of 5 (40%) in patients with normosmic autosomal recessive idiopathic hypogonadotropic hypogonadism. The remaining 3 probands with GNRHR mutations were from a subgroup of 18 patients without evidence of familial involvement, indicating a prevalence of 3 of 18 (16.7%) in patients with sporadic idiopathic hypogonadotropic hypogonadism and a normal sense of smell. Among the 5 individuals bearing GNRHR mutations, a broad spectrum of phenotypes was noted, including testicular sizes that varied from prepubertal to the normal adult male range. Bhagavath et al. (2005) analyzed DNA from 185 HH patients and identified compound heterozygous GNRHR mutations in 3 (1.6%). All 3 were Caucasian, from a cohort of 85 HH patients with documented normosmia, and both the male patients as well as the female patient had so-called 'complete' HH, in which there is no evidence of steroid production as evidenced by a completely prepubertal phenotype. No mutations were found in the hyposmic or anosmic HH patients. GNRHR mutations were identified in 1 (6.7%) of 15 families with at least 2 affected sibs and in 2 (11.1%) of 18 normosmic HH females. No mutations were found in presumed autosomal dominant families. Bhagavath et al. (2005) concluded that GNRHR mutations account for approximately 3.5% of all normosmic HH and 7 to 11% of presumed autosomal recessive HH, suggesting that additional genes play an important role in normal puberty. INHERITANCE \- Autosomal recessive HEAD & NECK Nose \- Normal sense of smell CHEST \- Delayed or absent thelarche \- Gynecomastia GENITOURINARY External Genitalia (Male) \- Small penis Internal Genitalia (Male) \- Small testes \- Cryptorchidism \- Infertility (in some patients) Internal Genitalia (Female) \- Infertility (in some patients) \- Primary amenorrhea SKIN, NAILS, & HAIR Hair \- Sparse to absent male facial hair \- Sparse to absent axillary hair \- Sparse to absent pubic hair VOICE \- Puerile voice ENDOCRINE FEATURES \- Isolated hypogonadotropic hypogonadism \- Delayed or absent puberty \- Infertility (in some patients) \- Low luteinizing hormone (LH, see 152780 ) levels \- Low follicle-stimulating hormone (FSH, see 136530 ) levels \- Low testosterone levels \- Low estradiol levels MISCELLANEOUS \- Phenotypic variability has been described, with some patients exhibiting partial and others complete hypogonadotropic hypogonadism MOLECULAR BASIS \- Caused by mutation in the gonadotropin-releasing hormone receptor gene (GNRHR, 138850.0001 ) ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA [kDa]: kilodalton [EPC]: Early Prostate Cancer [LAPC]: locally advanced prostate cancer [NSAAs]: nonsteroidal antiandrogens [NSAA]: nonsteroidal antiandrogen [GnRH]: gonadotropin-releasing hormone [ADT]: androgen deprivation therapy [LH]: luteinizing hormone [AR]: androgen receptor [CAB]: combined androgen blockade [LPC]: localized prostate cancer [CPA]: cyproterone acetate [U.S.]: United States [FDA]: Food and Drug Administration	HYPOGONADOTROPIC HYPOGONADISM 7 WITH OR WITHOUT ANOSMIA	c0342384	7,833	omim	https://www.omim.org/entry/146110	2019-09-22T16:39:46	{"doid": ["0090078"], "mesh": ["C562785"], "omim": ["146110"], "orphanet": ["432"], "synonyms": ["Gonadotropic deficiency", "HYPOGONADISM, ISOLATED HYPOGONADOTROPIC", "IDIOPATHIC HYPOGONADOTROPIC HYPOGONADISM", "Isolated congenital gonadotropin deficiency", "Alternative titles", "Normosmic idiopathic hypogonadotropic hypogonadism", "nIHH"], "genereviews": ["NBK1334"]}
This article has multiple issues. Please help improve it or discuss these issues on the talk page. (Learn how and when to remove these template messages) This article needs additional citations for verification. Please help improve this article by adding citations to reliable sources. Unsourced material may be challenged and removed. Find sources: "Disfigurement" – news · newspapers · books · scholar · JSTOR (September 2014) (Learn how and when to remove this template message) This article needs more medical references for verification or relies too heavily on primary sources. Please review the contents of the article and add the appropriate references if you can. Unsourced or poorly sourced material may be challenged and removed. Find sources: "Disfigurement" – news · newspapers · books · scholar · JSTOR (November 2014) (Learn how and when to remove this template message) This individual suffers from hand eczema, which causes much harm to the skin. "Disfigure" redirects here. For other uses, see Disfigure (disambiguation). Disfigurement is the state of having one's appearance deeply and persistently harmed medically, such as from a disease, birth defect, or wound. General societal attitudes towards disfigurement have varied greatly across cultures and over time, with cultures possessing strong social stigma against it often causing psychological distress to disfigured individuals. Alternatively, many societies have regarded some forms of disfigurement in a medical, scientific context where someone having ill will against the disfigured is viewed as anathema. In various religious and spiritual contexts, disfigurement has been variously described as being a punishment from the divine for sin (such as Yahweh's defacement of Cain for Abel's murder in Judaism), as being (such as Paul of the New Testament's arguments about Christ's sufferings) caused by supernatural forces of hate and evil against the good and just, which will be later atoned for, or as being without explanation per se with people just having to endure. The topic has been frequently commented on and referred to in a great many forms of fictional media as well. Villainous examples include the iconic fiend The Joker from various DC Comics and the mysterious figure with a "red right hand" from the song of the same name by the band Nick Cave and the Bad Seeds. Heroic examples include Daredevil, a crime-fighter who was rendered blind (from Marvel Comics), and the compassionate character Edward Scissorhands from the film of the same name. ## Contents * 1 Overview * 2 Causes * 3 Society and culture * 3.1 In American fiction * 4 See also * 5 References * 6 External links ## Overview[edit] Disfigurement, whether caused by a benign or malignant condition, often leads to severe psychosocial problems such as negative body image; depression; difficulties in one's social, sexual, and professional lives; prejudice; and intolerance. This is partly due to how the individual copes with looking 'visibly different', though the extent of the disfigurement rarely correlates with the degree of distress the sufferer feels. An additional factor which affects sufferers of a disfigurement is the reaction they get from other people. The general population responds to people with a disfigurement with less trust and respect, and often try to avoid making contact or having to look at the disfigurement.[1][2] Disfigurements affecting visible areas, such as the face, arms, and hands, are thought to present greater difficulty for sufferers to cope with than do other disfigurements. Deliberate mutilation resulting in physical disfigurement has also been practiced by many cultures throughout human history for religious or judicial purposes. During the Byzantine Empire, the emperor was considered God's viceregent on Earth, and as such, the physical wholeness of his person was an essential complement to the perfection of Heaven. For this reason, many deposed emperors were blinded, had their noses cut off, or their tongue split by their successors, as these permanent disfigurements disqualified them from ever reclaiming the throne. A case of voluntary disfigurement is that of St. Æbbe the Younger and the nuns of Coldingham Monastery in Scotland. When the monastery was attacked by Vikings and they feared being raped, the nuns and she cut off their own noses and upper lips. In revenge, the Vikings burned down the building with the nuns inside. This is said to be the origin of the phrase "cutting off the nose to spite the face". ## Causes[edit] Conditions that can cause disfigurement include: * severe acne * acromegaly * amniotic band constriction * amputation * argyria * birthmarks * burns * cancer * cataracts * circumcision * cleft lip * eczema * elephantiasis * erysipelas * frostbite * gangrene * gigantomastia * gynecomastia * keloids * leprosy * necrosis * McCune–Albright syndrome * neurofibromatosis * noma * paralysis * proteus syndrome * radiation poisoning * scalping * scars * smallpox * severe strabismus * synkinesis * syphilis * vitiligo * severe warts Plastic surgery or reconstructive surgery is available in many cases to disfigured people. Some health insurance companies and government health care systems cover plastic surgery for these problems when they do not generally cover plastic surgery for what is labeled as "cosmetic purposes". The term "disfigurement" is sometimes used pejoratively to describe the results of intentional body modification. Scarification and other forms of such modification are sometimes referred to as such by neutral parties or by advocates of the processes, as well. Many types of body modification are subject to strong social debate as such. ## Society and culture[edit] People with disfigurement are often treated poorly.[3] ### In American fiction[edit] This article needs additional citations for verification. Please help improve this article by adding citations to reliable sources. Unsourced material may be challenged and removed. Find sources: "Disfigurement" – news · newspapers · books · scholar · JSTOR (July 2016) (Learn how and when to remove this template message) Lon Chaney's version of "Erik" in the 1925 film The Phantom of the Opera had pervasive facial disfigurements, including jagged teeth and sunken-in eyes. * In most adaptations (literary, stage, film, or otherwise) of The Phantom of the Opera, the title character (known as "Erik" or "The Phantom") wears either a full- or half-face mask to conceal a disfigurement. Some adaptations infer that his disfigurement was present from birth, such as in the Andrew Lloyd Webber musical, whereas others infer or show it to be the result of a horrible accident such as burning from fire or chemicals. The Phantom's disfigured face is usually described as having caused him anguish and despair, thus influencing him to adopt the enigmatic "phantom" persona.[4] * The DC Comics character the Joker, often a foe of Batman, possesses a clown-like grin and a grotesque combination of bleached skin, red lips, and green hair that are typically described or inferred to be the result of injuries and disfigurement in most media. A common origin of his skin and hair colors revolve around chemical burns as the result of the Joker character either falling into, jumping into, or being thrown into a vat of noxious chemicals. In Tim Burton's 1989 film adaptation of Batman, the Joker character, in this version a criminal originally known as "Jack Napier", receives his distinct rictus grin as the result of a botched plastic surgery that he received after a ricocheted bullet that Napier intended to harm Batman badly injured the Joker's face. In most media, the Joker's mania and insanity begin as a result of him seeing his own disfigurement, the 1989 film being an example.[5][6][7][8] * Several enemies of fictional British secret agent James Bond have been known for their distinctive facial features. An example is the North Korean criminal and terrorist Zao from the film Die Another Day. Played by Rick Yune, the terrorist has partly translucent skin with thick veins shown on his face and numerous diamonds embedded into his skin.[9] * The Punisher, an antihero appearing in various Marvel Comics-related works, has confronted several enemies known for their drastic facial disfigurement. A prominent example is Jigsaw, a sadist and psychopath with incredible stamina, while having no superhuman powers that has a deeply mutilated face somewhat similar to a jigsaw puzzle. Perhaps the Punisher's most iconic nemesis, he was played in 2008's Punisher: War Zone by Dominic West.[10] * Nick Cave and the Bad Seeds' popular alternative rock song "Red Right Hand", first released in 1994's Let Love In, describes a nightmarish figure with a blood-red, disfigured hand (as referred to in the title[11]). ## See also[edit] * Medicine portal * AboutFace – Canadian charitable organization * Changing Faces (charity) – British charitable organization * Dermatology * Face transplant – experimental treatment for severe facial disfigurement * Corporal punishment, of which disfigurement is the most permanent type ## References[edit] 1. ^ Hartung, Franziska; Jamrozik, Anja; Rosen, Miriam E.; Aguirre, Geoffrey (29 May 2019). "Behavioural and Neural Responses to Facial Disfigurement". Scientific Reports. 9. doi:10.1038/s41598-019-44408-8. PMID 31142792. Retrieved 19 April 2020. 2. ^ Kleck, Robert E.; Nuessle, William (December 1968). "Congruence between the indicative and communicative functions of eye contact in interpersonal relations". British Journal of Social and Clinical Psychology. 7 (4): 241–246. doi:10.1111/j.2044-8260.1968.tb00565.x. PMID 5706460. 3. ^ MOSAIC, Neil Steinberg. "Facial discrimination: Living with a disfigured face". CNN. CNN. Retrieved 30 August 2016. 4. ^ The Phantom's Visage: What did the Phantom Look Like? 5. ^ Joker 6. ^ The Juxtaposition of Batman and Joker 7. ^ Jack Napier (Joker) falls into a vat of chemical on YouTube 8. ^ The Joker Transformation! "The Man In The Mirror" 9. ^ [1] 10. ^ "Archived copy". Archived from the original on 2015-05-22. Retrieved 2015-05-21.CS1 maint: archived copy as title (link) 11. ^ [2] ## External links[edit] Look up disfigurement in Wiktionary, the free dictionary. * Changing Faces – a British organization for people with facial disfigurements * Project Harar – a British organization helping children with facial disfigurements in Africa * Let's Face It – an American organization for people with facial disfigurements * Unique Face – a Japanese organization for people with facial disfigurements * Centre for Appearance Research - Psychological and psychosocial research at the University of the West of England, Bristol, UK * Derriford Appearance Scale - a standardised psychological measure of distress and dysfunction in relation to disfigurement and visible difference www.karibuanawim.com – Australian organisation for people with facial disfigurements [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA [kDa]: kilodalton [EPC]: Early Prostate Cancer [LAPC]: locally advanced prostate cancer [NSAAs]: nonsteroidal antiandrogens [NSAA]: nonsteroidal antiandrogen [GnRH]: gonadotropin-releasing hormone [ADT]: androgen deprivation therapy [LH]: luteinizing hormone [AR]: androgen receptor [CAB]: combined androgen blockade [LPC]: localized prostate cancer [CPA]: cyproterone acetate [U.S.]: United States [FDA]: Food and Drug Administration	Disfigurement	c1707791	7,834	wikipedia	https://en.wikipedia.org/wiki/Disfigurement	2021-01-18T19:00:54	{"umls": ["C1707791"], "wikidata": ["Q3043172"]}
A number sign (#) is used with this entry because of evidence that vertebral anomalies and variable endocrine and T-cell dysfunction (VETD) is caused by heterozygous mutation in the TBX2 gene (600747) on chromosome 17q23. Description Vertebral anomalies and variable endocrine and T-cell dysfunction is a syndrome characterized by an overlapping spectrum of features. Skeletal malformations primarily involve the vertebrae, and endocrine abnormalities involving parathyroid hormone (PTH; 168450), growth hormone (GH1; 139250), and the thyroid gland have been reported. T-cell abnormalities have been observed, with some patients showing thymus gland aplasia or hypoplasia. Patients have mild craniofacial dysmorphism, and some show developmental delay or behavioral problems. Cardiac defects may be present (Liu et al., 2018). Clinical Features Liu et al. (2018) reported 4 affected individuals from 2 unrelated families with congenital cardiac defects, skeletal abnormalities, facial dysmorphisms, variable developmental delay, and endocrine system disorders. In the first family, a mother, son, and daughter were affected. The son and daughter had thymus aplasia or hypoplasia, with absent or low T cell numbers, whereas their mother had low naive T cells. All 3 exhibited hypertelorism, epicanthal folds, ear deformities, cleft palate, Sprengel deformity, Klippel-Feil anomaly, and camptodactyly of the third and fourth fingers. The son also had atrial septal defect and the daughter had patent ductus arteriosus, both reported as closed at the time of assessment. Endocrine anomalies in this family included autoimmune hypothyroidism in the son, hypoparathyroidism in the daughter, and low-normal PTH in the mother. The son showed average intelligence with attention-deficit/hyperactivity disorder and autistic behaviors, whereas the daughter showed mild developmental delay; their mother had normal intelligence. The authors also studied an unrelated boy with short stature due to growth hormone deficiency, high-arched narrow palate, double-outlet right ventricle and pulmonary stenosis, congenital fusions of the thoracic spine and hemivertebrae, mild facial dysmorphism, and developmental delay. He had no immune-related symptoms, but did not undergo immune function testing. Molecular Genetics By whole-genome sequencing in a family with vertebral anomalies and variable endocrine and T-cell dysfunction, Liu et al. (2018) identified heterozygosity for a missense mutation in the TBX2 gene (R20Q; 600747.0001) in the affected mother and 2 children, but not in the unaffected father. In an unrelated boy with VETD, they identified heterozygosity for a de novo missense mutation in TBX2 (R305H; 600747.0002). INHERITANCE \- Autosomal dominant GROWTH Height \- Short stature HEAD & NECK Head \- Brachycephaly Face \- Triangular face \- Low anterior hairline \- Glabellar hemangioma Ears \- Low-set ears \- Cupped ears \- Overfolded helices Eyes \- Hypertelorism \- Epicanthal folds \- Corectopia Nose \- Depressed nasal bridge \- Depressed nasal tip \- Broad nasal tip Mouth \- Cleft palate \- High-arched narrow palate \- Cleft lip Neck \- Short neck \- Webbed neck CARDIOVASCULAR Heart \- Double-outlet right ventricle \- Pulmonary valve stenosis \- Atrial septal defect Vascular \- Patent ductus arteriosus CHEST Ribs Sternum Clavicles & Scapulae \- Sprengel deformity \- Fusion of 4th and 5th ribs SKELETAL Spine \- Klippel-Feil anomaly (fusion C2-C4) \- Congenital fusions of thoracic spine \- Open laminae posteriorly \- Hemivertebrae at T10-T11 \- Scoliosis \- Kyphosis Hands \- Camptodactyly 3rd and 4th digits NEUROLOGIC Central Nervous System \- Developmental delay, mild \- Attention-deficit hyperactivity disorder (ADHD) Behavioral Psychiatric Manifestations \- Autistic behaviors ENDOCRINE FEATURES \- Hashimoto thyroiditis \- Hypoparathyroidism \- Borderline low parathyroid hormone (PTH) \- Growth hormone deficiency IMMUNOLOGY \- Thymus aplasia or hypoplasia \- Low or no functional T cells \- Abnormal B cells \- Very low naive T cells (CD4 and CD8) MISCELLANEOUS \- Variable features may be present MOLECULAR BASIS \- Caused by mutation in the T-box 2 gene (TBX2, 600747.0001 ) ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA [kDa]: kilodalton [EPC]: Early Prostate Cancer [LAPC]: locally advanced prostate cancer [NSAAs]: nonsteroidal antiandrogens [NSAA]: nonsteroidal antiandrogen [GnRH]: gonadotropin-releasing hormone [ADT]: androgen deprivation therapy [LH]: luteinizing hormone [AR]: androgen receptor [CAB]: combined androgen blockade [LPC]: localized prostate cancer [CPA]: cyproterone acetate [U.S.]: United States [FDA]: Food and Drug Administration	VERTEBRAL ANOMALIES AND VARIABLE ENDOCRINE AND T-CELL DYSFUNCTION	None	7,835	omim	https://www.omim.org/entry/618223	2019-09-22T15:43:03	{"omim": ["618223"]}
Timothy syndrome is a rare disorder that primarily affects the heart but can affect many other areas of the body, including the fingers and toes, teeth, nervous system, and immune system. The severity of this condition varies among affected individuals, although it is often life-threatening due to the heart problems. Timothy syndrome is characterized by a heart condition called long QT syndrome, which causes the heart (cardiac) muscle to take longer than usual to recharge between beats. This abnormality in the heart's electrical system can cause severe abnormalities of the heart rhythm (arrhythmias), which can lead to sudden death. Some people with Timothy syndrome are also born with structural heart defects (cardiomyopathy) that affect the heart's ability to pump blood effectively. As a result of these serious heart problems, many people with Timothy syndrome live only into childhood. In about 80 percent of cases of Timothy syndrome, the cause of death is a severe form of arrhythmia called ventricular tachycardia, in which the lower chambers of the heart (the ventricles) beat abnormally fast, often leading to cardiac arrest and sudden death. Timothy syndrome is also characterized by webbing or fusion of the skin between some fingers or toes (cutaneous syndactyly). About half of affected people have distinctive facial features such as a flattened nasal bridge, low-set ears, a small upper jaw, and a thin upper lip. Children with this condition have small, misplaced teeth and frequent cavities (dental caries). Additional signs and symptoms of Timothy syndrome can include baldness at birth, frequent infections, episodes of low blood sugar (hypoglycemia), and an abnormally low body temperature (hypothermia). Researchers have found that many children with Timothy syndrome have the characteristic features of autism or similar conditions known as autistic spectrum disorders. Affected children tend to have impaired communication and socialization skills, as well as delayed development of speech and language. Other nervous system abnormalities that can occur in Timothy syndrome include intellectual disability and recurrent seizures (epilepsy); some affected individuals have photosensitive epilepsy, in which seizures are triggered by flashing lights. ## Frequency Timothy syndrome is a rare condition; fewer than 100 people with this disorder have been reported worldwide. ## Causes Mutations in the CACNA1C gene are responsible for all reported cases of Timothy syndrome. This gene provides instructions for making a protein that acts as a small hole or pore (a channel) across cell membranes. This channel, known as CaV1.2, transports positively charged calcium atoms (calcium ions) into cardiac cells (cardiomyocytes) and nerve cells (neurons) in the brain. Calcium ions are important for many cellular functions, including regulating the electrical activity of cells, cell-to-cell communication, the tensing of muscle fibers (muscle contraction), and the regulation of certain genes, particularly those involved in the development of the brain and bones before birth. Mutations in the CACNA1C gene change the structure of CaV1.2 channels. The altered channels stay open much longer than usual, which allows calcium ions to continue flowing into cells abnormally. The resulting overload of calcium ions within cardiac muscle cells changes the way the heart beats and can cause abnormal heart muscle contractions and arrhythmia. It is thought that the altered channels and flow of calcium ions also impair regulation of certain genes, resulting in the facial, dental, and neurological abnormalities in Timothy syndrome. ### Learn more about the gene associated with Timothy syndrome * CACNA1C ## Inheritance Pattern This condition is considered to have an autosomal dominant pattern of inheritance, which means one copy of the altered CACNA1C gene in each cell is sufficient to cause the disorder. Most cases result from new mutations in the gene, and occur in people with no history of the disorder in their family. Due to the severity of Timothy syndrome, it is rare for an affected individual to be able to pass on the disease-causing mutation. Although rare, some people with Timothy syndrome inherit the altered gene from an unaffected parent who is mosaic for a CACNA1C mutation. Mosaicism means that the parent has the mutation in some cells (including egg or sperm cells), but not in others. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA [kDa]: kilodalton [EPC]: Early Prostate Cancer [LAPC]: locally advanced prostate cancer [NSAAs]: nonsteroidal antiandrogens [NSAA]: nonsteroidal antiandrogen [GnRH]: gonadotropin-releasing hormone [ADT]: androgen deprivation therapy [LH]: luteinizing hormone [AR]: androgen receptor [CAB]: combined androgen blockade [LPC]: localized prostate cancer [CPA]: cyproterone acetate [U.S.]: United States [FDA]: Food and Drug Administration	Timothy syndrome	c1832916	7,836	medlineplus	https://medlineplus.gov/genetics/condition/timothy-syndrome/	2021-01-27T08:24:47	{"gard": ["9294"], "mesh": ["C536962"], "omim": ["601005"], "synonyms": []}
A rare, idiopathic, generalized form of reflex epilepsy characterized by childhood onset, unique seizure manifestations, striking light sensitivity, and possible occurrence of generalized tonic-clonic seizures. ## Epidemiology Prevalence is unknown but Jeavons syndrome appears to represent around 7-8% of all idiophatic generalized epilepsies (IGEs). The syndrome is slightly more frequent in females than in males. ## Clinical description Onset occurs in childhood, with a peak at 6-8 years of age. Eyelid myoclonia is the principle clinical feature and may or may not be associated with brief (less than 6s) absences. Eye closure in the presence of uninterrupted light is the major triggering factor. Eyelid myoclonic status epilepticus is reported in up to one fifth of the patients and self-induction, although rare, has been described. Generalized tonic-clonic seizures occur in most patients, but the frequency of the seizures is low. Mental development is usually normal but mild to moderate intellectual deficit has been reported in some cases. ## Etiology The etiology is unknown but Jeavons syndrome appears to be genetically determined: the majority of reported patients have a family history of IGE and a few cases of affected twins have been reported. ## Diagnostic methods Eyelid myoclonia is a highly distinctive seizure type and is strongly suggestive of Jeavons syndrome. Video-electroencephalography (video-EEG) is the only procedure required for diagnosis and reveals eye closure-related generalized paroxysmal activity. Thus, in patients with eyelid myoclonia with or without absences, associated with photosensitivity and EEG discharges triggered by eye closure, the diagnosis of Jeavons syndrome is straightforward. ## Differential diagnosis However, other forms of idiopathic, cryptogenic, and symptomatic epilepsy featuring eyelid myoclonia or eye closure sensitivity (juvenile myoclonic epilepsy, juvenile absence epilepsy, and idiopathic photosensitive occipital lobe epilepsy; see these terms) may also be considered in the differential diagnosis. Misdiagnosis of eyelid myoclonia as a facial tic has also been reported. ## Management and treatment The seizures in Jeavons syndrome usually respond well to antiepileptic treatment, with antimyoclonic drugs (valproate, benzodiazepines, levetiracetam, and zonisamide) showing the highest level of efficacy and generally allowing good seizure control. However, polytherapy is often needed and some cases may be drug-resistant. ## Prognosis The overall prognosis is good, although Jeavons syndrome is usually a lifelong condition. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA [kDa]: kilodalton [EPC]: Early Prostate Cancer [LAPC]: locally advanced prostate cancer [NSAAs]: nonsteroidal antiandrogens [NSAA]: nonsteroidal antiandrogen [GnRH]: gonadotropin-releasing hormone [ADT]: androgen deprivation therapy [LH]: luteinizing hormone [AR]: androgen receptor [CAB]: combined androgen blockade [LPC]: localized prostate cancer [CPA]: cyproterone acetate [U.S.]: United States [FDA]: Food and Drug Administration	Jeavons syndrome	c4274731	7,837	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=139431	2021-01-23T18:51:23	{"icd-10": ["G40.3"], "synonyms": ["EMEA", "Eyelid myoclonia with and without absences"]}
## Clinical Features Nievergelt syndrome is characterized by specific deformities of the radius, ulna, tibia, and fibula. Radioulnar synostosis and a typical rhomboid shape of the tibia and fibula are observed. Nievergelt (1944) reported an affected man who transmitted the syndrome to 3 sons, each by a different wife. In a second family, 9 persons (2 males and 7 females) in 3 generations were affected, although perhaps with a different disorder. The x-ray changes, completely specific, are well demonstrated in the sporadic cases reported by Solonen and Sulamaa (1958). The characteristic rhomboidal shape of the tibia and fibula help differentiate this condition from the Grebe, or Brazilian, form of achondrogenesis (200700) and from recessive mesomelic dwarfism (249700). The cases called Nievergelt syndrome by Blockey and Lawrie (1963) were in fact instances of mesomelic dwarfism. Young and Wood (1974) described a typical sporadic case. Hess et al. (1978) restudied Nievergelt's family. Tuysuz et al. (2002) applied the diagnosis of Nievergelt syndrome to a 33-day-old boy who had short and thick tibiae, symmetrical oligosyndactyly of the hands, and distinctive face. In addition to the characteristic mesomelic limb anomalies of Nievergelt syndrome, this patient exhibited 2 additional features: agenesis of the cerebellar vermis and cataracts, both of which had not been previously associated with Nievergelt syndrome. Nakamura et al. (2007) described a father-son pair with a severe form of mesomelic dysplasia that shared many features of the Savarirayan (605274) and Nievergelt types. Radiographs of the son at 6 months of age showed mild mesomelic shortening of the arms with proximal radius hypoplasia and broadening of the distal radius and proximal ulna. The lower limbs showed greater involvement with markedly short, broad tibia and absent fibular ossification. Rudimentary distal ossification occurred with age. The father demonstrated identical abnormalities of the tibia and fibula but had broader radii and ulnae with interosseous bridging on the left. The triad of severely deformed tibia, rudimentary fibula, and mildly affected radius and ulna in the son resembled that of the Savarirayan type. The broad, trapezoidal radius in the father showed greater similarity to the Nievergelt type. Nakamura et al. (2007) suggested that the Savarirayan and Nievergelt types may be allelic autosomal dominant disorders. History Urban and Kruger (1998) suggested that Nievergelt syndrome was the correct diagnosis in 24-year-old Alice Vance from Mount Pleasant, Texas, who was among the malformed individuals presented at the world exhibition in Antwerp in 1894. She was presented to the public under the stage name 'Das Baerenweib' (the 'bear-like woman'). Her mother was known to have similar malformations. INHERITANCE \- Autosomal dominant GROWTH Height \- Dwarfism, short limb mesomelic HEAD & NECK Face \- Normal face SKELETAL Limbs \- Lower leg mesomelia \- Genua valga \- Rhomboidal shape of tibiae and fibulae \- Relative overgrowth of fibula \- Radioulnar synostosis \- Radial head subluxation Feet \- Clubfoot \- Tarsal bone synostosis \- Metatarsal synostosis SKIN, NAILS, & HAIR Skin \- Dimples (medial and lateral aspect of lower leg) NEUROLOGIC Central Nervous System \- Normal intelligence ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA [kDa]: kilodalton [EPC]: Early Prostate Cancer [LAPC]: locally advanced prostate cancer [NSAAs]: nonsteroidal antiandrogens [NSAA]: nonsteroidal antiandrogen [GnRH]: gonadotropin-releasing hormone [ADT]: androgen deprivation therapy [LH]: luteinizing hormone [AR]: androgen receptor [CAB]: combined androgen blockade [LPC]: localized prostate cancer [CPA]: cyproterone acetate [U.S.]: United States [FDA]: Food and Drug Administration	NIEVERGELT SYNDROME	c0432231	7,838	omim	https://www.omim.org/entry/163400	2019-09-22T16:37:22	{"mesh": ["C536120"], "omim": ["163400"], "orphanet": ["2633"], "synonyms": ["Alternative titles", "MESOMELIC DYSPLASIA, NIEVERGELT TYPE"]}
Re-entry ventricular arrhythmia SpecialtyCardiology Re-entry ventricular arrhythmia is a type of paroxysmal tachycardia occurring in the ventricle where the cause of the arrhythmia is due to the electric signal not completing the normal circuit, but rather an alternative circuit looping back upon itself.[1] There develops a self-perpetuating rapid and abnormal activation. ("Circus Movement" is another term for this.) Conditions necessary for re-entry include a combination of unidirectional block and slowed conduction.[2] Circus movement may also occur on a smaller scale within the AV node (dual AV nodal physiology), a large bypass tract is not necessary.[3] Re-entry is divided into two major types: [Anatomically Defined] re-entry and [Functionally Defined] re-entry. The circus movement can occur around an anatomical or functional core. Either type may occur alone, or together. Anatomically defined re-entry has a fixed anatomic pathway. Anomalous conduction via accessory pathways (APs) create the re-entry circuit (which are also called bypass tracts), that exist between the atria and ventricles. Wolff–Parkinson–White syndrome (WPW) is an example of anatomically defined re-entry. WPW syndrome is an atrioventricular re-entrant tachycardia (AVRT), secondary to an accessory pathway that connects the epicardial surfaces of the atrium and ventricle along the AV groove.[4] The majority of time symptomatic WPW fits the definition of AVRT (Supraventricular tachycardia) however AVNRT (dual AV nodal physiology) exist in ~10% of patients with WPW syndrome creating the possibility of spontaneous atrial fibrillation degenerating into ventricular fibrillation (VF). The fact that WPW patients are young and do not have structural heart disease, lead to using catheter ablation of the APs with the elimination of the atrial fibrillation as well as the episodes of re-entrant ventricular tachycardia. This elimination of the atrial fibrillation with ablation implies APs have some pathophysiologic role in the development of a-fib in the WPW patient.[4] Functionally defined re-entry does not require the alternative anatomically defined circuit accessory pathways and it may not reside in just one location.[5] Ventricular fibrillation (VF) following ventricular tachycardia (VT) may be described as a functionally defined re-entry problem caused by multiple mini re-entrant circuits spontaneously created within the ventricular myocardium. The original re-entrant circuit breaks down into multiple mini reentrant circuits.[6] (VF becoming the grand finale of a single prolonged VT larger circus movement, propagating change in the "functional core" of the ventricular myocardium, dissipating mini reentrant circuits, exhibited as ventricular fibrillation.) Ischemia, electrolyte, pH abnormalities, or bradycardia are potential causes of functionally defined re-entry due to changes in the properties of the cardiac tissue's functional core.[2] (No accessory pathway required). For reentry to occur, the path length of circuit should be greater than the wave length (ERP × conduction velocity) of impulse. ## See also[edit] * AV reentrant tachycardia * AV nodal reentrant tachycardia ## References[edit] 1. ^ "Cardiac Arrhythmias". Retrieved 2007-07-21. 2. ^ a b Am J Cardiol. 1984 Jul 30;54(2):1A-6A. 3. ^ Cardiovascular Physiology & Anesthesia. Morgan, Jr. GE, Mikhail MS, Murray MJ. Chapter 19. Clinical Anesthesiology. 4th ed. New York: McGraw-Hill; 2006. 4. ^ a b Hurst's The Heart, 13e.(2011). Chapter 41. Supraventricular Tachycardia: Atrioventricular Nodal Reentry and Wolff-Parkinson-White Syndrome. 5. ^ Goodman & Gilman's The Pharmacological Basis of Therapeutics. 12th ed. \|Sampson KJ, Kass RS. Chapter 29. Anti-Arrhythmic Drugs. 6. ^ Hurst's The Heart, Chapter 38. Mechanisms of Cardiac Arrhythmias and Conduction Disturbances. In V. Fuster, R.A. Walsh, R.A. Harrington (Eds) ## External links[edit] Classification D * ICD-10: I47.0 [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA [kDa]: kilodalton [EPC]: Early Prostate Cancer [LAPC]: locally advanced prostate cancer [NSAAs]: nonsteroidal antiandrogens [NSAA]: nonsteroidal antiandrogen [GnRH]: gonadotropin-releasing hormone [ADT]: androgen deprivation therapy [LH]: luteinizing hormone [AR]: androgen receptor [CAB]: combined androgen blockade [LPC]: localized prostate cancer [CPA]: cyproterone acetate [U.S.]: United States [FDA]: Food and Drug Administration	Re-entry ventricular arrhythmia	c0349069	7,839	wikipedia	https://en.wikipedia.org/wiki/Re-entry_ventricular_arrhythmia	2021-01-18T18:58:35	{"icd-10": ["I47.0"], "wikidata": ["Q7299957"]}
A rare neurodegenerative disorder of the astrocytes comprised of two clinical forms: Alexander disease (AxD) type I and type II manifesting with various degrees of macrocephaly, spasticity, ataxia and seizures and leading to psychomotor regression and death. ## Epidemiology The prevalence is unknown. One population based study in Japan estimated an annual incidence of 1/ 2.7 million. ## Clinical description The clinical presentation depends on the subtype. Previously, AxD was classified either as infantile, juvenile or adult, based simply on age of onset. The currently used classification system is based on a constellation of clinical and radiologic features and includes AxD type I and AxD type II (see these terms). AxD type I is more likely to be of early onset (mean 1.74 years) and shorter survival (median 14 years) whereas type II exhibits onset throughout the lifespan (mean 21.64 years, but can occur in early childhood) and has longer survival (median 25 years). The two types also differ in their clinical symptoms. AxD type I manifests with symptoms of encephalopathy, epilepsy and failure to thrive and has an infantile presentation, while patients with AxD type II manifest with bulbar, autonomic and motor signs such as dysarthria, dysphonia, dysphagia, ataxia, spastic paraparesis and palatal myoclonus. AxD type II also has a slower progression and cognitive impairment can be completely absent. ## Etiology In the vast majority (95%) of patients, AxD is caused by gain-of-function de novo mutations in the glial fibrillary acidic protein (GFAP) gene. Several familial cases have also been reported with autosomal dominant transmission. This gene encodes GFAP, the major intermediate filament protein found in astrocytes. The over-expression and accumulation of this mutant protein leads to the formation of astrocytic inclusion bodies (Rosenthal fibers) throughout the central nervous system (CNS). It is currently unknown how Rosenthal fibers are involved in disease pathogenesis. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA [kDa]: kilodalton [EPC]: Early Prostate Cancer [LAPC]: locally advanced prostate cancer [NSAAs]: nonsteroidal antiandrogens [NSAA]: nonsteroidal antiandrogen [GnRH]: gonadotropin-releasing hormone [ADT]: androgen deprivation therapy [LH]: luteinizing hormone [AR]: androgen receptor [CAB]: combined androgen blockade [LPC]: localized prostate cancer [CPA]: cyproterone acetate [U.S.]: United States [FDA]: Food and Drug Administration	Alexander disease	c0270726	7,840	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=58	2021-01-23T17:56:07	{"gard": ["5774"], "mesh": ["D038261"], "omim": ["203450"], "umls": ["C0270726"], "icd-10": ["E75.2"], "synonyms": ["AxD"]}
Lepromatous leprosy Leonine facies in lepromatous leprosy SpecialtyInfectious disease Lepromatous leprosy is a form of leprosy characterized by pale macules in the skin.[1]:346 It results from the failure of Th1 cell activation which is necessary to eradicate the mycobacteria (Th1 response is required to activate macrophages that engulf and contain the disease). In lepromatous leprosy, TH2 response is turned on, and because of reciprocal inhibition (IL-4; IL-10), the cell-mediated response (TH1) is depressed. Lepromatous leprosy, in contrast to the tuberculoid form of leprosy, is characterized by the absence of epithelioid cells in the lesions. In this form of leprosy Mycobacterium leprae are found in lesion in large numbers. This is the most unfavorable clinical variant of leprosy.[2][3] This debilitating form of leprosy begins to spread causing the eyebrows to disappear and spongy tumor like swellings appear on the face and body. The disease attacks the internal organs, bones, joints and marrow of the body resulting in physical degeneration. The result is deformity with loss of feeling in the fingers and toes which eventually fall off. Contrary to popular belief, both forms of leprosy are curable, with the lepromatous form classically treated with antibiotics Dapsone, Rifampin and Clofazimine for as long as 2–5 years, but if left untreated the person may die up to 20 or 30 years from its inception.[4] Early detection of the disease is of utmost importance, since severe physical and neurological damage are irreversible even if cured (e.g. blindness, loss of digits/limbs/sensation). Early infection is characterized by a well demarcated, usually pale, skin lesion which has lost its hair, and there may be many of these lesions if the infection is more severe (most commonly found on the cooler parts of the body such as the elbows, knees, fingers, or scrotum, as the bacteria thrive in cooler environments). This early presentation is the same for both tuberculous and lepromatous forms of leprosy as they are a spectrum of the same disease (lepromatous being the more contagious and severe form in patients with impaired Th1 response). Disease progression is extremely slow, and signs of infection may not appear for years.[4] Family members of those with the disease, and especially children, are most at risk. The disease is believed to be spread through respiratory droplets in close quarters like its relative Mycobacterium tuberculosis, and similarly requires extended exposure to an individual in most situations, so outsiders and healthcare workers are normally not infected (except with the most infective individuals such as those in the most progressed lepromatous forms, as those patients have the highest bacterial loads).[4] ## See also[edit] * Medicine portal * Tuberculoid leprosy * Diffuse leprosy of Lucio and Latapí ## References[edit] 1. ^ James, William D.; Berger, Timothy G.; et al. (2006). Andrews' Diseases of the Skin: clinical Dermatology. Saunders Elsevier. ISBN 0-7216-2921-0. 2. ^ Bhat RM, Prakash C (2012). "Leprosy: an overview of pathophysiology". Interdiscip Perspect Infect Dis. 2012: 1–6. doi:10.1155/2012/181089. PMID 22988457. 3. ^ Lastoria JC, Abreu MA (2014). "Leprosy: a review of laboratory and therapeutic aspects". An Bras Dermatol. 89 (3): 389–401. doi:10.1590/abd1806-4841.20142460. PMID 24937811. 4. ^ a b c "Frequently Asked Questions about Hansen's Disease" (PDF). Health Resources and Services Administration. ## External links[edit] Classification D * ICD-10: A30.5 * ICD-9-CM: 030.0 * MeSH: D015440 * DiseasesDB: 8478 * v * t * e Gram-positive bacterial infection: Actinobacteria Actinomycineae Actinomycetaceae * Actinomyces israelii * Actinomycosis * Cutaneous actinomycosis * Tropheryma whipplei * Whipple's disease * Arcanobacterium haemolyticum * Arcanobacterium haemolyticum infection * Actinomyces gerencseriae Propionibacteriaceae * Propionibacterium acnes Corynebacterineae Mycobacteriaceae M. tuberculosis/ M. bovis * Tuberculosis: Ghon focus/Ghon's complex * Pott disease * brain * Meningitis * Rich focus * Tuberculous lymphadenitis * Tuberculous cervical lymphadenitis * cutaneous * Scrofuloderma * Erythema induratum * Lupus vulgaris * Prosector's wart * Tuberculosis cutis orificialis * Tuberculous cellulitis * Tuberculous gumma * Lichen scrofulosorum * Tuberculid * Papulonecrotic tuberculid * Primary inoculation tuberculosis * Miliary * Tuberculous pericarditis * Urogenital tuberculosis * Multi-drug-resistant tuberculosis * Extensively drug-resistant tuberculosis M. leprae * Leprosy: Tuberculoid leprosy * Borderline tuberculoid leprosy * Borderline leprosy * Borderline lepromatous leprosy * Lepromatous leprosy * Histoid leprosy Nontuberculous R1: * M. kansasii * M. marinum * Aquarium granuloma R2: * M. gordonae R3: * M. avium complex/Mycobacterium avium/Mycobacterium intracellulare/MAP * MAI infection * M. ulcerans * Buruli ulcer * M. haemophilum R4/RG: * M. fortuitum * M. chelonae * M. abscessus Nocardiaceae * Nocardia asteroides/Nocardia brasiliensis/Nocardia farcinica * Nocardiosis * Rhodococcus equi Corynebacteriaceae * Corynebacterium diphtheriae * Diphtheria * Corynebacterium minutissimum * Erythrasma * Corynebacterium jeikeium * Group JK corynebacterium sepsis Bifidobacteriaceae * Gardnerella vaginalis This infection-related cutaneous condition article is a stub. You can help Wikipedia by expanding it. * v * t * e [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA [kDa]: kilodalton [EPC]: Early Prostate Cancer [LAPC]: locally advanced prostate cancer [NSAAs]: nonsteroidal antiandrogens [NSAA]: nonsteroidal antiandrogen [GnRH]: gonadotropin-releasing hormone [ADT]: androgen deprivation therapy [LH]: luteinizing hormone [AR]: androgen receptor [CAB]: combined androgen blockade [LPC]: localized prostate cancer [CPA]: cyproterone acetate [U.S.]: United States [FDA]: Food and Drug Administration	Lepromatous leprosy	c0023348	7,841	wikipedia	https://en.wikipedia.org/wiki/Lepromatous_leprosy	2021-01-18T18:49:45	{"mesh": ["D015440"], "umls": ["C0023348"], "wikidata": ["Q6527832"]}
A number sign (#) is used with this entry because very long-chain acyl-CoA dehydrogenase deficiency is caused by homozygous or compound heterozygous mutation in the gene encoding very long-chain acyl-CoA dehydrogenase (ACADVL; 609575) on chromosome 17p13. Description Inborn errors of mitochondrial fatty acid beta-oxidation include medium-chain acyl-CoA dehydrogenase deficiency (201450), short-chain acyl-CoA dehydrogenase deficiency (201470), and very long-chain acyl-CoA dehydrogenase deficiency. VLCAD deficiency can be classified clinically into 3 forms: a severe early-onset form with high incidence of cardiomyopathy and high mortality; an intermediate form with childhood onset, usually with hypoketotic hypoglycemia and more favorable outcome; and an adult-onset, myopathic form with isolated skeletal muscle involvement, rhabdomyolysis, and myoglobinuria after exercise or fasting (Andresen et al., 1999). Patients reported with long-chain acyl-CoA dehydrogenase (LCAD) deficiency before VLCAD deficiency was defined were later found to have VLCAD deficiency (Strauss et al., 1995; Roe and Ding, 2001). Clinical Features Hale et al. (1985) reported 3 unrelated children who presented in early childhood with nonketotic hypoglycemia and episodes of cardiorespiratory arrest associated with fasting. Other features included hepatomegaly, cardiomegaly, and hypotonia. Total plasma carnitine concentration was low. The findings suggested a defect in mitochondrial fatty acid oxidation. Specific assays showed that the activity of long-chain acyl-CoA dehydrogenase was less than 10% of control values in fibroblasts, leukocytes, and liver. Activities of medium-chain, short-chain, and isovaleryl CoA dehydrogenases were normal. With cultured fibroblasts, CO2 evolution from medium-chain and short-chain fatty acids was normal and that from long-chain fatty acids was reduced. As in medium-chain acyl-CoA dehydrogenase deficiency, dicarboxylic acids in the urine and relatively low urinary beta-hydroxybutyrate levels were formed by omega-oxidation of fatty acids in the cytoplasm. The parents had intermediate levels of enzyme activity, suggesting autosomal recessive inheritance. Hale et al. (1985) also demonstrated deficiency of the long-chain dehydrogenase in fibroblasts from 2 sibs reported by Naylor et al. (1980) with features similar to those in their 3 patients. Treem et al. (1991) described an affected infant and compared the case with 7 previously published cases. The infant had hypotonia and marked cardiac enlargement as well as hypoglycemia. Ribes et al. (1992) provided follow-up information on a patient described by Riudor et al. (1986). LCAD deficiency had been documented in the fibroblasts from the patient and treatment with frequent low-fat high-carbohydrate feedings, riboflavin, and carnitine reduced the frequency and intensity of crises. However, the patient developed progressive cardiomegaly and persistent hepatosplenomegaly. Following a crisis similar to those suffered previously, he went into cardiorespiratory arrest at the age of 4.5 years. Bertrand et al. (1993) reported deficiency of very long-chain acyl-CoA dehydrogenase in a 2-year-old girl with a fatty acid oxidation defect. Yamaguchi et al. (1993) identified VLCAD deficiency in 3 patients previously diagnosed with LCAD deficiency. Aoyama et al. (1993) reported 2 male patients with VLCAD deficiency as evidenced by in vitro findings of very low palmitoyl-CoA dehydrogenase activity and lack of immunoreactivity to antibody against the VLCAD protein. One patient presented at age 3 months with hypoketotic hypoglycemia, hepatocellular disease, and cardiomyopathy. At autopsy, there was severe hepatocellular injury and marked lipid accumulation in many tissues. The other patient, reported by Tonsgard et al. (1991) as an instance of an unexplained defect of long-chain fatty acid oxidation, presented at age 4 months with hypoglycemia, hepatocellular dysfunction, and cardiomyopathy. Laboratory testing revealed hyperammonemia and increased urinary levels of adipate and sebacate. Microscopic examination at autopsy showed lipid accumulation in many tissues. Ogilvie et al. (1994) reported a 21-year-old man with VLCAD who presented with a 5-year history of exercise-induced muscle pain and myoglobinuria. Residual enzyme activity was approximately 10% of control values. The patient was able to decrease the amount of pain if he ate a carbohydrate snack before or during the exercise. Aoyama et al. (1995) used immunoblotting to analyze for VLCAD protein deficiency in skin fibroblasts from 26 patients suspected of having a disorder of mitochondrial beta-oxidation; 7 samples contained undetectable or trace levels of the VLCAD enzyme. Clinically, all patients with VLCAD deficiency exhibited cardiac disease, and at least 4 of them presented with hypertrophic cardiomyopathy. The biochemical work suggested a heterogeneity of mutations causing deficiency in the 7 patients. Six of the 7 patients studied by Aoyama et al. (1995) were North American Caucasians, and 1 was Asian. Clinical onset of abnormality was within 4 months after birth, 75% died within 2 months after onset, and all patients had liver dysfunction and cardiac disease. Fukao et al. (2001) reported a 14-year-old Japanese girl who presented with recurrent myalgia and elevated serum creatine kinase after moderate exercise. She was diagnosed as having a myopathic form of VLCAD deficiency confirmed by genetic analysis (609575.0013; 609575.0014). Her first clinical symptom of the disease appeared at age 6. She had never had hypoglycemic attacks, hepatomegaly, or cardiomyopathy. In vitro functional expression studies showed that the mutant proteins were temperature-sensitive and retained residual activity at 30 degrees Celsius. Fukao et al. (2001) concluded that the temperature-sensitive mild mutations in both alleles resulted in this patient's very mild manifestations. Brown et al. (2014) reported complete neuropsychologic assessment of 7 children with VLCAD deficiency, and 1 additional child with partial assessment. There were 2 females and 6 males in this group. IQs ranged from average to superior. No deficits were found in fine or gross motor skills. One patient had mild language deficit, and 2 had previously required speech therapy. Verbal memory, attention, and executive functioning skills were generally average or above average; visual memory scores were mostly above average. One child was identified as having social skills deficits, and 2 as having behavioral problems. One child rated high on an autism spectrum subscale, and another was formally diagnosed with ASD. Brown et al. (2014) concluded that VLCAD deficiency does not have significant impact on cognitive or motor skills. Pena et al. (2016) retrospectively analyzed early outcomes for individuals who were diagnosed with VLCAD deficiency by newborn screening in the USA and described initial presentations, diagnosis, clinical outcomes, and treatment in a cohort of 52 individuals aged 1 to 18 years. Maternal prenatal symptoms were not reported, and most newborns remained asymptomatic. Cardiomyopathy was uncommon in the cohort, diagnosed in 2 of 52 cases. Elevations in creatine kinase were a common finding, and usually first occurred during the toddler period (1 to 3 years of age). Of the 14 subjects with elevated creatine kinase, 11 developed rhabdomyolysis. Diagnostic evaluations required several testing modalities, most commonly plasma acylcarnitine profiles and molecular testing. Functional testing, including fibroblast acylcarnitine profiling and white blood cell or fibroblast enzyme assay, is a useful diagnostic adjunct if uncharacterized mutations are identified. Evans et al. (2016) reported on 22 patients with VLCAD deficiency identified by newborn screening in Victoria, Australia. Patients were treated with a low natural-fat diet which was relaxed at age 5 if the patients had been asymptomatic, but supplementation with medium-chain triglyceride (MCT) oil before and after physical activity was recommended to all. All patients were doing well with no episodes of encephalopathy or hypoglycemia, but 3 patients had episodes of muscle pain with or without rhabdomyolysis. Biochemical Features Onkenhout et al. (2001) determined the fatty acid composition of liver, skeletal muscle, and heart obtained postmortem from patients with deficiency of 1 of 3 types of acyl-CoA dehydrogenase: medium-chain, very long-chain, and multiple (MADD; 231680). Increased amounts of multiple unsaturated fatty acids were found exclusively in the triglyceride fraction. They could not be detected in the free fatty acid or phospholipid fractions. Onkenhout et al. (2001) concluded that intermediates of unsaturated fatty acid oxidation that accumulate in these disorders are transported to the endoplasmic reticulum for esterification into neutral glycerolipids. The pattern of accumulation was characteristic for each disease, making fatty acid analysis of total lipid of postmortem tissues a useful tool in the detection of mitochondrial fatty acid oxidation defects in patients who have died unexpectedly. Inheritance Deficiency of very long-chain acyl-CoA dehydrogenase is an autosomal recessive disorder (Strauss et al., 1995). Diagnosis Costa et al. (1996) described 2 patients with celiac disease and prolonged malnourishment whose urinary organic acid profile during a crisis of metabolic decompensation was similar to those frequently observed in long-chain fatty acid oxidation disorders. The first patient was a girl with a history of vomiting and poor weight gain since the introduction of solid food at the age of 3 months. Clinically she had failure to thrive, hypotonia, and motor retardation. Metabolic screening at the age of 12 months revealed normal amino acids, purines, pyrimidines, and mono- and oligosaccharides. Urinary organic acid analysis revealed an increased excretion of dicarboxylic (DC) and 3-hydroxydicarboxylic (3OHDC) acids without ketonuria. Celiac disease was suspected because of gastrointestinal problems. On a gluten-free diet, the organic acid profile normalized completely. The second patient, a girl, presented with a similar clinical history. Organic acid analysis from the urine collected at 12 months of age revealed hypoketotic dicarboxylic aciduria. After the diagnosis of celiac disease and the introduction of a gluten-free diet, the organic acid profile normalized completely. Costa et al. (1996) showed that neither the demonstration of hypoketotic dicarboxylic aciduria nor the analysis of the ratios between urinary DC and 3OHDC acids was sufficient grounds to prove a reliable diagnosis of a potential fatty acid oxidation defect. Ohashi et al. (2004) identified 13 patients with the myopathic form of VLCAD deficiency by using immunohistochemistry to analyze the VLCAD protein in skeletal muscle biopsies. Biochemical analysis confirmed that all 13 patients had low enzymatic activity and reduced amounts of VLCAD protein. Genetic analysis confirmed that they all had mutations in the ACADVL gene. Ohashi et al. (2004) concluded that the immunohistochemical technique was an effective diagnostic tool for VLCAD deficiency. Clinical Management Cox et al. (1998) described a 5-year-old girl with VLCAD deficiency confirmed by genetic analysis (see, e.g., 609575.0012). She was first seen at 5 months of age with severe hypertrophic cardiomyopathy, hepatomegaly, encephalopathy, and hypotonia. After initial treatment with intravenous glucose and carnitine, the patient thrived on a low-fat diet supplemented with medium-chain triglyceride oil and carnitine and avoidance of fasting. Her ventricular hypertrophy resolved significantly over 1 year, and cognitively, she was in the superior range for age. Cox et al. (1998) emphasized that clinical recognition of VLCAD deficiency is important because it is one of the few directly treatable causes of cardiomyopathy in children. Parini et al. (1998) described a 5-year-old boy with VLCAD deficiency who presented at the age of 5 years with acute severe cardiac and skeletal muscle damage, gross myoglobinuria, and normoglycemia. He was admitted to hospital with severe acute diarrhea, having previously been healthy. Over the next 6 years, he responded well to treatment with 5 meals per day, with medium-chain triglycerides as the main source of lipids, and with raw cornstarch after the last meal of the day. At the time of first presentation in 1992, the patient had been thought to have long-chain acyl-CoA deficiency. Djouadi et al. (2003, 2005) found that pharmacologic enhancement of a deficient enzyme could be achieved in cells carrying mild mutations of the CPT2 gene (600650), which underlies CPT2 deficiency. This was achieved through cell exposure to bezafibrate, a drug widely used for its hypolipidemic action and acting as an agonist of the peroxisomal proliferator-activated receptors (PPARs). Upon pharmacologic activation, PPARs trigger an upregulation of CTP2 gene expression, which results in an increase in CPT2 residual enzyme activity and thereby correction of fatty-acid oxidation (FAO) flux in treated cells. It was thought that this approach might be extended to other FAO defects, since the PPAR signaling pathway controls many different enzymes in the beta-oxidation pathway. Djouadi et al. (2005) found a beneficial effect of bezafibrate in a small series of VLCAD-deficient fibroblast cell lines. Gobin-Limballe et al. (2007) investigated response to bezafibrate as a function of genotype in 33 VLCAD-deficient fibroblast cell lines representing 45 mutations. Their results showed that, despite the great diversity of possible consequences of missense mutations for enzyme synthesis, activity, or steady-state level, pharmacologic stimulation of mutant VLCAD gene expression improved the beta-oxidation capacities in a relatively large panel of genotypes. In 2 unrelated adult men with VLCAD deficiency, Orngreen et al. (2007) found that neither intravenous glucose nor oral medium-chain triglycerides had a beneficial effect on exercise tolerance. Molecular Genetics In cultured fibroblasts of 2 patients with VLCAD deficiency, Aoyama et al. (1995) identified a 105-bp deletion in the ACADVL gene (609575.0001). In 2 unrelated patients with VLCAD deficiency, Strauss et al. (1995) identified mutations in the ACADVL gene (609575.0002-609575.0004). Both patients had originally been diagnosed with long-chain acyl-CoA deficiency (Hale et al., 1985). Mathur et al. (1999) identified 21 different mutations in the ACADVL gene in 18 of 37 children with cardiomyopathy, nonketotic hypoglycemia and hepatic dysfunction, skeletal myopathy, or sudden death in infancy with hepatic steatosis. Sixty-seven percent of children had severe dilated or hypertrophic cardiomyopathy at presentation. In 7 patients, only 1 mutation was found despite direct sequencing of all exons. Missense, frameshift, and splice consensus sequence mutations were seen, as well as in-frame deletions. Eighty percent of these mutations were associated with cardiomyopathy. The authors concluded that infantile cardiomyopathy is the most common clinical phenotype for VLCAD deficiency and highlighted the marked allelic heterogeneity in this disorder. Of the 52 patients with VLCAD deficiency reported by Pena et al. (2016), molecular testing was available for 46. Two mutations were identified in 44 of these while only 1 mutation was identified in the remaining 2. Most (38 of 46, 83%) were compound heterozygous, and of the 50 different alleles reported, 26 were novel. Evans et al. (2016) reported 5 novel mutations among 22 patients with VLCAD deficiency identified in Victoria, Australia. Genotype/Phenotype Correlations Andresen et al. (1999) studied 54 patients with VLCAD, several of whom had been previously reported. Twenty-five patients had the severe childhood form, 75% of whom had onset within the first 3 days of life. These patients had cardiomyopathy (92%), hepatomegaly (80%), hypotonia (52%), and early death (80%). Twenty-one patients had a milder childhood form with onset by 4 years of age. Clinical features in this group included cardiomyopathy (19%), hepatomegaly (62%), rhabdomyolysis or myoglobinuria (14%), hypotonia (62%), and hypoketotic hypoglycemia (76%). Eight patients had a myopathic adult form, with onset after age 13 years. All of these patients had rhabdomyolysis or myoglobinuria, whereas only 13% had cardiomyopathy and 13% had hypotonia. Genotype analysis identified 58 different ACADVL mutations among the whole group. In patients with the severe childhood form of VLCAD, the majority (71%) of mutant alleles were null, whereas in patients with the milder childhood and adult forms of VLCAD, the majority of alleles (82% and 93%, respectively) were predicted to result in some residual enzyme activity. Gregersen et al. (2001) reviewed current understanding of genotype-phenotype relationships in VLCAD, MCAD, and SCAD. They discussed both the structural implications of mutation type and the modulating effect of the mitochondrial protein quality control systems, composed of molecular chaperones and intracellular proteases. The realization that the effect of the monogene, such as disease-causing mutations in these 3 genes, may be modified by variations in other genes presages the need for profile analyses of additional genetic variations. They stated that the rapid development of mutation detection systems, such as chip technologies, made such profile analyses feasible. History In an abstract, Kelly et al. (1991) reported the identification of a mutation in the ACADL gene (gln303-to-lys; Q303K) in 3 unrelated patients with LCAD deficiency. No follow-up on this abstract was reported. INHERITANCE \- Autosomal recessive CARDIOVASCULAR Heart \- Hypertrophic cardiomyopathy \- Cardiac arrest \- Sudden cardiac death RESPIRATORY \- Tachypnea ABDOMEN Liver \- Hepatomegaly \- Hepatic steatosis \- Hepatocellular necrosis Gastrointestinal \- Vomiting MUSCLE, SOFT TISSUES \- Hypotonia \- Muscle weakness associated with fasting or infection \- Muscle pain with exercise (in older patients) \- Muscle stiffness (in older patients) \- Rhabdomyolysis with exercise (in older patients) \- Myopathic episodes triggered by exercise, fasting, infection, cold temperatures NEUROLOGIC Central Nervous System \- Lethargy METABOLIC FEATURES \- Nonketotic hypoglycemia LABORATORY ABNORMALITIES \- Dicarboxylic aciduria \- Decreased plasma carnitine \- Decreased very long-chain acyl-CoA dehydrogenase protein and activity \- Exercise-induced myoglobinuria in adults \- Increased serum creatine kinase in patients with muscle involvement MISCELLANEOUS \- Three main clinical forms \- Severe, early-onset, usually within the first days of life, with cardiomyopathy and early death \- Milder, childhood form, with onset by age 4 years, lesser cardiac involvement, and hypoketotic hypoglycemia \- Mild adult form, with onset after age 13 years, no cardiac involvement, and restricted to muscle involvement with rhabdomyolysis MOLECULAR BASIS \- Caused by mutation in the very long-chain acyl-CoA dehydrogenase gene (ACAVLD, 609575.0001 ) ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA [kDa]: kilodalton [EPC]: Early Prostate Cancer [LAPC]: locally advanced prostate cancer [NSAAs]: nonsteroidal antiandrogens [NSAA]: nonsteroidal antiandrogen [GnRH]: gonadotropin-releasing hormone [ADT]: androgen deprivation therapy [LH]: luteinizing hormone [AR]: androgen receptor [CAB]: combined androgen blockade [LPC]: localized prostate cancer [CPA]: cyproterone acetate [U.S.]: United States [FDA]: Food and Drug Administration	ACYL-CoA DEHYDROGENASE, VERY LONG-CHAIN, DEFICIENCY OF	c3887523	7,842	omim	https://www.omim.org/entry/201475	2019-09-22T16:31:27	{"doid": ["0080155"], "mesh": ["C536353"], "omim": ["201475"], "orphanet": ["26793"], "synonyms": ["Alternative titles", "VLCAD DEFICIENCY"], "genereviews": ["NBK6816"]}
Tonsil cancer that has material basis in squamous cells This article is an orphan, as no other articles link to it. Please introduce links to this page from related articles; try the Find link tool for suggestions. (October 2016) Tonsil carcinoma SpecialtyOncology Carcinoma of the tonsil is a type of squamous cell carcinoma. The tonsil is the most common site of squamous cell carcinoma in the oropharynx. It comprises 23.1% of all malignancies of the oropharynx.[1] The tumors frequently present at advanced stages, and around 70% of patients present with metastasis to the cervical lymph nodes.[2] . The most reported complaints include sore throat, otalgia or dysphagia. Some patients may complain of feeling the presence of a lump in the throat. Approximately 20% patients present with a node in the neck as the only symptom.[3] Main risk factors of developing carcinoma tonsil include tobacco smoking and regular intake of high amount of alcohol. It has also been linked to a virus called Human Papilloma Virus (HPV type HPV16).[4] Other risk factors include poor maintenance of oral hygiene, a genetic predisposition leading to inclination towards development of throat cancer, immunocompromised states (such as post solid-organ transplant), and chronic exposure to agents such as asbestos and perchloroethylene in certain occupations, radiation therapy and dietary factors.[5] ## Contents * 1 Signs and symptoms * 2 Cause * 3 Pathophysiology * 3.1 Routes of metastasis * 3.1.1 Local * 3.1.2 Lymphatic * 3.1.3 Distant metastasis * 4 Diagnosis * 4.1 Staging * 4.1.1 T Staging * 4.1.2 N staging * 4.1.3 M staging * 5 Treatment * 5.1 Radiotherapy * 5.2 Chemotherapy * 5.3 Surgery * 5.4 Combination therapy * 6 Prognosis * 6.1 HPV status * 6.2 Stage * 6.3 Lymphatic Infiltration * 6.4 Tumor extension * 6.5 Metastasis * 7 References * 8 External links ## Signs and symptoms[edit] The early lesions are usually asymptomatic. The patients presenting with an advanced stage of the disease comprises around 66-77% of the cases.[6] The most important signs include a lump in the neck when palpated and weight loss.[7] People may also present with fatigue as a symptom. The primary tumor does not have readily discernible signs or symptoms as they grow within the tonsillar capsule. It is difficult to notice anything suspicious on examination of the tonsil other than slight enlargement or the development of firmness around the area. The carcinoma may occur in one or more sites deep within the tonsillar crypts. It may be accompanied by the enlargement of the tonsil. The affected tonsil grows into the oropharyngeal space making it noticeable by the patient in the form of a neck mass mostly in the jugulodigastric region. As the tonsils consist of a rich network of lymphatics, the carcinoma may metastasize to the neck lymph nodes which many are cystic. Extension of tumor to skull or mediastinum can occur. The additional symptoms include a painful throat, dysphagia, otalgia (due to cranial nerve involvement), foreign body sensation, bleeding, fixation of tongue (infiltration of deep muscles) and trismus (if the pterygoid muscle is involved in the parapharyngeal space). On the other hand, the tumor may also present as a deep red or white fungating wound growing outwards, breaking the skin surface with a central ulceration. This wound-like ulcer fails to heal (non-healing) leading to bleeding and throat pain and other associated symptoms. During biopsy, the lesion may show three signs: Gritty texture, Firmness and cystification owing to keratinization, fribrosis and necrosis respectively.[8] Cervical lymphydenopathy may be present. ## Cause[edit] Smoking and alcohol abuse are the major risk factors.[9] Viral causes has recently been taken under consideration as one of the risk factors. Viruses such as Epstein-Barr virus (EBV) (majorly involved in causing nasopharyngeal carcinoma) and human papilloma virus are included in this category. Chewing of betel nut (Areca catechu) quid has been directly associated to cause oral cancers.[10] It has also been stated under the FDA poisonous plant data base by the U.S Food and Drug Administration [11] An unbalanced diet, deficit in fruits and vegetables has shown to increase the risk of cancer.[12] ## Pathophysiology[edit] Direction of spread Structures involved Along Glossotonsillar sulcus Base of tongue Superior Soft palate or nasopharynx Laterally (Infiltrating through the constrictor muscle) Pharyngeal space, Pterygoid musculature, Mandible Superior spread through parapharyngeal space Base of skull Inferior Lateral neck Extensive spread in parapharyngeal space Carotid artery, Carotid sheath. Metastasis to regional lymphnodes is common as the tonsil has a rich supply of lymphatics giving way to the tumor cells to metastasis to other lymph nodes (commonly the lymph nodes of neck) and cause lymphydenopathy. The cervical lyphydenopathy can be ipsilateral (70% or more patients) or bilateral (30% and fewer patients).[13] The carcinoma of tonsil usually spreads through the cervical lymph node levels II, III, IV, V, and retropharyngeal lymph nodes. The fourth edition of WHO' s classification of head and neck tumors subdivides squamous cell carcinoma of the tonsil into two types: HPV positive or negative. HPV positive tumors arise from the deep lymphoid tissue of the tonsillar crypts and are non-keratinizing. On the other hand HPV negative tumors develop from the tonsillar surface epithelium and hence have keratinizing dysplasia.[14] ### Routes of metastasis[edit] Metastasis is common in tonsillar carcinoma. It largely depends on the stage of the cancer and the route through with the cancer cells metastasize. The cancer cells may spread to adjacent structures, to lymphatics or to distant locations in the body producing secondary tumors. #### Local[edit] The tumor may spread locally to soft palate and pillars, base of tongue, pharyngeal wall and hypopharynx. It may invade pterygoid muscles and mandible, resulting in pain and trismus. Parapharyngeal space may also get invaded.[15] #### Lymphatic[edit] 50% of patients have initial cervical node involvement at the time of presentation. Jugulardigastric nodes are the first to be involved.[15] #### Distant metastasis[edit] The occurrence of distant metastasis varies extensively, ranging between 4%-31% in clinical studies. Factors influencing the incidence of distant metastasis are: * Location of primary tumor. * Initial staging * Histological differentiation * Loco-regional control of the primary tumor. The records of 471 male patients with tonsillar carcinoma seen at the Veterans Administration Medical Center, Hines, Illinois, have been reviewed to establish the incidence and site of distant metastasis. All the patients were histological diagnosed and proven cases of tonsillar carcinoma. 72(15%) out of 471 patients and 33 (29%) of 155 autopsied patients were reported to have distant metastasis. Squamous cell carcinoma was the most common reported cell type (88%); cases with Lymphoepithelioma had the highest incidence of distant metastasis.[16] The most common anatomical sites of incidence of distant metastasis include lung, liver and bones. Thorough investigation of these organs is highly recommended before treatment as well as during follow ups. ## Diagnosis[edit] The first step to diagnosing tonsil carcinoma is to obtain an accurate history from the patient. The physician will also examine the patient for any indicative physical signs. A few tests then, maybe conducted depending on the progress of the disease or if the doctor feels the need for. The tests include: Fine needle aspiration, blood tests, MRI, x-rays and PET scan. ### Staging[edit] The staging of a tumor mass is based on TNM staging.[17] T staging is the based on the tumor mass. The N staging is based on the extent of spread of cancer to the lymph nodes. Finally, the M stage indicates if the cancer has spread beyond the head and neck or not. #### T Staging[edit] The basis of deciding the T stage depends on physical examination and imaging of the tumor. T Stage Tumor Dimension Tx Primary tumor cannot be assessed T0 Primary tumor cannot be located Tis Carcinoma in situ T1 ≤ 2 cm in dimension T2 > 2 cm but ≤ 4 cm in dimension T3 > 4 cm and has grown till the epiglottis T4a Moderately advanced, tumor has grown into larynx, beyond muscles of tongue, hard palate, lower jawbone and/or medial pterygoid muscles T4b Extremely advanced, invasion of lateral pterygoin muscle, pterygoid plates, nasopharynx, into skull base or is encasing the carotid artery. #### N staging[edit] This stage is decided through the assessment of the lymph nodes. N Stage Lymph node dimension Nx No assessment of neck lymph nodes N0 No evidence of spread N1 Ipsilateral, Single lymph node, ≤ 3 cm in size N2a cancer cells have metastasised to a single lymph node, ipsilateral to main tumor, > 3 cm but ≤ 6 cm in size N2b Cancer cells have metastasised to multiple lymph nodes, ipsilateral to mail tumor, > 6 cm in size N2c Detection of lymph nodes in the neck, contralateral or bilateral to the main tumor, >6 cm in size N3 Metastasis of cancer cells to one or more lymph nodes, >6 cm in size #### M staging[edit] Based on the examination of the entire body. M Stage Metastasis beyond Head and neck M0 No evidence M1 Evidence of metastasis to structures outside head and neck present, commonly involved organs are: Lungs, bones, brain FInally, the stage is decided by concluding the above results and referring the following chart: Stage T Stage N Stage M Stage Stage I T1 N0 M0 Stage II T2 N0 M0 Stage III T3 N0 M0 T1 N1 M0 T2 N1 M0 T3 N1 M0 Stage IVA T4a N0 M0 T4a N1 M0 T1 N2 M0 T2 N2 M0 T3 N2 M0 T4a N2 M0 Stage IVB T4b Any N M0 Any T N3 M0 Stage IVC Any T Any N M1 ## Treatment[edit] The treatment for tonsil carcinoma includes the following methods:[18][19] ### Radiotherapy[edit] Early radio-sensitive tumors are treated by radiotherapy along with irradiation of cervical nodes. The radiation uses high-energy X-rays, electron beams, or radioactive isotopes to destroy cancer cells. ### Chemotherapy[edit] Induction chemotherapy is the treatment adapted for shrinking the tonsil tumor. It is given prior to other treatments, hence, the term induction. After the therapy is completed, the patient is asked to rest and is evaluated over a period of time. Then the patient is given chemo-radiation therapy (a combination of chemotherapy and radiation) to completely destroy the tumor cells.[20] ### Surgery[edit] If radiation and chemotherapy are unable to destroy the tumor, surgical intervention is considered.[19] Excision of the tonsil can be done for early superficial lesions. Large lesions and those which invade bone require wide surgical excision with hemimandibulectomy and neck dissection (Commando operation)[15] ### Combination therapy[edit] Surgery may be combined with pre- or post operative radiation. Chemotherapy may be given as an adjunct to surgery or radiation. ## Prognosis[edit] Prognosis is determined by various factors such as stage, Human Papilloma Virus (HPV) status, Lymph infiltration of cancer cells, spread of cancer cells beyond the lymph node capsule, margins of the tumor and the extent of metastasis. Many factors are unique to each individual patient and may affect the chances of success of the treatment. Factors determining the prognosis of tonsillar carcinoma are as follows:[21] ### HPV status[edit] Tonsillar carcinoma can be either HPV related or HPV unrelated. It is shown that cases which are HPV positive have a better prognosis than those with HPV negative oropharyngeal cancer. ### Stage[edit] The stage at which the cancer presents itself affects the type of definitive treatment, chance of cure, recurrence of cancer and survival rate of the patient. Generally the patient presents very late due to the lack of definitive symptoms in the early stages of the disease. Nearly three fourths of the patients present in Stage III or later.[22] The stages of oropharyngeal cancer are as follows:[23] • Stage 0 (carcinoma in situ): This stage indicates a good prognosis as most patients with stage 0 survive for a long period without the requirement of an intensive treatment. Although, the patient must cease smoking as it can increase the risk of developing a new cancer. • Stage I and II: Most patients presenting at this stage receive successful treatment, showing a good prognosis. The modes of treatment for this stage include chemotherapy, surgery, radiation therapy or chemoradiation. The main treatment at this stage is radiation, targeting the tumor and the cervical lymph nodes. Surgical removal of the tumor and lymphadenectomy of the cervical (neck) lymph nodes can also be taken up at the main treatment method instead of radiation. And remaining cancer cells post surgery are treated with chemoradiation. • Stage III and IVA: In this stage the cancer cells metastasize into the local tissues and cervical lymph nodes. The treatment used in these cases is chemo radiation. Any remaining cancer cells post chemoradiation are surgically removed. Lymphadenectomy may also be done after treatment with chemoradiation if the cancer cells have infiltrated the cervical lymph nodes. Another method of treatment includes, first, surgical removal of tumor as well as cervical lymph nodes followed by chemoradiation or radiation to decrease the chances of recurrence. • Stage IVB: In this stage the cancer has already undergone distant metastasis, hence showing poor prognosis. The treatment includes chemotherapy, cetuximab or both. Radiation may be used to aid in relieving symptoms arising from the cancer and also to prevent further development of complications. ### Lymphatic Infiltration[edit] Nearly half of the patients with anterior pillar lesions and three fourths of the patients with tonsillar fossa lesions have nodal metastasis at the time of presentation itself.[22] Metastasis of cancer cells to cervical lymph nodes diminishes the chance of cure. Specially, if there is evidence of metastasis of cancer cells beyond the lymph node capsule. Though, some data indicates that the metastasis of cancer cells outside the lymph node capsule is a bad prognosis for HPV-unrelated oropharynx cancer than it is for HPV-related oropharynx. ### Tumor extension[edit] Extension of the tumor to the base of tongue reduces the chances of cure drastically. It also increases the chances of recurrence after treatment[22] ### Metastasis[edit] Spread of cancer cells to local structures like tissues, vessels, large nerves and lymphatics worsens a patient's prognosis. A study that analyzed the survival rate in HPV-related oropharynx carcinoma to that in HPV-unrelated oropharynx carcinoma. The study revealed that based on the HPV status of the patient, for STAGE III and STAGE IV oropharynx carcinoma, there was a discrepancy in survival after three years. The survival was 82% in HPV positive and then also 57% in HPV negative cancers. ## References[edit] 1. ^ Williamson, Andrew J. (Jan 13, 2019). Cancer, Tonsil. NCBI. StatPearls. PMID 30725923. 2. ^ Seiden, Allen M.; Tami, Thomas A.; Pensak, Myles L.; Cotton, Robin T.; Gluckman, Jack L. Otolaryngology: The Essentials (2002 ed.). Theime Medical Publishers. p. 194. 3. ^ Hodder, Arnold (2006). Logan Turner's Diseases of the Nose, Throat and Ear (10th ed.). JAYPEE. p. 113. ISBN 978-93-5025-943-6. 4. ^ "Tonsil cancer". Cancer Research UK. 2014-08-05. Retrieved 2016-07-16. 5. ^ "Throat cancer (Squamous Cell Carcinoma of the Tonsil)". MyVMC.com. 2003-01-08. Retrieved 2016-07-16. 6. ^ Mankekar, G. (2000). "Tonsillar carcinoma- a review" (PDF). Indian J Otolaryngol Head Neck Surg. 52 (3): 310. doi:10.1007/BF03006216 (inactive 2021-01-17). PMC 3451114. PMID 23119708. Retrieved 25 September 2016.CS1 maint: DOI inactive as of January 2021 (link) 7. ^ "A Non-Profit Hospital in Los Angeles". 8. ^ "Malignant Tonsil Tumor Surgery". Medscape. Niels Kokot, MD Assistant Professor, Residency Program Director, Department of Otolaryngology–Head and Neck Surgery, Keck School of Medicine of the University of Southern California. Retrieved 25 September 2016. 9. ^ "Malignant Tonsil Tumor Surgery". Medscape. Niels Kokot, MD Assistant Professor, Residency Program Director, Department of Otolaryngology–Head and Neck Surgery, Keck School of Medicine of the University of Southern California. Retrieved 25 September 2016. 10. ^ Warnakulasuriya, Saman; Trivedy, Chetan; Peters, Timothy J (5 April 2002). "Areca nut use: an independent risk factor for oral cancer". BMJ. 324 (7341): 799–800. doi:10.1136/bmj.324.7341.799. PMC 1122751. PMID 11934759. 11. ^ "Second report of the expert advisory committee on herbs and botanical preparations". FDA. Retrieved 26 September 2016. 12. ^ Key, T J (3 January 2011). "Fruit and vegetables and cancer risk". British Journal of Cancer. 104 (1): 6–11. doi:10.1038/sj.bjc.6606032. PMC 3039795. PMID 21119663. 13. ^ "Oropharyngeal Cancer Treatment (PDQ®)–Health Professional Version". National Cancer Institute. 1980-01-01. Retrieved 25 September 2016. 14. ^ Westra, William H.; Lewis, James S. (2017-02-28). "Update from the 4th Edition of the World Health Organization Classification of Head and Neck Tumours: Oropharynx". Head and Neck Pathology. 11 (1): 41–47. doi:10.1007/s12105-017-0793-2. ISSN 1936-055X. PMC 5340734. PMID 28247229. 15. ^ a b c Dhingra (2013-10-01). Diseases of Ear, Nose and Throat and Neck Surgeries (6th ed.). Elsiver. p. 271. ISBN 978-81-312-3431-0. 16. ^ Chung TS, Stefani S (1980). "Distant metastases of carcinoma of tonsillar region: a study of 475 patients". Journal of Surgical Oncology. 14 (1): 5–9. doi:10.1002/jso.2930140103. PMID 7382512. S2CID 26204372. 17. ^ "Determining the Stage of the Cancer". Head and Neck Cancer Guide. Retrieved 25 September 2016. 18. ^ Dhingra, PL (2014). Diseases of Ear, Nose and Throat & Head and Neck Surgeries (6th ed.). Elsiver. ISBN 978-81-312-3431-0. 19. ^ a b "Tonsil Cancer". 20. ^ Vokes EE (2010). "Induction chemotherapy for head and neck cancer: recent data". The Oncologist. 15 (Suppl 3): 3–7. doi:10.1634/theoncologist.2010-S3-03. PMID 21036882. 21. ^ "Tonsil cancer". Head And Neck Cancer guide. 22. ^ a b c Mankekar, G. (January 2002). "Tonsillar carcinoma: A review". Indian Journal of Otolaryngology and Head and Neck Surgery. 54 (1): 67. doi:10.1007/BF02911013 (inactive 2021-01-17). ISSN 2231-3796. PMC 3450683. PMID 23119859.CS1 maint: DOI inactive as of January 2021 (link) 23. ^ "Treatment options for oral cavity and oropharyngeal cancer by stage". The American Cancer Society. ## External links[edit] Classification D * ICD-10: Xxx.x * ICD-9-CM: xxx [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA [kDa]: kilodalton [EPC]: Early Prostate Cancer [LAPC]: locally advanced prostate cancer [NSAAs]: nonsteroidal antiandrogens [NSAA]: nonsteroidal antiandrogen [GnRH]: gonadotropin-releasing hormone [ADT]: androgen deprivation therapy [LH]: luteinizing hormone [AR]: androgen receptor [CAB]: combined androgen blockade [LPC]: localized prostate cancer [CPA]: cyproterone acetate [U.S.]: United States [FDA]: Food and Drug Administration	Tonsil carcinoma	c0558355	7,843	wikipedia	https://en.wikipedia.org/wiki/Tonsil_carcinoma	2021-01-18T19:06:04	{"umls": ["C0558355"], "wikidata": ["Q18553563"]}
A rare primary immunodeficiency characterized by increased susceptibility to infection by human papillomavirus, presenting in childhood with disseminated flat wart-like cutaneous lesions. Burkitt lymphoma has also been reported. Whilst total T-cell counts are normal, there is impaired TCR signaling, profound peripheral naive T-cell lymphopenia with memory T-cells displaying an exhaustion phenotype. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA [kDa]: kilodalton [EPC]: Early Prostate Cancer [LAPC]: locally advanced prostate cancer [NSAAs]: nonsteroidal antiandrogens [NSAA]: nonsteroidal antiandrogen [GnRH]: gonadotropin-releasing hormone [ADT]: androgen deprivation therapy [LH]: luteinizing hormone [AR]: androgen receptor [CAB]: combined androgen blockade [LPC]: localized prostate cancer [CPA]: cyproterone acetate [U.S.]: United States [FDA]: Food and Drug Administration	T-cell immunodeficiency with epidermodysplasia verruciformis	None	7,844	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=324294	2021-01-23T17:50:41	{"omim": ["618307"], "icd-10": ["D84.8"], "synonyms": ["T-cell immunodeficiency due to RHOH deficiency"]}
## Clinical Features Somech et al. (2008) described 2 sisters, born of first-cousin parents of Sri Lankan descent, who presented in infancy with immunodeficiency, gonadal dysgenesis, and fatal pulmonary fibrosis. The infants displayed no dysmorphic features. Immune studies demonstrated combined humoral and cellular abnormalities including reduced immunoglobulin production, absence of lymphoid tissue, markedly reduced T lymphocyte numbers and function, and reduced newly thymus-derived T cells. Both infants succumbed to rapidly progressive pulmonary fibrosis; autopsy revealed streak ovaries bearing no discernible oocytes. Molecular Genetics In 2 sisters with normal 46,XX karyotype and immunodeficiency, gonadal dysgenesis, and fatal pulmonary fibrosis, Somech et al. (2008) performed FISH analysis that showed no deletion or duplication for the X centromeric region, the SRY gene (480000), and chromosome 22q11.2. Analysis of genes known to be associated with severe immune defects in infancy (IL7R, 146661; JAK3, 600173; CD3, see 186740) and ovarian dysgenesis (FSHR; 136435) showed no abnormality. INHERITANCE \- Autosomal recessive HEAD & NECK Neck \- Atrophic thymus CARDIOVASCULAR Heart \- Atrial septal defect, secundum type RESPIRATORY Nasopharynx \- Absent tonsils Lung \- Interalveolar fibrosis, rapidly progressive ABDOMEN Gastrointestinal \- Mucosal lymphoid tissue markedly reduced GENITOURINARY Internal Genitalia (Female) \- Streak ovaries with no discernable oocytes IMMUNOLOGY \- Reduced CD3+, CD4+, and CD8+ T-lymphocytes \- Normal numbers of CD19+ B-lymphocytes \- Normal numbers of CD56+ natural killer cells \- Low IgG \- Undetectable IgM and IgA MISCELLANEOUS \- Death due to rapidly progressive pulmonary fibrosis in infancy ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA [kDa]: kilodalton [EPC]: Early Prostate Cancer [LAPC]: locally advanced prostate cancer [NSAAs]: nonsteroidal antiandrogens [NSAA]: nonsteroidal antiandrogen [GnRH]: gonadotropin-releasing hormone [ADT]: androgen deprivation therapy [LH]: luteinizing hormone [AR]: androgen receptor [CAB]: combined androgen blockade [LPC]: localized prostate cancer [CPA]: cyproterone acetate [U.S.]: United States [FDA]: Food and Drug Administration	IMMUNODEFICIENCY, OVARIAN DYSGENESIS, AND PULMONARY FIBROSIS	c3150156	7,845	omim	https://www.omim.org/entry/611926	2019-09-22T16:02:37	{"omim": ["611926"], "orphanet": ["137631"], "synonyms": []}
Shingles (also known as herpes zoster) results from infection by the varicella zoster virus. This common virus causes chickenpox (also known as varicella), which is characterized by itchy spots on the skin that cover the whole body and usually occurs in childhood or adolescence. After the body fights the initial infection, the varicella zoster virus remains in nerve cells for the rest of a person's life. Because the virus is controlled by immune system cells called T cells, it is generally inactive (latent) and typically causes no health problems. However, in some people, the virus becomes active again (reactivates) and causes shingles. Shingles can occur at any age, although it is rare in childhood and becomes more common after age 50. Shingles is characterized by a severely painful, itchy, or tingling rash, most commonly on one side of the torso, although it can occur anywhere on the body. Reactivation of the virus usually occurs in a single nerve, leading to the symptoms of shingles in just the region of skin connected to that nerve. When the nerve connected to the eye and the skin surrounding it is affected, the condition is called herpes zoster ophthalmicus. This form of shingles, which accounts for about 20 percent of cases, can cause permanent vision impairment. Some individuals with shingles feel throbbing or tingling in the affected region shortly before the rash appears. Blisters form in the rash area, break open, and scab over in a few days. Healing usually takes 2 to 4 weeks. Most people have only one episode of shingles, although it can recur in rare cases. In 5 to 20 percent of people with shingles, severe pain continues in the affected region after healing of the rash, which is known as postherpetic neuralgia (PHN). PHN is the most common complication of shingles. It can also involve severe itchiness or an overactive pain response to things that do not usually cause pain (allodynia), such as a light touch. PHN can last weeks, months, or even years. The likelihood of developing PHN after shingles and its severity increase with age. The pain caused by shingles and PHN can disrupt day-to-day activities and reduce a person's quality of life. ## Frequency Because everyone infected with the varicella zoster virus is at risk of developing shingles, the condition is relatively common, particularly in older adults. Shingles occurs in 20 to 30 percent of people at some point in their lives, and about half of people over age 80 have had shingles. The risk of shingles varies by ethnic background. The condition is more common in people of non-Hispanic white ancestry than those of African American ancestry. For unknown reasons, women are more prone to develop shingles than men. A vaccine to prevent chickenpox was introduced in the United States in 1995. Since then, the incidence of chickenpox has been reduced by 76 to 85 percent. Doctors suspect the reduction of varicella zoster virus infections will reduce the incidence of shingles as the vaccinated children grow into adulthood; however, it is too early to tell. Vaccines for adults to protect against shingles and subsequent PHN have been used since 2006 and are also expected to reduce the incidence of shingles and its complications. ## Causes The causes of shingles are complex. Development of the condition is influenced by a combination of factors, including age, health, and genetics. The strongest risk factor for shingles is age. The varicella zoster virus is controlled by the immune system, particularly T cells that keep the virus from infecting other cells. As people age, growth and division (proliferation) of T cells are diminished, reducing the immune system's ability to control the virus, which can allow its reactivation. Health factors that impair T cells can also trigger reactivation of the varicella zoster virus. For example certain drugs, such as chemotherapies used to treat blood cancers like multiple myeloma or drugs that prevent rejection of a transplanted organ, impair the immune system and can lead to virus reactivation. Infection with human immunodeficiency virus (HIV), which infects and kills T cells, can also allow the virus to become active again. In addition, some studies suggest that emotional stress or physical trauma may be involved in virus reactivation. The role of genetics in shingles is not clear. Several studies indicate that having a family member who developed the condition increases a person's risk, suggesting a shared genetic risk factor, although other studies did not find such a link. Genes that help regulate the immune system have been found in some studies to be associated with the development of shingles or of PHN after shingles. In particular, the risk of developing PHN appears to be increased by certain variants of genes that belong to a family of genes called the human leukocyte antigen (HLA) complex. The HLA complex helps the immune system distinguish the body's own proteins from proteins made by foreign invaders such as viruses and bacteria. It is unclear if certain HLA variations also play a role in the development of shingles. ### Learn more about the genes associated with Shingles * HLA-B * POLR3A * STAT1 * STAT3 Additional Information from NCBI Gene: * HLA-A * IL10 * POLR3C ## Inheritance Pattern The inheritance pattern of shingles is unclear. Having a first-degree relative (such as a parent or sibling) who developed shingles appears to slightly increase the risk of developing the condition. However, shingles is relatively common in the general population, particularly among older adults, and so it would not be surprising to see more than one case in a family just by chance. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA [kDa]: kilodalton [EPC]: Early Prostate Cancer [LAPC]: locally advanced prostate cancer [NSAAs]: nonsteroidal antiandrogens [NSAA]: nonsteroidal antiandrogen [GnRH]: gonadotropin-releasing hormone [ADT]: androgen deprivation therapy [LH]: luteinizing hormone [AR]: androgen receptor [CAB]: combined androgen blockade [LPC]: localized prostate cancer [CPA]: cyproterone acetate [U.S.]: United States [FDA]: Food and Drug Administration	Shingles	c0019360	7,846	medlineplus	https://medlineplus.gov/genetics/condition/shingles/	2021-01-27T08:24:49	{"gard": ["7525"], "mesh": ["D006562"], "synonyms": []}
## Summary ### Clinical characteristics. SPTBN4 disorder is typically characterized by severe-to-profound developmental delay and/or intellectual disability, although two individuals in one family had a milder phenotype, including one individual with normal cognitive development. Speech and language skills are often severely limited. Affected individuals rarely achieve head control. Most are unable to sit, stand, or walk. Affected individuals typically have congenital hypotonia that may transition to hypertonia. Axonal motor neuropathy leads to hyporeflexia/areflexia and weakness, which can result in respiratory difficulties requiring ventilatory support. Most affected individuals require tube feeding for nutrition. Half of affected individuals develop seizures. Cortical visual impairment and auditory neuropathy have also been reported. ### Diagnosis/testing. The diagnosis of SPTBN4 disorder is established in a proband with congenital hypotonia and biallelic pathogenic variants in SPTBN4 identified by molecular genetic testing. ### Management. Treatment of manifestation: Hearing aids may be helpful for those with hearing loss; ventilator support (e.g., BiPAP) for respiratory distress; consideration of Robinul® or Botox® injections for severe sialorrhea; feeding therapy and consideration of gastrostomy tube placement for persistent feeding difficulties and/or concern about aspiration; standard treatment for developmental delay/intellectual disability, epilepsy, cortical vision impairment, constipation, and spasticity / joint contractures. Surveillance: Assessment for new neurologic manifestations and/or adequacy of seizure control, developmental progress, growth and nutritional status, constipation, and joint mobility at each visit; ophthalmology evaluation every one to two years in those with optic atrophy; audiology evaluation as clinically indicated; sleep study every one to two years. ### Genetic counseling. SPTBN4 disorder is inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Once the SPTBN4 pathogenic variants have been identified in an affected family member, carrier testing for at-risk relatives, prenatal testing for a pregnancy at increased risk, and preimplantation genetic testing are possible. ## Diagnosis Formal clinical diagnostic criteria for SPTBN4 disorder have not been established. However, affected individuals often have profound congenital neurologic deficits (including hypotonia, neuromuscular weakness, hyporeflexia/areflexia), severe cognitive delays, and seizures. ### Suggestive Findings SPTBN4 disorder should be considered in individuals with the following clinical, supportive laboratory, imaging, and functional findings. Clinical findings * Severe-to-profound developmental delay / intellectual disability * Congenital hypotonia * Neuromuscular weakness * Loss of deep tendon reflexes indicative of neuropathy * Epilepsy, including both focal and/or generalized seizures (infantile spasms) * Cortical visual impairment * Hearing impairment characterized as central deafness or auditory neuropathy * Respiratory difficulties * Feeding difficulties Supportive laboratory findings * Normal serum CK level * Muscle biopsy findings consistent with a neurogenic process with evidence of denervation, including fiber type disproportion and/or neurogenic changes Note: Muscle biopsy is not required to establish the diagnosis. Imaging findings. Brain MRI ranging from normal during the neonatal/early-infancy period to nonspecific changes including delayed myelination, thin corpus callosum, prominent ventricles, and atrophy in older children and adults Functional findings * Electromyography (EMG) / nerve conduction studies (NCS) demonstrating an axonal motor neuropathy/neuronopathy * Abnormal auditory brain stem response (ABR) suggestive of auditory neuropathy ### Establishing the Diagnosis The diagnosis of SPTBN4 disorder is established in a proband with congenital hypotonia and biallelic pathogenic variants in SPTBN4 identified by molecular genetic testing (see Table 1). Because the phenotype of SPTBN4 disorder overlaps with many other inherited disorders with congenital hypotonia and neuromuscular weakness, a broad molecular genetic testing approach is often required, including use of a multigene panel or comprehensive genomic testing (exome sequencing). Note: Single-gene testing (sequence analysis of SPTBN4, followed by gene-targeted deletion/duplication analysis) is rarely useful and typically NOT recommended. A hypotonia, neuropathy, intellectual disability, and/or epilepsy multigene panel that includes SPTBN4 and other genes of interest (see Differential Diagnosis) is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests. For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here. Comprehensive genomic testing (which does not require the clinician to determine which gene[s] are likely involved) is another good option. Exome sequencing is most commonly used; genome sequencing is also possible. For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here. ### Table 1. Molecular Genetic Testing Used in SPTBN4 Disorder View in own window Gene 1MethodProportion of Pathogenic Variants 2 Detectable by Method SPTBN4Sequence analysis 314/14 4, 5 Gene-targeted deletion/duplication analysis 6None reported 7 1\. See Table A. Genes and Databases for chromosome locus and protein. 2\. See Molecular Genetics for information on allelic variants detected in this gene. 3\. Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here. 4\. Anazi et al [2017], Knierim et al [2017], Wang et al [2018], Monies et al [2019], Pehlivan et al [2019], Häusler et al [2020] 5\. To date, 14 different pathogenic variants have been described in 12 families; 8 are truncating variants, 4 are missense, and 2 are splice variants. The majority of affected individuals reported to date are homozygous (12/14). 6\. Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. 7\. Data derived from the subscription-based professional view of Human Gene Mutation Database [Stenson et al 2017] ## Clinical Characteristics ### Clinical Description To date, 14 individuals from 12 families have been reported with pathogenic variants in SPTBN4 [Anazi et al 2017, Knierim et al 2017, Wang et al 2018, Monies et al 2019, Pehlivan et al 2019, Häusler et al 2020]. The following description of the phenotypic features associated with this condition is based on these reports. ### Table 2. Features of SPTBN4 Disorder View in own window Feature# of Persons w/FeatureComment Congenital hypotonia14/14 (100%) Neuromuscular weakness14/14 (100%)1 affected person reported w/some ambulation 1 Areflexia/Neuropathy13/14 (93%) Developmental delay / Intellectual disability13/14 (93%) * Typically severe to profound * 1 affected person reported w/normal cognitive development & 1 w/mild gross motor & speech delay at age 2 yrs 5 mos 1 Feeding difficulties9/14 (64%) Respiratory difficulties8/14 (57%) Visual impairment6/14 (43%) Joint contractures5/14 (36%) * Time of onset variable * Congenital arthrogryposis in at least 2 persons * Progressive spasticity & contractures also observed in at least 2 persons [Wang et al 2018] Seizures5/14 (36%) Hearing loss4/14 (29%)Typically due to an auditory neuropathy In most reports the phenotypic details were limited and pertinent negatives were often not provided. Therefore, the number of individuals with a specific clinical feature likely represents a minimum proportion. 1\. Häusler et al [2020] Developmental delay / intellectual disability. A vast majority of affected individuals reported to date have had severe-to-profound developmental delay and/or intellectual disability. Affected individuals rarely achieve head control. Most are unable to sit, stand, or walk. Speech and language skills are also severely limited, with very few reported individuals to date developing verbal language. In a recently reported family with two affected individuals, one individual had normal cognitive ability, including receptive language skills [Häusler et al 2020]. Neurologic * Hypotonia is typically congenital and does not improve significantly over time. Some affected individuals may progress to develop appendicular hypertonia while axial tone remains low. * Neuropathy. Hyporeflexia or areflexia due to axonal motor neuropathy and weakness on exam have been reported. Areflexia may be present at birth or becomes evident with age, suggesting a progressive neuropathy. * Seizures. About half of affected individuals develop epilepsy, including generalized seizures (infantile spasms) and drug-resistant epilepsy. No clear preferred medications to treat epilepsy are known at this point. * Brain MRI findings are variable and nonspecific, including thin corpus callosum. In the few affected individuals with serial imaging there has been evidence of cortical atrophy and prominent CSF spaces over time. One affected individual had prenatally identified hydrocephalus on ultrasound [Pehlivan et al 2019]. Growth. Details about growth have not been systematically reported. Anazi et al [2017] reported weight, height, and head circumference as below the third centile in a single affected individual, while Pehlivan et al [2019] reported an affected individual with normal length, but weight and head circumference well below the third centile (3.9 SD below the mean for length and 6.6 SD below the mean for head circumference). Eyes. Cortical visual impairment is common. Reports of optic atrophy are rare and it is unclear if this is progressive. Affected individuals are not known to have retinal involvement but this has not been thoroughly evaluated. Hearing. Auditory neuropathy leading to hearing loss has been reported. Respiratory difficulties. Affected children may need ventilator support due to neuromuscular weakness. Respiratory issues do not appear to be due to primary lung pathology. Many children also experience sialorrhea (excessive salivation or drooling), which needs to be monitored and managed due to aspiration risk. Two reported individuals died of respiratory failure. Feeding difficulties. Dysphagia usually results from hypotonia and neuromuscular weakness. Most affected individuals reported to date received nutrition via feeding tube due to aspiration risk. Musculoskeletal. Scoliosis due to neuromuscular weakness has been reported. Joint contractures (including congenital arthrogryposis) and spasticity (likely secondary to neuropathy) also occur. Nonspecific dysmorphic features. Myopathic facies and highly arched palate have been noted in four affected individuals [Knierim et al 2017, Pehlivan et al 2019, Häusler et al 2020]. ### Genotype-Phenotype Correlations No genotype-phenotype correlations have been identified. ### Prevalence The prevalence of this condition is unknown. To date, only 14 individuals from 12 families have been reported in the literature. Most affected individuals reported to date have been from consanguineous families. ## Differential Diagnosis ### Table 3. Genes of Interest in the Differential Diagnosis of SPTBN4 Disorder View in own window Gene(s) / Genetic MechanismDisorderMOIFeatures of Differential Diagnosis Disorder Overlapping w/SPTBN4 DisorderDistinguishing from SPTBN4 Disorder Abnormal parent-specific imprinting 1Prader-Willi syndromeSee footnote 2.Congenital hypotonia, poor feedingHyperphagia, obesity, cognitive delay in childhood CRPPA 2 DAG1 FKRP FKTN 3 LARGE1 POMGNT1 POMT1 POMT2Muscular dystrophy-dystroglycanopathy, type A (OMIM PS236670)ARCongenital hypotonia w/cognitive delays, often assoc w/hyporeflexia * ↑ CK * Congenital brain malformations on MRI * Typically normal hearing DMPKMyotonic dystrophy type 1ADCongenital hypotonia, weakness, & cognitive delaysMyotonia, cataracts SMN1Spinal muscular atrophyARCongenital hypotonia, areflexia, & nonspecific dysmorphic featuresNormal cognition & hearing TBCKHypotonia, infantile, w/psychomotor delay, & characteristic facies 3 (OMIM 616900)ARCongenital hypotonia w/hyporeflexia, cognitive delays, & seizures * White matter changes on MRI * Normal hearing UFC1Neurodevelopmental disorder w/spasticity & poor growth (OMIM 618076)ARContractures, hypotonia, delayed psychomotor development, inability to sit or walk, poor or absent speech, poor head control, seizures, poor feedingSignificant growth deficiency UNC80UNC80 deficiencyARCongenital hypotonia, developmental delay, seizures, poor feedingDysmorphic facial features & skull deformities AR = autosomal recessive; AD = autosomal dominant; MOI = mode of inheritance 1\. Prader-Willi syndrome (PWS) is caused by an absence of expression of imprinted genes in the paternally derived PWS/Angelman syndrome (AS) region of chromosome 15 by one of several genetic mechanisms (paternal deletion, maternal uniparental disomy 15, and rarely an imprinting defect). The risk to the sibs of an affected child of having PWS depends on the genetic mechanism that resulted in the absence of expression of the paternally contributed 15q11.2-q13 region. 2\. Listed genes represent a subset of those associated with muscular dystrophy-dystroglycanopathy, type A; for other genes associated with this phenotype in OMIM see Phenotypic Series: Muscular dystrophy-dystroglycanopathy, type A. 3\. See Fukuyama Congenital Muscular Dystrophy. ## Management ### Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with SPTBN4 disorder, the evaluations summarized in Table 4 (if not performed as part of the evaluation that led to the diagnosis) are recommended. ### Table 4. Recommended Evaluations Following Initial Diagnosis in Individuals with SPTBN4 Disorder View in own window System/ConcernEvaluationComment NeurologicNeurologic evalConsider EEG if seizures a concern. DevelopmentDevelopmental assessment * Incl motor, adaptive, cognitive, & speech/language eval. * Evaluate for early intervention / special education. EyesOphthalmologic evalTo assess for ↓ vision, cortical visual impairment, & optic nerve abnormalities HearingAudiologic eval * Incl BAER/ABR. * To assess for hearing loss & auditory neuropathy RespiratorySleep study * Risk of nocturnal hypoventilation due to neuromuscular weakness * May require ventilatory support Gastrointestinal/ FeedingGastroenterology / nutrition / feeding team eval * Incl eval of aspiration risk & nutritional status. * Consider eval for gastric tube placement if concern for dysphagia &/or aspiration risk. MusculoskeletalOrthopedist / physical medicine & rehab / PT/OT evalIncl assessment of: * Gross motor & fine motor skills; * Contractures, clubfoot, & kyphoscoliosis; * Need for adaptive devices; * Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills). Genetics/ OtherConsult w/clinical geneticist &/or genetic counselorIncl genetic counseling. Family support / resourcesAssess: * Use of community or online resources such as Parent To Parent; * Need for social work involvement for parental support; * Need for home nursing referral. ABR = auditory brainstem response; BAER = brain stem auditory evoked potential; OT = occupational therapy; PT = physical therapy ### Treatment of Manifestations ### Table 5. Treatment of Manifestations in Individuals with SPTBN4 Disorder View in own window Manifestation/ConcernTreatmentConsiderations/Other Developmental delay / Intellectual disabilitySee Developmental Delay / Intellectual Disability Management Issues. EpilepsyStandardized treatment w/AEDs by experienced neurologist * Many AEDs may be effective; none has been demonstrated effective specifically for this disorder. * A ketogenic diet has been used safely in at least 1 affected person [X Ortiz-Gonzalez, personal experience]. * Education of parents/caregivers 1 Cortical visual impairment * No specific treatment * Early intervention to help stimulate visual development Hearing lossHearing aids may be helpful per otolaryngologist.Community hearing services through early intervention or school district Respiratory distress/failureVentilatory support (e.g., BiPAP) as needed SialorrheaConsider medical mgmt (Robinul® or Botox® injections) if severe. Poor weight gain / Failure to thrive * Feeding therapy * Gastrostomy tube placement may be required for persistent feeding issues. Low threshold for clinical feeding eval &/or radiographic swallowing study when showing clinical signs or symptoms of dysphagia Bowel dysfunctionStool softeners, prokinetics, osmotic agents, or laxatives as needed for constipation Spasticity / Joint contracturesOrthopedist / physical medicine & rehabilitation / PT/OT incl stretching * To help avoid contractures & falls * Consider need for positioning & mobility devices, disability parking placard. Family / Community * Ensure appropriate social work involvement to connect families w/local resources, respite, & support. * Care coordination to manage multiple subspecialty appointments, equipment, medications, & supplies * Ongoing assessment for need of palliative care involvement &/or home nursing * Consider involvement in adaptive sports or Special Olympics. AED = antiepileptic drugs; OT = occupational therapy; PT = physical therapy 1\. Education of parents regarding common seizure presentations is appropriate. For information on nonmedical interventions and coping strategies for parents or caregivers of children diagnosed with epilepsy, see Epilepsy & My Child Toolkit. #### Developmental Disability / Intellectual Disability Management Issues The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country. Ages 0-3 years. Referral to an early intervention program is recommended for access to occupational, physical, speech, and feeding therapy as well as infant mental health services, special educators, and sensory impairment specialists. In the US, early intervention is a federally funded program available in all states that provides in-home services to target individual therapy needs. Ages 3-5 years. In the US, developmental preschool through the local public school district is recommended. Before placement, an evaluation is made to determine needed services and therapies and an individualized education plan (IEP) is developed for those who qualify based on established motor, language, social, or cognitive delay. The early intervention program typically assists with this transition. Developmental preschool is center based; for children too medically unstable to attend, home-based services are provided. All ages. Consultation with a developmental pediatrician is recommended to ensure the involvement of appropriate community, state, and educational agencies (US) and to support parents in maximizing quality of life. Some issues to consider: * Individualized education plan (IEP) services: * An IEP provides specially designed instruction and related services to children who qualify. * IEP services will be reviewed annually to determine if any changes are needed. * As required by special education law, children should be in the least restrictive environment feasible at school and included in general education as much as possible and when appropriate. * Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. * PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. * As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. * A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. * Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. * Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. #### Motor Dysfunction Gross motor dysfunction * Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation). * Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers). * For muscle tone abnormalities including hypertonia, consider involving appropriate specialists to aid in management of baclofen, Botox®, or orthopedic procedures. Fine motor dysfunction. Occupational therapy is recommended for difficulty with fine motor skills that affect adaptive function such as feeding, grooming, dressing, and writing. Oral motor dysfunction should be assessed at each visit and clinical feeding evaluations and/or radiographic swallowing studies should be obtained for choking/gagging during feeds, poor weight gain, frequent respiratory illnesses, or feeding refusal that is not otherwise explained. Assuming that the individual is safe to eat by mouth, feeding therapy (typically from an occupational or speech therapist) is recommended to help improve coordination or sensory-related feeding issues. Feeds can be thickened or chilled for safety. When feeding dysfunction is severe, an NG-tube or G-tube may be necessary. Communication issues. Consider evaluation for alternative means of communication (e.g., Augmentative and Alternative Communication [AAC]) for individuals who have expressive language difficulties. An AAC evaluation can be completed by a speech language pathologist who has expertise in the area. The evaluation will consider cognitive abilities and sensory impairments to determine the most appropriate form of communication. AAC devices can range from low-tech, such as picture exchange communication, to high-tech, such as voice generating devices. Contrary to popular belief, AAC devices do not hinder verbal development of speech and in many cases, can improve it. ### Surveillance ### Table 6. Recommended Surveillance for Individuals with SPTBN4 Disorder View in own window System/ConcernEvaluationFrequency EyesOphthalmologic evalEvery 1-2 yrs if optic atrophy is present; otherwise as needed if new concerns arise HearingAudiologic evalAs clinically indicated RespiratorySleep studyEvery 1-2 yrs Monitor for evidence of aspiration, respiratory insufficiencyAt each visit Neurologic * Monitor those w/seizures as clinically indicated. * Assess for new manifestations incl seizures & changes in tone. DevelopmentMonitor developmental progress & educational needs. Feeding * Measurement of growth parameters * Eval of nutritional status & safety of oral intake GastrointestinalMonitor for constipation. MusculoskeletalPhysical medicine, OT/PT assessment of mobility, self-help skills Miscellaneous / OtherAssess family need for social work support (e.g., palliative/respite care, home nursing, other local resources) & care coordination. OT = occupational therapy; PT = physical therapy ### Evaluation of Relatives at Risk See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes. ### Therapies Under Investigation Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA [kDa]: kilodalton [EPC]: Early Prostate Cancer [LAPC]: locally advanced prostate cancer [NSAAs]: nonsteroidal antiandrogens [NSAA]: nonsteroidal antiandrogen [GnRH]: gonadotropin-releasing hormone [ADT]: androgen deprivation therapy [LH]: luteinizing hormone [AR]: androgen receptor [CAB]: combined androgen blockade [LPC]: localized prostate cancer [CPA]: cyproterone acetate [U.S.]: United States [FDA]: Food and Drug Administration	SPTBN4 Disorder	c0442874	7,847	gene_reviews	https://www.ncbi.nlm.nih.gov/books/NBK559435/	2021-01-18T20:58:31	{"synonyms": ["Neurodevelopmental Disorder with Hypotonia", "Neuropathy", "and Deafness (NEDHND)"]}
Congenital central hypoventilation syndrome (CCHS) is a disorder of the autonomic nervous system that affects breathing. It causes a person to hypoventilate (especially during sleep), resulting in a shortage of oxygen and a buildup of carbon dioxide in the blood. It have two forms of presentation, a classic form that usually begin shortly after birth in newborns, and a milder later-onset presentaition in toddlers, children and adults. Affected infants hypoventilate upon falling asleep and exhibit a bluish appearance of the skin or lips (cyanosis). Other features may include difficulty regulating heart rate and blood pressure; decreased perception of pain; low body temperature; sporadic profuse sweating; Hirschsprung disease; constipation; learning difficulties; eye abnormalities; and a characteristic facial appearance (having a short, wide, somewhat flattened face). They can also have tumors of neural crest origin, such as neuroblastoma, ganglioneuroblastoma, and ganglioneuroma. The later-onset form is milder, and some cases may present as infants and children who die suddenly and unexpectedly (“SIDS” and “sudden unexplained death of childhood [SUDC]”). CCHS is caused by a variation (mutation) in the PHOX2B gene and is inherited in an autosomal dominant manner. However, over 90% of cases are due to a new mutation in the affected person and are not inherited from a parent. Diagnosis is made with the clinical symptoms and the genetic test showing the variation in the PHOX2B gene. Treatment typically includes mechanical ventilation or use of a diaphragm pacemaker. People who have been diagnosed as newborns and adequately ventilated throughout childhood may reach the age of 20 to 30 years, and can live independently. In the later-onset form, people who were diagnosed when they were 20 years or older have now reached the age of 30 to 55 years. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA [kDa]: kilodalton [EPC]: Early Prostate Cancer [LAPC]: locally advanced prostate cancer [NSAAs]: nonsteroidal antiandrogens [NSAA]: nonsteroidal antiandrogen [GnRH]: gonadotropin-releasing hormone [ADT]: androgen deprivation therapy [LH]: luteinizing hormone [AR]: androgen receptor [CAB]: combined androgen blockade [LPC]: localized prostate cancer [CPA]: cyproterone acetate [U.S.]: United States [FDA]: Food and Drug Administration	Congenital central hypoventilation syndrome	c1275808	7,848	gard	https://rarediseases.info.nih.gov/diseases/8535/congenital-central-hypoventilation-syndrome	2021-01-18T18:01:11	{"mesh": ["C536209"], "omim": ["209880"], "orphanet": ["661"], "synonyms": ["CCHS", "Idiopathic congenital central alveolar hypoventilation", "Congenital failure of autonomic control", "Primary alveolar hypoventilation", "Congenital Ondine curse", "Ondine's curse (formerly)", "Ondine curse (formerly)"]}
Kennedy's disease, also known as bulbospinal muscular atrophy (BSMA), is a rare X-linked recessive motor neuron disease characterized by proximal and bulbar muscle wasting. ## Epidemiology The prevalence of BSMA is 1/30,000 male births. The incidence is 1/526,315 males/year. ## Clinical description Disease onset occurs between 30-60 years of age. Initial clinical manifestations include tremor, muscle cramps, muscle twitching, fatigue and slurred speech. With disease progression patients additionally develop weakness and wasting of the limb and bulbar muscles, manifesting as dysarthria, dysphonia, hanging jaw, tongue wasting, chewing difficulty and impaired mobility. Intellectual decline is minimal to none. In the terminal stages of the disease some patients may be unable to swallow or breathe. Non-neurological manifestations include gynecomastia, hypogonadism (leading to infertility and impotence) and in rare cases Dupuytren's contracture, or groin hernia. ## Etiology BSMA is caused by an unstable expansion of a CAG triplet repeat (40-62 repeats) in exon 1 of the androgen receptor (AR) gene on chromosome Xq11-12. The abnormally increased repetition of this CAG triplet leads to an expanded stretch of glutamines within the androgen-receptor (AR). Polyglutamine-expansion results in misfolding and proteolysis of the mutated AR, rendering it insensitive to androgen hormones. In the nucleus AR fragments are produced, which aggregate and these aggregates are believed to cause dysregulation of the transcription of various other proteins and consecutively lead to motor neuron degeneration. Without a sufficient number of motor neurons, initiation and maintenance of muscle contractions can no longer occur, leading to progressive muscle wasting. Recently, a BSMA phenotype with distal predominance of limb weakness and wasting has been reported, caused by mutations in a subunit of the dynactin 1 DCTN1 gene. ## Diagnostic methods Diagnosis is established upon medical history, clinical examination, elevated creatine-kinase, testosterone, progesterone, follicle-stimulating hormone, luteinizing hormone, reduced nerve conduction velocities or reduced nerve action potential amplitudes, acute or chronic denervation and re-innervation on electromyography and documentation of the mutation. ## Differential diagnosis Differential diagnoses include hereditary spastic paraplegia, spinocerebellar ataxia (see these terms), other motor neuron diseases, myopathies, neuropathies, lead or aluminum poisoning, and cervical spondylosis. ## Antenatal diagnosis Antenatal diagnosis is possible for mothers carrying the mutation. ## Genetic counseling Female mutation carriers usually do not manifest clinically but have a 50% risk to transmit the mutation to their male and female offspring. Affected males do not transmit the disease but 100% of their daughters become mutation carriers. ## Management and treatment Symptomatic treatment includes physiotherapy and rehabilitation, agents against tremor and muscle cramps and hormone therapy or surgical treatment of gynecomastia. Recently, treatment of patients with the anti-testosterone leuprorelin was found to be beneficial. In advanced stages of the disease, tube feeding or ventilatory support may be indicated. ## Prognosis Disease progression is slow with only one third of patients requiring a wheelchair 20 years after diagnosis. Prognosis of BSMA is usually fair with only a small decrease in life expectancy. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA [kDa]: kilodalton [EPC]: Early Prostate Cancer [LAPC]: locally advanced prostate cancer [NSAAs]: nonsteroidal antiandrogens [NSAA]: nonsteroidal antiandrogen [GnRH]: gonadotropin-releasing hormone [ADT]: androgen deprivation therapy [LH]: luteinizing hormone [AR]: androgen receptor [CAB]: combined androgen blockade [LPC]: localized prostate cancer [CPA]: cyproterone acetate [U.S.]: United States [FDA]: Food and Drug Administration	Kennedy disease	c0752353	7,849	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=481	2021-01-23T18:34:45	{"gard": ["6818"], "omim": ["313200"], "umls": ["C0393547", "C0752353", "C1839259"], "icd-10": ["G12.2"], "synonyms": ["SBMA", "SMAX1", "X-linked BSMA", "X-linked bulbospinal amyotrophy", "X-linked bulbospinal muscular atrophy", "X-linked spinal and bulbar muscular atrophy"]}
Progeroid syndrome, Petty type is a rare premature aging syndrome characterized by pre-and postnatal growth retardation, a congenital premature-aged appearance with distinctive craniofacial dysmorphism (wide calvaria with large open anterior fontanel and wide metopic suture, broad forehead, small face, micrognathia), markedly diminished subcutaneous fat, cutis laxa and wrinkled skin, without delay in psychomotor development. Scant, brittle hair, hypoplastic nails and delayed, abnormal dentition, as well as hypoplastic distal phalanges, umbilical hernia and eye abnormalities (myopia/hyperopia, strabismus), are also commonly associated. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA [kDa]: kilodalton [EPC]: Early Prostate Cancer [LAPC]: locally advanced prostate cancer [NSAAs]: nonsteroidal antiandrogens [NSAA]: nonsteroidal antiandrogen [GnRH]: gonadotropin-releasing hormone [ADT]: androgen deprivation therapy [LH]: luteinizing hormone [AR]: androgen receptor [CAB]: combined androgen blockade [LPC]: localized prostate cancer [CPA]: cyproterone acetate [U.S.]: United States [FDA]: Food and Drug Administration	Progeroid syndrome, Petty type	c2931653	7,850	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=2963	2021-01-23T18:11:01	{"gard": ["4497"], "mesh": ["C537886"], "omim": ["612289"], "umls": ["C2931653"], "icd-10": ["E34.8"], "synonyms": ["Fontaine progeroid syndrome", "Petty syndrome", "Petty-Laxova-Wiedemann syndrome"]}
Hajdu–Cheney syndrome Other namesAcrodentoosteodysplasia, Arthrodentoosteodysplasia Hajdu-Cheney SpecialtyRheumatology, medical genetics Hajdu–Cheney syndrome, also called acroosteolysis with osteoporosis and changes in skull and mandible, arthrodentoosteodysplasia and Cheney syndrome,[1] is an extremely rare autosomal dominant congenital disorder[2][3] of the connective tissue characterized by severe and excessive bone resorption leading to osteoporosis and a wide range of other possible symptoms. Mutations in the NOTCH2 gene, identified in 2011, cause HCS. HCS is so rare that only about 50 cases have been reported worldwide since the discovery of the syndrome in 1948[4] ## Contents * 1 Signs and symptoms * 2 Genetics * 3 Pathogenesis * 4 Diagnosis * 4.1 Types * 5 Treatment * 6 Eponym * 7 References * 8 Further reading * 9 External links ## Signs and symptoms[edit] Hajdu–Cheney syndrome causes many issues with an individual’s connective tissues. Some general characteristics of an individual with Hajdu–Cheney syndrome include bone flexibility and deformities, short stature, delayed acquisition of speech and motor skills, dolichocephalic skull, Wormian bone, small maxilla, hypoplastic frontal sinuses, basilar impression, joint laxity, bulbous finger tips and severe osteoporosis. Wormian bone occurs when extra bones appear between cranial sutures. Fetuses with Hajdu–Cheney syndrome often will not be seen to unclench their hands on obstetrical ultrasound. They may also have low-set ears and their eyes may be farther apart than on a usual child, called hypertelorism. Children's heads can have some deformities in their shape and size (plagiocephaly). Early tooth loss and bone deformities, such as serpentine tibiae and fibulae, are also common in those affected.[citation needed] ## Genetics[edit] Hajdu–Cheney syndrome has an autosomal dominant pattern of inheritance. Hajdu–Cheney syndrome is a monogenic disorder. The disorder is inherited and controlled by a single pair of genes. A single copy of the mutant gene on an autosome causes HCS. HCS is an autosomal dominant disorder, only one parent with the defective gene is needed to pass the disorder to the offspring.[citation needed] Mutations within the last coding exon of NOTCH2 that remove the PEST domain and escape the nonsense-mediated mRNA decay have been shown to be the main cause of Hajdu–Cheney syndrome.[5][6][7] The NOTCH2 gene plays a very important role in skeletogenesis. Mutations of NOTCH2 that seem to cause HCS occur in the last coding exon of the gene (exon 34). These mutations remove PEST domains, which mediate proteosomal destruction of the protein. These PEST domains are removed due to the premature stop codon in the amino acid sequence. All HCS alleles are observed to have premature protein destruction before the PEST sequence is fully translated. The result is a mature NOTCH2 gene with a partially completed PEST sequence. In some cases, no PEST sequence at all is seen. This leads to the no proteosomal destruction of the protein.[citation needed] The NOTCH2 gene is ubiquitously expressed in all embryonic tissue. When researching HCS in mice, the homozygous deletion of NOTCH2 leads to death. This observation is important because it explains how the HCS phenotype is not isolated to only one system of the body. NOTCH2 is also shown to regulate RANK-L osteoclastogenesis, which is the production of functional osteoclasts. Osteoclasts are the component that breaks bone down. This is why bone loss is observed in HCS patients, due to the overactivation of RANK-L.[citation needed] ## Pathogenesis[edit] The mechanism thought to cause HCS is an abnormality in osteoblast and osteoid function. These are major components of bone development, and the low function of each leads to the weak bones that characterize HCS.[citation needed] ## Diagnosis[edit] One of the main methods of pinpointing a NOTCH2 mutation that leads to HCS is through whole genome sequencing. This is then followed by exome capture by means of in-solution hybridization. The exome part of the genome consists of exons. Parallel sequencing follows the hybridization, which results in about 3.5 Gb of sequence data. These sequence data are then analyzed. Through sequence analysis and symptom presentation in HCS patients, this proves to be the most definitive method of diagnosis.[citation needed] ### Types[edit] Laboratory testing reveals multiple mutations of HCS. Two genetic variants result in sporadic HCS symptoms, which are HCS-02 and HCS-03. These mutations produce symptoms that come and go, but have been present de novo. HCS-03 was identified as the variant that is passed through afflicted family members and presents symptoms throughout the lifetime of the individual. All variants of HCS lead to the same premature termination of PEST sequences which compromise normal function of NOTCH2. NOTCH has four different receptors, which have an affinity for similar ligands. They are classified as single-pass transmembrane receptors.[citation needed] ## Treatment[edit] Since about 2002, some patients with this disorder have been offered drug therapy with bisphosphonates (a class of osteoporosis drugs) to treat problems with bone resorption associated with the bone breakdown and skeletal malformations that characterize this disorder. Brand names include Actonel (risedronate/alendronate), made by Merck Pharmaceuticals. Other drugs include Pamidronate, made by Novartis and Strontium Ranelate, made by Eli Lilly. However, for more progressive cases, surgery and bone grafting are necessary. ## Eponym[edit] It is named after Nicholas Hajdu (1908–1987), a Hungarian-English radiologist working in the UK and William D. Cheney, MD (1899–1985), a US radiologist. ## References[edit] 1. ^ Online Mendelian Inheritance in Man (OMIM): 102500 2. ^ Crifasi PA, Patterson MC, Bonde D, Michels VV (June 1997). "Severe Hajdu-Cheney syndrome with upper airway obstruction". American Journal of Medical Genetics. 70 (3): 261–6. doi:10.1002/(SICI)1096-8628(19970613)70:3<261::AID-AJMG9>3.0.CO;2-Z. PMID 9188663. 3. ^ Brennan AM, Pauli RM (May 2001). "Hajdu--Cheney syndrome: evolution of phenotype and clinical problems". American Journal of Medical Genetics. 100 (4): 292–310. doi:10.1002/1096-8628(20010515)100:4<292::AID-AJMG1308>3.0.CO;2-4. PMID 11343321. 4. ^ Cortés-Martín J, Díaz-Rodríguez L, Piqueras-Sola B, Rodríguez-Blanque R, Bermejo-Fernández A, Sánchez-García JC (August 2020). "Hajdu-Cheney Syndrome: A Systematic Review of the Literature". International Journal of Environmental Research and Public Health. 17 (17): 6174. doi:10.3390/ijerph17176174. PMC 7504254. PMID 32854429. 5. ^ Simpson MA, Irving MD, Asilmaz E, Gray MJ, Dafou D, Elmslie FV, et al. (March 2011). "Mutations in NOTCH2 cause Hajdu-Cheney syndrome, a disorder of severe and progressive bone loss". Nature Genetics. 43 (4): 303–5. doi:10.1038/ng.779. PMID 21378985. S2CID 205357391. 6. ^ Isidor B, Lindenbaum P, Pichon O, Bézieau S, Dina C, Jacquemont S, et al. (March 2011). "Truncating mutations in the last exon of NOTCH2 cause a rare skeletal disorder with osteoporosis". Nature Genetics. 43 (4): 306–8. doi:10.1038/ng.778. PMID 21378989. S2CID 205357384. 7. ^ Majewski J, Schwartzentruber JA, Caqueret A, Patry L, Marcadier J, Fryns JP, et al. (October 2011). "Mutations in NOTCH2 in families with Hajdu-Cheney syndrome". Human Mutation. 32 (10): 1114–7. doi:10.1002/humu.21546. PMID 21681853. S2CID 39342783. ## Further reading[edit] * Adès LC, Morris LL, Haan EA (February 1993). "Hydrocephalus in Hajdu-Cheney syndrome". Journal of Medical Genetics. 30 (2): 175. doi:10.1136/jmg.30.2.175. PMC 1016286. PMID 8445627. * Bamshad MJ, Ng SB, Bigham AW, Tabor HK, Emond MJ, Nickerson DA, Shendure J (September 2011). "Exome sequencing as a tool for Mendelian disease gene discovery". Nature Reviews. Genetics. 12 (11): 745–55. doi:10.1038/nrg3031. PMID 21946919. S2CID 15615317. * Brennan AM, Pauli RM (May 2001). "Hajdu--Cheney syndrome: evolution of phenotype and clinical problems". American Journal of Medical Genetics. 100 (4): 292–310. doi:10.1002/1096-8628(20010515)100:4<292::AID-AJMG1308>3.0.CO;2-4. PMID 11343321. * Cremin B, Goodman H, Spranger J, Beighton P (1982). "Wormian bones in osteogenesis imperfecta and other disorders". Skeletal Radiology. 8 (1): 35–8. doi:10.1007/BF00361366. PMID 7079781. S2CID 21578356. * Iwaya T, Taniguchi K, Watanabe J, Iinuma K, Hamazaki Y, Yoshikawa S (1979). "Hajdu-Cheney syndrome". Archives of Orthopaedic and Traumatic Surgery. Archiv Fur Orthopadische und Unfall-Chirurgie. 95 (4): 293–302. doi:10.1007/bf00389701. PMID 547971. S2CID 2104135. ## External links[edit] * OMIM entry on Hajdu–Cheney syndrome * Acroosteolysis dominant type at Orphanet Classification D * ICD-10: M89.5 * OMIM: 102500 * MeSH: D031845 * DiseasesDB: 31486 External resources * Orphanet: 955 * v * t * e Bone and joint disease Bone Inflammation endocrine: * Osteitis fibrosa cystica * Brown tumor infection: * Osteomyelitis * Sequestrum * Involucrum * Sesamoiditis * Brodie abscess * Periostitis * Vertebral osteomyelitis Metabolic * Bone density * Osteoporosis * Juvenile * Osteopenia * Osteomalacia * Paget's disease of bone * Hypophosphatasia Bone resorption * Osteolysis * Hajdu–Cheney syndrome * Ainhum * Gorham's disease Other * Ischaemia * Avascular necrosis * Osteonecrosis of the jaw * Complex regional pain syndrome * Hypertrophic pulmonary osteoarthropathy * Nonossifying fibroma * Pseudarthrosis * Stress fracture * Fibrous dysplasia * Monostotic * Polyostotic * Skeletal fluorosis * bone cyst * Aneurysmal bone cyst * Hyperostosis * Infantile cortical hyperostosis * Osteosclerosis * Melorheostosis * Pycnodysostosis Joint Chondritis * Relapsing polychondritis Other * Tietze's syndrome Combined Osteochondritis * Osteochondritis dissecans Child leg: * hip * Legg–Calvé–Perthes syndrome * tibia * Osgood–Schlatter disease * Blount's disease * foot * Köhler disease * Sever's disease spine * * Scheuermann's_disease arm: * wrist * Kienböck's disease * elbow * Panner disease [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA [kDa]: kilodalton [EPC]: Early Prostate Cancer [LAPC]: locally advanced prostate cancer [NSAAs]: nonsteroidal antiandrogens [NSAA]: nonsteroidal antiandrogen [GnRH]: gonadotropin-releasing hormone [ADT]: androgen deprivation therapy [LH]: luteinizing hormone [AR]: androgen receptor [CAB]: combined androgen blockade [LPC]: localized prostate cancer [CPA]: cyproterone acetate [U.S.]: United States [FDA]: Food and Drug Administration	Hajdu–Cheney syndrome	c0917990	7,851	wikipedia	https://en.wikipedia.org/wiki/Hajdu%E2%80%93Cheney_syndrome	2021-01-18T18:43:31	{"gard": ["508"], "mesh": ["D030981", "D031845"], "umls": ["C0917990", "C0917715"], "orphanet": ["955"], "wikidata": ["Q632228"]}
Bálint's syndrome Other namesBalint-Holmes syndrome, Optic ataxia-gaze apraxia-simultanagnosia syndrome SpecialtyNeurology Bálint's syndrome is an uncommon and incompletely understood triad of severe neuropsychological impairments: inability to perceive the visual field as a whole (simultanagnosia), difficulty in fixating the eyes (oculomotor apraxia), and inability to move the hand to a specific object by using vision (optic ataxia).[1] It was named in 1909 for the Austro-Hungarian neurologist and psychiatrist Rezső Bálint who first identified it.[2][3][4] Bálint's syndrome occurs most often with an acute onset as a consequence of two or more strokes at more or less the same place in each hemisphere. Therefore, it occurs rarely. The most frequent cause of complete Bálint's syndrome is said by some to be sudden and severe hypotension, resulting in bilateral borderzone infarction in the occipito-parietal region.[1] More rarely, cases of progressive Bálint's syndrome have been found in degenerative disorders such as Alzheimer's disease[5][6] or certain other traumatic brain injuries at the border of the parietal and the occipital lobes of the brain. Lack of awareness of this syndrome may lead to a misdiagnosis and resulting inappropriate or inadequate treatment. Therefore, clinicians should be familiar with Bálint's syndrome and its various etiologies.[7] ## Contents * 1 Symptoms * 1.1 Simultanagnosia * 1.2 Oculomotor apraxia * 1.3 Optic ataxia * 2 Cause * 3 Diagnosis * 3.1 Neuroanatomical evidence * 3.2 Manifestations * 4 Treatment * 5 Case studies * 5.1 Criticism * 6 References * 7 External links ## Symptoms[edit] Bálint's syndrome symptoms can be quite debilitating since they impact visuospatial skills, visual scanning and attentional mechanisms.[8] Since it represents impairment of both visual and language functions, it is a significant disability that can affect the patient's safety—even in one's own home environment, and can render the person incapable of maintaining employment.[9] In many cases the complete trio of symptoms—inability to perceive the visual field as a whole (simultanagnosia), difficulty in fixating the eyes (oculomotor apraxia), and inability to move the hand to a specific object by using vision (optic ataxia)—may not be noticed until the patient is in rehabilitation. Therapists unfamiliar with Bálint's syndrome may misdiagnose a patient's inability to meet progress expectations in any of these symptom areas as simply indicating incapability of benefiting from further traditional therapy. The very nature of each Bálint symptom frustrates rehabilitation progress in each of the other symptoms. Much more research is needed to develop therapeutic protocols that address Bálint symptoms as a group since the disabilities are so intertwined.[10] ### Simultanagnosia[edit] See also: Simultanagnosia Simultanagnosia is the inability to perceive simultaneous events or objects in one's visual field.[11] Victims of Bálint's syndrome perceive the world erratically, as a series of single objects rather than seeing the wholeness of a scene.[12] This spatial disorder of visual attention—the ability to identify local elements of a scene, but not the global whole—has been referred to as a constriction of the individual's global gestalt window—their visual "window" of attention. People fixate their eyes to specific images in social scenes because they are informative to the meaning of the scene. Any forthcoming recovery in simultanagnosia may be related to somehow expanding the restricted attentional window that characterizes this disorder.[13] Simultanagnosia is a profound visual deficit. It impairs the ability to perceive multiple items in a visual display, while preserving the ability to recognize single objects. One study suggests that simultanagnosia may result from an extreme form of competition between objects which makes it difficult for attention to be disengaged from an object once it has been selected.[14] Patients with simultanagnosia have a restricted spatial window of visual attention and cannot see more than one object at a time. They see their world in a patchy, spotty manner. Therefore, they pick out a single object, or even components of an individual object, without being able to see the global "big picture."[citation needed] A study which directly tested the relationship between the restriction of the attentional window in simultanagnosia compared with the vision of healthy participants with normal limits of visual processing confirmed the limitations of difficulties of patients with simultanagnosia.[15] There is considerable evidence that a person's cortex is essentially divided into two functional streams: an occipital-parietal-frontal pathway that processes "where" information and an occipital-temporal-frontal pathway that provides "what" information to the individual.[16] ### Oculomotor apraxia[edit] Main article: Oculomotor apraxia See also: apraxia Bálint referred to this as "psychic paralysis of gaze"—the inability to voluntarily guide eye movements, changing to a new location of visual fixation. A major symptom of Oculomotor apraxia is that a person has no control over their eye movements, however, vertical eye movements are typically unaffected. For example, they often have difficulty moving their eyes in the desired direction. In other words, the saccades (rapid eye movements) are abnormal. Because of this, most patients with Oculomotor apraxia have to turn their heads in order to follow objects coming from their peripherals.[17] ### Optic ataxia[edit] See also: ataxia Optic ataxia is the inability to guide the hand toward an object using visual information[18] where the inability cannot be explained by motor, somatosensory, visual field deficits or acuity deficits. Optic ataxia is seen in Bálint's syndrome where it is characterized by an impaired visual control of the direction of arm-reaching to a visual target, accompanied by defective hand orientation and grip formation.[19] It is considered a specific visuomotor disorder, independent of visual space misperception. Optic ataxia is also known as misreaching or dysmetria (English: difficult to measure), secondary to visual perceptual deficits. A patient with Bálint's syndrome likely has defective hand movements under visual guidance, despite normal limb strength. The patient is unable to grab an object while looking at the object, due to a discoordination of eye and hand movement. It is especially true with their contralesional hand.[citation needed] Dysmetria refers to a lack of coordination of movement, typified by the undershoot or overshoot of intended position with the hand, arm, leg, or eye. It is sometimes described as an inability to judge distance or scale.[18] > As Bálint states, optic ataxia impaired his patient's daily activities, since, ‘while cutting a slice of meat...which he held with a fork in his left hand, ...would search for it outside the plate with the knife in his right hand’, or ‘...while lighting a cigarette he often lit the middle and not the end’. Bálint pointed out the systematic nature of this disorder, which was evident in the patient's behaviour when searching in space. ‘Thus, when asked to grasp a presented object with his right hand, he would miss it regularly, and would find it only when his hand knocked against it.[19] The reaching ability of the patient is also altered. It takes them longer to reach toward an object. Their ability to grasp an object is also impaired. The patient's performance is even more severely deteriorated when vision of either the hand or the target is prevented.[20] ## Cause[edit] The visual difficulties in Bálint's syndrome are usually due to damage to the parieto-occipital lobes on both sides of the brain. The parietal lobe is the middle area of the top part of the brain and the occipital lobe is the back part of the brain. (It usually does not affect the temporal lobes)[citation needed] ## Diagnosis[edit] Lack of awareness of the syndrome may lead to misdiagnosis such as blindness, psychosis, or dementia.[1] Symptoms of Bálint's syndrome are most likely to be noticed first by therapists providing rehabilitation following brain lesions. However, due to the scarcity among practitioners of familiarity with the syndrome, the symptoms are often explained away incorrectly without being considered as a possibility and followed by medical confirmation of clinical and neuroradiological findings.[21] Any severe disturbance of space representation, spontaneously appearing following bilateral parietal damage, strongly suggests the presence of Bálint's syndrome and should be investigated as such.[22] One study reports that damage to the bilateral dorsal occipitoparietal regions appeared to be involved in Bálint's syndrome.[23] ### Neuroanatomical evidence[edit] Bálint's syndrome has been found in patients with bilateral damage to the posterior parietal cortex. The primary cause of the damage and the syndrome can originate from multiple strokes, Alzheimer's disease, intracranial tumors, or brain injury. Progressive multifocal leukoencephalopathy and Creutzfeldt–Jakob disease have also been found to cause this kind of damage. This syndrome is caused by damage to the posterior superior watershed areas, also known as the parietal-occipital vascular border zone (Brodmann's areas 19 and 7).[24] ### Manifestations[edit] Some telltale signs suggesting Bálint's syndrome following bilateral brain insults may include: * limitation to perceive only stimuli that is presented at 35 to 40 degrees to the right. They are able to move their eyes but cannot fixate on specific visual stimuli (optic apraxia). * patient's field of attention is limited to one object at a time. making activities like reading difficult because each letter is perceived separately (simultanagnosia). * figure/ground defects in which a patient can see either the background but not the object residing somewhere in the whole scene, or conversely can see the object but sees no background around it (simultanagnosia) * a patient, while attempting to put one foot into a slipper by trying to insert the foot into a nonexistent slipper several inches from the real slipper, even as the patient focuses on the actual slipper (optic ataxia) * a patient raising a fork or spoon containing food to a point on the patient's face above or below the mouth, and possibly finding the mouth by trial and error by manually moving the utensil on the face (optic ataxia)[25][26] ## Treatment[edit] In terms of the specific rehabilitation of visuoperceptual disorders such as Bálint's syndrome, the literature is extremely sparse.[8] According to one study, rehabilitation training should focus on the improvement of visual scanning, the development of visually guided manual movements, and the improvement of the integration of visual elements.[10] Very few treatment strategies have been proposed, and some of those have been criticized as being poorly developed and evaluated.[citation needed] Three approaches to rehabilitation of perceptual deficits, such as those seen in Bálint's syndrome, have been identified: 1. The adaptive (functional) approach, which involves functional tasks utilising the person's strengths and abilities, helping them to compensate for problems or altering the environment to lessen their disabilities. This is the most popular approach. 2. The remedial approach, which involves restoration of the damaged CNS by training in the perceptual skills, which may be generalised across all activities of daily living. This could be achieved by tabletop activities or sensorimotor exercises. 3. The multicontext approach, which is based on the fact that learning is not automatically transferred from one situation to another. This involves practicing of a targeted strategy in a multiple environment with varied tasks and movement demands, and it incorporates self-awareness tasks.[26] ## Case studies[edit] Symptoms of Bálint's syndrome were found in the case of a 29-year-old migraine sufferer. In the aura before the migraine headache, she experienced an inability to see all of the objects in the visual field simultaneously; an inability to coordinate hand and eye movements; and an inability to look at an object on command.[27] Symptoms were not present before the onset of the migraine or after it passed. A study of a patient with Corticobasal Ganglionic Degeneration (CGBD) also showed a development of Bálint's syndrome. As a result of CGBD, the patient developed an inability to move his eyes to specific visual objects in his peripheral fields. He also was unable to reach out and touch objects in his peripheral fields. An inability to recognize more than one item at a time was also experienced when presented with the Cookie Theft Picture from the Boston Diagnostic Aphasia Examination.[28] A 58-year-old male presented with Bálint's syndrome secondary to severe traumatic brain injury 4-months post-injury onset. He had completed a comprehensive post-acute brain injury rehabilitation program. He received 6 months of rehabilitation services as an inpatient. A three-pronged approach included the implementation of (a) compensatory strategies, (b) remediation exercises and (c) transfer of learned skills in multiple environments and situations. Comprehensive neuropsychological and occupational therapy evaluations were performed at admission and at discharge. Neuropsychological test improvements were noted on tasks that assess visuospatial functioning, although most gains were noted for functional and physical abilities.[8] A patient with congenital deafness exhibited partial Bálint's syndrome symptoms. This patient experienced an inability to perceive simultaneous events in her visual field. She was also unable to fixate and follow an object with her eyes. In addition, her ability to point at targets under visual guidance was impaired.[21] Bálint's syndrome is rarely reported in children, but some recent studies provide evidence that cases do exist in children. A case involving a 10-year-old male child with Bálint's syndrome has been reported[29] Similar results were seen in a 7-year-old boy. In children this syndrome results in a variety of occupational difficulties, but most notably difficulties in schoolwork, especially reading. The investigators encourage more careful recognition of the syndrome to allow adequate rehabilitation and environmental adaptation.[30] ### Criticism[edit] The validity of Bálint's syndrome has been questioned by some.[by whom?] The components in the syndrome's triad of defects (simultanagnosia, oculomotor apraxia, optic ataxia) each may represent a variety of combined defects. > Because Bálint's syndrome is not common and is difficult to assess with standard clinical tools, the literature is dominated by case reports and confounded by case selection bias, non-uniform application of operational definitions, inadequate study of basic vision, poor lesion localisation, and failure to distinguish between deficits in the acute and chronic phases of recovery.[12] ## References[edit] 1. ^ a b c Udesen, H; Madsen, A. L. (1992). "Balint's syndrome--visual disorientation". Ugeskrift for Laeger. 154 (21): 1492–4. PMID 1598720. 2. ^ synd/1343 at Who Named It? 3. ^ Bálint, Dr. (1909). "Seelenlähmung des 'Schauens', optische Ataxie, räumliche Störung der Aufmerksamkeit. pp. 51–66" [Soul imbalance of 'seeing', optical ataxia, spatial disturbance of attention. pp. 51–66]. European Neurology (in German). 25: 51–66. doi:10.1159/000210464. 4. ^ Bálint, Dr.; Zeeberg, I; Sjö, O (1909). "Seelenlähmung des 'Schauens', optische Ataxie, räumliche Störung der Aufmerksamkeit. pp. 67–81" [Soul imbalance of 'seeing', optical ataxia, spatial disturbance of attention. pp. 67-81]. European Neurology (in German). 25 (1): 67–81. doi:10.1159/000210465. PMID 3940867. 5. ^ Kerkhoff, G. (2000). "Neurovisual rehabilitation: Recent developments and future directions". Journal of Neurology, Neurosurgery & Psychiatry. 68 (6): 691–706. doi:10.1136/jnnp.68.6.691. PMC 1736971. PMID 10811691. 6. ^ Ribai, P.; Vokaer, M.; De Tiege, X.; Massat, I.; Slama, H.; Bier, J.C. (2006). "Acute Balint's syndrome is not always caused by a stroke". European Journal of Neurology. 13 (3): 310–2. doi:10.1111/j.1468-1331.2006.01144.x. PMID 16618355. 7. ^ Perez, F. M.; Tunkel, R. S.; Lachmann, E. A.; Nagler, W. (2009). "Balint's syndrome arising from bilateral posterior cortical atrophy or infarction: Rehabilitation strategies and their limitation". Disability and Rehabilitation. 18 (6): 300–4. doi:10.3109/09638289609165884. PMID 8783001. 8. ^ a b c Zgaljardic, Dennis J.; Yancy, Sybil; Levinson, Jason; Morales, Gabrielle; Masel, Brent E. (2011). "Balint's syndrome and post-acute brain injury rehabilitation: A case report". Brain Injury. 25 (9): 909–17. doi:10.3109/02699052.2011.585506. PMID 21631186. 9. ^ Toyokura, M; Koike, T (2006). "Rehabilitative intervention and social participation of a case with Balint's syndrome and aphasia". The Tokai Journal of Experimental and Clinical Medicine. 31 (2): 78–82. PMID 21302228. 10. ^ a b Rosselli, Mónica; Ardila, Alfredo; Beltran, Christopher (2001). "Rehabilitation of Balint's Syndrome: A Single Case Report". Applied Neuropsychology. 8 (4): 242–7. doi:10.1207/S15324826AN0804_7. PMID 11989728. 11. ^ Rizzo, Matthew (2000). "Clinical Assessment of Complex Visual Dysfunction". Seminars in Neurology. 20 (1): 75–87. doi:10.1055/s-2000-6834. PMID 10874778. 12. ^ a b Rizzo, M (2002). "Psychoanatomical substrates of Balint's syndrome". Journal of Neurology, Neurosurgery & Psychiatry. 72 (2): 162–78. doi:10.1136/jnnp.72.2.162. PMC 1737727. PMID 11796765. 13. ^ Dalrymple, Kirsten A.; Birmingham, Elina; Bischof, Walter F.; Barton, Jason J.S.; Kingstone, Alan (2011). "Experiencing simultanagnosia through windowed viewing of complex social scenes". Brain Research. 1367: 265–77. doi:10.1016/j.brainres.2010.10.022. PMID 20950591. 14. ^ Jackson, Georgina M.; Swainson, Rachel; Mort, Dominic; Husain, Masud; Jackson, Stephen R. (2009). "Attention, competition, and the parietal lobes: Insights from Balint's syndrome". Psychological Research. 73 (2): 263–70. doi:10.1007/s00426-008-0210-2. PMID 19156438. 15. ^ Dalrymple, Kirsten A.; Bischof, Walter F.; Cameron, David; Barton, Jason J. S.; Kingstone, Alan (2010). "Simulating simultanagnosia: Spatially constricted vision mimics local capture and the global processing deficit". Experimental Brain Research. 202 (2): 445–55. doi:10.1007/s00221-009-2152-3. PMID 20066404. 16. ^ Kim, Min-Shik; Robertson, Lynn C. (2001). "Implicit Representations of Space after Bilateral Parietal Lobe Damage". Journal of Cognitive Neuroscience. 13 (8): 1080–7. CiteSeerX 10.1.1.579.299. doi:10.1162/089892901753294374. PMID 11784446. 17. ^ https://aapos.org/terms/conditions/138[full citation needed][permanent dead link] 18. ^ a b Perenin, M.-T.; Vighetto, A. (1988). "Optic Ataxia: A Specific Disruption in Visuomotor Mechanisms". Brain. 111 (3): 643–74. doi:10.1093/brain/111.3.643. PMID 3382915. 19. ^ a b Battaglia-Mayer, A.; Caminiti, R. (2002). "Optic ataxia as a result of the breakdown of the global tuning fields of parietal neurones". Brain. 125 (2): 225–37. doi:10.1093/brain/awf034. PMID 11844724. 20. ^ http://www.rightdiagnosis.com/b/balints_syndrome/intro.htm[full citation needed] 21. ^ a b Drane, Daniel L.; Lee, Gregory P.; Huthwaite, Justin S.; Tirschwell, David L.; Baudin, Brett C.; Jurado, Miguel; Ghodke, Basavaraj; Marchman, Holmes B. (2009). "Development of a Partial Balint's Syndrome in a Congenitally Deaf Patient Presenting as Pseudo-Aphasia". The Clinical Neuropsychologist. 23 (4): 715–28. doi:10.1080/13854040802448718. PMC 2836810. PMID 18923965. 22. ^ Valenza, Nathalie; Murray, Micah M.; Ptak, Radek; Vuilleumier, Patrik (2004). "The space of senses: Impaired crossmodal interactions in a patient with Balint syndrome after bilateral parietal damage". Neuropsychologia. 42 (13): 1737–48. doi:10.1016/j.neuropsychologia.2004.05.001. PMID 15351624. 23. ^ Kas, A.; De Souza, L. C.; Samri, D.; Bartolomeo, P.; Lacomblez, L.; Kalafat, M.; Migliaccio, R.; Thiebaut De Schotten, M.; Cohen, L.; Dubois, B.; Habert, M.-O.; Sarazin, M. (2011). "Neural correlates of cognitive impairment in posterior cortical atrophy". Brain. 134 (5): 1464–78. doi:10.1093/brain/awr055. PMID 21478188. 24. ^ Benson, D. F.; Davis, R. J.; Snyder, B. D. (1988). "Posterior Cortical Atrophy". Archives of Neurology. 45 (7): 789–93. doi:10.1001/archneur.1988.00520310107024. PMID 3390033. 25. ^ Rizzo, M (1993). "'Bálint's syndrome' and associated visuospatial disorders". Baillière's Clinical Neurology. 2 (2): 415–37. PMID 8137007. 26. ^ a b Al-Khawaja, I (2001). "Neurovisual rehabilitation in Balint's syndrome". Journal of Neurology, Neurosurgery & Psychiatry. 70 (3): 416. doi:10.1136/jnnp.70.3.416. PMC 1737281. PMID 11248903. 27. ^ Shah, P. A; Nafee, A (1999). "Migraine aura masquerading as Balint's syndrome". Journal of Neurology, Neurosurgery & Psychiatry. 67 (4): 554–5. doi:10.1136/jnnp.67.4.554. PMC 1736566. PMID 10610392. 28. ^ Mendez, M. F. (2000). "Corticobasal Ganglionic Degeneration with Balint's Syndrome". Journal of Neuropsychiatry. 12 (2): 273–5. doi:10.1176/appi.neuropsych.12.2.273. PMID 11001609. 29. ^ Gillen, Jennifer A; Dutton, Gordon N (2007). "Balint's syndrome in a 10-year-old male". Developmental Medicine & Child Neurology. 45 (5): 349–52. doi:10.1111/j.1469-8749.2003.tb00407.x. PMID 12729150. 30. ^ Drummond, Suzannah Rosalind; Dutton, Gordon N. (2007). "Simultanagnosia following perinatal hypoxia—A possible pediatric variant of Balint syndrome". Journal of American Association for Pediatric Ophthalmology and Strabismus. 11 (5): 497–8. doi:10.1016/j.jaapos.2007.03.007. PMID 17933675. ## External links[edit] * National Institute on Deafness and Other Communication Disorders - Apraxia of speech Classification D * ICD-10: H51.8 * ICD-9-CM: 368.16 External resources * Orphanet: 363746 * v * t * e * Diseases of the human eye Adnexa Eyelid Inflammation * Stye * Chalazion * Blepharitis * Entropion * Ectropion * Lagophthalmos * Blepharochalasis * Ptosis * Blepharophimosis * Xanthelasma * Ankyloblepharon Eyelash * Trichiasis * Madarosis Lacrimal apparatus * Dacryoadenitis * Epiphora * Dacryocystitis * Xerophthalmia Orbit * Exophthalmos * Enophthalmos * Orbital cellulitis * Orbital lymphoma * Periorbital cellulitis Conjunctiva * Conjunctivitis * allergic * Pterygium * Pseudopterygium * Pinguecula * Subconjunctival hemorrhage Globe Fibrous tunic Sclera * Scleritis * Episcleritis Cornea * Keratitis * herpetic * acanthamoebic * fungal * Exposure * Photokeratitis * Corneal ulcer * Thygeson's superficial punctate keratopathy * Corneal dystrophy * Fuchs' * Meesmann * Corneal ectasia * Keratoconus * Pellucid marginal degeneration * Keratoglobus * Terrien's marginal degeneration * Post-LASIK ectasia * Keratoconjunctivitis * sicca * Corneal opacity * Corneal neovascularization * Kayser–Fleischer ring * Haab's striae * Arcus senilis * Band keratopathy Vascular tunic * Iris * Ciliary body * Uveitis * Intermediate uveitis * Hyphema * Rubeosis iridis * Persistent pupillary membrane * Iridodialysis * Synechia Choroid * Choroideremia * Choroiditis * Chorioretinitis Lens * Cataract * Congenital cataract * Childhood cataract * Aphakia * Ectopia lentis Retina * Retinitis * Chorioretinitis * Cytomegalovirus retinitis * Retinal detachment * Retinoschisis * Ocular ischemic syndrome / Central retinal vein occlusion * Central retinal artery occlusion * Branch retinal artery occlusion * Retinopathy * diabetic * hypertensive * Purtscher's * of prematurity * Bietti's crystalline dystrophy * Coats' disease * Sickle cell * Macular degeneration * Retinitis pigmentosa * Retinal haemorrhage * Central serous retinopathy * Macular edema * Epiretinal membrane (Macular pucker) * Vitelliform macular dystrophy * Leber's congenital amaurosis * Birdshot chorioretinopathy Other * Glaucoma / Ocular hypertension / Primary juvenile glaucoma * Floater * Leber's hereditary optic neuropathy * Red eye * Globe rupture * Keratomycosis * Phthisis bulbi * Persistent fetal vasculature / Persistent hyperplastic primary vitreous * Persistent tunica vasculosa lentis * Familial exudative vitreoretinopathy Pathways Optic nerve Optic disc * Optic neuritis * optic papillitis * Papilledema * Foster Kennedy syndrome * Optic atrophy * Optic disc drusen Optic neuropathy * Ischemic * anterior (AION) * posterior (PION) * Kjer's * Leber's hereditary * Toxic and nutritional Strabismus Extraocular muscles Binocular vision Accommodation Paralytic strabismus * Ophthalmoparesis * Chronic progressive external ophthalmoplegia * Kearns–Sayre syndrome palsies * Oculomotor (III) * Fourth-nerve (IV) * Sixth-nerve (VI) Other strabismus * Esotropia / Exotropia * Hypertropia * Heterophoria * Esophoria * Exophoria * Cyclotropia * Brown's syndrome * Duane syndrome Other binocular * Conjugate gaze palsy * Convergence insufficiency * Internuclear ophthalmoplegia * One and a half syndrome Refraction * Refractive error * Hyperopia * Myopia * Astigmatism * Anisometropia / Aniseikonia * Presbyopia Vision disorders Blindness * Amblyopia * Leber's congenital amaurosis * Diplopia * Scotoma * Color blindness * Achromatopsia * Dichromacy * Monochromacy * Nyctalopia * Oguchi disease * Blindness / Vision loss / Visual impairment Anopsia * Hemianopsia * binasal * bitemporal * homonymous * Quadrantanopia subjective * Asthenopia * Hemeralopia * Photophobia * Scintillating scotoma Pupil * Anisocoria * Argyll Robertson pupil * Marcus Gunn pupil * Adie syndrome * Miosis * Mydriasis * Cycloplegia * Parinaud's syndrome Other * Nystagmus * Childhood blindness Infections * Trachoma * Onchocerciasis * v * t * e Symptoms, signs and syndromes associated with lesions of the brain and brainstem Brainstem Medulla (CN 8, 9, 10, 12) * Lateral medullary syndrome/Wallenberg * PICA * Medial medullary syndrome/Dejerine * ASA Pons (CN 5, 6, 7, 8) * Upper dorsal pontine syndrome/Raymond-Céstan syndrome * Lateral pontine syndrome (AICA) (lateral) * Medial pontine syndrome/Millard–Gubler syndrome/Foville's syndrome (basilar) * Locked-in syndrome * Internuclear ophthalmoplegia * One and a half syndrome Midbrain (CN 3, 4) * Weber's syndrome * ventral peduncle, PCA * Benedikt syndrome * ventral tegmentum, PCA * Parinaud's syndrome * dorsal, tumor * Claude's syndrome Other * Alternating hemiplegia Cerebellum * Latearl * Dysmetria * Dysdiadochokinesia * Intention tremor) * Medial * Cerebellar ataxia Basal ganglia * Chorea * Dystonia * Parkinson's disease Cortex * ACA syndrome * MCA syndrome * PCA syndrome * Frontal lobe * Expressive aphasia * Abulia * Parietal lobe * Receptive aphasia * Hemispatial neglect * Gerstmann syndrome * Astereognosis * Occipital lobe * Bálint's syndrome * Cortical blindness * Pure alexia * Temporal lobe * Cortical deafness * Prosopagnosia Thalamus * Thalamic syndrome Other * Upper motor neuron lesion * Aphasia [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA [kDa]: kilodalton [EPC]: Early Prostate Cancer [LAPC]: locally advanced prostate cancer [NSAAs]: nonsteroidal antiandrogens [NSAA]: nonsteroidal antiandrogen [GnRH]: gonadotropin-releasing hormone [ADT]: androgen deprivation therapy [LH]: luteinizing hormone [AR]: androgen receptor [CAB]: combined androgen blockade [LPC]: localized prostate cancer [CPA]: cyproterone acetate [U.S.]: United States [FDA]: Food and Drug Administration	Bálint's syndrome	c0270706	7,852	wikipedia	https://en.wikipedia.org/wiki/B%C3%A1lint%27s_syndrome	2021-01-18T18:55:36	{"umls": ["C0270706"], "icd-9": ["368.16"], "orphanet": ["363746"], "wikidata": ["Q174651"]}
Diastasis recti Other namesAbdominal separation Diastasis recti in an infant SpecialtyPediatrics Diastasis recti, or rectus abdominis diastasis, is defined as a gap of about 2.7 cm or greater between the two sides of the rectus abdominis muscle.[1] The distance between the right and left rectus abdominis muscles is created by the stretching of the linea alba, a connective collagen sheath created by the aponeurosis insertions of the transverse abdominis, internal oblique, and external oblique.[2] This condition has no associated morbidity or mortality.[3] Diastasis of the rectus abdominis muscle most frequently occurs in newborns and pregnant women; however, it may occur in any adult woman or man. In the newborn, the rectus abdominis is not fully developed and may not be sealed together at midline. Diastasis recti is more common in premature newborns. In pregnant or postpartum women, the condition is caused by the stretching of the rectus abdominis by the growing uterus. It is more common in multiparous women (women who have had multiple pregnancies) owing to repeated episodes of stretching. When the defect occurs during pregnancy, the uterus can sometimes be seen bulging through the abdominal wall beneath the skin. Non-pregnant women are more susceptible to develop diastasis recti when over the age of 35 or with high birth weight of child, multiple birth pregnancy, or multiple pregnancies. Additional causes can be attributed to excessive abdominal exercises after the first trimester of pregnancy.[4] Strength training of all the core muscles, including the abdominis recti muscle, may or may not reduce the size of the gap in pregnant or postpartum women. Crunches may increase the diastasis recti separation. All corrective exercises should be in the form of pulling in the abdominal muscles rather than pushing them outwards. In extreme cases, diastasis recti is corrected with a cosmetic surgery procedure known as an abdominoplasty by creating a plication or folding of the linea alba and suturing together, which results in a tighter abdominal wall. ## Contents * 1 Presentation * 2 Diagnosis * 3 Treatment * 3.1 Strength training * 3.2 Surgery * 4 References * 5 External links ## Presentation[edit] A diastasis recti may appear as a ridge running down the midline of the abdomen, anywhere from the xiphoid process to the umbilicus. It becomes more prominent with straining and may disappear when the abdominal muscles are relaxed. The medial borders of the right and left halves of the muscle may be palpated during contraction of the rectus abdominis.[5] The condition can be diagnosed by physical exam, and must be differentiated from an epigastric hernia or incisional hernia, if the patient has had abdominal surgery.[3] Hernias may be ruled out using ultrasound.[6] In infants, they typically result from a minor defect of the linea alba between the rectus abdominis muscles. This allows tissue from inside the abdomen to herniate anteriorly. On infants, this may manifest as an apparent 'bubble' under the skin of the belly between the umbilicus and xiphisternum (bottom of the breastbone).[7] Examination is performed with the subject lying on the back, knees bent at 90° with feet flat, head slightly lifted placing chin on chest. With muscles tense, the examiner then places fingers in the ridge that is presented. Measurement of the width of separation is determined by the number of fingertips that can fit within the space between the left and right rectus abdominis muscles. Separation consisting of a width of 2 fingertips (approximately 1 1/2 centimeters) or more is the determining factor for diagnosing diastasis recti.[8] ## Diagnosis[edit] Abdominal ultrasound of diastasis recti, being the distance between the green crosses. * Diastasis recti can be diagnosed by physical examination, which may include measuring the distance between the rectus abdominis muscles at rest and during contraction at several levels along the linea alba.[9] * Abdominal ultrasonography provides objective evidence for the diagnosis, and also confirms that the bulge is not a hernia.[9] * An abdominal CT scan is an acceptable alternative to an ultrasound.[9] ## Treatment[edit] * During pregnancy - No treatment is necessary for women while they are still pregnant. * After delivery - Typically the separation of the abdominal muscles will lessen in the mother within the first 8 weeks after childbirth; however, the connective tissue remains stretched for many. The weakening of the musculature may also cause lower back pain, weakened pelvic alignment, and altered posture.[8] * In children - Complications include development of an umbilical or ventral hernia, which is rare and can be corrected with surgery.[10] If an infant with the condition develops vomiting, or redness or pain in the abdominal area, medical attention should be sought. ### Strength training[edit] A systematic review of the evidence found that exercise may or may not reduce the size of the gap in pregnant or postpartum women. The authors looked at 8 studies totaling 336 women and concluded: “Due to the low number and quality of included articles, there is insufficient evidence to recommend that exercise may help to prevent or reduce DRAM,” also stating that "non-specific exercise may or may not help to prevent or reduce DRAM during the ante- and postnatal periods."[1] However, in a study conducted by the Columbia University Program in Physical Therapy stated: "Ninety percent of non‐exercising pregnant women exhibited DRA while only 12.5% of exercising women had the condition. The mean DRA located 4.5 cm above the umbilicus was 9.6 mm (± 6.6) for the exercise group and 38.9 mm (± 17.8) for the non‐exercise group. The mean DRA located at the umbilicus was 11.4 mm (± 3.82) for the exercise group and 59.5 mm (± 23.6) for the non‐exercise group. The mean DRA located 4.5 cm below the umbilicus was 8.2 mm (± 7.4) for the exercise group and 60.4 (± 29.0) for the non‐exercise group."[11] Nevertheless, the following exercises are often recommended to help build abdominal strength, which may or may not help reduce the size of diastasis recti[12] * Core contraction – In a seated position, place both hands on abdominal muscles. Take small controlled breaths. Slowly contract the abdominal muscles, pulling them straight back towards the spine. Hold the contraction for 30 seconds, while maintaining the controlled breathing. Complete 10 repetitions.[12] * Seated squeeze \- Again in a seated position, place one hand above the belly button, and the other below the belly button. With controlled breaths, with a mid-way starting point, pull the abdominals back toward the spine, hold for 2 seconds and return to the mid-way point. Complete 100 repetitions.[12] * Head lift – In a lying down position, knees bent at 90° angle, feet flat, slowly lift the head, chin toward your chest, (concentrate on isolation of the abdominals to prevent hip-flexors from being engaged),[8] slowly contract abdominals toward floor, hold for two seconds, lower head to starting position for 2 seconds. Complete 10 repetitions.[12] * Upright push-up – A stand-up push-up against the wall, with feet together arms-length away from wall, place hands flat against the wall, contract abdominal muscles toward spine, lean body towards wall, with elbows bent downward close to body, pull abdominal muscles in further, with controlled breathing. Release muscles as you push back to starting position. Complete 20 repetitions.[12] * Squat against the wall – Also known as a seated squat, stand with back against the wall, feet out in front of body, slowly lower body to a seated position so knees are bent at a 90° angle, contracting abs toward spine as you raise body back to standing position. Optionally, this exercise can also be done using an exercise ball placed against the wall and the lower back. Complete 20 repetitions.[12] * Squat with squeeze – A variation to the "squat against the wall" is to place a small resistance ball between the knees, and squeeze the ball while lowering the body to the seated position. Complete 20 repetitions.[12] Incorrect exercises, including crunches, can increase the diastasis recti separation. All corrective exercises should be in the form of pulling in the abdominal muscles rather than pushing them outwards. Consultation of a professional physiotherapist is recommended for correct exercise routines.[12] Furthermore, in a review of treatment methods for Diastasis recti abdominis, besides strengthening exercises there are other option to treat DRA by postural training, education and training for proper lifting mechanisms, manual therapy which includes soft tissue mobilization, myofacisal release, Noble technique i.e manual approximation of abdominal muscles during partial sit up and abdominal bracing and taping. Other techniques to strengthen abdominal muscles are using Pilaties and functional training.[13] In addition to the above exercises, the Touro College study concluded the "quadruped" position yielded the most effective results.[8] A quadruped position is defined as "a human whose body weight is supported by both arms as well as both legs".[14] In this position, the subject would start with a flat back, then slowly tilt the head down, and round the spine, contracting the abdominal muscles towards the spine, holding this position for 5 seconds, then releasing back to starting position. Complete two sets of 10 repetitions.[8] ### Surgery[edit] In extreme cases, diastasis recti is corrected with a cosmetic surgery procedure known as an abdominoplasty by creating a plication or folding of the linea alba and suturing together. This creates a tighter abdominal wall. There are two surgical methods, one through Plication method which is plication of the anterior rectus sheath is most commonly use to repair DRMA and other Hernia repair considering suture closure of hernia sac combined with mesh reinforcement, There were two studies showing few post - operative complications.[15] In adult females, a laparoscopic "Venetian blind" technique can be used for plication of the recti.[16] ## References[edit] 1. ^ a b Benjamin, D.R.; Van de Water, A.T.M; Peiris, C.L. (March 2014). "Effects of exercise on diastasis of the rectus abdominis muscle in the antenatal and postnatal periods: a systematic review". Physiotherapy. 100 (1): 1–8. doi:10.1016/j.physio.2013.08.005. PMID 24268942. 2. ^ Brauman, Daniel (November 2008). "Diastasis Recti: Clinical Anatomy". Plastic and Reconstructive Surgery. 122 (5): 1564–1569. doi:10.1097/prs.0b013e3181882493. PMID 18971741. S2CID 26635878. 3. ^ a b Norton, Jeffrey A. (2003). Essential practice of surgery: basic science and clinical evidence. Berlin: Springer. pp. 350. ISBN 0-387-95510-0. 4. ^ Harms, M.D., Roger W. "Why do abdominal muscles sometimes separate during pregnancy?". 5. ^ "University of Pennsylvania Health System \| Penn Medicine". www.pennmedicine.org. 6. ^ Iasiello, F.; Pizza, N. L.; Valente, T.; Stefano, M. L.; Grassi, R.; Muto, R. (2011). "Abdominal hernias: Radiological features". World Journal of Gastrointestinal Endoscopy. 3 (6): 110–117. doi:10.4253/wjge.v3.i6.110. PMC 3158902. PMID 21860678. `\|first1=` missing `\|last1=` (help) 7. ^ "Diastasis recti: MedlinePlus Medical Encyclopedia". medlineplus.gov. Retrieved 2020-10-29. 8. ^ a b c d e Engelhardt, Laura (1988). Comparison of two abdominal exercises on the reduction of the diastasis recti abdominis of postpartum women (Thesis). OCLC 60754579. ProQuest 303651963. 9. ^ a b c Maurice Nahabedian, David C Brooks. "Rectus abdominis diastasis". UpToDate. Retrieved 2018-01-26. Topic 100494 Version 5.0 10. ^ "Diastasis recti: MedlinePlus Medical Encyclopedia". medlineplus.gov. 11. ^ "Diastasis Recti Research and the Tupler Technique® \| Diastasis Rehab with the Tupler Technique® Program providing the best research and evidenced based non-surgical treatment of diastasis recti for women, men and children". diastasisrehab.com. 12. ^ a b c d e f g h Liao, Sharon (February 2012). "15 minutes and you're done: crunch-free abs". Real Simple. Time Inc. 13 (2). ISSN 1528-1701. EBSCOhost 70214001. 13. ^ Michalska, Agata; Rokita, Wojciech; Wolder, Daniel; Pogorzelska, Justyna; Kaczmarczyk, Krzysztof (2018). "Diastasis recti abdominis — a review of treatment methods". Ginekologia Polska. 89 (2): 97–101. doi:10.5603/GP.a2018.0016. PMID 29512814. 14. ^ Saunders (2007). "Definition of quadruped". Dorland's Medical Dictionary for Health Consumers. Elsevier, Inc. Retrieved 11 June 2013. 15. ^ Mommers, Elwin H. H.; Ponten, Jeroen E. H.; Al Omar, Aminah K.; de Vries Reilingh, Tammo S.; Bouvy, Nicole D.; Nienhuijs, Simon W. (December 2017). "The general surgeon's perspective of rectus diastasis. A systematic review of treatment options". Surgical Endoscopy. 31 (12): 4934–4949. doi:10.1007/s00464-017-5607-9. PMC 5715079. PMID 28597282. 16. ^ Palanivelu, C.; Rangarajan, M.; Jategaonkar, P. A.; Amar, V.; Gokul, K. S.; Srikanth, B. (June 2009). "Laparoscopic repair of diastasis recti using the 'Venetian blinds' technique of plication with prosthetic reinforcement: a retrospective study". Hernia. 13 (3): 287–292. doi:10.1007/s10029-008-0464-z. PMID 19214651. S2CID 6184110. ## External links[edit] Classification D * ICD-10: M62.0 * ICD-9-CM: 728.84 External resources * MedlinePlus: 001602 * v * t * e Symptoms and conditions relating to muscle Pain * Myalgia * Fibromyalgia * Acute * Delayed onset Inflammation * Myositis * Pyomyositis Destruction * Muscle weakness * Rhabdomyolysis * Muscle atrophy/Amyotrophy Other * Myositis ossificans * Fibrodysplasia ossificans progressiva * Compartment syndrome * Anterior * Diastasis of muscle * Diastasis recti * Muscle spasm [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA [kDa]: kilodalton [EPC]: Early Prostate Cancer [LAPC]: locally advanced prostate cancer [NSAAs]: nonsteroidal antiandrogens [NSAA]: nonsteroidal antiandrogen [GnRH]: gonadotropin-releasing hormone [ADT]: androgen deprivation therapy [LH]: luteinizing hormone [AR]: androgen receptor [CAB]: combined androgen blockade [LPC]: localized prostate cancer [CPA]: cyproterone acetate [U.S.]: United States [FDA]: Food and Drug Administration	Diastasis recti	c0221766	7,853	wikipedia	https://en.wikipedia.org/wiki/Diastasis_recti	2021-01-18T18:39:30	{"icd-9": ["728.84"], "icd-10": ["M62.0"], "wikidata": ["Q638370"]}
Part of a series on Reading Learning to read * Learning to read Scientific Theories & Models * Dual route theory * Simple view of reading Cognitive processes * Comprehension * Phonemic awareness * Phonological awareness * Subvocalization * Word recognition Reading instruction * Analytical phonics * Basal reader * Guided reading * Independent reading * Literature circle * Phonics * Reciprocal teaching * Structured word inquiry * Synthetic phonics * Whole language Reading rate * Fluency * Slow reading * Speed reading Readability * Readability * Readability test Reading differences & disabilities * Dyslexia * Hyperlexia * Reading disability * Reading for special needs Language * Alphabetic principle * Braille * Dolch word list * Grapheme * History of printing * Language * Languages by writing system * Morpheme * Orthography * Phoneme * Sight word * Vocabulary * Writing * Writing system Literacy * Children's literature * Critical literacy * Close reading * Distant reading * Great books * Literacy * Literature * Literary criticism * Functional illiteracy * Family literacy * v * t * e William-Adolphe Bouguereau, The Difficult Lesson (1884) Hyperlexia is a syndrome characterized by a child's precocious ability to read. It was initially identified by Norman E. Silberberg and Margaret C. Silberberg (1967), who defined it as the precocious ability to read words without prior training in learning to read, typically before the age of 5. They indicated that children with hyperlexia have a significantly higher word-decoding ability than their reading comprehension levels.[1] Children with hyperlexia also present with an intense fascination for written material at a very early age.[2] Hyperlexic children are characterized by word-reading ability well above what would be expected given their age.[3] First named and scientifically described in 1967 (Silverberg and Silverberg), it can be viewed as a superability in which word recognition ability goes far above expected levels of skill.[4] Some hyperlexics, however, have trouble understanding speech.[4] Some experts believe that most children with hyperlexia, or perhaps even all of them, lie on the autism spectrum.[4][2] However, one expert, Darold Treffert, proposes that hyperlexia has subtypes, only some of which overlap with autism.[5][6] Between 5 and 20 percent of autistic children have been estimated to be hyperlexic.[7][8] Hyperlexic children are often fascinated by letters or numbers. They are extremely good at decoding language and thus often become very early readers. Some English-speaking hyperlexic children learn to spell long words (such as elephant) before they are two years old and learn to read whole sentences before they turn three. An fMRI study of a single child showed that hyperlexia may be the neurological opposite of dyslexia.[9][dubious – discuss] ## Contents * 1 Etymology * 2 Development * 3 Types of hyperlexia * 4 Non-English studies * 5 Acquisition * 6 References * 7 Further reading ## Etymology[edit] The word hyperlexia is derived from the Greek terms hyper ("over, beyond, overmuch, above measure")[10] and lexis ("word").[11] ## Development[edit] Although hyperlexic children usually learn to read in a non-communicative way, several studies have shown that they can acquire reading comprehension and communicative language after the onset of hyperlexia.[2] They follow a different developmental trajectory relative to neurotypical individuals, with milestones being acquired in a different order. Despite hyperlexic children's precocious reading ability, they may struggle to communicate. Often, hyperlexic children will have a precocious ability to read but will learn to speak only by rote and heavy repetition, and may also have difficulty learning the rules of language from examples or from trial and error, which may result in social problems. Their language may develop using echolalia, often repeating words and sentences. Often, the child has a large vocabulary and can identify many objects and pictures, but cannot put their language skills to good use. Spontaneous language is lacking and their pragmatic speech is delayed. Hyperlexic children often struggle with Who? What? Where? Why? and How? questions. Between the ages of 4 and 5 years old, many children make great strides in communicating. The social skills of a child with hyperlexia often lag tremendously. Hyperlexic children often have far less interest in playing with other children than do their peers. ## Types of hyperlexia[edit] In one paper, Darold Treffert proposes three types of hyperlexia.[5] Specifically: * Type 1: Neurotypical children who are very early readers. * Type 2: Children on the autism spectrum who demonstrate very early reading as a splinter skill. * Type 3: Very early readers who are not on the autism spectrum, though they exhibit some "autistic-like" traits and behaviours which gradually fade as the child gets older. A different paper by Rebecca Williamson Brown, OD proposes only two types of hyperlexia.[12] These are: * Type 1: Hyperlexia marked by an accompanying language disorder. * Type 2: Hyperlexia marked by an accompanying visual-spatial learning disorder. ## Non-English studies[edit] In studies in Cantonese and Korean, subjects were able to read non-words in their native orthography without a delay relative to the speed with which they read real words in their native orthography. There is a delay noted with exception words in English, including the examples 'chaos', 'unique', and 'enough'. These studies also illustrate difficulties in understanding what it is that they are reading. The findings suggest that non-hyperlexic readers rely more heavily on word semantics in order to make inferences about word meaning.[13][14] The Cantonese study distinguish homographs and determine the readings for rarely used characters. In this study, the subject also made errors of phonetic analogy and regularization of sound. The authors of the study suggest that the two-routes model for reading Chinese characters may be in effect for hyperlexics. The two-routes model describes understanding of Chinese characters in a purely phonetic sense and the understanding of Chinese characters in a semantic sense.[14] The semantics deficit is also illustrated in the study of Korean hyperlexics through a priming experiment. Non-hyperlexic children read words primed with a related image faster than non-primed words while hyperlexics read them at the same pace. Lee Sunghee and Hwang Mina, the authors of the Korean study, also found that hyperlexics have fewer errors in non-word reading than non-hyperlexics. They suggest that this may be because of an imbalance in the phonological, orthographical, and semantic understandings of the subjects’ native language and writing system, in this case, Hangul. This combination of the parts of linguistics is known as connectionist theory, in which non-words are distinguished from words by differences in interaction between phonology, orthography, and semantics.[13] In the Lee and Hwang study, the subjects scored lower on general language test and vocabulary tests than the average for their age groups. Literacy education in South Korea involves teaching students entire words, rather than starting with the relationship between phonemes and letters in Hangul, despite evidence that letter name knowledge is useful for learning to read words that have not been taught. The results suggest that hyperlexics are able to obtain the relations between letters (or the smallest unit of the writing system) and their phonemes without knowing the names.[13][15] Comprehension difficulties can also be a result of hyperlexia. Semantics and comprehension both have ties to meaning. Semantics relates to the meaning of a certain word while comprehension is the understanding of a longer text. In both studies, interpretation-based and meaning-based tests proved difficult for the hyperlexic subjects. In the Weeks study, the subject was unable to identify characters based on the logographic aspect of the writing system, and in the Lee and Hwang study, priming was ineffective in decreasing reading times for hyperlexics.[13][14][15] ## Acquisition[edit] Although it is generally associated with autism, a 69-year-old woman appears to have been made hyperlexic because of a "cerebral infarction in the left anterior cingulate cortex and corpus callosum".[16] ## References[edit] 1. ^ Richman, Lynn, C.; Wood, K.M. (2002). "Learning disability subtypes: classification of high functioning hyperlexia". Brain and Language. 82 (1): 10–21. doi:10.1016/S0093-934X(02)00007-X. PMID 12174811. 2. ^ a b c Ostrolenk, Alexia (May 2017). "Hyperlexia: Systematic review, neurocognitive modelling, and outcome". Neuroscience & Biobehavioral Reviews. 79: 134–149. doi:10.1016/j.neubiorev.2017.04.029. PMID 28478182. 3. ^ Newman, Tina M.; Macomber, Donna; Naples, Adam J.; Babitz, Tammy; Volkmar, Fred; Grigorenko, Elena L. (19 September 2006). "Hyperlexia in Children with Autism Spectrum Disorders" (PDF). Journal of Autism and Developmental Disorders. 37 (4): 760–774. doi:10.1007/s10803-006-0206-y. PMID 17048093. Archived from the original (PDF) on 21 April 2015. Retrieved 12 February 2016. 4. ^ a b c Grigorenko, Elena L.; Klin, Ami; Volkmar, Fred (November 2003). "Annotation: Hyperlexia: disability or superability?". Journal of Child Psychology and Psychiatry. 44 (8): 1079–1091. CiteSeerX 10.1.1.456.6283. doi:10.1111/1469-7610.00193. PMID 14626452. 5. ^ a b Treffert, Darold A. (2011). "Hyperlexia: Reading Precociousness or Savant Skill? Distinguishing autistic-like behaviors from Autistic Disorder". Wisconsin Medical Society. Archived from the original on 23 August 2015. Retrieved 12 February 2016. 6. ^ Treffert, Darold A. (December 2011). "Hyperlexia III: Separating 'Autistic-like' Behaviors from Autistic Disorder; Assessing Children who Read Early or Speak Late" (PDF). WMJ. 110 (6): 281–287. Retrieved 12 February 2016. 7. ^ Burd, Larry; Kerbeshian, Jacob (June 1985). "Hyperlexia and a variant of hypergraphia". Perceptual and Motor Skills. 60 (3): 940–2. doi:10.2466/pms.1985.60.3.940. PMID 3927257. 8. ^ Grigorenko, Elena L.; Klin, Ami; Pauls, David L.; Senft, Riley; Hooper, Catalina; Volkmar, Fred (2002-02-01). "A Descriptive Study of Hyperlexia in a Clinically Referred Sample of Children with Developmental Delays". Journal of Autism and Developmental Disorders. 32 (1): 3–12. doi:10.1023/A:1017995805511. ISSN 0162-3257. PMID 11916330. 9. ^ Turkeltaub, Peter E; Flowers, D.Lynn; Verbalis, Alyssa; Miranda, Martha; Gareau, Lynn; Eden, Guinevere F (January 2004). "The Neural Basis of Hyperlexic Reading: An fMRI Case Study". Neuron. 41 (1): 11–25. doi:10.1016/S0896-6273(03)00803-1. PMID 14715131. 10. ^ Harper, Douglas. "hyper-". Etymonline. Retrieved 2020-05-25. 11. ^ Harper, Douglas. "dyslexia". Etymonline. Retrieved 2020-05-25. 12. ^ Brown, Rebecca Williamson. "Hyperlexia: Related to Vision and Language Problems". NLDline. Retrieved 12 February 2016. 13. ^ a b c d Lee, Sung Hee; Hwang, Mina (1 August 2014). "Word and nonword processing without meaning support in Korean-speaking children with and without hyperlexia". Reading and Writing. 28 (2): 217–238. doi:10.1007/s11145-014-9522-3. 14. ^ a b c Wong, W.; Weekes, B.; Iao, L.; To, K.; Su, I. (October 2013). "Is Reading Aloud Semantically Mediated in Chinese Hyperlexia?". Procedia - Social and Behavioral Sciences. 94: 153–154. doi:10.1016/j.sbspro.2013.09.075. 15. ^ a b Kim, Young-Suk (29 June 2008). "The foundation of literacy skills in Korean: the relationship between letter-name knowledge and phonological awareness and their relative contribution to literacy skills". Reading and Writing. 22 (8): 907–931. doi:10.1007/s11145-008-9131-0. 16. ^ Suzuki, T; Itoh, S; Hayashi, M; Kouno, M; Takeda, K (October 2009). "Hyperlexia and ambient echolalia in a case of cerebral infarction of the left anterior cingulate cortex and corpus callosum". Neurocase. 15 (5): 384–9. doi:10.1080/13554790902842037. PMID 19585352. ## Further reading[edit] * Gilman, Priscilla (2012). The Anti-Romantic Child: A Memoir of Unexpected Joy. Harper Perennial. ISBN 978-0061690280. * Newman, TM; Macomber, D; Naples, AJ; Babitz, T; Volkmar, F; Grigorenko, EL (April 2007). "Hyperlexia in children with autism spectrum disorders". Journal of Autism and Developmental Disorders. 37 (4): 760–74. doi:10.1007/s10803-006-0206-y. PMID 17048093. * Lamônica, DA; Gejão, MG; Prado, LM; Ferreira, AT (2013). "Reading skills in children diagnosed with hyperlexia: case reports". Codas. 25 (4): 391–5. doi:10.1590/S2317-17822013000400016. PMID 24408490. * Treffert, Darold (July 8, 2013). "Oops! When "Autism" Isn't Autistic Disorder: Hyperlexia and Einstein Syndrome". Scientific American Mind. Retrieved December 6, 2017. Look up hyperlexia in Wiktionary, the free dictionary. * v * t * e Pervasive developmental disorders and autism spectrum Main * Causes * Comorbid conditions * Epidemiology * Heritability * Societal and cultural aspects * Medical model * Therapies Diagnoses * Autism spectrum (High-functioning autism * Classic autism * Asperger syndrome * Pervasive developmental disorder not otherwise specified * Childhood disintegrative disorder * Rett syndrome) Related conditions * Alexithymia * Attention deficit hyperactivity disorder * Anxiety disorder (obsessive–compulsive disorder) * Late talker * Epilepsy * Fragile X syndrome * Hyperlexia * Savant syndrome * Sensory processing disorder * Intellectual disability * Developmental coordination disorder * Multiple complex developmental disorder Controversies * Autism rights movement * Autistic enterocolitis * Facilitated communication * MMR vaccine * Rapid prompting method * Thiomersal (Chelation) Diagnostic scales * Gilliam Asperger's disorder scale * 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(Canada) * Geneva Centre for Autism (Canada) Asia * Action for Autism (India) * Autism Resource Centre (Singapore) Caribbean * Autistic Society (Trinidad and Tobago) * Maia Chung Autism and Disabilities Foundation (Jamaica) Europe UK * Autism Anglia * The Autism Directory * Autism Awareness Campaign UK * Autism Cymru * Autism Plus * Autistica * National Autistic Society * Sacar other * Specialisterne (Denmark) * Aspies For Freedom * Alliance Autiste Oceania * Luke Priddis Foundation (Australia) International * Autism rights movement * Wrong Planet Literature Non-fiction * The Accidental Teacher: Life Lessons from My Silent Son * Animals in Translation * Aspergirls: Empowering Females with Asperger's Syndrome * Autism's False Prophets * Extreme Love: Autism * Fall Down 7 Times Get Up 8 * Freaks, Geeks, and Asperger Syndrome: A User Guide to Adolescence * In a Different Key * Life Animated * Like Colour to the Blind * Look Me in the Eye * Mother Warriors * My Autobiography * NeuroTribes * Nobody Nowhere * Overcoming Autism * The Reason I Jump * Somebody Somewhere * Son-Rise: The Miracle Continues * Strange Son * Switched On * Unstrange Minds Fiction * The Curious Incident of the Dog in the Night-Time * Dear John * House Rules * Mockingbird * Saving Max * Speed of Dark * The Winter Journey * With the Light For younger people * Everybody Is Different: A Book for Young People Who Have Brothers or Sisters With Autism * Ian's Walk: A Story about Autism * Marcelo in the Real World * Rage: A Love Story * Rules Journals * Autism * Journal of Autism and Developmental Disorders * Molecular Autism * Research in Autism Spectrum Disorders [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA [kDa]: kilodalton [EPC]: Early Prostate Cancer [LAPC]: locally advanced prostate cancer [NSAAs]: nonsteroidal antiandrogens [NSAA]: nonsteroidal antiandrogen [GnRH]: gonadotropin-releasing hormone [ADT]: androgen deprivation therapy [LH]: luteinizing hormone [AR]: androgen receptor [CAB]: combined androgen blockade [LPC]: localized prostate cancer [CPA]: cyproterone acetate [U.S.]: United States [FDA]: Food and Drug Administration	Hyperlexia	c1855928	7,854	wikipedia	https://en.wikipedia.org/wiki/Hyperlexia	2021-01-18T19:09:21	{"mesh": ["C565500"], "umls": ["C1855928"], "wikidata": ["Q776660"]}
The features of this syndrome, which resembles the Bardet-Biedl syndrome (209900), are iris coloboma, mental retardation, obesity, hypogenitalism, and postaxial polydactyly. The 3 brothers described by Blumel and Kniker (1959) as having the Laurence-Moon-Bardet-Biedl syndrome may have had this condition. Hydrocephalus and hypospadias were also present. Irregular autosomal dominant inheritance is suggested by the segregation of iris coloboma for 4 generations in the family reported by Grebe (1953) and by the occurrence of postaxial polydactyly of the toes in the father and a paternal aunt of the sibs described by Blumel and Kniker (1959). Verloes et al. (1997) proposed a new nosology for the so-called Biemond syndrome type 2 (BS2). They suggested that purported BS2 cases may be divided into: (1) Bardet-Biedl syndrome (see 209901) with fortuitous coloboma or aniridia; (2) BS2 sensu stricto, a recessively inherited syndrome of sexual infantilism, short stature, coloboma, and preaxial polydactyly without obesity, only known from the original report; (3) a 'new' dominantly inherited form of colobomatous microphthalmia occasionally associated with obesity, hypogonadism, and mental retardation (601794), which Verloes et al. (1997) described in their report; (4) a cytogenetically proven Rubinstein-Taybi syndrome (180849) in 1 case; (5) an unclassifiable, early lethal familial syndrome resembling Buntinx-Majewski syndrome (see 249620); and (6) a 'new' coloboma-zygodactyly-clefting syndrome. A chromosomal anomaly was suspected in the last 2 syndromes. INHERITANCE \- Autosomal recessive GROWTH Height \- Short stature HEAD & NECK Eyes \- Iris coloboma SKELETAL Hands \- Preaxial polydactyly NEUROLOGIC Central Nervous System \- Mental retardation \- Hydrocephalus ENDOCRINE FEATURES \- Hypogonadaism ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA [kDa]: kilodalton [EPC]: Early Prostate Cancer [LAPC]: locally advanced prostate cancer [NSAAs]: nonsteroidal antiandrogens [NSAA]: nonsteroidal antiandrogen [GnRH]: gonadotropin-releasing hormone [ADT]: androgen deprivation therapy [LH]: luteinizing hormone [AR]: androgen receptor [CAB]: combined androgen blockade [LPC]: localized prostate cancer [CPA]: cyproterone acetate [U.S.]: United States [FDA]: Food and Drug Administration	BIEMOND SYNDROME II	c1859487	7,855	omim	https://www.omim.org/entry/210350	2019-09-22T16:30:35	{"mesh": ["C565902"], "omim": ["210350"], "orphanet": ["141333"]}
Visual release hallucinations Other namesCharles Bonnet syndrome (CBS) SpecialtyPsychiatry, Ophthalmology Visual release hallucinations, also known as Charles Bonnet syndrome or CBS, are a type of psychophysical visual disturbance and the experience of complex visual hallucinations in a person with partial or severe blindness. First described by Charles Bonnet in 1760,[1][2] the term Charles Bonnet syndrome was first introduced into English-speaking psychiatry in 1982.[3] A related type of hallucination that also occurs with lack of visual input is the closed-eye hallucination. ## Contents * 1 Signs and symptoms * 2 Pathophysiology * 3 Diagnosis * 4 Prognosis * 5 History * 6 Society and culture * 7 See also * 8 References * 9 External links ## Signs and symptoms[edit] People with significant vision loss may have vivid recurrent visual hallucinations (fictive visual percepts).[4] One characteristic of these hallucinations is that they usually are "lilliputian" (hallucinations in which the characters or objects are smaller than normal).[5] Depending on the content, visual hallucinations can be classified as either simple or complex.[4] Simple visual hallucinations are commonly characterized by shapes, photopsias and grid-like patterns.[6] On the other hand, complex visual hallucinations consist of highly detailed representations of people and objects.[6] The most common hallucination is of faces or cartoons.[7] Sufferers understand that the hallucinations are not real, and the hallucinations are only visual, that is, they do not occur in any other senses, e.g. hearing, smell or taste.[8][9] Visual hallucinations generally appear when the eyes are open, fading once the visual gaze shifts.[4] It is widely claimed that sensory deprivation is instrumental in the progression of CBS.[10] During episodes of inactivity, hallucinations are more likely to occur.[4] Majority of those suffering from CBS describe the duration of hallucinations to continue for up to a few minutes, multiple times a day or week.[4] Even though people of all ages may be impacted by Charles Bonnet Syndrome, those within the age range of 70 to 80 are primarily affected.[4] Among older adults (> 65 years) with significant vision loss, the prevalence of Charles Bonnet syndrome has been reported to be between 10% and 40%; a 2008 Australian study found the prevalence to be 17.5%.[2] Two Asian studies, however, report a much lower prevalence.[11][12] The high incidence of underreporting this disorder is the greatest hindrance to determining the exact prevalence.[9] Underreporting is thought to be a result of sufferers being afraid to discuss the symptoms out of fear that they will be labeled of unsound mind.[9] ## Pathophysiology[edit] Anatomical illustration of human neuroanatomy There is no general consensus on the definition of CBS.[6] Predominant factors correlated with CBS are a decrease of visual acuity, visual field loss, and elderly age.[4] While characteristic features of visual hallucinations are not specifically linked to the anatomical site of the ocular injury, they usually match to the location of visual loss.[4] The most commonly accepted theory for Charles Bonnet Syndrome proposes that extreme visual impairment promotes sensory deafferentation, leading to disinhibition, thus resulting in sudden neural firings of the visual cortical regions.[4] A few studies record that visual hallucinations are likely to be concentrated in the blind regions.[10] Functional magnetic resonance imaging (fMRI) of Charles Bonnet Syndrome patients display a relationship between visual hallucinations and activity in the ventral occipital lobe.[4] A connection between age-related macular degeneration (AMD) and colored visual hallucinations has been presented.[6] Color vision signals travel through the parvocellular layers of the lateral geniculate nucleus (LGN), later transmitting down the color regions of the ventral visual pathway.[6] Due to cone photoreceptor damage located in the macula, there is a significant reduction of visual input to the visual association cortex, stirring endogenous activation in the color areas and thus leading to colored hallucinations.[6] Patients with CBS alongside macular degeneration exhibit hyperactivity in the color areas of the visual association cortex (as shown in fMRI’s).[6] Those with significant ocular disease yet maintain visual acuity may still be susceptible to CBS.[6] The Deep Boltzmann Machine (DBM) is a way of utilizing an undirected probabilistic process in a neural framework.[10] Researchers argue that the DBM has the ability to model features of cortical learning, perception, and the visual cortex (the locus of visual hallucinations).[10] Compelling evidence details the role homeostatic operations in the cortex play in regards to stabilizing neuronal activity.[10] By using the DBM, researchers show that when sensory input is absent, neuron excitability is influenced, thus potentially triggering complex hallucinations.[10] Acetylcholine Pathway A short-term change in the levels of feedforward and feedback flows of information may intensely affect the presence of hallucinations.[10] In periods of drowsiness, CBS related hallucinations are more prone to arise.[10] Disrupting cortical homeostatic processes after vision has been lost may prevent or setback the emergence of hallucinations.[10] At varying stages of the cortical grading, acetylcholine (ACh) may impact the balance of thalamic and intracortical inputs as well as the balance in between bottom-up and top-down.[10] Particularly in CBS, a shortage of acetylcholine at cortical locations should correspond to the onset of hallucinations.[10] The syndrome can also develop after bilateral optic nerve damage due to methyl alcohol poisoning.[13] ## Diagnosis[edit] A variety of disciplines including optometry, ophthalmology, geriatric medicine, psychiatry, and neurology play a part in securing the diagnosis of CBS.[6] Since CBS is not commonly recognized by all clinicians, it oftentimes goes misdiagnosed and identified as psychosis, delirium, or dementia.[4] As a result of this, it is estimated that almost 60% of CBS patients hesitate to notify their physicians.[4] By focusing on the specific type of visual hallucination, one may find an accurate diagnosis.[4] If a patient presents symptoms indicative of Charles Bonnet Syndrome, basic laboratory examinations like metabolic panel and blood count tests, as well as neuroimaging, may aid in an accurate diagnosis.[4] ## Prognosis[edit] There is no treatment of proven effectiveness for CBS.[6] For those experiencing CBS, knowing that they are suffering from this syndrome and not a mental illness seems to be the most comforting treatment so far, as it improves their ability to cope with the hallucinations.[6] As time passes from the initial onset of visual hallucinations, studies show that around 60% of those living with CBS feel that visual hallucinations have no effect on their lives, 33% of people feel that the hallucinations are disruptive to their lives, and 7% of people even find pleasure in the hallucinations.[6] A large proportion of those suffering from CBS develop the visual hallucinations as vision begins to deteriorate and stop hallucinating once vision is entirely gone.[10] Complex hallucinations may progress over time if the primary loss of vision is due to damage of the early cortical areas.[10] If activation of the early cortical areas is suppressed when CBS symptoms have already been exhibited, hallucinations may temporarily terminate.[10] Also, interrupting vision for a short time by closing the eyes or blinking may be helpful.[2] It is possible for a stressful life event to alter the disposition of hallucinatory experiences as well as the emotional experiences (from unconcerning to concerning) in CBS.[14] As expressed in some patients, an interplay between CBS and an acute or post-traumatic stress disorder may exist.[14] The role that trauma plays in CBS may affect how and when a hallucinatory episode is triggered.[14] ## History[edit] Charles Bonnet, the first person to describe the syndrome. The disease was first noted by the Swiss naturalist Charles Bonnet, who described the condition in 1760.[4] He documented it in his 89-year-old grandfather[15] who was nearly blind from cataracts in both eyes.[7] After Bonnet’s grandfather received bilateral cataract surgery, his vision evolved from slightly better to complete deterioration over time.[6] It was around this period that his visual hallucinations started.[6] His hallucinations consisted of perceptions of men, women, birds, carriages, buildings, tapestries, physically impossible circumstances and scaffolding patterns.[7][16] Even though his health was in good shape and he had an absence of any psychiatric disorders, the source of the hallucinations remained unknown.[6] At forty years old, Charles Bonnet himself suffered from an unrevealed cause of severe vision loss.[6] In 1967, French-Swiss neurologist, Georges de Morsier, coined the term Charles Bonnet Syndrome in Bonnet's honor.[4] De Morsier’s description of CBS implies a concentrated neurodegeneration, usually occurring in the elderly with typical cognition.[6] In 1936, well-renowned neuropsychiatrists, Jean Lhermitte and Julian de Ajuriaguerra, concluded that visual hallucinations consist of thalamic lesions as well as ocular pathology.[6] This definition contradicted De Morsier’s, as he believed there was no ocular pathology involvement in hallucinations.[6] In psychiatric literature, the most commonly accepted interpretation of CBS is that of Gold and Rabins’.[6] In 1989, they detailed that the hallucinations associated with CBS are not affecting other sensory modalities.[6] They believed that the visual hallucinations are oftentimes stereotyped, persistent, and/or repetitive in nature.[6] ## Society and culture[edit] The syndrome is discussed in * Vilayanur S. Ramachandran's book Phantoms in the Brain. Ramachandran suggests that James Thurber, who was blinded in one eye as a child, may have derived his extraordinary imagination from the syndrome.[17] * Vikram Chandra's book Sacred Games (2006) * David Eagleman's book Incognito: The Secret Lives of the Brain * Oliver Sacks' 2012 book Hallucinations * The Indian movie Jawan of Vellimala released in 2012, where Mammootty is a victim of this disease.[18] * "The Black Canvas" (2014), a chamber opera by the Greek composer Spyros Syrmos, is about a celebrated painter whose visions are caused by CBS. * Margaret Atwood's short story "Torching the Dusties" * Deborah Lawrenson's novel "The Lantern" (2011) * Gareth Brookes' graphic novel A Thousand Coloured Castles (2017) * Dealt, 2017 documentary about notable card engineer Richard Turner * The 2019 Netflix film Velvet Buzzsaw ## See also[edit] * Phantom eye syndrome * Musical ear syndrome – Auditory hallucination associated with hearing loss * Ganzfeld effect – psychological phenomenon * Hypnagogia – State of consciousness in transition from wakefulness to sleep * Anton–Babinski syndrome – Rare symptom of brain damage where sufferers deny being blind ## References[edit] 1. ^ de Morsier, G (1967). "Le syndrome de Charles Bonnet: hallucinations visuelles des vieillards sans deficience mentale" [Charles Bonnet syndrome: visual hallucinations of the elderly without mental impairment]. Ann. Méd.-Psychol. (in French). 125: 677–701. 2. ^ a b c Vukicevic, Meri; Fitzmaurice, Kerry (2008). "Butterflies and black lacy patterns: The prevalence and characteristics of Charles Bonnet hallucinations in an Australian population". Clinical & Experimental Ophthalmology. 36 (7): 659–65. doi:10.1111/j.1442-9071.2008.01814.x. PMID 18983551. S2CID 205492511. 3. ^ Berrios, German E.; Brook, Peter (1982). "The Charles Bonnet Syndrome and the Problem of Visual Perceptual Disorders in the Elderly". Age and Ageing. 11 (1): 17–23. doi:10.1093/ageing/11.1.17. PMID 7041567. 4. ^ a b c d e f g h i j k l m n o p Jan, Tiffany; del Castillo, Jorge (2012). "Visual Hallucinations: Charles Bonnet Syndrome". Western Journal of Emergency Medicine. 13 (6): 544–547. doi:10.5811/westjem.2012.7.12891. ISSN 1936-900X. PMC 3555593. PMID 23357937. 5. ^ Vojniković, Bozo; Radeljak, Sanja; Dessardo, Sandro; Zarković-Palijan, Tija; Bajek, Goran; Linsak, Zeljko (2010). "What associates Charles Bonnet syndrome with age-related macular degeneration?". Collegium Antropologicum. 34 Suppl 2: 45–48. ISSN 0350-6134. PMID 21305724. 6. ^ a b c d e f g h i j k l m n o p q r s t u v Pang, Linda (2016). "Hallucinations Experienced by Visually Impaired: Charles Bonnet Syndrome". Optometry and Vision Science. 93 (12): 1466–1478. doi:10.1097/OPX.0000000000000959. ISSN 1538-9235. PMC 5131689. PMID 27529611. 7. ^ a b c TED2009. "Oliver Sacks: What hallucination reveals about our minds \| Video on". Ted.com. Archived from the original on 2013-07-08. Retrieved 2013-07-03. 8. ^ Schultz, G; Melzack, R (1991). "The Charles Bonnet syndrome: 'phantom visual images'". Perception. 20 (6): 809–25. doi:10.1068/p200809. PMID 1816537. S2CID 22318715. 9. ^ a b c Mogk, Lylas G.; Riddering, Anne; Dahl, David; Bruce, Cathy; Brafford, Shannon (2000). "Charles Bonnet Syndrome In Adults with Visual Impairments from Age-Related Macular Degeneration". In Arditi, Aries; Horowitz, Amy; Lang, Mary Ann; Rosenthal, Bruce; Seidman, Karen; Stuen, Cynthia (eds.). Vision Rehabilitation. pp. 117–9. ISBN 978-90-265-1631-3. 10. ^ a b c d e f g h i j k l m n Reichert, David P.; Series, Peggy; Storkey, Amos J. "Hallucinations in Charles Bonnet Syndrome Induced by Homeostasis: a Deep Boltzmann Machine Model" (PDF). NIPS Proceedings. University of Edinburgh. 11. ^ Tan, C S H; Lim, V. S.; Ho, D. Y.; Yeo, E; Ng, B. Y.; Au Eong, K. G. (2004). "Charles Bonnet syndrome in Asian patients in a tertiary ophthalmic centre". British Journal of Ophthalmology. 88 (10): 1325–9. doi:10.1136/bjo.2004.041947. PMC 1772345. PMID 15377560. 12. ^ Abbott, Emily J.; Connor, Gillian B.; Artes, Paul H.; Abadi, Richard V. (2007). "Visual Loss and Visual Hallucinations in Patients with Age-Related Macular Degeneration (Charles Bonnet Syndrome)". Investigative Ophthalmology & Visual Science. 48 (3): 1416–23. doi:10.1167/iovs.06-0942. PMID 17325191. 13. ^ Olbrich, H. M.; Lodemann, E; Engelmeier, M. P. (1987). "Optical hallucinations in the aged with diseases of the eye". Zeitschrift für Gerontologie. 20 (4): 227–9. PMID 3660920. 14. ^ a b c Vukicevic, Meri (2010-08-02). "Frightening visual hallucinations: atypical presentation of Charles Bonnet syndrome triggered by the Black Saturday bushfires". The Medical Journal of Australia. 193 (3): 181–182. doi:10.5694/j.1326-5377.2010.tb03843.x. PMID 20678049. 15. ^ Bonnet Charles (1760) Essai Analytique sur les facultés de l’âme. Copenhagen: Philibert, pp 426–428 16. ^ "Bonnet's syndrome (Charles Bonnet)". Whonamedit. Archived from the original on 2014-02-23. Retrieved 2013-07-03. 17. ^ V.S. Ramachandran; Sandra Blakeslee (1988). Phantoms in the Brain. HarperCollins. pp. 85–7. 18. ^ "Movie Review: Jawan of Vellimala". NowRunning. Archived from the original on 1 January 2013. Retrieved 14 January 2013. ## External links[edit] * Information on Charles Bonnet syndrome from RNIB * National Public Radio article with an audio segment about Charles Bonnet syndrome * Oliver Sacks: What hallucination reveals about our minds Ted Talk, Feb 2009. * Fortean Times article on Charles Bonnet syndrome * 'Damn Interesting' article on Charles Bonnet syndrome * W Burke (2002). "The neural basis of Charles Bonnet hallucinations: a hypothesis". Journal of Neurology, Neurosurgery & Psychiatry. 73 (5): 535–541. doi:10.1136/jnnp.73.5.535. PMC 1738134. PMID 12397147. Classification D External resources * Patient UK: Visual release hallucinations [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA [kDa]: kilodalton [EPC]: Early Prostate Cancer [LAPC]: locally advanced prostate cancer [NSAAs]: nonsteroidal antiandrogens [NSAA]: nonsteroidal antiandrogen [GnRH]: gonadotropin-releasing hormone [ADT]: androgen deprivation therapy [LH]: luteinizing hormone [AR]: androgen receptor [CAB]: combined androgen blockade [LPC]: localized prostate cancer [CPA]: cyproterone acetate [U.S.]: United States [FDA]: Food and Drug Administration	Visual release hallucinations	c0339731	7,856	wikipedia	https://en.wikipedia.org/wiki/Visual_release_hallucinations	2021-01-18T18:44:10	{"gard": ["10343"], "mesh": ["D000075562"], "umls": ["C0339731"], "wikidata": ["Q921907"]}
Open fracture Gustilo Type 2 fracture SpecialtyOrthopedics An open fracture, also called a compound fracture, is a type of bone fracture in orthopedics that is frequently caused by high energy trauma. It is a bone fracture associated with a break in the skin continuity which can cause complications such as infection, malunion, and nonunion. Gustilo open fracture classification is the most commonly used method to classify open fractures, to guide treatment and to predict clinical outcomes. Advanced trauma life support is the first line of action in dealing with open fractures and to rule out other life-threatening condition in cases of trauma. Cephalosporins are generally the first line of antibiotics. The antibiotics are continued for 24 hours to minimize the risk of infections. Therapeutic irrigation, wound debridement, early wound closure and bone fixation are the main management of open fractures. All these actions aimed to reduce the risk of infections. ## Contents * 1 Causes * 1.1 Common fractures * 1.2 Pathological fractures * 1.3 Fracture-dislocations * 1.4 Gunshot wounds * 2 Diagnosis * 3 Management * 3.1 Acute Management * 3.2 Antibiotics * 3.3 Wound irrigation * 3.4 Wound debridement * 3.5 Surgical management * 3.6 Wound management * 4 Epidemiology * 5 History * 6 References ## Causes[edit] Open fractures can occur due to direct impacts such as high-energy physical forces (trauma), motor vehicular accidents, firearms, and falls from height.[1] Indirect mechanisms include twisting (torsional injuries) and falling from a standing position.[1] These mechanisms are usually associated with substantial degloving of the soft-tissues, but can also have a subtler appearance with a small poke hole and accumulation of clotted blood in the tissues. Depending on the nature of the trauma, it can cause different types of fractures:[2][3] ### Common fractures[edit] Result from significant trauma to the bone. This trauma can come from a variety of forces – a direct blow, axial loading, angular forces, torque, or a mixture of these.[citation needed] ### Pathological fractures[edit] Result from minor trauma to diseased bone. These preexisting processes include metastatic lesions, bone cysts, advanced osteoporosis, etc.[3] ### Fracture-dislocations[edit] Severe injury in which both fracture and dislocation take place simultaneously.[2] ### Gunshot wounds[edit] Caused by high-speed projectiles, they cause damage as they go through the tissue, through secondary shock wave and cavitation.[3] ## Diagnosis[edit] The initial evaluation for open fractures is to rule out any other life-threatening injuries. Advanced Trauma Life Support (ATLS) is the initial protocol to rule out such injuries. Once the patient is stabilised, orthopedic injuries can be evaluated. Mechanism of injury is important to know the amount energy that is transferred to the patient and the level of contamination. Every limb should be exposed to evaluate any other hidden injuries. Characteristics of the wound should be noted in detail. Neurology and the vascular status of the affected limb are important to rule out any nerve or blood vessels injuries. High index of suspicion of compartment syndrome should be maintained for leg and forearm fractures.[4] There are a number of classification systems attempting to categorise open fractures such as Gustilo open fracture classification, Tscherne classification, and Müller AO Classification of fractures. However, Gustilo open fracture classification is the most commonly used classification system. Gustilo system grades the fracture according to energy of injury, soft tissue damage, level of contamination, and comminution of fractures. The higher the grade, the worse the outcome of the fracture.[4] Gustilo open fracture Classification Gustilo Grade Definition I Open fracture, clean wound, wound <1 cm in length II Open fracture, wound > 1 cm but < 10 cm in length[5] without extensive soft-tissue damage, flaps, avulsions IIIA Open fracture with adequate soft tissue coverage of a fractured bone despite extensive soft tissue laceration or flaps, or high-energy trauma (gunshot and farm injuries) regardless of the size of the wound[5][6] IIIB Open fracture with extensive soft-tissue loss and periosteal stripping and bone damage. Usually associated with massive contamination.[5][6] Will often need further soft-tissue coverage procedure (i.e. free or rotational flap) IIIC Open fracture associated with an arterial injury requiring repair, irrespective of degree of soft-tissue injury. However, Gustilo system is not without its limitations. The system has limited interobserver reliability at 50% to 60%. The size of injury on the skin surface does not necessarily reflect the extent of deep underlying soft tissue injury. Therefore, the true grading of Gustilo can only be done in operating theatre.[4] ## Management[edit] ### Acute Management[edit] Urgent interventions, including therapeutic irrigation and wound debridement, are often necessary to clean the area of injury and minimize the risk of infection.[7] Other risks of delayed intervention include long-term complications, such as deep infection, vascular compromise and complete limb loss.[7] After wound irrigation, dry or wet gauze should be applied to the wound to prevent bacterial contamination. Taking photographs of the wound can help to reduce the need of multiple examinations by different doctors, which could be painful. Limb should be reduced and placed in a well-padded splint for immobilization of fractures. Pulses should be documented before and after reduction.[4] Wound cultures are positive in 22% of pre-debridement cultures and 60% of post-debridement cultures of infected cases. Therefore, pre-operative cultures no longer recommended. The value of post-operative cultures is unknown. Tetanus prophylaxis is routinely given to enhance immune response against Clostridium tetani. Anti-tetanus immunoglobulin is only indicated for those with highly contaminated wounds with uncertain vaccination history. Single intramuscular dose of 3000 to 5000 units of tetanus immunoglobulin is given to provide immediate immunity.[4] Another important clinical decision during acute management of open fractures involves the effort to avoid preventable amputations, where functional salvage of the limb is clearly desirable.[7] Care must be taken to ensure this decision is not solely based on an injury severity tool score, but rather a decision made following a full discussion of options between doctors and the person, along with their family and care team.[7] ### Antibiotics[edit] Administration of antibiotics as soon as possible is necessary to reduce the risk of infection. However, antibiotics may not provide necessary benefits in open finger fractures and low velocity firearms injury. First generation cephalosporin (cefazolin) is recommended as first line antibiotics for the treatment of open fractures. The antibiotic is useful against gram positive cocci and gram negative rods such as Escherichia coli, Proteus mirabilis, and Klebsiella pneumoniae. To extend the coverage of antibiotics against more bacteria in Type III Gustilo fractures, combination of first generation cephalosporin and aminoglycoside (gentamicin or tobramycin) or a third generation cephalosporin is recommended to cover against nosocomial gram negative bacilli such as Pseudomonas aeruginosa. Adding penicillin to cover for gas gangrene caused by anaerobic bacteria Clostridium perfringens is a controversial practice. Studies has shown that such practice may not be necessary as the standard antibiotic regimen is enough to cover for Clostridial infections. Antibiotic impregnated devices such as tobramycin impregnated Poly(methyl methacrylate) (PMMA) beads and antibiotic bone cement are helpful in reducing rates of infection.[4] The use of absorbable carriers with implant coatings at the time of surgical fixation is also an effective means of delivering local antibiotics.[8] There has been no agreement on the optimal duration of antibiotics. Studies has shown that there is no additional benefits of risk of infection when giving antibiotics for one day, when compared to giving antibiotics for three days or five days.[4][9] However, at present, there is only low to moderate evidence for this and more research is needed.[9] Some authors recommended that antibiotics to be given for three doses for Gustilo Grade I fractures, for one day after wound closure in Grade II fractures, three days in Grade IIIA fractures, and three days after wound closure for Grade IIIB and IIIC.[4] ### Wound irrigation[edit] There has been no agreement for the optimal solution for wound irrigation. Studies found out that there is no difference in infection rates by using normal saline or other various forms of water (distilled, boiled, or tap).[10] There is also no difference in infection rates when using normal saline with castile soap compared with normal saline together with bacitracin in irrigating wounds. Studies also have shown that there is no difference in infection rates using low pressure pulse lavage (LPPL) when compared to high pressure pulse lavage (HPPL) in irrigating wounds. Optimal amount of fluid for irrigation also has not been established. It is recommended that the amount of irrigation solution to be determined by the severity of the fracture, with 3 litres for type I fractures, 6 litres for type II fractures, and 9 litres for type III fractures.[4] ### Wound debridement[edit] The purpose of wound debridement is to remove all contaminated and non-viable tissues including skin, subcutaneous fat, muscles and bones. Viability of bones and soft tissues are determined by their capacity to bleed. Meanwhile, the viability of muscles is determined by colour, contractility, consistency, and their capacity to bleed. The optimal timing of performing wound debridement and closure is debated and dependent on the severity of the injury, resources and antibiotics available, and individual needs.[11] Debridement time can vary from 6 to 72 hours, and closure time can be immediate (less than 72 hours) or delayed (72 hours to up to 3 months).[11] There is no difference in infection rates for performing surgery within 6 hours of injury when compared to until 72 hours after injury.[4][12] ### Surgical management[edit] Early fracture immobilisation and fixation helps to prevent further soft tissue injury and promotes wound and bone healing. This is especially important in the treatment of intraarticular fractures where early fixation allows early joint motion to prevent joint stiffness. Fracture management depends on the person's overall well being, fracture pattern and location, and the extent of soft tissue injury. Both reamed and unreamed intramedullary nailing are accepted surgical treatments for open tibial fracture.[13] Both techniques have similar rates of postoperative healing, postoperative infection, implant failure and compartment syndrome.[13] Unreamed intramedullary nailing is advantageous because it has a lower incidence of superficial infection and malunion compared to external fixation.[14] However, unreamed intramedullary nailing can result in high rates of hardware failure if a person's weight bearing after surgery is not closely controlled.[14] Compared to external fixation, unreamed intramedullary nailing has similar rates of deep infection, delayed union and nonunion following surgery.[14] For open tibial fractures in children, there is an increasing trend of using orthopedic cast rather than external fixation. Bone grafting is also helpful in fracture repair. However, internal fixation using plates and screws is not recommended as it increase the rate of infection.[4] Amputation is a last resort intervention, and is determined by factors such as tissue viability and coverage, infection, and the extent of damage to the vascular system.[15] ### Wound management[edit] Early wound closure is recommended to reduce the rates hospital-acquired infection. For Grade I and II fractures, wound can be healed by secondary intention or through primary closure. There is conflicting evident to suggest the effectiveness of Negative-pressure wound therapy (vacuum dressing), with several sources citing a decreased risk in infection,[15][16] and others suggesting no proven benefit.[17] ## Epidemiology[edit] Crush injuries are the most common form of injuries, followed by falls from standing height, and road traffic accidents. Open fractures tend to occur more often in males than females at the ratio of 7 to 3 and the age of onset of 40.8 and 56 years respectively. In terms of anatomy location, fractures of finger phalanges are the most common one at the rate of 14 per 100,000 people per year in the general population, followed by fracture of tibia at 3.4 per 100,000 population per year, and distal radius fracture at 2.4 per 100,000 population per year.[4] Infection rates for Gustilo Grade I fractures is 1.4%, followed by 3.6% for Grade II fractures, 22.7% for Grade IIIA fractures, and 10 to 50% of Grade IIIB and IIIC fractures.[18] ## History[edit] Before the 1850s, surgeons usually amputated the limbs for those with open fractures, as it was associated with severe sepsis and gangrene which can be life threatening. It was only until the 20th century, when Joseph Lister adopted the aseptic technique in surgeries, that the rate of death from open fractures reduced from 50% to 9%.[4] ## References[edit] 1. ^ a b Halawi, Mohamad J.; Morwood, Michael P. (November 2015). "Acute Management of Open Fractures: An Evidence-Based Review". Orthopedics. 38 (11): e1025–1033. doi:10.3928/01477447-20151020-12. ISSN 1938-2367. PMID 26558667. S2CID 21482036. 2. ^ a b Vanderhave, Kelly (2015), Doherty, Gerard M. (ed.), "Orthopedic Surgery", CURRENT Diagnosis & Treatment: Surgery (14 ed.), McGraw-Hill Education, retrieved 2018-11-05 3. ^ a b c Menkes, Jeffrey S. (2016), Tintinalli, Judith E.; Stapczynski, J. Stephan; Ma, O. John; Yealy, Donald M. (eds.), "Initial Evaluation and Management of Orthopedic Injuries", Tintinalli’s Emergency Medicine: A Comprehensive Study Guide (8 ed.), McGraw-Hill Education, retrieved 2018-11-05 4. ^ a b c d e f g h i j k l m Mohamad J, Halawi; Michael P, Morwood (8 April 2015). "Acute Management of Open Fractures: An Evidence-Based Review". Orthopaedics. 38 (11): 1026–1033. doi:10.3928/01477447-20151020-12. PMID 26558667. S2CID 21482036. 5. ^ a b c Paul, H Kim; Seth, S Leopold (9 May 2012). "Gustilo-Anderson Classification". Clinical Orthopaedics and Related Research. 470 (11): 3270–3274. doi:10.1007/s11999-012-2376-6. PMC 3462875. PMID 22569719. 6. ^ a b "Ovid: Externer Link". ovidsp.tx.ovid.com. Retrieved 2017-11-10. 7. ^ a b c d National Clinical Guideline Centre (UK) (2016). Fractures (Complex): Assessment and Management. National Institute for Health and Care Excellence: Clinical Guidelines. London: National Institute for Health and Care Excellence (UK). PMID 26913311. 8. ^ Morgenstern, M.; Vallejo, A.; McNally, M. A.; Moriarty, T. F.; Ferguson, J. Y.; Nijs, S.; Metsemakers, W. J. (2018). "The effect of local antibiotic prophylaxis when treating open limb fractures: A systematic review and meta-analysis". Bone & Joint Research. 7 (7): 447–456. doi:10.1302/2046-3758.77.BJR-2018-0043.R1. ISSN 2046-3758. PMC 6076360. PMID 30123494. 9. ^ a b Chang, Yaping; Kennedy, Sean Alexander; Bhandari, Mohit; Lopes, Luciane Cruz; Bergamaschi, Cristiane de Cássia; Carolina de Oliveira E Silva, Maria; Bhatnagar, Neera; Mousavi, S. Mohsen; Khurshid, Saqib (2015-06-09). "Effects of Antibiotic Prophylaxis in Patients with Open Fracture of the Extremities: A Systematic Review of Randomized Controlled Trials". JBJS Reviews. 3 (6): 1. doi:10.2106/JBJS.RVW.N.00088. ISSN 2329-9185. PMID 27490013. S2CID 7011075. 10. ^ Olufemi, Olukemi Temiloluwa; Adeyeye, Adeolu Ikechukwu (2017). "Irrigation solutions in open fractures of the lower extremities: evaluation of isotonic saline and distilled water". Sicot-J. 3: 7. doi:10.1051/sicotj/2016031. ISSN 2426-8887. PMC 5278649. PMID 28134091. 11. ^ a b O'Brien, C.L; Menon, M; Jomha, N.M (2014). "Controversies in the Management of Open Fractures". The Open Orthopaedics Journal. 8 (20): 178–184. doi:10.2174/1874325001408010178. PMC 4110387. PMID 25067972. 12. ^ Davies, James; Roberts, Tobias; Limb, Richard; Mather, David; Thornton, Daniel; Wade, Ryckie G. (2020-02-17). "Time to surgery for open hand injuries and the risk of surgical site infection: a prospective multicentre cohort study" (PDF). Journal of Hand Surgery (European Volume). 45 (6): 622–628. doi:10.1177/1753193420905205. ISSN 1753-1934. PMID 32065001. S2CID 211136445. 13. ^ a b Shao, Yinchu; Zou, Hongxing; Chen, Shaobo; Shan, Jichun (2014-08-23). "Meta-analysis of reamed versus unreamed intramedullary nailing for open tibial fractures". Journal of Orthopaedic Surgery and Research. 9: 74. doi:10.1186/s13018-014-0074-7. ISSN 1749-799X. PMC 4145248. PMID 25149501. 14. ^ a b c Fu, Qiang; Zhu, Lei; Lu, Jiajia; Ma, Jun; Chen, Aimin (2018-08-24). "External Fixation versus Unreamed Tibial Intramedullary Nailing for Open Tibial Fractures: A Meta-analysis of Randomized Controlled Trials". Scientific Reports. 8 (1): 12753. Bibcode:2018NatSR...812753F. doi:10.1038/s41598-018-30716-y. ISSN 2045-2322. PMC 6109134. PMID 30143702. 15. ^ a b Manway, Jeffrey; Highlander, Peter (2014-11-14). "Open Fractures of the Foot and Ankle". Foot & Ankle Specialist. 8 (1): 59–64. doi:10.1177/1938640014557072. ISSN 1938-6400. PMID 25398852. S2CID 8695455. 16. ^ Schlatterer, Daniel R.; Hirschfeld, Adam G.; Webb, Lawrence X. (2015-01-17). "Negative Pressure Wound Therapy in Grade IIIB Tibial Fractures: Fewer Infections and Fewer Flap Procedures?". Clinical Orthopaedics and Related Research. 473 (5): 1802–1811. doi:10.1007/s11999-015-4140-1. ISSN 0009-921X. PMC 4385370. PMID 25595096. 17. ^ Iheozor-Ejiofor, Zipporah; Newton, Katy; Dumville, Jo C; Costa, Matthew L; Norman, Gill; Bruce, Julie (2018-07-03). "Negative pressure wound therapy for open traumatic wounds". Cochrane Database of Systematic Reviews. 7: CD012522. doi:10.1002/14651858.cd012522.pub2. ISSN 1465-1858. PMC 6513538. PMID 29969521. 18. ^ William W, Cross; Marc F, Swiontkowski (October 2008). "Treatment principles in the management of open fractures". Indian Journal of Orthopaedics. 42 (4): 377–386. doi:10.4103/0019-5413.43373. PMC 2740354. PMID 19753224. * v * t * e Fractures and cartilage damage General * Avulsion fracture * Chalkstick fracture * Greenstick fracture * Open fracture * Pathologic fracture * Spiral fracture Head * Basilar skull fracture * Blowout fracture * Mandibular fracture * Nasal fracture * Le Fort fracture of skull * Zygomaticomaxillary complex fracture * Zygoma fracture Spinal fracture * Cervical fracture * Jefferson fracture * Hangman's fracture * Flexion teardrop fracture * Clay-shoveler fracture * Burst fracture * Compression fracture * Chance fracture * Holdsworth fracture Ribs * Rib fracture * Sternal fracture Shoulder fracture * Clavicle * Scapular Arm fracture Humerus fracture: * Proximal * Supracondylar * Holstein–Lewis fracture Forearm fracture: * Ulna fracture * Monteggia fracture * Hume fracture * Radius fracture/Distal radius * Galeazzi * Colles' * Smith's * Barton's * Essex-Lopresti fracture Hand fracture * Scaphoid * Rolando * Bennett's * Boxer's * Busch's Pelvic fracture * Duverney fracture * Pipkin fracture Leg Tibia fracture: * Bumper fracture * Segond fracture * Gosselin fracture * Toddler's fracture * Pilon fracture * Plafond fracture * Tillaux fracture Fibular fracture: * Maisonneuve fracture * Le Fort fracture of ankle * Bosworth fracture Combined tibia and fibula fracture: * Trimalleolar fracture * Bimalleolar fracture * Pott's fracture Crus fracture: * Patella fracture Femoral fracture: * Hip fracture Foot fracture * Lisfranc * Jones * March * Calcaneal [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA [kDa]: kilodalton [EPC]: Early Prostate Cancer [LAPC]: locally advanced prostate cancer [NSAAs]: nonsteroidal antiandrogens [NSAA]: nonsteroidal antiandrogen [GnRH]: gonadotropin-releasing hormone [ADT]: androgen deprivation therapy [LH]: luteinizing hormone [AR]: androgen receptor [CAB]: combined androgen blockade [LPC]: localized prostate cancer [CPA]: cyproterone acetate [U.S.]: United States [FDA]: Food and Drug Administration	Open fracture	c0016662	7,857	wikipedia	https://en.wikipedia.org/wiki/Open_fracture	2021-01-18T19:04:30	{"mesh": ["D005597"], "wikidata": ["Q3080304"]}
Not to be confused with insomnia. Chronic mismatch between a person's normal daily rhythm, compared to other people and societal norms Delayed sleep phase disorder Other namesDelayed sleep–wake phase disorder, delayed sleep phase syndrome, delayed sleep phase type Comparison of standard (green) and DSPD (blue) circadian rhythms SpecialtyPsychiatry, sleep medicine Delayed sleep phase disorder (DSPD), more often known as delayed sleep phase syndrome and also as delayed sleep–wake phase disorder, is a chronic dysregulation of a person's circadian rhythm (biological clock), compared to those of the general population and societal norms. The disorder affects the timing of sleep, peak period of alertness, the core body temperature, rhythm, hormonal as well as other daily cycles. People with DSPD generally fall asleep some hours after midnight and have difficulty waking up in the morning.[1] People with DSPD probably have a circadian period significantly longer than 24 hours.[2] Depending on the severity, the symptoms can be managed to a greater or lesser degree, but no cure is known, and research suggests a genetic origin for the disorder.[3] Affected people often report that while they do not get to sleep until the early morning, they do fall asleep around the same time every day. Unless they have another sleep disorder such as sleep apnea in addition to DSPD, patients can sleep well and have a normal need for sleep. However, they find it very difficult to wake up in time for a typical school or work day. If they are allowed to follow their own schedules, e.g. sleeping from 4:00 am to 1:00 pm, their sleep is improved and they may not experience excessive daytime sleepiness.[4] Attempting to force oneself onto daytime society's schedule with DSPD has been compared to constantly living with jet lag; DSPD has been called "social jet lag".[5] Researchers in 2017 linked DSPD to at least one genetic mutation.[3] The syndrome usually develops in early childhood or adolescence.[6] An adolescent version may disappear in late adolescence or early adulthood; otherwise, DSPD is a lifelong condition. The best estimate of prevalence among adults is 0.13–0.17% (1 in 600).[7][8] Prevalence among adolescents is as much as 7–16%.[4] DSPD was first formally described in 1981 by Elliot D. Weitzman and others at Montefiore Medical Center.[9] It is responsible for 7–13% of patient complaints of chronic insomnia.[10] However, since many doctors are unfamiliar with the condition, it often goes untreated or is treated inappropriately; DSPD is often misdiagnosed as primary insomnia or as a psychiatric condition.[11] DSPD can be treated or helped in some cases by careful daily sleep practices, morning light therapy, evening dark therapy, earlier exercise and meal times, and medications such as aripiprazole, melatonin, and modafinil; melatonin is a natural neurohormone partly responsible for the human body clock. At its most severe and inflexible, DSPD is a disability. A chief difficulty of treating DSPD is in maintaining an earlier schedule after it has been established, as the patient's body has a strong tendency to reset the sleeping schedule to its intrinsic late times. People with DSPD may improve their quality of life by choosing careers that allow late sleeping times, rather than forcing themselves to follow a conventional 9-to-5 work schedule. ## Contents * 1 Presentation * 1.1 Comorbidity * 1.1.1 Depression * 1.1.2 Attention deficit hyperactivity disorder * 1.1.3 Overweight * 1.1.4 Obsessive–compulsive disorder * 2 Mechanism * 3 Diagnosis * 3.1 Definition * 4 Management * 4.1 Non-pharmacological * 4.2 Pharmacological * 5 Prognosis * 5.1 Risk of relapse * 5.2 Adaptation to late sleeping times * 5.3 Impact on patients * 6 Epidemiology * 7 See also * 8 References * 9 External links ## Presentation[edit] ### Comorbidity[edit] #### Depression[edit] In the DSPD cases reported in the literature, about half of the patients have suffered from clinical depression or other psychological problems, about the same proportion as among patients with chronic insomnia.[12] According to the ICSD: > Although some degree of psychopathology is present in about half of adult patients with DSPD, there appears to be no particular psychiatric diagnostic category into which these patients fall. Psychopathology is not particularly more common in DSPD patients compared to patients with other forms of "insomnia." ... Whether DSPD results directly in clinical depression, or vice versa, is unknown, but many patients express considerable despair and hopelessness over sleeping normally again.[12] A direct neurochemical relationship between sleep mechanisms and depression is another possibility.[5] DSPD may cause excessive or inappropriate production of melatonin. Serotonin, a mood regulator, is the precursor of melatonin. As a result, increased endogenous melatonin production can deplete serotonin levels and may cause depression.[citation needed] It is conceivable that DSPD has a role in causing depression because it can be such a stressful and misunderstood disorder. A 2008 study from the University of California, San Diego found no association of bipolar disorder (history of mania) with DSPD, and it states that > there may be behaviorally-mediated mechanisms for comorbidity between DSPD and depression. For example, the lateness of DSPD cases and their unusual hours may lead to social opprobrium and rejection, which might be depressing.[13] The fact that half of DSPD patients are not depressed indicates that DSPD is not merely a symptom of depression. Sleep researcher Michael Terman has suggested that those who follow their internal circadian clocks may be less likely to suffer from depression than those trying to live on a different schedule.[14] DSPD patients who also suffer from depression may be best served by seeking treatment for both problems. There is some evidence[clarification needed] that effectively treating DSPD can improve the patient's mood and make antidepressants more effective.[15] Vitamin D deficiency has been linked to depression. As it is a condition which comes from lack of exposure to sunlight, anyone who does not get enough sunlight exposure during daylight hours (about 20 to 30 minutes three times a week, depending on skin tone, latitude, and the time of year[16]) could be at risk, without adequate dietary sources or supplements. #### Attention deficit hyperactivity disorder[edit] DSPD is genetically linked to attention deficit hyperactivity disorder by findings of polymorphism in genes in common between those apparently involved in ADHD and those involved in the circadian rhythm[17][18] and a high proportion of DSPD among those with ADHD.[19] #### Overweight[edit] A 2019 study from Boston showed a relationship of evening chronotypes and greater social jet lag with greater body weight / adiposity in adolescent girls, but not boys, independent of sleep duration.[20] #### Obsessive–compulsive disorder[edit] Persons with obsessive–compulsive disorder are also diagnosed with DSPD at a much higher rate than the general public.[21] ## Mechanism[edit] Main article: Circadian rhythm sleep disorder DSPD is a disorder of the body's timing system—the biological clock. Individuals with DSPD might have an unusually long circadian cycle, might have a reduced response to the resetting effect of daylight on the body clock, and/or may respond overly to the delaying effects of evening light and too little to the advancing effect of light earlier in the day.[22] In support of the increased sensitivity to evening light hypothesis, "the percentage of melatonin suppression by a bright light stimulus of 1,000 lux administered 2 hours prior to the melatonin peak has been reported to be greater in 15 DSPD patients than in 15 controls."[23] The altered phase relationship between the timing of sleep and the circadian rhythm of body core temperature has been reported previously in DSPD patients studied in entrained conditions. That such an alteration has also been observed in temporal isolation (free-running clock) supports the notion that the etiology of DSPD goes beyond simply a reduced capacity to achieve and maintain the appropriate phase relationship between sleep timing and the 24-hour day. Rather, the disorder may also reflect a fundamental inability of the endogenous circadian timing system to maintain normal internal phase relationships among physiological systems, and to properly adjust those internal relationships within the confines of the 24-hour day. In normal subjects, the phase relationship between sleep and temperature changes in temporal isolation relative to that observed under entrained conditions: in isolation, tmin tends to occur toward the beginning of sleep, whereas under entrained conditions, tmin occurs toward the end of the sleep period—a change in phase angle of several hours; DSPD patients may have a reduced capacity to achieve such a change in phase angle in response to entrainment.[citation needed] Possibly as a consequence of these altered internal phase relationships, that the quality of sleep in DSPD may be substantially poorer than that of normal subjects, even when bedtimes and wake times are self-selected. A DSPD subject exhibited an average sleep onset latency twice that of the 3 control subjects and almost twice the amount of wakefulness after sleep onset (WASO) as control subjects, resulting in significantly poorer sleep efficiency. Also, the temporal distribution of slow wave sleep was significantly altered in the DSPD subject. This finding may suggest that, in addition to abnormal circadian clock function, DSPD may be characterized by alteration(s) in the homeostatic regulation of sleep, as well. Specifically, the rate with which Process S is depleted during sleep may be slowed. This could, conceivably, contribute to the excessive sleep inertia upon awakening that is often reported by DSPD sufferers. It has also been hypothesized that, due to the altered phase angle between sleep and temperature observed in DSPD, and the tendency for longer sleep periods, these individuals may simply sleep through the phase-advance portion of the light PRC. Though quite limited in terms of the total number of DSPD patients studied, such data seem to contradict the notion that DSPD is merely a disorder of sleep timing, rather than a disorder of the sleep system itself.[24] People with normal circadian systems can generally fall asleep quickly at night if they slept too little the night before. Falling asleep earlier will in turn automatically help to advance their circadian clocks due to decreased light exposure in the evening. In contrast, people with DSPD have difficulty falling asleep before their usual sleep time, even if they are sleep-deprived. Sleep deprivation does not reset the circadian clock of DSPD patients, as it does with normal people.[25] People with the disorder who try to live on a normal schedule cannot fall asleep at a "reasonable" hour and have extreme difficulty waking because their biological clocks are not in phase with that schedule. Non-DSPD people who do not adjust well to working a night shift have similar symptoms (diagnosed as shift-work sleep disorder). In most cases, it is not known what causes the abnormality in the biological clocks of DSPD patients. DSPD tends to run in families,[26] and a growing body of evidence suggests that the problem is associated with the hPer3 (human period 3) gene[27][28] and CRY1 gene.[3] There have been several documented cases of DSPD and non-24-hour sleep–wake disorder developing after traumatic head injury.[29][30] There have been cases of DSPD developing into non-24-hour sleep–wake disorder, a severe and debilitating disorder in which the individual sleeps later each day.[5] ## Diagnosis[edit] A sleep diary with nighttime at the top and the weekend in the middle, to better notice trends DSPD is diagnosed by a clinical interview, actigraphic monitoring, and/or a sleep diary kept by the patient for at least two weeks. When polysomnography is also used, it is primarily for the purpose of ruling out other disorders such as narcolepsy or sleep apnea. If a person can adjust to a normal daytime schedule on their own, with just the help of alarm clocks and will-power, the diagnosis is not given.[citation needed] DSPD is frequently misdiagnosed or dismissed. It has been named as one of the sleep disorders most commonly misdiagnosed as a primary psychiatric disorder.[31] DSPD is often confused with: psychophysiological insomnia; depression; psychiatric disorders such as schizophrenia, ADHD or ADD; other sleep disorders; or school refusal. Practitioners of sleep medicine point out the dismally low rate of accurate diagnosis of the disorder, and have often asked for better physician education on sleep disorders.[32] ### Definition[edit] According to the International Classification of Sleep Disorders, Revised (ICSD-R, 2001),[12] the circadian rhythm sleep disorders share a common underlying chronophysiologic basis: > The major feature of these disorders is a misalignment between the patient's sleep-wake pattern and the pattern that is desired or regarded as the societal norm... In most circadian rhythm sleep disorders, the underlying problem is that the patient cannot sleep when sleep is desired, needed or expected. Incorporating minor updates (ICSD-3, 2014),[33] the diagnostic criteria for delayed sleep phase disorder are: > 1. An intractable delay in the phase of the major sleep period occurs in relation to the desired clock time, as evidenced by a chronic or recurrent (for at least three months) complaint of inability to fall asleep at a desired conventional clock time together with the inability to awaken at a desired and socially acceptable time. > 2. When not required to maintain a strict schedule, patients exhibit improved sleep quality and duration for their age and maintain a delayed phase of entrainment to local time. > 3. Patients have little or no reported difficulty in maintaining sleep once sleep has begun. > 4. Patients have a relatively severe to absolute inability to advance the sleep phase to earlier hours by enforcing conventional sleep and wake times. > 5. Sleep–wake logs and/or actigraphy monitoring for at least two weeks document a consistent habitual pattern of sleep onsets, usually later than 2 am, and lengthy sleeps. > 6. Occasional noncircadian days may occur (i.e., sleep is "skipped" for an entire day and night plus some portion of the following day), followed by a sleep period lasting 12 to 18 hours. > 7. The symptoms do not meet the criteria for any other sleep disorder causing inability to initiate sleep or excessive sleepiness. > 8. If one of the following laboratory methods is used, it must demonstrate a significant delay in the timing of the habitual sleep period: 1) 24-hour polysomnographic monitoring (or two consecutive nights of polysomnography and an intervening multiple sleep latency test), 2) Continuous temperature monitoring showing that the time of the absolute temperature nadir is delayed into the second half of the habitual (delayed) sleep episode. > Some people with the condition adapt their lives to the delayed sleep phase, avoiding morning business hours as much as possible. The ICSD's severity criteria are: * Mild: Two-hour delay (relative to the desired sleep time) associated with little or mild impairment of social or occupational functioning. * Moderate: Three-hour delay associated with moderate impairment. * Severe: Four-hour delay associated with severe impairment. Some features of DSPD which distinguish it from other sleep disorders are: * People with DSPD have at least a normal—and often much greater than normal—ability to sleep during the morning, and sometimes in the afternoon as well. In contrast, those with chronic insomnia do not find it much easier to sleep during the morning than at night. * People with DSPD fall asleep at more or less the same time every night, and sleep comes quite rapidly if the person goes to bed near the time they usually fall asleep. Young children with DSPD resist going to bed before they are sleepy, but the bedtime struggles disappear if they are allowed to stay up until the time they usually fall asleep. * DSPD patients usually sleep well and regularly when they can follow their own sleep schedule, e.g., on weekends and during vacations. * DSPD is a chronic condition. Symptoms must have been present for at least three months before a diagnosis of DSPD can be made.[33] Often people with DSPD manage only a few hours sleep per night during the working week, then compensate by sleeping until the afternoon on weekends. Sleeping late on weekends, and/or taking long naps during the day, may give people with DSPD relief from daytime sleepiness but may also perpetuate the late sleep phase.[citation needed] People with DSPD can be called "night owls". They feel most alert and say they function best and are most creative in the evening and at night. People with DSPD cannot simply force themselves to sleep early. They may toss and turn for hours in bed, and sometimes not sleep at all, before reporting to work or school. Less-extreme and more-flexible night owls are within the normal chronotype spectrum.[citation needed] By the time those who have DSPD seek medical help, they usually have tried many times to change their sleeping schedule. Failed tactics to sleep at earlier times may include maintaining proper sleep hygiene, relaxation techniques, early bedtimes, hypnosis, alcohol, sleeping pills, dull reading, and home remedies. DSPD patients who have tried using sedatives at night often report that the medication makes them feel tired or relaxed, but that it fails to induce sleep. They often have asked family members to help wake them in the morning, or they have used multiple alarm clocks. As the disorder occurs in childhood and is most common in adolescence, it is often the patient's parents who initiate seeking help, after great difficulty waking their child in time for school.[citation needed] The current formal name established in the third edition of the International Classification of Sleep Disorders (ICSD-3) is delayed sleep-wake phase disorder. Earlier, and still common, names include delayed sleep phase disorder (DSPD), delayed sleep phase syndrome (DSPS), and circadian rhythm sleep disorder, delayed sleep phase type (DSPT).[34] ## Management[edit] Treatment, a set of management techniques, is specific to DSPD. It is different from treatment of insomnia, and recognizes the patients' ability to sleep well on their own schedules, while addressing the timing problem. Success, if any, may be partial; for example, a patient who normally awakens at noon may only attain a wake time of 10 or 10:30 with treatment and follow-up. Being consistent with the treatment is paramount.[citation needed] Before starting DSPD treatment, patients are often asked to spend at least a week sleeping regularly, without napping, at the times when the patient is most comfortable. It is important for patients to start treatment well-rested.[citation needed] ### Non-pharmacological[edit] One treatment strategy is light therapy (phototherapy), with either a bright white lamp providing 10,000 lux at a specified distance from the eyes or a wearable LED device providing 350–550 lux at a shorter distance. Sunlight can also be used. The light is typically timed for 30–90 minutes at the patient's usual time of spontaneous awakening, or shortly before (but not long before), which is in accordance with the phase response curve (PRC) for light. Only experimentation, preferably with specialist help, will show how great an advance is possible and comfortable. For maintenance, some patients must continue the treatment indefinitely; some may reduce the daily treatment to 15 minutes; others may use the lamp, for example, just a few days a week or just every third week. Whether the treatment is successful is highly individual. Light therapy generally requires adding some extra time to the patient's morning routine. Patients with a family history of macular degeneration are advised to consult with an eye doctor. The use of exogenous melatonin administration (see below) in conjunction with light therapy is common.[citation needed] Light restriction in the evening, sometimes called darkness therapy or scototherapy, is another treatment strategy. Just as bright light upon awakening should advance one's sleep phase, bright light in the evening and night delays it (see the PRC). It is suspected that DSPD patients may be overly sensitive to evening light.[35] The photopigment of the retinal photosensitive ganglion cells, melanopsin, is excited by light mainly in the blue portion of the visible spectrum (absorption peaks at ~480 nanometers).[36][37] A formerly popular treatment, phase delay chronotherapy, is intended to reset the circadian clock by manipulating bedtimes. It consists of going to bed two or more hours later each day for several days until the desired bedtime is reached, and it often must be repeated every few weeks or months to maintain results. Its safety is uncertain,[38] notably because it has led to the development of non-24-hour sleep-wake rhythm disorder, a much more severe disorder.[5] A modified chronotherapy is called controlled sleep deprivation with phase advance, SDPA. One stays awake one whole night and day, then goes to bed 90 minutes earlier than usual and maintains the new bedtime for a week. This process is repeated weekly until the desired bedtime is reached.[39] Earlier exercise and meal times can also help promote earlier sleep times.[40] ### Pharmacological[edit] Aripiprazole (brand name Abilify) is an atypical antipsychotic that has been shown to be effective in treating DSPD by advancing sleep onset, sleep midpoint, and sleep offset at relatively low doses.[41][42] Phase response curves for light and for melatonin administration Melatonin taken an hour or so before the usual bedtime may induce sleepiness. Taken this late, it does not, of itself, affect circadian rhythms,[43] but a decrease in exposure to light in the evening is helpful in establishing an earlier pattern. In accordance with its phase response curve (PRC), a very small dose of melatonin can also, or instead, be taken some hours earlier as an aid to resetting the body clock;[44] it must then be small enough not to induce excessive sleepiness. Side effects of melatonin may include sleep disturbance, nightmares, daytime sleepiness, and depression, though the current tendency to use lower doses has decreased such complaints. Large doses of melatonin can even be counterproductive: Lewy et al.[45] provide support to "the idea that too much melatonin may spill over onto the wrong zone of the melatonin phase-response curve." The long-term effects of melatonin administration have not been examined. In some countries, the hormone is available only by prescription or not at all. In the United States and Canada, melatonin is on the shelf of most pharmacies and herbal stores. The prescription drug Rozerem (ramelteon) is a melatonin analogue that selectively binds to the melatonin MT1 and MT2 receptors and, hence, has the possibility of being effective in the treatment of DSPD.[citation needed] A review by the US Department of Health and Human Services found little difference between melatonin and placebo for most primary and secondary sleep disorders. The one exception, where melatonin is effective, is the "circadian abnormality" DSPD.[46] Another systematic review found inconsistent evidence for the efficacy of melatonin in treating DSPD in adults, and noted that it was difficult to draw conclusions about its efficacy because many recent studies on the subject were uncontrolled.[47] Modafinil (brand name Provigil) is a stimulant approved in the US for treatment of shift-work sleep disorder, which shares some characteristics with DSPD. A number of clinicians prescribe it for DSPD patients, as it may improve a sleep-deprived patient's ability to function adequately during socially desirable hours. It is generally not recommended to take modafinil after noon; modafinil is a relatively long-acting drug with a half-life of 15 hours, and taking it during the later part of the day can make it harder to fall asleep at bedtime.[48] Vitamin B12 was, in the 1990s, suggested as a remedy for DSPD, and is still recommended by some sources. Several case reports were published. However, a review for the American Academy of Sleep Medicine in 2007 concluded that no benefit was seen from this treatment.[49] ## Prognosis[edit] ### Risk of relapse[edit] A strict schedule and good sleep hygiene are essential in maintaining any good effects of treatment. With treatment, some people with mild DSPD may sleep and function well with an earlier sleep schedule. Caffeine and other stimulant drugs to keep a person awake during the day may not be necessary and should be avoided in the afternoon and evening, in accordance with good sleep hygiene. A chief difficulty of treating DSPD is in maintaining an earlier schedule after it has been established. Inevitable events of normal life, such as staying up late for a celebration or deadline, or having to stay in bed with an illness, tend to reset the sleeping schedule to its intrinsic late times.[citation needed] Long-term success rates of treatment have seldom been evaluated. However, experienced clinicians acknowledge that DSPD is extremely difficult to treat. One study of 61 DSPD patients, with average sleep onset at about 3:00 am and average waking time of about 11:30 am, was followed with questionnaires to the subjects after a year. Good effect was seen during the six-week treatment with a large daily dose of melatonin. After ceasing melatonin use over 90% had relapsed to pre-treatment sleeping patterns within the year, 29% reporting that the relapse occurred within one week. The mild cases retained changes significantly longer than the severe cases.[50] ### Adaptation to late sleeping times[edit] Working the evening or night shift, or working at home, makes DSPD less of an obstacle for some. Many of these people do not describe their pattern as a "disorder". Some DSPD individuals nap, even taking 4–5 hours of sleep in the morning and 4–5 in the evening. DSPD-friendly careers can include security work, the entertainment industry, hospitality work in restaurants, theaters, hotels or bars, call center work, manufacturing, emergency medicine, commercial cleaning, taxi or truck driving, the media, and freelance writing, translation, IT work, or medical transcription. Some other careers that have an emphasis on early morning work hours, such as bakers, coffee baristas, pilots and flight crews, teachers, mail carriers, waste collection, and farming, can be particularly difficult for people who naturally sleep later than is typical. Some careers, such as over-the-road truck drivers, firefighters, law enforcement, nursing, can be suitable for both people with delayed sleep phase syndrome and people with the opposite condition, advanced sleep phase disorder, as these workers are needed both very early in the morning and also late at night.[51] Some people with the disorder are unable to adapt to earlier sleeping times, even after many years of treatment. Sleep researchers Dagan and Abadi have proposed that the existence of untreatable cases of DSPD be formally recognized as a "sleep-wake schedule disorder (SWSD) disability", an invisible disability.[52] Rehabilitation for DSPD patients includes acceptance of the condition and choosing a career that allows late sleeping times or running a home business with flexible hours. In a few schools and universities, students with DSPD have been able to arrange to take exams at times of day when their concentration levels may be good. > Patients suffering from SWSD disability should be encouraged to accept the fact that they suffer from a permanent disability, and that their quality of life can only be improved if they are willing to undergo rehabilitation. It is imperative that physicians recognize the medical condition of SWSD disability in their patients and bring it to the notice of the public institutions responsible for vocational and social rehabilitation.[52] In the United States, the Americans with Disabilities Act requires that employers make reasonable accommodations for employees with sleeping disorders. In the case of DSPD, this may require that the employer accommodate later working hours for jobs normally performed on a "9 to 5" work schedule.[53] The statute defines "disability" as a "physical or mental impairment that substantially limits one or more major life activities", and Section 12102(2)(a) itemizes sleeping as a "major life activity".[54] ### Impact on patients[edit] Lack of public awareness of the disorder contributes to the difficulties experienced by people with DSPD, who are commonly stereotyped as undisciplined or lazy. Parents may be chastised for not giving their children acceptable sleep patterns, and schools and workplaces rarely tolerate chronically late, absent, or sleepy students and workers, failing to see them as having a chronic illness. > By the time DSPD sufferers receive an accurate diagnosis, they often have been misdiagnosed or labelled as lazy and incompetent workers or students for years. Misdiagnosis of circadian rhythm sleep disorders as psychiatric conditions causes considerable distress to patients and their families, and leads to some patients being inappropriately prescribed psychoactive drugs. For many patients, diagnosis of DSPD is itself a life-changing breakthrough.[52] As DSPD is so little-known and so misunderstood, peer support may be important for information, self-acceptance, and future research studies.[55][56][57] People with DSPD who force themselves to follow a normal 9–5 workday "are not often successful and may develop physical and psychological complaints during waking hours, e.g., sleepiness, fatigue, headache, decreased appetite, or depressed mood. Patients with circadian rhythm sleep disorders often have difficulty maintaining ordinary social lives, and some of them lose their jobs or fail to attend school."[5] ## Epidemiology[edit] There have been several studies that have attempted to estimate the prevalence of DSPD. Results vary due to differences in methods of data collection and diagnostic criteria. A particular issue is where to draw the line between extreme evening chronotypes and clinical DSPD.[58] Using the ICSD-1 diagnostic criteria (current edition ICSD-3) a study by telephone questionnaire in 1993 of 7,700 randomly selected adults (aged 18–67) in Norway estimated the prevalence of DSPD at 0.17%.[7] A similar study in 1999 of 1,525 adults (aged 15–59) in Japan estimated its prevalence at 0.13%.[8] A somewhat higher prevalence of 0.7% was found in a 1995 San Diego study.[58] A 2014 study of 9100 New Zealand adults (age 20–59) using a modified version of the Munich Chronotype Questionnaire found a DSPD prevalence of 1.5% to 8.9% depending on the strictness of the definition used.[59] A 2002 study of older adults (age 40–65) in San Diego found 3.1% had complaints of difficulty falling asleep at night and waking in the morning, but did not apply formal diagnostic criteria.[60] Actimetry readings showed only a small proportion of this sample had delays of sleep timing.[citation needed] A marked delay of sleep patterns is a normal feature of the development of adolescent humans. 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S2CID 44634036. ## External links[edit] Classification D * ICD-10: G47.2 * ICD-9-CM: 327.31 * MeSH: D021081 External resources * eMedicine: neuro/655 * v * t * e Sleep and sleep disorders Stages of sleep cycles * Rapid eye movement (REM) * Non-rapid eye movement * Slow-wave Brain waves * Alpha wave * Beta wave * Delta wave * Gamma wave * K-complex * Mu rhythm * PGO waves * Sensorimotor rhythm * Sleep spindle * Theta wave Sleep disorders Dyssomnia * Excessive daytime sleepiness * Hypersomnia * Insomnia * Kleine–Levin syndrome * Narcolepsy * Night eating syndrome * Nocturia * Sleep apnea * Catathrenia * Central hypoventilation syndrome * Obesity hypoventilation syndrome * Obstructive sleep apnea * Periodic breathing * Sleep state misperception Circadian rhythm disorders * Advanced sleep phase disorder * Cyclic alternating pattern * Delayed sleep phase disorder * Irregular sleep–wake rhythm * Jet lag * Non-24-hour sleep–wake disorder * Shift work sleep disorder Parasomnia * Bruxism * Nightmare disorder * Night terror * Periodic limb movement disorder * Rapid eye movement sleep behavior disorder * Sleepwalking * Somniloquy Benign phenomena * Dreams * Exploding head syndrome * Hypnic jerk * Hypnagogia / Sleep onset * Hypnopompic state * Sleep paralysis * Sleep inertia * Somnolence * Nocturnal clitoral tumescence * Nocturnal penile tumescence * Nocturnal emission Treatment * Sleep diary * Sleep hygiene * Sleep induction * Hypnosis * Lullaby * Somnology * Polysomnography Other * Sleep medicine * Behavioral sleep medicine * Sleep study Daily life * Bed * Bunk bed * Daybed * Four-poster bed * Futon * Hammock * Mattress * Sleeping bag * Bed bug * Bedding * Bedroom * Bedtime * Bedtime story * Bedtime toy * Biphasic and polyphasic sleep * Chronotype * Dream diary * Microsleep * Mouth breathing * Nap * Nightwear * Power nap * Second wind * Siesta * Sleep and creativity * Sleep and learning * Sleep deprivation / Sleep debt * Sleeping while on duty * Sleepover * Snoring [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA [kDa]: kilodalton [EPC]: Early Prostate Cancer [LAPC]: locally advanced prostate cancer [NSAAs]: nonsteroidal antiandrogens [NSAA]: nonsteroidal antiandrogen [GnRH]: gonadotropin-releasing hormone [ADT]: androgen deprivation therapy [LH]: luteinizing hormone [AR]: androgen receptor [CAB]: combined androgen blockade [LPC]: localized prostate cancer [CPA]: cyproterone acetate [U.S.]: United States [FDA]: Food and Drug Administration	Delayed sleep phase disorder	None	7,858	wikipedia	https://en.wikipedia.org/wiki/Delayed_sleep_phase_disorder	2021-01-18T18:55:30	{"icd-9": ["327.31"], "icd-10": ["G47.2"], "wikidata": ["Q1470530"]}
Abortion in Vanuatu is severely restricted by criminal law.[1] Abortion is illegal under the provisions of section 117 of the Vanuatu Penal Code, Act No. 17 or 7 August 1981.[2] The code states that any woman who intentionally induces a miscarriage is subject to up to two years' imprisonment.[1] Abortion is illegal in cases of rape, incest, and threats to fetal health.[3] The only allocations for abortion are "for good medical reasons",[4] which a United Nations report interprets as to save the life of the pregnant woman and to preserve her physical and mental health.[5] Section 113 of the code states that "No person shall, when a woman is about to be delivered of the child, prevent the child from being born alive by any act or omission of such a nature that, if the child had been born alive and had, then died..." although the italicized statement is vague about its meaning.[4] ## Self-induced abortions[edit] The Vanuatu Family Health Association reports various methods women use for self-induced abortions, including the use of local leaves or bark from a tree.[3] Abortions like this that are outside of the medical system endanger the lives of women, as even an immediate visit to a nearby hospital or clinic may be futile if that medical facility does not have the equipment to repair any damage.[3] ## References[edit] 1. ^ a b Abortion Policies: Oman to Zimbabwe. United Nations Publications. 2001. ISBN 9789211513653. Retrieved 23 November 2014. 2. ^ "Abortion Policies: a review of policies, legislation and social indicators for the South Pacific". www.vanuatu.usp.ac.fj. Retrieved 2018-09-19. 3. ^ a b c Graue, Catherine (20 June 2014). "New study to research Vanuatu's illegal abortions with fears rates are increasing". ABC News. Retrieved 23 November 2014. 4. ^ a b "Penal Code Act 1981". www.paclii.org. Retrieved 2020-03-06. 5. ^ World Population Policies 2017: Abortion Laws and Policies, United Nations Department of Economic and Social Affairs, 2020. * v * t * e Abortion in Oceania Sovereign states * Australia * Federated States of Micronesia * Fiji * Kiribati * Marshall Islands * Nauru * New Zealand * Palau * Papua New Guinea * Samoa * Solomon Islands * Tonga * Tuvalu * Vanuatu Associated states of New Zealand * Cook Islands * Niue Dependencies and other territories * American Samoa * Christmas Island * Cocos (Keeling) Islands * Easter Island * French Polynesia * Guam * Hawaii * New Caledonia * Norfolk Island * Northern Mariana Islands * Pitcairn Islands * Tokelau * Wallis and Futuna * v * t * e Abortion Main topics * Definitions * History * Methods * Abortion debate * Philosophical aspects * Abortion law Movements * Abortion-rights movements * Anti-abortion movements Issues * Abortion and mental health * Beginning of human personhood * Beginning of pregnancy controversy * Abortion-breast cancer hypothesis * Anti-abortion violence * Abortion under communism * Birth control * Crisis pregnancy center * Ethical aspects of abortion * Eugenics * Fetal rights * Forced abortion * Genetics and abortion * Late-term abortion * Legalized abortion and crime effect * Libertarian perspectives on abortion * Limit of viability * Malthusianism * Men's rights * Minors and abortion * Natalism * One-child policy * Paternal rights and abortion * Prenatal development * Reproductive rights * Self-induced abortion * Sex-selective abortion * Sidewalk counseling * Societal attitudes towards abortion * Socialism * Toxic abortion * Unsafe abortion * Women's rights By country Africa * Algeria * Angola * Benin * Botswana * Burkina Faso * Burundi * Cameroon * Cape Verde * Central African Republic * Chad * Egypt * Ghana * Kenya * Namibia * Nigeria * South Africa * Uganda * Zimbabwe Asia * Afghanistan * Armenia * Azerbaijan * Bahrain * Bangladesh * Bhutan * Brunei * Cambodia * China * Cyprus * East Timor * Georgia * India * Iran * Israel * Japan * Kazakhstan * South Korea * Malaysia * Nepal * Northern Cyprus * Philippines * Qatar * Saudi Arabia * Singapore * Turkey * United Arab Emirates * Vietnam * Yemen Europe * Albania * Andorra * Austria * Belarus * Belgium * Bosnia and Herzegovina * Bulgaria * Croatia * Czech Republic * Denmark * Estonia * Finland * France * Germany * Greece * Hungary * Iceland * Ireland * Italy * Kazakhstan * Latvia * Liechtenstein * Lithuania * Luxembourg * Malta * Moldova * Monaco * Montenegro * Netherlands * North Macedonia * Norway * Poland * Portugal * Romania * Russia * San Marino * Serbia * Slovakia * Slovenia * Spain * Sweden * Switzerland * Ukraine * United Kingdom North America * Belize * Canada * Costa Rica * Cuba * Dominican Republic * El Salvador * Guatemala * Mexico * Nicaragua * Panama * Trinidad and Tobago * United States Oceania * Australia * Micronesia * Fiji * Kiribati * Marshall Islands * New Zealand * Papua New Guinea * Samoa * Solomon Islands * Tonga * Tuvalu * Vanuatu South America * Argentina * Bolivia * Brazil * Chile * Colombia * Ecuador * Guyana * Paraguay * Peru * Suriname * Uruguay * Venezuela Law * Case law * Constitutional law * History of abortion law * Laws by country * Buffer zones * Conscientious objection * Fetal protection * Heartbeat bills * Informed consent * Late-term restrictions * Parental involvement * Spousal consent Methods * Vacuum aspiration * Dilation and evacuation * Dilation and curettage * Intact D&X * Hysterotomy * Instillation * Menstrual extraction * Abortifacient drugs * Methotrexate * Mifepristone * Misoprostol * Oxytocin * Self-induced abortion * Unsafe abortion Religion * Buddhism * Christianity * Catholicism * Hinduism * Islam * Judaism * Scientology * Category This abortion-related article is a stub. You can help Wikipedia by expanding it. * v * t * e [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA [kDa]: kilodalton [EPC]: Early Prostate Cancer [LAPC]: locally advanced prostate cancer [NSAAs]: nonsteroidal antiandrogens [NSAA]: nonsteroidal antiandrogen [GnRH]: gonadotropin-releasing hormone [ADT]: androgen deprivation therapy [LH]: luteinizing hormone [AR]: androgen receptor [CAB]: combined androgen blockade [LPC]: localized prostate cancer [CPA]: cyproterone acetate [U.S.]: United States [FDA]: Food and Drug Administration	Abortion in Vanuatu	None	7,859	wikipedia	https://en.wikipedia.org/wiki/Abortion_in_Vanuatu	2021-01-18T18:46:49	{"wikidata": ["Q19568869"]}
This article needs attention from an expert on the subject. Please add a reason or a talk parameter to this template to explain the issue with the article. When placing this tag, consider associating this request with a WikiProject. (August 2018) HIV drug resistance occurs when microevolution causes virions to become tolerant to antiretroviral treatments (ART). ART can be used to successfully manage HIV infection, but a number of factors can contribute to the virus mutating and becoming resistant. Drug resistance occurs as bacterial or viral populations evolve to no longer respond to medications that previously worked. In the case of HIV, there have been recognized cases of treatment resistant strains since 1989, with drug resistance being a major contributor to treatment failure.[1] While global incidence varies greatly from region to region, there has been a general increase in overall HIV drug resistance. The two main types of resistance, primary and induced, differ mostly in causation, with the biggest cause of resistance being a lack of adherence to the specific details of treatment. These newly created resistant strains of HIV pose a public health issue as they infect a growing number of people because they are harder to treat, and can be spread to other individuals.[2] For this reason, the reaction to the growing number of cases of resistant HIV strains has mostly been to try to increase access to treatment and implement other measures to make sure people stay in care, as well as to look into the development of a HIV vaccine or cure.[3][4] ## Contents * 1 Mechanisms of resistance * 1.1 Types of resistance * 1.1.1 Induced resistance * 1.1.2 Primary resistance * 1.2 Causes of resistance * 1.2.1 Importance of drug regimen adherence * 2 Potential limited effects of current drugs * 3 Contemporary treatment issues * 3.1 ART use in developing countries * 3.2 Future steps to control HIV resistance * 4 See also * 5 References ## Mechanisms of resistance[edit] HIV is considered resistant when it no longer respond to known treatments.[5] Because currently there is no known cure for HIV, the goal of treatment is to reduce an infected individual's viral load to the point where it is no longer detectable in order to alleviate their symptoms and reduce their risk of infecting others.[6] HIV drug resistance poses an issue because it reduces the possible HIV medications a person can take due to cross resistance. In cross resistance, an entire class of medication is considered ineffective in lowering a patient's HIV viral load because all the drugs in a given class share the same mechanism of action.[7] Therefore, development of resistance to one medication in a class precludes the use of all other medications in the same class. A blood test can be done to determine which drugs may be effective prior to initiation of treatment or during treatment to ensure resistance has not developed.[7] ### Types of resistance[edit] #### Induced resistance[edit] One of the two types of HIV drug resistance is induced resistance. Induced resistance refers to resistance that occurs as a result of drug therapy. HIV is a retrovirus that replicates quickly using reverse transcriptase, known for its lack of error correcting mechanisms, resulting in a high mutation rate. Mutations that confer a substantial selective advantage to HIV survival can therefore quickly replicate within an individual, creating a new, resistant strain.[8][5] These mutations accumulate over generations and in populations, resulting in the great genetic variation within populations of HIV, and an increased probability of a virion developing an evolutionary selective advantage over other virions.[5] Natural selection then acts on HIV by selecting for virions with higher fitness, as all others are eventually killed off by drug treatments.[9] The virions that are able to escape the harmful effects of the drug then create an entirely new, drug resistant population. The selected-for virions continue reproducing until the patient's viral load returns to pre-treatment levels, creating a cycle in which treatment is initially successful in reducing the viral load, but becomes less effective as the virus becomes resistant and virion levels once again increase.[10] #### Primary resistance[edit] The other type of HIV drug resistance is primary resistance. Primary resistance refers to resistance that is not incurred as a result of ART therapy. It is thought that some strains of HIV-1 are naturally resistant to ART drugs, and that the prevalence of these strains varies across the globe.[8] Primary resistance is acquired when an individual's initial infection with HIV comes from an already resistant strain.[3] An individual infected by a resistant strain begins their course of treatment with already limited drug options, which can pose problems later down the line if they develop additional resistance.[10] ### Causes of resistance[edit] #### Importance of drug regimen adherence[edit] As previously described, mutations occur as a result of random mutations that are especially prevalent in HIV due to characteristic elements of the viral reproductive process, namely the use of reverse transcriptase. Several mechanisms of resistance have been identified, including mutations that block the incorporation of nucleosides, a class of HIV drug, into the viral DNA.[11] One known cause of HIV drug resistance is lack of adherence to the prescribed drug regiment. Low levels of adherence can be attributed to lack of access to healthcare, stigmatization of HIV, and a lack of availability of drugs due to prohibitive cost or other factors. Missing doses of medication or taking them late poses a major issue because it can allow for the virus to once again begin to replicate inside the body. Proper adherence also greatly reduces the risk of the spread of the virus, thereby improving general public health and lowering health care spending.[12] Some drugs are known to have lower incidences of resistance and may be preferable for individuals known to have difficulty adhering to a drug routine, but these benefits have to be weighed with the potential risks, including severity of side effects.[13] ## Potential limited effects of current drugs[edit] In 2004, one study estimated the percentage of the American HIV positive population with some form of drug resistance to be 76.3%.[14] A more recent study in South Korea estimated that 50% of their HIV positive population had multi-drug resistant strains of HIV, while 10% had multi-class resistant strains. Multi-class resistant strains pose a larger problem because each class includes many drugs, and eliminating use of an entire class of drugs severely limits treatment options.[15] These studies indicate that the incidence of resistance varies greatly based on geographic location. In their 2017 HIV Drug Resistance Report, the World Health Organization conducted surveys in 14 countries to estimate the prevalence of resistance to HIV medications. One subgroup included only HIV-positive patients who had just initiated antiretroviral therapy in order to assess the prevalence of HIV drug resistance in treatment-naive patients, deemed "pretreatment drug resistance." Resistance to NNRTIs in this patient population ranged from 2.7% (in Myanmar) to 15.9% (in Uganda). Resistance to NRTIs ranged from 0.3% (in Namibia) to 6.8% (in Nicaragua). Resistance to protease inhibitors ranged from 0.3% (in Cameroon and Myanmar) to 2.6% (in Mexico). Resistance to NNRTI + NRTI combination therapy ranged from 0.2% (in Myanmar) to 4.6% (in Uganda).[16] ## Contemporary treatment issues[edit] Current medical and scientific opinion is mixed on the most effective treatment methods, but is focused on drug cocktails and the importance of first-line regimens.[17] The World Health Organization advocates a public-health approach to HIV treatment in order to make treatment uniform and available to patients around the world.[18] As of July 2017, the WHO is implementing the Global Action Plan on HIV drug resistance 2017-2021. It is a 5-year initiative intended to help countries around the world manage HIV drug resistance.[19] Among treatment methods, the World Health Organization acknowledges the importance of successful first-line treatments.[18] First-line treatments are known to affect the virus’ future response to other treatments, making the effectiveness of first-line treatments an issue of vital importance.[18] The most successful treatments are combinations of three drugs used simultaneously, as this greatly reduces the probability of the virus developing resistance.[20] ### ART use in developing countries[edit] Shortly after the advent of ART therapy, there was much controversy about how to make the drugs accessible to the developing world in countries where the disease was most widespread. Because of the strict regimen that had to be followed in taking the drugs, critics were hesitant to distribute the drugs in under-resourced countries where they worried patients would be unwilling or unable to follow the regimen.[21] However, studies comparing drug regimen adherence rates between high and low income countries showed that individuals in low income countries were no less likely to correctly follow drug instructions. In one study, 77% of African patients were found to satisfy the standard of adherence, compared to just 55% of North American patients studied.[12] These high adherence rates in resource-poor countries can be attributed to the success of community-based approaches like the HIV Equity Initiative in Haiti, which employed local workers and trained them in how to safely distribute HIV medication, as well as programs such as that in Brazil, in which generic drugs are able to be mass produced and distributed for little to no cost.[22][21] ### Future steps to control HIV resistance[edit] The number of people with resistant strains of HIV are growing, making the matter a more pressing issue for health care officials. If current trends continue, infection rates will rise, as will government spending on HIV/AIDS.[23] HIV drug resistance also has the potential to disrupt the progress being made in the global fight against AIDS, such as with the "90-90-90" target to diagnose 90% of cases, provide treatment to 90% of infected individuals, and successfully suppress the viral load in 90% of the treated individuals.[3] New classes of drugs are constantly being researched and produced to help address the issue of resistance, as well as to try to alleviate the steep costs associated with managing HIV.[24] However, UNAIDS believes that the issue is currently under control, with ART treatment being effective for a majority of patients. Instead, they support research into developing a vaccine or cure as being more central to the mission of reducing the spread of AIDS.[25] ## See also[edit] * Drug resistance ## References[edit] 1. ^ Larder B (2001). "Mechanisms of HIV-1 drug resistance". AIDS. 15 Suppl 5: S27–34. doi:10.1097/00002030-200100005-00005. PMID 11816171. 2. ^ "HIV and drug resistance". www.unaids.org. Retrieved 30 October 2018. 3. ^ a b c HIV drug resistance report 2017. Geneva: World Health Organization; 2017. Licence: CC BY-NC-SA 3.0 IGO. 4. ^ "Antiretroviral Drug Discovery and Development". National Institute of Allergy and Infectious Diseases. Retrieved 25 October 2018. 5. ^ a b c Freeman S, Herron JC (2007). "Evolutionary Analysis.". A case for evolutionary thinking: understanding HIV (4th ed.). San Francisco, CA: Pearson Benjamin Cummings. 6. ^ "Treatment Goals Adult and Adolescent ARV". AIDSinfo. Retrieved 9 November 2018. 7. ^ a b "Drug Resistance". AIDSinfo. U.S. Department of Health and Human Services. Retrieved 31 October 2017. 8. ^ a b Clavel F, Hance AJ (March 2004). "HIV drug resistance". The New England Journal of Medicine. 350 (10): 1023–35. doi:10.1056/nejmra025195. PMID 14999114. 9. ^ Kozal MJ (January 2009). "Drug-resistant human immunodefiency virus". Clinical Microbiology and Infection. 15 Suppl 1: 69–73. doi:10.1111/j.1469-0691.2008.02687.x. PMID 19220361. 10. ^ a b Pascu ML (2017). Laser Optofluidics in Fighting Multiple Drug Resistance. Bentham Science Publishers. p. 119. 11. ^ "Mechanisms of HIV-1 drug resistance : AIDS". LWW. Retrieved 30 October 2018. 12. ^ a b Nachega JB, Marconi VC, van Zyl GU, Gardner EM, Preiser W, Hong SY, Mills EJ, Gross R (April 2011). "HIV treatment adherence, drug resistance, virologic failure: evolving concepts". Infectious Disorders Drug Targets. 11 (2): 167–74. doi:10.2174/187152611795589663. PMC 5072419. PMID 21406048. 13. ^ "Adherence Limitations to Treatment Safety and Efficacy Adult and Adolescent ARV". AIDSinfo. Retrieved 9 November 2018. 14. ^ Richman DD, Morton SC, Wrin T, Hellmann N, Berry S, Shapiro MF, Bozzette SA (July 2004). "The prevalence of antiretroviral drug resistance in the United States". AIDS. 18 (10): 1393–401. doi:10.1097/01.aids.0000131310.52526.c7. PMID 15199315. S2CID 15960179. 15. ^ Choi JY, Kwon OK, Choi BS, Kee MK, Park M, Kim SS (June 2014). "The prevalence of antiretroviral multidrug resistance in highly active antiretroviral therapy-treated patients with HIV/AIDS between 2004 and 2009 in South Korea". Journal of Clinical Virology. 60 (2): 154–60. doi:10.1016/j.jcv.2014.02.004. PMID 24680255. 16. ^ "HIV drug resistance report. Geneva: World Health Organization; 2017. Licence: CC BY-NC-SA 3.0 IGO" (PDF). 17. ^ "Consolidated guidelines on the use of antiretroviral drugs for treating and preventing HIV infection". World Health Organization. Retrieved 1 November 2017. 18. ^ a b c Gilks CF, Crowley S, Ekpini R, Gove S, Perriens J, Souteyrand Y, Sutherland D, Vitoria M, Guerma T, De Cock K (August 2006). "The WHO public-health approach to antiretroviral treatment against HIV in resource-limited settings". Lancet. 368 (9534): 505–10. doi:10.1016/S0140-6736(06)69158-7. PMID 16890837. S2CID 22499739. 19. ^ "Global action plan on HIV drug resistance 2017–2021". World Health Organization. Retrieved 1 November 2017. 20. ^ Cane PA (September 2009). "New developments in HIV drug resistance". The Journal of Antimicrobial Chemotherapy. 64 Suppl 1: i37–40. doi:10.1093/jac/dkp258. PMID 19675018. 21. ^ a b Rosenberg T. "Look at Brazil". Retrieved 9 November 2018. 22. ^ Dugger CW. "Rural Haitians Are Vanguard in AIDS Battle". Retrieved 25 October 2018. 23. ^ "WHO urges action against HIV drug resistance threat". World Health Organization. Retrieved 25 October 2018. 24. ^ "Antiretroviral Drug Discovery and Development \| NIH: National Institute of Allergy and Infectious Diseases". www.niaid.nih.gov. Retrieved 25 October 2018. 25. ^ "HIV and drug resistance". www.unaids.org. 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* South Africa * Uganda * Zambia * Zimbabwe North America * Canada * Mexico * El Salvador * Guatemala * Honduras * Nicaragua United States * New York City Caribbean * Haiti * Jamaica * Dominican Republic South America * Bolivia * Brazil * Colombia * Guyana * Peru Asia * Afghanistan * Armenia * Azerbaijan * Bahrain * Bangladesh * Bhutan * Cambodia * China (PRC) (Yunnan) * East Timor * India * Indonesia * Iran * Iraq * Japan * Jordan * North Korea * Laos * Malaysia * Myanmar (Burma) * Nepal * Pakistan * Philippines * Saudi Arabia * Sri Lanka * Taiwan (ROC) * Thailand * United Arab Emirates * Turkey * Vietnam Europe * United Kingdom * Russia * Ukraine Oceania * Australia * New Zealand * Papua New Guinea * List of countries by HIV/AIDS adult prevalence rate * List of HIV/AIDS cases and deaths registered by region [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA [kDa]: kilodalton [EPC]: Early Prostate Cancer [LAPC]: locally advanced prostate cancer [NSAAs]: nonsteroidal antiandrogens [NSAA]: nonsteroidal antiandrogen [GnRH]: gonadotropin-releasing hormone [ADT]: androgen deprivation therapy [LH]: luteinizing hormone [AR]: androgen receptor [CAB]: combined androgen blockade [LPC]: localized prostate cancer [CPA]: cyproterone acetate [U.S.]: United States [FDA]: Food and Drug Administration	HIV drug resistance	None	7,860	wikipedia	https://en.wikipedia.org/wiki/HIV_drug_resistance	2021-01-18T19:05:37	{"wikidata": ["Q5629934"]}
For a general phenotypic description and a discussion of genetic heterogeneity of neural tube defects, see 182940 and 601634. Inheritance Toriello et al. (1980) observed either anencephaly or spina bifida in 5 males in 5 different sibships spanning 4 generations genealogically connected through females. Baraitser and Burn (1984) and Toriello (1984) reported additional kindreds with pedigree patterns strongly supporting X-linked recessive inheritance. Baraitser and Burn (1984) reported a nonconsanguineous Pakistani Muslim family in which a woman had 3 brothers and 3 sons with neural tube defects, including posterior encephalocele and spina bifida cystica. Jensson et al. (1988) reported an Icelandic family in which 5 males had either anencephaly or spina bifida: 2 had spina bifida, 2 sibs had anencephaly, and 1 had both high and low spinal lesions. Affected persons came from 4 sibships in 3 generations connected through females. Mapping Newton et al. (1991) presented initial linkage data suggesting linkage of spina bifida with DNA probes on Xp. However, in the large Icelandic family reported by Jensson et al. (1988), the largest family showing apparent X-linked recessive inheritance of neural tube defects, Newton et al. (1994) performed 2-point linkage analysis using markers from 62 informative loci and found no significant evidence for linkage to the X chromosome. Haplotypes were extensively analyzed and found to exclude linkage to the X chromosome. Newton et al. (1994) concluded that involvement of a major X-linked gene is unlikely. Cytogenetics Fryns et al. (1996) reported a de novo/autosomal translocation, t(X;22)(q27;q12.1), associated with lumbosacral spina bifida and myeloschisis. Hol et al. (2000) performed detailed molecular analysis on the U.S. family reported in abstract by Goerss et al. (1993) in which 2 brothers, their mother, and their maternal grandmother had a duplication of Xq26-q27. The brothers carrying the duplication displayed spina bifida and panhypopituitarism (312000), whereas a third healthy brother inherited the normal X chromosome. Preferential inactivation of the X chromosome containing the duplication was evident in healthy carrier females. Hol et al. (2000) hypothesized that the spina bifida in the 2 brothers was due to an interruption of a critical gene in the Xq27 breakpoint region and narrowed the interval to Xq27.3 between DXS369 and DXS1200. Neuro \- Anencephaly or spina bifida Inheritance \- X-linked form ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA [kDa]: kilodalton [EPC]: Early Prostate Cancer [LAPC]: locally advanced prostate cancer [NSAAs]: nonsteroidal antiandrogens [NSAA]: nonsteroidal antiandrogen [GnRH]: gonadotropin-releasing hormone [ADT]: androgen deprivation therapy [LH]: luteinizing hormone [AR]: androgen receptor [CAB]: combined androgen blockade [LPC]: localized prostate cancer [CPA]: cyproterone acetate [U.S.]: United States [FDA]: Food and Drug Administration	NEURAL TUBE DEFECTS, X-LINKED	c0080178	7,861	omim	https://www.omim.org/entry/301410	2019-09-22T16:18:47	{"doid": ["0080074"], "mesh": ["D016135"], "omim": ["301410"], "orphanet": ["823", "268357"]}
A number sign (#) is used with this entry because of evidence that this form of type A1 brachydactyly (BDA1C) is caused by homozygous mutation in the GDF5 gene (601146) on chromosome 20q11. A milder form of BDA1C is caused by heterozygous mutation in this gene. Mutation in the GDF5 gene has also been reported to cause brachydactyly type A2 (BDA2; 112600) and type C (BDAC; 113100). For a general phenotypic description and discussion of genetic heterogeneity of type A1 brachydactyly, see BDA1 (112500). Clinical Features Byrnes et al. (2010) studied a consanguineous French Canadian family in which 3 sibs had type A1 brachydactyly. Radiographs and metacarpophalangeal profiles of the proband showed significantly shortened middle phalanges of digits 2 to 5 as well as the first distal phalanx. A very short first metacarpal was observed, giving the appearance of a proximally placed thumb. The third to fifth metacarpals showed less marked shortening, and the ulnar styloid process was truncated. The feet were similarly affected. The proband and an affected sister were both 5 feet tall (5th centile) and both were treated for clubfeet as children; neither had fibular hypoplasia. Their affected brother was 5 feet 6 inches tall (10th centile), and all 3 affected sibs were shorter than their 2 unaffected sisters. The proband had a son who was of average height and appeared to be unaffected; however, radiography revealed subtle but significant changes, and his metacarpophalangeal profile showed that the middle phalanges of the second to fifth digits were short and below -2 SD when controlled for age and sex, and his first metacarpal was also short. Mapping In a consanguineous French Canadian family with type A1 brachydactyly, in whom mutation in the IHH (600726) and SHH (600725) genes had been excluded as well as linkage to the BDA1B (607004) locus on chromosome 5p13, Byrnes et al. (2010) performed a genomewide linkage screen and found linkage to chromosome 20q11, with the highest maximum lod score at marker D20S870 (Zmax = 2.15 at theta = 0). Molecular Genetics In 3 affected sibs from a consanguineous French Canadian family with type A1 brachydactyly mapping to chromosome 20q11, Byrnes et al. (2010) identified homozygosity for a missense mutation in the candidate gene GDF5 (R399C; 601146.0020). The proband's son, who had a milder phenotype, was heterozygous for the R399C mutation, consistent with a semidominant pattern of inheritance. INHERITANCE \- Autosomal recessive \- Autosomal dominant (milder phenotype) GROWTH Height \- Short stature (fifth to tenth centile) SKELETAL Limbs \- Truncated ulnar styloid process \- Normally developed fibula Hands \- Shortening of middle phalanges of digits 2 to 5 \- Shortening of first distal phalanx \- Shortening of first metacarpal \- Third to fifth metacarpals less shortened Feet \- Shortening of middle phalanges of digits 2 to 5 \- Shortening of first distal phalanx \- Shortening of first metatarsal \- Third to fifth metatarsals less shortened \- Clubfeet (in some patients) <2 of 3 sibs MISCELLANEOUS \- Heterozygotes demonstrate a milder phenotype, consistent with a semidominant inheritance pattern MOLECULAR BASIS \- Caused by mutation in the growth/differentiation factor-5 gene (GDF5, 601146.0020 ) ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA [kDa]: kilodalton [EPC]: Early Prostate Cancer [LAPC]: locally advanced prostate cancer [NSAAs]: nonsteroidal antiandrogens [NSAA]: nonsteroidal antiandrogen [GnRH]: gonadotropin-releasing hormone [ADT]: androgen deprivation therapy [LH]: luteinizing hormone [AR]: androgen receptor [CAB]: combined androgen blockade [LPC]: localized prostate cancer [CPA]: cyproterone acetate [U.S.]: United States [FDA]: Food and Drug Administration	BRACHYDACTYLY, TYPE A1, C	c1862151	7,862	omim	https://www.omim.org/entry/615072	2019-09-22T15:53:15	{"doid": ["0110977"], "mesh": ["C537088"], "omim": ["615072"], "orphanet": ["93388"]}
For a phenotypic description and a discussion of genetic heterogeneity of specific language impairment, see SLI1 (602081). The SLI Consortium (2002) compiled 98 families drawn from epidemiologic and clinical populations, all with probands whose standard language scores fell 1.5 standard deviations or more below the mean for their age, indicating 'specific language impairment.' The authors performed systematic genomewide quantitative trait locus (QTL) analysis of 3 language-related measures: the Clinical Evaluation of Language Fundamentals, Revised (CELF-R), receptive and expressive scales, and the nonword repetition (NWR) test. They identified 2 regions, one on chromosome 16q (SLI1; 606711) and the other on chromosome 19q (SLI2), both of which had maximum lod scores of 3.55. Simulations suggested that, of these 2 multipoint results, the NWR linkage to 16q was the most significant. Both the clinical and epidemiologic samples showed independent evidence of linkage on both 16q and 19q, indicating that these may represent universally important loci in SLI and, thus, general risk factors for language impairment. In a sample colected by the SLI Consortium (2004) consisting of 86 families, all with probands whose language skills were 1.5 standard deviations or more below the mean for their age, Haseman-Elston linkage analysis resulted in a maximum lod score of 2.31 on chromosome 19. The authors commented that whereas the study of SLI Consortium (2002) reported that chromosome 19 linkage appeared to be specific to the test for expressive language, the study of SLI Consortium (2004) found that all the chromosome 19 linkage came from the test evaluating the 'nonsense word' trait, in which subjects repeat nonsensical words of increasing length and complexity. See also SLI3 (607134) on chromosome 13q21. INHERITANCE \- Multifactorial NEUROLOGIC Central Nervous System \- Language development deficit \- Normal intelligence \- No other neurologic deficits \- Deficit in nonword repetition (NWR) \- Deficit in phonologic short-term memory \- Deficit in expressive language MISCELLANEOUS \- Prevalence of 2-7% in English-speaking preschool children \- Phenotypic variation (may affect language expression, reception, and/or articulation) \- Genetic heterogeneity (see, e.g., SLI1 606711 and SLI3 607134 ) ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA [kDa]: kilodalton [EPC]: Early Prostate Cancer [LAPC]: locally advanced prostate cancer [NSAAs]: nonsteroidal antiandrogens [NSAA]: nonsteroidal antiandrogen [GnRH]: gonadotropin-releasing hormone [ADT]: androgen deprivation therapy [LH]: luteinizing hormone [AR]: androgen receptor [CAB]: combined androgen blockade [LPC]: localized prostate cancer [CPA]: cyproterone acetate [U.S.]: United States [FDA]: Food and Drug Administration	SPECIFIC LANGUAGE IMPAIRMENT 2	c1847605	7,863	omim	https://www.omim.org/entry/606712	2019-09-22T16:10:05	{"omim": ["606712"], "synonyms": ["Alternative titles", "SPECIFIC LANGUAGE IMPAIRMENT QUANTITATIVE TRAIT LOCUS ON CHROMOSOME 19"]}
Lymphatic filariasis Other namesElephantiasis tropica,[1] elephantiasis arabum[1] Bellevue Venus; Oscar G. Mason's portrait of a woman with elephantiasis. SpecialtyInfectious disease SymptomsNone, severe swelling of the arms, legs, breasts, or genitals[2] CausesFilarial worms spread by mosquitos[3] Diagnostic methodMicroscopic examination of blood[4] PreventionBed nets, mass deworming[2] MedicationAlbendazole with ivermectin or diethylcarbamazine[2] Frequency38.5 million (2015)[5] Lymphatic filariasis is a human disease caused by parasitic worms known as filarial worms.[2][3] Most cases of the disease have no symptoms.[2] Some people, however, develop a syndrome called elephantiasis, which is marked by severe swelling in the arms, legs, breasts, or genitals.[2][6] The skin may become thicker as well, and the condition may become painful.[2] The changes to the body have the potential to harm the person's social and economic situation.[2] The worms are spread by the bites of infected mosquitoes.[2] Three types of worms are known to cause the disease: Wuchereria bancrofti, Brugia malayi, and Brugia timori, with Wuchereria bancrofti being the most common.[2] These worms damage the lymphatic system.[2] The disease is diagnosed by microscopic examination of blood collected during the night.[4] The blood is typically examined as a smear after being stained with Giemsa stain.[4] Testing the blood for antibodies against the disease may also permit diagnosis.[4] Other roundworms from the same family are responsible for river blindness.[7] Prevention can be achieved by treating entire groups in which the disease exists, known as mass deworming.[2] This is done every year for about six years, in an effort to rid a population of the disease entirely.[2] Medications used include antiparasitics such as albendazole with ivermectin, or albendazole with diethylcarbamazine.[2] The medications do not kill the adult worms but prevent further spread of the disease until the worms die on their own.[2] Efforts to prevent mosquito bites are also recommended, including reducing the number of mosquitoes and promoting the use of bed nets.[2] In 2015 about 38.5 million people were infected.[5] About 950 million people are at risk of the disease in 54 countries.[2] It is most common in tropical Africa and Asia.[2] Lymphatic filariasis is classified as a neglected tropical disease and one of the four main worm infections.[7] The impact of the disease results in economic losses of billions of dollars a year.[2] ## Contents * 1 Signs and symptoms * 2 Causes * 3 Diagnosis * 4 Prevention * 5 Treatment * 5.1 Anthelmintic * 5.2 Antibiotics * 5.3 Vaccine * 5.4 Supportive treatments * 6 Epidemiology * 7 History * 8 Research directions * 9 References * 10 External links ## Signs and symptoms[edit] The most spectacular symptom of lymphatic filariasis is elephantiasis, a stage 3 lymphedema with thickening of the skin and underlying tissues. This was the first mosquito-borne disease to be discovered.[8] Elephantiasis results when the parasites lodge in the lymphatic system and cause blockages to the flow of lymph. Infections usually begin in childhood.[2] The skin condition the disease causes is called "elephantiasis tropica" (also known as "elephantiasis arabum").[9]:438 Elephantiasis mainly affects the lower limbs and various species of filarial worms tend to affect different parts of the body: Wuchereria bancrofti can affect the arms, breasts, legs, scrotum, and vulva (causing hydrocele formation), while Brugia timori rarely affects the genitals.[10]:665 Those who develop the chronic stages of elephantiasis are usually amicrofilaraemic and often have adverse immunological reactions to the microfilariae as well as the adult worms.[10] The subcutaneous worms present with skin rashes, urticarial papules, and arthritis, as well as hyper- and hypopigmentation macules. The related Onchocerca volvulus manifests itself in the eyes, causing "river blindness" (onchocerciasis), one of the leading causes of blindness in the world.[11] [12] Serous cavity filariasis presents with symptoms similar to subcutaneous filariasis; it may also be associated with ascites following the severe inflammatory reaction in the lymphatics.[13]:818 Elephantiasis leads to marked swelling of the lower half of the body and thickening of the skin, making it look like that of an elephant, a term called "pachyderm". * Drawn from the collection at the National Museum of Health and Medicine and shows the effect of elephantiasis in an historic context. Anatomical items: Left Leg, Scrotum. * Elephantiasis of the legs due to filariasis. Luzon, Philippines. * Man with massive scrotal elephantiasis, Tanzania, early 20th century ## Causes[edit] Life cycle of Wuchereria bancrofti, a parasite that causes lymphatic filariasis Elephantiasis occurs in the presence of microscopic, thread-like parasitic worms such as Wuchereria bancrofti (the most common[2]), Brugia malayi, and Brugia timori, all of which are transmitted by bites from infected mosquitoes.[14] It is a type of helminth infection. Three types of worm cause the disease and damage the lymphatic system. The disease itself is a result of a complex interplay between several factors: the worm, the endosymbiotic Wolbachia bacteria within the worm, the host’s immune response, and the numerous opportunistic infections and disorders that arise. The adult worms only live in the human lymphatic system.[15] The parasite infects the lymph nodes and blocks the flow of lymph throughout the body; this results in chronic lymphedema, most often noted in the lower torso (typically in the legs and genitals).[16] ## Diagnosis[edit] The standard method for diagnosing active infection is by finding the microfilariae via microscopic examination.[17] This may be difficult, as in most parts of the world, microfilariae only circulate in the blood at night.[4][17] For this reason, the blood has to be collected nocturnally.[17] The blood sample is typically in the form of a thick smear and stained with Giemsa stain. Testing the blood serum for antibodies against the disease may also be used.[4] ## Prevention[edit] Main article: Eradication of lymphatic filariasis The present objective of prevention is the eradication of lymphatic filariasis, which is achievable since the disease has no known animal reservoir. The World Health Organization recommends mass deworming—treating entire groups of people who are at risk with a single annual dose of two medicines, namely albendazole in combination with either ivermectin or diethylcarbamazine citrate.[18] With consistent treatment, since the disease needs a human host, the reduction of microfilariae means the disease will not be transmitted, the adult worms will die out, and the cycle will be broken.[19] In sub-Saharan Africa, albendazole (donated by GlaxoSmithKline) is being used with ivermectin (donated by Merck & Co.) to treat the disease, whereas elsewhere in the world, albendazole is used with diethylcarbamazine.[20] As of 2019 WHO recommends prevention with a combination of ivermectin, diethylcarbamazine, and albendazole in areas were onchocerciasis does not occur.[21] Transmission of the infection can be broken when a single dose of these combined oral medicines is consistently maintained annually for a duration of four to six years.[18] Using a combination of treatments better reduces the number of microfilariae in blood. Avoiding mosquito bites, such as by using insecticide-treated mosquito bed nets, also reduces the transmission of lymphatic filariasis.[19][22] The Carter Center's International Task Force for Disease Eradication declared lymphatic filariasis one of six potentially eradicable diseases.[19] According to medical experts, the worldwide effort to eliminate lymphatic filariasis is on track to potentially succeed by 2020.[23] For similar-looking but causally unrelated podoconiosis, international awareness of the disease will have to increase before elimination is possible. In 2011, podoconiosis was added to the World Health Organization's Neglected Tropical Diseases list, which was an important milestone in raising global awareness of the condition.[24] The efforts of the Global Programme to Eliminate LF are estimated to have prevented 6.6 million new filariasis cases from developing in children between 2000 and 2007, and to have stopped the progression of the disease in another 9.5 million people who had already contracted it.[25] Dr. Mwele Malecela, who chairs the programme, said: "We are on track to accomplish our goal of elimination by 2020."[23] In 2010, the WHO published a detailed progress report on the elimination campaign in which they assert that of the 81 countries with endemic LF, 53 have implemented mass drug administration, and 37 have completed five or more rounds in some areas, though urban areas remain problematic.[26] ## Treatment[edit] ### Anthelmintic[edit] Treatments for lymphatic filariasis differ depending on the geographic location of the area of the world in which the disease was acquired.[20] In sub-Saharan Africa, albendazole is being used with ivermectin to treat the disease, whereas elsewhere in the world, albendazole is used with diethylcarbamazine.[20] Geo-targeting treatments is part of a larger strategy to eventually eliminate lymphatic filariasis by 2020.[20] ### Antibiotics[edit] The antibiotic doxycycline is also effective in treating lymphatic filariasis.[27] Its drawbacks over anthelmintic drugs are that it requires 4 to 6 weeks of treatment, should not be used in young children and pregnant women, and is photosensitizing, which limits its use for mass prevention.[27] The parasites responsible for elephantiasis have a population of endosymbiotic bacteria, Wolbachia, that live inside the worm. When the symbiotic bacteria of the adult worms are killed by the antibiotic, they no longer provide chemicals which the nematode larvae need to develop, which either kills the larvae or prevents their normal development. This permanently sterilizes the adult worms, which also die within 1 to 2 years instead of their normal 10 to 14 year lifespan.[28] ### Vaccine[edit] A vaccine is not yet available, but in 2013 the University of Illinois College of Medicine was reporting 95% efficacy in testing against B. malayi in mice.[29] ### Supportive treatments[edit] Additionally, surgical treatment may be helpful for issues related to scrotal elephantiasis and hydrocele. However, surgery is generally ineffective at correcting elephantiasis of the limbs.[30] ## Epidemiology[edit] Disability-adjusted life year for lymphatic filariasis per 100,000 inhabitants no data less than 10 10-50 50-70 70-80 80-90 90-100 100-150 150-200 200-300 300-400 400-500 more than 500 Elephantiasis caused by lymphatic filariasis is one of the most common causes of disability in the world.[20] A 2012 report noted that lymphatic filariasis affected 120 million people[31] and one billion people at risk for infection.[32] About 40 million people were disfigured or incapacitated by the disease in 2015.[33] It is considered endemic in tropical and subtropical regions of Africa, Asia, Central and South America, and Pacific Island nations. In areas endemic for podoconiosis, prevalence can be 5% or higher.[34] In communities where lymphatic filariasis is endemic, as many as 10% of women can be afflicted with swollen limbs, and 50% of men can suffer from mutilating genital symptoms.[20] Filariasis is considered endemic in 73 countries; 37 of these are in Africa. * Togo is the first Africa country to have been validated by the World Health Organization (WHO) as having eliminated LF as public health problem * In the Americas, it is present in Brazil, Costa Rica, the Dominican Republic, Guyana, Haiti, Suriname, and Trinidad and Tobago. * In Asia, it is present in Bangladesh, Cambodia, India, Indonesia, Laos, Malaysia, Maldives, the Philippines, Sri Lanka, Thailand, Timor-Leste, and Vietnam. * In the Middle East, it was present only in Yemen until August 2019 when the World Health Organization (WHO) validated Yemen as having eliminated LF as public health problem * In the Pacific region, it is endemic in American Samoa, the Cook Islands, Fiji, French Polynesia, Micronesia, Niue, Papua New Guinea, Samoa, Tonga, Tuvalu, and Vanuatu. In many of these countries, considerable progress has been made towards elimination of filariasis. In July 2017, the World Health Organization (WHO) announced that the disease had been eliminated in Tonga.[35] Elimination of the disease has also occurred in Cambodia, the Cook Islands, Egypt, Kiribati, Maldives, Marshall Islands, Niue, Palau, Sri Lanka, Thailand, Vanuatu, Viet Nam and Wallis and Fortuna. This list is constantly updates and adds on the China and South Korea that were among the first countries to eliminate LF, according to the WHO.[35] ## History[edit] A man in Japan is helped to carry his enlarged scrotum Lymphatic filariasis is thought to have affected humans for about 4000 years.[36] Artifacts from ancient Egypt (2000 BC) and the Nok civilization in West Africa (500 BC) show possible elephantiasis symptoms. The first clear reference to the disease occurs in ancient Greek literature, wherein scholars differentiated the often similar symptoms of lymphatic filariasis from those of leprosy, describing leprosy as elephantiasis graecorum and lymphatic filariasis as elephantiasis arabum.[36] The first documentation of symptoms occurred in the 16th century, when Jan Huyghen van Linschoten wrote about the disease during the exploration of Goa. Similar symptoms were reported by subsequent explorers in areas of Asia and Africa, though an understanding of the disease did not begin to develop until centuries later. In 1866, Timothy Lewis, building on the work of Jean Nicolas Demarquay [de] and Otto Henry Wucherer, made the connection between microfilariae and elephantiasis, establishing the course of research that would ultimately explain the disease. In 1876, Joseph Bancroft discovered the adult form of the worm.[37] In 1877, the lifecycle involving an arthropod vector was theorized by Patrick Manson, who proceeded to demonstrate the presence of the worms in mosquitoes. Manson incorrectly hypothesized that the disease was transmitted through skin contact with water in which the mosquitoes had laid eggs.[38] In 1900, George Carmichael Low determined the actual transmission method by discovering the presence of the worm in the proboscis of the mosquito vector.[36] > Many people in Malabar, Nayars as well as Brahmans and their wives — in fact about a quarter or a fifth of the total population, including the people of the lowest castes — have very large legs, swollen to a great size; and they die of this, and it is an ugly thing to see. They say that this is due to the water through which they go, because the country is marshy. This is called pericaes in the native language, and all the swelling is the same from the knees downward, and they have no pain, nor do they take any notice of this infirmity. > > — Portuguese diplomat Tomé Pires, Suma Oriental, 1512–1515.[39] ## Research directions[edit] Researchers at the University of Illinois at Chicago (UIC) have developed a novel vaccine for the prevention of lymphatic filariasis. This vaccine has been shown to elicit strong, protective immune responses in mouse models of lymphatic filariasis infection. The immune response elicited by this vaccine has been demonstrated to be protective against both W. bancrofti and B. malayi infection in the mouse model and may prove useful in the human.[40] On September 20, 2007, geneticists published the first draft of the complete genome (genetic content) of Brugia malayi, one of the roundworms which causes lymphatic filariasis.[41] This project had been started in 1994 and by 2000, 80% of the genome had been determined. Determining the content of the genes might lead to the development of new drugs and vaccines.[42] ## References[edit] 1. ^ a b James WD, Berger T, Elston D (2015). Andrews' Diseases of the Skin: Clinical Dermatology. Elsevier Health Sciences. p. 432. ISBN 9780323319690. Archived from the original on 2016-10-12. 2. ^ a b c d e f g h i j k l m n o p q r s t u "Lymphatic filariasis Fact sheet N°102". World Health Organization. March 2014. Archived from the original on 25 March 2014. Retrieved 20 March 2014. 3. ^ a b "Lymphatic filariasis". World Health Organization. Archived from the original on 5 May 2016. Retrieved 7 May 2016. 4. ^ a b c d e f "Parasites - Lymphatic Filariasis Diagnosis". CDC. June 14, 2013. Archived from the original on 22 February 2014. Retrieved 21 March 2014. 5. ^ a b GBD 2015 Disease and Injury Incidence and Prevalence Collaborators (October 2016). "Global, regional, and national incidence, prevalence, and years lived with disability for 310 diseases and injuries, 1990–2015: a systematic analysis for the Global Burden of Disease Study 2015". Lancet. 388 (10053): 1545–1602. doi:10.1016/S0140-6736(16)31678-6. PMC 5055577. PMID 27733282. 6. ^ "CDC - Lymphatic Filariasis". www.cdc.gov. Archived from the original on 11 May 2016. Retrieved 7 May 2016. 7. ^ a b "Working to overcome the global impact of neglected tropical diseases – Summary" (PDF). Relevé Épidémiologique Hebdomadaire. 86 (13): 113–20. March 2011. PMID 21438440. Archived (PDF) from the original on 9 October 2016. 8. ^ "Lymphatic filariasis". Health Topics A to Z. World Health Organization. Archived from the original on 2011-09-18. Retrieved 2011-09-25. 9. ^ James WD, Berger TG, et al. (2006). Andrews' Diseases of the Skin: clinical Dermatology. Saunders Elsevier. ISBN 978-0-7216-2921-6. 10. ^ a b Pfarr KM, Debrah AY, Specht S, Hoerauf A (November 2009). "Filariasis and lymphoedema". Parasite Immunology. 31 (11): 664–72. doi:10.1111/j.1365-3024.2009.01133.x. PMC 2784903. PMID 19825106. 11. ^ "Onchocerciasis Fact sheet N°374". World Health Organization. March 2014. Archived from the original on 16 March 2014. Retrieved 20 March 2014. 12. ^ "Onchocerciasis (also known as River Blindness)". Parasites. CDC. May 21, 2013. Archived from the original on 26 February 2014. Retrieved 20 March 2014. 13. ^ Lizaola B, Bonder A, Trivedi HD, Tapper EB, Cardenas A (November 2017). "Review article: the diagnostic approach and current management of chylous ascites". Alimentary Pharmacology & Therapeutics. 46 (9): 816–824. doi:10.1111/apt.14284. PMID 28892178. 14. ^ Centers for Disease Control and Prevention. (2008). "Lymphatic Filariasis". Archived from the original on 11 May 2012. Retrieved 24 March 2012. 15. ^ Niwa S. "Prevalence of Vizcarrondo worms in early onset lymphatic filariasis: A case study in testicular elephantiasis". Univ Puerto Rico Med J. 22: 187–193.[verification needed] 16. ^ Saladin K (2007). Anatomy & Physiology: The Unity of Form and Function. McGraw-Hill. ISBN 978-0-07-287506-5. 17. ^ a b c "Parasites - Lymphatic Filariasis". cdc.gov. June 14, 2013. Archived from the original on 15 February 2015. Retrieved 11 February 2015. 18. ^ a b "Lymphatic filariasis. Fact sheet N°102". WHO. March 2014. Archived from the original on 2015-02-17. Retrieved 2015-02-22. 19. ^ a b c The Carter Center. "Lymphatic Filariasis Elimination Program" (PDF). Archived (PDF) from the original on 2016-03-04. Retrieved 2015-11-28. 20. ^ a b c d e f The Carter Center. "Lymphatic Filariasis Elimination Program". Archived from the original on 2008-07-20. Retrieved 2008-07-17. 21. ^ "Lymphatic filariasis". www.who.int. Retrieved 4 October 2019. 22. ^ U.S. Centers for Disease Control and Prevention. "Lymphatic". Archived from the original on 2010-07-18. Retrieved 2010-07-08. 23. ^ a b "'End in sight' for elephantiasis". BBC News. October 8, 2008. Archived from the original on May 4, 2010. Retrieved March 29, 2010. 24. ^ Visser BJ (May 2014). "How soil scientists help combat podoconiosis, a neglected tropical disease". International Journal of Environmental Research and Public Health. 11 (5): 5133–6. doi:10.3390/ijerph110505133. PMC 4053901. PMID 24828083. 25. ^ Ottesen EA, Hooper PJ, Bradley M, Biswas G (October 2008). "The global programme to eliminate lymphatic filariasis: health impact after 8 years". PLOS Neglected Tropical Diseases. 2 (10): e317. doi:10.1371/journal.pntd.0000317. PMC 2556399. PMID 18841205. 26. ^ Progress report 2000-2009 and strategic plan 2010-2020 of the global programme to eliminate lymphatic filariasis: halfway towards eliminating lymphatic filariasis (PDF). World Health Organization. 2010. ISBN 978-92-4-150072-2. Archived (PDF) from the original on 2013-01-24. 27. ^ a b Taylor MJ, Hoerauf A, Townson S, Slatko BE, Ward SA (January 2014). "Anti-Wolbachia drug discovery and development: safe macrofilaricides for onchocerciasis and lymphatic filariasis". Parasitology. 141 (1): 119–27. doi:10.1017/s0031182013001108. PMC 3884836. PMID 23866958. 28. ^ Landmann F, Voronin D, Sullivan W, Taylor MJ (November 2011). "Anti-filarial activity of antibiotic therapy is due to extensive apoptosis after Wolbachia depletion from filarial nematodes". PLOS Pathogens. 7 (11): e1002351. doi:10.1371/journal.ppat.1002351. PMC 3207916. PMID 22072969. 29. ^ Dakshinamoorthy G, Samykutty AK, Munirathinam G, Reddy MV, Kalyanasundaram R (March 2013). "Multivalent fusion protein vaccine for lymphatic filariasis". Vaccine. 31 (12): 1616–22. doi:10.1016/j.vaccine.2012.09.055. PMC 3554871. PMID 23036503. 30. ^ Gloviczki P (1995). "The management of lymphatic disorders". In Rutherford RB (ed.). Vascular surgery (4th ed.). Philadelphia: WB Saunders. pp. 1883–1945. 31. ^ Fenwick A (March 2012). "The global burden of neglected tropical diseases". Public Health. 126 (3): 233–236. doi:10.1016/j.puhe.2011.11.015. PMID 22325616. 32. ^ The Carter Center (October 2002). "Summary of the Third Meeting of the International Task Force for Disease Eradication" (PDF). Archived (PDF) from the original on 2009-02-06. Retrieved 2008-07-17. 33. ^ "Lymphatic filariasis". World Health Organization (WHO). Archived from the original on 2017-07-13. 34. ^ Deribe K, Tomczyk S, Tekola-Ayele F (2013). Phillips RO (ed.). "Ten years of podoconiosis research in Ethiopia". PLOS Neglected Tropical Diseases. 7 (10): e2301. doi:10.1371/journal.pntd.0002301. PMC 3794913. PMID 24130908. 35. ^ a b World Health Organization in Manila (31 July 2017). "Congratulations, Tonga! Pacific island state eliminates lymphatic filariasis as a public health problem". Archived from the original on 8 September 2017. Retrieved 7 August 2017. 36. ^ a b c "Lymphatic Filariasis Discovery". Archived from the original on 2008-12-10. Retrieved 2008-11-21. 37. ^ Grove, David I (1990). A history of human helminthology. Wallingford: CAB International. pp. 1–848. ISBN 0-85198-689-7. 38. ^ Grove, David I (2014). Tapeworms, lice and prions: a compendium of unpleasant infections. Oxford: Oxford University Press. pp. 1–602. ISBN 978-0-19-964102-4. 39. ^ Burma D.P. (2010). Project Of History Of Science, Philosophy And Culture In Indian Civilization, Volume Xiii Part 2: From Physiology And Chemistry To Biochemistry. Pearson Education India. p. 49. ISBN 978-81-317-3220-5. Archived from the original on 2017-09-08. 40. ^ Dakshinamoorthy G, Samykutty AK, Munirathinam G, Reddy MV, Kalyanasundaram R (March 2013). "Multivalent fusion protein vaccine for lymphatic filariasis". Vaccine. 31 (12): 1616–22. doi:10.1016/j.vaccine.2012.09.055. PMC 3554871. PMID 23036503. (primary source) 41. ^ Ghedin E, Wang S, Spiro D, Caler E, Zhao Q, Crabtree J, et al. (September 2007). "Draft genome of the filarial nematode parasite Brugia malayi". Science. 317 (5845): 1756–60. Bibcode:2007Sci...317.1756G. doi:10.1126/science.1145406. PMC 2613796. PMID 17885136. 42. ^ Williams SA, Lizotte-Waniewski MR, Foster J, Guiliano D, Daub J, Scott AL, Slatko B, Blaxter ML (April 2000). "The filarial genome project: analysis of the nuclear, mitochondrial and endosymbiont genomes of Brugia malayi". International Journal for Parasitology. 30 (4): 411–9. doi:10.1016/s0020-7519(00)00014-x. PMID 10731564. ## External links[edit] Classification D * ICD-10: B74 * ICD-9-CM: 125.0-125.9 * MeSH: D005368 External resources * eMedicine: derm/888 * v * t * e Eradication of infectious diseases Eradication of human diseases Successful * Smallpox/Alastrim (Eradication of smallpox) Underway (global) * Dracunculiasis (Eradication of dracunculiasis) * Poliomyelitis (Eradication of poliomyelitis) * Malaria (Eradication of malaria) * Yaws (Eradication of yaws) Underway (regional) * Hookworm * Lymphatic filariasis * Measles * vaccine * epidemiology * Rubella * Trachoma * Onchocerciasis * Syphilis * Rabies Eradication of agricultural diseases Successful * Rinderpest (Eradication of rinderpest) Underway * Ovine rinderpest * Bovine spongiform encephalopathy Eradication programs Global * Global Polio Eradication Initiative * Global Certification Commission * Malaria Eradication Scientific Alliance Regional * United States * Boll Weevil Eradication Program * National Malaria Eradication Program * India * India National PolioPlus * Pulse Polio * Poliomyelitis in Pakistan * Every Last Child * The Final Inch Related topics * Globalization and disease * Mathematical modelling of disease * Pandemic * Transmission * horizontal * vertical * Vaccination * Zoonosis [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA [kDa]: kilodalton [EPC]: Early Prostate Cancer [LAPC]: locally advanced prostate cancer [NSAAs]: nonsteroidal antiandrogens [NSAA]: nonsteroidal antiandrogen [GnRH]: gonadotropin-releasing hormone [ADT]: androgen deprivation therapy [LH]: luteinizing hormone [AR]: androgen receptor [CAB]: combined androgen blockade [LPC]: localized prostate cancer [CPA]: cyproterone acetate [U.S.]: United States [FDA]: Food and Drug Administration	Lymphatic filariasis	c0013884	7,864	wikipedia	https://en.wikipedia.org/wiki/Lymphatic_filariasis	2021-01-18T18:58:49	{"gard": ["3321"], "mesh": ["D004605"], "umls": ["C0013884"], "icd-9": ["457.1", "125.9"], "orphanet": ["2035"], "wikidata": ["Q192100"]}
Eosinophilic ulcer of the oral mucosa Other namesEosinophilic ulcer of the tongue,[1] Riga–Fede disease,[1] Eosinophilic ulcer of the oral mucosa – H&E stain Eosinophilic ulcer of the oral mucosa (also known as traumatic eosinophilic granuloma[1]) is a condition characterized by an ulcer with an indurated and elevated border.[2]:803 The lesion might be tender, fast-growing and the patient often not be aware of any trauma in the area. ## Contents * 1 Causes * 2 Diagnosis * 2.1 Differential Diagnosis * 2.2 Definition * 3 Treatment * 4 See also * 5 References ## Causes[edit] It is often associated with trauma. However, other causes are suspected, such as drugs, inherent predisposition, immune reaction, or lymphoproliferative disorder. ## Diagnosis[edit] ### Differential Diagnosis[edit] Squamous Cell Carcinoma, Pyogenic granulomas, Lesions of a chronic granulomatous disease and Mesenchymal tumors ### Definition[edit] Traumatic eosinophilic granuloma of the tongue (TEGT) is a reactive condition that commonly occurs on the ventral tongue. ## Treatment[edit] When the lesion is excised, recurrence often occurs. Palliative care with nonsteroidal anti-inflammatory drugs (NSAIDs) may be used, and topical steroids can be curative. If the lesion does not respond to treatment, biopsy is required. ## See also[edit] * Eruptive lingual papillitis * List of cutaneous conditions ## References[edit] 1. ^ a b c Rapini, Ronald P.; Bolognia, Jean L.; Jorizzo, Joseph L. (2007). Dermatology: 2-Volume Set. St. Louis: Mosby. ISBN 978-1-4160-2999-1. 2. ^ James, William D.; Berger, Timothy G. (2006). Andrews' Diseases of the Skin: Clinical Dermatology. Saunders Elsevier. ISBN 978-0-7216-2921-6. 3\. Ficarra G, Prignano F, Romagnoli P. Traumatic eosinophilic granuloma of the oral mucosa: A lymphoproliferative disorder? Oral Oncol.1997;33(5):375-379. * v * t * e Oral and maxillofacial pathology Lips * Cheilitis * Actinic * Angular * Plasma cell * Cleft lip * Congenital lip pit * Eclabium * Herpes labialis * Macrocheilia * Microcheilia * Nasolabial cyst * Sun poisoning * Trumpeter's wart Tongue * Ankyloglossia * Black hairy tongue * Caviar tongue * Crenated tongue * Cunnilingus tongue * Fissured tongue * Foliate papillitis * Glossitis * Geographic tongue * Median rhomboid glossitis * Transient lingual papillitis * Glossoptosis * Hypoglossia * Lingual thyroid * Macroglossia * Microglossia * Rhabdomyoma Palate * Bednar's aphthae * Cleft palate * High-arched palate * Palatal cysts of the newborn * Inflammatory papillary hyperplasia * Stomatitis nicotina * Torus palatinus Oral mucosa – Lining of mouth * Amalgam tattoo * Angina bullosa haemorrhagica * Behçet's disease * Bohn's nodules * Burning mouth syndrome * Candidiasis * Condyloma acuminatum * Darier's disease * Epulis fissuratum * Erythema multiforme * Erythroplakia * Fibroma * Giant-cell * Focal epithelial hyperplasia * Fordyce spots * Hairy leukoplakia * Hand, foot and mouth disease * Hereditary benign intraepithelial dyskeratosis * Herpangina * Herpes zoster * Intraoral dental sinus * Leukoedema * Leukoplakia * Lichen planus * Linea alba * Lupus erythematosus * Melanocytic nevus * Melanocytic oral lesion * Molluscum contagiosum * Morsicatio buccarum * Oral cancer * Benign: Squamous cell papilloma * Keratoacanthoma * Malignant: Adenosquamous carcinoma * Basaloid squamous carcinoma * Mucosal melanoma * Spindle cell carcinoma * Squamous cell carcinoma * Verrucous carcinoma * Oral florid papillomatosis * Oral melanosis * Smoker's melanosis * Pemphigoid * Benign mucous membrane * Pemphigus * Plasmoacanthoma * Stomatitis * Aphthous * Denture-related * Herpetic * Smokeless tobacco keratosis * Submucous fibrosis * Ulceration * Riga–Fede disease * Verruca vulgaris * Verruciform xanthoma * White sponge nevus Teeth (pulp, dentin, enamel) * Amelogenesis imperfecta * Ankylosis * Anodontia * Caries * Early childhood caries * Concrescence * Failure of eruption of teeth * Dens evaginatus * Talon cusp * Dentin dysplasia * Dentin hypersensitivity * Dentinogenesis imperfecta * Dilaceration * Discoloration * Ectopic enamel * Enamel hypocalcification * Enamel hypoplasia * Turner's hypoplasia * Enamel pearl * Fluorosis * Fusion * Gemination * Hyperdontia * Hypodontia * Maxillary lateral incisor agenesis * Impaction * Wisdom tooth impaction * Macrodontia * Meth mouth * Microdontia * Odontogenic tumors * Keratocystic odontogenic tumour * Odontoma * Dens in dente * Open contact * Premature eruption * Neonatal teeth * Pulp calcification * Pulp stone * Pulp canal obliteration * Pulp necrosis * Pulp polyp * Pulpitis * Regional odontodysplasia * Resorption * Shovel-shaped incisors * Supernumerary root * Taurodontism * Trauma * Avulsion * Cracked tooth syndrome * Vertical root fracture * Occlusal * Tooth loss * Edentulism * Tooth wear * Abrasion * Abfraction * Acid erosion * Attrition Periodontium (gingiva, periodontal ligament, cementum, alveolus) – Gums and tooth-supporting structures * Cementicle * Cementoblastoma * Gigantiform * Cementoma * Eruption cyst * Epulis * Pyogenic granuloma * Congenital epulis * Gingival enlargement * Gingival cyst of the adult * Gingival cyst of the newborn * Gingivitis * Desquamative * Granulomatous * Plasma cell * Hereditary gingival fibromatosis * Hypercementosis * Hypocementosis * Linear gingival erythema * Necrotizing periodontal diseases * Acute necrotizing ulcerative gingivitis * Pericoronitis * Peri-implantitis * Periodontal abscess * Periodontal trauma * Periodontitis * Aggressive * As a manifestation of systemic disease * Chronic * Perio-endo lesion * Teething Periapical, mandibular and maxillary hard tissues – Bones of jaws * Agnathia * Alveolar osteitis * Buccal exostosis * Cherubism * Idiopathic osteosclerosis * Mandibular fracture * Microgenia * Micrognathia * Intraosseous cysts * Odontogenic: periapical * Dentigerous * Buccal bifurcation * Lateral periodontal * Globulomaxillary * Calcifying odontogenic * Glandular odontogenic * Non-odontogenic: Nasopalatine duct * Median mandibular * Median palatal * Traumatic bone * Osteoma * Osteomyelitis * Osteonecrosis * Bisphosphonate-associated * Neuralgia-inducing cavitational osteonecrosis * Osteoradionecrosis * Osteoporotic bone marrow defect * Paget's disease of bone * Periapical abscess * Phoenix abscess * Periapical periodontitis * Stafne defect * Torus mandibularis Temporomandibular joints, muscles of mastication and malocclusions – Jaw joints, chewing muscles and bite abnormalities * Bruxism * Condylar resorption * Mandibular dislocation * Malocclusion * Crossbite * Open bite * Overbite * Overeruption * Overjet * Prognathia * Retrognathia * Scissor bite * Maxillary hypoplasia * Temporomandibular joint dysfunction Salivary glands * Benign lymphoepithelial lesion * Ectopic salivary gland tissue * Frey's syndrome * HIV salivary gland disease * Necrotizing sialometaplasia * Mucocele * Ranula * Pneumoparotitis * Salivary duct stricture * Salivary gland aplasia * Salivary gland atresia * Salivary gland diverticulum * Salivary gland fistula * Salivary gland hyperplasia * Salivary gland hypoplasia * Salivary gland neoplasms * Benign: Basal cell adenoma * Canalicular adenoma * Ductal papilloma * Monomorphic adenoma * Myoepithelioma * Oncocytoma * Papillary cystadenoma lymphomatosum * Pleomorphic adenoma * Sebaceous adenoma * Malignant: Acinic cell carcinoma * Adenocarcinoma * Adenoid cystic carcinoma * Carcinoma ex pleomorphic adenoma * Lymphoma * Mucoepidermoid carcinoma * Sclerosing polycystic adenosis * Sialadenitis * Parotitis * Chronic sclerosing sialadenitis * Sialectasis * Sialocele * Sialodochitis * Sialosis * Sialolithiasis * Sjögren's syndrome Orofacial soft tissues – Soft tissues around the mouth * Actinomycosis * Angioedema * Basal cell carcinoma * Cutaneous sinus of dental origin * Cystic hygroma * Gnathophyma * Ludwig's angina * Macrostomia * Melkersson–Rosenthal syndrome * Microstomia * Noma * Oral Crohn's disease * Orofacial granulomatosis * Perioral dermatitis * Pyostomatitis vegetans Other * Eagle syndrome * Hemifacial hypertrophy * Facial hemiatrophy * Oral manifestations of systemic disease [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA [kDa]: kilodalton [EPC]: Early Prostate Cancer [LAPC]: locally advanced prostate cancer [NSAAs]: nonsteroidal antiandrogens [NSAA]: nonsteroidal antiandrogen [GnRH]: gonadotropin-releasing hormone [ADT]: androgen deprivation therapy [LH]: luteinizing hormone [AR]: androgen receptor [CAB]: combined androgen blockade [LPC]: localized prostate cancer [CPA]: cyproterone acetate [U.S.]: United States [FDA]: Food and Drug Administration	Eosinophilic ulcer of the oral mucosa	None	7,865	wikipedia	https://en.wikipedia.org/wiki/Eosinophilic_ulcer_of_the_oral_mucosa	2021-01-18T19:05:37	{"wikidata": ["Q5381907"]}
Pure autonomic failure Other namesBradbury-Eggleston syndrome, idiopathic orthostatic hypotension SpecialtyNeurology Symptomsprimarily the same as orthostatic hypotension Complicationsprimarily the same as orthostatic hypotension; can convert to synucleinopathy Differential diagnosispresence of central nervous system dysfunctions including ataxia and/or parkinsonisms indicates the presence of autoimmune autonomic ganglionopathy or multiple system atrophy Pure autonomic failure (PAF) is a form of dysautonomia that first occurs in middle age or later in life; diagnosed more often in men than in women. ## Contents * 1 Signs and symptoms * 2 Pathology * 3 Treatment * 4 History * 5 Eponym * 6 References * 7 External links ## Signs and symptoms[edit] A degenerative disease of the autonomic nervous system, symptoms include dizziness and fainting (caused by orthostatic hypotension), visual disturbances and neck pain. Chest pain, fatigue and sexual dysfunction are less common symptoms that may also occur. Symptoms are worse when standing; sometimes one may relieve symptoms by lying down. More pervasive autonomic dysfunction involving any of the following: night sweats or abnormal lack of sweating, urogenital problems (frequent UTIs, incontinence, frequency, urgency), gastrointestinal problems (chronic constipation, chronic constipation alternating with diarrhea, poor gastric motility), or esophageal/respiratory problems (sleep apnea, abnormal breath sounds during sleep or while awake) indicate possible autoimmune autonomic ganglionopathy or multiple system atrophy. ## Pathology[edit] The pathology of pure autonomic failure is not yet completely understood. However, a loss of cells in the intermediolateral column of the spinal cord has been documented, as has a loss of catecholamine uptake and catecholamine fluorescence in sympathetic postganglionic neurons. In general, levels of catecholamines in these patients are very low while lying down, and do not increase much upon standing. ## Treatment[edit] Pharmacological methods of treatment include fludrocortisone, midodrine, somatostatin, erythropoietin, and other vasopressor agents. However, often a patient with pure autonomic failure can mitigate his or her symptoms with far less costly means. Compressing the legs and lower body, through crossing the legs, squatting, or the use of compression stockings can help. Use of an abdominal binder is even more effective. Also, ingesting more water than usual can increase blood pressure and relieve some symptoms.[citation needed] ## History[edit] In 1925, Bradbury and Eggleston first characterized three patients seemingly with a common syndrome, with what they described as "the occurrence of syncopal attacks after or during exertion or even after standing erect for some minutes. Other features in the three patients are a slow, unchanging pulse rate, incapacity to perspire, a lowered basal metabolism and signs of slight and indefinite changes in the nervous system. Each of these patients felt much worse during the heat of summer."[1][2] Further research identified multiple causes for these syndromic findings, now grouped as primary autonomic disorders (also called primary dysautonomia), including Pure Autonomic Failure, Multiple System Atrophy, and Parkinson's. The primary differentiating characteristic of Pure autonomic failure is decreased circulation and synthesis of norepinephrine, and dysfunction localized peripherally. It is relevant to note that progression to central nervous system neurodegeneration can also occur.[2] ## Eponym[edit] It is also known as Bradbury-Eggleston syndrome, named after Samuel Bradbury and Cary Eggleston who first described it in 1925.[3][1][4] ## References[edit] 1. ^ a b S. Bradbury, C. Eggleston. Postural hypotension: A report of three cases. American Heart Journal, St. Louis, 1925, 1: 73-86. 2. ^ a b Garland, Emily M.; Hooper, William B.; Robertson, David (2013-01-01). Swaab, Ruud M. Buijs and Dick F. (ed.). "Chapter 20 - Pure autonomic failure". Handbook of Clinical Neurology. Autonomic Nervous System. Elsevier. 117: 243–257. doi:10.1016/b978-0-444-53491-0.00020-1. PMID 24095130. 3. ^ "Critical review of pure autonomic failure raises awareness for early signs of Parkinson's disease, Lewy body dementia, and Multiple System Atrophy". ean.org. Retrieved 2020-09-09. 4. ^ synd/2102 at Who Named It? ## External links[edit] Classification D * MeSH: D001342 * DiseasesDB: 32777 * v * t * e Diseases of the autonomic nervous system General * Dysautonomia * Autonomic dysreflexia * Autonomic neuropathy * Pure autonomic failure Hereditary * Hereditary sensory and autonomic neuropathy * Familial dysautonomia * Congenital insensitivity to pain with anhidrosis Orthostatic intolerance * Orthostatic hypotension * Postural orthostatic tachycardia syndrome Other * Horner's syndrome * Multiple system atrophy [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA [kDa]: kilodalton [EPC]: Early Prostate Cancer [LAPC]: locally advanced prostate cancer [NSAAs]: nonsteroidal antiandrogens [NSAA]: nonsteroidal antiandrogen [GnRH]: gonadotropin-releasing hormone [ADT]: androgen deprivation therapy [LH]: luteinizing hormone [AR]: androgen receptor [CAB]: combined androgen blockade [LPC]: localized prostate cancer [CPA]: cyproterone acetate [U.S.]: United States [FDA]: Food and Drug Administration	Pure autonomic failure	c0393911	7,866	wikipedia	https://en.wikipedia.org/wiki/Pure_autonomic_failure	2021-01-18T18:56:34	{"gard": ["10428"], "mesh": ["D054970"], "umls": ["C0393911", "C2931939"], "orphanet": ["441"], "wikidata": ["Q896883"]}
A number sign (#) is used with this entry because Witkop syndrome is caused by heterozygous mutation in the MSX1 gene (142983) on chromosome 4p16. Description Some ectodermal dysplasias are here classified as congenital disorders characterized by abnormal development in 2 or more ectodermal structures (hair, nails, teeth, and sweat glands) without other systemic findings. Witkop syndrome is a rare autosomal dominant ectodermal dysplasia involving the teeth and nails. Although a few reported cases have sparse or fine hair, almost all affected individuals have normal hair, sweat glands, and ability to tolerate heat. Affected individuals have a variable number and variable types of congenitally missing permanent and/or primary teeth, which frequently results in lip eversion due to loss of occlusion in the vertical dimension. Nails are generally thin, slow-growing, brittle, and spoon-shaped (koilonychia). Toenails are usually more severely affected than fingernails. The nail defects are alleviated with age and may not be easily detectable during adulthood (summary by Jumlongras et al., 2001). Clinical Features Changes are limited largely to teeth (some of which are missing) and nails (which are poorly formed early in life, especially toenails). The teeth are not as severely affected. Witkop (1965) stated that the condition is frequent among Dutch Mennonites in Canada. He presented a pedigree supporting autosomal dominant inheritance. Giansanti et al. (1974) reported a single case. The main features were hypoplastic nails and hypodontia. Eyebrows and eyelashes were normal, but the scalp hair was fine. The patient showed bilateral polycystic ovaries. Redpath and Winter (1969) probably reported cases. Hudson and Witkop (1975) presented clinical details on 23 cases in 6 families, with several instances of male-to-male transmission. Characteristic, centrally hollowed, dysplastic toenails were frequently apparent only in childhood. The condition is usually not detected until the permanent teeth fail to erupt. Mandibular incisors, second molars, and maxillary canines are most often absent. Somewhat pouting lower lip was described. Wicomb et al. (2004) documented the manifestations of Witkop syndrome in an affected child and his father. The paternal grandfather was also affected. Inheritance Witkop syndrome is inherited as an autosomal dominant trait (Hudson and Witkop, 1975; Jumlongras et al., 2001). Mapping Jumlongras et al. (2001) found linkage between the tooth-and-nail syndrome, which they referred to as Witkop syndrome, and polymorphic markers in the region of the MSX1 locus (142983) in a 3-generation family. Molecular Genetics In a 3-generation family with Witkop syndrome, Jumlongras et al. (2001) identified a nonsense mutation in the MSX1 gene (142983.0003) that cosegregated with the phenotype. Animal Model Jumlongras et al. (2001) generated Msx1-deficient mice. Histologic analysis of Msx1-knockout mice, combined with a finding of Msx1 expression in mesenchyme of developing nail beds, revealed that not only was tooth development disrupted in these mice, but nail development was affected as well. Nail plates in Msx1-null mice were defective and were thinner than those of their wildtype littermates. INHERITANCE \- Autosomal dominant HEAD & NECK Face \- Normal facies Mouth \- Lip eversion Teeth \- Normal to small primary teeth \- Partial to total absence of permanent teeth SKIN, NAILS, & HAIR Skin \- Normal sweat glands Nails \- Thin, small friable nails \- Koilonychia \- Longitudinal ridging \- Nail pits \- Toenails often more affected than fingernails \- Nail changes improve with age Hair \- Normal hair MISCELLANEOUS \- Estimated incidence of 1-2 in 10,000 \- Normal ability to tolerate heat \- Thin, fine hair described in few individuals MOLECULAR BASIS \- Caused by mutation in the MSH homeobox 1 gene (MSX1, 142983.0003 ) ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA [kDa]: kilodalton [EPC]: Early Prostate Cancer [LAPC]: locally advanced prostate cancer [NSAAs]: nonsteroidal antiandrogens [NSAA]: nonsteroidal antiandrogen [GnRH]: gonadotropin-releasing hormone [ADT]: androgen deprivation therapy [LH]: luteinizing hormone [AR]: androgen receptor [CAB]: combined androgen blockade [LPC]: localized prostate cancer [CPA]: cyproterone acetate [U.S.]: United States [FDA]: Food and Drug Administration	WITKOP SYNDROME	c0406716	7,867	omim	https://www.omim.org/entry/189500	2019-09-22T16:32:28	{"doid": ["6678"], "omim": ["189500"], "orphanet": ["2228"], "synonyms": ["Alternative titles", "ECTODERMAL DYSPLASIA 3, WITKOP TYPE", "ECTODERMAL DYSPLASIA 3, TOOTH/NAIL TYPE", "NAIL DYSPLASIA WITH HYPODONTIA", "TOOTH-AND-NAIL SYNDROME"]}
Generalized pustular psoriasis SpecialtyDermatology Generalized pustular psoriasis (GPP) is an extremely rare type of psoriasis that can present in a variety of forms. Unlike the most general and common forms of psoriasis, GPP usually covers the entire body and with pus-filled blisters rather than plaques. GPP can present at any age, but is rarer in young children. It can appear with or without previous psoriasis conditions or history, and can reoccur in periodic episodes. ## Contents * 1 Signs and symptoms * 2 Causes * 3 Genetic factors * 4 Diagnosis * 4.1 Classification * 4.1.1 von Zumbusch acute generalized pustular psoriasis * 4.1.2 Generalized pustular psoriasis of pregnancy (Impetigo herpetiformis) * 4.1.2.1 Infantile and juvenile * 4.1.3 Circinate and annular * 5 Treatments * 6 Prognosis * 7 Case reports * 7.1 Case report 1 * 7.2 Case report 2 * 7.3 Case report 3 * 7.4 Case report 4 * 7.5 Case report 5 * 8 See also * 9 References * 10 External links ## Signs and symptoms[edit] GPP presents as pustules and plaques over a wide area of the body. It differs from the localized form of pustular psoriasis in that patients are often febrile and systemically ill.[1] However, the most prominent symptom, as described in the Archives of Dermatology, is "sheeted, pinhead-sized, sterile, sub-corneal pustules".[2] The IPC roundtable adds that these pustules often occur either at the edges "of expanding, intensely inflammatory plaques" or "within erythrodermic skin".[3] ## Causes[edit] Most cases of generalized pustular psoriasis present in patients with existing or prior psoriasis conditions.[2][3] However, there are many cases of GPP that arise without a history of psoriasis.[3] The Department of Dermatology of the University of São Paulo proposed a classification for these two conditions. Pso+ represents patients with a personal history of psoriasis and pso- represents patients with no history of psoriasis. They also identified a common factor among patients in each group: In the pso+ group, the most common precipitating factor is corticosteroid withdrawal. In the pso- group, the most common precipitating factor is infection.[4] In a large portion of cases, the disease is brought on by some triggering factor. Through research and observation, many of these factors have been identified. The following table, from an article in Cutis, lists a few factors that have been observed as influential in the onset of GPP. Provocative Factors Influencing Pustular Psoriasis Drugs: lithium, aspirin, salicylates, methotrexate, corticosteroids, progesterone, phenylbutazone, trazodone, penicillin, hydrochloroquine Irritation from topical therapy: coal tar, anthralin Infections: dental, upper respiratory Pregnancy Solar irradiation Source: "Table II", "Pustular Psoriasis" Farber and Nall, 1993[5] ## Genetic factors[edit] Although there are likely to be multiple genetic factors and environmental triggers, mutations causing defects in the IL-36RN, CARD14 and AP1S3 genes have been shown to cause GPP.[6][7][8] ## Diagnosis[edit] ### Classification[edit] It is important to note that while there are different forms of GPP, they are not exclusive of each other. One can morph into another, or multiple forms can occur simultaneously.[1] #### von Zumbusch acute generalized pustular psoriasis[edit] See also: (von Zumbusch) acute generalized pustular psoriasis Von Zumbusch psoriasis is named after the German dermatologist Leo Ritter von Zumbusch (1874–1940), son of Kaspar von Zumbusch, who described the first documented case of generalized pustular psoriasis in the early 1900s. See Case Report #1. Sometimes all or any of GPP is referred to as von Zumbusch psoriasis, but in the literature it is often distinguished as one specific form of GPP.[1][5] Eugene M. Farber, MD and colleagues provide a description of von Zumbusch psoriasis in "Pustular Psoriasis", published in Cutis. They describe the pattern as having "waves of widespread or universally fiery redness". The affected areas are "painful and tender". Small sub-corneal pustules form, with sizes originally between 1 and 10 mm in diameter. These pustules may merge to form "yellow-green lakes of pus". The pustules dry out, and "Waves of scarlatiniform [resembling scarlet fever] peeling follow, removing the desiccating pustules". In regards to the onset, the von Zumbusch form may "supervene on any previous pattern of psoriasis". It also may or may not recur periodically.[5] #### Generalized pustular psoriasis of pregnancy (Impetigo herpetiformis)[edit] See also: Impetigo herpetiformis This form of GPP tends to have symmetrical and grouped features. It usually onsets early in the third trimester of pregnancy, and generally persists until the child is born, but occasionally long after. In 2009, Dr. Debeeka Hazarika, president of the North East States branch of the Indian Association of Dermatologists, Venereologists and Leprologists (IADVL), published an article titled "Generalized pustular psoriasis of pregnancy successfully treated with cyclosporine" in Indian J Dermatol Venereol Leprol. As reported by Hazarika, there have been up to nine instances where the disease was recurrent in subsequent pregnancies.[9] See Case Report 2 In 1979, Frank R. Murphy, MD and Lewis P. Stolman, MD reported on the case of a woman who developed generalized pustular psoriasis in response to doses of progestins, suggesting a link between progestogens and GPP. Most cases of GPP in pregnancy occur late in the third trimester, generally when production of progesterone increases.[1] ##### Infantile and juvenile[edit] GPP is a rare disease in general, but even more so in children. In 2010, an article was published in Pediatric Dermatology by the Department of Dermatology, University of São Paulo. The report acknowledged that psoriasis is a relatively common skin condition in children, but "the pustular variant is rare." Out of 1,262 cases of psoriasis in children, a "0.6% rate of pustular variants" was found.[4] When GPP does occur in children, it usually appears during the first year of life.[10] Khan et al. reported that in GPP patients ten or younger, less than 12% of cases are preceded by ordinary psoriasis. This differs greatly from GPP cases in adults, where 85% of GPP is preceded by typical psoriatic lesions.[2] According to the article by the University of São Paulo, mentioned above, "The onset of childhood GPP is generally abrupt and accompanied by toxic features." The original acute episode usually lasts a few days, but "repeated waves of inflammation and pustulation may follow." It is important that the disease is managed immediately in order to prevent life-threatening complications, such as infection or [sepsis]. Other complications include "metabolical, hemo-dynamic, and thermoregulatory disturbances" which occur as a result of "alterations of the epidermal barrier."[4] See Case Report 3 #### Circinate and annular[edit] This type of psoriasis appears as round lesions. It begins as discrete areas that become raised and swollen. Pustules appear at the edges of the round lesions, creating rings. The pustules then dry out and leave a trail of scale as the lesion grows.[5] See Case Report 4 ## Treatments[edit] Treatments vary widely, and many different drugs have been documented as being successful. Some medications are successful in some patients, while unsuccessful in others. Below is a list of some medications used to treat GPP:[5][9][10][11][12] * Etanercept * PUVA * Hydroxyurea * Dapsone * Systemic corticosteroids * Cyclosporin A * Adalimumab * Etretinate * Isotretinoin * Acitretin ## Prognosis[edit] GPP is a rare and severe type of psoriasis. It in rare cases it is said to be fatal and in some cases has driven patients to intensive burn units.[13] An article published in Pediatric Dermatology said, "The GPP pattern is as an acute, episodic, and potentially life-threatening form of psoriasis."[4] There is no cure-all treatment for GPP, and as such, the mortality rate is high. Ryan and Baker observed 155 patients with GPP, 106 of which were followed up with. 26 of those 106 died as a result of the psoriasis or the treatment.[14] Their data gives a 25% mortality rate. ## Case reports[edit] ### Case report 1[edit] Von Zumbusch observed a male patient, who had had classic psoriasis for several years, and who then went through recurrent episodes of bright [erythema] and [edema], which became studded with multiple pustules. Von Zumbusch observed this patient through nine hospital admissions over 10 years.[2][12] ### Case report 2[edit] Hazarika gave a report of a 29-year-old woman with no family history of psoriasis, having had a normal first pregnancy, who presented with GPP in the twenty-eighth week of her second pregnancy. Steroid therapy caused a worsening of the symptoms. With cyclosporine the lesions cleared in 10–14 days, but new lesions appeared. The patient gave birth to a healthy baby in the thirty-eighth week of pregnancy. A month and a half after delivery, the woman presented with a psoriatic plaque on her leg.[9] ### Case report 3[edit] An eleven-year-old boy had an eight-year history of recurrent GPP. He suffered from "fever, malaise and pain". He was treated with acitretin, and improvement was seen in five weeks.[12] ### Case report 4[edit] In 1991, a case was reported of a man having plaque psoriasis and treating it with UV radiation at a tanning salon. After receiving a partial thickness burn from overexposure, he presented with annular pustular psoriasis, which cleared after 21 days, only to reoccur every 3 to 6 weeks for a year.[15] ### Case report 5[edit] A case report published in the Journal of Dermatological Treatment documents the successful use of adalimumab to control symptoms and induce relapse for 72 weeks. "Adalimumab is ... approved for the treatment of moderate to severe rheumatoid arthritis ... and more recently for the treatment of psoriatic arthritis".[11] ## See also[edit] * List of cutaneous conditions * Psoriasis ## References[edit] 1. ^ a b c d Murphy FR, Stolman LP (1979). "Generalized pustular psoriasis". Arch Dermatol. 115 (10): 1215–6. doi:10.1001/archderm.1979.04010100035015. PMID 507868. 2. ^ a b c d Khan SA, Peterkin GA, Mitchell PC (1972). "Juvenile generalized pustular psoriasis. A report of five cases and a review of the literature". Arch Dermatol. 105 (1): 67–72. doi:10.1001/archderm.1972.01620040039007. PMID 4400368. 3. ^ a b c Griffiths CE, Christophers E, Barker JN, Chalmers RJ, Chimenti S, Krueger GG, Leonardi C, Menter A, Ortonne JP, Fry L (2007). "A classification of psoriasis vulgaris according to phenotype". Br. J. Dermatol. 156 (2): 258–62. doi:10.1111/j.1365-2133.2006.07675.x. PMID 17223864. S2CID 45917573. 4. ^ a b c d de Oliveira ST, Maragno L, Arnone M, Fonseca Takahashi MD, Romiti R (2010). "Generalized pustular psoriasis in childhood". Pediatr Dermatol. 27 (4): 349–54. doi:10.1111/j.1525-1470.2010.01084.x. PMID 20403118. 5. ^ a b c d e Farber EM, Nall L (1993). "Pustular psoriasis". Cutis. 51 (1): 29–32. PMID 8419106. 6. ^ Marrakchi S, Guigue P, Renshaw BR, Puel A, Pei XY, Fraitag S, Zribi J, Bal E, Cluzeau C, Chrabieh M, Towne JE, Douangpanya J, Pons C, Mansour S, Serre V, Makni H, Mahfoudh N, Fakhfakh F, Bodemer C, Feingold J, Hadj-Rabia S, Favre M, Genin E, Sahbatou M, Munnich A, Casanova JL, Sims JE, Turki H, Bachelez H, Smahi A (2011). "Interleukin-36-receptor antagonist deficiency and generalized pustular psoriasis". N. Engl. J. Med. 365 (7): 620–8. doi:10.1056/NEJMoa1013068. PMID 21848462. 7. ^ Berki, DM; Liu, L; Choon, SE; David Burden, A; Griffiths, CEM; Navarini, AA; Tan, ES; Irvine, AD; Ranki, A; Ogo, T; Petrof, G; Mahil, SK; Duckworth, M; Allen, MH; Vito, P; Trembath, RC; McGrath, J; Smith, CH; Capon, F; Barker, JN (December 2015). "Activating CARD14 Mutations Are Associated with Generalized Pustular Psoriasis but Rarely Account for Familial Recurrence in Psoriasis Vulgaris". The Journal of Investigative Dermatology. 135 (12): 2964–2970. doi:10.1038/jid.2015.288. PMID 26203641. 8. ^ Mahil, SK; Twelves, S; Farkas, K; Setta-Kaffetzi, N; Burden, AD; Gach, JE; Irvine, AD; Képíró, L; Mockenhaupt, M; Oon, HH; Pinner, J; Ranki, A; Seyger, MM; Soler-Palacin, P; Storan, ER; Tan, ES; Valeyrie-Allanore, L; Young, HS; Trembath, RC; Choon, SE; Szell, M; Bata-Csorgo, Z; Smith, CH; Di Meglio, P; Barker, JN; Capon, F (November 2016). "AP1S3 Mutations Cause Skin Autoinflammation by Disrupting Keratinocyte Autophagy and Up-Regulating IL-36 Production". The Journal of Investigative Dermatology. 136 (11): 2251–2259. doi:10.1016/j.jid.2016.06.618. PMC 5070969. PMID 27388993. 9. ^ a b c Hazarika D (2009). "Generalized pustular psoriasis of pregnancy successfully treated with cyclosporine" (PDF). Indian Journal of Dermatology, Venereology and Leprology. 75 (6): 638. doi:10.4103/0378-6323.57743. PMID 19915261. 10. ^ a b Zelickson BD, Muller SA (1991). "Generalized pustular psoriasis in childhood. Report of thirteen cases". Journal of the American Academy of Dermatology. 24 (2 Pt 1): 186–94. doi:10.1016/0190-9622(91)70025-w. PMID 2007662. 11. ^ a b Zangrilli A, Papoutsaki M, Talamonti M, Chimenti S (2008). "Long-term efficacy of adalimumab in generalized pustular psoriasis". Journal of Dermatological Treatment. 19 (3): 185–7. doi:10.1080/09546630701759587. PMID 18569276. S2CID 24853353. 12. ^ a b c Karamfilov T, Wollina U (1998). "Juvenile generalized pustular psoriasis". Acta Derm. Venereol. 78 (3): 220. doi:10.1080/000155598441576. PMID 9602231. 13. ^ Pomahac B, Lim J, Liu A (2008). "A case report of generalized pustulosis with systemic manifestations requiring burn intensive care unit admission". J Burn Care Res. 29 (6): 1004–8. doi:10.1097/BCR.0b013e31818ba0d3. PMID 18849840. 14. ^ Ryan TJ, Baker H (1971). "The prognosis of generalized pustular psoriasis". Br. J. Dermatol. 85 (5): 407–11. doi:10.1111/j.1365-2133.1971.tb14044.x. PMID 5132156. S2CID 71849073. 15. ^ Rosen RM (1991). "Annular pustular psoriasis induced by UV radiation from tanning salon use". Journal of the American Academy of Dermatology. 25 (2 Pt 1): 336–7. doi:10.1016/s0190-9622(08)80478-1. PMID 1918477. ## External links[edit] Classification D * ICD-10: L40.1 (ILDS L40.100) [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA [kDa]: kilodalton [EPC]: Early Prostate Cancer [LAPC]: locally advanced prostate cancer [NSAAs]: nonsteroidal antiandrogens [NSAA]: nonsteroidal antiandrogen [GnRH]: gonadotropin-releasing hormone [ADT]: androgen deprivation therapy [LH]: luteinizing hormone [AR]: androgen receptor [CAB]: combined androgen blockade [LPC]: localized prostate cancer [CPA]: cyproterone acetate [U.S.]: United States [FDA]: Food and Drug Administration	Generalized pustular psoriasis	c0343055	7,868	wikipedia	https://en.wikipedia.org/wiki/Generalized_pustular_psoriasis	2021-01-18T19:02:30	{"gard": ["12819"], "umls": ["C0343055"], "icd-10": ["L40.1"], "orphanet": ["247353", "404546"], "wikidata": ["Q5532501"]}
Congenital radioulnar synostosis is a rare bone disorder that may be isolated or associated with other disorders and that is characterized by failure of segmentation of the radius and ulna during embryological development, causing limited rotational movements of the forearm, which may lead to difficulties with some activities of daily living. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA [kDa]: kilodalton [EPC]: Early Prostate Cancer [LAPC]: locally advanced prostate cancer [NSAAs]: nonsteroidal antiandrogens [NSAA]: nonsteroidal antiandrogen [GnRH]: gonadotropin-releasing hormone [ADT]: androgen deprivation therapy [LH]: luteinizing hormone [AR]: androgen receptor [CAB]: combined androgen blockade [LPC]: localized prostate cancer [CPA]: cyproterone acetate [U.S.]: United States [FDA]: Food and Drug Administration	Congenital radioulnar synostosis	c0158761	7,869	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=3269	2021-01-23T17:59:59	{"gard": ["10876"], "mesh": ["C562408"], "omim": ["179300"], "umls": ["C0158761", "C0431795"], "icd-10": ["Q74.0"], "synonyms": ["Radioulnar fusion"]}
The harm caused to a patient's lungs by high gas flows as delivered by mechanical ventilation A Neonatal mechanical ventilator. High gas flows are often used in neonatal ventilation which carries the risk of rheotrauma. Rheotrauma is a medical term for the harm caused to a patient's lungs by high gas flows as delivered by mechanical ventilation.[1][2][3] Although mechanical ventilation may prevent death of a patient from the hypoxia or hypercarbia which may be caused by respiratory failure, it can also be damaging to the lungs, leading to ventilator-associated lung injury.[4] Rheotrauma is one of the ways in which mechanical ventilation may do this, alongside volutrauma, barotrauma, atelectotrauma and biotrauma. Attempts have been made to combine all of the mechanical forces caused by the ventilator on the patient's lungs in an all encompassing term: mechanical power. ## References[edit] 1. ^ Bach KP, Kuschel CA, Oliver MH, Bloomfield FH (2009). "Ventilator gas flow rates affect inspiratory time and ventilator efficiency index in term lambs". Neonatology. 96 (4): 259–64. doi:10.1159/000220765. PMID 19478530. S2CID 20216584. 2. ^ Donn SM, Sinha SK (May 2006). "Minimising ventilator induced lung injury in preterm infants". Arch. Dis. Child. Fetal Neonatal Ed. 91 (3): F226–30. doi:10.1136/adc.2005.082271. PMC 2672704. PMID 16632652. 3. ^ Steven M. Donn; Sunil K. Sinha (19 December 2016). Manual of Neonatal Respiratory Care. Springer. pp. 314–5. ISBN 978-3-319-39839-6. 4. ^ Asim Kurjak; Frank A. Chervenak (25 September 2006). Textbook of Perinatal Medicine, Second Edition. CRC Press. pp. 39–41. ISBN 978-1-4398-1469-7. * v * t * e Mechanical ventilation Fundamentals * Modes of mechanical ventilation * Mechanical ventilation in emergencies * Nomenclature of mechanical ventilation Modes * IMV/SIMV * CMV * ACV * CSV * PAP * BPAP/NIV * CPAP * APRV * MMV * PAV * ASV * HFV Related illness * ARDS * Atelectotrauma * Biotrauma * Pulmonary barotrauma * Pulmonary volutrauma * Rheotrauma * Ventilator-associated pneumonia * Oxygen toxicity * Ventilator-associated lung injury Pressure * PEEP * FiO2 * ΔP * PIP * PS * PAW * Pplat Volumes * VT * VE * Vf Other * Cdyn * Cstatic * PAO2 * VD/VT * OI * A-a gradient * Mechanical power [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA [kDa]: kilodalton [EPC]: Early Prostate Cancer [LAPC]: locally advanced prostate cancer [NSAAs]: nonsteroidal antiandrogens [NSAA]: nonsteroidal antiandrogen [GnRH]: gonadotropin-releasing hormone [ADT]: androgen deprivation therapy [LH]: luteinizing hormone [AR]: androgen receptor [CAB]: combined androgen blockade [LPC]: localized prostate cancer [CPA]: cyproterone acetate [U.S.]: United States [FDA]: Food and Drug Administration	Rheotrauma	None	7,870	wikipedia	https://en.wikipedia.org/wiki/Rheotrauma	2021-01-18T18:30:39	{"wikidata": ["Q48844398"]}
A number sign (#) is used with this entry because glycogen storage disease II (GSD2) is caused by homozygous or compound heterozygous mutation in the GAA gene (606800), which encodes acid alpha-1,4-glucosidase, also known as acid maltase, on chromosome 17q25. Description Glycogen storage disease II, an autosomal recessive disorder, is the prototypic lysosomal storage disease. In the classic infantile form (Pompe disease), cardiomyopathy and muscular hypotonia are the cardinal features; in the juvenile and adult forms, involvement of skeletal muscles dominates the clinical picture Matsuishi et al. (1984). Clinical Features ### Infantile Onset (Pompe Disease) In classic cases of Pompe disease, affected children are prostrate and markedly hypotonic with large hearts. The tongue may be enlarged. Although the enzyme is deficient in all tissues, muscle weakness and heart involvement are the most common features. The liver is rarely enlarged, except as a result of heart failure, and hypoglycemia and acidosis do not occur as they do in glycogen storage disease I (232200). Death usually occurs in the first year of life in the classic form of the disorder and cardiac involvement is striking. Indeed, Pompe (1932) reported this condition as 'idiopathic hypertrophy of the heart,' and 'cardiomegalia glycogenica' is a synonym. Slonim et al. (2000) proposed a second, milder subtype of the infantile form. They reported 12 infants who showed less severe cardiomyopathy, absence of left ventricular outflow obstruction, and traces (less than 5%) of residual acid maltase activity; 9 of the 12 had longer survival with assisted ventilation and intubation. Smith et al. (1967) reported a boy with a myotonic form of disease and survival to the age of almost 11 years. The heart was not significantly involved. Alpha-1,4-glucosidase was absent from liver and muscle. There were heavy glycogen deposits and an anomalous polysaccharide with short outer chains was identified. Smith et al. (1966) reported a similar case in a boy who survived to the age of 4.5 years. Zellweger et al. (1965) described brothers, aged 15 and 4.5 years, with minimal manifestations limited to skeletal muscle. A deficiency of muscle alpha-1,4-glucosidase was demonstrated. Muscle showed abnormal accumulations of glycogen. A maternal uncle may have also been affected. On analysis of questionnaire data from 255 children and adults with Pompe disease, Hagemans et al. (2005) found that disease severity, including wheelchair use and use of respiratory support, increased with disease duration, but was not related to the age of the patients. However, there was a subset of patients under age 15 years with a more severe disease, requiring increased use of ventilatory support, wheelchair support, and nutritional support. All within this patient subgroup had onset of symptoms within the first 2 years of life. Forsha et al. (2011) studied the prevalence of cardiovascular abnormalities and the efficacy and safety of enzyme replacement therapy in patients with late-onset Pompe disease. Ninety patients were randomized 2:1 to enzyme replacement therapy or placebo in a double-blinded protocol. ECGs and echocardiograms were obtained at baseline and scheduled intervals during the 78-week study period. Eighty-seven patients were included. Median age was 44 years, and half were men. At baseline, a short PR interval was present in 10%, 7% had decreased left ventricular systolic function, and 5% had elevated left ventricular mass on echocardiogram (all in the mild range). There was no change in cardiovascular status associated with enzyme replacement therapy. No significant safety concerns were identified. Although some patients with late-onset Pompe disease had abnormalities on ECG or echocardiogram, those classically seen in infantile Pompe disease, such as significant ventricular hypertrophy, were not noted. Banugaria et al. (2011) retrospectively analyzed 34 infants with Pompe disease; 11 were cross-reactive immunologic material (CRIM)-negative patients; 9 were high-titer CRIM-positive patients; and 14 were low-titer CRIM-positive patients. Clinical outcome measures included survival, ventilator-free survival, left ventricular mass index, the Alberta Infant Motor Scale score, and urine Glc4 levels. Clinical outcomes in the high-titer CRIM-positive group were poor across all areas evaluated relative to the low-titer CRIM-positive group. For the CRIM-negative and high-titer CRIM-positive groups, no statistically significant differences were observed for any outcome measures, and both patient groups did poorly. Banugaria et al. (2011) concluded that, irrespective of CRIM material status, patients with infantile Pompe disease and high sustained antibody titer have an attenuated therapeutic response to enzyme replacement therapy. Banugaria et al. (2011) concluded that with the advent of immunomodulation therapies, identification of patients at risk for developing high sustained antibody titer is critical. Prater et al. (2012) described the phenotype of long-term survivors with infantile Pompe disease. Inclusion criteria included ventilator-free status and age less than 6 months at treatment initiation, as well as survival to age greater than 5 years. Eleven of 17 patients met these study criteria; all were CRIM-positive, alive, and invasive ventilator-free at most recent assessment, with a median age of 8.0 years (range 5.4-12.0 years). All had marked improvements in cardiac parameters. Commonly present were gross motor weakness, motor speech deficits, sensorineural and/or conductive hearing loss, osteopenia, gastroesophageal reflux, and dysphagia with aspiration risk. Seven of 11 patients were independently ambulatory and 4 required the use of assistive ambulatory devices. All long-term survivors had low or undetectable anti-alglucosidase alfa antibody titers. Prater et al. (2012) concluded that long-term survivors exhibited sustained improvements in cardiac parameters and gross motor function. Residual muscle weakness, hearing loss, risk for arrhythmias, hypernasal speech, dysphagia with risk for aspiration, and osteopenia were commonly observed findings. ### Adult Onset Hudgson et al. (1968) reported the case of a Portuguese girl who died at age 19 and that of a living 44-year-old housewife. Other experiences suggesting the existence of more than one type of glycogenosis II were reported by Swaiman et al. (1968). Adult-onset acid maltase deficiency may simulate limb-girdle dystrophy and the only clinical clue may be early involvement of the diaphragm (Engel, 1970; Newsom-Davis et al., 1976; Sivak et al., 1981). Trend et al. (1985) reported 4 of 5 patients who presented with acute respiratory insufficiency or chronic nocturnal ventilatory insufficiency. They reported that long-term domiciliary ventilatory support using a rocking bed or intermittent positive pressure respirations with a tracheostomy permitted patients to return to work. Molho et al. (1987) reported the cases of monozygotic twin brothers who at age 50 developed bilateral paralysis of the diaphragm. Severe dyspnea in the supine position necessitated mechanical ventilation by pneumobelts during the night. The possibility of adult acid maltase deficiency should be considered in these cases. Francesconi and Auff (1982) described Wolff-Parkinson-White syndrome (194200) and second-degree atrioventricular block in a patient with the adult form of glycogenosis II. Byrne et al. (1986) stated that 'cardiac involvement has only been reported in 1 patient with noninfantile acid maltase deficiency.' Makos et al. (1987) described 3 brothers with alpha-glucosidase deficiency, each of whom developed a fusiform basilar artery aneurysm as young adults, which was complicated by fatal rupture in 2 of them and by a cerebellar infarction in the third. Postmortem examination demonstrated severe vacuolization of skeletal muscle, liver, and vascular smooth muscle with accumulation of glycogen. In the surviving brother, similar glycogen deposition was demonstrated in the smooth muscle of the superficial temporal artery. Glycogen deposition in vascular smooth muscle had been demonstrated previously in this disorder but had not been considered clinically significant. One of the brothers had onset of weakness at age 19, demonstration at age 27 of basilar artery aneurysm by cerebral angiography, which was performed because of throbbing, occipital headaches, and, at age 32, cerebellar infarction. He had 2 sons who were normal. The patients in this family had normal alpha-glucosidase activity in leukocytes but barely detectable alpha-glucosidase in muscle homogenates at acid pH. Kretzschmar et al. (1990) described a 40-year-old male with adult acid maltase deficiency who, in addition to involvement of the liver and skeletal muscles, had extensive involvement of large and small cerebral arteries with aneurysm formation. Chancellor et al. (1991) described the case of a 68-year-old man who first developed difficulty walking at the age of 65 and for several months had experienced urinary incontinence with exercise. Chancellor et al. (1991) pointed out that many patients with detrusor instability remain asymptomatic, probably because they augment urethral closure pressure by increasing striatal muscle activity in the sphincter mechanism. They postulated that the inability to withstand increases in detrusor pressure only occurred because of striated pelvic floor muscle fatigue associated with exercise. Alternatively, there may have been a neurogenic component in the muscle weakness because of involvement of spinal motor neurons. Laforet et al. (2000) reported the clinical features of 21 unrelated patients with juvenile- or adult-onset GAA deficiency. The mean age at onset of obvious muscle complaints was 36 years, although most patients (16 of 21) reported mild muscular symptoms since childhood, including scapular winging, scoliosis, and difficulty running. Most patients had predominant involvement of pelvic girdle muscles without significant distal leg involvement. Eight (40%) patients had severe respiratory muscle involvement, which was not correlated with the severity of limb muscle weakness. Biochemical studies showed residual GAA activity in leukocytes ranging from 0 to 17% of normal values; there was no correlation between leukocyte GAA activity and clinical severity. Genetic analysis identified the common -13T-G transversion in the GAA gene (606800.0006) in 17 patients (16 compound heterozygotes and 1 homozygote). There were no genotype/phenotype correlations. Anneser et al. (2005) reported a 30-year-old woman with alpha-glucosidase deficiency confirmed by mutation in the GAA gene (606800.0016; 606800.0017). She presented with a 4-year history of progressive proximal muscle weakness, and examination showed marked vacuolar myopathy, marked reduction in GAA enzyme activity, increased serum creatine kinase, and increased transaminase levels. After diagnosis, she experienced 3 stroke-like episodes within 3 months. Brain CT showed dilatative angiopathy of the intracerebral vessels, especially of the basilar artery, with calcifications of the carotid and medial cerebral arteries. MRI showed several white matter lesions. She had no other additional risk factors for atherosclerosis. Anneser et al. (2005) suggested that similar extramuscular vascular changes may be the most relevant prognostic factor for adult patients with slowly progressive Pompe disease. Groen et al. (2006) found that 4 (33%) of 12 patients with adult-onset GSD II had ptosis, which was the presenting feature in 3 patients. Six (50%) of the 12 had measurable evidence of decreased levator palpebral muscle function. The prevalence of ptosis was significantly higher in patients compared to the general population, suggesting that it may be considered a clinical feature of adult-onset GSD II. Genotype/Phenotype Correlations Koster et al. (1978) and Loonen et al. (1981) described a grandfather with acid maltase deficiency leading to difficulty climbing stairs after age 52, and a granddaughter with typical Pompe disease leading to death at 16 weeks. The muscle of both subjects showed residual activity. It seems likely that the grandfather was a genetic compound. In this same family, Hoefsloot et al. (1990) showed that 3 sibs were homozygous for an allele that caused complete deficiency of acid alpha-glucosidase; these patients had a severe infantile form of the disease. The eldest patient in the family, with very mild clinical symptoms, was shown to be a compound heterozygote for this allele and for a second allele characterized by a reduced net production of catalytically active acid alpha-glucosidase, resulting in partial enzyme deficiency. The mutant alleles were segregated in human-mouse somatic cell hybrids to investigate their individual function. Danon et al. (1986) also reported instances of the probable genetic compound state. Nishimoto et al. (1988) described a family in which the proband, aged 15, had the juvenile muscular dystrophy form of glycogenosis type II, whereas both parents and 2 sisters had pseudodeficiency of acid alpha-glucosidase. It was almost impossible to distinguish the homozygote from the heterozygous members by lymphocyte assays alone. Both parents may have been compound heterozygotes for the pseudodeficiency allele and the allele for the juvenile form. Allelic heterogeneity was demonstrated further by the patient reported by Suzuki et al. (1988): a male developed cardiomyopathy at 12 years of age and died of heart failure at age 15 years without any sign of skeletal muscle involvement, either clinically or histologically. A Km mutant of acid alpha-glucosidase was demonstrated. Iancu et al. (1988) described an affected 12-year-old boy who presented with a right lumbar mass which appeared to represent local pseudohypertrophy. Pathogenesis The defect in type II glycogen storage disease involves acid alpha-1,4-glucosidase (acid maltase), a lysosomal enzyme. Whereas the glycogen is distributed rather uniformly in the cytoplasm in the other glycogen storage diseases (e.g., GSD I; 232200), it is enclosed in lysosomal membranes in this form. In a case of infantile acid alpha-glucosidase deficiency, Beratis et al. (1978) concluded that the defect was a structural mutation causing synthesis of a catalytically inactive, cross-reacting material (CRM)-positive, enzyme protein. On the other hand, the mutation in the adult form causes a reduction in the amount of enzyme protein. Of 9 fibroblast lines from patients with the infantile form of acid alpha-glucosidase deficiency, Beratis et al. (1983) found that 8 were CRM-negative and 1 was CRM-positive. No difference in apparent enzyme activity was detected between the 2 forms. In 2 fibroblast strains from the adult form, rocket immunoelectrophoresis showed a reduction in the amount of enzyme protein that was directly proportional to the reduction in enzyme activity. In another 'adult' fibroblast line, enzyme activity was in the same range as in the infantile form and no CRM was identified. Fibroblasts with phenotype 2 of acid alpha-glucosidase, considered a normal variant, showed reduction both in the amount of enzyme protein and in the ability to cleave glycogen; catalytic activity for maltose was normal, however. Reuser et al. (1978) studied fibroblasts from the infantile, juvenile, and adult forms of acid alpha-glucosidase deficiency. An inverse correlation was found between the severity of clinical manifestations and the level of residual enzyme activity in fibroblasts. The kinetic and electrophoretic properties of residual enzyme in fibroblasts from adult patients were identical to those from controls. The mutation may, therefore, affect the production or degradation of enzyme rather than its catalytic function. Complementation studies by fusion of fibroblasts from different types yielded no sign of nonallelism of the several forms. Reuser et al. (1987) investigated the nature of the acid alpha-glucosidase deficiency in cultured fibroblasts from 30 patients. Deficiency of catalytically active mature enzyme in lysosomes was common to all clinical phenotypes but, in most cases, was more profound in early-onset than in late-onset forms of the disease. The role of secondary factors cannot be excluded, however, because 3 adult patients were found with very low activity and little enzyme in the lysosomes. Diagnosis Angelini et al. (1972) showed that the adult form of the disease can be diagnosed in cultured skin fibroblasts. Askanas et al. (1976) established muscle tissue cultures from a 34-year-old patient with the adult-onset myopathy. Morphologically and biochemically, the newly grown fibers of cultured muscle showed the same changes as did biopsied muscle. Ausems et al. (1999) found that creatine kinase (CK) elevation is a sensitive marker of GSD II. CK levels were elevated in all 18 patients in their cohort and in 94.3% of GSD II patients reported in the literature. They proposed a diagnostic protocol for adult-onset GSD II. In patients presenting with a slowly progressive proximal muscle weakness or with respiratory insufficiency, they recommended measurement of serum levels of CK, followed by measurement of acid alpha-glucosidase activity in leukocytes, using glycogen as a substrate. To rule out the pseudodeficiency state seen in carriers of the GAA2 allele, they recommended that patients with depressed leukocyte activity have a repeat assay in cultured fibroblasts using artificial substrate. Kallwass et al. (2007) reported a simple and reliable method to measure alpha-glucosidase activity in dried blood spots using Acarbose, a highly selective alpha-glucosidase inhibitor, to eliminate isoenzyme interference. The authors demonstrated that this method efficiently detected late-onset Pompe patients who were frequently misdiagnosed by conventional methods due to residual GAA activity in other tissue types. Bembi et al. (2008) provided a detailed guide to the diagnosis of GSD II, with emphasis on the importance of early recognition of clinical manifestations. Diagnosis is confirmed by biochemical assays showing absent or decreased GAA enzyme and enzyme activity in peripheral blood cells, skin fibroblasts, or muscle biopsy. Affected adults usually present with skeletal muscle weakness and cramps and may often have respiratory failure. Progression is usually slow. Muscle imaging may be useful to assess the extent of involvement in older patients. Affected infants can present with hypertrophic cardiomyopathy in the first months of life and show rapid progression, often leading to death within the first 2 years. Patients with juvenile onset have a more attenuated course compared to infantile onset, and do not have cardiomyopathy. Other features include generalized hypotonia and hepatomegaly. Clinical Management Slonim et al. (1983) and Margolis and Hill (1986) concluded that a high-protein diet is effective therapy in adults with acid maltase deficiency. Striking improvement in respiratory function was observed. The effect was serendipitously discovered when a high-protein diet for weight reduction was given. Correction of obesity was not thought to be the exclusive or even the major mechanism of the respiratory improvement. Isaacs et al. (1986) observed benefit from a high-protein, low-carbohydrate diet in a patient with adult acid maltase deficiency. Amalfitano et al. (2001) reported the results of a phase I/II open-label single-dose study of recombinant human alpha-glucosidase infused intravenously twice weekly in 3 infants with infantile GSD II. The results of more than 250 infusions showed that recombinant human GAA was generally well tolerated. Steady decreases in heart size and maintenance of normal cardiac function for more than 1 year were observed in all 3 infants. These infants lived well past the critical age of 1 year (16, 18, and 22 months old at the time of this study) and continued to have normal cardiac function. Improvements of skeletal muscle functions were also noted; 1 patient showed marked improvement and had normal muscle tone and strength as well as normal neurologic and developmental evaluations. Van den Hout et al. (2003) studied the natural course of infantile Pompe disease in 20 Dutch patients and reviewed the findings in 133 published cases. They concluded that survival, decrease of the diastolic thickness of the left ventricular posterior wall, and achievement of major motor milestones are valid endpoints for therapeutic studies. Bembi et al. (2008) provided a detailed review of the clinical management of GSD II and emphasized a multidisciplinary approach. Enzyme replacement therapy with alglucosidase-alpha has been shown to be effective, particularly in infants. Wang et al. (2011) described the ACMG standards and guidelines for the diagnostic confirmation and management of presymptomatic individuals with lysosomal storage diseases. Inheritance Glycogen storage disease type II is inherited as an autosomal recessive trait. Smith et al. (2007) studied sib phenotype discordance in classic infantile Pompe disease by reviewing the medical literature for affected sibships in which at least 1 sib had clinical or biochemical findings consistent with infantile Pompe disease, including symptoms beginning in infancy, early hypotonia, cardiomegaly by 6 months of age, and early death. Since 1931, the literature has documented 13 families with 31 affected infants (11 probands; 20 affected sibs). The median age at symptom onset for all affected infants was 3 months (range, 0 to 6 months) with a significant correlation between probands and affected sibs (R = 0.60, p = 0.04). The median age at death for all affected infants was 6 months (range, 1.5 to 13 months); probands were slightly older at death than their sibs. The median length of disease course for all affected infants was 3 months (range, 0 to 10 months) and was slightly longer for probands. There was phenotypic concordance, particularly with respect to cardiomyopathy. Smith et al. (2007) concluded that there is minimal phenotypic and life span variation among sibs with infantile Pompe disease, which is important for genetic counseling. Molecular Genetics Multiple mutations in the acid maltase gene have been shown to cause glycogen storage disease II. Martiniuk et al. (1990) demonstrated a single basepair substitution of G to A at position 271 (606800.0001). Wokke et al. (1995) found a single mutation in intron 1 of the acid maltase (606800.0006) in 16 patients with adult-onset acid maltase deficiency. Lam et al. (2003) reported compound heterozygosity for mutations in the GAA gene in a 16-year-old Chinese boy with juvenile-onset GSD II. The patient had mild symptoms in early childhood, but his condition worsened at age 12 years, with severe weakness, sleep-disordered breathing, and respiratory difficulties. His asymptomatic 13-year-old brother, who had the same mutations, had only biochemical abnormalities suggestive of disease (elevated CK, lack of GAA activity in leukocytes). The authors commented on the intrafamilial variability. Amartino et al. (2006) reported severe infantile and asymptomatic adult forms of GSD II in 2 generations of the same family. The proband was a 2-month-old male infant of nonconsanguineous Argentinian parents who was admitted to the hospital at 5 days with cyanosis and found to have cardiomegaly, an elevated CK level, high-voltage QRS complexes on ECG, and a thick interventricular septum and hypertrophic ventricular walls on echocardiogram. Pompe disease was suspected and confirmed by measuring GAA activity in leukocytes, and Amartino et al. (2006) identified homozygosity for mutations in the GAA gene, inherited from the parents, respectively. The asymptomatic father was found to have a second mutation on his other allele, the common adult-onset IVS1 splice site mutation (606800.0006). Subsequent evaluation revealed a normal physical examination with no neuromuscular complaints and normal ECG and echocardiogram, but he had elevated CK, short duration potentials on electromyography, and reductions in maximal expiratory and inspiratory pressures on spirometry. Among 40 Italian patients with late-onset GSD II, Montalvo et al. (2006) identified 26 different mutations, including 12 novel mutations, in the GAA gene. The most common mutation was a splice site mutation in intron 1 (606800.0006), present in heterozygosity in 34 (85%) of 40 patients (allele frequency 42.3%). ### Modifier Genes De Filippi et al. (2010) studied 38 patients with late-onset Pompe disease, aged 44.6 +/- 19.8 years, and compared the distribution of angiotensin I-converting enzyme (ACE) polymorphism (106180.0001) according to demographic and disease parameters. The distribution of ACE polymorphism was in line with the general population, with 16% of patients carrying the II genotype, 37% carrying the DD genotype, and the remaining patients with the ID genotype. The 3 groups did not differ in mean age, disease duration, Walton score, and other scores used to measure disease severity. The DD polymorphism was associated with earlier onset of disease (P = 0.041), higher creatine kinase levels at diagnosis (P = 0.024), presence of muscle pain (P = 0.014), and more severe rate of disease progression (P = 0.037, analysis of variance test for interaction). Population Genetics In Israel, almost all cases of Pompe disease have occurred in Palestinian Arabs (Bashan et al., 1988). On the basis of Hardy-Weinberg equilibrium and the fact that 7 mutations they tested represented only 29% of the total, Martiniuk et al. (1998) estimated the actual carrier frequency to be about 1 in 100. Mutant gene frequency, q, was calculated to be 0.005. The expected number of individuals born with GSD II was estimated to be 1 in 40,000 births. Three mutations in the GAA gene are common in the Dutch patient population: IVS1-13T-G (606800.0006), 525delT (606800.0014), and EX18DEL (606800.0012). Sixty-three percent of Dutch GSD II patients carry 1 or 2 of these mutations, and the genotype-phenotype correlation is known (Kroos et al., 1995). To determine the frequency of GSD II, Ausems et al. (1999) screened an unselected sample of neonates for these 3 mutations. Based on the calculated carrier frequencies so derived, the predicted frequency of the disease was 1 in 40,000, divided into 1 in 138,000 for infantile GSD II and 1 in 57,000 for adult GSD II. This was about 2 to 4 times higher than previously suggested. Animal Model Acid maltase-deficient Japanese quails exhibit progressive myopathy and cannot lift their wings, fly, or right themselves from the supine position in the flip test. Kikuchi et al. (1998) injected 6 4-week-old acid maltase-deficient quails, with the clinical symptoms listed, with 14 or 4.2 mg/kg of the precursor form of recombinant human GAA enzyme or buffer alone every 2 to 3 days for 18 days (7 injections). On day 18, both high dose-treated birds (14 mg/kg) scored positive flip tests and flapped their wings, and 1 bird flew up more than 100 cm. GAA activity increased in most of the tissues examined. In heart and liver, glycogen levels dropped to normal and histopathology was normal. In pectoralis muscle, morphology was essentially normal, except for increased glycogen granules. In sharp contrast, sham-treated quail muscle had markedly increased glycogen granules, multivesicular autophagosomes, and inter- and intrafascicular fatty infiltrations. Low dose-treated birds (4.2 mg/kg) improved less biochemically and histopathologically than high dose birds, indicating a dose-dependent response. Additional experiments with intermediate doses and extended treatment halted the progression of the disease. Data were claimed to be the first to show that an exogenous protein can target to muscle and produce muscle improvement. The data also suggested that enzyme replacement with recombinant human GAA is a promising therapy for human Pompe disease. In mice in whom the Gaa gene was disrupted by gene targeting in embryonic stem cells, Raben et al. (1998) found that homozygosity for the knockout was associated with lack of enzyme activity and accumulation of glycogen in cardiac and skeletal muscle lysosomes by 3 weeks of age, with a progressive increase thereafter. By 3.5 weeks of age, these mice had markedly reduced mobility and strength. They grew normally, however, reached adulthood, remained fertile, and, as in the human adult disease, older mice accumulated glycogen in the diaphragm. By 8 to 9 months of age, the animals developed obvious muscle wasting and a weak, waddling gait. In contrast, in a second model, mutant mice with deletion of exon 6, like the knockout mice with disruption of exon 13 reported by Bijvoet et al., 1998, had unimpaired strength and mobility (up to 6.5 months of age) despite indistinguishable biochemical and pathologic changes. Bijvoet et al. (1999) produced recombinant human acid alpha-glucosidase on an industrial scale in the milk of transgenic rabbits, and administered the purified enzyme intravenously to knockout mice. Full correction of acid alpha-glucosidase activity was obtained in all tissues except brain after a single dose of 17mg/kg. Weekly enzyme infusions over a period of 6 months resulted in normalization of hepatic glycogen, but only partial degradation of lysosomal glycogen in heart, skeletal and smooth muscle. The tissue morphology improved substantially despite the advanced state of disease at the start of treatment. The authors stated that although neurologic symptoms had not been documented in human GSD II patients, the inability of the enzyme to cross the blood-brain barrier in the mouse model remained a point of concern. Dennis et al. (2000) identified mutations in the bovine Gaa gene that led to generalized glycogenosis in Brahman and Shorthorn bovine breeds. All 3 mutations resulted in premature termination of translation. The authors also presented evidence for a missense mutation segregating with the Brahman population, which is responsible for a 70 to 80% reduction in alpha-glucosidase activity. Using Gaa-knockout mice and transgenes containing cDNA for the human enzyme under muscle- or liver-specific promoters controlled by tetracycline, Raben et al. (2001) demonstrated that the liver provided enzyme far more efficiently. The achievement of therapeutic levels with skeletal muscle transduction required the entire muscle mass to produce high levels of enzyme of which little found its way to the plasma, whereas liver, comprising less than 5% of body weight, secreted 100-fold more enzyme, all of which was in the active 110-kD precursor form. Skeletal and cardiac muscle pathology was completely reversible if the treatment was begun early. DeRuisseau et al. (2009) found that Gaa-null mice had increased glycogen levels in cervical spinal cord motor neurons and larger soma size of phrenic neurons. Gaa-null mice had decreased ventilation during quiet breathing and hypercapnic challenge compared to wildtype mice, indicating respiratory insufficiency. Mice with skeletal muscle-specific Gaa expression (MTP) showed normal diaphragm force generation similar to wildtype mice, but decreased ventilation during quiet breathing, similar to Gaa-null mice. The compromised ventilation observed in both mutant mouse models was associated with decreased phrenic nerve motor output. Spinal cord samples from a patient with Pompe disease showed increased neuronal glycogen. DeRuisseau et al. (2009) suggested that respiratory impairment in individuals with Pompe disease results from a combination of muscular and neural deficits. Douillard-Guilloux et al. (2010) analyzed the effect of a complete genetic elimination of glycogen synthesis in a murine GSDII model. Gaa/Gys1 (138570) double-knockout mice exhibited a profound reduction of the amount of glycogen in the heart and skeletal muscles, a significant decrease in lysosomal swelling and autophagic build-up as well as a complete correction of cardiomegaly. In addition, the abnormalities in glucose metabolism and insulin tolerance observed in the GSDII model were corrected in Gaa/Gys1 double-knockout mice. Muscle atrophy observed in 11-month-old GSDII mice was less pronounced in Gaa/Gys1 double-knockout mice, resulting in improved exercise capacity. Douillard-Guilloux et al. (2010) concluded that long-term elimination of muscle glycogen synthesis leads to a significant improvement of structural, metabolic and functional defects in the GSDII mouse model and offers a novel perspective for the treatment of Pompe disease. INHERITANCE \- Autosomal recessive HEAD & NECK Ears \- Hearing loss Mouth \- Macroglossia CARDIOVASCULAR Heart \- Cardiomegaly \- Shortened P-R interval on EKG \- Huge QRS complexes \- Wolf-Parkinson-White syndrome Vascular \- Cerebral artery aneurysm RESPIRATORY \- Respiratory failure due to muscle weakness \- Dyspnea \- Respiratory infections CHEST Ribs Sternum Clavicles & Scapulae \- Diaphragmatic paralysis ABDOMEN Liver \- Hepatomegaly Spleen \- Splenomegaly MUSCLE, SOFT TISSUES \- Weakness \- Proximal muscle weakness \- Myopathic pattern on EMG \- Firm muscles NEUROLOGIC Central Nervous System \- Hypotonia \- Abnormal brain myelination Peripheral Nervous System \- Absent deep tendon reflexes METABOLIC FEATURES \- Fever of central origin LABORATORY ABNORMALITIES \- Elevated serum creatine kinase \- Elevated AST and LDH, especially infantile-onset \- Presence of vacuoles on muscle biopsy \- Deficiency of alpha-1,4-glucosidase (acid maltase) MISCELLANEOUS \- Two presentations - rapid, fatal disorder of infancy and slowly progressive muscular disorder of childhood \- Patients with later onset have better prognosis \- Incidence of 1 in 40,000 infants worldwide MOLECULAR BASIS \- Caused by mutation in the alpha-1,4-glucosidase gene (GAA, 606800.0002 ) ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA [kDa]: kilodalton [EPC]: Early Prostate Cancer [LAPC]: locally advanced prostate cancer [NSAAs]: nonsteroidal antiandrogens [NSAA]: nonsteroidal antiandrogen [GnRH]: gonadotropin-releasing hormone [ADT]: androgen deprivation therapy [LH]: luteinizing hormone [AR]: androgen receptor [CAB]: combined androgen blockade [LPC]: localized prostate cancer [CPA]: cyproterone acetate [U.S.]: United States [FDA]: Food and Drug Administration	GLYCOGEN STORAGE DISEASE II	c0017921	7,871	omim	https://www.omim.org/entry/232300	2019-09-22T16:27:27	{"doid": ["2752"], "mesh": ["D006009"], "omim": ["232300"], "icd-10": ["E74.02"], "orphanet": ["365"], "synonyms": ["Alternative titles", "GSD II", "GAA DEFICIENCY", "POMPE DISEASE", "GLYCOGENOSIS, GENERALIZED, CARDIAC FORM", "CARDIOMEGALIA GLYCOGENICA DIFFUSA", "ACID MALTASE DEFICIENCY", "ALPHA-1,4-GLUCOSIDASE DEFICIENCY"], "genereviews": ["NBK1261"]}
A number sign (#) is used with this entry because of evidence that spermatogenic failure-33 (SPGF33) is caused by homozygous or compound heterozygous mutation in the WDR66 gene (618146) on chromosome 12q24. Description Spermatogenic failure-33 is characterized by multiple morphologic abnormalities of the flagella (MMAF), resulting in immotile spermatozoa and infertility. Short and irregular-caliber flagella are primarily observed, as well as absent and coiled flagella, and abnormalities of the acrosome, head, and base are also present (Kherraf et al., 2018). For a general phenotypic description and a discussion of genetic heterogeneity of spermatogenic failure, see SPGF1 (258150). Clinical Features Kherraf et al. (2018) studied 7 unrelated Tunisian men with infertility due to multiple morphologic abnormalities of sperm flagella, who were all homozygous for the same deletion in the WDR66 gene (see MOLECULAR GENETICS). Although they had normal semen volume and concentration, a total absence of sperm motility was observed in all patients. Under light microscopy, 100% of sperm showed abnormal morphology, primarily involving reduced length and irregular caliber of the flagella, as well as absent flagella and coiled flagella. In addition, a high rate (56-95%) of acrosomal abnormalities were observed, and abnormal head and base morphology was also present in some spermatozoa. Under transmission electron microscopy (TEM), longitudinal sections of sperm showed severe axonemal and periaxonemal defects with complete disorganization of the outer dense fibers, fibrous sheath, and mitochondrial sheath, resulting in aborted flagella or their replacement by a cytoplasmic mass encompassing unassembled axonemal components. All cross-sections were abnormal, and the most consistently observed defects involved the axonemal and periaxonemal structures, such as the unassembled fibrous sheath. Auguste et al. (2018) described a consanguineous Lebanese family (LIBM) in which 6 of 10 brothers had complete asthenozoospermia associated with MMAF, as well as an unrelated similarly affected French man (patient 21141). Sperm analysis showed no motile sperm, and flagellar abnormalities included a high frequency of short (20-41%), absent (11-36%), bent (18-36%) or coiled (16-24%) flagella. No symptoms of primary ciliary dyskinesia were observed in the patients studied. The French couple underwent intracytoplasmic sperm injection resulting in pregnancy. TEM of sperm from the French patient revealed mitochondrial sheath (MS) dysplasia: on the flagella that had a discernible MS and fibrous sheath, the MS was extremely short with very low mitochondrial density, and only a single MS axoneme transverse section was found. Molecular Genetics In a cohort of 78 infertile men with multiple morphologic abnormalities of sperm flagella, Kherraf et al. (2018) analyzed whole-exome sequencing data and identified 7 apparently unrelated Tunisian men who were homozygous for a 2-exon deletion in the WDR66 gene (618146.0001). Noting that the deletion was present in 7 of the 46 Tunisian men in the cohort, the authors concluded that the WDR66 deletion accounts for 15% of cases of MMAF in that population. All affected individuals had the same nucleic acid sequence at the breakpoint locus, suggesting inheritance of the deleted allele from a common ancestor. Using shared ancestral haplotypes surrounding the WDR66 deletion, the age of the mutation was calculated to be in the range of 27 to 43 generations, arising 675 to 1,075 years earlier. In a consanguineous Lebanese family (LIBM) in which 6 of 10 brothers had complete asthenozoospermia, Auguste et al. (2018) performed whole-exome sequencing and identified homozygosity for a 1-bp deletion in the WDR66 gene (618146.0002) that segregated with disease. Sequencing of WDR66 in 2 similarly affected unrelated men identified a French man (patient 21141) who was compound heterozygous for a nonsense mutation (E111X; 618146.0003) and a 2-bp deletion (618146.0004). INHERITANCE \- Autosomal recessive GENITOURINARY Internal Genitalia (Male) \- Infertility \- Asthenozoospermia \- No motile sperm \- Morphologic defects of all sperm flagella \- Short sperm flagella \- Absent sperm flagella \- Irregular width of sperm flagella \- Coiled sperm flagella \- Axonemal and periaxonemal defects seen on transmission electron microscopy \- Disorganization of outer dense fibers \- Disorganization of mitochondrial sheath \- Unassembled fibrous sheath MOLECULAR BASIS \- Caused by mutation in the WD repeat-containing protein-66 gene (WDR66, 618146.0001 ) ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA [kDa]: kilodalton [EPC]: Early Prostate Cancer [LAPC]: locally advanced prostate cancer [NSAAs]: nonsteroidal antiandrogens [NSAA]: nonsteroidal antiandrogen [GnRH]: gonadotropin-releasing hormone [ADT]: androgen deprivation therapy [LH]: luteinizing hormone [AR]: androgen receptor [CAB]: combined androgen blockade [LPC]: localized prostate cancer [CPA]: cyproterone acetate [U.S.]: United States [FDA]: Food and Drug Administration	SPERMATOGENIC FAILURE 33	None	7,872	omim	https://www.omim.org/entry/618152	2019-09-22T15:43:21	{"omim": ["618152"], "orphanet": ["276234"], "synonyms": ["Non-syndromic male infertility due asthenozoospermia"]}
Not to be confused with Brown-Séquard syndrome. Bernard-Soulier syndrome Other namesHemorrhagiparous thrombocytic dystrophy[1] Bernard-Soulier syndrome has an autosomal recessive pattern of inheritance (rarely autosomal dominant)[2] SpecialtyHematology CausesMutations in GP1BA, GP1BB and GP9[3] Diagnostic methodFlow cytometry analysis[1] TreatmentPlatelet transfusion[4] Bernard–Soulier syndrome (BSS), is a rare autosomal recessive bleeding disorder that is caused by a deficiency of glycoprotein Ib (GpIb), the receptor for von Willebrand factor.[5] The incidence of BSS is estimated to be less than 1 case per million persons, based on cases reported from Europe, North America, and Japan. BSS is a giant platelet disorder, meaning that it is characterized by abnormally large platelets.[6] ## Contents * 1 Signs and symptoms * 2 Genetics * 3 Diagnosis * 3.1 Differential diagnosis * 4 Treatment * 5 Prevalence * 6 See also * 7 References * 8 Further reading * 9 External links ## Signs and symptoms[edit] Bernard–Soulier syndrome often presents as a bleeding disorder with symptoms of:[7] * Perioperative (and postoperative) bleeding * Bleeding gums * Bruising * Epistaxis (nosebleeds) * Abnormal bleeding (from small injuries) * Unusual menstrual periods ## Genetics[edit] In regards to mechanism, there are three genes: GP1BA, GP1BB and GP9 that are involved (due to mutations).[3] These mutations do not allow GPIb-IX-V complex to bind to the von Willebrand factor, which in turn is what would help platelets adhere to a site of injury which eventually helps stop bleeding.[2] ## Diagnosis[edit] Megakaryocytes (arrows) In terms of diagnosis Bernard–Soulier syndrome is characterized by prolonged bleeding time, thrombocytopenia, increased megakaryocytes, and enlarged platelets, Bernard–Soulier syndrome is associated with quantitative or qualitative defects of the platelet glycoprotein complex GPIb/V/IX. The degree of thrombocytopenia may be estimated incorrectly, due to the possibility that when the platelet count is performed with automatic counters, giant platelets may reach the size of red blood cells. The large platelets and low platelet count in BSS are seemingly due to the absence of GPIbα and the filamin A binding site that links the GPIb-IX-V complex to the platelet membrane skeleton.[5][8] ### Differential diagnosis[edit] The differential diagnosis for Bernard–Soulier syndrome includes both Glanzmann thrombasthenia and pediatric Von Willebrand disease.[5] BSS platelets do not aggregate to ristocetin, and this defect is not corrected by the addition of normal plasma, distinguishing it from von Willebrand disease.[4] ## Treatment[edit] Tranexamic acid Bleeding events can be controlled by platelet transfusion. Most heterozygotes, with few exceptions, do not have a bleeding diathesis. BSS presents as a bleeding disorder due to the inability of platelets to bind and aggregate at sites of vascular endothelial injury.[4] In the event of an individual with mucosal bleeding tranexamic acid can be given.[5] The affected individual may need to avoid contact sports and medications such as aspirin, which can increase the possibility of bleeding. A potential complication is the possibility of the individual producing anti-platelet antibodies.[9] ## Prevalence[edit] The frequency of Bernard–Soulier syndrome is approximately 1 in 1,000,000 people.[10] The syndrome, identified in the year 1948, is named after Dr. Jean Bernard and Dr. Jean Pierre Soulier.[11] ## See also[edit] * Gray platelet syndrome * Glanzmann's thrombasthenia * von Willebrand disease * May–Hegglin anomaly ## References[edit] 1. ^ a b Lanza F (2006). "Bernard-Soulier syndrome (hemorrhagiparous thrombocytic dystrophy)". Orphanet J Rare Dis. 1: 46. doi:10.1186/1750-1172-1-46. PMC 1660532. PMID 17109744. 2. ^ a b Reference, Genetics Home. "Bernard-Soulier syndrome". Genetics Home Reference. Retrieved 17 July 2016. 3. ^ a b Online Mendelian Inheritance in Man (OMIM): GIANT PLATELET SYNDROME - 231200 4. ^ a b c Pham A, Wang J (2007). "Bernard-Soulier syndrome: an inherited platelet disorder". Arch. Pathol. Lab. Med. 131 (12): 1834–6. doi:10.1043/1543-2165(2007)131[1834:BSAIPD]2.0.CO;2 (inactive 2021-01-17). PMID 18081445.CS1 maint: DOI inactive as of January 2021 (link) 5. ^ a b c d "Bernard-Soulier Syndrome: Practice Essentials, Background, Pathophysiology and Etiology". 2018-09-13. Cite journal requires `\|journal=` (help) 6. ^ Mhawech, Paulette; Saleem, Abdus (2000). "Inherited Giant Platelet Disorders". American Journal of Clinical Pathology. 113 (2): 176–190. doi:10.1309/FC4H-LM5V-VCW8-DNJU. PMID 10664620. 7. ^ Dugdale, David. "Congenital platelet function defects". NIH. Retrieved 13 October 2012. 8. ^ Kanaji, T; Russell, S; Ware, J (Sep 15, 2002). "Amelioration of the macrothrombocytopenia associated with the murine Bernard-Soulier syndrome". Blood. 100 (6): 2102–7. doi:10.1182/blood-2002-03-0997. PMID 12200373. 9. ^ "Bernard-Soulier Syndrome; BSS & giant platelet information. Patient \| Patient". Patient. Retrieved 17 July 2016. 10. ^ RESERVED, INSERM US14 -- ALL RIGHTS. "Orphanet: Bernard Soulier syndrome". www.orpha.net. Retrieved 2016-07-17. 11. ^ Richmond, Caroline (10 June 2006). "Jean Bernard". BMJ: British Medical Journal. 332 (7554): 1395. doi:10.1136/bmj.332.7554.1395. ISSN 0959-8138. PMC 1476743. ## Further reading[edit] * Berndt, Michael C.; Andrews, Robert K. (1 March 2011). "Bernard-Soulier syndrome". Haematologica. 96 (3): 355–359. doi:10.3324/haematol.2010.039883. ISSN 0390-6078. PMC 3046265. PMID 21357716. * Bick, Rodger L. (2002). Disorders of Thrombosis and Hemostasis: Clinical and Laboratory Practice. Lippincott Williams & Wilkins. ISBN 9780397516902. Retrieved 17 July 2016. * Turgeon, Mary Louise (2005). Clinical Hematology: Theory and Procedures (4th ed.). Lippincott Williams & Wilkins. ISBN 9780781750073. Retrieved 17 July 2016. ## External links[edit] Classification D * ICD-10: D69.1 * ICD-9-CM: 287.1 * OMIM: 231200 * MeSH: D001606 * DiseasesDB: 1356 External resources * eMedicine: ped/230 Scholia has a topic profile for Bernard–Soulier syndrome. * v * t * e Disorders of bleeding and clotting Coagulation · coagulopathy · Bleeding diathesis Clotting By cause * Clotting factors * Antithrombin III deficiency * Protein C deficiency * Activated protein C resistance * Protein S deficiency * Factor V Leiden * Prothrombin G20210A * Platelets * Sticky platelet syndrome * Thrombocytosis * Essential thrombocythemia * DIC * Purpura fulminans * Antiphospholipid syndrome Clots * Thrombophilia * Thrombus * Thrombosis * Virchow's triad * Trousseau sign of malignancy By site * Deep vein thrombosis * Bancroft's sign * Homans sign * Lisker's sign * Louvel's sign * Lowenberg's sign * Peabody's sign * Pratt's sign * Rose's sign * Pulmonary embolism * Renal vein thrombosis Bleeding By cause Thrombocytopenia 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Pharmacy * Physiotherapy * Molecular oncology * Nanomedicine * Personalized medicine * Public health * Rural health * Therapy * Traditional medicine * Veterinary medicine * Physician * Chief physician * History of medicine * Book * Category * Commons * Wikiproject * Portal * Outline [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA [kDa]: kilodalton [EPC]: Early Prostate Cancer [LAPC]: locally advanced prostate cancer [NSAAs]: nonsteroidal antiandrogens [NSAA]: nonsteroidal antiandrogen [GnRH]: gonadotropin-releasing hormone [ADT]: androgen deprivation therapy [LH]: luteinizing hormone [AR]: androgen receptor [CAB]: combined androgen blockade [LPC]: localized prostate cancer [CPA]: cyproterone acetate [U.S.]: United States [FDA]: Food and Drug Administration	Bernard–Soulier syndrome	c0005129	7,873	wikipedia	https://en.wikipedia.org/wiki/Bernard%E2%80%93Soulier_syndrome	2021-01-18T18:37:33	{"gard": ["2470"], "mesh": ["D001606"], "umls": ["C0005129"], "icd-9": ["287.1"], "icd-10": ["D69.1"], "orphanet": ["274"], "wikidata": ["Q822228"]}
A number sign (#) is used with this entry because pyruvate dehydrogenase E1-beta deficiency is caused by homozygous mutation in the PDHB gene (179060) on chromosome 3p14. For a general phenotypic description and a discussion of genetic heterogeneity of pyruvate dehydrogenase deficiency, see 312170. Clinical Features Brown et al. (2004) reported 2 unrelated patients with pyruvate dehydrogenase deficiency. The first patient, the son of first-cousin parents, was investigated at age 3 months because of lactic acidosis and hypotonia. Two previous sibs had died early, one with lactic acidosis. The patient developed metabolic acidosis on day 1. He required ventilation from day 3 to day 22. MRI demonstrated agenesis of the corpus callosum. At age 3 months, he showed global hypotonia and reduced reflexes. He developed severe lactic acidosis following general anesthesia for muscle biopsy and lumbar puncture. He suffered respiratory arrest but was successfully treated with ventilation and bicarbonate. The second patient, also the son of consanguineous parents, was hypotonic at birth with poor respiratory effort. He was investigated at 9 weeks of age because of continuing hypotonia, lack of visual attention, and respiratory stridor. MRI of the brain was normal. He made little developmental progress and died at 12 months of age. Molecular Genetics In 2 unrelated patients with pyruvate dehydrogenase deficiency, Brown et al. (2004) identified homozygous mutations in the PDHB gene (179060.0001-179060.0002). [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA [kDa]: kilodalton [EPC]: Early Prostate Cancer [LAPC]: locally advanced prostate cancer [NSAAs]: nonsteroidal antiandrogens [NSAA]: nonsteroidal antiandrogen [GnRH]: gonadotropin-releasing hormone [ADT]: androgen deprivation therapy [LH]: luteinizing hormone [AR]: androgen receptor [CAB]: combined androgen blockade [LPC]: localized prostate cancer [CPA]: cyproterone acetate [U.S.]: United States [FDA]: Food and Drug Administration	PYRUVATE DEHYDROGENASE E1-BETA DEFICIENCY	c0034345	7,874	omim	https://www.omim.org/entry/614111	2019-09-22T15:56:26	{"doid": ["3649"], "mesh": ["D015325"], "omim": ["614111"], "orphanet": ["765", "255138"]}
Multiple acyl-CoA dehydrogenation deficiency (MADD) is a disorder of fatty acid and amino acid oxidation and is a clinically heterogeneous disorder ranging from a severe neonatal presentation with metabolic acidosis, cardiomyopathy and liver disease, to a mild childhood/adult disease with episodic metabolic decompensation, muscle weakness, and respiratory failure. ## Epidemiology Birth prevalence is estimated at 1/200,000 but great variation is seen between countries/ethnicities. ## Clinical description Patients with MADD fall into 3 broad clinical phenotypes: 1) neonatal onset with congenital anomalies, 2) neonatal onset without anomalies, (together called MADD-severe (S); see this term) and 3) mild and/or late onset (MADD-mild (M); see this term). The first group of MADD-S patients are often premature presenting with severe non-ketotic hypoglycemia, hypotonia, hepatomegaly and severe metabolic acidosis within the first 24 hours of life. They usually have dysplastic kidneys with multiple cysts and may also have facial dysmorphism (low-set ears, high forehead, hypertelorism and hypoplastic midface), rocker-bottom feet and anomalies of external genitalia. Death usually occurs within the first week of life. The second group of patients usually present within the first 24-48 hours of life with hypotonia, tachypnea, hepatomegaly, metabolic acidosis and hypoketotic hypoglycemia. Most die during the first week(s) of life but some have survived for several months, usually dying with severe cardiomyopathy. MADD-M patients show a broad clinical spectrum of disease ranging from onset of intermittent episodes of vomiting, metabolic acidosis and hypoketotic hypoglycaemia (+/- cardiac involvement) during the first few months of life to adolescent/adult presentation with acute Reye-like illness with ketoacidosis and lipid storage myopathy. The latter subgroup often responds to pharmacological doses of riboflavin (rr-MADD). ## Etiology MADD is caused by mutations in the ETFA (15q23-q25), ETFB (19q13.3-q13.4) and ETFDH (4q32-q35) genes which encode the alpha and beta subunits of electron transfer flavoprotein (ETF) and ETF-coenzyme Q oxidoreductase. Dysfunction of either of these two flavoproteins leads to compromised fatty acid oxidation.. ## Diagnostic methods Urinary organic acid analysis usually displays various combinations of increased dicarboxylic acids, glutaric acid, ethylmalonic acid, 2-hydroxyglutarate, and glycine conjugates. Blood acylcarnitines show increased C4-C18 species although patients may be severely carnitine depleted, which may limit the degree of these abnormalities. Fibroblast fatty acid oxidation flux and fibroblast acylcarnitine analysis following incubation with palmitic acid is usually abnormal. Final confirmation is by mutation analysis. Newborn screening programs are available in Austria, Belgium, Hungary, Iceland, Portugal and Spain. ## Differential diagnosis Differential diagnosis includes autosomal resessive polycystic kindney disease; carnitine palmitoyl transferase II deficiency, neonatal form; Zellweger syndrome and sterol biosynthesis disorders (see these terms). ## Antenatal diagnosis Prenatal diagnosis is possible when 2 pathogenic mutations have been identified in the family. ## Genetic counseling MADD is an autosomal recessive disorder and genetic counseling is available. ## Management and treatment Treatment for the more severe phenotypes involves restriction of both fat and protein and reliance on a high carbohydrate diet. Strict avoidance of fasting and of other precipitating stresses is essential. Emergency regimens should be available for any metabolic decompensation. Riboflavin supplementation of 100-400 mg/day is a very effective treatment for patients with rr-MADD as is CoQ10 supplementation in some. For moderately severe cases, 3-hydroxybutyrate has been used successfully, but further studies are still needed. ## Prognosis MADD-S is invariably fatal. Milder phenotypes have a more favorable prognosis. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA [kDa]: kilodalton [EPC]: Early Prostate Cancer [LAPC]: locally advanced prostate cancer [NSAAs]: nonsteroidal antiandrogens [NSAA]: nonsteroidal antiandrogen [GnRH]: gonadotropin-releasing hormone [ADT]: androgen deprivation therapy [LH]: luteinizing hormone [AR]: androgen receptor [CAB]: combined androgen blockade [LPC]: localized prostate cancer [CPA]: cyproterone acetate [U.S.]: United States [FDA]: Food and Drug Administration	Multiple acyl-CoA dehydrogenase deficiency	c0268596	7,875	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=26791	2021-01-23T18:35:39	{"gard": ["6523"], "mesh": ["D054069"], "omim": ["231680"], "umls": ["C0268596", "C2931346"], "icd-10": ["E71.3"], "synonyms": ["Glutaric acidemia type 2", "Glutaric aciduria type 2", "MAD deficiency", "MADD"]}
Osteofibrous dysplasia is a rare, genetic primary bone dysplasia characterized by the presence of a benign, fibro-osseous, osteolytic tumor typically located in the tibia (occasionally the fibula, or both) and usually involving the anterior diaphyseal cortex with adjacent cortical expansion. It may on occasion be asymptomatic or may present with a palpable mass, pain, tenderness and/or anterior bowing of the tibia. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA [kDa]: kilodalton [EPC]: Early Prostate Cancer [LAPC]: locally advanced prostate cancer [NSAAs]: nonsteroidal antiandrogens [NSAA]: nonsteroidal antiandrogen [GnRH]: gonadotropin-releasing hormone [ADT]: androgen deprivation therapy [LH]: luteinizing hormone [AR]: androgen receptor [CAB]: combined androgen blockade [LPC]: localized prostate cancer [CPA]: cyproterone acetate [U.S.]: United States [FDA]: Food and Drug Administration	Osteofibrous dysplasia	c4085248	7,876	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=488265	2021-01-23T18:17:29	{"omim": ["607278"], "synonyms": ["OFD"]}
The inability to smell Anosmia Other namesLoss of smell, smell blindness,[1] odor blindness Inflamed nasal mucosa causing anosmia Pronunciation * /ænˈɒzmiə/ SpecialtyOtorhinolaryngology TypesPartial, total[2] Anosmia, also known as smell blindness, is the loss of the ability to detect one or more smells.[1][2] Anosmia may be temporary or permanent.[3] It differs from hyposmia, which is a decreased sensitivity to some or all smells.[2] Anosmia can be due to a number of factors, including an inflammation of the nasal mucosa, blockage of nasal passages or a destruction of one temporal lobe. Inflammation is due to chronic mucosa changes in the lining of the paranasal sinus and in the middle and superior turbinates. When anosmia is caused by inflammatory changes in the nasal passageways, it is treated simply by reducing inflammation.[4] It can be caused by chronic meningitis and neurosyphilis that would increase intracranial pressure over a long period of time,[5] and in some cases by ciliopathy,[6] including ciliopathy due to primary ciliary dyskinesia.[7] The term derives from the New Latin anosmia, based on Ancient Greek ἀν- (an-) + ὀσμή (osmḗ, "smell"; another related term, hyperosmia, refers to an increased ability to smell). Some people may be anosmic for one particular odor, a condition known as "specific anosmia". The absence of the sense of smell from birth is known as congenital anosmia. In the United States 3% of people age over 40 are affected by anosmia.[3] ## Contents * 1 Definition * 2 Signs and symptoms * 3 Causes * 3.1 COVID-19-related anosmia * 3.2 List of causes * 4 Diagnosis * 5 Treatment * 6 Epidemiology * 7 See also * 8 References * 9 Further reading * 10 External links ## Definition[edit] Anosmia is the inability to smell.[1] It may be partial or total, and can be specific to certain smells.[2] Reduced sensitivity to some or all smells is hyposmia.[2] ## Signs and symptoms[edit] Anosmia can have a number of harmful effects.[8] People with sudden onset anosmia may find food less appetizing, though congenital anosmics rarely complain about this, and none report a loss in weight. Loss of smell can also be dangerous because it hinders the detection of gas leaks, fire, and spoiled food. The common view of anosmia as trivial can make it more difficult for a patient to receive the same types of medical aid as someone who has lost other senses, such as hearing or sight.[citation needed] Many experience one sided loss of smell, often as a result of minor head trauma. This type of anosmia is normally only detected if both of the nostrils are tested separately. Using this method of testing each nostril separately will often show a reduced or even completely absent sense of smell in either one nostril or both, something which is often not revealed if both nostrils are simultaneously tested.[9] Losing an established and sentimental smell memory (e.g. the smell of grass, of the grandparents' attic, of a particular book, of loved ones, or of oneself) has been known to cause feelings of depression.[10][better source needed] Loss of the ability to smell may lead to the loss of libido, though this usually does not apply to loss of smell present at birth.[10][better source needed] Often people who have loss of smell at birth report that they pretended to be able to smell as children because they thought that smelling was something that older/mature people could do, or did not understand the concept of smelling but did not want to appear different from others. When children get older, they often realize and report to their parents that they do not actually possess a sense of smell, often to the surprise of their parents.[citation needed] A study done on patients suffering from anosmia found that when testing both nostrils, there was no anosmia revealed; however, when testing each nostril individually, tests showed that the sense of smell was usually affected in only one of the nostrils as opposed to both. This demonstrated that unilateral anosmia is not uncommon in anosmia patients.[9] ## Causes[edit] A temporary loss of smell can be caused by a blocked nose or infection. In contrast, a permanent loss of smell may be caused by death of olfactory receptor neurons in the nose or by brain injury in which there is damage to the olfactory nerve or damage to brain areas that process smell (see olfactory system). The lack of the sense of smell at birth, usually due to genetic factors, is referred to as congenital anosmia. Family members of the patient suffering from congenital anosmia are often found with similar histories; this suggests that the anosmia may follow an autosomal dominant pattern.[11] Anosmia may very occasionally be an early sign of a degenerative brain disease such as Parkinson's disease and Alzheimer's disease. Another specific cause of permanent loss could be from damage to olfactory receptor neurons because of use of certain types of nasal spray; i.e., those that cause vasoconstriction of the nasal microcirculation. To avoid such damage and the subsequent risk of loss of smell, vasoconstricting nasal sprays should be used only when absolutely necessary and then for only a short amount of time. Non-vasoconstricting sprays, such as those used to treat allergy-related congestion, are safe to use for prescribed periods of time.[12] Anosmia can also be caused by nasal polyps. These polyps are found in people with allergies, histories of sinusitis, and family history. Individuals with cystic fibrosis often develop nasal polyps.[citation needed] Amiodarone is a drug used in the treatment of arrhythmias of the heart. A clinical study demonstrated that the use of this drug induced anosmia in some patients. Although rare, there was a case in which a 66-year-old male was treated with amiodarone for ventricular tachycardia. After the use of the drug he began experiencing olfactory disturbance, however after decreasing the dosage of amiodarone, the severity of the anosmia decreased accordingly hence correlating the use of amiodarone to the development of anosmia.[13] ### COVID-19-related anosmia[edit] Chemosensory disturbances, including loss of smell or taste, are the predominant neurological symptom of COVID-19.[14][15] As many as 80% of COVID-19 patients exhibit some change in chemesthesis, including smell. Loss of smell has also been found to be more predictive of COVID-19 than all other symptoms, including fever, cough or fatigue, based on a survey of 2 million participants in the UK and US.[16] Google searches for "smell", "loss of smell", "anosmia", and other similar terms increased since the early months of the pandemic, and strongly correlated with increases in daily cases and deaths.[17] Research into the mechanisms underlying these symptoms are currently ongoing.[18] Many countries list anosmia as an official COVID-19 symptom, and some have developed "smell tests" as potential screening tools.[19][20] In 2020, the Global Consortium for Chemosensory Research, a collaborative research organization of international smell and taste researchers, formed to investigate loss of smell and related chemosensory symptoms.[21] ### List of causes[edit] * Upper respiratory tract infection (such as sinusitis, the common cold)[22] * COVID-19[23][24] * Nasal polyps[25] * Idiopathic hypogonadotropic hypogonadism * Hypothyroidism * Head trauma, damage to the ethmoid bone[26] * Dementia with Lewy bodies * Tumors of the frontal lobe * Antibiotics * Fibromyalgia * Multiple sclerosis * Hypoglycaemia * Diabetes * Asthma or allergy * Hayfever * Chronic obstructive pulmonary disease (COPD) * Long term alcoholism * Cushing's syndrome * Exposure to a chemical that burns the inside of the nose * Stroke * Epilepsy * Radiation therapy to the head and neck * Liver or kidney disease * Parkinson's disease[27] * Alzheimer's disease[28] * Toxins (especially acrylates, methacrylates[29] and cadmium[30][31]) * Old age[32] * Kallmann syndrome * Primary ciliary dyskinesia * Post-perfusion syndrome * Laryngectomy with permanent tracheostomy * Esthesioneuroblastoma is an exceedingly rare cancerous tumor that originates in or near the olfactory nerve. Symptoms are anosmia (loss of sense of smell) often accompanied by chronic sinusitis.[33] * Intranasal drug use * Samter's triad also known as AERD (aspirin exacerbated respiratory disease) * Foster Kennedy syndrome * Cadmium poisoning * Smoking * Neurotropic virus[34] * Schizophrenia[35] * Pernicious anemia * Zinc deficiency * Bell's Palsy or nerve paralysis and damage * Idiopathic intracranial hypertension * Suprasellar meningioma * Refsum's disease * Adrenergic agonists or withdrawal from alpha blockers (vasoconstriction) * Sarcoidosis[36] * Zinc-based intranasal cold products, including remedies labelled as "homeopathic"[37] * Chronic atrophic rhinitis * Paget's disease of bone[38] * Cerebral aneurysm[39] * Granulomatosis with polyangiitis * Primary amoebic meningoencephalitis * Myasthenia gravis[40] * Snakebite[41] * Idiopathic anosmia (cause cannot be determined)[3] ## Diagnosis[edit] Anosmia can be diagnosed by doctors by using acetylcysteine tests. Doctors will begin with a detailed elicitation of history. Then the doctor will ask for any related injuries in relation to anosmia which could include upper respiratory infections or head injury. Psychophysical Assessment of order and taste identification can be used to identify anosmia. A nervous system examination is performed to see if the cranial nerves are damaged.[42] The diagnosis, as well as the degree of impairment, can now be tested much more efficiently and effectively than ever before thanks to "smell testing kits" that have been made available as well as screening tests which use materials that most clinics would readily have.[43] Occasionally, after accidents, there is a change in a patient's sense of smell. Particular smells that were present before are no longer present. On occasion, after head traumas, there are patients who have unilateral anosmia. The sense of smell should be tested individually in each nostril.[9] Many cases of congenital anosmia remain unreported and undiagnosed. Since the disorder is present from birth the individual may have little or no understanding of the sense of smell, hence is unaware of the deficit.[44] It may also lead to reduction of appetite.[45] ## Treatment[edit] Though anosmia caused by brain damage cannot be treated, anosmia caused by inflammatory changes in the mucosa may be treated with glucocorticoids. Reduction of inflammation through the use of oral glucocorticoids such as prednisone, followed by long term topical glucocorticoid nasal spray, would easily and safely treat the anosmia. A prednisone regimen is adjusted based on the degree of the thickness of mucosa, the discharge of oedema and the presence or absence of nasal polyps.[4] However, the treatment is not permanent and may have to be repeated after a short while.[4] Together with medication, pressure of the upper area of the nose must be mitigated through aeration and drainage.[46] Anosmia caused by a nasal polyp may be treated by steroidal treatment or removal of the polyp.[47] Although very early in development, gene therapy has restored a sense of smell in mice with congenital anosmia when caused by ciliopathy. In this case, a genetic condition had affected cilia in their bodies which normally enabled them to detect air-borne chemicals, and an adenovirus was used to implant a working version of the IFT88 gene into defective cells in the nose, which restored the cilia and allowed a sense of smell.[48][49] ## Epidemiology[edit] In the United States 3% of people age over 40 are affected by anosmia.[3] In 2012 smell was assessed in persons aged 40 years and older with rates of anosmia/severe hyposmia was 0.3% at age 40–49 rising to 14.1% at age 80+. Rates of hyposmia was much higher: 3.7% at age 40–49 and 25.9% at 80+.[50] ## See also[edit] * Phantosmia * Parosmia * Anosmia Awareness Day * Zicam, a medicine that caused some users to permanently lose their sense of smell * Ageusia, the loss of the sense of taste ## References[edit] 1. ^ a b c Coon D, Mitterer J (2014). "4. Sensation and perception". Introduction to Psychology: Gateways to Mind and Behavior. Boston: Cengage Learning. p. 136. ISBN 978-1-305-09187-0. LCCN 2014942026. 2. ^ a b c d e Jones, Nicholas (2010). "2. Making sense of symptoms". In Jones, Nicholas (ed.). Practical Rhinology. CRC Press. p. 24-25. ISBN 978-1-4441-0861-3. 3. ^ a b c d Li, Xi; Lui, Forshing (6 July 2020), "Anosmia", StatPearls, StatPearls Publishing, PMID 29489163, retrieved 1 December 2020 4. ^ a b c Knight, A. (27 August 1988). "Anosmia". The Lancet. 2 (8609): 512. doi:10.1016/s0140-6736(88)90160-2. ISSN 0140-6736. PMID 2900434. S2CID 208793859.(subscription required) 5. ^ "Anosmia". The Lancet. 241 (6228): 55. 1943. doi:10.1016/S0140-6736(00)89085-6. 6. ^ Uytingco, Cedric R.; Green, Warren W.; Martens, Jeffrey R. (2019). "Olfactory loss and dysfunction in ciliopathies: Molecular mechanisms and potential therapies". Current Medicinal Chemistry. 26 (17): 3103–3119. doi:10.2174/0929867325666180105102447. ISSN 0929-8673. PMC 6034980. PMID 29303074. 7. ^ Ul Hassan A, Hassan G, Khan SH, Rasool Z, Abida A (January 2009). "Ciliopathy with special emphasis on kartageners syndrome". International Journal of Health Sciences. 3 (1): 65–9. PMC 3068795. PMID 21475513. 8. ^ Toller, Steve Van (1 December 1999). "Assessing the Impact of Anosmia: Review of a Questionnaire's Findings". Chemical Senses. 24 (6): 705–712. doi:10.1093/chemse/24.6.705. ISSN 0379-864X. PMID 10587505. 9. ^ a b c Harvey P (February 2006). "Anosmia". Practical Neurology. 6 (1): 65. 10. ^ a b Heald C (December 27, 2006). "Sense and scent ability". BBC News. Retrieved April 25, 2010. 11. ^ Waguespack, R. W. (1992). "Congenital Anosmia". Archives of Otolaryngology–Head & Neck Surgery. 118 (1): 10. doi:10.1001/archotol.1992.01880010012002. 12. ^ Preventing Anosmia from Intranasal Zinc Administration[unreliable medical source?] 13. ^ Maruyama T, Yasuda S, Odashiro K, Kaji Y, Harada M (November 2007). "Anosmia induced by amiodarone". The American Journal of Medicine. 120 (11): e9. doi:10.1016/j.amjmed.2006.08.029. PMID 17976411. 14. ^ Lechien JR, Chiesa-Estomba CM, De Siati DR, Horoi M, Le Bon SD, Rodriguez A, et al. (August 2020). "Olfactory and gustatory dysfunctions as a clinical presentation of mild-to-moderate forms of the coronavirus disease (COVID-19): a multicenter European study". European Archives of Oto-Rhino-Laryngology. 277 (8): 2251–2261. doi:10.1007/s00405-020-05965-1. PMC 7134551. PMID 32253535. 15. ^ Xydakis MS, Dehgani-Mobaraki P, Holbrook EH, Geisthoff UW, Bauer C, Hautefort C, et al. (September 2020). "Smell and taste dysfunction in patients with COVID-19". The Lancet. Infectious Diseases. 20 (9): 1015–1016. doi:10.1016/S1473-3099(20)30293-0. PMC 7159875. PMID 32304629. 16. ^ Menni C, Valdes AM, Freidin MB, Sudre CH, Nguyen LH, Drew DA, et al. (July 2020). "Real-time tracking of self-reported symptoms to predict potential COVID-19". Nature Medicine. 26 (7): 1037–1040. doi:10.1038/s41591-020-0916-2. PMC 7751267. PMID 32393804. 17. ^ Walker A, Hopkins C, Surda P (July 2020). "Use of Google Trends to investigate loss-of-smell-related searches during the COVID-19 outbreak". International Forum of Allergy & Rhinology. 10 (7): 839–847. doi:10.1002/alr.22580. PMC 7262261. PMID 32279437. 18. ^ Cooper KW, Brann DH, Farruggia MC, Bhutani S, Pellegrino R, Tsukahara T, et al. (July 2020). "COVID-19 and the Chemical Senses: Supporting Players Take Center Stage". Neuron. 107 (2): 219–233. doi:10.1016/j.neuron.2020.06.032. PMC 7328585. PMID 32640192. 19. ^ Iravani B, Arshamian A, Ravia A, Mishor E, Snitz K, Shushan S, et al. (11 May 2020). "Relationship between odor intensity estimates and COVID-19 population prediction in a Swedish sample". MedRxiv: 2020.05.07.20094516. doi:10.1101/2020.05.07.20094516. S2CID 218580260. 20. ^ Rodriguez S, Cao L, Rickenbacher GT, Benz EG, Magdamo C, Ramirez Gomez LA, et al. (June 2020). "Innate immune signaling in the olfactory epithelium reduces odorant receptor levels: modeling transient smell loss in COVID-19 patients". MedRxiv: 2020.06.14.20131128. doi:10.1101/2020.06.14.20131128. PMC 7310652. PMID 32587994. 21. ^ "Global Consortium for Chemosensory Research". Global Consortium for Chemosensory Research (GCCR). Retrieved 10 July 2020. 22. ^ Doty RL, Mishra A (March 2001). "Olfaction and its alteration by nasal obstruction, rhinitis, and rhinosinusitis". The Laryngoscope. 111 (3): 409–23. doi:10.1097/00005537-200103000-00008. PMC 7165948. PMID 11224769. 23. ^ Grant MC, Geoghegan L, Arbyn M, Mohammed Z, McGuinness L, Clarke EL, Wade RG (23 June 2020). "The prevalence of symptoms in 24,410 adults infected by the novel coronavirus (SARS-CoV-2; COVID-19): A systematic review and meta-analysis of 148 studies from 9 countries". PLOS ONE. 15 (6): e0234765. Bibcode:2020PLoSO..1534765G. doi:10.1371/journal.pone.0234765. PMC 7310678. PMID 32574165. 24. ^ "Coronavirus Disease 2019 (COVID-19) – Symptoms". Centers for Disease Control and Prevention. 13 May 2020. Retrieved 14 May 2020. 25. ^ Ta NH (January 2019). "Will we ever cure nasal polyps?". Annals of the Royal College of Surgeons of England. 101 (1): 35–39. doi:10.1308/rcsann.2018.0149. PMC 6303820. PMID 30286644. 26. ^ Doty RL, Yousem DM, Pham LT, Kreshak AA, Geckle R, Lee WW (September 1997). "Olfactory dysfunction in patients with head trauma". Archives of Neurology. 54 (9): 1131–40. doi:10.1001/archneur.1997.00550210061014. PMID 9311357. 27. ^ Doty RL, Deems DA, Stellar S (August 1988). "Olfactory dysfunction in parkinsonism: a general deficit unrelated to neurologic signs, disease stage, or disease duration". Neurology. 38 (8): 1237–44. doi:10.1212/WNL.38.8.1237. PMID 3399075. S2CID 3009692. 28. ^ Murphy C (April 1999). "Loss of olfactory function in dementing disease". Physiology & Behavior. 66 (2): 177–82. doi:10.1016/S0031-9384(98)00262-5. PMID 10336141. S2CID 26110446. 29. ^ Schwartz BS, Doty RL, Monroe C, Frye R, Barker S (May 1989). "Olfactory function in chemical workers exposed to acrylate and methacrylate vapors". American Journal of Public Health. 79 (5): 613–8. doi:10.2105/AJPH.79.5.613. PMC 1349504. PMID 2784947. 30. ^ Rose CS, Heywood PG, Costanzo RM (June 1992). "Olfactory impairment after chronic occupational cadmium exposure". Journal of Occupational Medicine. 34 (6): 600–5. PMID 1619490. 31. ^ Rydzewski B, Sułkowski W, Miarzyńska M (1998). "Olfactory disorders induced by cadmium exposure: a clinical study". International Journal of Occupational Medicine and Environmental Health. 11 (3): 235–45. PMID 9844306. 32. ^ Doty RL, Shaman P, Applebaum SL, Giberson R, Siksorski L, Rosenberg L (December 1984). "Smell identification ability: changes with age". Science. 226 (4681): 1441–3. Bibcode:1984Sci...226.1441D. doi:10.1126/science.6505700. PMID 6505700. 33. ^ Somenek M (October 30, 2009). Harris JE (ed.). "Esthesioneuroblastoma". eMedicine. 34. ^ Seo BS, Lee HJ, Mo JH, Lee CH, Rhee CS, Kim JW (October 2009). "Treatment of postviral olfactory loss with glucocorticoids, Ginkgo biloba, and mometasone nasal spray". Archives of Otolaryngology--Head & Neck Surgery. 135 (10): 1000–4. doi:10.1001/archoto.2009.141. PMID 19841338. Lay summary – ScienceDaily (October 19, 2009). 35. ^ Rupp CI, Fleischhacker WW, Kemmler G, Kremser C, Bilder RM, Mechtcheriakov S, et al. (May 2005). "Olfactory functions and volumetric measures of orbitofrontal and limbic regions in schizophrenia". Schizophrenia Research. 74 (2–3): 149–61. doi:10.1016/j.schres.2004.07.010. PMID 15721995. S2CID 11026266. 36. ^ Kieff DA, Boey H, Schaefer PW, Goodman M, Joseph MP (December 1997). "Isolated neurosarcoidosis presenting as anosmia and visual changes". Otolaryngology–Head and Neck Surgery. 117 (6): S183-6. doi:10.1016/S0194-5998(97)70097-4. PMID 9419143. 37. ^ Harris G (June 16, 2009). "F.D.A. Warns Against Use of Popular Cold Remedy". New York Times. 38. ^ Wheeler TT, Alberts MA, Dolan TA, McGorray SP (December 1995). "Dental, visual, auditory and olfactory complications in Paget's disease of bone". Journal of the American Geriatrics Society. 43 (12): 1384–91. doi:10.1111/j.1532-5415.1995.tb06618.x. PMID 7490390. S2CID 26893932. 39. ^ Eriksen KD, Bøge-Rasmussen T, Kruse-Larsen C (June 1990). "Anosmia following operation for cerebral aneurysms in the anterior circulation". Journal of Neurosurgery. 72 (6): 864–5. doi:10.3171/jns.1990.72.6.0864. PMID 2338570. 40. ^ Leon-Sarmiento FE, Bayona EA, Bayona-Prieto J, Osman A, Doty RL (2012). "Profound olfactory dysfunction in myasthenia gravis". PLOS ONE. 7 (10): e45544. Bibcode:2012PLoSO...745544L. doi:10.1371/journal.pone.0045544. PMC 3474814. PMID 23082113. 41. ^ Churchman A, O'Leary MA, Buckley NA, Page CB, Tankel A, Gavaghan C, et al. (December 2010). "Clinical effects of red-bellied black snake (Pseudechis porphyriacus) envenoming and correlation with venom concentrations: Australian Snakebite Project (ASP-11)". The Medical Journal of Australia. 193 (11–12): 696–700. doi:10.5694/j.1326-5377.2010.tb04108.x. PMID 21143062. S2CID 15915175. 42. ^ "Anosmia / Loss Of Smell".[unreliable medical source?] 43. ^ Holbrook EH, Leopold DA (February 2003). "Anosmia: diagnosis and management". Current Opinion in Otolaryngology & Head and Neck Surgery. 11 (1): 54–60. doi:10.1097/00020840-200302000-00012. PMID 14515104. S2CID 35835436. 44. ^ Vowles RH, Bleach NR, Rowe-Jones JM (August 1997). "Congenital anosmia". International Journal of Pediatric Otorhinolaryngology. 41 (2): 207–14. doi:10.1016/S0165-5876(97)00075-X. PMID 9306177. 45. ^ Sumner, D (1971). "Appetite and Anosmia". The Lancet. 297 (7706): 970. doi:10.1016/S0140-6736(71)91470-X. 46. ^ Turnley WH (April 1963). "Anosmia". The Laryngoscope. 73 (4): 468–73. doi:10.1288/00005537-196304000-00012. PMID 13994924. S2CID 221921289. 47. ^ McClay JE (May 1, 2014). "Nasal Polyps Treatment & Management". Medscape. 48. ^ McIntyre JC, Davis EE, Joiner A, Williams CL, Tsai IC, Jenkins PM, et al. (September 2012). "Gene therapy rescues cilia defects and restores olfactory function in a mammalian ciliopathy model". Nature Medicine. 18 (9): 1423–8. doi:10.1038/nm.2860. PMC 3645984. PMID 22941275. 49. ^ Gallagher J (September 3, 2012). "Gene therapy restores sense of smell in mice". BBC News. 50. ^ Hoffman HJ, Rawal S, Li CM, Duffy VB (June 2016). "New chemosensory component in the U.S. National Health and Nutrition Examination Survey (NHANES): first-year results for measured olfactory dysfunction". Reviews in Endocrine & Metabolic Disorders. 17 (2): 221–40. doi:10.1007/s11154-016-9364-1. PMC 5033684. PMID 27287364. ## Further reading[edit] Scholia has a profile for anosmia (Q468433). * Blodgett B (2010). Remembering Smell: A Memoir of Losing—and Discovering—the Primal Sense. Houghton Mifflin Harcourt. ISBN 978-0-618-86188-0. * Birnbaum M (2011). Season to Taste: How I Lost my Sense of Smell and Found my Way. Ecco. ISBN 978-0-06-191531-4. * DeVere R, Calvert M (2010). Navigating Smell and Taste Disorders. Demos Health. ISBN 978-1-932603-96-5. * Gilbert A (2008). What the Nose Knows.The Science of Scent in Everyday Life. Crown. ISBN 978-1-4000-8234-6. * Herz R (2007). The Scent of Desire. Discovering Our Enigmatic Sense of Smell. HarperCollins. ISBN 978-0-06-082538-6. * Tafalla M (2010). Nunca sabrás a qué huele Bagdad (You will never know the smell of Bagdad) (in Spanish). Autonomous University of Barcelona. ISBN 978-84-490-2611-9. \- Novel dealing with congenital anosmia. * Keller A, Malaspina D (July 2013). "Hidden consequences of olfactory dysfunction: a patient report series". BMC Ear, Nose and Throat Disorders. 13 (1): 8. doi:10.1186/1472-6815-13-8. PMC 3733708. PMID 23875929. * Tafalla M (September 2013). "A world without the olfactory dimension". Anatomical Record. 296 (9): 1287–96. doi:10.1002/ar.22734. PMID 23907763. * Tafalla M (2013). "Anosmic Aesthetics". Estetika: The Central European Journal of Aesthetics. Prag. 50 (1/2013): 53–80. doi:10.33134/eeja.103. * Wilson DA, Stevenson RJ (2006). Learning to Smell. Olfactory Perception from Neurobiology to Behavior. The Johns Hopkins University Press. ISBN 978-0-8018-8368-2. ## External links[edit] Classification D * ICD-10: R43.0 * ICD-9-CM: 781.1 * MeSH: D000857 * v * t * e Symptoms and signs relating to perception, emotion and behaviour Cognition * Confusion * Delirium * Psychosis * Delusion * Amnesia * Anterograde amnesia * Retrograde amnesia * Convulsion * Dizziness * Disequilibrium * Presyncope/Lightheadedness * Vertigo Emotion * Anger * Anxiety * Depression * Fear * Paranoia * Hostility * Irritability * Suicidal ideation Behavior * Verbosity * Russell's sign Perception * Sensory processing disorder * Hallucination (Auditory hallucination) * Smell * Anosmia * Hyposmia * Dysosmia * Parosmia * Phantosmia * Hyperosmia * Synesthesia * Taste * Ageusia * Hypogeusia * Dysgeusia * Hypergeusia [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA [kDa]: kilodalton [EPC]: Early Prostate Cancer [LAPC]: locally advanced prostate cancer [NSAAs]: nonsteroidal antiandrogens [NSAA]: nonsteroidal antiandrogen [GnRH]: gonadotropin-releasing hormone [ADT]: androgen deprivation therapy [LH]: luteinizing hormone [AR]: androgen receptor [CAB]: combined androgen blockade [LPC]: localized prostate cancer [CPA]: cyproterone acetate [U.S.]: United States [FDA]: Food and Drug Administration	Anosmia	c0003126	7,877	wikipedia	https://en.wikipedia.org/wiki/Anosmia	2021-01-18T18:31:35	{"mesh": ["D000857"], "icd-9": ["781.1"], "icd-10": ["R43.0"], "wikidata": ["Q468433"]}
Exstrophy-epispadias complex (EEC) refers to a spectrum of birth defects that includes epispadias, classical bladder exstrophy, and exstrophy of the cloaca and several variants. EEC is characterized by a visible defect of the lower abdominal wall and other problems. In normal development, the cloacal membrane temporarily separates the cloaca (final part of the intestine) into urogenital and anal regions, and it ruptures after fusing with a structure known as the urogenital septum, which is made up of the tissue that will form the abdominal muscles (mesoderm). If the cloacal membrane does not fuse correctly with the urogenital septum, it does not form the mesoderm and, as a result, the abdominal muscles do not form. The exact timing of the rupture determines whether the child is born with isolated epispadias, classic bladder exstrophy, or cloacal exstrophy. Depending on severity, EEC may involve the urinary system, musculoskeletal system, pelvis, pelvic floor, abdominal wall, genitalia, and sometimes the spine and anus. There is no known cause for EEC. Treatment may involve several surgeries to repair the abdominal wall and any associated malformations. The University of Michigan has a webpage about the development of the embryo and its parts, including the formation of the cloaca. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA [kDa]: kilodalton [EPC]: Early Prostate Cancer [LAPC]: locally advanced prostate cancer [NSAAs]: nonsteroidal antiandrogens [NSAA]: nonsteroidal antiandrogen [GnRH]: gonadotropin-releasing hormone [ADT]: androgen deprivation therapy [LH]: luteinizing hormone [AR]: androgen receptor [CAB]: combined androgen blockade [LPC]: localized prostate cancer [CPA]: cyproterone acetate [U.S.]: United States [FDA]: Food and Drug Administration	Exstrophy-epispadias complex	c1838703	7,878	gard	https://rarediseases.info.nih.gov/diseases/2207/exstrophy-epispadias-complex	2021-01-18T18:00:38	{"mesh": ["C564009"], "orphanet": ["322"], "synonyms": ["BEEC", "Bladder exstrophy-epispadias-cloacal extrophy complex", "EEC"]}
## Clinical Features Viljoen and Smart (1993) described a woman with mental retardation, borderline microcephaly, microphthalmia, prognathism, cleft lip and palate, ectrodactyly of the feet, and premature aging of the skin. Her karyotype showed a de novo translocation 46,XX,t(6;13)(q21;q12). Suthers and Morris (1996) reported a mentally retarded man with borderline microcephaly, microphthalmia, microcornea, prognathism, wide gap between his upper central incisors, ventricular septal defect, split-feet, cryptorchidism, and normal karyotype. They proposed that their patient and that of Viljoen and Smart (1993) represented a distinct syndrome which could be related to mutation in a gene located on either 6q21 or 13q12. Van den Ende et al. (1996) described the association of congenital heart defects and split-feet in 4 infants who had the additional manifestations of short palpebral fissures and micrognathia; see 601348. It is possible that the various facial abnormalities reflect age-related differences. Cytogenetics In the patient with MMEP and translocation 46,XX,t(6;13)(q21;q12) reported by Viljoen and Smart (1993), Vervoort et al. (2002) localized the breakpoint on chromosome 6q21 close to marker D6S1250. Cloning of the breakpoint fragment allowed localization of the der(13) breakpoint close to a marker in the region 13q11-q12. Sequencing of the chromosome 13 breakpoint confirmed that the translocation was balanced, with no missing or duplicated material. No gene on chromosome 13 appeared to be disrupted, whereas the SNX3 gene on 6q21 was. Mutation screening of another sporadic case of MMEP failed to detect any point mutations or deletions in the SNX3 coding sequence. Because of the possibility of positional effect, Vervoort et al. (2002) suggested that another candidate gene in the vicinity of the chromosome 6 breakpoint may have been responsible for MMEP in the original patient or, just as likely, the MMEP phenotype in the 2 patients resulted from different genetic causes. Limbs \- Ectrodactyly of feet Neuro \- Mental retardation Inheritance \- ? Autosomal dominant Eyes \- Microphthalmia \- Microcornea \- Short palpebral fissures Teeth \- Wide gap between upper central incisors Head \- Borderline microcephaly Mandible \- Prognathism GU \- Cryptorchidism Lab \- De novo translocation 46,XX,t(6,13)(q21,q12) Mouth \- Cleft lip/palate Skin \- Premature skin aging ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA [kDa]: kilodalton [EPC]: Early Prostate Cancer [LAPC]: locally advanced prostate cancer [NSAAs]: nonsteroidal antiandrogens [NSAA]: nonsteroidal antiandrogen [GnRH]: gonadotropin-releasing hormone [ADT]: androgen deprivation therapy [LH]: luteinizing hormone [AR]: androgen receptor [CAB]: combined androgen blockade [LPC]: localized prostate cancer [CPA]: cyproterone acetate [U.S.]: United States [FDA]: Food and Drug Administration	MICROPHTHALMIA, SYNDROMIC 8	c1832440	7,879	omim	https://www.omim.org/entry/601349	2019-09-22T16:14:59	{"mesh": ["C537686"], "omim": ["601349"], "orphanet": ["3434"], "synonyms": ["Alternative titles", "MICROCEPHALY, MICROPHTHALMIA, ECTRODACTYLY OF LOWER LIMBS, AND PROGNATHISM"]}
Focal facial dermal dysplasia type I (FFDD1), also known as Brauer syndrome, is a focal facial dysplasia (FFDD; see this term) characterized by congenital bitemporal cutis aplasia. ## Epidemiology FFDD1 has been reported in over 80 cases including three large multi-generational families (German, English, Australian) and several sporadic cases. ## Clinical description The bitemporal, rarely unilateral, hypoplastic scar-like lesions in FFDD, resembling forceps marks, are usually the only manifestations of FFDD1. Other very rarely described and usually mild facial dysmorphic features may comprise a low frontal hairline, sparse hair, sparse lateral eyebrows, distichiasis (upper lashes), flattened nasal tip, bulbous nasal tip, prominent upper lip, skin dimples lateral to lips, horizontal chin furrow, vertical chin cleft, and linear grooves on the forehead. Most patients usually have normal intelligence. ## Etiology Etiology is unknown. ## Diagnostic methods Clinical examination reveals bitemporal scars. ## Differential diagnosis Differential diagnosis includes focal facial dermal dysplasia type 2 and 3 (see these terms). ## Antenatal diagnosis Prenatal diagnosis is not available ## Genetic counseling FFDD1 is transmitted in an autosomal dominant manner with full penetrance. ## Management and treatment No specific treatment exists. There is limited experience with plastic surgery for the facial scar-like lesions. ## Prognosis Affected individuals have a normal intelligence and life span. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA [kDa]: kilodalton [EPC]: Early Prostate Cancer [LAPC]: locally advanced prostate cancer [NSAAs]: nonsteroidal antiandrogens [NSAA]: nonsteroidal antiandrogen [GnRH]: gonadotropin-releasing hormone [ADT]: androgen deprivation therapy [LH]: luteinizing hormone [AR]: androgen receptor [CAB]: combined androgen blockade [LPC]: localized prostate cancer [CPA]: cyproterone acetate [U.S.]: United States [FDA]: Food and Drug Administration	Focal facial dermal dysplasia type I	c1744559	7,880	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=79133	2021-01-23T18:50:29	{"gard": ["8416"], "mesh": ["C537068", "C536385"], "omim": ["136500"], "umls": ["C1744559", "C2936827"], "icd-10": ["Q82.8"], "synonyms": ["Bitemporal aplasia cutis congenita", "Brauer syndrome", "FFDD type I", "FFDD1", "Focal facial dermal dysplasia 1, Brauer type", "Focal facial dermal dysplasia type 1"]}
Tuberculosis (TB) is a contagious-infectious disease caused mainly by Mycobacterium tuberculosis that in most individuals is usually asymptomatic but that in at risk individuals (e.g. with diabetes or with HIV infection) can cause weakness, fever, weight loss, night sweat, and respiratory anomalies such as chronic cough, chest pain, hemoptysis or respiratory insufficiency. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA [kDa]: kilodalton [EPC]: Early Prostate Cancer [LAPC]: locally advanced prostate cancer [NSAAs]: nonsteroidal antiandrogens [NSAA]: nonsteroidal antiandrogen [GnRH]: gonadotropin-releasing hormone [ADT]: androgen deprivation therapy [LH]: luteinizing hormone [AR]: androgen receptor [CAB]: combined androgen blockade [LPC]: localized prostate cancer [CPA]: cyproterone acetate [U.S.]: United States [FDA]: Food and Drug Administration	Tuberculosis	c0041296	7,881	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=3389	2021-01-23T17:15:18	{"gard": ["7827"], "mesh": ["D014376"], "omim": ["607948"], "umls": ["C0041296"], "icd-10": ["A16.9"]}
A number sign (#) is used with this entry because of evidence that keratosis pilaris atrophicans (KPA) is caused by homozygous mutation in the LRP1 gene (107770) on chromosome 12q13. One such family has been reported. Description Keratosis pilaris atrophicans (KPA) represents a group of rare genodermatoses characterized by perifollicular keratosis and inflammation that progresses to atrophy and scarring of the facial skin. Keratosis pilaris of extensor surfaces of limbs is a common associated finding. Affected individuals may present with features that overlap between 3 subtypes, keratosis pilaris atrophicans faciei (KPAF), keratosis follicularis spinulosa decalvans (KFSD), and atrophoderma vermiculata (AVA; see 209700) (summary by Klar et al., 2015). Clinical Features Klar et al. (2015) studied a consanguineous Pakistani family in which 3 sibs and their cousin had keratosis pilaris atrophicans (KPA). Affected family members had normal facial skin at birth, but at approximately 1 year of age lacrimation in response to sunlight or cool air was noted, followed by the development of erythema, nonpurulent follicular papules, and atrophy on cheeks. With age, pit-like areas of follicular atrophy spread to the chin, upper lip, forehead, nasal ridge, and earlobes; the atrophic pits were separated by apparently normal skin. At age 7 to 8 years, the lacrimation stopped, but eyelashes were lost and eyebrows became sparse. All 4 affected children developed atrophic keratosis pilaris on the extensor surface of arms and legs, with the absence of body hair most evident in the postpubertal individuals. The affected children displayed no other ectodermal symptoms or signs, and they had normal psychomotor development, growth, and vision. Histologic analysis of skin biopsies from affected areas of the cheeks showed follicular plugging, comedo formation, and perifollicular lymphocyte infiltration consistent with KPA. Noting that the affected individuals showed features of both AVA and KFSD, the authors designated this to be a mixed type of KPA. Cytogenetics Nazarenko et al. (1999) presented a patient with partial monosomy of 18p caused by a de novo translocation t(Y;18) and a generalized form of keratosis pilaris (keratosis pilaris affecting the skin follicles of the trunk, limbs, and face, i.e., ulerythema ophryogenes). Two-color fluorescence in situ hybridization (FISH) with centromere-specific Y and 18 DNA probes identified the derivative chromosome 18 as a dicentric with breakpoints in p11.2 on both the Y chromosome and chromosome 18. The patient had another normal Y chromosome. This was the third report of an 18p deletion, and the first case of a translocation involving 18p and a sex chromosome, with this genodermatosis. The data suggested that the short arm of chromosome 18 is a candidate region for a gene causing keratosis pilaris. Unmasking of a recessive mutation at the disease locus by deletion of the wildtype allele could be the cause of the recessive genodermatosis. Earlier reports of the 18p deletion in association with keratosis pilaris were provided by Zouboulis et al. (1994) and Horsley et al. (1998). Mapping By autozygosity mapping in a consanguineous Pakistani family with a mixed type of KPA, Klar et al. (2015) identified homozygosity for a region at chromosome 12q (chr12:63,359,011-67,072,557, GRCh37) that segregated with disease, yielding a maximum 2-point lod score of 2.55. Molecular Genetics By whole-exome sequencing in 2 affected cousins from a consanguineous Pakistani family with a mixed type of KPA mapping to chromosome 12q, Klar et al. (2015) identified homozygosity for a missense mutation in the LRP1 gene (K1245R; 107770.0002). The mutation segregated fully with disease in the family and was not found in 200 Swedish or 200 Pakistani control chromosomes, in 900 in-house exomes, or in the dbSNP, EVS, ESP, or ExAC databases. Nomenclature Keratosis pilaris defines a group of cutaneous disorders of ectodermal origin characterized by follicular hyperkeratosis and frequently occurring with ichthyosis or atopy. Ulerythema ophryogenes is classified as one of the types of this genodermatosis (Azambuja et al., 1987). Ulerythema is an erythematous disorder of the skin characterized by the formation of cicatrices and by atrophy; ulerythema ophryogenes is keratosis pilaris affecting the follicles of the eyebrow hairs, associated with erythema, and often leading to scarring and atrophy. The prefix 'ophryo-' refers to the eyebrow. INHERITANCE \- Autosomal recessive HEAD & NECK Eyes \- Lacrimation in response to sunlight or cool air (in early childhood) SKIN, NAILS, & HAIR Skin \- Erythema of cheeks \- Atrophic skin on cheeks \- Nonpurulent follicular papules on cheeks \- Pit-like areas of follicular atrophy on forehead, nasal ridge, upper lip, chin, and earlobes \- Atrophic pits separated by areas of normal-appearing skin \- Atrophic keratosis pilaris on the extensor surface of arms and legs Skin Histology \- Follicular plugging \- Comedo formation \- Perifollicular lymphocyte infiltration Hair \- Absence of body hair, especially after puberty MISCELLANEOUS \- Based on report of 1 family (last curated November 2016) MOLECULAR BASIS \- Caused by mutation in the low density lipoprotein receptor-related protein-1 gene (LRP1, 107770.0002 ) ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA [kDa]: kilodalton [EPC]: Early Prostate Cancer [LAPC]: locally advanced prostate cancer [NSAAs]: nonsteroidal antiandrogens [NSAA]: nonsteroidal antiandrogen [GnRH]: gonadotropin-releasing hormone [ADT]: androgen deprivation therapy [LH]: luteinizing hormone [AR]: androgen receptor [CAB]: combined androgen blockade [LPC]: localized prostate cancer [CPA]: cyproterone acetate [U.S.]: United States [FDA]: Food and Drug Administration	KERATOSIS PILARIS ATROPHICANS	c0263429	7,882	omim	https://www.omim.org/entry/604093	2019-09-22T16:12:30	{"mesh": ["C537412"], "omim": ["604093"], "orphanet": ["79100", "2340", "3406"]}
Abortion in Minnesota is legal. 52% of Minnesota adults said in a poll by the Pew Research Center that abortion should be legal in all or most cases. ## Contents * 1 Background * 2 Terminology * 3 Context * 4 History * 4.1 Legislative history * 4.2 Judicial history * 4.3 Clinic history * 5 Statistics * 6 Criminal prosecutions of abortion * 7 Abortion financing * 8 Abortion rights views and activities * 8.1 Activities * 8.2 Protests * 9 Anti-abortion views and activities * 9.1 Organizations * 9.2 Violence * 10 Footnotes * 11 References ## Background[edit] Abortion bans were instituted by 1900 with the rationale of trying to prevent deaths because of unsafe abortion practices[citation needed]. Abortion was a criminal offense for women by 1950. By 2007, the state had informed consent laws on the book, providing information that contradicted Journal of the American Medical Association conclusions[citation needed]. The state legislature tried and failed to pass abortion restrictions in 2012, 2018 and 2019. The number of abortion clinics have been declining in recent years, going from twenty in 1982 to fourteen in 1992 to six in 2014. There were 10,123 legal abortions in 2014, and 9,861 in 2015.[citation needed] Abortion was criminally prosecuted between 1911 and 1930, resulting in 30 convictions against women in that period. Doctors were being convicted of performing illegal abortions in the early 1970s. The state has an abortion rights community, involved in activities such as facilitating travel for women seeking abortions and protesting in support of abortion rights. There is also an active anti-abortion rights community, which includes organizations like Minnesota Family Council and Minnesota Citizens Concerned for Life. ## Terminology[edit] Main article: Abortion The abortion debate most commonly relates to the "induced abortion" of an embryo or fetus at some point in a pregnancy, which is also how the term is used in a legal sense.[note 1] Some also use the term "elective abortion", which is used in relation to a claim to an unrestricted right of a woman to an abortion, whether or not she chooses to have one. The term elective abortion or voluntary abortion describes the interruption of pregnancy before viability at the request of the woman, but not for medical reasons.[1] Anti-abortion advocates tend to use terms such as "unborn baby", "unborn child", or "pre-born child",[2][3] and see the medical terms "embryo", "zygote", and "fetus" as dehumanizing.[4][5] Both "pro-choice" and "pro-life" are examples of terms labeled as political framing: they are terms which purposely try to define their philosophies in the best possible light, while by definition attempting to describe their opposition in the worst possible light. "Pro-choice" implies that the alternative viewpoint is "anti-choice", while "pro-life" implies the alternative viewpoint is "pro-death" or "anti-life".[6] The Associated Press encourages journalists to use the terms "abortion rights" and "anti-abortion".[7] ## Context[edit] The neutrality of this section is disputed. Relevant discussion may be found on the talk page. Please do not remove this message until conditions to do so are met. (June 2019) (Learn how and when to remove this template message) See also: Abortion in the United States Free birth control correlates to teenage girls having a fewer pregnancies and fewer abortions. A 2014 New England Journal of Medicine study found such a link. At the same time, a 2011 study by Center for Reproductive Rights and Ibis Reproductive Health also found that states with more abortion restrictions have higher rates of maternal death, higher rates of uninsured pregnant women, higher rates of infant and child deaths, higher rates of teen drug and alcohol abuse, and lower rates of cancer screening.[8] According to a 2017 report from the Center for Reproductive Rights and Ibis Reproductive Health, states that tried to pass additional constraints on a women's ability to access legal abortions had fewer policies supporting women's health, maternal health and children's health. These states also tended to resist expanding Medicaid, family leave, medical leave, and sex education in public schools.[9] According to Megan Donovan, a senior policy manager at the Guttmacher Institute, states have legislation seeking to protect a woman's right to access abortion services have the lowest rates of infant mortality in the United States.[9] Poor women in the United States had problems paying for menstrual pads and tampons in 2018 and 2019. Almost two-thirds of American women could not pay for them. These were not available through the federal Women, Infants, and Children Program (WIC).[10] Lack of menstrual supplies has an economic impact on poor women. A study in St. Louis found that 36% had to miss days of work because they lacked adequate menstrual hygiene supplies during their period. This was on top of the fact that many had other menstrual issues including bleeding, cramps and other menstrual induced health issues.[10] Connecticut, Florida, Illinois, Maryland, Massachusetts, Minnesota, New Jersey, New York, Nevada, and Pennsylvania all had exemptions for essential hygiene products like tampons and menstrual pads as of November 2018.[11][12][13][14] Minnesota was one of only two states in the nation in 2019 (along with Alabama) that did not have a law that terminated parental rights of men who produced a child via rape or incest.[15][16] ## History[edit] ### Legislative history[edit] In the 19th century, bans by state legislatures on abortion were about protecting the life of the mother given the number of deaths caused by abortions; state governments saw themselves as looking out for the lives of their citizens.[17] By 1950, the state legislature would pass a law that stating that a woman who had an abortion or actively sought to have an abortion regardless of whether she went through with it were guilty of a criminal offense.[17] Parental consent laws passed by Massachusetts and Minnesota in the 1980s created over 12,000 petitions to bypass consent. Of these, 21 were denied and half of these denials were overturned on appeal.[18][19] The state was one of 23 states in 2007 to have a detailed abortion-specific informed consent requirement.[20] Arkansas, Minnesota and Oklahoma all require that women seeking abortions after 20-weeks be verbally informed that the fetus may feel pain during the abortion procedure despite a Journal of the American Medical Association conclusion that pain sensors do not develop in the fetus until between weeks 23 and 30.[21] Alaska and Minnesota both require that women seeking abortions after 20-weeks be informed that, while experts disagree on the issue of whether or not a fetus can feel pain at 20 weeks, it is possible. This expert confusion written into the law is there despite a Journal of the American Medical Association conclusion that pain sensors do not develop in the fetus until between weeks 23 and 30.[21] The state legislature was one of four states nationwide that tried, and failed, to pass a fetal heartbeat bill in 2012.[22] In 2018, the state was one of eleven where the legislature introduced a bill that would have banned abortion in almost all cases. It did not pass.[22] The state legislature was one of ten states nationwide that tried to unsuccessfully pass a fetal heartbeat bill in 2018. Only Iowa successfully passed such a bill, but it was struck down by the courts.[22] As of May 14, 2019, the state prohibited abortions after the fetus was viable, generally some point between week 24 and 28. This period uses a standard defined by the US Supreme Court in 1973 with the Roe v. Wade ruling.[22] On January 22, 2019, Tim Miller filed HF 271 in the Minnesota House of Representatives.[23] ### Judicial history[edit] In a 1894 case on abortion, the Minnesota Supreme Court said, "As a first impression, it may seem to be an unsound rule that one who solicits the commission of an offense, and willingly submits to its being committed upon her own person, should not be deemed an accomplice, while those whom she has thus solicited should be deemed principal criminals in the transaction. But in cases of this kind the public welfare demands the application of this rule, and its exceptions from the general rule seems to be justified by the wisdom of experience. The wife, then, in this case, was not, within the rules of the law, an accomplice. She was the victim of the cruel act which resulted in her death. Misguided by her own desires, and mistaken in her belief, she, by the advice of the defendant, submitted to his treatment, willing, it may be; but the desire of one, and the criminal act of the other, resulted in the death of one, and the imprisonment of the other."[17] The US Supreme Court's decision in 1973's Roe v. Wade ruling meant the state could no longer regulate abortion in the first trimester.[17] The 1990 US Supreme Court case Hodgson v. Minnesota said that parental consent can cause danger for minors seeking abortions if physical, emotional or sexual abuse is already present.[18][24] The case concerned a Minnesota law. The law required notice to both parents of a minor before she could undergo an abortion; it also contained a judicial bypass provision designed to take effect only if a court found one to be necessary.[25] Dr. Jane Hodgson, a Minneapolis gynecologist, challenged the law. The Eighth Circuit had ruled that the law would be unconstitutional without a judicial bypass, but that the bypass provision saved it.[25] While Justice Stevens delivered a majority opinion for one of the holdings, there were five votes for each of two holdings, with Justice O'Connor proving as the decisive vote for each.[25] Justices Stevens, Brennan, Marshall, Blackmun and O'Connor formed a majority holding that the two-parent notice requirement by itself was unconstitutional.[25] Justice O'Connor believed that the two-parent requirement entailed risk to a pregnant teenager; she also argued that the rule failed to meet even the lowest standard of judicial review, a rationality standard.[25] She joined the Court's more conservative Justices (Chief Justice Rehnquist and Justices White, Scalia and Kennedy), to form a majority for the law being valid with the judicial bypass; Justice Kennedy had pointed out the usefulness of the bypass procedure, as judges granted all but a handful of requests to authorize abortions without parental notice.[25] ### Clinic history[edit] Number of abortion clinics in Minnesota by year. See also: Abortion clinic Between 1982 and 1992, the number of abortion clinics in the state decreased by six, going from twenty in 1982 to fourteen in 1992.[26] In 2014, there were six abortion clinics in the state.[27] In 2014, 95% of the counties in the state did not have an abortion clinic. That year, 59% of women in the state aged 15 – 44 lived in a county without an abortion clinic.[28] In March 2016, there were eighteen Planned Parenthood clinics in the state.[29] In 2017, there were eighteen Planned Parenthood clinics in a state with a population of 1,227,431 women aged 15 – 49 of which one offered abortion services.[30] ## Statistics[edit] In the period between 1972 and 1974, there were zero recorded illegal abortion death in the state.[31] In 1990, 529,000 women in the state faced the risk of an unintended pregnancy.[26] In 2013, among white women aged 15–19, there were abortions 510, 260 abortions for black women aged 15–19, 80 abortions for Hispanic women aged 15–19, and 140 abortions for women of all other races.[32] In 2014, 52% of adults said in a poll by the Pew Research Center that abortion should be legal in all or most cases.[33] In 2017, the state had an infant mortality rate of 4.8 deaths per 1,000 live births.[9] Number of reported abortions, abortion rate and percentage change in rate by geographic region and state in 1992, 1995 and 1996[34] Census division and state Number Rate % change 1992–1996 1992 1995 1996 1992 1995 1996 West North Central 57,340 48,530 48,660 14.3 11.9 11.9 –16 Iowa 6,970 6,040 5,780 11.4 9.8 9.4 –17 Kansas 12,570 10,310 10,630 22.4 18.3 18.9 –16 Minnesota 16,180 14,910 14,660 15.6 14.2 13.9 –11 Missouri 13,510 10,540 10,810 11.6 8.9 9.1 –21 Nebraska 5,580 4,360 4,460 15.7 12.1 12.3 –22 North Dakota 1,490 1,330 1,290 10.7 9.6 9.4 –13 South Dakota 1,040 1,040 1,030 6.8 6.6 6.5 –4 Number, rate, and ratio of reported abortions, by reporting area of residence and occurrence and by percentage of abortions obtained by out-of-state residents, US CDC estimates Location Residence Occurrence % obtained by out-of-state residents Year Ref No. Rate^ Ratio^^ No. Rate^ Ratio^^ Minnesota 15.6 1992 [34] Minnesota 14,910 14.2 1995 [34] Minnesota 14,660 13.9 1996 [34] Minnesota 9,533 9.1 136 10,123 9.6 145 9.3 2014 [35] Minnesota 9,234 8.8 132 9,861 9.4 141 9.8 2015 [36] Minnesota 9,425 8.9 135 10,017 9.5 144 9.0 2016 [37] ^number of abortions per 1,000 women aged 15–44; ^^number of abortions per 1.000 live births ## Criminal prosecutions of abortion[edit] Between 1911 and 1930, there were 100 indictments and 30 convictions for women having abortions.[17] Dr. Jane Hodgson was convicted in 1970 of performing an illegal abortion on a 23-year-old woman in Minnesota. Hodgson was an abortion rights activist.[38] ## Abortion financing[edit] State Medicaid coverage of medically necessary abortion services. Navy blue: Medicaid covers medically necessary abortion for low-income women through legislation. Royal blue: Medicaid covers medically necessary abortions for low-income women under court order. Gray: Medicaid denies abortion coverage for low-income women except for cases of rape, incest, or life endangerment. Seventeen states including this one use their own funds to cover all or most "medically necessary" abortions sought by low-income women under Medicaid, thirteen of which are required by State court orders to do so.[39] In 2010, the state had 3,941 publicly funded abortions, of which sixteen were federally funded and 3,925 were state funded.[40] ## Abortion rights views and activities[edit] ### Activities[edit] Around 1981, when the doctors who ran abortion clinics in Grand Forks, North Dakota and Jamestown, North Dakota were getting close to an age where they wanted to retire, they reached out to Jane Bovard and asked her to open a clinic in Fargo. Bovard had a history of supporting abortion rights in the state by assisting women in traveling to Minneapolis or cities in other states to get abortions.[41] St. Paul, Minnesota, January 21, 2017. Over 30,000 people gathered in St. Paul and marched to the Minnesota capitol to protest Republican President Donald Trump. This protest was in solidarity with the national Women's March on Washington DC. The protesters spoke out against Trump's proposed policies and decried the rhetoric of the 2016 election for being insulting and threatening to women. ### Protests[edit] Women from the state participated in marches supporting abortion rights as part of a #StoptheBans movement in May 2019.[42] Protesters were at the State Capitol building, where they chanted, "Our bodies, our choice!"[43] ## Anti-abortion views and activities[edit] ### Organizations[edit] Minnesota Family Council (MFC), a Christian organization founded to work against the teaching in schools of tolerance for homosexuals and is also opposed to abortion, stating that: "human life is sacred from conception to natural death and must be protected by government".[44] The Marriage Vow or "The Marriage Vow - A Declaration of Dependence Upon Marriage and Family" is a political pledge created by Bob Vander Plaats, a former candidate for Iowa governor, and the Iowa-based conservative group; The Family Leader, a public advocacy organization affiliated with the Iowa Family Policy Center, that he heads.[45] The 2 most notable signatures came from Rick Santorum and Michele Bachmann. Rick Santorum was the first presidential candidate to contact The Family Leader after the organization publicly announced the pledge. Michele Bachmann also contacted The Family Leader to sign the pledge, and became the first Candidate to send her signed document to the organization.[46] Although Newt Gingrich did not sign the pledge, he wrote a lengthy letter in which he upheld many of the principles of the pledge including personal fidelity to his wife, respecting the marital bonds of others, enforcing the defense of marriage act, to support a federal marriage amendment, and to oppose any definition of marriage outside of "one man and one woman." [47] The pledge was also signed by former Texas governor Rick Perry.[48] ### Violence[edit] In 1977, there were four arson attacks on abortion clinics. These took place in Minnesota, Vermont, Nebraska and Ohio. Combined, they caused over US$1.1 million in damage.[49] By 2000, an act of violence had taken place at an abortion clinic in Wing County, Minnesota.[49] On January 22, 2009, Matthew L. Derosia, 32, who was reported to have had a history of mental illness,[50] rammed an SUV into the front entrance of a Planned Parenthood clinic in Saint Paul, Minnesota,[50] causing between $2,500 and $5,000 in damage.[51] Derosia, who told police that Jesus told him to "stop the murderers," was ruled competent to stand trial. He pleaded guilty in March 2009 to one count of criminal damage to property.[51] ## Footnotes[edit] 1. ^ According to the Supreme Court's decision in Roe v. Wade: > (a) For the stage prior to approximately the end of the first trimester, the abortion decision and its effectuation must be left to the medical judgement of the pregnant woman's attending physician. (b) For the stage subsequent to approximately the end of the first trimester, the State, in promoting its interest in the health of the mother, may, if it chooses, regulate the abortion procedure in ways that are reasonably related to maternal health. (c) For the stage subsequent to viability, the State in promoting its interest in the potentiality of human life may, if it chooses, regulate, and even proscribe, abortion except where it is necessary, in appropriate medical judgement, for the preservation of the life or health of the mother. Likewise, Black's Law Dictionary defines abortion as "knowing destruction" or "intentional expulsion or removal". ## References[edit] 1. ^ Watson, Katie (20 Dec 2019). "Why We Should Stop Using the Term "Elective Abortion"". AMA Journal of Ethics. 20: E1175-1180. doi:10.1001/amajethics.2018.1175. PMID 30585581. Retrieved 17 May 2019. 2. ^ Chamberlain, Pam; Hardisty, Jean (2007). "The Importance of the Political 'Framing' of Abortion". The Public Eye Magazine. 14 (1). 3. ^ "The Roberts Court Takes on Abortion". New York Times. November 5, 2006. Retrieved January 18, 2008. 4. ^ Brennan 'Dehumanizing the vulnerable' 2000 5. ^ Getek, Kathryn; Cunningham, Mark (February 1996). "A Sheep in Wolf's Clothing – Language and the Abortion Debate". Princeton Progressive Review. 6. ^ "Example of "anti-life" terminology" (PDF). Archived from the original (PDF) on 2011-07-27. Retrieved 2011-11-16. 7. ^ Goldstein, Norm, ed. The Associated Press Stylebook. Philadelphia: Basic Books, 2007. 8. ^ Castillo, Stephanie (2014-10-03). "States With More Abortion Restrictions Hurt Women's Health, Increase Risk For Maternal Death". Medical Daily. Retrieved 2019-05-27. 9. ^ a b c "States pushing abortion bans have highest infant mortality rates". NBC News. Retrieved 2019-05-25. 10. ^ a b Mundell, E.J. (January 16, 2019). "Two-Thirds of Poor U.S. Women Can't Afford Menstrual Pads, Tampons: Study". US News & World Report. Retrieved May 26, 2019. 11. ^ Larimer, Sarah (January 8, 2016). "The 'tampon tax,' explained". The Washington Post. Archived from the original on December 11, 2016. Retrieved December 10, 2016. 12. ^ Bowerman, Mary (July 25, 2016). "The 'tampon tax' and what it means for you". USA Today. Archived from the original on December 11, 2016. Retrieved December 10, 2016. 13. ^ Hillin, Taryn. "These are the U.S. states that tax women for having periods". Splinter. Retrieved 2017-12-15. 14. ^ "Election Results 2018: Nevada Ballot Questions 1-6". KNTV. Retrieved 2018-11-07. 15. ^ Wax-Thibodeaux, Emily (June 9, 2019). "In Alabama — where lawmakers banned abortion for rape victims — rapists' parental rights are protected". The Washington Post. Retrieved June 10, 2019. 16. ^ Michaels, Samantha. "Alabama banned abortions. Then its lawmakers remembered rapists can get parental rights". Mother Jones. Retrieved 2019-06-08. 17. ^ a b c d e Buell, Samuel (1991-01-01). "Criminal Abortion Revisited". New York University Law Review. 66: 1774–1831. 18. ^ a b Adolescence, Committee On (2017-02-01). "The Adolescent's Right to Confidential Care When Considering Abortion". Pediatrics. 139 (2): e20163861. doi:10.1542/peds.2016-3861. ISSN 0031-4005. PMID 28115537. 19. ^ Crosby, Margaret C.; English, Abigail (March 1991). "Mandatory parental involvement/judicial bypass laws: Do they promote adolescents' health?". Journal of Adolescent Health. 12 (2): 143–147. doi:10.1016/0197-0070(91)90457-w. ISSN 1054-139X. 20. ^ "State Policy On Informed Consent for Abortion" (PDF). Guttmacher Policy Review. Fall 2007. Retrieved May 22, 2019. 21. ^ a b "State Abortion Counseling Policies and the Fundamental Principles of Informed Consent". Guttmacher Institute. 2007-11-12. Retrieved 2019-05-22. 22. ^ a b c d Lai, K. K. Rebecca (2019-05-15). "Abortion Bans: 8 States Have Passed Bills to Limit the Procedure This Year". The New York Times. ISSN 0362-4331. Retrieved 2019-05-24. 23. ^ "Minnesota Legislature - HF271 - 91st Legislature (2019–2020)". revisor.mn.gov. Office of the Revisor of Statutes. Retrieved February 13, 2019. "Description: Abortion prohibited when a fetal heartbeat is detected with certain exceptions, and penalties provided." 24. ^ "Timeline of Important Reproductive Freedom Cases Decided by the Supreme Court". American Civil Liberties Union. Retrieved 2019-05-25. 25. ^ a b c d e f Greenhouse, Linda (2005), Becoming Justice Blackmun, Times Books, pp. 196–197 26. ^ a b Arndorfer, Elizabeth; Michael, Jodi; Moskowitz, Laura; Grant, Juli A.; Siebel, Liza (December 1998). A State-By-State Review of Abortion and Reproductive Rights. DIANE Publishing. ISBN 9780788174810. 27. ^ Gould, Rebecca Harrington, Skye. "The number of abortion clinics in the US has plunged in the last decade — here's how many are in each state". Business Insider. Retrieved 2019-05-23. 28. ^ businessinsider (2018-08-04). "This is what could happen if Roe v. Wade fell". Business Insider (in Spanish). Retrieved 2019-05-24. 29. ^ Bohatch, Emily. "27 states with the most Planned Parenthood clinics". thestate. Retrieved 2019-05-24. 30. ^ "Here's Where Women Have Less Access to Planned Parenthood". Retrieved 2019-05-23. 31. ^ Cates, Willard; Rochat, Roger (March 1976). "Illegal Abortions in the United States: 1972–1974". Family Planning Perspectives. 8 (2): 86. doi:10.2307/2133995. JSTOR 2133995. PMID 1269687. 32. ^ "No. of abortions among women aged 15–19, by state of residence, 2013 by racial group". Guttmacher Data Center. Retrieved 2019-05-24. 33. ^ "Views about abortion by state - Religion in America: U.S. Religious Data, Demographics and Statistics". Pew Research Center. Retrieved 2019-05-23. 34. ^ a b c d "Abortion Incidence and Services in the United States, 1995-1996". Guttmacher Institute. 2005-06-15. Retrieved 2019-06-02. 35. ^ Jatlaoui, Tara C. (2017). "Abortion Surveillance — United States, 2014". MMWR. Surveillance Summaries. 66 (24): 1–48. doi:10.15585/mmwr.ss6624a1. ISSN 1546-0738. PMID 29166366. 36. ^ Jatlaoui, Tara C. (2018). "Abortion Surveillance — United States, 2015". MMWR. Surveillance Summaries. 67 (13): 1–45. doi:10.15585/mmwr.ss6713a1. ISSN 1546-0738. PMC 6289084. PMID 30462632. 37. ^ Jatlaoui, Tara C. (2019). "Abortion Surveillance — United States, 2016". MMWR. Surveillance Summaries. 68. doi:10.15585/mmwr.ss6811a1. ISSN 1546-0738. 38. ^ Tribune, Chicago. "Timeline of abortion laws and events". chicagotribune.com. Retrieved 2019-05-23. 39. ^ Francis Roberta W. "Frequently Asked Questions". Equal Rights Amendment. Alice Paul Institute. Archived from the original on 2009-04-17. Retrieved 2009-09-13. 40. ^ "Guttmacher Data Center". data.guttmacher.org. Retrieved 2019-05-24. 41. ^ McCann, Allison (May 23, 2017). "Seven states have only one remaining abortion clinic. We talked to the people keeping them open". Vice News. Retrieved 2019-05-23. 42. ^ Bacon, John. "Abortion rights supporters' voices thunder at #StopTheBans rallies across the nation". USA Today. Retrieved 2019-05-25. 43. ^ FOX. "Thousands protest restrictive abortion legislation at #StopTheBans events nationwide". WNYW. Retrieved 2019-05-25. 44. ^ "Our Mission". Minnesota Family Foundation. Archived from the original on 31 August 2012. Retrieved 15 September 2012. 45. ^ "Marriage Vow" (PDF). The Family Leader. Retrieved 18 March 2014. 46. ^ PETROSKI, WILLIAM (8 July 2011). "Santorum, Bachmann, sign Family Leader's marriage vow". DesMoines Register. Retrieved 19 March 2014. 47. ^ Falcone, Michael (12 December 2011). "Newt Gingrich Pledges 'Personal Fidelity to My Spouse'". ABC. Retrieved 19 March 2014. 48. ^ Travis, Shannon (21 November 2011). "Perry signs Family Leader's controversial marriage vow". CNN. Retrieved 19 March 2014. 49. ^ a b Jacobson, Mireille; Royer, Heather (December 2010). "Aftershocks: The Impact of Clinic Violence on Abortion Services". American Economic Journal: Applied Economics. 3: 189–223. doi:10.1257/app.3.1.189. 50. ^ a b "Man charged with driving into Planned Parenthood facility". Star Tribune. Retrieved 2019-05-22. 51. ^ a b Pat Pheifer, Cottage Grove man pleads guilty to driving SUV into clinic, Minneapolis Star-Tribune (March 26, 2009). Abortion in the United States by state States * Alabama * Alaska * Arizona * Arkansas * California * Colorado * Connecticut * Delaware * Florida * Georgia * Hawaii * Idaho * Illinois * Indiana * Iowa * Kansas * Kentucky * Louisiana * Maine * Maryland * Massachusetts * Michigan * Minnesota * Mississippi * Missouri * Montana * Nebraska * Nevada * New Hampshire * New Jersey * New Mexico * New York * North Carolina * North Dakota * Ohio * Oklahoma * Oregon * Pennsylvania * Rhode Island * South Carolina * South Dakota * Tennessee * Texas * Utah * Vermont * Virginia * Washington * West Virginia * Wisconsin * Wyoming Federal district Washington, D.C. Insular areas * American Samoa * Guam * Northern Mariana Islands * Puerto Rico * U.S. Virgin Islands [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA [kDa]: kilodalton [EPC]: Early Prostate Cancer [LAPC]: locally advanced prostate cancer [NSAAs]: nonsteroidal antiandrogens [NSAA]: nonsteroidal antiandrogen [GnRH]: gonadotropin-releasing hormone [ADT]: androgen deprivation therapy [LH]: luteinizing hormone [AR]: androgen receptor [CAB]: combined androgen blockade [LPC]: localized prostate cancer [CPA]: cyproterone acetate [U.S.]: United States [FDA]: Food and Drug Administration	Abortion in Minnesota	None	7,883	wikipedia	https://en.wikipedia.org/wiki/Abortion_in_Minnesota	2021-01-18T18:39:00	{"wikidata": ["Q64876928"]}
Paralexia is a reduction in reading ability characterized by the transposition or supplementation of words or syllables. It usually is an acquired condition associated with brain injury such as alexia or acquired dyslexia, for example, as the result of a stroke.[1][2][3][4] There are several types of paralexias depending on the type of reading errors: orthographic paralexias, semantic paralexias, inflectional and derivational paralexias, function word substitutions, regularization errors and orthographic-then-semantic paralexias.[5] ## References[edit] 1. ^ Alexia, Rhonda B. Friedman, Georgetown University Medical Center 2. ^ Paralexia, Dr Donna Polelle, Encyclopedia of Clinical Neuropsychology 3. ^ Alexia, Walt Kilcullen, Strokenet 4. ^ Hoffmann, M (2012). "Thalamic semantic paralexia". Neurol Int. 4 (1): e6. doi:10.4081/ni.2012.e6. PMC 3349961. PMID 22593810. 5. ^ Alexia, Rhonda B. Friedman, Georgetown University Medical Center [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA [kDa]: kilodalton [EPC]: Early Prostate Cancer [LAPC]: locally advanced prostate cancer [NSAAs]: nonsteroidal antiandrogens [NSAA]: nonsteroidal antiandrogen [GnRH]: gonadotropin-releasing hormone [ADT]: androgen deprivation therapy [LH]: luteinizing hormone [AR]: androgen receptor [CAB]: combined androgen blockade [LPC]: localized prostate cancer [CPA]: cyproterone acetate [U.S.]: United States [FDA]: Food and Drug Administration	Paralexia	None	7,884	wikipedia	https://en.wikipedia.org/wiki/Paralexia	2021-01-18T18:39:03	{"wikidata": ["Q2051550"]}
A rare viral hemorrhagic fever characterized by virus-induced microvascular leakage rapidly leading to a severe illness with diffuse pulmonary edema and respiratory failure. These symptoms set in after a short first disease stage with fever, myalgia, and headache, followed by severe gastrointestinal symptoms such as abdominal pain, vomiting, and diarrhea. The high lethality of the disease is due to the possible development of hypotension and cardiogenic shock. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA [kDa]: kilodalton [EPC]: Early Prostate Cancer [LAPC]: locally advanced prostate cancer [NSAAs]: nonsteroidal antiandrogens [NSAA]: nonsteroidal antiandrogen [GnRH]: gonadotropin-releasing hormone [ADT]: androgen deprivation therapy [LH]: luteinizing hormone [AR]: androgen receptor [CAB]: combined androgen blockade [LPC]: localized prostate cancer [CPA]: cyproterone acetate [U.S.]: United States [FDA]: Food and Drug Administration	Hantavirus pulmonary syndrome	c0243025	7,885	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=319247	2021-01-23T18:30:51	{"gard": ["69"], "mesh": ["D018804"], "umls": ["C0243025"], "icd-10": ["B33.4+", "J17.1*"]}
A number sign (#) is used with this entry because adult-onset type II citrullinemia, also known as citrin deficiency, is caused by homozygous or compound heterozygous mutation in the SLC25A13 gene (603859) on chromosome 7q21. Neonatal-onset type II citrullinemia (605814) is caused by mutation in the same gene. Classic citrullinemia (CTLN1; 215700) is a genetically distinct disorder caused by mutation in the gene encoding argininosuccinate synthetase (ASS1; 603470). Description Adult-onset type II citrullinemia is an autosomal recessive metabolic disorder characterized clinically by the sudden onset of various neuropsychologic symptoms such as disorientation, abnormal behavior, convulsions, and coma due to hyperammonemia. In some cases, rapid progression can lead to brain edema and death if liver transplantation is not possible. Some patients may present with nonalcoholic hepatic steatosis or may develop hepatic fibrosis or hepatocellular carcinoma. Patients with this disorder have a natural aversion to carbohydrates and favor protein, which is in contrast to protein aversion usually observed in patients with urea cycle defects (summary by Komatsu et al., 2008). Clinical Features In Japan a distinct late-onset form of citrullinemia was reported; see review by Walser (1983). Significant clinical abnormality had onset in childhood or not until adulthood, age 48 years in 1 case. Symptoms included enuresis, delayed menarche, insomnia, sleep reversal, nocturnal sweats and terrors, recurrent vomiting (especially at night), diarrhea, tremors, episodes of confusion after meals, lethargy, convulsions, delusions, hallucinations, and brief episodes of coma. Delayed mental and physical development was shown by some patients. Most had a peculiar fondness for beans, peas, and peanuts from early childhood and a dislike for rice, other vegetables, and sweets. Since the preferred foods are high in arginine, the dietary predilection of these patients may reflect an arginine deficiency. As the patients get older, episodic disturbances become more frequent, and bizarre behavior, including manic episodes, echolalia, and frank psychosis, appears. Citrulline concentrations in the plasma were increased. The late-onset form is apparently autosomal recessive because sibs have been affected and some of the parents have been consanguineous. Most of the reports of the late-onset form appeared in Japanese journals; see Walser (1983) for references. An exception was the report by Matsuda et al. (1976). Also see Scott-Emuakpor et al. (1972) for a similar case reported from the United States. In the study of adult-onset type II citrullinemia in Japanese, Yasuda et al. (2000) found that the onset of serious and recurring symptoms in CTLN2 varied from age 11 to age 79, with a mean of 34.4 years. Almost all patients suffered from a sudden disturbance of consciousness associated with disorientation, restlessness, drowsiness, and coma, and most died mainly of cerebral edema within a few years of onset. Komatsu et al. (2008) found that 17 (89%) of 19 patients with genetically confirmed CTLN2 had hepatic steatosis. Four (21%) had been diagnosed with nonalcoholic fatty liver disease before the appearance of neuropsychologic symptoms that are usually characteristic of CTLN2. Hepatic steatosis occurred in the absence of obesity or features of the metabolic syndrome; all patients were lean. Some patients showed hepatic fibrosis, suggesting progression of liver damage. Laboratory abnormalities in CTLN2 patients included citrullinemia, abnormal liver enzymes, low albumin, increased serum triglycerides, and decreased activity of argininosuccinate synthetase. CTLN2 patients had a higher frequency of pancreatitis compared to those without mutations. Increased levels of pancreatic secretory protease inhibitor (PSTI, SPINK1; 167790) were associated with citrin deficiency, which could be a useful method of distinguishing CTLN2 patients from those with nonalcoholic fatty liver disease. Batshaw et al. (2014) reported the results of an analysis of 614 patients with urea cycle disorders (UCDs) enrolled in the Urea Cycle Disorders Consortium's longitudinal study protocol. Citrullinemia type II occurred in 2 patients (0.3%), of whom 1 had the late-onset form and the other the neonatal form. Biochemical Features Most patients with adult-onset citrullinemia in Japan were found to have type II citrullinemia, which is associated with decreased activity of argininosuccinate synthetase activity and protein in the liver but normal ASS1 levels in other tissues such as kidney, brain, and fibroblasts. Patients suffer from a disturbance of consciousness, such as disorientation, restlessness, and coma, and may die with cerebral edema within a few years of onset. Although there is a decrease in ASS enzyme protein with normal kinetic properties, there was no apparent abnormality in the amount, translational activity, or gross structure of hepatic ASS mRNA (Kobayashi et al., 1993). Mapping Kobayashi et al. (1999) studied 118 CTLN2 families in Japan and localized the CTLN2 locus to chromosome 7q21.3 by homozygosity mapping analysis of individuals from 18 consanguineous unions. Molecular Genetics ### Exclusion of Mutations in the ASS1 Gene Kobayashi et al. (1993) found on sequence analysis no mutation in the ASS1 mRNA from 2 patients with adult-onset type II citrullinemia. They also reported RFLP analysis of a consanguineous family with type II citrullinemia in which 3 polymorphisms located within the ASS1 gene locus were examined. In spite of having consanguineous parents, the patient was not homozygous for the ASS1 gene haplotype. The RFLP analysis of 16 affected patients from consanguineous parents showed that 5 of 16 had the heterozygous pattern for 1 of the 3 DNA probes and that the frequency of the heterozygous haplotype was not different from the control frequency. These results suggested that the primary defect of type II citrullinemia was not within the ASS1 gene locus. ### Pathogenic Mutations in the SLC25A13 Gene In 18 adult patients with CTLN2 from consanguineous parents, Kobayashi et al. (1999) identified 5 distinct mutations (603859.0001-603859.0005) in the SLC25A13 gene, encoding citrin, and confirmed their causative role in the disease. The studies of adult-onset type II citrullinemia in Japanese were extended by Yasuda et al. (2000), who identified 2 novel mutations in the SLC25A13 gene (see, e.g., 603859). Diagnostic analysis for the 7 known mutations in 103 CTLN2 patients diagnosed by biochemical and enzymatic studies revealed that 102 patients had 1 or 2 of the 7 mutations and 93 patients were homozygotes or compound heterozygotes. Five of 22 patients from consanguineous unions were compound heterozygotes, suggesting a high frequency of the mutated genes. The frequency of homozygotes was calculated to be more than 1 in 20,000 from carrier detection (6 in 400 individuals tested) in the Japanese population. By Western blot analysis with antihuman citrin antibody, the authors detected no cross-reactive immune materials in the liver of CTLN2 patients with any of the 7 mutations. From these findings, Yasuda et al. (2000) hypothesized that CTLN2 is caused by a complete deletion of citrin, although this did not explain the mechanism of argininosuccinate synthetase deficiency. In a 38-year-old Pakistani man living in Europe who had episodic confusion, elevated plasma ammonia and arginine levels, citrullinemia, normal glutamine, low serine levels, and fatal hyperammonemic encephalopathy, Fiermonte et al. (2008) identified homozygosity for a mutation at a highly conserved residue in the SLC25A13 gene (R588Q; 603859.0007). The authors noted that type II citrullinemia has rarely been reported outside of East Asia but must be considered in adults presenting with hyperammonemic encephalopathy, since the management is different from the management of classic urea-cycle defects (see 311250). Pathogenesis Saheki and Kobayashi (2002) concluded that citrin deficiency causes 2 different phenotypes, NICCD in neonates (605814) and CTLN2 in adults, through the additional effects of genetic or environmental modifiers. Since citrin and aralar (SLC25A12; 603667) are mitochondrial aspartate glutamate carriers, the various symptoms of NICCD and CTLN2 may be caused by defective aspartate export from the mitochondria to the cytosol and defects in the malate aspartate shuttle. Komatsu et al. (2008) hypothesized that the hepatic steatosis observed in patients with CTLN2 may result from a compensatory upregulation of the malate-citrate shuttle, which increases citrate in the cytosol, resulting in increased acetyl-CoA and an overproduction of fatty acids in hepatocytes. Clinical Management Saheki et al. (2010) noted that conventional treatments for hyperammonemia and brain edema, such as glycerol, are harmful in patients with CTLN2 because use of carbohydrates can exacerbate hyperammonemia. The most effective treatment for this disorder is liver transplantation, although many patients can be managed by a low-carbohydrate/high-protein diet. Use of dietary arginine or sodium pyruvate may also be potentially therapeutic. Population Genetics Kobayashi et al. (1999) stated that the frequency of CTLN2 in Japan is approximately 1 in 100,000. Yasuda et al. (2000) calculated the frequency of homozygotes of SLC25A13 mutations to be more than 1 in 20,000 from carrier detection (6 in 400 individuals tested) in the Japanese population. Among 1,315 Japanese individuals tested, Yamaguchi et al. (2002) found that 18 were carriers of an SLC25A13 mutation; this provided an estimate of minimally 1 in 21,000 for homozygotes. They referred to 2 Chinese CTLN2 patients in Taiwan and a Vietnamese neonatal-onset type II citrullinemia (NICCD) patient in Australia who had the same SLC25A13 mutations as those identified in Japanese patients. Lu et al. (2005) estimated the frequencies of SLC25A13 homozygotes to be 1 in 19,000 in Japan, 1 in 50,000 in Korea, and 1 in 17,000 in China. Specific mutations were identified in all Asian countries tested, with the most common mutations being a 4-bp deletion (603859.0001) and a splice site mutation (603859.0002). The frequencies of SLC25A13 homozygotes in China were calculated to be 1 in 9,200 to the south of the Yangtze River and 1 in 3,500,000 to the north of the Yangtze River. The findings were consistent with the historical boundary of the Yangtze River; modern Chinese are thought to derive from 2 distinct populations, 1 originating in the Yellow River valley and the other in the Yangtze River valley, during early Neolithic times (3,000 to 7,000 years ago). Animal Model Slc25a13-knockout mice show reduced mitochondrial Asp transport, but have no apparent phenotype, likely due to increased hepatic activity of mitochondrial glycerol-3-phosphate dehydrogenase (GPD2; 138430), which can transport NADH reducing equivalents into mitochondria. Saheki et al. (2007) found that mice with a combined disruption of the Slc25a13 and Gpd2 genes had poor growth and developed citrullinemia, hyperammonemia, hypoglycemia, and fatty liver, all features of human citrin deficiency. An altered cytosolic NADH/NAD(+) ratio was closely associated with hyperammonemia. The data indicated that the more severe phenotype present in the Slc25a13/Gpd2 double-knockout mice represents a more accurate model of human citrin deficiency than Slc25a13-knockout mice. INHERITANCE \- Autosomal recessive ABDOMEN Liver \- Nonalcoholic fatty liver disease \- Hepatic steatosis \- Fibrosis \- Hepatocyte ballooning Pancreas \- Pancreatitis NEUROLOGIC Central Nervous System \- Sudden onset of neuropsychiatric symptoms \- Disorientation \- Confusion \- Disturbance of consciousness \- Coma \- Brain edema NEOPLASIA \- Hepatocellular carcinoma LABORATORY ABNORMALITIES \- Hyperammonemia \- Citrullinemia \- Abnormal liver enzymes \- Low serum albumin \- Increased serum triglycerides \- Increased serum pancreatic secretory trypsin inhibitor (PSTI) \- Secondary decreased activity of argininosuccinate synthetase (ASS1) MISCELLANEOUS \- Mean age of diagnosis is 40 years (range 11 to 79 years) \- Some patients may be asymptomatic \- Natural aversion to carbohydrates \- Favoring of fat and protein \- Increased frequency in individuals of Asian descent \- 1 in 19,000 in Japan \- 1 in 50,000 in Korea \- 1 in 17,000 in China MOLECULAR BASIS \- Caused by mutation in the solute carrier family 25 (mitochondrial carrier, citrin), member 13 (SLC25A13, 603859.0001 ) ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA [kDa]: kilodalton [EPC]: Early Prostate Cancer [LAPC]: locally advanced prostate cancer [NSAAs]: nonsteroidal antiandrogens [NSAA]: nonsteroidal antiandrogen [GnRH]: gonadotropin-releasing hormone [ADT]: androgen deprivation therapy [LH]: luteinizing hormone [AR]: androgen receptor [CAB]: combined androgen blockade [LPC]: localized prostate cancer [CPA]: cyproterone acetate [U.S.]: United States [FDA]: Food and Drug Administration	CITRULLINEMIA, TYPE II, ADULT-ONSET	c1863844	7,886	omim	https://www.omim.org/entry/603471	2019-09-22T16:13:02	{"doid": ["9273"], "mesh": ["C538053"], "omim": ["603471"], "orphanet": ["247585"], "synonyms": ["Alternative titles", "CITRIN DEFICIENCY"], "genereviews": ["NBK1181"]}
## Description Systemic sclerosis is a clinically heterogeneous connective tissue disorder characterized by immune activation, vascular damage, and fibrosis of the skin and major internal organs. Clinical and experimental data suggest that the disorder is multifactorial, involving both genetic and environmental factors (Fonseca et al., 2007). Gabrielli et al. (2009) provided a detailed review of scleroderma, including clinical manifestations and pathophysiology. See also Reynolds syndrome (613471), which shares some clinical features with scleroderma and CREST syndrome. Clinical Features Greger (1975) described 3 males, including father and son, with progressive systemic scleroderma (systemic sclerosis) in an inbred triracial isolate of southern Maryland, known as the Brandywine group. A sister of the aforementioned son had rheumatoid arthritis. The father and son had similar skin changes, sclerodactyly, Raynaud phenomenon, gastrointestinal involvement, and pulmonary symptoms. Sheldon et al. (1981) described a kindred in which 3 sibs had scleroderma and 2 others had Raynaud phenomenon. The father died at age 43, having had, over the previous 20 years, 'flexion deformity of the fingers, cold intolerance, cyanosis, and pallor of the fingers with sores described as bone felons requiring lancing several times.' Sheldon et al. (1981) found reports of 19 instances of familial occurrence of scleroderma. Black et al. (1983) found in scleroderma due to vinyl chloride the same relationship to HLA types B8 and DR3 and the same anticentromere and other antibodies as in idiopathic scleroderma. ### CREST Syndrome Winterbauer (1964) defined and named the CRST syndrome (calcinosis, Raynaud syndrome, sclerodactyly, telangiectasia), a variant of scleroderma, when he was a Johns Hopkins medical student. (The CRST syndrome simulates hereditary telangiectasia; see 187300.) The initialism CRST was expanded to the acronym CREST by Shulman's group (Frayha et al., 1973; Velayos et al., 1979), also at Johns Hopkins, who added esophageal involvement to the cardinal manifestations. (The same group (Stevens et al., 1964) had pointed out a correlation between Raynaud phenomenon and aperistalsis of the esophagus in connective tissue disorders. They proposed that the connection may indicate that the esophageal abnormality is due to autonomic dysfunction rather than sclerosis. Stevens (1984) suggested that if this is the case, E of CREST may stand for 'epiphenomenon.') The disorder had been called Thibierge-Weissenbach syndrome. Thibierge and Weissenbach (1911) described 'subcutaneous calcareous concretions and scleroderma' in a single patient and found 8 other similar cases in the literature. Although telangiectases were not noted in the summaries of the earlier reported cases or in their discussion and certainly were not conceived by them as an integral part of the syndrome, the authors commented that 'there exists also in our patient a third type of skin lesion, namely telangiectases, remarkably prominent on the face, neck and thorax.' Frayha et al. (1977) described the CRST syndrome in mother and daughter. McColl and Buchanan (1994) described the CREST syndrome in 2 sisters of 1 family and a grandmother and grandson in a second family. Biochemical Features In a study of chemokine expression in fibroblasts from patients with systemic sclerosis and controls, Galindo et al. (2001) found that systemic sclerosis fibroblasts displayed increased constitutive expression of monocyte chemotactic protein-1 (MCP1; 158105) mRNA and protein and showed a blunted response to oxidative stress. In systemic sclerosis skin sections, expression of MCP1 was detected in fibroblasts, keratinocytes, and mononuclear cells, whereas it was undetectable in normal skin. Using in situ hybridization and immunohistochemistry studies for MCP1 on skin biopsy specimens, Distler et al. (2001) found that MCP1 was expressed by fibroblasts, keratinocytes, and perivascular infiltrates throughout the skin, in involved as well as uninvolved areas, from 10 of 11 systemic sclerosis patients, whereas no expression of MCP1 was found in healthy controls. Stimulation with platelet-derived growth factor (PDGF; see 173430) resulted in a significant increase in MCP1 mRNA and protein. The chemotactic activity of peripheral blood mononuclear cells in systemic sclerosis fibroblast supernatants decreased when MCP1-blocking antibodies were added. No effect of recombinant MCP1 on the synthesis of type I collagen (see 120150) was observed. Distler et al. (2001) suggested that MCP1 may contribute to the initiation of inflammatory infiltrates in systemic sclerosis, possibly in response to stimulation by PDGF. Using dermal fibroblasts from patients with systemic sclerosis and controls and from type 1 tight-skin (Tsk1) mice, Ong et al. (2003) demonstrated overexpression of the chemokine CCL7 (158106) in early-stage systemic sclerosis and neonatal Tsk1 skin. Pro-alpha-2(I) collagen (120160) promoter-reporter gene constructs were activated by CCL7 in transgenic mice and in transient transfection assays. The authors concluded that CCL7 may operate as a profibrotic mediator in addition to promoting an inflammatory cellular response, and may be an important early member of the cytokine cascade driving the pathogenesis of systemic sclerosis. Svegliati Baroni et al. (2006) presented evidence showing that stimulatory autoantibodies to PDGFR (173410) are a specific hallmark of scleroderma. These antibodies appeared to trigger an intracellular loop that involves Ras (190020), ERK1 (601795)/ERK2 (176948), and reactive oxygen species (ROS) and that leads to increased type I collagen (120150) expression. The authors suggested that the biologic activity of PDGFR antibodies on fibroblasts has a causal role in the pathogenesis of the disease. Tan (2006) suggested that the profibrotic phenotype of fibroblasts in patients with scleroderma is maintained by at least 3 mechanisms involving TGFB1 (190180), PDGFR, and the RAS-ERK1/ERK2-ROS cascade. Using proteome analysis, van Bon et al. (2014) identified increased levels of CXCL4 (173460) in skin and plasma plasmacytoid dendritic cells from patients with systemic sclerosis. The study included 779 patients from 5 independent cohorts. The levels of CXLC4 in patients with systemic sclerosis was significantly higher than in controls or compared to patients with systemic lupus erythematosus, ankylosing spondylitis, or liver fibrosis. CXLC4 levels were particularly increased in patients with early diffuse disease. In sclerosis patients, circulating CXCL4 levels correlated with skin and lung fibrosis and with pulmonary arterial hypertension. Among chemokines, only CXCL4 predicted the risk and progression of systemic sclerosis. In vitro cellular studies showed that CXCL4 downregulated expression of transcription factor FLI1 (193067) and induced secretion of interferon I via toll-like receptors. In mice, infusion of CXCL4 induced the expression of inflammatory markers, promoted the infiltration of inflammatory cells in the skin, and resulted in increased skin thickening. Van Bon et al. (2014) suggested that CXCL4 is a biomarker for fibrosis and pulmonary arterial hypertension in systemic sclerosis, and may be useful in early diagnosis and risk assessment. The findings also implicated a central role for plasmacytoid dendritic cells in the pathogenesis of the disease. Pathogenesis Makino et al. (2013) found that the microRNA LET7A1 (605386) was downregulated in both systemic and localized human scleroderma in vivo and in vitro compared with normal or keloid skin. Inhibition of LET7A1 expression in human or mouse skin fibroblasts affected expression of type I collagen. Serum levels of LET7A1 were reduced in scleroderma patients, particularly those with the localized form. Intermittent overexpression of Let7a1 in mouse skin by intraperitoneal injection improved skin fibrosis in a mouse model of scleroderma. Makino et al. (2013) proposed that LET7A1 has a negative effect on type I collagen expression in normal fibroblasts, but that downregulation of LET7A1 by TGFB stimulation contributes to type I collagen overexpression in scleroderma fibroblasts. In scleroderma, patients make antibodies to a limited group of autoantigens, including RPC1, encoded by the POLR3A gene (614258). As patients with scleroderma and antibodies against RPC1 are at increased risk for cancer, Joseph et al. (2014) hypothesized that the 'foreign' antigens in this autoimmune disease are encoded by somatically mutated genes in the patients' incipient cancers. Studying cancers from scleroderma patients, Joseph et al. (2014) found genetic alterations of the POLR3A locus in 6 of 8 patients with antibodies to RPC1, but not in 8 patients without antibodies to RPC1. Analyses of peripheral blood lymphocytes and serum suggested that POLR3A mutations triggered cellular immunity and cross-reactive humoral immune responses. Joseph et al. (2014) concluded that these results offered insight into the pathogenesis of scleroderma and provided support for the idea that acquired immunity helps to control naturally occurring cancers. Cytogenetics Rittner et al. (1988) found increased chromosomal breakage rate (ICBR) in 27 of 28 patients with systemic sclerosis; 5 patients with CREST syndrome, 4 with incomplete CREST, 1 with overlapping syndrome, and 18 with progressive systemic sclerosis were studied. In addition to the patients, about half of their first-degree relatives showed increased chromosomal breakage rate, segregating as a dominant marker in 9 families. In the 6 informative of the 9 families, the ICBR trait showed close linkage with HLA (maximum lod = 5.5 at theta = 0). ICBR was predominantly observed in linkage disequilibrium with HLA haplotype A1, Cw7, B8, C4AQ0B1, DR3, which is frequently observed in autoimmune diseases. In a 67-year-old male patient with the CREST variant of systemic sclerosis and in his 34-year-old daughter, Schmid et al. (1989) found a supernumerary chromosome in over half of metaphases. The microchromosome consisted of constitutive heterochromatin and contained nuclear antigens reacting with specific antikinetochore antibodies. Furthermore, it showed a close association with the centromere of normal chromosomes. Kinetochore-specific autoantibodies are demonstrable in the sera of over 90% of CREST patients (Fritzler and Kinsella, 1980; Moroi et al., 1980; Tan et al., 1980). The daughter, who inherited the microchromosome from her father, was clinically healthy, and none of 15 other CREST patients was found to have a supernumerary microchromosome. Using FISH, Invernizzi et al. (2005) assessed the presence of monosomy X in women with systemic sclerosis (SSC) or autoimmune thyroid disease (AITD; see 140300) and age-matched healthy women. The rate of monosomy X increased with age in all 3 groups, but it was significantly higher for women with SSC or AITD. Monosomy X was more frequent in peripheral T and B lymphocytes than in other blood cell populations, and there was no evidence of male fetal microchimerism. Invernizzi et al. (2005) proposed that chromosome instability is common in women with these autoimmune diseases and that haploinsufficiency for X-linked genes may be a critical factor for the female predominance in autoimmune disease. Mapping ### Association with the FBN1 Gene on Chromosome 15q21.1 Tan et al. (1998) reported a candidate gene approach to the study of systemic sclerosis in a population of Choctaw Native Americans in which there was evidence of a possible founder effect. Microsatellite alleles on human 15q and 2q, homologous to the murine tight skin-1 (tsk1) and tsk2 loci, respectively, were analyzed in Choctaw cases and race-matched normal controls for possible disease association. Genotyping first-degree relatives of the cases identified potential disease haplotypes, and haplotype frequencies were obtained by expectation-maximization and maximum-likelihood estimation methods. Simultaneously, the ancestral origins of contemporary Choctaw systemic sclerosis cases were ascertained using census and historical records. A multilocus 2-cM haplotype was identified on 15q that showed significantly increased frequency in systemic sclerosis cases compared with controls. The haplotype contained 2 intragenic markers for the fibrillin-1 (FBN1; 134797) gene. Genealogic studies demonstrated that the systemic sclerosis cases were distantly related, and their ancestry could be traced back to 5 founding families in the mid-18th century. The probability that the systemic sclerosis cases share this haplotype due to familial aggregation effects alone was calculated and found to be very low. No evidence for a microsatellite allele disturbance on chromosome 2q in a region homologous to tsk2 or the region containing the interleukin-1 family of genes was found. Zhou et al. (2003) performed a genomewide microsatellite screen using 400 markers in 20 Choctaw patients with systemic sclerosis and 76 ethnically matched controls. Twelve markers showed highly significant and 5 showed significant association with the disorder. Along with some potentially novel systemic sclerosis loci (1p32-p31, 7q35, 8q24.12, 19p13.2, 22q13.1, and Xq21-q23), 4 loci (6p22.3, 15q21.1, 5q31-q33, and 20q12) had previously been linked to the disorder. Several markers were located within the same candidate regions reported for other autoimmune diseases. Tan et al. (2001) sequenced all 69 known FBN1 exons to ascertain the presence of changes that might show associations with systemic sclerosis in Choctaw and Japanese patients and controls. They identified 5 SNPs in FBN1: SNP1 in the 5-prime untranslated region, SNP2 in exon 15, SNP3 in intron 17, SNP4 in exon 27, and SNP5 in intron 27. Only SNP1 (T-to-C) demonstrated an association with systemic sclerosis in the Choctaw. They found 11 FBN1 SNP haplotypes in the Choctaw population, 2 of which were found only in the systemic sclerosis patients. These same FBN1 SNP haplotypes were associated with systemic sclerosis in the Japanese. The data were considered consistent with the hypothesis that FBN1 or a nearby gene on chromosome 15q is involved in systemic sclerosis susceptibility in the Choctaw and the Japanese. In further studies in the Choctaw, Tan et al. (2003) concluded that polymorphisms in the THBS1 (188060) gene at 15q15, the FGF7 gene (148180) at 15q15-q21.1, the FUR gene (136950) at 15q25-q26, and the MFAP1 gene (600215) at 15q15-q12 cannot account for the high prevalence of systemic sclerosis in the Oklahoma Choctaw. These data, together with reports showing functional abnormalities in fibrillin-1 protein in systemic sclerosis fibroblasts (Wallis et al., 2001) and disease-specific autoimmune responses directed against fibrillin-1 in systemic sclerosis (Tan et al. (1999, 2000)), support the notion that FBN1 is the most likely candidate gene on the chromosome 15 haplotype previously associated with systemic sclerosis in the Choctaw. ### Association with the CTGF Gene on Chromosome 6q23 In a study involving 1,000 subjects in 2 groups, Fonseca et al. (2007) found that a polymorphism (G-945C) in the promoter of the connective tissue growth factor (CTGF; 121009) gene on chromosome 6q23 was associated with susceptibility to systemic sclerosis. The GG genotype was significantly more common in patients with systemic sclerosis than in control subjects, with an odds ratio for the combined group of 2.2 (95% confidence interval, 1.5 to 3.2; P less than 0.001 for trend). Analysis of the combined group of patients with systemic sclerosis showed a significant association between homozygosity for the G allele and the presence of antitopoisomerase I antibodies (odds ratio, 3.3; 95% confidence interval, 2.0 to 5.6; P less than 0.001) and fibrosing alveolitis (odds ratio, 3.1; 95% confidence interval, 1.9 to 5.0; P less than 0.001). Fonseca et al. (2007) observed that the substitution of cytosine for guanine created a binding site of the transcriptional regulators Sp1 and Sp3. The C allele has high affinity for Sp3 and is associated with severely reduced transcriptional activity. A chromatin immunoprecipitation assay showed a marked shift in the ratio of Sp1 to Sp3 binding at this region, demonstrating functional relevance in vivo. Fonseca et al. (2007) concluded that the G-945C substitution represses CTGF transcription, and the -945G allele is significantly associated with susceptibility to systemic sclerosis. ### Association with the STAT4 Gene on Chromosome 2q32.2-q32.3 Rueda et al. (2009) observed that the T allele of rs7574865 of the STAT4 gene (600558) was significantly associated with susceptibility to limited cutaneous systemic sclerosis (LCSSC) (p = 1.9 x 10(-5); odds ratio, 1.61), but not with diffuse cutaneous systemic sclerosis (DCSSC) in a Spanish case-control study of 242 LCSSC patients, 90 DSSSC patients, and 1,296 controls A dosage effect was observed with the TT genotype increased in LCSSC patients compared with controls (p = 1.02 x 10(-7); odds ratio, 3.34). Combined metaanalysis of the Spanish cohort and 5 independent cohorts of European ancestry showed a strong risk effect for the rs7574865 T allele and LCSSC susceptibility (pooled odds ratio, 1.54; p less than 0.0001). Molecular Genetics See 142460 for discussion of a possible association between susceptibility to systemic sclerosis and variation in the SDC2 gene. Animal Model Green et al. (1976) described a new mouse mutant, 'tight-skin' (Tsk). Heterozygotes had tight skin with marked hyperplasia of subcutaneous loose connective tissue. Increased growth of cartilage and bone was a feature different from the human mutation. Tendons were small with hyperplasia of the sheaths. Homozygotes die in utero. Growth hormone was normal. The authors speculated that the mutation may cause defective cell receptors with high affinity for a somatomedin-like factor promoting growth of connective tissue. Muryoi et al. (1991) showed that Tsk mice spontaneously produce anti-topoisomerase I antibodies, which are characteristically found only in patients with progressive systemic sclerosis but not in patients with the CREST syndrome, a systemic sclerosis-related disorder. The autoantibodies produced in the tight-skin mouse are encoded primarily by heavy-chain variable genes from the J558 family. Kasturi et al. (1994) showed that the J558 genes encoding these antibodies are not derived from a selected germline gene(s) or a single subfamily but rather from genes belonging to diverse J558 subfamilies. All the results strongly suggested that the establishment of the autoimmune repertoire is mediated by V(H)-gene-dependent selection of B cells, though the contribution of an antigen-mediated selection mechanism could not be ruled out. The Tsk locus maps to a region on chromosome 2 that includes a segment that is syntenic with human chromosome 15 (Doute and Clark, 1994). Since the microfibrillar glycoprotein gene, fibrillin-1 (FBN1; 134797), is located on human 15q, it became a candidate for the Tsk mutation in the mouse. Siracusa et al. (1996) demonstrated that the Tsk chromosome harbors a 30- to 40-kb genomic duplication within the Fbn1 gene that results in a larger than normal in-frame Fbn1 transcript. The findings provided possible explanations for the phenotypic features of Tsk/+ mice and the lethality of Tsk/Tsk embryos. Inheritance \- Autosomal dominant form Immunology \- Anticentromere and other antibodies Lab \- Increased chromosomal breakage rate GI \- Esophageal aperistalsis Skin \- Progressive systemic scleroderma \- Calcinosis \- Raynaud syndrome \- Sclerodactyly \- Telangiectasia ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA [kDa]: kilodalton [EPC]: Early Prostate Cancer [LAPC]: locally advanced prostate cancer [NSAAs]: nonsteroidal antiandrogens [NSAA]: nonsteroidal antiandrogen [GnRH]: gonadotropin-releasing hormone [ADT]: androgen deprivation therapy [LH]: luteinizing hormone [AR]: androgen receptor [CAB]: combined androgen blockade [LPC]: localized prostate cancer [CPA]: cyproterone acetate [U.S.]: United States [FDA]: Food and Drug Administration	SCLERODERMA, FAMILIAL PROGRESSIVE	c0036421	7,887	omim	https://www.omim.org/entry/181750	2019-09-22T16:34:54	{"doid": ["418"], "mesh": ["D012595"], "omim": ["181750"], "icd-10": ["M34.1"], "orphanet": ["90291", "90290"], "synonyms": ["Alternative titles", "SYSTEMIC SCLEROSIS, SUSCEPTIBILITY TO"]}
A rare neurologic disease characterized by the presence of Duane retraction syndrome (i. e. a congenital cranial dysinnervation disorder with unilateral or bilateral limitation of abduction and/or adduction of the eye, as well as globe retraction and palpebral fissure narrowing on attempted adduction) in combination with congenital unilateral or bilateral hearing loss. The sidedness of hearing loss corresponds to the sidedness of the retraction syndrome. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA [kDa]: kilodalton [EPC]: Early Prostate Cancer [LAPC]: locally advanced prostate cancer [NSAAs]: nonsteroidal antiandrogens [NSAA]: nonsteroidal antiandrogen [GnRH]: gonadotropin-releasing hormone [ADT]: androgen deprivation therapy [LH]: luteinizing hormone [AR]: androgen receptor [CAB]: combined androgen blockade [LPC]: localized prostate cancer [CPA]: cyproterone acetate [U.S.]: United States [FDA]: Food and Drug Administration	Duane retraction syndrome with congenital deafness	c4310752	7,888	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=529574	2021-01-23T17:53:49	{"omim": ["617041"], "synonyms": ["DRS with deafness", "DRS with hearing loss", "DURS with deafness", "DURS with hearing loss", "Duane retraction syndrome with congenital hearing loss"]}
Exercise-induced collapse (EIC) is a genetic disorder that causes dogs of certain breeds to collapse after a period of intense exercise. The breeds affected are primarily sporting dogs (retrievers, spaniels). ## Contents * 1 Description * 2 Symptoms and diagnosis * 3 Research * 4 Testing * 5 Other collapse disorders * 6 References ## Description[edit] Exercise-induced collapse (EIC) is a genetic disorder, mainly found in Labrador Retrievers,[1] Chesapeake Bay Retrievers , Curly Coated Retrievers, and Boykin Spaniels. The genetic mutation has also been seen in a few cases in Cocker spaniels, German wire-haired pointers, Old English Sheepdogs, Bouvier des Flandres, Pembroke Welsh Corgis and Clumber Spaniels. Signs are most likely to first become apparent in young dogs when they enter heavy training, which is usually between 5 months and 1 year of age.[2] Dogs of either sex can be affected. Dogs with this condition are always normal at rest and are described as being extremely fit, prime athletic specimens of their breed. Dogs affected with this have no problem with regular exercise. The collapse occurs only with very strenuous exercise such as retrieving or participating in trials. Added excitement coincidental with the heavy exercise is more likely to bring on the collapse. [2] Not all dogs with the disorder have an episode each time they exercise. It appears that the condition is more likely to occur with warmer temperatures. The lives of dogs with EIC are normal if extreme exercise is avoided.[3] ## Symptoms and diagnosis[edit] During collapse the dog’s hind legs become weak until they are no longer able to support the dog’s weight.[2][3] In the most extreme cases the dog’s front legs also go weak and the dog collapses, its leg muscles loose. [3] The episode generally lasts no more than 15 minutes over which time the dog returns to normal. The dog does not appear to be in pain during the collapse. Physiological systems (nervous system, cardiovascular and musculoskeletal systems) all appear normal in these dogs, as is a blood analysis both apart from and during an episode of collapse. Although tests have revealed elevated body temperature during collapse (average 107.1F (41.7C), many up to 108F (42.2C)), these temperatures are no different to those in normal dogs who have undertaken the same level of exercise.[3] ## Research[edit] Research into the condition has been done at the Western College of Veterinary Medicine at the University of Saskatchewan, the College of Veterinary Medicine at the University of Minnesota, and the Comparative Neuromuscular Laboratory at the School of Medicine of the University of California. The cause has been identified as a mutation is in the gene for dynamin-1 (DNM1). This gene is a protein that plays a key role in repackaging synaptic vesicles containing neurotransmitters. The action of DNM1 is only triggered with a high level of sustained exercise when it is needed for synaptic transmission in the brain and spinal cord. The gene is recessive and for the dog to exhibit the exercise-induced collapse it must have two copies of the gene.[4] Nearly 40% of all Labrador retrievers that were tested for the gene between 2008 and 2017 were carriers, meaning they had one copy of the mutation. Approximately 6% had two copies of the gene and therefore had the potential to exhibit the collapse during exercise. There has been widespread testing and selective breeding in the years since the test for EIC was developed which has led to a decline in EIC in Labrador retrievers. [4][5] ## Testing[edit] Through grants from the AKC CHF a patented DNA test was developed by the University of MN.[6] The Orthopedic Foundation for Animals provides a public database for those dogs that are DNA tested. ## Other collapse disorders[edit] The UMN VBS Genetics Lab is also investigating cases of "atypical collapse"[7] and also "Border Collie Collapse]"[8] where the dog is a carrier or clear of the disease on the DNA test, but continues to exhibit signs of the EIC disease. ## References[edit] 1. ^ Patterson, E. E.; Minor, K. M.; Tchernatyskaia, A. V. (2008). "A canine DNMI mutation is highly associated with the syndrome of exercise-induced collapse". Nature Genetics. 40 (10): 1235–9. doi:10.1038/ng.224. PMID 18806795. S2CID 7103858. 2. ^ a b c Taylor, SM; Shmon, CL; Shelton, GD; Patterson, EE; Minor, K; Mickelson, JR (2008). "Exercise Induced Collapse of Labrador Retrievers: Survey results and preliminary investigation of heritability". J Am Anim Hosp Assoc. 44 (6): 295–301. doi:10.5326/0440295. PMID 18981194. 3. ^ a b c Taylor, SM; Shmon, CL; Adams, VJ; Mickelson, JR; Patterson, EE; Shelton, GD (2009). "Evaluations of Labrador Retrievers with Exercise Induced Collapse, including response to a standardized strenuous exercise protocol". J Am Anim Hosp Assoc. 45 (1): 3–13. doi:10.5326/0450003. PMID 19122058. 4. ^ Minor, KM; Patterson, EE; Keating, M.K.; Gross, SD; Ekenstedt, KJ; Taylor, SM; Mickelson, JR (2011). "Presence and impact of the exercise-induced collapse associated DNM1 mutation inh Labrador retrievers and other breeds". The Veterinary Journal. 189 (2): 214–219. doi:10.1016/j.tvjl.2011.06.022. PMID 21782486. 5. ^ Furrow, E; Minor, KM; Taylor, SM; Mickelson, JR; Patterson, EE (2013). "Relationship between dynamin 1 mutation status and characteristics of recurrent episodes of exercise-induced collapse in Labrador Retrievers". Journal of the American Veterinary Medical Association. 242 (6): 786–791. doi:10.2460/javma.242.6.786. PMID 23445289. 6. ^ "Exercise Induced Collapse". Veterinary Diagnostic Laboratory, University of Minnesota. Archived from the original on 2013-06-16. Retrieved 2013-05-22. 7. ^ http://www.cvm.umn.edu/vbs/faculty/Mickelson/lab/EIC/AtypicalCollapse/home.html 8. ^ http://www.cvm.umn.edu/vbs/faculty/Mickelson/lab/EIC/bordercollieEIC/home.html [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA [kDa]: kilodalton [EPC]: Early Prostate Cancer [LAPC]: locally advanced prostate cancer [NSAAs]: nonsteroidal antiandrogens [NSAA]: nonsteroidal antiandrogen [GnRH]: gonadotropin-releasing hormone [ADT]: androgen deprivation therapy [LH]: luteinizing hormone [AR]: androgen receptor [CAB]: combined androgen blockade [LPC]: localized prostate cancer [CPA]: cyproterone acetate [U.S.]: United States [FDA]: Food and Drug Administration	Exercise-induced collapse	None	7,889	wikipedia	https://en.wikipedia.org/wiki/Exercise-induced_collapse	2021-01-18T19:02:42	{"wikidata": ["Q1383693"]}
Acne aestivalis Other namesMallorca acne SpecialtyDermatology Acne aestivalis also known as acne mallorca, is a special kind of polymorphous light eruption induced by ultra violet A radiation. This condition is said to be seasonal, usually affecting people in the spring time and goes away in the fall time when there is less sun light. This photo induced skin reaction leads to a monomorphous eruption that consists of multiple, uniform, red, popular lesions.[1][2] This skin reaction is classified as a delayed-type hypersensitivity because the onset is 24–72 hours after sun exposure.[3] The condition equally affects men and women between the ages of 20–40 years old with no prior history of acne vulgaris. The eruption is unusual because it spares the face but it affects the lateral aspects of the upper arms, shoulder girdle, back, and chest.[1] This condition’s pathogenesis is not very well understood but scientists believe it an unfortunate side effect that results from a strong immune response to potentially cancer-causing cell damage.[4][2] ## Contents * 1 Signs and Symptoms * 2 Cause * 3 Mechanism/pathophysiology * 4 Diagnosis * 5 Treatment * 6 Prognosis * 7 Epidemiology * 8 Recent Research * 9 References * 10 External links ## Signs and Symptoms[edit] Patients present numerous lesions of small papules that are dull red, dome shaped, hard, and usually not more than 2–4 mm in diameter. These lesions do not affect the face but affect lateral aspects of upper arms, shoulder girdle, back, and chest. The papules have an onset of 1–3 days after sun exposure and may last for many weeks. Comedones are not present in this type of skin reaction.[1] ## Cause[edit] The main cause of this condition is sun exposure.[1] Hypersensitivity to the sun may be experienced due to genetic predisposition.[4] It is also speculated that cosmetics and sun care products containing hydroxyl peroxides may trigger this condition through free radical and ultra violet A radiation photo-toxic reactions.[5][2][1] ## Mechanism/pathophysiology[edit] The actual mechanism of disease is not very well understood but there are a few speculations. It is believed that acne aestivalis has a genetic predisposition involved in which people who show acne aestivalis have lower expression of apoptosis inducing genes which leads to inflammation. Inflammation is believed to be triggered by circulating ultra violet radiation damaged cells that could not go through apoptosis and the cell fragments they release.[4] Also, it is speculated that this sun induced acne form is caused by a photo allergic reaction between sunscreen, skin, and the sun. A photo-toxic reaction pathogenesis is also possible through free radical release in sun screen oxidation by ultra violet radiation.[2][1] ## Diagnosis[edit] The diagnosis is by visual examination of skin lesions and sun exposure history. A diagnosis of acne aestivalis is made once the patient reports the onset of papules was 1–3 days after sun exposure.[1] ## Treatment[edit] The treatment for this condition is topical tretinoin or benzoyl peroxide applied to the skin. The use of topical steroids should be avoided. Currently, there is no systemic treatment for acne aestivalis.[1] ## Prognosis[edit] This condition is alleviated during the fall season when there is less sun light available. The papules do not leave a scar on the affected person's skin.[1] ## Epidemiology[edit] There is limited information on the epidemiology of this condition. This disease was first noticed in Scandinavian men and women between the ages of 20 and 40 years old. The skin eruption would present in this population after sunbathing in Mallorca beach after a long and dark winter season.[1] ## Recent Research[edit] This section needs to be updated. The reason given is: 2001 is no longer recent. Please update this article to reflect recent events or newly available information. (January 2020) In 2001, a study was conducted to test a prophylaxis regimen containing alpha-glucosylrutin, a strong plant-derived antioxidant. The focus of the experiment was to evaluate the effects of alpha-glucosylrutin on polymorphous light eruption and acne aestivalis development. The study demonstrated that applying alpha-glucosylrutin along with SPF 15 sunscreen decreases severe polymorphous light eruption cases from 96.2% to 7.4%.The study included 20 people with polymorphous light eruption and 3 people with acne aestivalis. In this study, 2 out of the 3 people with acne aestivalis did not have an episode of lesions after being prophylactically treated with alpha-glucosylrutin and SPF 15.[6] ## References[edit] 1. ^ a b c d e f g h i j Plewig G, Kligman AM (1975). "Acne Aestivalis (Mallorca Acne)". Acne. Springer Berlin Heidelberg. pp. 257–259. doi:10.1007/978-3-642-96246-2_25. ISBN 978-3-642-96248-6. 2. ^ a b c d Jung K, Heinrich U, Tronnier H, Schnyder M, Herzog B, Herrling T (2016). "High levels of free radicals in suncare products induce acne aestivalis in sensitive subjects" (PDF). SOFW Journal. 142: 2–8. 3. ^ Gruber-Wackernagel A, Byrne SN, Wolf P (July 2014). "Polymorphous light eruption: clinic aspects and pathogenesis". Dermatologic Clinics. 32 (3): 315–34, viii. doi:10.1016/j.det.2014.03.012. PMID 24891054. 4. ^ a b c Lembo S, Raimondo A (2018-09-10). "Polymorphic Light Eruption: What's New in Pathogenesis and Management". Frontiers in Medicine. 5: 252. doi:10.3389/fmed.2018.00252. PMC 6139322. PMID 30250845. 5. ^ "Editorial: Summer acne". BMJ. 4 (5989): 125. 1975-10-18. doi:10.1136/bmj.4.5989.125. 6. ^ Rippke F, Wendt G, Bohnsack K, Dörschner A, Stäb F, Hölzle E, Moll I (March 2001). "Results of photoprovocation and field studies on the efficacy of a novel topically applied antioxidant in polymorphous light eruption". The Journal of Dermatological Treatment. 12 (1): 3–8. doi:10.1080/095466301750163491. PMID 12171679. S2CID 25658207. ## External links[edit] Classification D * ICD-10: L56.4 * ICD-9-CM: 692.72 * DiseasesDB: 10327 External resources * eMedicine: derm/342 * v * t * e Radiation-related disorders / Photodermatoses Ultraviolet/ionizing * Sunburn * Phytophotodermatitis * Solar urticaria * Polymorphous light eruption * Benign summer light eruption * Juvenile spring eruption * Acne aestivalis * Hydroa vacciniforme * Solar erythema Non-ionizing Actinic rays * Actinic keratosis * Atrophic actinic keratosis * Hyperkeratotic actinic keratosis * Lichenoid actinic keratosis * Pigmented actinic keratosis * Actinic cheilitis * Actinic granuloma * Actinic prurigo * Chronic actinic dermatitis Infrared/heat * Erythema ab igne (Kangri ulcer * Kairo cancer * Kang cancer * Peat fire cancer) * Cutis rhomboidalis nuchae * Poikiloderma of Civatte Other * Radiation dermatitis * Acute * Chronic radiodermatitis) * Favre–Racouchot syndrome * Photoaging * Photosensitivity with HIV infection * Phototoxic tar dermatitis [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA [kDa]: kilodalton [EPC]: Early Prostate Cancer [LAPC]: locally advanced prostate cancer [NSAAs]: nonsteroidal antiandrogens [NSAA]: nonsteroidal antiandrogen [GnRH]: gonadotropin-releasing hormone [ADT]: androgen deprivation therapy [LH]: luteinizing hormone [AR]: androgen receptor [CAB]: combined androgen blockade [LPC]: localized prostate cancer [CPA]: cyproterone acetate [U.S.]: United States [FDA]: Food and Drug Administration	Acne aestivalis	c0263459	7,890	wikipedia	https://en.wikipedia.org/wiki/Acne_aestivalis	2021-01-18T18:32:05	{"umls": ["C0263459"], "icd-9": ["692.72"], "icd-10": ["L56.4"], "wikidata": ["Q341986"]}
A number sign (#) is used with this entry because of evidence that a mild variant of maple syrup urine disease (MSUDMV) is caused by homozygous mutation in the PPM1K gene (611065) on chromosome 4q22. One such family has been reported. Description The mild variant of MSUD is characterized by increased plasma levels of branched-chain amino acids (BCAA) apparent at birth. Treatment with a low-protein diet free of BCAA can result in normal psychomotor development and lack of metabolic episodes; however, plasma levels of BCAA may remain elevated (summary by Oyarzabal et al., 2013). For a general description and a discussion of genetic heterogeneity of maple syrup urine disease, see 248600. Clinical Features Oyarzabal et al. (2013) reported a 21-year-old woman with a mild variant of maple syrup urine disease. Newborn screening had detected increased blood concentrations of leucine and isoleucine, and cultured fibroblasts showed decreased leucine decarboxylation activity (14% of control values). She was started on an MSUD diet, and showed normal psychomotor development without metabolic episodes. At age 21, she worked as a nurse and had an IQ of 90. Brain MRI was normal, but blood levels of branched-chain amino and keto acids remained mildly increased. Inheritance The transmission pattern in the patient with MSUDMV reported by Oyarzabal et al. (2013) was consistent with autosomal recessive inheritance. Molecular Genetics In a 21-year-old woman with a mild variant of maple syrup urine disease, Oyarzabal et al. (2013) identified a homozygous truncating mutation in the PPM1K gene (611065.0001). Her unaffected father was heterozygous for the mutation, and the proband had uniparental disomy of chromosome 4. The mutant protein was not detected in patient cells or in COS-7 cells transfected with the mutation, suggesting that it is prone to degradation and consistent with a loss of function. Transfection of patient cells with wildtype PPM1K resulted in an increase in activity of the branched-chain alpha-keto acid dehydrogenase (BCKDH) complex. In addition, patient cells showed a 2-fold increase in reactive oxygen species compared to control, suggesting an increase in metabolic stress. Animal Model Lu et al. (2009) found that Pp2cm-deficient mice developed defects in the catabolism of branched-chain amino acids and showed a metabolic phenotype similar to human maple syrup urine disease, with an increase in plasma concentrations of branched-chain amino acids. Pp2cm-null mice on a high protein diet showed increased neonatal lethality and increased oxidative stress. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA [kDa]: kilodalton [EPC]: Early Prostate Cancer [LAPC]: locally advanced prostate cancer [NSAAs]: nonsteroidal antiandrogens [NSAA]: nonsteroidal antiandrogen [GnRH]: gonadotropin-releasing hormone [ADT]: androgen deprivation therapy [LH]: luteinizing hormone [AR]: androgen receptor [CAB]: combined androgen blockade [LPC]: localized prostate cancer [CPA]: cyproterone acetate [U.S.]: United States [FDA]: Food and Drug Administration	MAPLE SYRUP URINE DISEASE, MILD VARIANT	c0024776	7,891	omim	https://www.omim.org/entry/615135	2019-09-22T15:53:11	{"doid": ["9269"], "mesh": ["D008375"], "omim": ["615135"], "orphanet": ["511", "268162"]}
Thrombophilia An ultrasound image demonstrating a blood clot in the left common femoral vein. SpecialtyHematology 3D Medical animation still explaining the Thrombophilia Thrombophilia (sometimes called hypercoagulability or a prothrombotic state) is an abnormality of blood coagulation that increases the risk of thrombosis (blood clots in blood vessels).[1][2] Such abnormalities can be identified in 50% of people who have an episode of thrombosis (such as deep vein thrombosis in the leg) that was not provoked by other causes.[3] A significant proportion of the population has a detectable thrombophilic abnormality, but most of these develop thrombosis only in the presence of an additional risk factor.[2] There is no specific treatment for most thrombophilias, but recurrent episodes of thrombosis may be an indication for long-term preventive anticoagulation.[2] The first major form of thrombophilia to be identified by medical science, antithrombin deficiency, was identified in 1965, while the most common abnormalities (including factor V Leiden) were described in the 1990s.[4][5] ## Contents * 1 Signs and symptoms * 2 Causes * 2.1 Congenital * 2.2 Acquired * 2.3 Unclear * 3 Mechanism * 4 Diagnosis * 5 Screening * 6 Treatment * 7 Prognosis * 8 Epidemiology * 9 History * 10 References * 11 External links ## Signs and symptoms[edit] A right-sided acute deep vein thrombosis (to the left in the image). The leg is swollen and red due to venous outflow obstruction. The most common conditions associated with thrombophilia are deep vein thrombosis (DVT) and pulmonary embolism (PE), which are referred to collectively as venous thromboembolism (VTE). DVT usually occurs in the legs, and is characterized by pain, swelling and redness of the limb. It may lead to long-term swelling and heaviness due to damage to valves in the veins.[6] The clot may also break off and migrate (embolize) to arteries in the lungs. Depending on the size and the location of the clot, this may lead to sudden-onset shortness of breath, chest pain, palpitations and may be complicated by collapse, shock and cardiac arrest.[2][7] Venous thrombosis may also occur in more unusual places: in the veins of the brain, liver (portal vein thrombosis and hepatic vein thrombosis), mesenteric vein, kidney (renal vein thrombosis) and the veins of the arms.[2] Whether thrombophilia also increases the risk of arterial thrombosis (which is the underlying cause of heart attacks and strokes) is less well established.[2][8][9] Thrombophilia has been linked to recurrent miscarriage,[10] and possibly various complications of pregnancy such as intrauterine growth restriction, stillbirth, severe pre-eclampsia and abruptio placentae.[2] Protein C deficiency may cause purpura fulminans, a severe clotting disorder in the newborn that leads to both tissue death and bleeding into the skin and other organs. The condition has also been described in adults. Protein C and protein S deficiency have also been associated with an increased risk of skin necrosis on commencing anticoagulant treatment with warfarin or related drugs.[2][11] ## Causes[edit] Thrombophilia can be congenital or acquired. Congenital thrombophilia refers to inborn conditions (and usually hereditary, in which case "hereditary thrombophilia" may be used) that increase the tendency to develop thrombosis, while, on the other hand, acquired thrombophilia refers to conditions that arise later in life. ### Congenital[edit] The most common types of congenital thrombophilia are those that arise as a result of overactivity of coagulation factors. They are relatively mild, and are therefore classified as "type II" defects.[12] The most common ones are factor V Leiden (a mutation in the F5 gene at position 1691) and prothrombin G20210A, a mutation in prothrombin (at position 20210 in the 3' untranslated region of the gene).[1][13] The rare forms of congenital thrombophilia are typically caused by a deficiency of natural anticoagulants. They are classified as "type I" and are more severe in their propensity to cause thrombosis.[12] The main ones are antithrombin III deficiency, protein C deficiency and protein S deficiency.[1][13] Milder rare congenital thrombophilias are factor XIII mutation[13] and familial dysfibrinogenemia (an abnormal fibrinogen).[13] It is unclear whether congenital disorders of fibrinolysis (the system that destroys clots) are major contributors to thrombosis risk.[12] Congenital deficiency of plasminogen, for instance, mainly causes eye symptoms and sometimes problems in other organs, but the link with thrombosis has been more uncertain.[14] Blood group determines thrombosis risk to a significant extent. Those with blood groups other than type O are at a 2- to 4-fold relative risk. O blood group is associated with reduced levels of von Willebrand factor – because of increased clearance – and factor VIII, which is related to thrombotic risk .[5] ### Acquired[edit] A number of acquired conditions augment the risk of thrombosis. A prominent example is antiphospholipid syndrome,[1][13] which is caused by antibodies against constituents of the cell membrane, particularly lupus anticoagulant (first found in people with the disease systemic lupus erythematosus but often detected in people without the disease), anti-cardiolipin antibodies, and anti-β2-glycoprotein 1 antibodies; it is therefore regarded as an autoimmune disease. In some cases antiphospholipid syndrome can cause arterial as well as venous thrombosis. It is also more strongly associated with miscarriage, and can cause a number of other symptoms (such as livedo reticularis of the skin and migraine).[15] Heparin-induced thrombocytopenia (HIT) is due to an immune system reaction against the anticoagulant drug heparin (or its derivatives).[1] Though it is named for associated low platelet counts, HIT is strongly associated with risk of venous and arterial thrombosis.[16] Paroxysmal nocturnal hemoglobinuria (PNH) is a rare condition resulting from acquired alterations in the PIGA gene, which plays a role in the protection of blood cells from the complement system. PNH increases the risk of venous thrombosis but is also associated with hemolytic anemia (anemia resulting from destruction of red blood cells).[17] Both HIT and PNH require particular treatment.[16][17] Hematologic conditions associated with sluggish blood flow can increase risk for thrombosis. For example, sickle-cell disease (caused by mutations of hemoglobin) is regarded as a mild prothrombotic state induced by impaired flow.[1] Similarly, myeloproliferative disorders, in which the bone marrow produces too many blood cells, predispose to thrombosis, particularly in polycythemia vera (excess red blood cells) and essential thrombocytosis (excess platelets). Again, these conditions usually warrant specific treatment when identified.[18] Cancer, particularly when metastatic (spread to other places in the body), is a recognised risk factor for thrombosis.[2][13] A number of mechanisms have been proposed, such as activation of the coagulation system by cancer cells or secretion of procoagulant substances. Furthermore, particular cancer treatments (such as the use of central venous catheters for chemotherapy) may increase the risk of thrombosis further.[19] Nephrotic syndrome, in which protein from the bloodstream is released into the urine due to kidney diseases, can predispose to thrombosis;[1] this is particularly the case in more severe cases (as indicated by blood levels of albumin below 25 g/l) and if the syndrome is caused by the condition membranous nephropathy.[20] Inflammatory bowel disease (ulcerative colitis and Crohn's disease) predispose to thrombosis, particularly when the disease is active. Various mechanisms have been proposed.[2][21] Pregnancy is associated with an increased risk of thrombosis of 2- to 7-fold.[22] This probably results from a physiological hypercoagulability in pregnancy that protects against postpartum hemorrhage.[23] This hypercoagulability in turn is likely related to the high levels of estradiol and progesterone that occur during pregnancy.[24] Estrogens, when used in combined hormonal birth control and in menopausal hormone therapy (in combination with progestogens), have been associated with a 2- to 6-fold increased risk of venous thrombosis. The risk depends on the types of hormones used, the dose of estrogen, and the presence of other thrombophilic risk factors.[25] Various mechanisms, such as deficiency of protein S and tissue factor pathway inhibitor, are said to be responsible.[26] Obesity has long been regarded as a risk factor for venous thrombosis. It more than doubles the risk in numerous studies, particularly in combination with the use of oral contraceptives or in the period after surgery. Various coagulation abnormalities have been described in the obese. Plasminogen activator inhibitor-1, an inhibitor of fibrinolysis, is present in higher levels in people with obesity. Obese people also have larger numbers of circulating microvesicles (fragments of damaged cells) that bear tissue factor. Platelet aggregation may be increased, and there are higher levels of coagulation proteins such as von Willebrand factor, fibrinogen, factor VII and factor VIII. Obesity also increases the risk of recurrence after an initial episode of thrombosis.[27] ### Unclear[edit] A number of conditions that have been linked with venous thrombosis are possibly genetic and possibly acquired.[13] These include: elevated levels of factor VIII, factor IX, factor XI, fibrinogen and thrombin-activatable fibrinolysis inhibitor, and decreased levels of tissue factor pathway inhibitor. Activated protein C resistance that is not attributable to factor V mutations is probably caused by other factors and remains a risk factor for thrombosis.[13] There is an association between the blood levels of homocysteine and thrombosis,[13] although this has not been reported consistently in all studies.[5] Homocysteine levels are determined by mutations in the MTHFR and CBS genes, but also by levels of folic acid, vitamin B6 and vitamin B12, which depend on diet.[12] ## Mechanism[edit] Main article: Coagulation The coagulation system, often described as a "cascade", consists of a group of proteins that interact in the formation of a fibrin-rich clot. Thrombosis is a multifactorial problem because there are often multiple reasons why a person might develop thrombosis. These risk factors may include any combination of abnormalities in the blood vessel wall, abnormalities in the blood flow (as in immobilization), and abnormalities in the consistency of the blood. Thrombophilia is caused by abnormalities in blood consistency, which is determined by the levels of coagulation factors and other circulating blood proteins that participate in the "coagulation cascade".[13] Normal coagulation is initiated by the release of tissue factor from damaged tissue. Tissue factor binds to circulating factor VIIa. The combination activates factor X to factor Xa and factor IX to factor IXa. Factor Xa (in the presence of factor V) activates prothrombin into thrombin. Thrombin is a central enzyme in the coagulation process: it generates fibrin from fibrinogen, and activates a number of other enzymes and cofactors (factor XIII, factor XI, factor V and factor VIII, TAFI) that enhance the fibrin clot.[12] The process is inhibited by TFPI (which inactivates the first step catalyzed by factor VIIa/tissue factor), antithrombin (which inactivates thrombin, factor IXa, Xa and XIa), protein C (which inhibits factors Va and VIIIa in the presence of protein S), and protein Z (which inhibits factor Xa).[12] In thrombophilia, the balance between "procoagulant" and "anticoagulant" activity is disturbed. The severity of the imbalance determines the likelihood that someone develops thrombosis. Even small perturbances of proteins, such as the reduction of antithrombin to only 70–80% of the normal level, can increase the thrombosis risk; this is in contrast with hemophilia, which only arises if levels of coagulation factors are markedly decreased.[12] In addition to its effects on thrombosis, hypercoagulable states may accelerate the development of atherosclerosis, the arterial disease that underlies myocardial infarction and other forms of cardiovascular disease.[28][29] ## Diagnosis[edit] A mutation of coagulation factor V (schematic representation drawn here) is much more common in people with thrombosis than in those without, but is only regarded as a weak risk factor. Tests for thrombophilia include complete blood count (with examination of the blood film), prothrombin time, partial thromboplastin time, thrombodynamics test, thrombin time and reptilase time, lupus anticoagulant, anti-cardiolipin antibody, anti-β2 glycoprotein 1 antibody, activated protein C resistance, fibrinogen tests, factor V Leiden and prothrombin mutation, and basal homocysteine levels.[2] Testing may be more or less extensive depending on clinical judgement and abnormalities detected on initial evaluation.[2] For hereditary cases, the patient must have at least two abnormal tests plus family history. ## Screening[edit] There are divergent views as to whether everyone with an unprovoked episode of thrombosis should be investigated for thrombophilia. Even those with a form of thrombophilia may not necessarily be at risk of further thrombosis, while recurrent thrombosis is more likely in those who have had previous thrombosis even in those who have no detectable thrombophilic abnormalities.[8][11][30] Recurrent thromboembolism, or thrombosis in unusual sites (e.g. the hepatic vein in Budd-Chiari syndrome), is a generally accepted indication for screening. It is more likely to be cost-effective in people with a strong personal or family history of thrombosis.[31] In contrast, the combination of thrombophilia with other risk factors may provide an indication for preventive treatment, which is why thrombophilia testing may be performed even in those who would not meet the strict criteria for these tests.[30] Searching for a coagulation abnormality is not normally undertaken in patients in whom thrombosis has an obvious trigger. For example, if the thrombosis is due to immobilization after recent orthopedic surgery, it is regarded as "provoked" by the immobilization and the surgery and it is less likely that investigations will yield clinically important results.[11][30] When venous thromboembolism occurs when a patient is experiencing transient major risk factors such as prolonged immobility, surgery, or trauma, testing for thrombophilia is not appropriate because the outcome of the test would not change a patient's indicated treatment.[32][33] In 2013, the American Society of Hematology, as part of recommendations in the Choosing Wisely campaign, cautioned against overuse of thrombophilia screening; false positive results of testing would lead to people inappropriately being labeled as having thrombophilia, and being treated with anticoagulants without clinical need[32] In the United Kingdom, professional guidelines give specific indications for thrombophilia testing. It is recommended that testing be done only after appropriate counseling, and hence the investigations are usually not performed at the time when thrombosis is diagnosed but at a later time.[11] In particular situations, such as retinal vein thrombosis, testing is discouraged altogether because thrombophilia is not regarded as a major risk factor. In other rare conditions generally linked with hypercoagulability, such as cerebral venous thrombosis and portal vein thrombosis, there is insufficient data to state for certain whether thrombophilia screening is helpful, and decisions on thrombophilia screening in these conditions are therefore not regarded as evidence-based.[11] If cost-effectiveness (quality-adjusted life years in return for expenditure) is taken as a guide, it is generally unclear whether thrombophilia investigations justify the often high cost,[34] unless the testing is restricted to selected situations.[35] Recurrent miscarriage is an indication for thrombophilia screening, particularly antiphospholipid antibodies (anti-cardiolipin IgG and IgM, as well as lupus anticoagulant), factor V Leiden and prothrombin mutation, activated protein C resistance and a general assessment of coagulation through an investigation known as thromboelastography.[10] Women who are planning to use oral contraceptives do not benefit from routine screening for thrombophilias, as the absolute risk of thrombotic events is low. If either the woman or a first-degree relative has suffered from thrombosis, the risk of developing thrombosis is increased. Screening this selected group may be beneficial,[26] but even when negative may still indicate residual risk.[11] Professional guidelines therefore suggest that alternative forms of contraception be used rather than relying on screening.[11] Thrombophilia screening in people with arterial thrombosis is generally regarded unrewarding and is generally discouraged,[11] except possibly for unusually young patients (especially when precipitated by smoking or use of estrogen-containing hormonal contraceptives) and those in whom revascularization, such as coronary arterial bypass, fails because of rapid occlusion of the graft.[9] ## Treatment[edit] People considered to be at a high risk of repeated thrombosis due to thrombophilia are often advised to take warfarin for prolonged periods of time or even indefinitely. There is no specific treatment for thrombophilia, unless it is caused by an underlying medical illness (such as nephrotic syndrome), where the treatment of the underlying disease is needed. In those with unprovoked and/or recurrent thrombosis, or those with a high-risk form of thrombophilia, the most important decision is whether to use anticoagulation medications, such as warfarin, on a long-term basis to reduce the risk of further episodes.[3] This risk needs to weighed against the risk that the treatment will cause significant bleeding, as the reported risk of major bleeding is over 3% per year, and 11% of those with major bleeding may die as a result.[3] Apart from the abovementioned forms of thrombophilia, the risk of recurrence after an episode of thrombosis is determined by factors such as the extent and severity of the original thrombosis, whether it was provoked (such as by immobilization or pregnancy), the number of previous thrombotic events, male sex, the presence of an inferior vena cava filter, the presence of cancer, symptoms of post-thrombotic syndrome, and obesity.[3] These factors tend to be more important in the decision than the presence or absence of a detectable thrombophilia.[11][36] Those with antiphospholipid syndrome may be offered long-term anticoagulation after a first unprovoked episode of thrombosis. The risk is determined by the subtype of antibody detected, by the antibody titer (amount of antibodies), whether multiple antibodies are detected, and whether it is detected repeatedly or only on a single occasion.[15] Women with a thrombophilia who are contemplating pregnancy or are pregnant usually require alternatives to warfarin during pregnancy, especially in the first 13 weeks, when it may produce abnormalities in the unborn child. Low molecular weight heparin (LMWH, such as enoxaparin) is generally used as an alternative.[37] Warfarin and LMWH may safely be used in breastfeeding.[37] When women experience recurrent pregnancy loss secondary to thrombophilia, some studies have suggested that low molecular weight heparin reduces the risk of miscarriage. When the results of all studies are analysed together, no statistically significant benefit could be demonstrated.[38] ## Prognosis[edit] In people without a detectable thrombophilia, the cumulative risk of developing thrombosis by the age of 60 is about 12%. About 60% of people who are deficient in antithrombin will have experienced thrombosis at least once by age 60, as will about 50% of people with protein C deficiency and about a third of those with protein S deficiency. People with activated protein C resistance (usually resulting from factor V Leiden), in contrast, have a slightly raised absolute risk of thrombosis, with 15% having had at least one thrombotic event by the age of sixty.[12] In general, men are more likely than women to experience repeated episodes of venous thrombosis.[5] People with factor V Leiden are at a relatively low risk of thrombosis, but may develop thrombosis in the presence of an additional risk factor, such as immobilization. Most people with the prothrombin mutation (G20210A) never develop thrombosis.[12] ## Epidemiology[edit] The major ("type 1") thrombophilias are rare. Antithrombin deficiency is present in 0.2% of the general population and 0.5–7.5% of people with venous thrombosis. Protein C deficiency, too, is present in 0.2% of the population, and can be found in 2.5–6% of people with thrombosis. The exact prevalence of protein S deficiency in the population is unknown; it is found 1.3–5% of people with thrombosis.[12] The minor ("type 2") thrombophilias are much more common. Factor V Leiden is present in 5% of the population of Northern European descent, but much rarer in those of Asian or African extraction. In people with thrombosis, 10% have factor V Leiden. In those who are referred for thrombophilia testing, 30–50% have the defect. The prothrombin mutation occurs at rates of 1–4% in the general population, 5–10% of people with thrombosis, and 15% of people referred for thrombophilia testing. Like factor V Leiden, this abnormality is uncommon in Africans and Asians.[12] The exact prevalence of antiphospholipid syndrome is not well known, as different studies employ different definitions of the condition. Antiphospholipid antibodies are detected in 24% of those referred to thrombophilia testing.[15] ## History[edit] Rudolf Virchow, the German pathologist who distinguished the various causes of thrombosis, and whose work led to the development of thrombophilia as a concept. German physician Rudolf Virchow categorized abnormalities in the consistency of the blood as a factor in the development of thrombosis in 1856. The exact nature of these abnormalities remained elusive until the first form of thrombophilia, antithrombin deficiency, was recognized in 1965 by the Norwegian hematologist Olav Egeberg.[39] Protein C deficiency followed in 1981, when described by researchers from the Scripps Research Institute and the U.S. Centers of Disease Control.[40] Protein S deficiency followed in 1984, described by researchers at the University of Oklahoma.[4][5][41] Antiphospholipid syndrome was described in full in the 1980s, after various previous reports of specific antibodies in people with systemic lupus erythematosus and thrombosis.[15][42] The syndrome is often attributed to the British rheumatologist Graham R.V. Hughes, and is often referred to as Hughes syndrome for that reason.[43] The more common genetic thrombophilias were described in the 1990s. Many studies had previously indicated that many people with thrombosis showed resistance activated protein C. In 1994 a group in Leiden, The Netherlands, identified the most common underlying defect—a mutation in factor V that made it resistant to the action of activated protein C. The defect was called factor V Leiden, as genetic abnormalities are typically named after the place where they are discovered.[44] Two years later, the same group described a common mutation in the prothrombin gene that caused elevation of prothrombin levels and a mild increase in thrombosis risk.[4][5][45] It is suspected that other genetic abnormalities underlying familial thrombosis will in future be discovered through studies of the entire genetic code, looking for small alternations in genes.[4][5] ## References[edit] 1. ^ a b c d e f g Mitchell RS, Kumar V, Abbas AK, Fausto N (2007). "Chapter 4". Robbins Basic Pathology (Eighth ed.). Philadelphia: Saunders. ISBN 978-1-4160-2973-1. 2. ^ a b c d e f g h i j k l Heit JA (2007). "Thrombophilia: common questions on laboratory assessment and management". 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J.; Keeling, D.; Machin, S.; MacKie, I.; Makris, M.; Nokes, T.; Perry, D.; Tait, R. C.; Walker, I.; Watson, H.; British Committee for Standards in Haematology (2010). "Clinical guidelines for testing for heritable thrombophilia". British Journal of Haematology. 149 (2): 209–220. doi:10.1111/j.1365-2141.2009.08022.x. PMID 20128794. 33. ^ Hicks LK, Bering H, Carson KR, et al. (2013). "The ASH Choosing Wisely(R) campaign: five hematologic tests and treatments to question". Blood. 122 (24): 3879–83. doi:10.1182/blood-2013-07-518423. PMID 24307720. 34. ^ Simpson EL, Stevenson MD, Rawdin A, Papaioannou D (January 2009). "Thrombophilia testing in people with venous thromboembolism: systematic review and cost-effectiveness analysis". Health Technol. Assess. 13 (2): iii, ix–x, 1–91. doi:10.3310/hta13020. PMID 19080721. 35. ^ Wu O, Greer IA (September 2007). "Is screening for thrombophilia cost-effective?". Curr. Opin. Hematol. 14 (5): 500–3. doi:10.1097/MOH.0b013e32825f5318. PMID 17934357. S2CID 22896788. 36. ^ Kearon C, Kahn SR, Agnelli G, Goldhaber S, Raskob GE, Comerota AJ (June 2008). "Antithrombotic therapy for venous thromboembolic disease: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition)". Chest. 133 (6 Suppl): 454S–545S. doi:10.1378/chest.08-0658. PMID 18574272. Archived from the original on 2013-01-12. 37. ^ a b Bates SM, Greer IA, Pabinger I, Sofaer S, Hirsh J (June 2008). "Venous thromboembolism, thrombophilia, antithrombotic therapy, and pregnancy: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition)". Chest. 133 (6 Suppl): 844S–886S. doi:10.1378/chest.08-0761. PMID 18574280. Archived from the original on 2013-01-12. 38. ^ Skeith L, Carrier M, Kaaja R, Martinelli I, Petroff D, Schleußner E, Laskin CA, Rodger MA (2016). "A meta-analysis of low-molecular-weight heparin to prevent pregnancy loss in women with inherited thrombophilia". Blood. 127 (13): 1650–55. doi:10.1182/blood-2015-12-626739. PMID 26837697. 39. ^ Egeberg O (June 1965). "Inherited antithrombin deficiency causing thrombophilia". Thromb. Diath. Haemorrh. 13 (2): 516–30. doi:10.1055/s-0038-1656297. PMID 14347873. 40. ^ Griffin JH, Evatt B, Zimmerman TS, Kleiss AJ, Wideman C (November 1981). "Deficiency of protein C in congenital thrombotic disease". J. Clin. Invest. 68 (5): 1370–3. doi:10.1172/JCI110385. PMC 370934. PMID 6895379. 41. ^ Comp PC, Esmon CT (December 1984). "Recurrent venous thromboembolism in patients with a partial deficiency of protein S". N. Engl. J. Med. 311 (24): 1525–8. doi:10.1056/NEJM198412133112401. PMID 6239102. 42. ^ Hughes GR (October 1983). "Thrombosis, abortion, cerebral disease, and the lupus anticoagulant". Br. Med. J. (Clin. Res. Ed.). 287 (6399): 1088–89. doi:10.1136/bmj.287.6399.1088. PMC 1549319. PMID 6414579. 43. ^ Sanna G, D'Cruz D, Cuadrado MJ (August 2006). "Cerebral manifestations in the antiphospholipid (Hughes) syndrome". Rheum. Dis. Clin. North Am. 32 (3): 465–90. doi:10.1016/j.rdc.2006.05.010. PMID 16880079. 44. ^ Bertina RM, Koeleman BP, Koster T, et al. (May 1994). "Mutation in blood coagulation factor V associated with resistance to activated protein C". Nature. 369 (6475): 64–7. Bibcode:1994Natur.369...64B. doi:10.1038/369064a0. PMID 8164741. S2CID 4314040. 45. ^ Poort SR, Rosendaal FR, Reitsma PH, Bertina RM (November 1996). "A common genetic variation in the 3'-untranslated region of the prothrombin gene is associated with elevated plasma prothrombin levels and an increase in venous thrombosis" (PDF). Blood. 88 (10): 3698–703. doi:10.1182/blood.V88.10.3698.bloodjournal88103698. PMID 8916933. ## External links[edit] Classification D * ICD-10: D68.5-D68.6 * ICD-9-CM: 286.9 * OMIM: 188050 * MeSH: D019851 * DiseasesDB: 29080 External resources * eMedicine: article/211039 * Patient UK: Thrombophilia * "Thrombophilia". Patient UK. * v * t * e Disorders of bleeding and clotting Coagulation · coagulopathy · Bleeding diathesis Clotting By cause * Clotting factors * Antithrombin III deficiency * Protein C deficiency * Activated protein C resistance * Protein S deficiency * Factor V Leiden * Prothrombin G20210A * Platelets * Sticky platelet syndrome * Thrombocytosis * Essential thrombocythemia * DIC * Purpura fulminans * Antiphospholipid syndrome Clots * Thrombophilia * Thrombus * Thrombosis * Virchow's triad * Trousseau sign of malignancy By site * Deep vein thrombosis * Bancroft's sign * Homans sign * Lisker's sign * Louvel's sign * Lowenberg's sign * Peabody's sign * Pratt's sign * Rose's sign * Pulmonary embolism * Renal vein thrombosis Bleeding By cause Thrombocytopenia * Thrombocytopenic purpura: ITP * Evans syndrome * TM * TTP * Upshaw–Schulman syndrome * Heparin-induced thrombocytopenia * May–Hegglin anomaly Platelet function * adhesion * Bernard–Soulier syndrome * aggregation * Glanzmann's thrombasthenia * platelet storage pool deficiency * Hermansky–Pudlak syndrome * Gray platelet syndrome Clotting factor * Hemophilia * A/VIII * B/IX * C/XI * von Willebrand disease * Hypoprothrombinemia/II * Factor VII deficiency * Factor X deficiency * Factor XII deficiency * Factor XIII deficiency * Dysfibrinogenemia * Congenital afibrinogenemia Signs and symptoms * Bleeding * Bruise * Hematoma * Petechia * Purpura * Nonthrombocytopenic purpura By site * head * Epistaxis * Hemoptysis * Intracranial hemorrhage * Hyphema * Subconjunctival hemorrhage * torso * Hemothorax * Hemopericardium * Pulmonary hematoma * abdomen * Gastrointestinal bleeding * Hemobilia * Hemoperitoneum * Hematocele * Hematosalpinx * joint * Hemarthrosis [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA [kDa]: kilodalton [EPC]: Early Prostate Cancer [LAPC]: locally advanced prostate cancer [NSAAs]: nonsteroidal antiandrogens [NSAA]: nonsteroidal antiandrogen [GnRH]: gonadotropin-releasing hormone [ADT]: androgen deprivation therapy [LH]: luteinizing hormone [AR]: androgen receptor [CAB]: combined androgen blockade [LPC]: localized prostate cancer [CPA]: cyproterone acetate [U.S.]: United States [FDA]: Food and Drug Administration	Thrombophilia	c3160733	7,892	wikipedia	https://en.wikipedia.org/wiki/Thrombophilia	2021-01-18T19:06:59	{"mesh": ["D019851"], "umls": ["C3160733", "C0398623"], "icd-9": ["286.9"], "wikidata": ["Q1570013"]}
Carcinoma ex pleomorphic adenoma Micrograph of a carcinoma ex pleomorphic adenoma. The carcinoma component is on the lower right of the image. Benign parotid gland is seen at the left and pleomorphic adenoma is seen at the upper right. H&E stain. SpecialtyOncology Carcinoma ex pleomorphic adenoma (ca ex PA) is a type of cancer typically found in the parotid gland. It arises from the benign tumour pleomorphic adenoma. Its prognosis depends on the stage. Early tumours have essentially a benign behaviour.[1] ## Contents * 1 Signs and symptoms * 2 Diagnosis * 3 See also * 4 References * 5 External links ## Signs and symptoms[edit] The signs and symptoms are similar to other malignant salivary gland tumours; however, it may have been preceded by an appreciable mass that was long-standing and did not appear to be growing. Findings that suggest a malignant salivary gland tumour include rapid growth, facial weakness (due to facial nerve compression), pain, skin ulceration, fixation of the mastoid tip and parasthesias. ## Diagnosis[edit] Carcinoma ex pleomorphic adenoma is diagnosed by examining it under the microscope with consideration of the individual history. In approximately 75% of cases ca ex PAs arise in a pleomorphic adenoma that is apparent when the tumour is excised.[2] In the other approximately 25% of cases the individual had a pleomorphic adenoma excised previously and the diagnosis is made based on (1) the presence of a carcinoma, and (2) the history of a pleomorphic adenoma at that location. ## See also[edit] * Salivary gland * Pleomorphic adenoma ## References[edit] 1. ^ Di Palma, S. (Jul 2013). "Carcinoma ex pleomorphic adenoma, with particular emphasis on early lesions". Head Neck Pathol. 7 Suppl 1: S68-76. doi:10.1007/s12105-013-0454-z. PMC 3712089. PMID 23821206. 2. ^ Antony, J.; Gopalan, V.; Smith, RA.; Lam, AK. (Mar 2012). "Carcinoma ex pleomorphic adenoma: a comprehensive review of clinical, pathological and molecular data". Head Neck Pathol. 6 (1): 1–9. doi:10.1007/s12105-011-0281-z. PMC 3311945. PMID 21744105. ## External links[edit] Classification D [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA [kDa]: kilodalton [EPC]: Early Prostate Cancer [LAPC]: locally advanced prostate cancer [NSAAs]: nonsteroidal antiandrogens [NSAA]: nonsteroidal antiandrogen [GnRH]: gonadotropin-releasing hormone [ADT]: androgen deprivation therapy [LH]: luteinizing hormone [AR]: androgen receptor [CAB]: combined androgen blockade [LPC]: localized prostate cancer [CPA]: cyproterone acetate [U.S.]: United States [FDA]: Food and Drug Administration	Carcinoma ex pleomorphic adenoma	c0344460	7,893	wikipedia	https://en.wikipedia.org/wiki/Carcinoma_ex_pleomorphic_adenoma	2021-01-18T18:55:31	{"wikidata": ["Q5038165"]}
Drug-resistant epilepsy (DRE), also known as refractory epilepsy or pharmacoresistant epilepsy, is defined as failure of adequate trials of two tolerated and appropriately chosen and used antiepileptic drugs (AED schedules) (whether as monotherapies or in combination) to achieve sustained seizure freedom.[1][2] The probability that the next medication will achieve seizure freedom drops with every failed AED. For example, after two failed AEDs, the probability that the third will achieve seizure freedom is around 4%.[3] Drug-resistant epilepsy is commonly diagnosed after several years of uncontrolled seizures, however, in most cases, it is evident much earlier. Approximately 30% of people with epilepsy have a drug-resistant form.[4] When 2 AEDs regimens have failed to produce sustained seizure-freedom, it is important to initiate other treatments to control seizures. Next to indirect consequences like injuries from falls, accidents, drowning and impairment in daily life, seizure control is critical because uncontrolled seizures -specifically generalized tonic clonic seizures- can damage the brain and increase the risk for sudden unexpected death in epilepsy called SUDEP.[5][6] The first step is for physicians to refer their DRE patients to an epilepsy center in which a presurgical evaluation can be carried out in order to assess whether a patient is a candidate for epilepsy surgery or not. For those patients who are not surgical candidates, those who decline brain surgery or those in which brain surgery fails to produce long term seizure freedom, vagus nerve stimulation and/or a diet can be recommended. ## Contents * 1 Surgery * 1.1 Lobe resection * 1.2 Lesionectomy * 1.3 Corpus callosotomy * 1.4 Functional hemispherectomy * 1.5 Multiple subpial transection * 1.6 Vagus nerve stimulation * 1.7 VNS with cardiac-based seizure detection * 2 Diets * 2.1 Ketogenic diet * 2.2 MCT-Ketogenic diet * 2.3 Modified Atkins * 2.4 Other * 3 References ## Surgery[edit] In epilepsy surgery, a distinction can be made between resective and disconnective procedures. In a resective procedure the area of the brain that causes the seizures is removed. In a disconnective procedure the neural connections in the brain that allow the seizures to spread are disconnected. In most cases epilepsy surgery is only an option when the area of the brain that causes the seizures - the so-called epileptic focus can be clearly identified and is not responsible for critical functions such as language. Several imaging techniques such as magnetic resonance tomography and functional techniques like electrocorticography are used to demarcate the epileptic focus clearly. ### Lobe resection[edit] Temporal lobe epilepsy (TLE) in which the epileptic focus is in the temporal lobe, is one of the most common types of epilepsy in adolescents and adults. Hence temporal lobe resection, during which the whole temporal lobe or just a part of the temporal lobe for example the hippocampus or the amygdala is removed, is the most common epilepsy surgery procedure. Between 40 and 60% of patients that undergo temporal lobe resection are continuously seizure free[7][8] The surgery itself is very safe with a mortality of 0%[9][10]. The risk for neurologic complications from a temporal lobe resection is around 3 to 7%[11][12] ### Lesionectomy[edit] if the source of seizures is a lesion for example a scar tissue from a brain injury a tumor or malformed blood vessels this lesion can be removed surgically in a lesionectomy. ### Corpus callosotomy[edit] Corpus callosotomy is a palliative procedure for specially severe cases of epilepsy. This corpus callosum is a large bundle of nerve fibers that connects both brain halves with each other. To prevent the spreading of seizures from one brain hemisphere (brain half) to the other the corpus callosum can be split. This procedure is mostly carried out on patients with so-called drop attacks that come with a very high risk of injury and in which the epileptic focus is not clearly delimitable. It is very rare that a corpus callosotomy causes seizure freedom however in half of the patients the dangerous drop attacks are less severe.[13] After a corpus callosotomy among others there is the risk that language is temporarily or permanently impaired. The younger a patient is at the time of the corpus callosotomy, the better the prognosis. ### Functional hemispherectomy[edit] This procedure is a modern adaptation of the radical hemispherectomy in which one brain hemisphere is removed to prevent the spread of seizures from one brain hemisphere to the other. In the functional version only a part of the hemisphere is removed but the connections to the other brain hemisphere are cut through. This procedure is only performed on a small group of patients under the age of 13 that have severe damage or malformation of one hemisphere, patients with Sturge Weber syndrome or patients with Rasmussen's encephalitis. The functional hemispherectomy can achieve long-term seizure freedom in over 80% of patients however often at the price of hemiplegia and hemianopsy. The death rate is around 1 to 2% and 5% of patients develop a hydrocephalus that needs to be treated with a shunt.[14] ### Multiple subpial transection[edit] Multiple subpial transection (MST) is a palliative procedure that is considered when an epileptic focus can be identified but cannot be removed because it is in a functionally relevant brain region- a so-called eloquent region. In an MST nerve fibers are disconnected so that seizures cannot spread from the epileptic focus into the rest of the brain. Between 60 and 70% of patients experienced a seizure reduction of over 95% after an MST and the risk for neurologic deficits is around 19%.[15] ### Vagus nerve stimulation[edit] Vagus nerve stimulation (VNS) involves implanting a pacemaker-like generator below the skin in the chest area that intermittently sends electrical impulses to the left vagus nerve in the neck. The impulses are mediated to the brain by the vagus nerve and thereby help to inhibit electrical disturbances that cause seizures. The antiepileptic effect of vagus nerve stimulation increases over several months: after two years around half of VNS patients experience a reduction of their seizures by at least 50%[16][17] and after 10 years the average seizure reduction is around 75%[18] Furthermore, in most patients mood (VNS has a significant anti-depressent effect and is approved for depression in some countries), alertness and quality-of-life are increased significantly within the first year of vagus nerve stimulation.[19][20] VNS patients can induce an extra stimulation themselves with a VNS magnet when they noticed that a seizure is approaching and it has been shown that the majority of seizures can be interrupted this type of on-demand stimulation.[21][22] The procedure to implant a vagus nerve stimulator is very safe: no case of death related to VNS implantation surgery has ever occurred. Infection of the tissue pocket in which the generator is located that requires antibiotic treatment occurs in around 3% of patients.[23][24] The most common side effect is hoarseness or change in voice. Headaches and shortness of breath are less common. In most cases, side effects only occur during activity of the stimulation (mostly every 3 to 5 minutes) and reduce over time.[25] In most cases VNS does not replace antiepileptic medication. Patients must continue their antiepileptic medication however in many cases the dose can be reduced over time so that patients suffer less from side effects of the medication. The battery of the VNS generator can depending on the model and the settings can last between 3 and 10 years. ### VNS with cardiac-based seizure detection[edit] In 82% of epilepsy patients the heart rate increases quickly and suddenly upon a seizure[26] This is known as ictal tachycardia. Ictal tachycardia is so characteristic that it can be distinguished from the slow gradual increase of heart rate that occurs during physical activity. This way in the majority of epilepsy patients seizures can be detected in the ECG. In addition to classical VNS, some new VNS generators continuously monitor heart rate and identify fast and sudden heart rate increases associated with seizures with intelligent software. Then an automatic additional stimulation can be triggered to interrupt, prevent or alleviate the seizure. This new generator type was shown to detect and treat at least four out of five seizures and 60% of seizures were shown to be interrupted with this heart-rate triggered stimulation.[27] The earlier in the course of the seizure the stimulation occurred the quicker the seizure ended generally seizures were shown to be reduced by around 35% by stimulation[28][29] ## Diets[edit] For over 100 years it has been known that a diet with a high fat content and a low carbohydrate content can reduce seizures. Radically curbing carbohydrate intake imitates starvation and forces the body to draw energy from ketone bodies that form when fat is metabolized instead of drawing its energy from sugar. This state is called ketosis and it changes several biochemical processes in the brain in a way that inhibits epileptic activity. On this basis there are several diets that are often recommended to children under 12 years old, but are also effective in adults. ### Ketogenic diet[edit] In Europe the ketogenic diet is the diet that is most commonly recommended by doctors for patients with epilepsy. In this diet the ratio of fat to carbohydrates and proteins is 4:1. That means that the fat content of the consumed food must be around 80%, the protein content must be around 15%, and the carbohydrate content must be around 5%. For comparison the average western diet consists of a carbohydrate content of over 50%. After one year on the ketogenic diet the success rate (seizure reduction over 50%) is between 30 and 50% and the dropout rate is around 45%.[30][31] Although the ketogenic diet can be very effective some families report that it's not compatible with daily life on the long run because it's too restrictive as bread pasta and sweets are forbidden in the ketogenic diet. In puberty with increasing autonomy it can be difficult for adolescents to follow the diet strictly. For this reason a fat ratio of 3: 1 instead of 4: 1 can be recommended to make meals more palatable. Side effects of the ketogenic diet can be constipation, tiredness and after a long term diet, in one out of 20 patients, kidney stones.[32] ### MCT-Ketogenic diet[edit] In the 1960s it was discovered that when medium-chain triglycerides (MCT) fats are metabolized in the body more ketone bodies are produced then from metabolizing any other fat. Based on this mechanism the MCT ketogenic diet a modification of the ketogenic diet was developed and it has nearly replaced the classic ketogenic diet in the USA. In the MCT ketogenic diet MCT oil is added to ketogenic meals, which allows the carbohydrate content to be increased to around 15 to 20%. This way some patients find the meals more enjoyable. The success rate of the MCT ketogenic diet does not differ from the classic ketogenic diet however not all children can tolerate the necessary large amounts of MCT oil which is also very expensive. ### Modified Atkins[edit] A modified Atkins diet describes the long term practice of the first phase of the popular Atkins diet the so-called induction phase to reduce seizures through ketosis. In this diet the fat content of the nutrition is slightly lower than in the ketogenic diet at around 60%, the protein content is around 30% and the carbohydrate content is around 10% rendering the diet less restrictive and more compatible with the daily life compared to the ketogenic diet. Several studies show that the modified Atkins diet produces a similar or slightly lower seizure reduction to the ketogenic diet.[33] Some physicians, especially in the USA, recommend the modified Atkins diet because they assume that patients will adhere to it on the long-term because it is more compatible with daily life and the meals are more enjoyable. It has also been concluded in another study that the diet is well tolerated and effective in hard to treat childhood epilepsy.[34] ### Other[edit] Deep brain stimulation of the anterior nuclei of the thalamus is approved for DRE in some countries in Europe, but has been and continues to only be used in a very few patients. After 5 years of DBS a seizure reduction of 69% and a 50%-responder rate of 68% was reported in a randomized-double blinded trial.[35] The rate of serious device related events was 34% in this study. Responsive neurostimulation (RNS) is approved for DRE in the USA and involves stimulation directly to 1 or 2 seizure foci when abnormal electrocorticographic activity is detected by the devices software. After 2 years of RNS a seizure reduction of 53% was reported in a randomized-double blinded trial as well as a rate of serious device related events of 2.5%.[36] Transcutaneous vagus nerve stimulation (tVNS) is approved for DRE in some European countries and involves externally stimulating the auricular branch of the vagus nerve in the ear. tVNS failed to demonstrate efficacy in a first randomized-double blinded trial: responder rates did not differ between active and control groups potentially indicating a placebo effect behind the 34% seizure reduction seen in the patients who completed the full follow-up period.[37] ## References[edit] 1. ^ Kwan, Patrick; Arzimanoglou, Alexis; Berg, Anne T.; Brodie, Martin J.; Allen Hauser, W.; Mathern, Gary; Moshé, Solomon L.; Perucca, Emilio; Wiebe, Samuel (2010-06-01). "Definition of drug resistant epilepsy: Consensus proposal by the ad hoc Task Force of the ILAE Commission on Therapeutic Strategies". Epilepsia. 51 (6): 1069–1077. doi:10.1111/j.1528-1167.2009.02397.x. ISSN 1528-1167. PMID 19889013. 2. ^ Bresnahan, Rebecca; Panebianco, Mariangela; Marson, Anthony G. (28 March 2019). "Brivaracetam add-on therapy for drug-resistant epilepsy". The Cochrane Database of Systematic Reviews. 3: CD011501. doi:10.1002/14651858.CD011501.pub2. ISSN 1469-493X. PMC 6437881. PMID 30920649. 3. ^ Kwan, Patrick; Brodie, Martin J. (2000-02-03). "Early Identification of Refractory Epilepsy". New England Journal of Medicine. 342 (5): 314–319. doi:10.1056/NEJM200002033420503. ISSN 0028-4793. PMID 10660394. 4. ^ Brodie, Martin J. (2013-05-01). "Road to refractory epilepsy: The Glasgow story". Epilepsia. 54: 5–8. doi:10.1111/epi.12175. ISSN 1528-1167. PMID 23646962. 5. ^ Hesdorffer, Dale C.; Tomson, Torbjorn; Benn, Emma; Sander, Josemir W.; Nilsson, Lena; Langan, Yvonne; Walczak, Thaddeus S.; Beghi, Ettore; Brodie, Martin J. (2011-06-01). "Combined analysis of risk factors for SUDEP". Epilepsia. 52 (6): 1150–1159. doi:10.1111/j.1528-1167.2010.02952.x. ISSN 1528-1167. PMID 21671925. 6. ^ Langan, Y.; Nashef, L.; Sander, J. W. (2005-04-12). "Case-control study of SUDEP". Neurology. 64 (7): 1131–1133. doi:10.1212/01.WNL.0000156352.61328.CB. ISSN 0028-3878. PMID 15824334. 7. ^ Marks, William J. (2003-09-01). "Long-term Outcomes of Temporal Lobe Epilepsy Surgery". Epilepsy Currents. 3 (5): 178–180. doi:10.1046/j.1535-7597.2003.03509.x. ISSN 1535-7597. PMC 557956. PMID 15902315. 8. ^ Jutila, L.; Immonen, A.; Mervaala, E.; Partanen, J.; Partanen, K.; Puranen, M.; Kälviäinen, R.; Alafuzoff, I.; Hurskainen, H. (2002-11-01). "Long term outcome of temporal lobe epilepsy surgery: analyses of 140 consecutive patients". Journal of Neurology, Neurosurgery & Psychiatry. 73 (5): 486–494. doi:10.1136/jnnp.73.5.486. ISSN 1468-330X. PMC 1738104. PMID 12397139. 9. ^ McClelland S; III; Guo H; Okuyemi KS (2011-06-13). "POpulation-based analysis of morbidity and mortality following surgery for intractable temporal lobe epilepsy in the united states". Archives of Neurology. 68 (6): 725–729. doi:10.1001/archneurol.2011.7. ISSN 0003-9942. PMID 21320984. 10. ^ Fisch, Bruce (2011-11-01). "Anterior Temporal Lobectomy – How Safe Is It?". Epilepsy Currents. 11 (6): 186–188. doi:10.5698/1535-7511-11.6.186. ISSN 1535-7597. PMC 3220424. PMID 22129637. 11. ^ Salanova, V.; Markand, O.; Worth, R. (2002-02-01). "Temporal Lobe Epilepsy Surgery: Outcome, Complications, and Late Mortality Rate in 215 Patients". Epilepsia. 43 (2): 170–174. doi:10.1046/j.1528-1157.2002.33800.x. ISSN 1528-1167. PMID 11903464. 12. ^ Fisch, Bruce (2011-11-01). "Anterior Temporal Lobectomy – How Safe Is It?". Epilepsy Currents. 11 (6): 186–188. doi:10.5698/1535-7511-11.6.186. ISSN 1535-7597. PMC 3220424. PMID 22129637. 13. ^ Maehara, Taketoshi; Shimizu, Hiroyuki (2001-01-23). "Surgical Outcome of Corpus Callosotomy in Patients with Drop Attacks". Epilepsia. 42 (1): 67–71. doi:10.1046/j.1528-1157.2001.081422.x. ISSN 1528-1167. PMID 11207787. 14. ^ Schramm, J.; Kuczaty, S.; Sassen, R.; Elger, C. E.; Lehe, M. von (2012-09-01). "Pediatric functional hemispherectomy: outcome in 92 patients". Acta Neurochirurgica. 154 (11): 2017–2028. doi:10.1007/s00701-012-1481-3. ISSN 0001-6268. PMID 22941395. 15. ^ Spencer, Susan S.; Schramm, Johannes; Wyler, Allen; O'Connor, Michael; Orbach, Darren; Krauss, Gregory; Sperling, Michael; Devinsky, Orrin; Elger, Christian (2002-02-01). "Multiple Subpial Transection for Intractable Partial Epilepsy: An International Meta-analysis". Epilepsia. 43 (2): 141–145. doi:10.1046/j.1528-1157.2002.28101.x. ISSN 1528-1167. PMID 11903459. 16. ^ Elliott, Robert E.; Morsi, Amr; Kalhorn, Stephen P.; Marcus, Joshua; Sellin, Jonathan; Kang, Matthew; Silverberg, Alyson; Rivera, Edwin; Geller, Eric (January 2011). "Vagus nerve stimulation in 436 consecutive patients with treatment-resistant epilepsy: Long-term outcomes and predictors of response". Epilepsy & Behavior. 20 (1): 57–63. doi:10.1016/j.yebeh.2010.10.017. PMID 21144802. 17. ^ Orosz, Iren; McCormick, David; Zamponi, Nelia; Varadkar, Sophia; Feucht, Martha; Parain, Dominique; Griens, Roger; Vallée, Louis; Boon, Paul (2014-10-01). "Vagus nerve stimulation for drug-resistant epilepsy: A European long-term study up to 24 months in 347 children". Epilepsia. 55 (10): 1576–1584. doi:10.1111/epi.12762. ISSN 1528-1167. PMID 25231724. 18. ^ Elliott, Robert E.; Morsi, Amr; Tanweer, Omar; Grobelny, Bartosz; Geller, Eric; Carlson, Chad; Devinsky, Orrin; Doyle, Werner K. (March 2011). "Efficacy of vagus nerve stimulation over time: Review of 65 consecutive patients with treatment-resistant epilepsy treated with VNS >10years". Epilepsy & Behavior. 20 (3): 478–483. doi:10.1016/j.yebeh.2010.12.042. PMID 21296622. 19. ^ Ryvlin, Philippe; Gilliam, Frank G.; Nguyen, Dang K.; Colicchio, Gabriella; Iudice, Alfonso; Tinuper, Paolo; Zamponi, Nelia; Aguglia, Umberto; Wagner, Louis (2014-06-01). "The long-term effect of vagus nerve stimulation on quality of life in patients with pharmacoresistant focal epilepsy: The PuLsE (Open Prospective Randomized Long-term Effectiveness) trial". Epilepsia. 55 (6): 893–900. doi:10.1111/epi.12611. ISSN 1528-1167. PMC 4283995. PMID 24754318. 20. ^ Vonck, Kristl; Raedt, Robrecht; Naulaerts, Joke; De Vogelaere, Frederick; Thiery, Evert; Van Roost, Dirk; Aldenkamp, Bert; Miatton, Marijke; Boon, Paul (2014-09-01). "Vagus nerve stimulation…25 years later! What do we know about the effects on cognition?". Neuroscience & Biobehavioral Reviews. 45: 63–71. doi:10.1016/j.neubiorev.2014.05.005. PMID 24858008. 21. ^ Fisher, R. S.; Eggleston, K. S.; Wright, C. W. (2015-01-01). "Vagus nerve stimulation magnet activation for seizures: a critical review". Acta Neurologica Scandinavica. 131 (1): 1–8. doi:10.1111/ane.12288. ISSN 1600-0404. PMID 25145652. 22. ^ Morris, George L.; Gloss, David; Buchhalter, Jeffrey; Mack, Kenneth J.; Nickels, Katherine; Harden, Cynthia (2013-01-01). "Evidence-Based Guideline Update: Vagus Nerve Stimulation for the Treatment of Epilepsy". Epilepsy Currents. 13 (6): 297–303. doi:10.5698/1535-7597-13.6.297. ISSN 1535-7597. PMC 3854750. PMID 24348133. 23. ^ Ben-Menachem, Elinor (September 2001). "Vagus Nerve Stimulation, Side Effects, and Long-Term Safety : Journal of Clinical Neurophysiology". Journal of Clinical Neurophysiology. 18 (5): 415–418. doi:10.1097/00004691-200109000-00005. PMID 11709646. 24. ^ Kahlow, Hannes; Olivecrona, Magnus (December 2013). "Complications of vagal nerve stimulation for drug-resistant epilepsy". Seizure. 22 (10): 827–833. doi:10.1016/j.seizure.2013.06.011. PMID 23867218. 25. ^ Ben-Menachem, Elinor (September 2001). "Vagus Nerve Stimulation, Side Effects, and Long-Term Safety : Journal of Clinical Neurophysiology". Journal of Clinical Neurophysiology. 18 (5): 415–418. doi:10.1097/00004691-200109000-00005. PMID 11709646. 26. ^ Eggleston, Katherine S.; Olin, Bryan D.; Fisher, Robert S. (August 2014). "Ictal tachycardia: The head–heart connection". Seizure. 23 (7): 496–505. doi:10.1016/j.seizure.2014.02.012. PMID 24698385. 27. ^ Boon, Paul; Vonck, Kristl; Rijckevorsel, Kenou van; Tahry, Riem El; Elger, Christian E.; Mullatti, Nandini; Schulze-Bonhage, Andreas; Wagner, Louis; Diehl, Beate (2015). "A prospective, multicenter study of cardiac-based seizure detection to activate vagus nerve stimulation". Seizure. 32: 52–61. doi:10.1016/j.seizure.2015.08.011. PMID 26552564. 28. ^ Fisher, Robert S.; Afra, Pegah; Macken, Micheal; Minecan, Daniela N.; Bagić, Anto; Benbadis, Selim R.; Helmers, Sandra L.; Sinha, Saurabh R.; Slater, Jeremy (2016-02-01). 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PMID 9832569. 31. ^ Li, Hai-feng; Zou, Yan; Ding, Gangqiang (2013-12-01). "Therapeutic Success of the Ketogenic Diet as a Treatment Option for Epilepsy: a Meta-analysis". Iranian Journal of Pediatrics. 23 (6): 613–620. ISSN 2008-2142. PMC 4025116. PMID 24910737. 32. ^ Kossoff, Eric H.; Zupec-Kania, Beth A.; Rho, Jong M. (2009-08-01). "Ketogenic Diets: An Update for Child Neurologists". Journal of Child Neurology. 24 (8): 979–988. doi:10.1177/0883073809337162. ISSN 0883-0738. PMID 19535814. 33. ^ GHAZAVI, Ahad; TONEKABONI, Seyed Hassan; KARIMZADEH, Parvaneh; NIKIBAKHSH, Ahmad Ali; KHAJEH, Ali; FAYYAZI, Afshin (2014-01-01). "The Ketogenic and Atkins Diets Effect on Intractable Epilepsy: A Comparison". Iranian Journal of Child Neurology. 8 (3): 12–17. ISSN 1735-4668. PMC 4135275. PMID 25143768. 34. ^ Kossoff, EH; McGrogan, JR; Bluml, RM; Pillas, DJ; Rubenstein, JE; Vining, EP (February 2006). "A modified Atkins diet is effective for the treatment of intractable pediatric epilepsy". Epilepsia. 47 (2): 421–4. doi:10.1111/j.1528-1167.2006.00438.x. PMID 16499770. 35. ^ Salanova, Vicenta; Witt, Thomas; Worth, Robert; Henry, Thomas R.; Gross, Robert E.; Nazzaro, Jules M.; Labar, Douglas; Sperling, Michael R.; Sharan, Ashwini (2015-03-10). "Long-term efficacy and safety of thalamic stimulation for drug-resistant partial epilepsy". Neurology. 84 (10): 1017–1025. doi:10.1212/WNL.0000000000001334. ISSN 0028-3878. PMC 4352097. PMID 25663221. 36. ^ Bergey, Gregory K.; Morrell, Martha J.; Mizrahi, Eli M.; Goldman, Alica; King-Stephens, David; Nair, Dileep; Srinivasan, Shraddha; Jobst, Barbara; Gross, Robert E. (2015-02-24). "Long-term treatment with responsive brain stimulation in adults with refractory partial seizures". Neurology. 84 (8): 810–817. doi:10.1212/WNL.0000000000001280. ISSN 0028-3878. PMC 4339127. PMID 25616485. 37. ^ Bauer, S.; Baier, H.; Baumgartner, C.; Bohlmann, K.; Fauser, S.; Graf, W.; Hillenbrand, B.; Hirsch, M.; Last, C. (2016). "Transcutaneous Vagus Nerve Stimulation (tVNS) for Treatment of Drug-Resistant Epilepsy: A Randomized, Double-Blind Clinical Trial (cMPsE02)". Brain Stimulation. 9 (3): 356–363. doi:10.1016/j.brs.2015.11.003. PMID 27033012. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA [kDa]: kilodalton [EPC]: Early Prostate Cancer [LAPC]: locally advanced prostate cancer [NSAAs]: nonsteroidal antiandrogens [NSAA]: nonsteroidal antiandrogen [GnRH]: gonadotropin-releasing hormone [ADT]: androgen deprivation therapy [LH]: luteinizing hormone [AR]: androgen receptor [CAB]: combined androgen blockade [LPC]: localized prostate cancer [CPA]: cyproterone acetate [U.S.]: United States [FDA]: Food and Drug Administration	Management of drug-resistant epilepsy	c1096063	7,894	wikipedia	https://en.wikipedia.org/wiki/Management_of_drug-resistant_epilepsy	2021-01-18T19:03:04	{"mesh": ["D000069279"], "wikidata": ["Q18975053"]}
Shoulder problem Diagram of the human shoulder joint SpecialtyOrthopedic surgery Shoulder problems including pain, are one of the more common reasons for physician visits for musculoskeletal symptoms. The shoulder is the most movable joint in the body. However, it is an unstable joint because of the range of motion allowed. This instability increases the likelihood of joint injury, often leading to a degenerative process in which tissues break down and no longer function well. Shoulder pain may be localized or may be referred to areas around the shoulder or down the arm. Other regions within the body (such as gallbladder, liver, or heart disease, or disease of the cervical spine of the neck) also may generate pain that the brain may interpret as arising from the shoulder.[1] ## Contents * 1 Shoulder structures and functions * 2 Diagnosis * 2.1 Medical history and physical exam * 2.2 Diagnostic tests * 3 Dislocation * 3.1 Description * 3.2 Signs and diagnosis * 3.3 Treatment * 4 Separation * 4.1 Description * 4.2 Signs and diagnosis * 4.3 Treatment * 5 Sternoclavicular separation * 5.1 Description * 5.2 Signs and diagnosis * 5.3 Treatment * 6 Tendinitis, bursitis, impingement syndrome, and rotator cuff tears * 6.1 Description * 6.2 Signs * 6.3 Diagnosis * 6.4 Treatment * 6.5 Rotator cuff tear * 7 SLAP tear (lesion) * 7.1 Symptoms * 7.2 Diagnosis * 7.3 Treatment * 7.4 Recovery * 8 Frozen shoulder (adhesive capsulitis) * 9 Fracture * 9.1 Description * 9.2 Signs and diagnosis * 9.3 Treatment * 10 Arthritis of the shoulder (glenohumeral joint) * 10.1 Description * 10.2 Signs and diagnosis * 10.3 Treatment * 11 Arthritis or osteolysis of the AC (acromioclavicular) joint * 11.1 Description * 11.2 Signs and diagnosis * 11.3 Treatment * 12 Treatment * 13 References * 14 External links ## Shoulder structures and functions[edit] The shoulder joint is composed of three bones: the clavicle (collarbone), the scapula (shoulder blade), and the humerus (upper arm bone) (see diagram). Two joints facilitate shoulder movement. The acromioclavicular (AC) joint is located between the acromion (part of the scapula that forms the highest point of the shoulder) and the clavicle. The glenohumeral joint, to which the term "shoulder joint" commonly refers, is a ball-and-socket joint that allows the arm to rotate in a circular fashion or to hinge out and up away from the body. The "ball" is the top, rounded portion of the upper arm bone or humerus; the "socket," or glenoid, is a dish-shaped part of the outer edge of the scapula into which the ball fits. Arm movement is further facilitated by the ability of the scapula itself to slide along the rib cage. The capsule is a soft tissue envelope that encircles the glenohumeral joint. It is lined by a thin, smooth synovial membrane.[citation needed] The bones of the shoulder are held in place by muscles, tendons, and ligaments. Tendons are tough cords of tissue that attach the shoulder muscles to bone and assist the muscles in moving the shoulder. Ligaments attach shoulder bones to each other, providing stability. For example, the front of the joint capsule is anchored by three glenohumeral ligaments.[citation needed] The rotator cuff is a structure composed of tendons that, with associated muscles, holds the ball at the top of the humerus in the glenoid socket and provides mobility and strength to the shoulder joint.[citation needed] Four filmy sac-like structures called bursa permit smooth gliding between bone, muscle, and tendon. They cushion and protect the rotator cuff from the bony arch of the acromion.[citation needed] ## Diagnosis[edit] Following are some of the ways doctors diagnose shoulder problems: ### Medical history and physical exam[edit] * Medical history (the patient tells the doctor about an injury). For shoulder problems the medical history includes the patient's age, dominant hand, if injury affects normal work/activities as well as details on the actual shoulder problem including acute versus chronic and the presence of shoulder catching, instability, locking, pain, paresthesias (burning sensation), stiffness, swelling, and weakness.[2] Other salutary information includes OPQRST (onset, palliation/provocation, quality, radiation, severity, timing) and a history of issues that could lead to referred pain (pain felt at the shoulder but actually coming from another part of the body) including cervical spine disorders, heart attacks, peptic ulcer disease, and pneumonia. Standardized questionnaires like the Penn Shoulder Score that assess shoulder pain and function can aid in eliciting the required history to make a diagnosis and monitor condition progression.[3] * Physical examination of the shoulder to feel for injury and discover the limits of movement, location of pain, and extent of joint instability. The steps to elicit this information are inspection (looking), palpation (feeling), testing range of motion, and performing special maneuvers.[2] Information collected on inspection are asymmetry, atrophy, ecchymosis, scars, swelling, and venous distention. Palpation can help find pain and deformities, and should specifically include the anterior glenohumeral joint, acromioclavicular joint, biceps tendon, cervical spine, coracoid process, scapula, and sternoclavicular joint. Range of motion tests external and internal rotation, abduction and adduction, passive and active weakness, and true weakness versus weakness due to pain. The Apley scratch test is the most useful: touch opposite scapular by reaching behind the head for adduction and external rotation and behind the back for abduction and internal rotation. Finally, there are more specific maneuvers that can home in on a diagnosis, however their accuracy is limited.[4] ### Diagnostic tests[edit] * Tests to confirm the diagnosis of certain conditions. Some of these tests include:[citation needed] * X-ray * Arthrogram—Diagnostic record that can be seen on an X-ray after injection of a contrast fluid into the shoulder joint to outline structures such as the rotator cuff. In disease or injury, this contrast fluid may either leak into an area where it does not belong, indicating a tear or opening, or be blocked from entering an area where there normally is an opening. * MRI (magnetic resonance imaging)--A non-invasive procedure in which a machine produces a series of cross-sectional images of the shoulder. * Other diagnostic tests, such as injection of an anesthetic into and around the shoulder joint. ## Dislocation[edit] Main article: Dislocated shoulder ### Description[edit] The shoulder joint is the most frequently dislocated major joint of the body. In a typical case of a dislocated shoulder, a strong force that pulls the shoulder outward (abduction) or extreme rotation of the joint pops the ball of the humerus out of the shoulder socket. Dislocation commonly occurs when there is a backward pull on the arm that either catches the muscles unprepared to resist or overwhelms the muscles. When a shoulder dislocates frequently, the condition is referred to as shoulder instability. A partial dislocation where the upper arm bone is partially in and partially out of the socket is called a subluxation. In the medical community, dislocation is commonly referred to as luxation.[citation needed] ### Signs and diagnosis[edit] Almost all shoulder dislocations are downwards (inferior) and of these, 95 percent are in a forward direction. Clinically this is referred to as an anterior dislocation of the glenohumeral joint. Not only does the arm appear out of position when the shoulder dislocates, but the dislocation also produces pain. Muscle spasms may increase the intensity of pain. Swelling and bruising normally develop, and in some cases there may be numbness and muscle weakness. Problems seen with a dislocated shoulder are tearing of the ligaments or tendons reinforcing the joint capsule and, less commonly, nerve damage. Doctors usually diagnose a dislocation by a physical examination, but X-rays are taken to confirm the diagnosis and to rule out a related fracture and other complications. X-rays are also taken after relocation to ensure it is in the correct place.[citation needed] ### Treatment[edit] Doctors treat a dislocation by putting the head of the humerus back into the joint socket (glenoid fossa) of the scapula—a procedure called manipulation and reduction. This is usually followed up with an X-ray to make sure the reduction did not fracture the surrounding bones. The arm is then immobilized in a sling or a device called a shoulder immobilizer for several days. Usually the doctor recommends resting the shoulder and applying ice three or four times a day. After pain and swelling have been controlled, the patient enters a rehabilitation program that includes exercises to restore the range of motion of the shoulder and strengthen the muscles to prevent future dislocations. These exercises may progress from simple motion to the use of weights.[citation needed] After treatment and recovery, a previously dislocated shoulder may remain more susceptible to reinjury, especially in young, active individuals. Ligaments are stretched and may tear due to dislocation. Torn ligaments and other problems resulting from dislocation can increase the chance of repeated dislocation. A shoulder that dislocates severely or often, injuring surrounding tissues or nerves, usually requires surgery to repair the damaged parts of the shoulder.[citation needed] Sometimes the doctor performs surgery through a tiny incision into which a small scope (arthroscope) is inserted to observe the inside of the joint. After this procedure, called arthroscopic surgery, the shoulder is generally restrained by a sling for three to six weeks, while full recovery, including physical therapy, takes several months. Arthroscopic techniques involving the shoulder are relatively new and many surgeons prefer to repair a recurrent dislocating shoulder by the time-tested open surgery under direct vision. There are usually fewer repeat dislocations and improved movement following open surgery, but it may take a little longer to regain motion.[citation needed] ## Separation[edit] Main article: Separated shoulder ### Description[edit] A shoulder separation occurs where the collarbone (clavicle) meets the shoulder blade (scapula). When ligaments that hold the AC (acromioclavicular) joint together are partially or completely torn, the outer end of the clavicle may slip out of place, preventing it from properly meeting the scapula. Most often the injury is caused by a blow to the shoulder or by falling on an outstretched hand. After injury it is hard to do a 180 degrees rotation.[citation needed] ### Signs and diagnosis[edit] Shoulder pain or tenderness and, occasionally, a bump in the middle of the top of the shoulder (over the AC joint) are signs that a separation may have occurred. Sometimes the severity of a separation can be detected by taking X-rays while the patient holds a light weight that pulls on the muscles, making a separation more pronounced.[citation needed] ### Treatment[edit] A shoulder separation is usually treated conservatively by rest and wearing a sling. Soon after injury, an ice bag may be applied to relieve pain and swelling. After a period of rest, a therapist helps the patient perform exercises that put the shoulder through its range of motion. Most shoulder separations heal within two or three months without further intervention. However, if ligaments are severely torn, surgical repair may be required to hold the clavicle in place. A doctor may wait to see if conservative treatment works before deciding whether surgery is required.[citation needed] ## Sternoclavicular separation[edit] ### Description[edit] While not directly a shoulder problem, this may affect shoulder functionality due to problems with sternoclavicular rotation. A sternoclavicular separation occurs when the sternum separates from the clavicle at the sternoclavicular joint. Sternoclavicular separations (dislocation and subluxation) are rare[5] and generally caused by accident. If the clavicle is separated posteriorly (i.e. the clavicle separates and goes behind the sternum) the situation can be dangerous and the clavicle can cause damage to interior arteries, veins or organs.[citation needed] ### Signs and diagnosis[edit] An X-ray or CT Scan may be necessary to accurately diagnose a sternoclavicular separation.[citation needed] ### Treatment[edit] Treatment consists of the standard use of plenty of rest, icing, NSAIDs and a sling. The joint may need to be reduced (i.e. put back in place), especially after posterior separations. In severe cases, surgery may be advised.[citation needed] ## Tendinitis, bursitis, impingement syndrome, and rotator cuff tears[edit] Main article: Rotator cuff ### Description[edit] These conditions are closely related and may occur alone or in combination. If the rotator cuff and bursa are irritated, inflamed, and swollen, they may become squeezed between the head of the humerus and the acromion. Repeated motion involving the arms, or the aging process involving shoulder motion over many years, may also irritate and wear down the tendons, muscles, and surrounding structures.[citation needed] Tendinitis is inflammation (redness, soreness, and swelling) of a tendon. In tendinitis of the shoulder, the rotator cuff and/or biceps tendon become inflamed, usually as a result of being pinched by surrounding structures. The injury may vary from mild inflammation to involvement of most of the rotator cuff. When the rotator cuff tendon becomes inflamed and thickened, it may get trapped under the acromion. Squeezing of the rotator cuff is called impingement syndrome.[citation needed] An inflamed bursa is called bursitis. Tendinitis and impingement syndrome are often accompanied by inflammation of the bursa sacs that protect the shoulder. Inflammation caused by a disease such as rheumatoid arthritis may cause rotator cuff tendinitis and bursitis. Sports involving overuse of the shoulder and occupations requiring frequent overhead reaching are other potential causes of irritation to the rotator cuff or bursa and may lead to inflammation and impingement.[citation needed] ### Signs[edit] Signs of these conditions include the slow onset of discomfort and pain in the upper shoulder or upper third of the arm and/or difficulty sleeping on the shoulder, similar condition can have sharp pain or discomfort when the upper shoulder is positioned at certain angles. Tendinitis and bursitis also cause pain when the arm is lifted away from the body or overhead. If tendinitis involves the biceps tendon (the tendon located in front of the shoulder that helps bend the elbow and turn the forearm), pain will occur in the front or side of the shoulder and may travel down to the elbow and forearm. Pain may also occur when the arm is forcefully pushed upward overhead.[citation needed] ### Diagnosis[edit] Diagnosis of tendinitis and bursitis begins with a medical history and physical examination. X-rays do not show tendons or the bursae but may be helpful in ruling out bony abnormalities or arthritis. The doctor may remove and test fluid from the inflamed area to rule out infection. Ultrasound scans are frequently used to confirm a suspected tendinitis or bursitis as well as rule out a tear in the rotator cuff muscles. Impingement syndrome may be confirmed when injection of a small amount of anesthetic (lidocaine hydrochloride) into the space under the acromion relieves pain.[citation needed] ### Treatment[edit] Anti-inflammatory medicines such as aspirin, naproxen or ibuprofen among others can be taken to help with pain. In some cases the physical therapist will use ultrasound and electrical stimulation, as well as manipulation. Gentle stretching and strengthening exercises are added gradually. If there is no improvement, the doctor may inject a corticosteroid medicine into the space under the acromion. However, recent level one evidence showed limited efficacy of corticosteroid injections for pain relief.[6] While steroid injections are a common treatment, they must be used with caution because they may lead to tendon rupture. If there is still no improvement after six to 12 months, the doctor may perform either arthroscopic or open surgery to repair damage and relieve pressure on the tendons and bursae.[7] In those with calcific tendinitis of the shoulder high energy extracorporeal shock-wave therapy can be useful.[8] It is not useful in other types of tendonitis.[8] ### Rotator cuff tear[edit] Main article: Rotator cuff tear The term "rotator cuff" refers to a group of four tendons that blend together as they attach to the upper end of the arm bone (humerus). Normally these tendons transmit the force of muscles originating on the shoulder Blade (scapula) to the arm providing motion and stability. The most commonly affected tendon is that of the supraspinatus muscle. Defects in the rotator cuff can come from an injury (cuff tear) or from degeneration (cuff wear). The degree to which a tendon is reparable depends on its quantity and quality. Degenerated tendons are often frail and retracted and may not be amenable to repair. Individuals that are elderly, smokers, or those having had cortisone injections often have weaker tendon tissue that fails without a significant injury. By contrast those whose tendon was torn by a substantial fall often have good quality tendon that can be repaired if surgery is performed promptly after the injury. The symptoms of rotator cuff disease include difficulty lifting the arm. Repair of a rotator cuff requires that the tendon be securely anchored to the bone at surgery and that the repair be protected for several months during healing.[citation needed] Tentative evidence suggests exercise may reduce pain in the short-term.[9] Combination of exercise and joint mobilization can result in long term benefits.[9] Other evidence demonstrates the use of corticosteroids injections to be more effective.[9] ## SLAP tear (lesion)[edit] Main article: Slap lesion A SLAP (superior labrum anterior to posterior) tear occurs when the cartilage of the shoulder (labrum) delaminates from glenoid. This causes an instability of the shoulder, typically in overhead movements.[citation needed] ### Symptoms[edit] Symptoms include a dull ache deep in the shoulder joint, trouble sleeping due to the instability and discomfort, and extreme weakness in overhead activities.[citation needed] ### Diagnosis[edit] The best diagnosis for a SLAP tear is a clinical exam followed by an MRI combined with a contrast agent.[citation needed] ### Treatment[edit] Very few cases recover to complete mobility without surgical intervention. Some patients are able to strengthen their shoulders to limit the day to day dull ache, but with limited mobility and function. Surgery reattaches the labrum to the glenoid through the use of surgical anchors.[citation needed] ### Recovery[edit] Recovery is often a lengthy process. The first four or so weeks the patient is required to wear a sling. Following this, there is a month of physical therapy to regain range of motion. At two months limited strength training occurs. At six months the patient is typically released to full active use, although many patients find that full recovery takes longer than this.[citation needed] ## Frozen shoulder (adhesive capsulitis)[edit] Main article: Adhesive capsulitis of shoulder As the name implies, movement of the shoulder is severely restricted in people with a "frozen shoulder". This condition, which doctors call adhesive capsulitis, is frequently caused by injury that leads to lack of use due to pain. Rheumatic disease progression and recent shoulder surgery can also cause frozen shoulder. Intermittent periods of use may cause inflammation. Adhesions (abnormal bands of tissue) grow between the joint surfaces, restricting motion. There is also a lack of synovial fluid, which normally lubricates the gap between the arm bone and socket to help the shoulder joint move. It is this restricted space between the capsule and ball of the humerus that distinguishes adhesive capsulitis from a less complicated painful, stiff shoulder. People with diabetes, stroke, lung disease, rheumatoid arthritis, and heart disease, or who have been in an accident, are at a higher risk for frozen shoulder. The condition rarely appears in people under the age of 40.[citation needed] ## Fracture[edit] Further information: Clavicle fracture, Scapular fracture, and Humerus fracture ### Description[edit] A bone fracture of the shoulder involves a partial or total crack through one of the three bones in the shoulder, the clavicle, the scapula, and the humerus. The break in a bone usually occurs as a result of an impact injury, such as a fall or blow to the shoulder. Fractures usually involve the clavicle or the neck (area below the ball) of the humerus. Fractures of the scapula sometimes occur through the coracoid process.[citation needed] ### Signs and diagnosis[edit] A shoulder fracture that occurs after a major injury is usually accompanied by severe pain. Within a short time, there may be redness and bruising around the area. Sometimes a fracture is obvious because the bones appear out of position. (However this occur in non-involved dislocations and separations.) Both diagnosis and severity can be confirmed by X-rays.[citation needed] ### Treatment[edit] When a fracture occurs, the doctor tries to bring the bones into a position that will promote healing and restore arm movement. If the clavicle is fractured, the patient must at first wear a strap and sling around the chest to keep the clavicle in place. After removing the strap and sling, the doctor will prescribe exercises to strengthen the shoulder and restore movement. Surgery is occasionally needed for certain clavicle fractures, especially for disunions.[citation needed] Fracture of the neck of the humerus is usually treated with a sling or shoulder immobilizer. If the bones are out of position, surgery may be necessary to reset them. Exercises are also part of restoring shoulder strength and motion.[citation needed] ## Arthritis of the shoulder (glenohumeral joint)[edit] Main article: Shoulder arthritis ### Description[edit] In arthritis of the shoulder, the cartilage of the ball and socket (glenohumeral joint) is lost so that bone rubs on bone. It may be caused by wear and tear (degenerative joint disease), injury (traumatic arthritis), surgery (secondary degenerative joint disease), inflammation (rheumatoid arthritis) or infection (septic arthritis).[citation needed] ### Signs and diagnosis[edit] X-ray of shoulder osteoarthritis. Arthritis of the shoulder causes pain and loss of motion and use of the shoulder.X-rays of the shoulder show loss of the normal space between the ball and socket. X-ray can provide radiographic staging of shoulder osteoarthritis.[citation needed] ### Treatment[edit] Early on arthritis of the shoulder can be managed with mild analgesics and gentle exercises.[10] Known gentle exercises include warm water therapy pool exercises that are provided by a trained and licensed physical therapist; approved land exercises to assure free movement of the arthritic area; cortisone injections (administered at the minimum of every six months according to orthopedic physicians) to reduce inflammation; ice and hot moist pact application are very effective. Moist heat is preferred over ice whereas ice is preferred if inflammation occurs during the daytime hours. Local analgesics along with ice or moist heat are adequate treatments for acute pain.[citation needed] In the case of rheumatoid arthritis, specific medications selected by a rheumatologist may offer substantial relief. When exercise and medication are no longer effective, shoulder replacement surgery for arthritis may be considered. In this operation, a surgeon replaces the shoulder joint with an artificial ball for the top of the humerus and a cap (glenoid) for the scapula. Passive shoulder exercises (where someone else moves the arm to rotate the shoulder joint) are started soon after surgery. Patients begin exercising on their own about three to six weeks after surgery. Eventually, stretching and strengthening exercises become a major part of the rehabilitation programme. The success of the operation often depends on the condition of rotator cuff muscles prior to surgery and the degree to which the patient follows the exercise programme.[citation needed] In young and active patients a partial shoulder replacement with a non-prosthetic glenoid arthroplasty may also be a consideration ## Arthritis or osteolysis of the AC (acromioclavicular) joint[edit] ### Description[edit] The acromioclavicular articulation consists of the acromioclavicular ligament and a small disk of cartilage located in between the acromion and the clavicle. This disk can wear down through injury, extreme joint stress (via bodybuilding) or normal wear.[citation needed] ### Signs and diagnosis[edit] Pain is perceived on shoulder motion, especially on certain movements. Often a crossover arm test is utilized in diagnosis because this compresses the AC joint, exacerbating the symptoms. X-rays of the shoulder joint may show either arthritic changes of the ac joint or osteolysis. ### Treatment[edit] Conservative treatment for this joint is similar to treatments for other types of arthritis, including restricting activity, anti-inflammatory medications (or supplements), physical therapy, and occasionally cortisone shots. If the pain is severe, surgery may be an option. The most common surgical treatment, known as resection arthroplasty, involves cutting a very small portion off the clavicle end and letting scar tissue fill in its place. Some portions of the acromioclavicular ligament may still remain attached.[11] ## Treatment[edit] A mnemonic for the basic treatment principles of any musculoskeletal problems is PRICE: Protection, Rest, Ice, Compression, and Elevation:[citation needed] * Protection: Guard the shoulder to prevent further injury. * Rest: Reduce or stop using the injured area for 48 hours. * Ice: Put an ice pack on the injured area for 20 minutes at a time, 4 to 8 times per day. Use a cold pack, ice bag, or a plastic bag filled with crushed ice that has been wrapped in a towel. * Compression: Compress the area with bandages, such as an elastic wrap, to help stabilize the shoulder. * Elevation: Keep the injured area elevated above the level of the heart. Use a pillow to help elevate the injury. If pain and stiffness persist, see a doctor. According to the American Academy of Orthopaedic Surgeons (AAOS) visits to orthopedic specialists for shoulder pain has been rising since 1998 and in 2005 over 13 million patients sought medical care for shoulder pain, of which only 34 percent were related to injury.[12] ## References[edit] 1. ^ "Referred Shoulder Pain - Topic Overview". WebMD, LLC. 14 November 2014. Retrieved 28 July 2016. 2. ^ a b Woodward, T. W.; Best, T. M. (15 May 2000). "The painful shoulder: part I. Clinical evaluation". American Family Physician. 61 (10): 3079–88. PMID 10839557. 3. ^ "Penn Shoulder Score description and calculator – orthotoolkit". Retrieved January 10, 2018. 4. ^ E. J. Hegedus; A. Goode; S. Campbell; A. Morin; M. Tamaddoni; C. T. Moorman III; C. Cook (2007). "Physical Examination Tests of the Shoulder: A Systematic Review with Meta-analysis of Individual Tests". Br J Sports Med. 42 (2): 80–92. doi:10.1136/bjsm.2007.038406. PMID 17720798. 5. ^ Sternoclavicular Joint Dislocations http://lifeinthefastlane.com/2010/02/sternoclavicular-joint-dislocation/ 6. ^ Mohamadi, Amin; Chan, Jimmy J.; Claessen, Femke M. A. P.; Ring, David; Chen, Neal C. (January 2017). "Corticosteroid Injections Give Small and Transient Pain Relief in Rotator Cuff Tendinosis: A Meta-analysis". Clinical Orthopaedics and Related Research. 475 (1): 232–243. doi:10.1007/s11999-016-5002-1. ISSN 1528-1132. PMC 5174041. PMID 27469590. 7. ^ "Injured Shoulder". Retrieved 2015-12-17. 8. ^ a b Bannuru, R. R.; Flavin, N. E.; Vaysbrot, E.; Harvey, W.; McAlindon, T. (15 April 2014). "High-energy extracorporeal shock-wave therapy for treating chronic calcific tendinitis of the shoulder: a systematic review". Annals of Internal Medicine. 160 (8): 542–9. doi:10.7326/m13-1982. PMID 24733195. 9. ^ a b c Green, Sally; Buchbinder, Rachelle; Hetrick, Sarah E (2003-04-22). "Physiotherapy interventions for shoulder pain". Cochrane Database of Systematic Reviews (2): CD004258. doi:10.1002/14651858.cd004258. ISSN 1465-1858. PMID 12804509. 10. ^ "Introduction - Home Exercises for the Rough Shoulder". Orthop.washington.edu. 2006-10-09. Retrieved 2010-01-10. 11. ^ "Osteoarthritis of the Acromioclavicular Joint". eOrthopod. Medical Multimedia Group, LLC. 2015-07-08. Retrieved 28 July 2016. 12. ^ American Academy of Orthopaedic Surgeons Physician Visits for Musculoskeletal Symptoms http://www.aaos.org/Research/stats/Common%20Orthopaedic%20Symptoms%20Seen%20by%20a%20Physician.pdf This article contains and extends text from the public domain document "Questions and Answers about Shoulder Problems", NIH Publication No. 01-4865, available from URL http://www.niams.nih.gov/hi/topics/shoulderprobs/shoulderqa.htm ## External links[edit] Classification D * ICD-10: S40-S49 * MeSH: D000070599 * v * t * e Pain By region/system Head and neck * Headache * Neck * Odynophagia (swallowing) * Toothache Respiratory system * Sore throat * Pleurodynia Musculoskeletal * Arthralgia (joint) * Bone pain * Myalgia (muscle) * Acute * Delayed-onset Neurologic * Neuralgia * Pain asymbolia * Pain disorder * Paroxysmal extreme pain disorder * Allodynia * Chronic pain * Hyperalgesia * Hypoalgesia * Hyperpathia * Phantom pain * Referred pain * Congenital insensitivity to pain * congenital insensitivity to pain with anhidrosis * congenital insensitivity to pain with partial anhidrosis Other * Pelvic pain * Proctalgia * Back * Low back pain Measurement and testing * Pain scale * Cold pressor test * Dolorimeter * Grimace scale (animals) * Hot plate test * Tail flick test * Visual analogue scale Pathophysiology * Nociception * Anterolateral system * Posteromarginal nucleus * Substance P Management * Analgesia * Anesthesia * Cordotomy * Pain eradication Related concepts * Pain threshold * Pain tolerance * Suffering * SOCRATES * Philosophy of pain * Cancer pain * Drug-seeking behavior [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA [kDa]: kilodalton [EPC]: Early Prostate Cancer [LAPC]: locally advanced prostate cancer [NSAAs]: nonsteroidal antiandrogens [NSAA]: nonsteroidal antiandrogen [GnRH]: gonadotropin-releasing hormone [ADT]: androgen deprivation therapy [LH]: luteinizing hormone [AR]: androgen receptor [CAB]: combined androgen blockade [LPC]: localized prostate cancer [CPA]: cyproterone acetate [U.S.]: United States [FDA]: Food and Drug Administration	Shoulder problem	c4277656	7,895	wikipedia	https://en.wikipedia.org/wiki/Shoulder_problem	2021-01-18T18:58:28	{"mesh": ["D000070599"], "icd-10": ["M75"], "wikidata": ["Q7502714"]}
urge to continuously gamble despite harmful negative consequences or a desire to stop Problem gambling Other namesLudomania, degenerate gambling, gambling addiction, compulsive gambling, gambling disorder SpecialtyPsychiatry, clinical psychology SymptomsSpending a lot of money and time in casino/sports betting, Video game addiction[1] Addiction and dependence glossary[2][3][4][5] * addiction – a biopsychosocial disorder characterized by persistent use of drugs (including alcohol) despite substantial harm and adverse consequences * addictive behavior – a behavior that is both rewarding and reinforcing * addictive drug – a drug that is both rewarding and reinforcing * dependence – an adaptive state associated with a withdrawal syndrome upon cessation of repeated exposure to a stimulus (e.g., drug intake) * drug sensitization or reverse tolerance – the escalating effect of a drug resulting from repeated administration at a given dose * drug withdrawal – symptoms that occur upon cessation of repeated drug use * physical dependence – dependence that involves persistent physical–somatic withdrawal symptoms (e.g., fatigue and delirium tremens) * psychological dependence – dependence that involves emotional–motivational withdrawal symptoms (e.g., dysphoria and anhedonia) * reinforcing stimuli – stimuli that increase the probability of repeating behaviors paired with them * rewarding stimuli – stimuli that the brain interprets as intrinsically positive and desirable or as something to approach * sensitization – an amplified response to a stimulus resulting from repeated exposure to it * substance use disorder – a condition in which the use of substances leads to clinically and functionally significant impairment or distress * tolerance – the diminishing effect of a drug resulting from repeated administration at a given dose * v * t * e Problem gambling is an urge to gamble continuously despite negative consequences or a desire to stop. Problem gambling is often defined by whether harm is experienced by the gambler or others, rather than by the gambler's behaviour. Severe problem gambling may be diagnosed as clinical pathological gambling if the gambler meets certain criteria. Pathological gambling is a common disorder that is associated with both social and family costs. The DSM-5 has re-classified the condition as an addictive disorder, with sufferers exhibiting many similarities to those who have substance addictions. The term gambling addiction has long been used in the recovery movement.[6] Pathological gambling was long considered by the American Psychiatric Association to be an impulse control disorder rather than an addiction.[7] However, data suggest a closer relationship between pathological gambling and substance use disorders than exists between PG and obsessive-compulsive disorder, largely because the behaviors in problem gambling and most primary substance use disorders (i.e. those not resulting from a desire to "self-medicate" for another condition such as depression) seek to activate the brain's reward mechanisms while the behaviors characterizing obsessive-compulsive disorder are prompted by overactive and misplaced signals from the brain's fear mechanisms.[8] Problem gambling is an addictive behavior with a high comorbidity with alcohol problems. A common feature shared by people who suffer from gambling addiction is impulsivity. ## Contents * 1 Signs and symptoms * 2 Factors that lead to gambling addiction * 2.1 Suicide rates * 3 Mechanisms * 3.1 Biology * 3.2 Psychological * 4 Diagnosis * 5 Treatment * 5.1 Step-based programs * 5.2 Motivational interviewing * 5.3 Peer support * 5.4 Self-help * 5.5 Anti-addiction drugs * 5.6 Self-exclusion * 5.7 Impact (Australia) * 6 Prevalence * 6.1 Europe * 6.2 North America * 6.3 Oceania (Australia) * 7 See also * 8 References * 9 External links ## Signs and symptoms[edit] Research by governments in Australia led to a universal definition for that country which appears to be the only research-based definition not to use diagnostic criteria: "Problem gambling is characterized by many difficulties in limiting money and/or time spent on gambling which leads to adverse consequences for the gambler, others, or for the community."[9] The University of Maryland Medical Center defines pathological gambling as "being unable to resist impulses to gamble, which can lead to severe personal or social consequences".[10] Most other definitions of problem gambling can usually be simplified to any gambling that causes harm to the gambler or someone else in any way; however, these definitions are usually coupled with descriptions of the type of harm or the use of diagnostic criteria.[citation needed] The DSM-V has since reclassified pathological gambling as "gambling disorder" and has listed the disorder under substance-related and addictive disorders rather than impulse-control disorders. This is due to the symptomatology of the disorder resembling an addiction not dissimilar to that of substance-abuse.[11] \|In order to be diagnosed, an individual must have at least four of the following symptoms in a 12-month period:[12] * Needs to gamble with increasing amounts of money in order to achieve the desired excitement * Is restless or irritable when attempting to cut down or stop gambling * Has made repeated unsuccessful efforts to control, cut back, or stop gambling * Is often preoccupied with gambling (e.g., having persistent thoughts of reliving past gambling experiences, handicapping or planning the next venture, thinking of ways to get money with which to gamble) * Often gambles when feeling distressed (e.g., helpless, guilty, anxious, depressed) * After losing money gambling, often returns another day to get even ("chasing" one's losses) * Lies to conceal the extent of involvement with gambling * Has jeopardized or lost a significant relationship, job, education, or career opportunity because of gambling * Relies on others to provide money to relieve desperate financial situations caused by gambling ## Factors that lead to gambling addiction[edit] Mayo Clinic specialists state that compulsive gambling may be a reason for biological, genetic, and environmental factors [1], such as: * mental health disorders (the presence of substance abuse problems, personality disorders, emotional states) * age and sex (usually found in the youth and middle-aged people, and more common to men than women) * family or friends impact * personality traits * drugs with rare side-effects (for example, antipsychotic medications or dopamine agonists). Other studies add the following triggers to the mentioned above [2]: * traumatic conditions * job-related stress * solitude * other addictions If not interfered, the problem gambling may cause very serious and lasting effects for individuals' life [3]: * relationship related issues * problems with money, bankruptcy as well * legal problems, imprisonment * health problems * suicide, including suicidal thoughts and attempts ### Suicide rates[edit] A gambler who does not receive treatment for pathological gambling when in his or her desperation phase may contemplate suicide.[13] Problem gambling is often associated with increased suicidal ideation and attempts compared to the general population.[14][15] Early onset of problem gambling may increase lifetime risk of suicide.[16] Both comorbid substance use[17][18] and comorbid mental disorders increase the risk of suicide in people with problem gambling.[19] A 2010 Australian hospital study found that 17% of suicidal patients admitted to the Alfred Hospital's emergency department were problem gamblers.[20] ## Mechanisms[edit] ### Biology[edit] According to the Illinois Institute for Addiction Recovery, evidence indicates that pathological gambling is an addiction similar to chemical addiction.[21] It has been observed that some pathological gamblers have lower levels of norepinephrine than normal gamblers.[22] According to a study conducted by Alec Roy, formerly at the National Institute on Alcohol Abuse and Alcoholism, norepinephrine is secreted under stress, arousal, or thrill, so pathological gamblers gamble to make up for their under-dosage.[23] Studies have compared pathological gamblers to substance addicts, concluding that addicted gamblers display more physical symptoms during withdrawal.[24] Deficiencies in serotonin might also contribute to compulsive behavior, including a gambling addiction. There are three important points discovered after these antidepressant studies:[25] 1. Antidepressants can reduce pathological gambling in case when there is an effect on serotonergic reuptake inhibitors and 5-HT1/5-HT2 receptor antagonists. 2. Pathological gambling, as the part of obsessive-compulsive disorder, requires the higher doses of antidepressants as it usually required for depressive disorders. 3. In cases where participants do not have or have minimal symptoms of anxiety or depression, antidepressants still have those effect. A limited study was presented at a conference in Berlin, suggesting opioid release differs in problem gamblers from the general population, but in a very different way from alcoholics or other substance abusers.[26] The findings in one review indicated the sensitization theory is responsible.[27] Dopamine dysregulation syndrome has been observed in the aforementioned theory in people with regard to such activities as gambling.[28] Some medical authors suggest that the biomedical model of problem gambling may be unhelpful because it focuses only on individuals. These authors point out that social factors may be a far more important determinant of gambling behaviour than brain chemicals and they suggest that a social model may be more useful in understanding the issue.[29] For example, an apparent increase in problem gambling in the UK may be better understood as a consequence of changes in legislation which came into force in 2007 and enabled casinos, bookmakers, and online betting sites to advertise on TV and radio for the first time and which eased restrictions on the opening of betting shops and online gambling sites.[30] Pathological gambling is similar to many other impulse control disorders such as kleptomania.[31] According to evidence from both community- and clinic-based studies, individuals who are pathological gamblers are highly likely to exhibit other psychiatric problems concurrently, including substance use disorders, mood and anxiety disorders, or personality disorders.[32] Pathological gambling shows several similarities with substance abuse. There is a partial overlap in diagnostic criteria; pathological gamblers are also likely to abuse alcohol and other drugs. The "telescoping phenomenon" reflects the rapid development from initial to problematic behavior in women compared with men. This phenomenon was initially described for alcoholism, but it has also been applied to pathological gambling. Also biological data provide a support for a relationship between pathological gambling and substance abuse.[25] A comprehensive UK Gambling Commission study from 2018 has also hinted at the link between gambling addiction and a reduction in physical activity, poor diet and overall well-being. The study links problem gambling to a myriad of issues affecting relationships, and social stability. ### Psychological[edit] Several psychological mechanisms are thought to be implicated in the development and maintenance of problem gambling.[33] First, reward processing seems to be less sensitive with problem gamblers. Second, some individuals use problem gambling as an escape from the problems in their lives (an example of negative reinforcement). Third, personality factors play a role, such as narcissism, risk-seeking, sensation-seeking, and impulsivity. Fourth, problem gamblers suffer from a number of cognitive biases, including the illusion of control,[34] unrealistic optimism, overconfidence and the gambler's fallacy (the incorrect belief that a series of random events tends to self-correct so that the absolute frequencies of each of various outcomes balance each other out). Fifth, problem gamblers represent a chronic state of a behavioral spin process, a gambling spin, as described by the criminal spin theory.[35] Spain's gambling watchdog has made an update to its 2019–2020 Responsible Gaming Program, classifying problem gambling as a mental disorder.[citation needed] ## Diagnosis[edit] The most common instrument used to screen for "probable pathological gambling" behavior is the South Oaks Gambling Screen (SOGS) developed by Lesieur and Blume (1987) at the South Oaks Hospital in New York City.[36] In recent years the use of SOGS has declined due to a number of criticisms, including that it overestimates false positives (Battersby, Tolchard, Thomas & Esterman, 2002). The DSM-IV diagnostic criteria presented as a checklist is an alternative to SOGS, it focuses on the psychological motivations underpinning problem gambling and was developed by the American Psychiatric Association. It consists of ten diagnostic criteria. One frequently used screening measure based upon the DSM-IV criteria is the National Opinion Research Center DSM Screen for Gambling Problems (NODS). The Canadian Problem Gambling Inventory (CPGI) and the Victorian Gambling Screen (VGS) are newer assessment measures. The Problem Gambling Severity Index, which focuses on the harms associated with problem gambling, is composed of nine items from the longer CPGI.[37] The VGS is also harm based and includes 15 items. The VGS has proven validity and reliability in population studies as well as Adolescents and clinic gamblers. ## Treatment[edit] Most treatment for problem gambling involves counseling, step-based programs, self-help, peer-support, medication, or a combination of these. However, no one treatment is considered to be most efficacious and, in the United States, no medications have been approved for the treatment of pathological gambling by the U.S. Food and Drug Administration (FDA). Gamblers Anonymous (GA) is a commonly used treatment for gambling problems. Modeled after Alcoholics Anonymous, GA is a twelve-step program that emphasizes a mutual-support approach. There are three in-patient treatment centers in North America.[38] One form of counseling, cognitive behavioral therapy (CBT) has been shown to reduce symptoms and gambling-related urges. This type of therapy focuses on the identification of gambling-related thought processes, mood and cognitive distortions that increase one's vulnerability to out-of-control gambling. Additionally, CBT approaches frequently utilize skill-building techniques geared toward relapse prevention, assertiveness and gambling refusal, problem solving and reinforcement of gambling-inconsistent activities and interests.[39] As to behavioral treatment, some recent research supports the use of both activity scheduling and desensitization in the treatment of gambling problems.[40] In general, behavior analytic research in this area is growing[41] There is evidence that the SSRI paroxetine is efficacious in the treatment of pathological gambling.[42] Additionally, for patients suffering from both pathological gambling and a comorbid bipolar spectrum condition, sustained-release lithium has shown efficacy in a preliminary trial.[43] The opioid antagonist drug nalmefene has also been trialled quite successfully for the treatment of compulsive gambling.[44] Group concepts based on CBT, such as the metacognitive training for problem gambling[45] have also proven effective. ### Step-based programs[edit] 12 Step-based programs such as Gambler's Anonymous are specific to gambling and generic to healing addiction, creating financial health, and improving mental wellness. Commercial alternatives that are designed for clinical intervention, using the best of health science and applied education practices, have been used as patient-centered tools for intervention since 2007. They include measured efficacy and resulting recovery metrics.[medical citation needed] ### Motivational interviewing[edit] Motivational interviewing is one of the treatments of compulsive gambling. The motivational interviewer's basic goal is promoting readiness to change through thinking and resolving mixed feelings. Avoiding aggressive confrontation, argument, labeling, blaming, and direct persuasion, the interviewer supplies empathy and advice to compulsive gamblers who define their own goal. The focus is on promoting freedom of choice and encouraging confidence in the ability to change.[46] ### Peer support[edit] A growing method of treatment is peer support. With the advancement of online gambling, many gamblers experiencing issues use various online peer-support groups to aid their recovery. This protects their anonymity while allowing them to attempt recovery on their own, often without having to disclose their issues to loved ones.[medical citation needed] ### Self-help[edit] Research into self-help for problem gamblers has shown benefits.[47] A study by Wendy Slutske of the University of Missouri concluded one-third of pathological gamblers overcome it by natural recovery.[48] ### Anti-addiction drugs[edit] Main article: Addiction § Medication See also: § Biology ### Self-exclusion[edit] Main article: Self-exclusion Gambling self-exclusion (voluntary exclusion) programs are available in the US, the UK, Canada, Australia, South Africa, France, and other countries. They seem to help some (but not all) problem gamblers to gamble less often.[49] Some experts maintain that casinos in general arrange for self-exclusion programs as a public relations measure without actually helping many of those with problem gambling issues. A campaign of this type merely "deflects attention away from problematic products and industries", according to Natasha Dow Schull, a cultural anthropologist at New York University and author of the book Addiction by Design.[50] There is also a question as to the effectiveness of such programs, which can be difficult to enforce.[51] In the province of Ontario, Canada, for example, the Self-Exclusion program operated by the government's Ontario Lottery and Gaming Corporation (OLG) is not effective, according to investigation conducted by the television series, revealed in late 2017. \|"Gambling addicts ... said that while on the ... self-exclusion list, they entered OLG properties on a regular basis" in spite of the facial recognition technology in place at the casinos, according to the Canadian Broadcasting Corporation. As well, a CBC journalist who tested the system found that he was able to enter Ontario casinos and gamble on four distinct occasions, in spite of having been registered and photographed for the self-exclusion program. An OLG spokesman provided this response when questioned by the CBC: "We provide supports to self-excluders by training our staff, by providing disincentives, by providing facial recognition, by providing our security officers to look for players. No one element is going to be foolproof because it is not designed to be foolproof".[50] ### Impact (Australia)[edit] According to the Productivity Commission's 2010 final report into gambling, the social cost of problem gambling is close to 4.7 billion dollars a year. Some of the harms resulting from problem gambling include depression, suicide, lower work productivity, job loss, relationship breakdown, crime and bankruptcy.[52] A survey conducted in 2008 found that the most common motivation for fraud was problem gambling, with each incident averaging a loss of $1.1 million.[52] According to Darren R. Christensen. Nicki A. Dowling, Alun C. Jackson and Shane A.Thomas a survey done from 1994–2008 in Tasmania gave results that gambling participation rates have risen rather than fallen over this period.[53] ## Prevalence[edit] ### Europe[edit] In Europe, the rate of problem gambling is typically 0.5 to 3 percent.[54] The "British Gambling Prevalence Survey 2007", conducted by the United Kingdom Gambling Commission, found approximately 0.6 percent of the adult population had problem gambling issues—the same percentage as in 1999.[55] The highest prevalence of problem gambling was found among those who participated in spread betting (14.7%), fixed odds betting terminals (11.2%), and betting exchanges (9.8%).[55] In Norway, a December 2007 study showed the amount of present problem gamblers was 0.7 percent.[56] With gambling addiction on the rise and across Europe in particular, the voices calling gambling a disease has been gaining grounds. The UK Gambling Commission announced a significant shift in their approach to gambling as they said that gambling is a disease, and therefore, it should be addressed adequately by the NHS. The World Health Organization has also called gambling a disease. In its 72nd World Health Assembly held on Saturday, May 25 2019, decided that ‘gaming disorder’ is an official illness. The 194-member meet added excessive gaming to a classified list of diseases as it revised its International Statistical Classification of Diseases and Related Health Problem (ICD-11). ### North America[edit] In the United States, the percentage of pathological gamblers was 0.6 percent, and the percentage of problem gamblers was 2.3 percent in 2008.[57] Studies commissioned by the National Gambling Impact Study Commission Act has shown the prevalence rate ranges from 0.1 percent to 0.6 percent.[58] Nevada has the highest percentage of pathological gambling; a 2002 report estimated 2.2 to 3.6 percent of Nevada residents over the age of 18 could be called problem gamblers. Also, 2.7 to 4.3 percent could be called probable pathological gamblers.[59] According to a 1997 meta-analysis by Harvard Medical School's division on addictions, 1.1 percent of the adult population of the United States and Canada could be called pathological gamblers.[60] A 1996 study estimated 1.2 to 1.9 percent of adults in Canada were pathological.[61] In Ontario, a 2006 report showed 2.6 percent of residents experienced "moderate gambling problems" and 0.8 percent had "severe gambling problems".[62] In Quebec, an estimated 0.8 percent of the adult population were pathological gamblers in 2002.[63] Although most who gamble do so without harm, approximately 6 million American adults are addicted to gambling.[64] Signs of a gambling problem include:[medical citation needed] * Using income or savings to gamble while letting bills go unpaid * Repeated unsuccessful attempts to stop gambling * Chasing losses * Losing sleep over thoughts of gambling * Arguing with friends or family about gambling behavior * Feeling depressed or suicidal because of gambling losses ### Oceania (Australia)[edit] Casinos and poker machines in pubs and clubs facilitate problem gambling in Australia. The building of new hotels and casinos has been described as "one of the most active construction markets in Australia"; for example, AUD$860 million was allocated to rebuild and expand the Star Complex in Sydney.[65] A 2010 study, conducted in the Northern Territory by researchers from the Australian National University (ANU) and Southern Cross University (SCU), found that the proximity of a person's residence to a gambling venue is significant in terms of prevalence. Harmful gambling in the study was prevalent among those living within 100 metres of any gambling venue, and was over 50% higher than among those living ten kilometres from a venue. The study's data stated: > "Specifically, people who lived 100 metres from their favourite venue visited an estimated average of 3.4 times per month. This compared to an average of 2.8 times per month for people living one kilometre away, and 2.2 times per month for people living ten kilometres away".[66] According to the Productivity Commission's 2016 report into gambling, 0.5% to 1% (80,000 to 160,000)[67] of the Australian adult population suffered with significant problems resulting from gambling. A further 1.4% to 2.1% (230,000 to 350,000) of the Australian adult population experienced moderate risks making them likely to be vulnerable to problem gambling.[68] Estimates show that problem gamblers account for an average of 41% of the total gaming machine spending.[68] ## See also[edit] * Gamblers Anonymous * Gambler's Lament, an ancient poem about gambling * Gambling Commission (Great Britain) * GamCare * Gaming law * National Council on Problem Gambling (Singapore) * National Council on Problem Gambling (United States) * Problem Gambling Foundation of New Zealand * Video game addiction ## References[edit] 1. ^ David Zendle; Rachel Meyer; Harriet Over (June 2019). "Adolescents and loot boxes: links with problem gambling and motivations for purchase". Royal Society Open Science. 6 (6). doi:10.1098/rsos.190049. 2. ^ Nestler EJ (December 2013). "Cellular basis of memory for addiction". Dialogues in Clinical Neuroscience. 15 (4): 431–443. PMC 3898681. PMID 24459410. "Despite the importance of numerous psychosocial factors, at its core, drug addiction involves a biological process: the ability of repeated exposure to a drug of abuse to induce changes in a vulnerable brain that drive the compulsive seeking and taking of drugs, and loss of control over drug use, that define a state of addiction. ... A large body of literature has demonstrated that such ΔFosB induction in D1-type [nucleus accumbens] neurons increases an animal's sensitivity to drug as well as natural rewards and promotes drug self-administration, presumably through a process of positive reinforcement ... Another ΔFosB target is cFos: as ΔFosB accumulates with repeated drug exposure it represses c-Fos and contributes to the molecular switch whereby ΔFosB is selectively induced in the chronic drug-treated state.41 ... Moreover, there is increasing evidence that, despite a range of genetic risks for addiction across the population, exposure to sufficiently high doses of a drug for long periods of time can transform someone who has relatively lower genetic loading into an addict." 3. ^ Malenka RC, Nestler EJ, Hyman SE (2009). "Chapter 15: Reinforcement and Addictive Disorders". In Sydor A, Brown RY (eds.). Molecular Neuropharmacology: A Foundation for Clinical Neuroscience (2nd ed.). New York: McGraw-Hill Medical. pp. 364–375. ISBN 9780071481274. 4. ^ "Glossary of Terms". Mount Sinai School of Medicine. Department of Neuroscience. Retrieved February 9, 2015. 5. ^ Volkow ND, Koob GF, McLellan AT (January 2016). "Neurobiologic Advances from the Brain Disease Model of Addiction". New England Journal of Medicine. 374 (4): 363–371. doi:10.1056/NEJMra1511480. PMC 6135257. PMID 26816013. "Substance-use disorder: A diagnostic term in the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) referring to recurrent use of alcohol or other drugs that causes clinically and functionally significant impairment, such as health problems, disability, and failure to meet major responsibilities at work, school, or home. Depending on the level of severity, this disorder is classified as mild, moderate, or severe. Addiction: A term used to indicate the most severe, chronic stage of substance-use disorder, in which there is a substantial loss of self-control, as indicated by compulsive drug taking despite the desire to stop taking the drug. In the DSM-5, the term addiction is synonymous with the classification of severe substance-use disorder." 6. ^ Eades, John (2003). Gambling Addiction: The Problem, the Pain, and the Path to Recovery. Vine Books. ISBN 978-0-8307-3425-2.[page needed] 7. ^ Petry, Nancy (September 2006). "Should the Scope of Addictive Behaviors be Broadened to Include Pathological Gambling?". Addiction. 101 (s1): 152–60. doi:10.1111/j.1360-0443.2006.01593.x. PMID 16930172. 8. ^ Potenza, M. N (October 12, 2008). "The neurobiology of pathological gambling and drug addiction: an overview and new findings". Philosophical Transactions of the Royal Society B: Biological Sciences. 363 (1507): 3181–3189. doi:10.1098/rstb.2008.0100. PMC 2607329. PMID 18640909. 9. ^ Problem Gambling and Harm: Towards a National Definition (PDF) (Report). gamblingresearch.org.au. p. i. Archived from the original (PDF) on August 19, 2006. 10. ^ Vorvick, Linda; Merrill, Michelle (February 18, 2010). "Pathological Gambling". University of Maryland Medical Center. Retrieved April 4, 2012. 11. ^ Christensen, D. R.; Jackson, Alun C.; Dowling, Nicki A.; Volberg, Rachel A.; Thomas, Shane A. (2014). "An Examination of a Proposed DSM-IV Pathological Gambling Hierarchy in a Treatment Seeking Population: Similarities with Substance Dependence and Evidence for Three Classification Systems". Journal of Gambling Studies. 31 (3): 1–20. doi:10.1007/s10899-014-9449-2. hdl:10133/3418. PMID 24627139. 12. ^ American Psychiatric Association (May 18, 2013). Diagnostic and Statistical Manual of Mental Disorders (5th ed.). Washington, DC: American Psychiatric Publishing. 13. ^ Paul, Laura. "High Stakes: Teens Gambling with Their Futures". Teenagers Today. Disney. Archived from the original on July 16, 2011.CS1 maint: unfit URL (link) 14. ^ Moreyra, Paula; Ibáñez, Angela; Saiz-Ruiz, Jerónimo; Nissenson, Kore; Blanco, Carlos (2000). "Review of the Phenomenology, Etiology and Treatment of Pathological Gambling". German Journal of Psychiatry. 3 (2): 37–52. ISSN 1433-1055. 15. ^ Volberg, Rachel (March 2002). "The Epidemiology of Pathological Gambling". Psychiatric Annals. 32 (3): 171–178. doi:10.3928/0048-5713-20020301-06. 16. ^ Kaminer, Yifrah; Burleson, Joseph; Jadamec, Agnes (September 2002). "Gambling Behavior in Adolescent Substance Abuse". Substance Abuse. 23 (3): 191–198. doi:10.1080/08897070209511489. PMID 12444352. 17. ^ Kausch, Otto (December 2003). "Patterns of Substance Abuse Among Treatment-Seeking Pathological Gamblers". Journal of Substance Abuse Treatment. 25 (4): 263–270. doi:10.1016/S0740-5472(03)00117-X. PMID 14693255. 18. ^ Ladd, George; Petry, Nancy (August 2003). "A Comparison of Pathological Gamblers with and without Substance Abuse Treatment Histories". Experimental and Clinical Psychopharmacology. 11 (3): 202–209. doi:10.1037/1064-1297.11.3.202. PMID 12940499. 19. ^ Kausch, Otto (September 2003). "Suicide Attempts Among Veterans Seeking Treatment for Pathological Gambling". Journal of Clinical Psychiatry. 64 (9): 1031–1038. doi:10.4088/JCP.v64n0908. PMID 14628978. 20. ^ Hagan, Kate (April 21, 2010). "Gambling linked to one in five suicidal patients". The Age. Melbourne. Retrieved May 7, 2012. 21. ^ "Illinois Institute for Addiction Recovery – WEEK News 25 – News, Sports, Weather – Peoria, Illinois". Archived from the original on May 5, 2015. Retrieved June 7, 2015. 22. ^ "We Put Troubled Lives Back Together". CINewsNow.com. Broadcast Interactive. Archived from the original on June 29, 2012. Retrieved May 7, 2012. 23. ^ Roy, Alec; Adinoff, Brian; Roehrich, Laurie; Lamparski, Danuta; Custer, Robert; Lorenz, Valerie; Barbaccia, Maria; Guidotti, Alessandro; Costa, Erminio; Linnoila, Markku (April 1988). "Pathological Gambling: A Psychobiological Study". Archives of General Psychiatry. 45 (4): 369–373. doi:10.1001/archpsyc.1988.01800280085011. PMID 2451490. 24. ^ Griffiths, Mark (November 2003). "Action plan: Problem Gambling". The Psychologist. 16 (11): 582–585. 25. ^ a b Grant, Jon E.; Kim, Suck Won (September 1, 2006). "Medication Management of Pathological Gambling". Minnesota Medicine. 89 (9): 44–48. ISSN 0026-556X. PMC 1857322. PMID 17024925. 26. ^ Shweta Iyer. "Gambling Addicts' Brains Don't Have The Same Opioid Systems As Others". Retrieved September 3, 2015. (source: Mick I, et al. Endogenous opioid release in pathological gamblers after an oral amphetamine challenge. At The European College of Neuropsychopharmacology Congress. 2014.) 27. ^ Probst, Catharina C.; van Eimeren, Thilo (2013). "The Functional Anatomy of Impulse Control Disorders". Current Neurology and Neuroscience Reports. 13 (10): 386. doi:10.1007/s11910-013-0386-8. ISSN 1528-4042. PMC 3779310. PMID 23963609. 28. ^ Olsen, Christopher M. (2011). "Natural Rewards, Neuroplasticity, and Non-Drug Addictions". Neuropharmacology. 61 (7): 1109–1122. doi:10.1016/j.neuropharm.2011.03.010. ISSN 0028-3908. PMC 3139704. PMID 21459101. 29. ^ Moscrop, A. (2011). "Medicalisation, morality, and addiction: Why we should be wary of problem gamblers in primary care". British Journal of General Practice. 61 (593): 836–838. doi:10.3399/bjgp11X613197. PMC 3223781. PMID 22137420. 30. ^ "Moran E. Letter: Gambling with lives". Guardian. April 21, 2009. Retrieved April 10, 2014. 31. ^ Abbott, Max (June 2001). What do We Know About Gambling and Problem Gambling in New Zealand? (PDF) (Report). The New Zealand Department of Internal Affairs. p. 28. Archived from the original (PDF) on March 21, 2012. Retrieved July 26, 2012. 32. ^ Black, Donald; Shaw, Martha (October 2008). "Psychiatric Comorbidity Associated With Pathological Gambling". Psychiatric Times. 25 (12). 33. ^ Gobet, Fernand; Schiller, Marvin, eds. (2014). Problem gambling: Cognition, prevention and treatment. London: Palgrave Macmillan. ISBN 9781137272416. 34. ^ Hudgens-Haney, Matthew E; Hamm, Jordan P; Goodie, Adam S; Krusemark, Elizabeth A; McDowell, Jennifer E; Clementz, Brett A (2013). "Neural Correlates of Perceived Control and Risky Decision Making in Pathological Gamblers". Biological Psychology. 92 (2): 365–372. doi:10.1016/j.biopsycho.2012.11.015. PMID 23201037. 35. ^ Bensimon, M.; Baruch, A.; Ronel, N. (2013). "The experience of gambling in an illegal casino: The gambling spin process". European Journal of Criminology. 10 (1): 3–21. doi:10.1177/1477370812455124. 36. ^ "The South Oaks Gambling Screen (SOGS): a new instrument for the identification of pathological gamblers". 37. ^ "Problem Gambling Severity Index PGSI". ProblemGambling.ca. Centre for Addiction and Mental Health. Archived from the original on February 22, 2010.CS1 maint: unfit URL (link) 38. ^ "Treatment Facilities \| National Council on Problem Gambling". www.ncpgambling.org. Retrieved September 15, 2016. 39. ^ "Cognitive–Behavioral Therapy for Pathological Gamblers" (PDF). 40. ^ Dowling, Nicki; Jackson, Alun C.; Thomas, Shane A. (2008). "Behavioral Interventions in the Treatment of Pathological Gambling: A Review of Activity Scheduling and Desensitization". International Journal of Behavioral Consultation and Therapy. 4 (2): 172–188. doi:10.1037/h0100841. hdl:10536/DRO/DU:30059283. 41. ^ Weatherly, Jeffrey N.; Flannery, Kathryn A. (2007). "Facing the challenge: The behavior analysis of gambling". The Behavior Analyst Today. 9 (2): 130–142. doi:10.1037/h0100652. 42. ^ Kim SW, Grant JE, Adson DE, Shin YC, Zaninelli R (2002). "A double-blind placebo-controlled study of the efficacy and safety of paroxetine in the treatment of pathological gambling". Journal of Clinical Psychiatry. 63 (6): 501–507. doi:10.4088/JCP.v63n0606. PMID 12088161. 43. ^ Hollander E, Pallanti S, Allen A, Sood E, Baldini Rossi N (2005). "Does sustained release lithium reduce impulsive gambling and affective instability versus placebo in pathological gamblers with bipolar spectrum disorders?". American Journal of Psychiatry. 162 (1): 137–145. doi:10.1176/appi.ajp.162.1.137. PMID 15625212. 44. ^ "Best Practice in Problem Gambling Services" (PDF). Gambling Research Panel. June 1, 2003. Retrieved September 22, 2015. 45. ^ Gehlenborg, Josefine; Bücker, Lara; Berthold, Mira; Miegel, Franziska; Moritz, Steffen (September 21, 2020). "Feasibility, Acceptance, and Safety of Metacognitive Training for Problem and Pathological Gamblers (Gambling-MCT): A Pilot Study". Journal of Gambling Studies. doi:10.1007/s10899-020-09975-w. ISSN 1573-3602. 46. ^ Harvard Medical School (2004). "The Harvard mental health letter". Factiva. 20 (9): 1. 47. ^ "Minimal Intervention Approach to Problem Gambling" (PDF). Archived from the original (PDF) on March 20, 2009. 48. ^ Slutske, Wendy (February 2006). "Natural Recovery and Treatment-Seeking in Pathological Gambling: Results of Two U.S. National Surveys". American Journal of Psychiatry. 163 (2): 297–302. doi:10.1176/appi.ajp.163.2.297. PMID 16449485. 49. ^ Gainsbury, Sally M. (January 22, 2013). "Review of Self-exclusion from Gambling Venues as an Intervention for Problem Gambling". Journal of Gambling Studies. 30 (2): 229–251. doi:10.1007/s10899-013-9362-0. PMC 4016676. PMID 23338831. 50. ^ a b 'Nobody stopped me' at the casino: Ontario self-exclusion program fails to keep gambling addicts out 51. ^ Casino Industry in Asia Pacific: Development, Operation, and Impact, page 153 52. ^ a b Productivity Commission Inquiry Report, Gambling, Vol 1, 2010</ 53. ^ Christensen, Darren R.; Dowling, Nicki A.; Jackson, Alun C.; Thomas, Shane A. (December 1, 2015). "Gambling Participation and Problem Gambling Severity in a Stratified Random Survey: Findings from the Second Social and Economic Impact Study of Gambling in Tasmania". Journal of Gambling Studies. 31 (4): 1317–1335. doi:10.1007/s10899-014-9495-9. ISSN 1573-3602. PMID 25167843. 54. ^ "Problem Gaming" (PDF). European Gaming and Betting Association. Retrieved April 4, 2012. 55. ^ a b Wardle, Heather; Sproston, Kerry; Orford, Jim; Erens, Bob; Griffiths, Mark; Constantine, Rebecca; Pigott, Sarah (September 2007). "British Gambling Prevalence Survey 2007" (PDF). National Centre for Social Research. p. 10. Archived from the original on November 28, 2009.CS1 maint: unfit URL (link) 56. ^ Pengespill og Pengespillproblem i Norge 2007 (Report). SINTEF. December 2007. p. 3. 57. ^ "History of Problem Gambling Prevalence Rates". American Gaming Association. Archived from the original on November 16, 2012. Retrieved April 4, 2012. 58. ^ National Opinion Research Center (April 1, 1999). "The Prevalence and Correlates of Gambling Problems Among Adults". Gambling Impact and Behavior Study. National Gambling Impact Study Commission. p. 25. 59. ^ Voberg, Rachel (March 22, 2002). Gambling and Problem Gambling in Nevada (PDF) (Report). Nevada Department of Human Resources. Archived from the original (PDF) on March 18, 2012. Retrieved April 8, 2012. 60. ^ Shaffer, Howard; Hall, Mathew; Vander Bilt, Joni (September 1999). 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PMID 16127962. 64. ^ http://www.ncpgambling.org/files/Press/Super%20Bowl%20XLVII%20Release%202013.pdf 65. ^ "Hotel refurbishment market continues boom phase". Hotel Management. HM – The business of Accommodation. January 11, 2012. Retrieved December 15, 2013. 66. ^ Martin Young, Bruce Doran & Francis Markham (December 6, 2013). "Too close to home: people who live near pokie venues at risk". The Conversation Australia. Retrieved December 15, 2013. 67. ^ "Statistics of Gambling Addiction 2016". North American Foundation for Gambling Addiction Help. 68. ^ a b Productivity Commission Inquiry Report, Gambling, Vol 1, 2010, p. 203 ## External links[edit] Classification D * ICD-10: F63.0 * ICD-9-CM: 312.31 * OMIM: 606349 * MeSH: D005715 External resources * MedlinePlus: 001520 * v * t * e Reinforcement disorders: Addiction and Dependence Addiction Drug * Alcohol * Amphetamine * Cocaine * Methamphetamine * Methylphenidate * Nicotine * Opioid Behavioral * Financial * Gambling * Shopping * Palatable food * Sex-related * Intercourse * Pornography * Internet-related * Internet addiction disorder * Internet sex addiction * Video game addiction * Digital media addictions Cellular mechanisms * Transcriptional * ΔFosB * c-Fos * Cdk5 * CREB * GluR2 * NF-κB * Epigenetic * G9a * G9a-like protein * HDAC1 * HDAC2 * HDAC3 * HDAC4 * HDAC5 * HDAC9 * HDAC10 * SIRT1 * SIRT2 * ... 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Rare genetic disorder involving calcification of the basal ganglia Primary familial brain calcification Other namesFamilial idiopathic basal ganglia calcification CT scan of characteristic calcifications of the disease SpecialtyNeurology Primary familial brain calcification[1] (PFBC), also known as familial idiopathic basal ganglia calcification (FIBGC) and Fahr's disease,[1] is a rare,[2] genetically dominant, inherited neurological disorder characterized by abnormal deposits of calcium in areas of the brain that control movement. Through the use of CT scans, calcifications are seen primarily in the basal ganglia and in other areas such as the cerebral cortex.[3] ## Contents * 1 Signs and symptoms * 2 Causes * 2.1 Mutation * 2.2 Differential diagnosis * 3 Pathology * 4 Diagnosis * 5 Management * 6 Prognosis * 7 History * 8 See also * 9 References * 10 External links ## Signs and symptoms[edit] Symptoms of this disease include deterioration of motor functions and speech, seizures, and other involuntary movement. Other symptoms are headaches, dementia, and vision impairment. Characteristics of Parkinson's Disease are also similar to PFBC.[4] The disease usually manifests itself in the third to fifth decade of life but may appear in childhood or later in life.[5] It usually presents with clumsiness, fatigability, unsteady gait, slow or slurred speech, difficulty swallowing, involuntary movements or muscle cramping. Seizures of various types are common. Neuropsychiatric symptoms, which may be the first or the most prominent manifestations, range from mild difficulty with concentration and memory to changes in personality and/or behavior, to psychosis and dementia.[6] ## Causes[edit] This condition can be inherited in an autosomal dominant or recessive fashion. Several genes has been associated with this condition[citation needed] ### Mutation[edit] A locus at 14q has been suggested, but no gene has been identified.[7] A second locus has been identified on chromosome 8[8] and a third has been reported on chromosome 2.[9] This suggests there may be some genetic heterogeneity in this disease.[10] A mutation in the gene encoding the type III sodium dependent phosphate transporter 2 (SLC20A2) located on chromosome 8 has been reported.[11] Biochemical evidence suggests that phosphate transport may be involved in this disease.[citation needed] Two other genes have been associated with this condition: PDGFB on chromosome 22 and PDGFRB on chromosome 5.[12] These genes are biochemically linked: PDGFRB encodes the platelet-derived growth factor receptor β and PDGFB encodes the ligand of PDGF-Rβ. These genes are active during angiogenesis to recruit pericytes which suggests that alterations in the blood brain barrier may be involved in the pathogenesis of this condition.[citation needed] A fourth gene associated with this condition is XPR1. This gene is the long arm of located on chromosome 1 (1q25.3).[citation needed] Another gene that has been associated with this condition is MYORG.[13][14] This gene is located on the long arm of chromosome 9 (9p13.3). This gene is associated with an autosomal recessive inheritance pattern in this condition.[citation needed] Another gene junctional adhesion molecule 2 (JAM2) has been associated with an autosomal recessive form of this condition.[15] Other genes that have been associated with this condition are Junctional adhesion molecule C (JAM3) and Occludin (OCLN).[citation needed] ### Differential diagnosis[edit] Basal ganglia calcification may occur as a consequence of several other known genetic conditions and these have to be excluded before a diagnosis can be made.[16][17][18][19] ## Pathology[edit] The most commonly affected region of the brain is the lenticular nucleus and in particular the internal globus pallidus.[20] Calcifications in the caudate, dentate nuclei, putamen and thalami are also common. Occasionally calcifications begin or predominate in regions outside the basal ganglia.[citation needed] Calcification seems to be progressive, since calcifications are generally more extensive in older individuals and an increase in calcification can sometimes be documented on follow up of affected subjects.[citation needed] As well as the usual sites the cerebellar gyri, brain stem, centrum semiovale and subcortical white matter may also be affected.Diffuse atrophic changes with dilatation of the subarachnoid space and/or ventricular system may coexist with the calcifications.Histologically concentric calcium deposits within the walls of small and medium-sized arteries are present. Less frequently the veins may also be affected. Droplet calcifications can be observed along capillaries. These deposits may eventually lead to closure of the lumina of vessels.[citation needed] The pallidal deposits stain positively for iron. Diffuse gliosis may surround the large deposits but significant loss of nerve cells is rare.On electron microscopy the mineral deposits appear as amorphous or crystalline material surrounded by a basal membrane. Calcium granules are seen within the cytoplasm of neuronal and glial cells.The calcifications seen in this condition are indistinguishable from those secondary to hypoparathyroidism or other causes.[citation needed] ## Diagnosis[edit] In addition to the usual routine haematologic and biochemical investigations, the serum calcium, phosphorus, magnesium, alkaline phosphatase, calcitonin and parathyroid hormone should also be measured. The cerebrospinal fluid (CSF) should be examined to exclude bacteria, viruses and parasites.[21] The Ellsworth Howard test (a 10-20 fold increase of urinary cyclic AMP excretion following stimulation with 200 micromoles of parathyroid hormone) may be worth doing also.[citation needed] Serology for toxoplasmosis is also indicated. Brain CT scan is the preferred method of localizing and assessing the extent of cerebral calcifications.[citation needed] Elevated levels of copper, iron, magnesium and zinc but not calcium have been reported in the CSF but the significance of this finding — if any — is not known.[22] The diagnosis requires the following criteria be met:[citation needed] 1. the presence of bilateral calcification of the basal ganglia 2. the presence of progressive neurologic dysfunction 3. the absence of an alternative metabolic, infectious, toxic or traumatic cause 4. a family history consistent with autosomal dominant inheritance The calcification is usually identified on CT scan but may be visible on plain films of the skull.[citation needed] ## Management[edit] There is currently no cure for PFBC nor a standard course of treatment. The available treatment is directed symptomatic control. If parkinsonian features develop, there is generally poor response to levodopa therapy. Case reports have suggested that haloperidol or lithium carbonate may help with psychotic symptoms.[23] One case report described an improvement with the use of a bisphosphonate.[24] ## Prognosis[edit] The prognosis for any individual with PFBC is variable and hard to predict. There is no reliable correlation between age, extent of calcium deposits in the brain, and neurological deficit. Since the appearance of calcification is age-dependent, a CT scan could be negative in a gene carrier who is younger than the age of 55.[25] Progressive neurological deterioration generally results in disability and death.[citation needed] ## History[edit] The disease was first noted by German pathologist Karl Theodor Fahr in 1930.[26][27] A less common name for the condition is Chavany-Brunhes syndrome and Fritsche's syndrome, the former named after Jacques Brunhes, Jean Alfred Émile Chavany, while the later named after R. Fritsche.[28][29] Fewer than 20 families had been reported in the literature up to 1997.[30] ## See also[edit] * Primrose syndrome ## References[edit] 1. ^ a b Eliana Marisa Ramos, PhD, Joao Oliveira, MD, PhD, Maria J Sobrido, MD, PhD, and Giovanni Coppola, MD. (1993). "Primary Familial Brain Calcification". GeneReviews, at National Center for Biotechnology Information. University of Washington, Seattle.CS1 maint: multiple names: authors list (link) Initial Posting: April 18, 2004; Last Update: August 24, 2017. 2. ^ "Genetic and Rare Diseases Information Center (GARD) – an NCATS Program \| Providing information about rare or genetic diseases". Archived from the original on 2009-05-11. Retrieved 2009-06-13. 3. ^ Benke T, Karner E, Seppi K, Delazer M, Marksteiner J, Donnemiller E (August 2004). "Subacute dementia and imaging correlates in a case of Fahr's disease". J. Neurol. Neurosurg. Psychiatry. 75 (8): 1163–5. doi:10.1136/jnnp.2003.019547. PMC 1739167. PMID 15258221. 4. ^ "NINDS Fahr's Syndrome Information Page". National Institute of Neurological Disorders and Stroke. Archived from the original on 5 February 2007. Retrieved 13 January 2007. 5. ^ Sobrido MJ, Hopfer S, Geschwind DH (2007) "Familial idiopathic basal ganglia calcification." In: Pagon RA, Bird TD, Dolan CR, Stephens K, editors. SourceGeneReviews [Internet]. Seattle (WA): University of Washington, Seattle; 1993–2004 6. ^ Chiu HF, Lam LC, Shum PP, Li KW (January 1993). "Idiopathic calcification of the basal ganglia". Postgrad Med J. 69 (807): 68–70. doi:10.1136/pgmj.69.807.68. PMC 2399589. PMID 8446558. 7. ^ Geschwind DH, Loginov M, Stern JM (September 1999). "Identification of a locus on chromosome 14q for idiopathic basal ganglia calcification (Fahr disease)". Am. J. Hum. Genet. 65 (3): 764–72. doi:10.1086/302558. PMC 1377984. PMID 10441584. 8. ^ Dai X, Gao Y, Xu Z, et al. (October 2010). "Identification of a novel genetic locus on chromosome 8p21.1-q11.23 for idiopathic basal ganglia calcification". Am. J. Med. Genet. B Neuropsychiatr. Genet. 153B (7): 1305–10. doi:10.1002/ajmg.b.31102. PMID 20552677. 9. ^ Volpato CB, De Grandi A, Buffone E, et al. (November 2009). "2q37 as a susceptibility locus for idiopathic basal ganglia calcification (IBGC) in a large South Tyrolean family". J. Mol. Neurosci. 39 (3): 346–53. doi:10.1007/s12031-009-9287-3. PMID 19757205. 10. ^ Oliveira JR, Spiteri E, Sobrido MJ, et al. (December 2004). "Genetic heterogeneity in familial idiopathic basal ganglia calcification (Fahr disease)". Neurology. 63 (11): 2165–7. doi:10.1212/01.wnl.0000145601.88274.88. PMID 15596772. 11. ^ Wang C, Li Y, Shi L, et al. (March 2012). "Mutations in SLC20A2 link familial idiopathic basal ganglia calcification with phosphate homeostasis". Nat. Genet. 44 (3): 254–6. doi:10.1038/ng.1077. PMID 22327515. 12. ^ Westenberger A1, Klein C (2014) The genetics of primary familial brain calcifications. Curr Neurol Neurosci Rep 14(10):490 doi: 10.1007/s11910-014-0490-4 13. ^ Arkadir D, Lossos A, Rahat D, Abu Snineh M, Schueler-Furman O, Nitschke S, Minassian BA, Sadaka Y, Lerer I, Tabach Y, Meiner V (2018) MYORG is associated with recessive primary familial brain calcification. Ann Clin Transl Neurol 6(1):106-113 14. ^ Yao XP, Cheng X, Wang C, Zhao M, Guo XX, Su HZ, Lai LL, Zou XH, Chen XJ, Zhao Y, Dong EL, Lu YQ, Wu S, Li X, Fan G, Yu H, Xu J, Wang N, Xiong ZQ, Chen WJ (2018) Biallelic Mutations in MYORG cause autosomal recessive primary familial brain calcification. Neuron 98(6):1116-1123 15. ^ Cen Z, Chen Y, Chen S, Wang H, Yang D, Zhang H, Wu H, Wang L, Tang S, Ye J, Shen J, Wang H, Fu F, Chen X, Xie F, Liu P, Xu X, Cao J, Cai P, Pan Q1,12, Li J, Yang W, Shan PF, Li Y, Liu JY, Zhang B, Luo W (2019) Biallelic loss-of-function mutations in JAM2 cause primary familial brain calcification. Brain 16. ^ Niwa A, Naito Y, Kuzuhara S (2008). "Severe cerebral calcification in a case of LEOPARD syndrome". Intern. Med. 47 (21): 1925–9. doi:10.2169/internalmedicine.47.1365. PMID 18981639. 17. ^ Preusser M, Kitzwoegerer M, Budka H, Brugger S (October 2007). "Bilateral striopallidodentate calcification (Fahr's syndrome) and multiple system atrophy in a patient with longstanding hypoparathyroidism". Neuropathology. 27 (5): 453–6. doi:10.1111/j.1440-1789.2007.00790.x. PMID 18018479. 18. ^ Saito Y, Shibuya M, Hayashi M, et al. (July 2005). "Cerebellopontine calcification: a new entity of idiopathic intracranial calcification?". Acta Neuropathol. 110 (1): 77–83. doi:10.1007/s00401-005-1011-y. PMID 15959794. Archived from the original on 2013-02-12. 19. ^ Tojyo K, Hattori T, Sekijima Y, Yoshida K, Ikeda S (June 2001). "[A case of idiopathic brain calcification associated with dyschromatosis symmetrica hereditaria, aplasia of dental root, and aortic valve sclerosis]". Rinsho Shinkeigaku (in Japanese). 41 (6): 299–305. PMID 11771159. 20. ^ Bonazza S, La Morgia C, Martinelli P, Capellari S (August 2011). "Strio-pallido-dentate calcinosis: a diagnostic approach in adult patients". Neurol. Sci. 32 (4): 537–45. doi:10.1007/s10072-011-0514-7. PMID 21479613. 21. ^ Morita M, Tsuge I, Matsuoka H, et al. (May 1998). "Calcification in the basal ganglia with chronic active Epstein-Barr virus infection". Neurology. 50 (5): 1485–8. doi:10.1212/wnl.50.5.1485. PMID 9596016. 22. ^ Hozumi I, Kohmura A, Kimura A, et al. (2010). "High Levels of Copper, Zinc, Iron and Magnesium, but not Calcium, in the Cerebrospinal Fluid of Patients with Fahr's Disease". Case Rep Neurol. 2 (2): 46–51. doi:10.1159/000313920. PMC 2905580. PMID 20671856. 23. ^ Munir KM (February 1986). "The treatment of psychotic symptoms in Fahr's disease with lithium carbonate". J Clin Psychopharmacol. 6 (1): 36–8. doi:10.1097/00004714-198602000-00008. PMID 3081601. 24. ^ Loeb JA (March 1998). "Functional improvement in a patient with cerebral calcinosis using a bisphosphonate". Mov. Disord. 13 (2): 345–9. doi:10.1002/mds.870130225. PMID 9539353. 25. ^ "NINDS Fahr's Syndrome Information Page". National Institute of Neurological Disorders and Stroke. Archived from the original on 5 February 2007. Retrieved 13 February 2007. 26. ^ Fahr, T. (1930–1931). "Idiopathische Verkalkung der Hirngefässe". Zentralblatt für Allgemeine Pathologie und Pathologische Anatomie. 50: 129–133. 27. ^ Fahr's disease at Who Named It? 28. ^ Chavany-Brunhes syndrome at Who Named It? 29. ^ http://rarediseases.info.nih.gov/GARD/QnA.aspx?PageID=4&CaseID=22373&DiseaseID=8272 30. ^ Kobari M, Nogawa S, Sugimoto Y, Fukuuchi Y (March 1997). "Familial idiopathic brain calcification with autosomal dominant inheritance". Neurology. 48 (3): 645–9. doi:10.1212/wnl.48.3.645. PMID 9065541. ## External links[edit] Classification D * ICD-10: G23.8 * OMIM: 213600 * MeSH: C536275 * DiseasesDB: 32200 External resources * GeneReviews: Familial Idiopathic Basal Ganglia Calcification * Fahr Syndrome Images (MedPix) * National Organization for Rare Disorders (NORD) * National Institute on Aging (NIA) * National Institute of Mental Health (NIMH) [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA [kDa]: kilodalton [EPC]: Early Prostate Cancer [LAPC]: locally advanced prostate cancer [NSAAs]: nonsteroidal antiandrogens [NSAA]: nonsteroidal antiandrogen [GnRH]: gonadotropin-releasing hormone [ADT]: androgen deprivation therapy [LH]: luteinizing hormone [AR]: androgen receptor [CAB]: combined androgen blockade [LPC]: localized prostate cancer [CPA]: cyproterone acetate [U.S.]: United States [FDA]: Food and Drug Administration	Primary familial brain calcification	c0393590	7,897	wikipedia	https://en.wikipedia.org/wiki/Primary_familial_brain_calcification	2021-01-18T18:57:11	{"gard": ["6406"], "mesh": ["C536275"], "umls": ["C0393590"], "orphanet": ["1980"], "wikidata": ["Q1947307"]}
IRF6-related disorders include two different disorders caused by abnormalities in the interferon regulatory factor 6 (IRF6) gene. Van der Woude syndrome (VWS) is at the mild end of the spectrum and popliteal pterygium syndrome (PPS) is at the severe end of the spectrum. The symptoms of IRF6-related disorders vary greatly from case to case. People with VWS can have lip pits alone, cleft lip or cleft palate alone, or a combination of these anomalies. People with PPS have a thick web of skin (pterygium) on the backs of both legs (popliteal), extending from the hip (ischial tuberosity) to the heel (calcaneus) or in other locations, as well as other problems. A cone-shaped fold of skin on the nail of the big toe is a very distinctive finding in PPS. Supportive/symptomatic treatment may include surgery, pediatric dentistry, orthodontia, speech therapy, feeding and hearing evaluation, physical therapy, and orthopedic care. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA [kDa]: kilodalton [EPC]: Early Prostate Cancer [LAPC]: locally advanced prostate cancer [NSAAs]: nonsteroidal antiandrogens [NSAA]: nonsteroidal antiandrogen [GnRH]: gonadotropin-releasing hormone [ADT]: androgen deprivation therapy [LH]: luteinizing hormone [AR]: androgen receptor [CAB]: combined androgen blockade [LPC]: localized prostate cancer [CPA]: cyproterone acetate [U.S.]: United States [FDA]: Food and Drug Administration	IRF6-Related disorders	None	7,898	gard	https://rarediseases.info.nih.gov/diseases/12940/irf6-related-disorders	2021-01-18T17:59:43	{"synonyms": []}
In Saskatchewan, Shokeir (1978) identified 3 sibships in 2 possibly related kindreds of German-Austrian extraction with a syndrome of absent thumbs, short stature with skeletal abnormalities such as unfused olecranon, and severe combined immunodeficiency. Severe chickenpox and chronic candidiasis were features. Congenital heart malformation (septal defect) also occurred in 1 kindred. Delayed puberty and anosmia were features in both males and females. Inheritance of this distinct syndrome is almost certainly autosomal recessive. INHERITANCE \- Autosomal recessive GROWTH Height \- Short stature HEAD & NECK Nose \- Anosmia CARDIOVASCULAR Heart \- Congenital septal defects SKELETAL Limbs \- Unfused olecranon Hands \- Absent thumbs SKIN, NAILS, & HAIR Skin \- Chronic candidiasis ENDOCRINE FEATURES \- Delayed puberty IMMUNOLOGY \- Severe combined immunodeficiency ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA [kDa]: kilodalton [EPC]: Early Prostate Cancer [LAPC]: locally advanced prostate cancer [NSAAs]: nonsteroidal antiandrogens [NSAA]: nonsteroidal antiandrogen [GnRH]: gonadotropin-releasing hormone [ADT]: androgen deprivation therapy [LH]: luteinizing hormone [AR]: androgen receptor [CAB]: combined androgen blockade [LPC]: localized prostate cancer [CPA]: cyproterone acetate [U.S.]: United States [FDA]: Food and Drug Administration	THUMB AGENESIS, SHORT STATURE, AND IMMUNODEFICIENCY	c1848818	7,899	omim	https://www.omim.org/entry/274190	2019-09-22T16:21:43	{"mesh": ["C564770"], "omim": ["274190"], "orphanet": ["2951"]}

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