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A number sign (#) is used with this entry because of evidence that 46,XY sex reversal-10 (SRXY10) is caused by heterozygous deletion of a 32.5-kb regulatory region (XYSR) -640 to -607 kb upstream of the SOX9 gene (608160) on chromosome 17q24. Description 46,XY females with gonadal dysgenesis have streak gonads but look like normal females at birth. They do not develop secondary sexual characteristics at puberty and do not menstruate. They are chromatin-negative and are usually of normal stature, without the somatic stigmata of Turner syndrome (see 163950) (summary by Mann et al., 1983). For a discussion of genetic heterogeneity of 46,XY sex reversal, see SRXY1 (400044). Clinical Features German et al. (1978) reported a family in which 2 sisters, a maternal aunt, and a female cousin were 46,XY phenotypic females who in adulthood were found to have gonadal streaks or gonadoblastoma. At birth and throughout childhood, each had appeared to be a normal girl, in whom axillary and pubic hair developed at puberty; breast development and menarche failed to occur but were inducible by hormone administration. Examination revealed unambiguously female genitalia, and each had a normally developed uterus and fallopian tubes of prepubertal size. Endocrine analysis in the 2 sisters showed greatly elevated levels of follicle-stimulating hormone (FSH; see 136530) and luteinizing hormone (LH; see 152780), with a plasma testosterone level of 0.028 ug/100 mL in 1 sister. Pelvic surgery was performed in all 4 patients between the ages of 19 years and 29 years. The 2 sisters had bilateral streak ovaries that were grossly and histologically similar to those seen in 45,X gonadal dysgenesis (Turner syndrome); their affected cousin had gonads resembling the streaks grossly, but histopathology revealed bilateral gonadoblastoma. Surgical records for the affected maternal aunt were unavailable, but a 'purplish, probably calcified abdominal tumor' was known to have been removed. Mann et al. (1983) described a family in which 3 sisters, a maternal aunt, and a cousin's child were 46,XY phenotypic females. All had gonadal germ cell tumors. The proband was evaluated at 13 years of age for short stature, at which time she was found to have a 46,XY chromosome constitution. She was of dull intelligence (reading age 10 years), with height and weight just below the 3rd centile, and had no breast development and only scant pubic hair. At 14.5 years of age, she developed a large pelvic mass; at laparotomy the unresectable tumor was biopsied, and histology showed a malignant yolk sac tumor with an epithelial appearance, some papillary areas, Schiller-Duval bodies, and much necrosis. After chemotherapy, subtotal excision was performed, histologic examination of which showed necrotic tumor with some viable areas consisting of yolk sac tumor and small areas of well-differentiated teratoma containing respiratory epithelium, plain muscle, and glial tissue. The patient underwent postoperative chemotherapy and radiotherapy, but she eventually refused further treatment and died of tumor recurrence within 2 years. Examination of all available family members revealed that both of the proband's younger sisters and a cousin's child also had 46,XY gonadal dysgenesis; their gonads were removed prophylactically and histologic examination showed gonadoblastoma, dysgerminoma, and/or dysgenesis in all tissue. A maternal aunt who had been treated for bilateral 'ovarian' dysgerminomas was also found to be 46,XY. Family history revealed 4 phenotypic females from previous generations who were said to have been infertile, but all were deceased and could not be evaluated. Benko et al. (2011) reported two 46,XY cousins (family DSD4) with gonadal dysgenesis. In the first patient, a severe disorder of sex development (DSD) was apparent at birth, with asymmetric external genitalia consisting of a urogenital sinus with a 2-cm phallus, right hemiscrotum with palpable gonad, and left labioscrotal fold with nonpalpable gonad. At day 45, hormonal data resembled that of classic minipuberty observed in normal 46,XY males, with normal LH, FSH, and serum testosterone concentrations. Anti-mullerian hormone (AMH; 600957) was low, indicating testicular dysgenesis. As the decision was made to rear the neonate as a girl, feminizing genitoplasty and bilateral gonadectomy were performed at age 4 months. Microscopic examination revealed that the right gonad was a small testis with normal architecture and spermatogonia in seminiferous tubules, whereas the left gonad was a streak gonad associated with a fallopian tube and hemi-uterus. The proband's cousin, who had a normal external female phenotype, presented with dispersed pubic hair at age 8 years and was found to have elevated urinary FSH, which prompted karyotyping that showed the patient to be 46,XY. Ultrasonography revealed the presence of a uterus with 'ovaries.' Hormonal evaluation at age 9 years showed low AMH and high FSH, suggestive of gonadal dysgenesis. Bilateral gonadectomy was performed; the left gonad was compatible with an ovary, whereas the right gonad was a streak gonad with gonadoblastoma. The well-limited gonadoblastoma contained calcifications as well as 2 types of cells: germ cells expressing placental-like alkaline phosphatase and CD117 (KIT; 164920), and sex cord cells expressing inhibin (INHA; 147380) and WT1 (607102). Examination of the index cases and their parents excluded any bone or craniofacial abnormalities reminiscent of campomelic dysplasia (114290). Molecular Genetics In a cohort of patients with 46,XY DSD, including 29 with complete female phenotype and 118 with undermasculinized external genitalia, Benko et al. (2011) used MLPA and quantitative PCR to screen for copy number variation (CNV) in the SOX9 (608160) proximal gene desert. They identified two 46,XY cousins, 1 with a normal external female phenotype and the other with severe ambiguous and asymmetric external genitalia; both were heterozygous for an approximately 240-kb deletion (608160.0018) between 405 and 645 kb upstream of the SOX9 transcription start site. The affected cousins were negative for mutation in 6 known 46,XY DSD-associated genes. Their unaffected mothers were sisters and carried the same deletion, which was not found in the Database of Genomic Variants. Benko et al. (2011) stated that the region of overlap between the deletion in this 46,XY DSD family and duplications in 3 other families with 46,XX DSD reveals a minimal noncoding 78-kb sex-determining region (RevSex) located in a gene desert approximately 517 to 595 kb upstream of the SOX9 promoter. By performing CNV analysis in 100 patients with SRY-positive 46,XY nonsyndromic partial or complete gonadal dysgenesis, Kim et al. (2015) identified 4 unrelated individuals with heterozygous deletions upstream of the SOX9 gene, including a patient from the family originally reported by German et al. (1978) (608160.0019) and a patient from the family studied by Mann et al. (1983) (608160.0020). Both of the latter deletions segregated with disease in the respective families. Together, the 4 deletions defined a 32.5-kb interval, which Kim et al. (2015) designated XYSR for 'XY sex-reversal region,' noting that it overlapped with previously described SOX9 upstream deletions but not with the RevSex region. The authors also defined a distinct 68-kb XX sex-reversal region (XXSR) upstream of the SOX9 gene, based on 46,XX patients with duplications (see 278850), which was largely identical to the RevSex region. Kim et al. (2015) stated that the XYSR and XXSR intervals do not overlap, being separated by 23 kb, and proposed that each harbors a differently-acting gonad-specific regulatory element. Animal Model Using in vivo high-throughput chromatin accessibility techniques, transgenic assays, and genome editing, Gonen et al. (2018) detected several novel gonadal regulatory elements in the 2-megabase gene desert upstream of Sox9. Although others are redundant, enhancer-13 (Enh13), a 557-basepair element located 565 kilobases 5-prime from the transcriptional start site, is essential to initiate mouse testis development; its deletion results in XY females with Sox9 transcript levels equivalent to those in XX gonads. Gonen et al. (2018) concluded that their data are consistent with the time-sensitive activity of SRY and indicate a strict order of enhancer usage. Enh13 is conserved and embedded within the 32.5-kilobase SR XY region, whose deletion in humans is associated with XY sex reversal, suggesting that it is also critical in humans. INHERITANCE \- Autosomal dominant CHEST Breasts \- Absent thelarche GENITOURINARY External Genitalia (Male) \- Ambiguous genitalia (in some patients) \- Urogenital sinus \- Micropenis External Genitalia (Female) \- Unambiguously female-appearing genitalia (in some patients) Internal Genitalia (Male) \- Small testis (rare) \- Dysgenetic male gonads (rare) Internal Genitalia (Female) \- Absent menarche \- Vagina present (in some patients) \- Uterus present \- Absent or rudimentary uterus (rare) \- Fallopian tube(s) present \- Streak ovaries \- Gonadoblastoma \- Dysgerminoma \- Yolk sac tumor, malignant (rare) SKELETAL \- No skeletal abnormalities detected ENDOCRINE FEATURES \- Elevated follicle-stimulating hormone (FSH) levels \- Elevated luteinizing hormone (LH) levels \- Low anti-Mullerian hormone (AMH) levels \- Testosterone level in normal male range NEOPLASIA \- Gonadal germ cell tumors (in some patients) MISCELLANEOUS \- 46,XX carriers are unaffected MOLECULAR BASIS \- Caused by deletion of a 32.5-kb regulatory region (XYSR) -640 to -607 kb upstream of the SRY-box-9 gene (SOX9, 608160.0018 ) ▲ 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 inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors	46,XY SEX REVERSAL 10	c2936694	1,800	omim	https://www.omim.org/entry/616425	2019-09-22T15:48:55	{"mesh": ["D006061"], "omim": ["616425"], "orphanet": ["242", "251510"], "synonyms": ["Alternative titles", "CHROMOSOME 17q24 DELETION SYNDROME"]}
Myopericytoma Other namesGlomangiopericytoma Micrograph of a myopericytoma. H&E stain. SpecialtyOncology Myopericytoma is a rare perivascular soft tissue tumour. It is usually benign and typically in the distal extremities.[1] It is thought to overlap with myofibroma.[2] ## See also[edit] * Glomus tumour ## References[edit] 1. ^ Zidane A, Arsalane A, Harkat A, et al. (November 2010). "[Myopericytoma: an uncommon chest wall tumor]". Rev Mal Respir (in French). 27 (9): 1089–91. doi:10.1016/j.rmr.2010.09.017. PMID 21111282. 2. ^ Dray MS, McCarthy SW, Palmer AA, et al. (January 2006). "Myopericytoma: a unifying term for a spectrum of tumours that show overlapping features with myofibroma. A review of 14 cases". J. Clin. Pathol. 59 (1): 67–73. doi:10.1136/jcp.2005.028704. PMC 1860256. PMID 16394283. ## External links[edit] Classification D External resources * Orphanet: 289685 [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 inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors	Myopericytoma	c1302808	1,801	wikipedia	https://en.wikipedia.org/wiki/Myopericytoma	2021-01-18T18:52:38	{"mesh": ["D000077777"], "umls": ["C1302808"], "orphanet": ["289685"], "wikidata": ["Q1956699"]}
Barr et al. (1995) described 2 sisters with intrauterine growth retardation, shortness of all limbs, coronal craniosynostosis, micrognathia, absent or hypoplastic gallbladder, and hypoplastic ileum, lungs, uterus, and fallopian tubes. The older sister also manifested talon-like nails, bilateral absence of the middle phalanx of the index finger, and hydronephrosis; the younger sister had cleft palate. The authors suggested that craniomicromelic syndrome is a distinct autosomal recessive disorder. Baralle and Firth (1999) reported a third case of craniomicromelic syndrome in a fetus at 29 weeks gestation. This infant had intrauterine growth retardation, ossification defects of the skull with posterior encephalocele, large fontanels and wide cranial sutures, absent phalanges, and digit syndactyly. The authors concluded that this case provides further support for craniomicromelic syndrome as a distinct entity. [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 inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors	CRANIOMICROMELIC SYNDROME	c1865184	1,802	omim	https://www.omim.org/entry/602558	2019-09-22T16:13:34	{"mesh": ["C566522"], "omim": ["602558"], "orphanet": ["1524"]}
Wilms tumor is a form of kidney cancer that primarily develops in children. Nearly all cases of Wilms tumor are diagnosed before the age of 10, with two-thirds being found before age 5. Wilms tumor is often first noticed because of abdominal swelling or a mass in the kidney that can be felt upon physical examination. Some affected children have abdominal pain, fever, a low number of red blood cells (anemia), blood in the urine (hematuria), or high blood pressure (hypertension). Additional signs of Wilms tumor can include loss of appetite, weight loss, nausea, vomiting, and tiredness (lethargy). Wilms tumor can develop in one or both kidneys. About 5 to 10 percent of affected individuals develop multiple tumors in one or both kidneys. Wilms tumor may spread from the kidneys to other parts of the body (metastasize). In rare cases, Wilms tumor does not involve the kidneys and occurs instead in the genital tract, bladder, abdomen, chest, or lower back. It is unclear how Wilms tumor develops in these tissues. With proper treatment, children with Wilms tumor have a 90 percent survival rate. However, the risk that the cancer will come back (recur) is between 15 and 50 percent, depending on traits of the original tumor. Tumors usually recur in the first 2 years following treatment and develop in the kidneys or other tissues, such as the lungs. Individuals who have had Wilms tumor may experience related health problems or late effects of their treatment in adulthood, such as decreased kidney function, heart disease, and development of additional cancers. ## Frequency Wilms tumor is the most common kidney cancer in children. In Europe and North America, Wilms tumor affects 1 in 10,000 children. In the United States, 500 children develop Wilms tumor each year. The incidence of Wilms tumor seems to vary among populations, with African Americans having a higher-than-average risk of developing this cancer and Asians having a lower-than-average risk. Wilms tumor rarely develops in adults; only about 300 such cases have been described. ## Causes Changes in any of several genes are involved in the formation of Wilms tumor. Wilms tumor is often associated with mutations in the WT1 gene, CTNNB1 gene, or AMER1 gene. These genes provide instructions for making proteins that regulate gene activity and promote the growth and division (proliferation) of cells. WT1, CTNNB1, and AMER1 gene mutations all lead to the unchecked proliferation of cells, allowing tumor development. Changes on the short (p) arm of chromosome 11 are also associated with developing Wilms tumor. Two genes in this area, IGF2 and H19, are either turned on or off depending on whether the copy of the gene was inherited from the mother or the father. This parent-specific difference in gene activation is a phenomenon called genomic imprinting. In some cases of Wilms tumor, abnormalities in the process of genomic imprinting on chromosome 11 lead to a loss of H19 gene activity and increased activity of the IGF2 gene in kidney cells. The resulting loss of H19 gene activity, which normally restrains cell growth, and increase in IGF2 gene activity, which promotes cell growth, together lead to uncontrolled cell growth and tumor development in people with Wilms tumor. In most cases of Wilms tumors involving one kidney and nearly all cases involving both kidneys, the tumors are thought to arise from immature kidney tissue that never developed properly. These immature tissues are known as nephrogenic rests. It is likely that genetic changes are involved in the presence of nephrogenic rests and that additional genetic changes trigger nephrogenic rests to develop into a tumor. Genetic conditions that share a genetic cause with Wilms tumor can also have this cancer as a feature. These conditions include WAGR syndrome, Denys-Drash syndrome, and Frasier syndrome, which are caused by mutations in the WT1 gene. Wilms tumor has also been seen in individuals with Beckwith-Wiedemann syndrome, which can be caused by changes in the genomic imprinting of the IGF2 and H19 genes. Wilms tumor can be a feature of other genetic conditions caused by mutations in other genes. Many children with Wilms tumor do not have identified mutations in any of the known genes. In these cases, the cause of the condition is unknown. It is likely that other, unknown genes are also associated with the development of Wilms tumor. ### Learn more about the genes associated with Wilms tumor * AMER1 * CTNNB1 * H19 * IGF2 * TP53 * WT1 Additional Information from NCBI Gene: * DGCR8 * DROSHA * POU6F2 * REST ## Inheritance Pattern Most cases of Wilms tumor are not caused by inherited genetic factors and do not cluster in families. Approximately 90 percent of these cancers are due to somatic mutations, which means that the mutations are acquired during a person's lifetime and are present only in the tumor cells. Mutations that are present in cells throughout the body (called germline mutations) are responsible for the remaining 10 percent of Wilms tumor cases and cause either Wilms tumor without any other signs or symptoms or syndromes in which Wilms tumor is one of multiple features. These cases follow autosomal dominant inheritance, which means one copy of the altered gene in each cell can cause a Wilms tumor-related syndrome or increase a person's chance of developing the cancer alone. Most of these cases result from new (de novo) mutations in the gene that occur during the formation of reproductive cells (eggs or sperm) or in early embryonic development. The AMER1 gene is located on the X chromosome (one of the two sex chromosomes), so when Wilms tumor is caused by mutations in this gene, the condition follows an X-linked dominant pattern. In females (who have two X chromosomes), a mutation in one of the two copies of the gene in each cell is sufficient to increase a person's chance of developing cancer. In males (who have only one X chromosome), a mutation in the only copy of the gene in each cell increases their cancer risk. In many cases, the genetic basis for Wilms tumor and the mechanism of inheritance are unclear. [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 inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors	Wilms tumor	c0027708	1,803	medlineplus	https://medlineplus.gov/genetics/condition/wilms-tumor/	2021-01-27T08:25:51	{"gard": ["8559", "7892"], "mesh": ["D009396"], "omim": ["194070", "194071", "194090", "601363", "601583", "616806"], "synonyms": []}
Nance-Horan syndrome is a rare genetic disorder that may be evident at birth. It is characterized by teeth abnormalities and cataracts, resulting in poor vision. Additional eye abnormalities are also often present, including a very small cornea and nystagmus. In some cases, the condition may also be associated with physical abnormalities and/or intellectual disability. The range and severity of symptoms may vary greatly from one person to another, even among affected members of the same family. Nance-Horan syndrome is caused by a mutation in the NHS gene and is inherited as an X-linked dominant trait, which means that both males and females can be affected, but males often have more severe symptoms.The treatment is directed toward the specific symptoms that are apparent in the individual. [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 inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors	Nance-Horan syndrome	c0796085	1,804	gard	https://rarediseases.info.nih.gov/diseases/7161/nance-horan-syndrome	2021-01-18T17:58:48	{"mesh": ["C538336"], "omim": ["302350"], "umls": ["C0796085"], "orphanet": ["627"], "synonyms": ["Cataract dental syndrome", "Cataract X-linked with Hutchinsonian teeth", "Mesiodens cataract syndrome"]}
A rare primary bone dysplasia characterized by short stature, joint laxity, vertebral anomalies, severe progressive spinal malalignment leading to spinal cord compression, progressive kyphoscoliosis, thoracic asymmetry, and elbow and foot deformities. Additional features include mild skin hyperelasticity, spatulate terminal phalanges, cleft palate and lip, structural cardiac malformations, and mild facial dysmorphism (oval face, prominent eyes with blue sclerae, and a long upper lip). [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 inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors	Spondyloepimetaphyseal dysplasia with joint laxity	c0432243	1,805	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=93359	2021-01-23T17:14:44	{"gard": ["4982"], "mesh": ["C562968"], "omim": ["271640", "618395"], "umls": ["C0432243"], "icd-10": ["Q77.7"], "synonyms": ["SEMD-JL", "SEMDJL1", "Spondyloepimetaphyseal dysplasia with joint laxity type 1", "Spondyloepimetaphyseal dysplasia with joint laxity, Beighton type"]}
For a phenotypic description and a discussion of genetic heterogeneity of alopecia areata, see 104000. Mapping In an effort to define a genetic basis of alopecia areata, Martinez-Mir et al. (2007) performed a genomewide search for linkage to 20 families with 102 affected and 118 unaffected individuals from the United States and Israel. The analysis revealed evidence of at least 4 susceptibility loci on chromosome 6, 10, 16, and 18 using several different statistical approaches. Fine-mapping analysis with additional families yielded a maximum multipoint lod score of 3.93 on chromosome 18 (AA1; 104000), a 2-point affected sib pair (ASP) lod score of 3.11 on chromosome 16 at marker D16S415 (AA2), several ASP lod scores greater than 2.00 on chromosome 6q, and a haplotype-based relative risk lod of 2.00 on chromosome 6p, in the major histocompatibility complex locus. INHERITANCE \- Autosomal dominant \- Autosomal recessive SKIN, NAILS, & HAIR Hair \- Well-circumscribed patches of hair loss on scalp \- Alopecia universalis \- Selective loss of pigmented hair MISCELLANEOUS \- Incomplete penetrance \- Autosomal dominant and recessive models are under consideration \- Onset of disease can be sudden and the progression of the disorder unpredictable ▲ 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 inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors	ALOPECIA AREATA 2	c0263505	1,806	omim	https://www.omim.org/entry/610753	2019-09-22T16:04:10	{"doid": ["986"], "mesh": ["C537055"], "omim": ["610753"], "orphanet": ["701", "700"]}
Congenital contractural arachnodactyly is a disorder that affects many parts of the body. People with this condition typically are tall with long limbs (dolichostenomelia) and long, slender fingers and toes (arachnodactyly). They often have permanently bent joints (contractures) that can restrict movement in their hips, knees, ankles, or elbows. Additional features of congenital contractural arachnodactyly include underdeveloped muscles, a rounded upper back that also curves to the side (kyphoscoliosis), permanently bent fingers and toes (camptodactyly), ears that look "crumpled," and a protruding chest (pectus carinatum). Rarely, people with congenital contractural arachnodactyly have heart defects such as an enlargement of the blood vessel that distributes blood from the heart to the rest of the body (aortic root dilatation) or a leak in one of the valves that control blood flow through the heart (mitral valve prolapse). The life expectancy of individuals with congenital contractural arachnodactyly varies depending on the severity of symptoms but is typically not shortened. A rare, severe form of congenital contractural arachnodactyly involves both heart and digestive system abnormalities in addition to the skeletal features described above; individuals with this severe form of the condition usually do not live past infancy. ## Frequency The prevalence of congenital contractural arachnodactyly is estimated to be less than 1 in 10,000 worldwide. ## Causes Mutations in the FBN2 gene cause congenital contractural arachnodactyly. The FBN2 gene provides instructions for producing the fibrillin-2 protein. Fibrillin-2 binds to other proteins and molecules to form threadlike filaments called microfibrils. Microfibrils become part of the fibers that provide strength and flexibility to connective tissue that supports the body's joints and organs. Additionally, microfibrils regulate the activity of molecules called growth factors. Growth factors enable the growth and repair of tissues throughout the body. Mutations in the FBN2 gene can decrease fibrillin-2 production or result in the production of a protein with impaired function. As a result, microfibril formation is reduced, which probably weakens the structure of connective tissue and disrupts regulation of growth factor activity. The resulting abnormalities of connective tissue underlie the signs and symptoms of congenital contractural arachnodactyly. ### Learn more about the gene associated with Congenital contractural arachnodactyly * FBN2 ## Inheritance Pattern This condition is inherited in an autosomal dominant pattern, which means one copy of the altered gene in each cell is sufficient to cause the 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 inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors	Congenital contractural arachnodactyly	c0220668	1,807	medlineplus	https://medlineplus.gov/genetics/condition/congenital-contractural-arachnodactyly/	2021-01-27T08:25:47	{"gard": ["5899"], "mesh": ["C536211"], "omim": ["121050"], "synonyms": []}
Rheumatoid arthritis is a disease that causes chronic abnormal inflammation, primarily affecting the joints. The most common signs and symptoms are pain, swelling, and stiffness of the joints. Small joints in the hands and feet are involved most often, although larger joints (such as the shoulders, hips, and knees) may become involved later in the disease. Joints are typically affected in a symmetrical pattern; for example, if joints in the hand are affected, both hands tend to be involved. People with rheumatoid arthritis often report that their joint pain and stiffness is worse when getting out of bed in the morning or after a long rest. Rheumatoid arthritis can also cause inflammation of other tissues and organs, including the eyes, lungs, and blood vessels. Additional signs and symptoms of the condition can include a loss of energy, a low fever, weight loss, and a shortage of red blood cells (anemia). Some affected individuals develop rheumatoid nodules, which are firm lumps of noncancerous tissue that can grow under the skin and elsewhere in the body. The signs and symptoms of rheumatoid arthritis usually appear in mid- to late adulthood. Many affected people have episodes of symptoms (flares) followed by periods with no symptoms (remissions) for the rest of their lives. In severe cases, affected individuals have continuous health problems related to the disease for many years. The abnormal inflammation can lead to severe joint damage, which limits movement and can cause significant disability. ## Frequency Rheumatoid arthritis affects about 1.3 million adults in the United States. Worldwide, it is estimated to occur in up to 1 percent of the population. The disease is two to three times more common in women than in men, which may be related to hormonal factors. ## Causes Rheumatoid arthritis probably results from a combination of genetic and environmental factors, many of which are unknown. Rheumatoid arthritis is classified as an autoimmune disorder, one of a large group of conditions that occur when the immune system attacks the body's own tissues and organs. In people with rheumatoid arthritis, the immune system triggers abnormal inflammation in the membrane that lines the joints (the synovium). When the synovium is inflamed, it causes pain, swelling, and stiffness of the joint. In severe cases, the inflammation also affects the bone, cartilage, and other tissues within the joint, causing more serious damage. Abnormal immune reactions also underlie the features of rheumatoid arthritis affecting other parts of the body. Variations in dozens of genes have been studied as risk factors for rheumatoid arthritis. Most of these genes are known or suspected to be involved in immune system function. The most significant genetic risk factors for rheumatoid arthritis are variations in human leukocyte antigen (HLA) genes, especially the HLA-DRB1 gene. The proteins produced from HLA genes help the immune system distinguish the body's own proteins from proteins made by foreign invaders (such as viruses and bacteria). Changes in other genes appear to have a smaller impact on a person's overall risk of developing the condition. Other, nongenetic factors are also believed to play a role in rheumatoid arthritis. These factors may trigger the condition in people who are at risk, although the mechanism is unclear. Potential triggers include changes in sex hormones (particularly in women), occupational exposure to certain kinds of dust or fibers, and viral or bacterial infections. Long-term smoking is a well-established risk factor for developing rheumatoid arthritis; it is also associated with more severe signs and symptoms in people who have the disease. ### Learn more about the genes associated with Rheumatoid arthritis * HLA-B * HLA-DPB1 * HLA-DRB1 * IRF5 * PTPN22 * RBPJ * RUNX1 * STAT4 Additional Information from NCBI Gene: * AFF3 * ARID5B * BLK * C5 * CCL21 * CCR6 * CD2 * CD28 * CD40 * CD5 * CD58 * CTLA4 * FCGR2A * FCGR2B * GATA3 * IKZF3 * IL2 * IL21 * IL2RA * IL2RB * IL6R * IL6ST * IRAK1 * IRF8 * KIF5A * NFKBIL1 * PADI4 * PIP4K2C * POU3F1 * PRDM1 * PRKCQ * PTPRC * PXK * RASGRP1 * RCAN1 * REL * SPRED2 * TAGAP * TLE3 * TNFAIP3 * TNFRSF14 * TRAF1 * TRAF6 * TYK2 ## Inheritance Pattern The inheritance pattern of rheumatoid arthritis is unclear because many genetic and environmental factors appear to be involved. However, having a close relative with rheumatoid arthritis likely increases a person's risk of developing the 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 inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors	Rheumatoid arthritis	c0003873	1,808	medlineplus	https://medlineplus.gov/genetics/condition/rheumatoid-arthritis/	2021-01-27T08:24:45	{"mesh": ["D001172"], "omim": ["180300"], "synonyms": []}
Weimer (1949) described a family in which at least 1 male in 4 successive generations had bilateral inguinal hernia. Autosomal dominance with sex influence was suggested. Familial hernia was reported also by Edwards (1974) and by Simpson et al. (1974). Smith and Sparkes (1968) observed 2 brothers with atypical inguinal hernias of similar type and a strong family history of hernia. They reviewed evidence in man and animals supporting genetic causation. Hernia occurs, of course, in the Marfan (154700) and Ehlers-Danlos (130000) syndromes. Abdomen \- Bilateral inguinal hernia Inheritance \- Autosomal dominant with sex influence ▲ 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 inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors	HERNIA, DOUBLE INGUINAL	c0860251	1,809	omim	https://www.omim.org/entry/142350	2019-09-22T16:40:20	{"mesh": ["C563164"], "omim": ["142350"], "icd-10": ["K40"]}
Patch-type granuloma annulare SpecialtyDermatology Patch-type granuloma annulare (also known as macular granuloma annulare) is a skin condition of unknown cause, more commonly affecting women between 30 and 70 years of age, characterized by flat or slightly palpable erythematous or red-brown skin lesions.[1]:704 ## See also[edit] * Granuloma annulare * Skin lesion ## References[edit] 1. ^ James, William D.; Berger, Timothy G.; et al. (2006). Andrews' Diseases of the Skin: clinical Dermatology. Saunders Elsevier. ISBN 978-0-7216-2921-6. 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 inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors	Patch-type granuloma annulare	None	1,810	wikipedia	https://en.wikipedia.org/wiki/Patch-type_granuloma_annulare	2021-01-18T18:46:15	{"wikidata": ["Q7144317"]}
A rare disorder characterized by pterygium colli, digital anomalies (abnormal small thumbs, widened interphalangeal joints, and broad terminal phalanges), and craniofacial abnormalities (brachycephaly, epicanthic folds, angulated eyebrows, upward slanting of the palpebral fissures, ptosis, hypertelorism, and prominent low-set, posteriorly rotated ears). It has been described in a woman and her son, but the manifestations were much less severe in the mother. The son also had intellectual deficit. The inheritance is either X-linked dominant or autosomal dominant. [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 inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors	Pterygium colli-intellectual disability-digital anomalies syndrome	c1838562	1,811	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=2988	2021-01-23T18:29:38	{"gard": ["4568"], "mesh": ["C535831"], "omim": ["600159"], "umls": ["C1838562"], "icd-10": ["Q87.0"], "synonyms": ["Khalifa-Graham syndrome"]}
A number sign (#) is used with this entry because of evidence that autosomal dominant mental retardation-53 (MRD53) is caused by heterozygous mutation in the CAMK2A gene (114078) on chromosome 5q32. Clinical Features Kury et al. (2017) reported 14 unrelated patients of northern European descent or from the United States with delayed psychomotor development and mild to severe intellectual disability (ID). The patients ranged in age from 1.5 to 18 years; 7 patients were classified as having severe ID. Common features included hypotonia, delayed walking or inability to walk, delayed or absent speech, and behavioral abnormalities, including autistic features. Four patients had seizures, but only 2 patients had EEG abnormalities. Brain imaging was normal in most patients, although 1 had a thickened corpus callosum and another had postnatal microcephaly and mild white matter deficiency. Several patients had variable dysmorphic facial features such as hypotelorism, epicanthal folds, downslanting palpebral fissures, or strabismus. There were no significant common additional features. One of the patients (patient 5) had previously been reported by Iossifov et al. (2014). Akita et al. (2018) reported 3 unrelated patients with MRD53. All patients had onset of seizures in infancy as well as severely impaired neurologic development. Two patients had refractory seizures, whereas 1 became seizure-free at 11 months of age. They had poor overall growth, small head circumference, and profound intellectual disability. One was bedridden, another could not sit, and the third was able to walk at 1 year. All were nonverbal at ages 13, 5, and 16 years, respectively. Other features included hypotonia, myoclonus, hyperkinetic movements, and stereotypic behavior. Brain imaging showed progressive cerebellar atrophy in 1 patient. The patients were ascertained from a cohort of 976 individuals with neurodevelopmental disorders who underwent whole-exome sequencing. Molecular Genetics In 14 unrelated patients with MRD53, Kury et al. (2017) identified 12 different heterozygous mutations in the CAMK2A gene (see, e.g., 114078.0001-114078.0005). The mutations were found by exome sequencing and confirmed by Sanger sequencing in most patients. Thirteen of the variants occurred de novo; paternal DNA from 1 patient was unavailable. There were 8 missense variants, including 1 recurrent variant (P212L) that was found in 3 patients, 3 splicing variants, and 1 frameshift variant. In vitro functional expression studies of some of the variants showed variable abnormalities: H282R (114078.0004) resulted in decreased levels of the mutant protein, whereas other missense variants did not. CAMK2A autophosphorylation at Thr286 is critical for autonomous (calcium-independent) function. E109D (114078.0002) and H282R caused a significant increase in autophosphorylation at Thr286, whereas F98S (114078.0001) and E183V (114078.0003) showed a significant reduction of Thr286 phosphorylation, and T286P (114078.0005) showed no phosphorylation. Several other variants (P212L, P138A, and P235L) showed similar levels of Thr286 phosphorylation as wildtype. Transfection of human CAMK2A variants into mouse embryonic neurons in the subventricular zone using in utero electroporation showed that variants with reduced (F98S and E183V) or increased (E109D and H282R) Thr286 phosphorylation caused decreased neuronal migration compared to wildtype. T286P completely blocked neuronal migration, but also appeared to show a dominant gain-of-function effect in vitro. In contrast, overexpression or knockdown of CAMK2A, and expression of the variants that had no effect on Thr286 phosphorylation, did not affect neuronal migration. The variants appeared to act in a dominant-negative manner. The findings highlighted the importance of tightly controlled autophosphorylation of CAMK2A for normal neuronal function, and suggested that disruption of this event can impair synaptic plasticity and learning, resulting in neurodevelopmental defects. In 3 unrelated patients with MRD53, Akita et al. (2018) identified de novo heterozygous mutations in the CAMK2A gene (114078.0007-114078.0009). The mutations were found by whole-exome sequencing and confirmed by Sanger sequencing. Molecular modeling and in vitro studies of some of the variants indicated that they would disrupt the autoregulatory domain, leading to a loss of autoinhibition and constitutive activation, consistent with a gain of function. Animal Model Stephenson et al. (2017) found that transgenic mice carrying the Camk2a E183V mutation (114078.0003) showed behavioral abnormalities, including hyperactivity, repetitive behaviors, social deficits, and decreased exploratory behavior. These changes were associated with disrupted Camk2a localization and autophosphorylation at Thr286. Further studies indicated that the mutant protein had reduced stability and increased turnover via the ubiquitination system. INHERITANCE \- Autosomal dominant HEAD & NECK Face \- Dysmorphic features, variable (in some patients) Eyes \- Hypertelorism \- Epicanthal folds \- Downslanting palpebral fissures \- Strabismus MUSCLE, SOFT TISSUES \- Hypotonia NEUROLOGIC Central Nervous System \- Delayed psychomotor development \- Intellectual disability, mild to severe \- Delayed or absent speech \- Delayed walking \- Seizures (in some patients) \- Brain imaging usually normal MISCELLANEOUS \- Variable phenotype \- De novo mutation MOLECULAR BASIS \- Caused by mutation in the calcium/calmodulin-dependent protein kinase II-alpha gene (CAMK2A, 114078.0001 ) ▲ 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 inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors	MENTAL RETARDATION, AUTOSOMAL DOMINANT 53	c4540481	1,812	omim	https://www.omim.org/entry/617798	2019-09-22T15:44:45	{"doid": ["0080228"], "omim": ["617798"], "orphanet": ["178469"], "synonyms": []}
Wellens' syndrome Other namesWellens' sign, Wellens' warning, Wellens' waves EKG of a 69-year-old black male with Wellens' syndrome. Visible in leads V1-V4, here with a biphasic T-wave with negativisation. SpecialtyCardiology Wellens' syndrome is an electrocardiographic manifestation of critical proximal left anterior descending (LAD) coronary artery stenosis in people with unstable angina. Originally thought of as two separate types, A and B, it is now considered an evolving wave form, initially of biphasic T wave inversions and later becoming symmetrical, often deep (>2 mm), T wave inversions in the anterior precordial leads.[1] First described by Hein J. J. Wellens and colleagues in 1982 in a subgroup of people with unstable angina,[2] it does not seem to be rare, appearing in 18% of patients in his original study. A subsequent prospective study identified this syndrome in 14% of patients at presentation and 60% of patients within the first 24 hours.[3] The presence of Wellens' syndrome carries significant diagnostic and prognostic value. All people in the De Zwann's study with characteristic findings had more than 50% stenosis of the left anterior descending artery (mean = 85% stenosis) with complete or near-complete occlusion in 59%. In the original Wellens' study group, 75% of those with the typical syndrome manifestations had an anterior myocardial infarction. Sensitivity and specificity for significant (more or equal to 70%) stenosis of the LAD artery was found to be 69% and 89%, respectively, with a positive predictive value of 86%.[4] Wellens' sign has also been seen as a rare presentation of Takotsubo cardiomyopathy or stress cardiomyopathy.[citation needed] ## Diagnosis[edit] This section is in list format, but may read better as prose. You can help by converting this section, if appropriate. Editing help is available. (September 2014) * Progressive symmetrical deep T wave inversion in leads V2 and V3 * Slope of inverted T waves generally at 60°-90° * Little or no cardiac marker elevation * Discrete or no ST segment elevation * No loss of precordial R waves. * Coronary angiogram, with video on the left showing tight, critical (95%) stenosis of the proximal LAD in a patient who had Wellens' warning; video on the right shows the same patient after reperfusion. * EKG/ECG in someone with Wellens' syndrome when having chest pain * EKG/ECG of the same person when pain-free, note the biphasic T waves in leads V2 and V3 ## References[edit] 1. ^ Tandy, TK; Bottomy DP; Lewis JG (March 1999). "Wellens' syndrome". Annals of Emergency Medicine. 33 (3): 347–351. doi:10.1016/S0196-0644(99)70373-2. PMID 10036351. 2. ^ de Zwaan, C; Bär FW; Wellens HJJ (April 1982). "Characteristic electrocardiographic pattern indicating a critical stenosis high in left anterior descending coronary artery in patients admitted because of impending myocardial infarction". American Heart Journal. 103 (4): 730–736. doi:10.1016/0002-8703(82)90480-X. PMID 6121481. 3. ^ de Zwaan, C; Bär FW; Janssen JH; et al. (March 1989). "Angiographic and clinical characteristics of patients with unstable angina showing an ECG pattern indicating critical narrowing of the proximal LAD coronary artery". American Heart Journal. 117 (3): 657–665. doi:10.1016/0002-8703(89)90742-4. PMID 2784024. 4. ^ Haines, DE; Raabe DS; Gundel WD; Wackers FJ (July 1983). "Anatomic and prognostic significance of new T-wave inversion in unstable angina". American Journal of Cardiology. 52 (1): 14–18. doi:10.1016/0002-9149(83)90061-9. PMID 6602539. * v * t * e Cardiovascular disease (heart) Ischaemic Coronary disease * Coronary artery disease (CAD) * Coronary artery aneurysm * Spontaneous coronary artery dissection (SCAD) * Coronary thrombosis * Coronary vasospasm * Myocardial bridge Active ischemia * Angina pectoris * Prinzmetal's angina * Stable angina * Acute coronary syndrome * Myocardial infarction * Unstable angina Sequelae * hours * Hibernating myocardium * Myocardial stunning * days * Myocardial rupture * weeks * Aneurysm of heart / Ventricular aneurysm * Dressler syndrome Layers Pericardium * Pericarditis * Acute * Chronic / Constrictive * Pericardial effusion * Cardiac tamponade * Hemopericardium Myocardium * Myocarditis * Chagas disease * Cardiomyopathy * Dilated * Alcoholic * Hypertrophic * Tachycardia-induced * Restrictive * Loeffler endocarditis * Cardiac amyloidosis * Endocardial fibroelastosis * Arrhythmogenic right ventricular dysplasia Endocardium / valves Endocarditis * infective endocarditis * Subacute bacterial endocarditis * non-infective endocarditis * Libman–Sacks endocarditis * Nonbacterial thrombotic endocarditis Valves * mitral * regurgitation * prolapse * stenosis * aortic * stenosis * insufficiency * tricuspid * stenosis * insufficiency * pulmonary * stenosis * insufficiency Conduction / arrhythmia Bradycardia * Sinus bradycardia * Sick sinus syndrome * Heart block: Sinoatrial * AV * 1° * 2° * 3° * Intraventricular * Bundle branch block * Right * Left * Left anterior fascicle * Left posterior fascicle * Bifascicular * Trifascicular * Adams–Stokes syndrome Tachycardia (paroxysmal and sinus) Supraventricular * Atrial * Multifocal * Junctional * AV nodal reentrant * Junctional ectopic Ventricular * Accelerated idioventricular rhythm * Catecholaminergic polymorphic * Torsades de pointes Premature contraction * Atrial * Junctional * Ventricular Pre-excitation syndrome * Lown–Ganong–Levine * Wolff–Parkinson–White Flutter / fibrillation * Atrial flutter * Ventricular flutter * Atrial fibrillation * Familial * Ventricular fibrillation Pacemaker * Ectopic pacemaker / Ectopic beat * Multifocal atrial tachycardia * Pacemaker syndrome * Parasystole * Wandering atrial pacemaker Long QT syndrome * Andersen–Tawil * Jervell and Lange-Nielsen * Romano–Ward Cardiac arrest * Sudden cardiac death * Asystole * Pulseless electrical activity * Sinoatrial arrest Other / ungrouped * hexaxial reference system * Right axis deviation * Left axis deviation * QT * Short QT syndrome * T * T wave alternans * ST * Osborn wave * ST elevation * ST depression * Strain pattern Cardiomegaly * Ventricular hypertrophy * Left * Right / Cor pulmonale * Atrial enlargement * Left * Right * Athletic heart syndrome Other * Cardiac fibrosis * Heart failure * Diastolic heart failure * Cardiac asthma * Rheumatic fever [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 inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors	Wellens' syndrome	c3874318	1,813	wikipedia	https://en.wikipedia.org/wiki/Wellens%27_syndrome	2021-01-18T19:08:52	{"umls": ["C3874318"], "wikidata": ["Q7981210"]}
## Description Ocular coloboma is a developmental defect of the eye resulting from abnormal or incomplete fusion of the optic fissure. The defect can be unilateral or bilateral and can involve the cornea, iris, ciliary body, lens, choroid, retina, and/or optic nerves. Clinically, coloboma is often associated with microphthalmia or clinical anophthalmia and can occur as part of complex malformation syndromes (summary by Wang et al., 2012). ### Genetic Heterogeneity of Isolated Microphthalmia With Coloboma Isolated colobomatous microphthalmia-1 (MCOPCB1) has been mapped to the X chromosome. MCOPCB2 (605738) has been mapped to chromosome 15q12-q15. MCOPCB3 (610092) is caused by mutation in the CHX10 gene (142993) on chromosome 14q24. MCOPCB5 (611638) is caused by mutation in the SHH gene (600725) on chromosome 7q36. MCOPCB6 (613703) is caused by mutation in the GDF3 gene (606522) on chromosome 12p13.1. MCOPCB7 (614497) is caused by mutation in the ABCB6 gene (605452) on chromosome 2q36. MCOPCB8 (see 601186) is caused by mutation in the STRA6 gene (601745) on chromosome 15q24. MCOPCB9 (615145) is caused by mutation in the TENM3 gene (610083) on chromosome 4q35. See 251505 for a discussion of MCOPCB4. Clinical Features Lehman et al. (2001) reported a large 3-generation Mexican American family with apparent X-linked recessive transmission of isolated colobomatous microphthalmia. The affected family members were 9 males and 1 female in the third generation and their maternal grandfather. Their features included microphthalmia, ocular coloboma, microcornea with narrowed palpebral fissures, and elevated intraocular pressure. Mapping By genotyping and linkage analysis on a portion of the Mexican American family with isolated colobomatous microphthalmia, Lehman et al. (2001) obtained a maximum 2-point lod score of 2.71 with microsatellite markers DXS1058, DXS6810, DXS1199, and DXS7132, placing the disease locus on the proximal short arm or proximal long arm of the X chromosome. A single affected heterozygous female was observed in this family. She had a normal karyotype and normal, random X inactivation in her lymphocyte DNA. However, skewed X inactivation in the cell lineages from which the eye was derived could not be ruled out. [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 inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors	MICROPHTHALMIA, ISOLATED, WITH COLOBOMA 1	c2931501	1,814	omim	https://www.omim.org/entry/300345	2019-09-22T16:20:32	{"mesh": ["C537463"], "omim": ["300345"], "orphanet": ["98938"], "synonyms": ["Alternative titles", "MICROPHTHALMIA, COLOBOMATOUS, ISOLATED 1"]}
Tracheoesophageal fistula SpecialtyMedical genetics A tracheoesophageal fistula (TEF, or TOF; see spelling differences) is an abnormal connection (fistula) between the esophagus and the trachea. TEF is a common congenital abnormality, but when occurring late in life is usually the sequela of surgical procedures such as a laryngectomy. ## Contents * 1 Presentation * 1.1 Complications * 1.2 Associations * 2 Cause * 3 Diagnosis * 3.1 Classification * 4 Treatment * 5 References * 6 External links ## Presentation[edit] Radiograph with oral contrast showing h-type tracheoesophageal fistula in a newborn Tracheoesophageal fistula is suggested in a newborn by copious salivation associated with choking, coughing, vomiting, and cyanosis coincident with the onset of feeding. Esophageal atresia and the subsequent inability to swallow typically cause polyhydramnios in utero. Rarely it may present in an adult.[1] ### Complications[edit] Surgical repair can sometimes result in complications, including: * Stricture, due to gastric acid erosion of the shortened esophagus * Leak of contents at the point of anastomosis * Recurrence of fistula * Gastro-esophageal reflux disease * Dysphagia * Asthma-like symptoms, such as persistent coughing/wheezing * Recurrent chest infections * Tracheomalacia ### Associations[edit] Neonates with TEF or esophageal atresia are unable to feed properly. Once diagnosed, prompt surgery is required to allow the food intake.[2] Some children experience problems following TEF surgery; they can develop dysphagia and thoracic problems. Children with TEF can also be born with other abnormalities, most commonly those described in VACTERL association - a group of anomalies which often occur together, including heart, kidney and limb deformities. 6% of babies with TEF also have a laryngeal cleft.[3] ## Cause[edit] Congenital TEF can arise due to failed fusion of the tracheoesophageal ridges after the fourth week of embryological development.[4] A fistula, from the Latin meaning 'a pipe', is an abnormal connection running either between two tubes or between a tube and a surface. In tracheo-esophageal fistula it runs between the trachea and the esophagus. This connection may or may not have a central cavity; if it does, then food within the esophagus may pass into the trachea (and on to the lungs) or alternatively, air in the trachea may cross into the esophagus.[citation needed] TEF can also occur due to pressure necrosis by a tracheostomy tube in apposition to a nasogastric tube (NGT).[5] ## Diagnosis[edit] TEF should be suspected once the baby fails to swallow after their first feeding during the first day of life. Esophageal atresia can be diagnosed by Ryle nasogastric tube; if the Ryle fails to pass into the stomach, then this indicates esophageal atresia and loss of communication between stomach and esophagus. TEF may be diagnosed by MRI which clarifies the atretic esophagus (if presents) and TEF, as well as its location and anatomy. Gastrographin contrast swallow should not be used if TEF is suspected, due to its high risk of allergy and severe intractable chest infection.[citation needed] ### Classification[edit] Fistulae between the trachea and esophagus in the newborn can be of diverse morphology and anatomical location.[6][7] However, various pediatric surgical publications have attempted a classification system based on the below specified types. Not all types include both esophageal agenesis and tracheoesophageal fistula, but the most common types do. Gross Vogt[8] Description EA? TEF? - Type 1 Esophageal agenesis. Very rare, and not included in the classification by Gross.[9] Yes No Type A Type 2 Proximal and distal esophageal bud—a normal esophagus with a missing mid-segment. Yes No Type B Type 3A Proximal esophageal termination on the lower trachea with distal esophageal bud. Yes Yes Type C Type 3B Proximal esophageal atresia (esophagus continuous with the mouth ending in a blind loop superior to the sternal angle) with a distal esophagus arising from the lower trachea or carina. (Most common, up to 90% of cases.) Yes Yes Type D Type 3C Proximal esophageal termination on the lower trachea or carina with distal esophagus arising from the carina. Yes Yes Type E (or H-Type) - A variant of type D: if the two segments of esophagus communicate, this is sometimes termed an H-type fistula due to its resemblance to the letter H. TEF without EA. No Yes The letter codes are usually associated with the system used by Gross,[10] while number codes are usually associated with Vogt.[11] An additional type, "blind upper segment only" has been described,[12] but this type is not usually included in most classifications. (For the purposes of this discussion, proximal esophagus indicates normal esophageal tissue arising normally from the pharynx, and distal esophagus indicates normal esophageal tissue emptying into the proximal stomach.) ## Treatment[edit] It is surgically corrected, with resection of any fistula and anastomosis of any discontinuous segments.[2] Babies often need to spend time in a neonatal intensive care unit for feeding with a stomach feeding tube.[2] Antibiotics, pain relief, a chest drain, oxygen, and ventilation may all be needed.[2] ## References[edit] 1. ^ Newberry D., Sharma V., Reiff D., De Lorenzo F. (1999). "A "little cough" for 40 years". Lancet. 354 (9185): 1174. doi:10.1016/s0140-6736(99)10014-x. PMID 10513712. S2CID 39432557.CS1 maint: multiple names: authors list (link) 2. ^ a b c d "Oesophageal atresia and tracheo-oesophageal fistula". nhs.uk. 2017-10-18. Retrieved 2020-11-13. 3. ^ Bluestone, Charles D. (2003). Pediatric otolaryngology, Volume 2. Elsevier Health Sciences. p. 1468. ISBN 0-7216-9197-8. 4. ^ Clark DC (February 1999). "Esophageal atresia and tracheoesophageal fistula". American Family Physician. 59 (4): 910–6, 919–20. PMID 10068713. 5. ^ Dr. Lorne H. Blackbourne, Advanced Surgical Recall, 3rd Ed., pg. 206. 6. ^ Spitz L (2007). "Oesophageal atresia". Orphanet Journal of Rare Diseases. 2 (1): 24. doi:10.1186/1750-1172-2-24. PMC 1884133. PMID 17498283. 7. ^ Kovesi T, Rubin S (2004). "Long-term complications of congenital esophageal atresia and/or tracheoesophageal fistula". Chest. 126 (3): 915–25. doi:10.1378/chest.126.3.915. PMID 15364774. 8. ^ "Long-term Complications of Congenital Esophageal Atresia and/or Tracheoesophageal Fistula -- Kovesi and Rubin 126 (3): 915 Figure 1 -- Chest". Retrieved 2008-10-11. 9. ^ P. Puri (2005). M. E. Höllwarth (ed.). Pediatric Surgery (Springer Surgery Atlas Series). Berlin: Springer. p. 30. ISBN 3-540-40738-3. 10. ^ Gross, RE. The surgery of infancy and childhood. Philadelphia, WB Saunders; 1953. 11. ^ Vogt EC. Congenital esophageal atresia. Am J of Roentgenol. 1929;22:463–465. 12. ^ Cotran, Ramzi S.; Kumar, Vinay; Fausto, Nelson; Nelso Fausto; Robbins, Stanley L.; Abbas, Abul K. (2005). Robbins and Cotran pathologic basis of disease. St. Louis, Mo: Elsevier Saunders. p. 800. ISBN 0-7216-0187-1. ## External links[edit] Classification D * ICD-10: J95.0, Q39.1-Q39.2 * ICD-9-CM: 530.84, 750.3 * MeSH: D014138 * DiseasesDB: 30034 External resources * eMedicine: med/3416 * v * t * e Congenital malformations and deformations of digestive system Upper GI tract Tongue, mouth and pharynx * Cleft lip and palate * Van der Woude syndrome * tongue * Ankyloglossia * Macroglossia * Hypoglossia Esophagus * EA/TEF * Esophageal atresia: types A, B, C, and D * Tracheoesophageal fistula: types B, C, D and E * esophageal rings * Esophageal web (upper) * Schatzki ring (lower) Stomach * Pyloric stenosis * Hiatus hernia Lower GI tract Intestines * Intestinal atresia * Duodenal atresia * Meckel's diverticulum * Hirschsprung's disease * Intestinal malrotation * Dolichocolon * Enteric duplication cyst Rectum/anal canal * Imperforate anus * Rectovestibular fistula * Persistent cloaca * Rectal atresia Accessory Pancreas * Annular pancreas * Accessory pancreas * Johanson–Blizzard syndrome * Pancreas divisum Bile duct * Choledochal cysts * Caroli disease * Biliary atresia Liver * Alagille syndrome * Polycystic liver 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 inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors	Tracheoesophageal fistula	c0040588	1,815	wikipedia	https://en.wikipedia.org/wiki/Tracheoesophageal_fistula	2021-01-18T18:45:12	{"gard": ["7792"], "mesh": ["D014138"], "umls": ["C0040588"], "icd-9": ["530.84", "750.3"], "icd-10": ["Q39.2", "Q39.1", "J95.0"], "orphanet": ["454750"], "wikidata": ["Q7831319"]}
A number sign (#) is used with this entry because of evidence that autosomal dominant isolated mitochondrial myopathy (IMMD) is caused by heterozygous mutation in the CHCHD10 gene (615903) on chromosome 22q11. One such family has been reported. Description Autosomal dominant isolated mitochondrial myopathy is characterized by onset of proximal lower limb weakness and exercise intolerance in the first decade of life. The disorder is slowly progressive, with later involvement of facial muscles, muscles of the upper limbs, and distal muscles. Patients may also have respiratory compromise (summary by Heiman-Patterson et al., 1997). Clinical Features Heiman-Patterson et al. (1997) reported a 5-generation family of Puerto Rican descent in which 15 members had childhood onset of slowly progressive exercise intolerance and proximal lower limb muscle weakness. Neck flexor, shoulder girdle, and distal leg muscles became affected in the second decade, and mild facial weakness appeared in the third to fourth decades. All patients had moderate to severe restrictive lung function, but no cardiac involvement. Short stature was also present. Cognitive, sensory, and cerebellar function were normal. Laboratory studies showed lactic acidemia and increased serum creatine kinase. EMG showed a myopathic pattern. Muscle biopsy of 3 patients showed ragged-red fibers and increased numbers of mitochondria with abnormal cristae and globular mitochondrial inclusions. Two patients studied showed variable decreases in activity of mitochondrial complexes II, III, and IV. Six patients treated with steroids reported clinical improvement. In 1 patient, Southern blot analysis excluded large scale rearrangements of mitochondrial DNA, and sequencing of several candidate mitochondrial genes did not reveal any mutations. In a follow-up of the patients reported by Heiman-Patterson et al. (1997), Ajroud-Driss et al. (2015) noted that skeletal muscle biopsies also showed glycogen and lipid accumulation. Inheritance The transmission pattern of isolated mitochondrial myopathy in the family reported by Heiman-Patterson et al. (1997) was consistent with autosomal dominant inheritance. Molecular Genetics In affected members of the family with isolated mitochondrial myopathy reported by Heiman-Patterson et al. (1997), Ajroud-Driss et al. (2015) identified a heterozygous missense mutation in the CHCHD10 gene (R15S/G58R; 615903.0004). The mutation, which was found by linkage analysis and candidate gene sequencing, segregated completely with the disorder in the family. Cells transfected with the G58R mutation or the R15S/G58R mutants showed fragmentation of the mitochondria compared to wildtype or cells transfected only with R15S. The findings suggested that the R15S variant may not be pathogenic. INHERITANCE \- Autosomal dominant GROWTH Height \- Short stature HEAD & NECK Face \- Facial weakness Neck \- Neck flexor weakness RESPIRATORY \- Restrictive pulmonary function MUSCLE, SOFT TISSUES \- Exercise intolerance \- Muscle weakness, proximal, lower limbs (upper limbs may become affected later) \- Distal muscle weakness occurs later \- Ragged red fibers seen on muscle biopsy \- Increased mitochondria with abnormal cristae \- Variably decreased activities of mitochondrial respiratory complexes I, II, and IV LABORATORY ABNORMALITIES \- Increased serum lactate \- Increased serum creatine kinase MISCELLANEOUS \- Onset in the first decade \- Slowly progressive \- One family of Puerto Rican descent has been reported (last curated January 2015) MOLECULAR BASIS \- Caused by mutation in the coiled-coil-helix-coiled-coil-helix domain-containing protein 10 gene (CHCHD10, 615903.0004 ) ▲ 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 inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors	MYOPATHY, ISOLATED MITOCHONDRIAL, AUTOSOMAL DOMINANT	c4015513	1,816	omim	https://www.omim.org/entry/616209	2019-09-22T15:49:40	{"omim": ["616209"], "orphanet": ["457050"], "synonyms": [], "genereviews": ["NBK304142"]}
A number sign (#) is used with this entry because of evidence that radioulnar synostosis with amegakaryocytic thrombocytopenia-1 (RUSAT1) is caused by heterozygous mutation in the HOXA11 gene (142958) on chromosome 7p15. Description Radioulnar synostosis with amegakaryocytic thrombocytopenia (RUSAT) is characterized by thrombocytopenia that progresses to pancytopenia, in association with congenital proximal fusion of the radius and ulna that results in extremely limited pronation and supination of the forearm (summary by Niihori et al., 2015). ### Genetic Heterogeneity of Radioulnar Synostosis with Amegakaryocytic Thrombocytopenia Radioulnar synostosis with amegakaryocytic thrombocytopenia-2 (RUSAT2; 616738) is caused by heterozygous mutation in the MECOM gene (165215) on chromosome 3q26. Clinical Features Thompson and Nguyen (2000) observed 2 families with autosomal dominant inheritance of radioulnar synostosis (see 179300) in association with amegakaryocytic thrombocytopenia. The fathers and all affected children in both families (2 of 3 in 1 family and both children in the other) had the same skeletal defect, proximal fusion of the radius and ulna, resulting in extremely limited pronation and supination of the forearm. Three of the 4 children with radioulnar synostosis also had symptomatic thrombocytopenia, with bruising and bleeding problems since birth, necessitating correction by bone marrow or umbilical cord stem cell transplantation. The fathers had normal platelet counts and no history of bleeding or bruising. Thompson et al. (2001) provided full clinical details on the 2 families with autosomal dominant radioulnar synostosis and amegakaryocytic thrombocytopenia. Their family 1 had 2 affected sisters in whom thrombocytopenia was treated successfully with bone marrow transplantation. The father had proximal radioulnar synostosis, bilateral clinodactyly of the fifth digits (present also on the right hand of the older sister), and webbed fingers, but no hematologic abnormality. Both sisters had hip dysplasia with dislocation. In their family 2, Thompson et al. (2001) observed an affected sister and brother. The father had radioulnar synostosis and bilateral fifth digit clinodactyly. Inheritance Thompson et al. (2001) reported 2 families with autosomal dominant inheritance of radioulnar synostosis and amegakaryocytic thrombocytopenia. Molecular Genetics In affected members of 2 families segregating radioulnar synostosis and amegakaryocytic thrombocytopenia, Thompson and Nguyen (2000) identified a heterozygous mutation in the HOXA11 gene (142958.0001). INHERITANCE \- Autosomal dominant HEAD & NECK Ears \- Hearing loss, sensorineural SKELETAL Pelvis \- Shallow acetabulae \- Hip dislocation Limbs \- Proximal radio-ulnar synostosis \- Limited pronation/supination of forearm \- Radial bowing \- Ulnar bowing Hands \- Fifth finger clinodactyly \- Syndactyly SKIN, NAILS, & HAIR Skin \- Petechiae \- Purpura HEMATOLOGY \- Thrombocytopenia, congenital \- Megakaryocytopenia \- Aplastic anemia \- Pancytopenia LABORATORY ABNORMALITIES \- No chromosomal breakage \- Normal karyotype MOLECULAR BASIS \- Caused by mutation in the homeobox-A11 gene (HOXA11, 142958.0001 ) ▲ 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 inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors	RADIOULNAR SYNOSTOSIS WITH AMEGAKARYOCYTIC THROMBOCYTOPENIA 1	c1854273	1,817	omim	https://www.omim.org/entry/605432	2019-09-22T16:11:16	{"mesh": ["C565328"], "omim": ["605432"], "orphanet": ["71289"], "synonyms": ["Alternative titles", "RUSAT", "THROMBOCYTOPENIA, CONGENITAL, WITH RADIOULNAR SYNOSTOSIS"]}
A number sign (#) is used with this entry because mitochondrial DNA depletion syndrome-6 (MTDPS6), also known as Navajo neurohepatopathy (NNH), is caused by homozygous or compound heterozygous mutation in the MPV17 gene (137960) on chromosome 2p23. Biallelic mutations in the MPV17 gene can also caused CMT2EE (618400), a much less severe disorder. Description Mitochondrial DNA depletion syndrome-6 is an autosomal recessive disorder characterized by infantile onset of progressive liver failure, often leading to death in the first year of life. Those that survive develop progressive neurologic involvement, including ataxia, hypotonia, dystonia, and psychomotor regression (Spinazzola et al., 2008). For a discussion of genetic heterogeneity of autosomal recessive mtDNA depletion syndromes, see MTDPS1 (603041). Clinical Features Appenzeller et al. (1976) described 4 Navajo children with a mutilating neuropathy with severe motor involvement. The disorder appeared to be recessively inherited and was present from a very early age. Manifestations included severe anesthesia leading to corneal ulceration, painless fractures, and acral mutilation; muscle weakness; absent or markedly decreased deep tendon reflexes; and normal IQ. Sural nerve biopsy showed nearly complete absence of myelinated fibers without evidence of regeneration, and degenerative unmyelinated fibers with evidence of regeneration. Snyder et al. (1988) reported 4 children with Navajo neuropathy, including 1 previously reported by Appenzeller et al. (1976), and extended the clinical spectrum to include progressive central nervous system white matter abnormalities with spinal cord atrophy in older children and onset during early infancy. Singleton et al. (1990) performed a major epidemiologic survey of Navajo neuropathy, identifying 20 definite and 4 possible cases from a review of reservation hospital records and a questionnaire directed to all health providers on the Navajo reservation. The 24 cases identified came from 13 families, with 6 families having more than 1 affected child. Clinical features included sensorimotor neuropathy, corneal ulcerations, acral mutilation, poor weight gain, short stature, serious systemic infections, sexual infantilism, and liver disease. The liver disease presented as hepatomegaly, persistent neonatal jaundice, and even a Reye-like syndrome of acute hepatic failure. Brain imaging showed progressive CNS white matter lesions. Diagnosis was usually at the end of the first year of life or in the beginning of the second year, either because of neurologic symptoms or liver disease. The mean age of death was approximately 10 years, frequently due to liver disease. The incidence of this syndrome on the Western Navajo reservation was 5 times higher than on the Eastern reservations (38 compared to 7 cases per 100,000 births). Singleton et al. (1990) suggested an inborn error of metabolism, inherited in an autosomal recessive pattern. In a review of 20 children with Navajo neuropathy, Holve et al. (1999) found that all had liver disease. Three phenotypes were observed, based on age at presentation and disease course: 5 patients had onset before 6 months of age with jaundice and failure to thrive followed by progression to liver failure before 2 years of age; 6 children had onset between 1 and 5 years of age with liver dysfunction progressing to liver failure and death within 6 months; and 9 children had variable onset of liver disease, but progressive neurologic deterioration. Liver histologic findings included multinucleated giant cells, macrovesicular and microvesicular steatosis, pseudo-acini, inflammation, cholestasis, and bridging fibrosis and cirrhosis. Cases of all 3 phenotypes occurred within the same kindred. Holve et al. (1999) emphasized that liver disease is an important component of Navajo neuropathy and may be the predominant feature in infants and young children. They proposed changing the name of the disorder to Navajo neurohepatopathy. Erickson (1999) reviewed genetic diseases among the Navajo population. Spinazzola et al. (2006) studied 3 families with the hepatocerebral form of mtDNA depletion syndrome caused by MPV17 mutations. In a multigeneration family originating from southern Italy, 2 children died of liver failure during the first year of life, but liver transplantation at 1 year of age in another child and dietary control of hypoglycemia in a fourth were effective in maintaining relative metabolic compensation and long-term survival. However, growth in the surviving children, who were 4 and 9 years old at the time of report, remained below the fifth percentile and the older child had developed neurologic symptoms and multiple brain lesions documented by MRI. The probands of the other 2 families died of liver failure in the first months after birth. Spinazzola et al. (2008) reported 2 sisters, born of Iraqi consanguineous parents, with a hepatocerebral form of MTDPS confirmed by genetic analysis (137960.0005). The family history was positive for 2 miscarriages. At age 2 months, the older sister developed jaundice and hepatomegaly associated with clinical liver failure that progressed rapidly over the next few months. Initial MRI at age 3 months was normal but later showed edema of the white matter. She developed dystonic movements and deteriorating neurologic status and died from liver failure at age 11 months. The younger sister showed hypotonia and died of rapidly progressive liver failure at age 5 months. A third unrelated girl, conceived by artificial insemination because of a history of endometriosis in the mother, cried immediately after birth, fed poorly, and was jittery. At age 2 weeks, she was lethargic and had abnormal liver function tests. Brain MRI showed bilateral subdural hemorrhages with an area of periventricular leukomalacia in the right parietal region. Physical examination at age 5 months showed poor growth, hypotonia, roving eye movements, and nystagmus. She died of liver failure at 9 months of age. Genetic analysis showed compound heterozygosity for 2 mutations in the MPV17 gene (137960.0006; 137960.0007). Spinazzola et al. (2008) concluded that MPV17 mutations are associated with rapidly progressive infantile hepatic failure with subsequent neurologic involvement. El-Hattab et al. (2018) reviewed 75 individuals with biallelic MPV17 mutations and added 25 newly described patients. The vast majority of patients presented with an early-onset encephalohepatic disease consistent with MTDPS6. Patients had failure to thrive, lactic acidemia, and mtDNA depletion, mainly in liver tissue. Hepatic abnormalities included elevated liver enzymes, jaundice, hyperbilirubinemia, cholestasis, steatosis, hepatomegaly, and frank liver failure. Neurologic abnormalities included hypotonia, developmental delay, and neurologic deterioration later in childhood. Common, but not universal, features included feeding difficulties, seizures, microcephaly, and sensorimotor peripheral neuropathy. Less common features (in less than 10% of patients) included dystonia, ataxia, retinopathy, corneal ulcerations, nystagmus, renal tubulopathy, nephrocalcinosis, and hypoparathyroidism. Brain imaging showed diffuse white matter abnormalities consistent with leukodystrophy or hypomyelination, but many had normal scans. The prognosis was very poor: most patients (about 75%) died in the first decade of liver or multiorgan failure. Four of the 100 patients presented with later onset of a neuromyopathic disease with little or no liver involvement (see CMT2EE; 618400). ### Navajo Familial Neurogenic Arthropathy Johnsen et al. (1993) reported 8 Navajo children with a disorder that they termed 'Navajo familial neurogenic arthropathy,' which was characterized by Charcot joints (neurogenic arthropathy) and unrecognized fractures, but with intact reflexes and normal strength. The sensory examination was variable: many had no discernible sensory deficit, whereas others had subtle deficiency in deep pain sensation, temperature discrimination, and corneal sensitivity. Nerve conduction velocities were normal, but sural nerve biopsy showed a marked reduction in small myelinated and unmyelinated nerve fibers. The 8 patients were distributed in 3 families in a pattern consistent with autosomal recessive inheritance. Johnsen et al. (1993) concluded that the disorder was distinct from that described by Appenzeller et al. (1976) as an acromutilating sensory neuropathy. Diagnosis ### Confounding Phenotypes Ebermann et al. (2008) reported an 11-year-old boy, born of Egyptian consanguineous parents, with a phenotype suggestive of Navajo neurohepatopathy, including short stature, frequent painless fractures, bruises, and cuts, hepatomegaly with elevated liver enzymes, corneal ulcerations, and mild hypotonia. His 22-month-old sister had short stature, hepatomegaly, increased liver enzymes, and hypotonia. A cousin had died at age 8 years from liver failure. After genetic analysis excluded a mutation in the MPV17 gene, Ebermann et al. (2008) postulated 2 recessive diseases. Genomewide linkage analysis and gene sequencing of the proband identified a homozygous mutation in the AGL gene (610860), consistent with glycogen storage disease III (GSD3; 232400), and a homozygous mutation in the SCN9A gene (603415), consistent with congenital insensitivity to pain (CIPA; 243000). His sister had the AGL mutation and GSD3 only. Ebermann et al. (2008) emphasized that consanguineous matings increase the risk of homozygous genotypes and recessive diseases, which may complicate genetic counseling. Mapping The clinical, pathologic, and biochemical features seen in patients with NNH resembles those in patients with mtDNA depletion syndrome, suggesting that abnormal regulation of mtDNA copy number may be the primary defect in NNH (Vu et al., 2001). Homozygosity mapping of 2 families with NNH suggested linkage to chromosome 2p24 (Karadimas et al., 2006). This locus includes the MPV17 gene, which, when mutated, was known to cause hepatocerebral mtDNA depletion syndrome. Molecular Genetics In affected members of an Italian and Moroccan family with the hepatocerebral form of mtDNA depletion syndrome, Spinazzola et al. (2006) identified homozygous mutations in the MPV17 gene (137960.0001-137960.0002). An affected proband from a Canadian family was found to be compound heterozygous for 2 MPV17 mutations (137960.0003 and 137960.0004). Karadimas et al. (2006) sequenced the MPV17 gene in 6 patients with Navajo neurohepatopathy from 5 families and found the homozygous arg50-to-gln mutation previously described in a southern Italian family (137960.0001) with hepatocerebral mtDNA depletion syndrome (Spinazzola et al., 2006). Identification of a single missense mutation in patients with NNH confirmed that the disease is probably due to a founder effect, and extended the phenotypic spectrum associated with MPV17 mutations. Genotype/Phenotype Correlations In a large review of 100 patients, El-Hattab et al. (2018) found that about half of the pathogenic MPV17 variants were missense, but other types of mutations (nonsense, frameshift, in-frame deletions, splice site) occurred throughout the gene. In general, those with biallelic missense mutations tended to have a less severe phenotype, in particular those with homozygous R50Q (137960.0001), P98L (137960.0008), or R41Q (137960.0009) mutations. Animal Model In an Mpv17-knockout mouse model, Viscomi et al. (2009) found severe mtDNA depletion in liver and skeletal muscle, whereas hardly any depletion was detected in brain and kidney. Mouse embryonic fibroblasts only showed mtDNA depletion after several culturing passages or in serum-free medium. In spite of severe mtDNA depletion, only moderate decreases in respiratory chain enzymatic activities and mild cytoarchitectural alterations were observed in Mpv17 -/- livers, but neither cirrhosis nor failure ever occurred. The mtDNA transcription rate was markedly increased in liver, which could contribute to compensation for the severe mtDNA depletion. This phenomenon was associated with specific downregulation of Mterf (602318), a negative modulator of mtDNA transcription. The most relevant clinical features involved skin, inner ear, and kidney. The coat of the Mpv17 -/- mice turned gray early in adulthood, and 18-month or older mice developed focal segmental glomerulosclerosis (FSGS) with massive proteinuria. Concomitant degeneration of cochlear sensory epithelia was reported as well. These symptoms were associated with significantly shorter life span. Coincidental with the onset of FSGS, minimal mtDNA was measurable in glomerular tufts. INHERITANCE \- Autosomal recessive GROWTH Height \- Short stature Weight \- Poor weight gain Other \- Failure to thrive HEAD & NECK Eyes \- Corneal ulcerations \- Nystagmus ABDOMEN Liver \- Hepatomegaly \- Acute hepatic failure \- Reye syndrome-like episodes \- Biopsy shows multinucleated giant cells \- Macrovesicular steatosis \- Microvesicular steatosis \- Pseudo-acini \- Inflammation \- Cholestasis \- Bridging fibrosis \- Cirrhosis \- Mitochondrial DNA depletion in liver tissue Gastrointestinal \- Vomiting \- Diarrhea SKELETAL \- Painless fractures due to injury Hands \- Acral ulceration and osteomyelitis leading to autoamputation Feet \- Acral ulceration and osteomyelitis leading to autoamputation SKIN, NAILS, & HAIR Skin \- Neonatal jaundice NEUROLOGIC Central Nervous System \- Progressive white matter lesions in the brain \- Hypotonia \- Dystonia \- Ataxia \- Developmental delay Peripheral Nervous System \- Progressive sensorimotor neuropathy \- Pain insensitivity \- Hyporeflexia \- Areflexia \- Muscle weakness, distal \- Delayed motor nerve conduction velocities (NCV) \- Loss of large and small myelinated fibers seen on nerve biopsy METABOLIC FEATURES \- Lactic acidosis \- Hypoglycemia IMMUNOLOGY \- Systemic infections LABORATORY ABNORMALITIES \- Elevated liver enzymes \- Increased total and conjugated bilirubin MISCELLANEOUS \- Early onset (1 month to 4 years) \- Frequently occurs in Navajo children, especially in Western reservations \- Death in the first decade, usually from liver failure \- Liver disease may be the most predominant finding \- Progressive disorder \- Phenotypic variability MOLECULAR BASIS \- Caused by mutation in the mitochondrial inner membrane protein MPV17 gene (MPV17, 137960.0001 ) ▲ 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 inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors	MITOCHONDRIAL DNA DEPLETION SYNDROME 6 (HEPATOCEREBRAL TYPE)	c1850406	1,818	omim	https://www.omim.org/entry/256810	2019-09-22T16:24:24	{"doid": ["0080125"], "mesh": ["C538344"], "omim": ["256810"], "orphanet": ["255229"], "synonyms": ["Alternative titles", "NAVAJO NEUROHEPATOPATHY", "NAVAJO NEUROPATHY"], "genereviews": ["NBK92947", "NBK487393"]}
A number sign (#) is used with this entry because biotinidase deficiency, a form of multiple carboxylase deficiency, is caused by homozygous or compound heterozygous mutation in the BTD gene (609019) on chromosome 3p25. Description Multiple carboxylase deficiency (MCD) is an autosomal recessive metabolic disorder characterized primarily by cutaneous and neurologic abnormalities. Symptoms result from the patient's inability to reutilize biotin, a necessary nutrient. Sweetman (1981) recognized that multiple carboxylase deficiency could be classified into early (see 253270) and late forms. The early form showed higher urinary excretion of 3-hydroxyisovaleric acid and 3-hydroxypropionic acid than the late form and was associated with normal plasma biotin concentrations. Sweetman (1981) proposed a defect in holocarboxylase synthetase and intestinal biotin absorption, respectively. Some patients with biotinidase deficiency present in infancy (Baumgartner et al., 1985; Kalayci et al., 1994), and some individuals with this deficiency are asymptomatic (Wolf et al., 1997). Clinical Features Gompertz et al. (1971) reported a patient with biotin-responsive beta-methylcrotonylglycinuria who had a deficiency of 3-methylcrotonyl-CoA carboxylase (Gompertz et al., 1973). On restudy of this patient, Sweetman et al. (1977) found that the patient was severely ketoacidotic, responded both clinically and biochemically to biotin, and excreted tiglylglycine, a metabolite of isoleucine that is excreted by patients with propionic acidemia due to propionyl-CoA carboxylase deficiency (606054). The deficiency of 2 mitochondrial carboxylases, both containing biotin, suggested that the fundamental defect was either in the transport of biotin or in the holocarboxylase synthetase that attaches biotin covalently to both carboxylases. Charles et al. (1979) reported a presumed case of biotinidase deficiency in a 10-month-old boy who presented with dermatitis, alopecia, severe hypotonia, and developmental regression. Urinary organic acid analysis showed high levels of 3-hydroxyisovaleric acid, beta-methylcrotonylglycine, and 3-hydroxypropionic acid. Activities of propionyl CoA-carboxylase, beta-methylcrotonyl CoA-carboxylase, and pyruvate carboxylase in cultured fibroblasts were normal. Treatment with oral biotin resulted in a dramatic clinical improvement, and the authors postulated a defect in biotin absorption or transport. Lehnert et al. (1979) described a 10-week-old girl with hypotonia, recurrent seizures, and 3-methylcrotonylglycine and 3-hydroxyisovaleric acid in the urine. She also had small, but pathologic amounts of urinary propionic acid and methylcitric acid, suggesting a defect in the metabolism of biotin. Clinically and metabolically, the child responded to biotin. Bartlett et al. (1980) reported a child with a combined deficiency of propionyl-CoA carboxylase, 3-methlycrotonyl-CoA carboxylase, and pyruvate carboxylase. Cultured fibroblasts responded to administration of biotin. The primary defect was thought to involve either biotin metabolism or its intracellular transport. Sander et al. (1980) reported a family with biotin-responsive MCD. Affected children presented with a skin rash, infections, acute intermittent ataxia, and lactic acidosis. Postmortem examination of 1 patient showed atrophy of the superior vermis of the cerebellum, similar to that seen in chronic alcoholism. Wolf et al. (1983) reported 3 children with late-onset multiple carboxylase deficiency from 2 unrelated families. All patients had almost undetectable levels of biotinidase, whereas all 3 parents tested had an intermediate level. Wolf et al. (1983) suggested that the defect in the late-onset form of the disorder may not reside in intestinal absorption of biotin as had been suggested (Munnich et al., 1981; Thoene et al., 1982), but rather in biotinidase. Thoene and Wolf (1983) suggested that juvenile MCD probably results from impaired generation of free biotin from biotinyl residues of dietary protein. They noted that affected children are born with presumably normal stores of free biotin, but become deficient once dependent on dietary protein-bound biotin. This mechanism explained the clinical variability of the disorder and the relative delay in onset of symptoms compared to the neonatal onset in holocarboxylase synthetase deficiency. Gaudry et al. (1983) confirmed biotinidase deficiency in a patient with multiple carboxylase deficiency and showed that the deficiency is present also in liver. Fischer et al. (1982) reported a patient with MCD and impaired immunoregulatory functions due to defective prostaglandin E (PGE) monocyte production. Both PGE deficiency and immunoregulatory dysfunction responded to biotin administration. The authors suggested that the PGE deficiency resulted from impaired activity of acetyl-CoA carboxylase, which produces malonyl-CoA required for prostaglandin synthesis. Wolf et al. (1985) reviewed the clinical presentation of 31 children with late-onset multiple carboxylase deficiency due to biotinidase deficiency. Symptoms usually appeared by about 3 months of age with seizures as the most frequent initial symptom. Other main features included hypotonia, ataxia, hearing loss, optic atrophy, skin rash, and alopecia. Metabolic abnormalities included ketolactic acidosis and organic aciduria. If untreated, symptoms became progressively worse, resulting in coma and death. Treatment with massive doses of biotin reversed the symptoms of alopecia, skin rash, ataxia, and developmental delay. See review of Sweetman and Nyhan (1986). Baumgartner et al. (1985) observed that clinical and biochemical consequences of severe biotin deficiency occur within 12 days of birth. In affected patients with BTD deficiency, they found normal intestinal absorption of biotin and urinary loss of biotin and biocytin. Suormala et al. (1985) also found normal intestinal biotin absorption and increased urinary excretion of free biotin compared to controls. They concluded that renal loss of biotin was one of the factors contributing to the high biotin requirements in patients with BTD deficiency. Oral biotin supplementation resulted in increased activity of biotin-dependent carboxylases as early as 45 minutes. Wolf et al. (1985) reported 2 patients with biotinidase deficiency who were identified among 81,243 newborns screened in the first year of a statewide screening program in Virginia. Both probands had mild neurologic symptoms at 2 and 4 months, respectively, and the 2 older sibs of 1 proband had more severe neurologic abnormalities, cutaneous findings, and developmental delay. None of the affected children had acute metabolic decompensation. Wastell et al. (1988) studied 10 patients with biotinidase deficiency. Clinical findings at presentation varied, with dermatologic signs (dermatitis and alopecia), neurologic abnormalities (seizures, hypotonia, and ataxia), and recurrent infections being the most common features, although none of these occurred in every case. Treatment with biotin resulted in pronounced, rapid clinical and biochemical improvement, but some patients had residual neurologic damage: neurosensory hearing loss, visual pathway defects, ataxia, and mental retardation. Taitz et al. (1983) reported sensorineural deafness and severe myopia associated with a progressive retinal pigment epithelium dysplasia in a child with biotinidase deficiency, despite normal intelligence and neuromotor function. Thuy et al. (1986) reported a patient who first presented at age 5 years and had already developed sensorineural abnormalities of the optic and auditory nerves. The abnormalities did not resolve with treatment. Schulz et al. (1988) described bilateral basal ganglia calcifications in a 29-month-old girl with biotinidase deficiency who presented with ataxia. Laryngeal stridor was a striking feature in cases of biotinidase deficiency reported by Giardini et al. (1981), Dionisi-Vici et al. (1988), and Tokatli et al. (1992). The patient of Tokatli et al. (1992) was a 30-month-old girl admitted with acute spastic laryngitis. At the ages of 10, 18, and 29 months, she had developed a noisy breathing pattern diagnosed as bronchitis that persisted for several weeks despite antibiotic therapy. At age 23 months, she developed erythematous cutaneous lesions involving the entire body, followed by seborrheic dermatitis of the scalp and sudden-onset alopecia. Laboratory analysis showed lactic acidosis and increased serum and urinary alanine. Normalization of both the respiratory symptoms and the metabolic abnormalities occurred within 2 hours of starting biotin therapy. Kalayci et al. (1994) described 2 patients with biotinidase deficiency who were diagnosed with infantile spasms at 1 month of age. They concluded that biotinidase deficiency may present early in the neonatal period without characteristic findings such as alopecia and seborrheic dermatitis. Suormala et al. (1990) compared 13 infants with partial biotinidase deficiency, detected in neonatal screening in Switzerland, Germany, and Austria, with 4 patients with classic biotinidase deficiency. Residual enzyme activity was present in the 'partial' cases. Wolf et al. (1997) reported 2 unrelated asymptomatic adults with biotinidase deficiency who were diagnosed only because their affected children were identified by newborn screening. One patient was a 32-year-old Caucasian man who had never had symptoms of the disorder and showed no physical or neurologic abnormalities. His diet was not unusually enriched with biotin-containing foods, he did not pursue a low-protein diet, and he did not take supplemental vitamins. His parents were consanguineous and he was related to his wife. The family of this man and his wife was of German ancestry and could be traced back to the 1750s to a common founding ancestor who lived in the same small rural community in northwestern Virginia where they lived. The second asymptomatic adult reported by Wolf et al. (1997) was a 36-year-old Caucasian woman who had had no symptoms of the disorder and no dietary restrictions or abnormalities. A 15-year-old daughter was also found to have profound biotinidase deficiency but no clinical symptoms of the disorder, with the possible exception of a skin rash that occurred a few months earlier, was described as 'hives,' and resolved spontaneously. The mother's parentage was French Canadian and consanguineous; her husband was of northern Irish background and not known to be related to her. Biochemical Features Hart et al. (1992) studied the biochemical and immunologic characteristics of biotinidase in sera from 68 children with profound biotinidase deficiency (defined as less than 10% of mean normal activity) who had been identified symptomatically and by newborn screening. Patients could be classified into at least 9 distinct biochemical phenotypes, on the basis of the presence or absence of crossreacting material (CRM) to biotinidase, the number of isoelectric focusing isoforms, and the distribution frequency of the isoforms. No relationship was found between either the age at onset or the severity of symptoms and the isoform patterns or CRM status of the symptomatic children. Clinical Management Suormala et al. (1990) suggested treatment with biotin for all patients with residual activities below 10%. Molecular Genetics In 10 of 25 patients with biotinidase deficiency, Pomponio et al. (1995) identified an allele with a 7-bp deletion and a 3-bp insertion in the BTD gene (609019.0001). In 37 symptomatic children (30 index cases and 7 sibs) with profound biotinidase deficiency, Pomponio et al. (1997) identified 21 mutations in the BTD gene. The 2 most common mutations were the del7/ins3 mutation and R538C (609019.0003); these 2 mutations were found in 31 of 60 alleles (52%), whereas the remainder of the alleles were accounted for by the 19 other unique mutations. In 2 unrelated asymptomatic adults with biotinidase deficiency who were diagnosed because their children were identified by newborn screening, Wolf et al. (1997) identified 2 different homozygous mutations in the BTD gene (609019.0005; 609019.0006). Wolf et al. (1997) concluded that epigenetic factors may protect some enzyme-deficient individuals from developing symptoms. Pomponio et al. (2000) identified mutations in the BTD gene (609019.0001; 609019.0009-609019.0011) in Turkish children with biotinidase deficiency identified both clinically and by newborn screening. Genotype/Phenotype Correlations Sivri et al. (2007) reported 20 Turkish patients with biotinidase deficiency. All except 1 were born of consanguineous parents. Variable hearing loss was present in 11 (55%) children. There were no significant differences in mean age of onset of symptoms, age of diagnosis, or time from onset to diagnosis between those with hearing loss and those with normal hearing. However, all symptomatic children with hearing loss were homozygous for null mutations in the BTD gene, whereas symptomatic children without hearing loss were all homozygous for missense mutations resulting in some residual protein function. Most notably, 3 symptom-free children, who had been ascertained and treated soon after birth because an older sib was affected, had normal hearing despite being homozygous for a null mutation. Combined with previous data, Sivri et al. (2007) concluded that homozygosity or compound heterozygosity for null mutations increases the risk that a symptomatic patient with biotinidase deficiency will have hearing loss, and noted that early treatment is beneficial. Population Genetics ### Newborn Screening Newborn screening for biotinidase deficiency identifies children with profound biotinidase deficiency (less than 10% of mean normal serum activity) and those with partial biotinidase deficiency (10 to 30% of mean normal serum activity). Children with partial biotinidase deficiency who are not treated with biotin do not exhibit symptoms unless they are stressed by prolonged infection (Swango et al., 1998). Wolf et al. (1985) described a simple, rapid, semiquantitative colorimetric method that could be done on whole blood spotted on filter paper as for PKU (261600) testing. In northeastern Italy, Burlina et al. (1988) incorporated screening of biotinidase deficiency into a neonatal mass screening program. During a 6-month period, 1 affected infant was identified among 24,300 newborns, which the authors noted was as common as other well-known metabolic disorders for which mass screening was available. On the basis of the screening of 163,000 newborn filter-paper blood samples for serum biotinidase deficiency, Dunkel et al. (1989) identified 3 with complete deficiency, representing an incidence of 18.4 cases per million live births, and 12 with partial deficiency. The complete deficiency cases represented homozygotes and the partial deficiency cases heterozygotes. The number of heterozygotes found by screening was much less than predicted, probably because the screening test detected only outliers. Biotinidase deficiency was found to be more common in French Canadians than in other ethnic groups in Quebec; however, no evidence of regional clustering or founder effect was detected. Weissbecker et al. (1991) explored 3 statistical methods for identifying heterozygotes on the basis of serum biotinidase activity. By the preferred method, frequency of heterozygotes in an adult French population was estimated to be 0.012, which was similar to that estimated from the results of neonatal screening. Kennedy et al. (1989) reported the results of a neonatal screening program for biotinidase deficiency in Scotland. Of 102,393 infants screened from 1985 to 1987, no positive cases were found. Minns and Kirk (1994) reported that, after discontinuation of the pilot study, 3 cases of biotinidase deficiency had been diagnosed in Scotland. Norrgard et al. (1999) compared the mutations in a group of 59 children with profound biotinidase deficiency who were identified by newborn screening in the United States with those in 33 children ascertained by exhibiting symptoms. Of the 40 total mutations identified among the 2 populations, 4 mutations comprised 59% of the disease alleles studied. Two of these mutations occurred in both populations, but in the symptomatic group at a significantly greater frequency. The other 2 common mutations occurred only in the newborn screening group. Because 2 common mutations did not occur in the symptomatic population, Norrgard et al. (1999) considered it possible that individuals with these mutations either developed mild or no symptoms if left untreated. However, biotin treatment was still recommended. Hymes et al. (2001) reported that 61 mutations in 3 of the 4 exons of the BTD gene and 1 mutation in an intron had been described as the cause of profound BTD deficiency. Two mutations, del7/ins3 and R538C, were present in 52% or 31 of 60 alleles found in symptomatic patients. Three other mutations accounted for 52% of alleles detected by newborn screening in the United States. Muhl et al. (2001) identified 21 patients with profound and 13 unrelated patients with partial biotinidase deficiency from 30 unrelated families during a 12-year nationwide newborn screening in nearly 1 million newborns in Austria. By DGGE analysis and sequencing, they detected 59 of the 60 (98%) expected mutant alleles. A total of 13 different mutations were identified, with 4 common mutations comprising 78% of the BTD alleles. Of 13 children with partial biotinidase deficiency, the D444H mutation (609019.0005) was found in 12, usually with a mutation causing profound deficiency in the other allele. Only 2 patients homozygous for a frameshift mutation had no measurable residual enzyme activity, and both patients developed clinical symptoms before biotin supplementation. The authors concluded that mutation analysis could not predict whether or not an untreated patient will develop symptoms; however, they found it essential to differentiate biochemically between patients with lower or higher than 1% residual biotinidase activity. INHERITANCE \- Autosomal recessive HEAD & NECK Ears \- Hearing loss, sensorineural Eyes \- Conjunctivitis \- Optic atrophy \- Vision loss RESPIRATORY \- Tachypnea \- Apnea \- Breathing problems ABDOMEN Liver \- Hepatomegaly Spleen \- Splenomegaly Gastrointestinal \- Feeding difficulties \- Vomiting \- Diarrhea SKIN, NAILS, & HAIR Skin \- Skin rash \- Seborrheic dermatitis \- Skin infections Hair \- Alopecia NEUROLOGIC Central Nervous System \- Seizures \- Hypotonia \- Ataxia \- Developmental delay \- Diffuse cerebral atrophy \- Diffuse cerebellar atrophy \- Lethargy METABOLIC FEATURES \- Metabolic ketoacidosis \- Organic aciduria LABORATORY ABNORMALITIES \- Organic aciduria (elevated beta-hydroxyisovalerate, lactate, beta-methylcrotonylglycine, beta-hydroxypropionate, methylcitrate) \- Mild hyperammonemia \- Biotinidase deficiency MISCELLANEOUS \- Age of onset usually 1 week to 2 years MOLECULAR BASIS \- Caused by mutation in the biotinidase gene (BTD, 253260.0001 ) ▲ 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 inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors	BIOTINIDASE DEFICIENCY	c1854698	1,819	omim	https://www.omim.org/entry/253260	2019-09-22T16:24:54	{"doid": ["856"], "mesh": ["C565365"], "omim": ["253260"], "icd-10": ["D81.810"], "orphanet": ["79241"], "synonyms": ["Alternative titles", "BTD DEFICIENCY", "MULTIPLE CARBOXYLASE DEFICIENCY, LATE-ONSET", "MULTIPLE CARBOXYLASE DEFICIENCY, JUVENILE-ONSET"], "genereviews": ["NBK1322"]}
Muscle–eye–brain disease Other namesMuscular dystrophy-dystroglycanopathy congenital with brain and eye anomalies A3 [1] Muscle–eye–brain disease has an autosomal recessive inheritance. SpecialtyNeurology Usual onsetBirth or infancy Muscle–eye–brain (MEB) disease, also known as muscular dystrophy-dystroglycanopathy congenital with brain and eye anomalies A3 (MDDGA3),[2] is a kind of rare congenital muscular dystrophy (CMD), largely characterized by hypotonia at birth. Patients suffer from muscular dystrophy, central nervous system abnormalities and ocular abnormalities, the condition is degenerative. MEB is caused by mutations in the POMGnT1 gene, it is congenital and inherited as an autosomal recessive disorder. There is no cure for MEB. Supportive care mainly focuses on symptoms alleviation which varies in different clinical settings. Symptomatic treatment may include physiological therapies, occupational therapies, medications, and surgeries. The life expectancy of patients with MEB is over 70 years old. ## Contents * 1 Signs and symptoms * 1.1 Muscle dystrophies * 1.2 Ocular abnormalities * 1.3 Central nervous system abnormalities * 1.4 Physical appearances * 2 Causes * 3 Pathophysiology * 4 Diagnosis * 4.1 Physical examination * 4.2 Genetic test * 4.3 Medical imaging * 4.4 Muscle biopsy * 4.4.1 Histological analysis * 4.4.2 Enzymatic assay * 4.4.3 Immunochemistry * 4.5 Difficulties * 5 Management * 6 Prognosis * 7 Epidemiology * 8 History * 9 References ## Signs and symptoms[edit] The main signs and symptoms of MEB includes:[3] * Muscle dystrophies: muscle weakness, hypotonia, muscle atrophy * Ocular abnormalities: lack of visual response, severe myopia, glaucoma * Central nervous system abnormalities: mental retardation, cortical malformation ### Muscle dystrophies[edit] The most prevalent signs of MEB is infants being born floppy.[4] It refers to the condition of hypotonia. The types of hypotonia found on patients include generalized hypotonia, diffuse hypotonia, congenital hypotonia and the other subtypes.[5] Its cause behind is mainly the severe muscular dystrophy and partly brain abnormalities.[6] 80% - 99% individuals display various myopathy.[2] In general, they manifest severe muscle weakness and retarded motor development. Hence, gait disturbance (abnormal walking) is found in 80% - 99% of the diseased individuals.[2] A significant portion of them have limited mobility that fail to walk or even rotate the head.[4] The muscle weakness affects facial muscles apart from skeletal muscles. It gives rise to speech impairment in most of the cases.[citation needed] The other signs include joint and/or spinal rigidity, reduced muscle mass, hyporeflexia, muscular contracture, spasticity, muscle atrophy and spinal deformities.[4] ### Ocular abnormalities[edit] Visual problems are often found in the majority of people with MEB. Patients have low visual acuity and fail to fixate to the visual stimuli. Depends on the severity, some display no visual response, some can response to light and some to object.[7] More than 80% of the patients reported visual impairment.[2] Common problems include glaucoma, myopia, strabismus (“crossed-eye”) and optic atrophy which all occurs in 80-99%.[2] Optic atrophy contains poor pigmentation of ocular fundi, thin blood vessels of retina, small optic discs and scleral border and optic coloboma (degeneration of the inferior optic nerve).[3][8] Cataract affects 30% - 79% of individuals.[2] Buphthalmos (enlargement of the eyeball), megalocornea (enlargement of cornea) and nystagmus (uncontrollable eyeball movement) are present in some rare case.[2][8] Although ocular abnormalities account for the poor vision to a large extend, some of the visual problems is associated with the brain abnormalities.[7] ### Central nervous system abnormalities[edit] MEB impairs the cognition gravely. This is reflected by the abnormal EEG and EMG reading in 80% - 99% individuals.[2] At the same frequency, hydrocephalus present in many cases.[2] The severe form of it is associated with the compression of other nerves and results in more complications.[9] Clinical features include severe mental retardation in all aspects. Most individuals have intellectual disabilities of a range of severity.[2][10] Progressive deterioration in behavioral development has been recorded.[8] Epilepsy and seizures are found in 30% - 79% of the affected individuals.[2] Manifestations in structural malformation are common as well. Hypoplasia of mesencephalon, pons, cerebellum and medulla are often.[11][12] Aplasia may occur on top of hypoplasia. Flattened brainstem, ventriculomegaly, pachygyria, Type II lissencephaly have been reported.[10][12] At the rate between 5% and 29% holoprosencephaly and meningocele occurs in patients too.[2] ### Physical appearances[edit] Distinctive facial features for MEB found are high prominent forehead, bulging eye and narrow temporal regions.[13] ## Causes[edit] Cytogenetic location of the POMGnT 1 gene is 1p34.1.[14] MEB is caused by mutations of the protein O-linked mannose β1,2-N-acetylglucosaminyltransferase 1 (POMGnT1) gene. Pathogenic variants mutate the gene and lead to dysfunction of the POMGnT1 enzyme. Currently, there are 14 clinically identified mutations, the locations are dispersed and scattered throughout the POMGnT1 gene.[10][6] Different mutations were observed in MEB patients from different countries, namely Finland, Sweden, Norway, Estonia, USA, Israel, Spain and Italy.[6] From 14 non-Finnish patients, 9 different types of mutation were identified.[6] The location of the mutation is slightly correlated with the severity of the symptoms in terms of brain structural abnormalities.[10] Mutations close to the 5′ terminus of the POMGnT1 coding region lead to relatively more severe phenotype such as hydrocephalus. Mutations that occurred close to the 3′ terminus shows weaker symptoms.[10] MEB is an autosomal recessive disease inherited from parents. Patients with MEB have two copies of a pathogenic variant in their gene. There will be a risk of having a child with MEB given that both parents are carriers of a pathogenic variant in their gene. The affected child inherits a mutated copy of the gene from each carrier parent. The chance of inheritance is 1 in 4 when both parents carry the pathogenic variant.[15] ## Pathophysiology[edit] The pathogenesis of MEB is related to an abnormal level of α‐dystroglycan glycosylation. Genetic mutations of the POMGnT1 gene reduced the O-mannosyl glycosylation of α-dystroglycan. The POMGnT1 gene encodes the enzyme POMGnT1, a type II transmembrane protein residing in the Golgi Apparatus.[14] The role of the enzyme POMGnT1 is to catalyse glycosylation specific for alpha-linked terminal mannose, the process where N-acetylglucosamine is added to O-linked mannose of α-dystroglycan.[14] In humans, O-mannosylation is a rare type of glycosylation, occurring in skeletal muscle, brain and nerve glycoproteins.[10] O-mannosylation is used to increase the stability of the interaction between the extracellular basement membrane and α-dystroglycan. Without stabilization, the glycoprotein cannot anchor to the cell, leading to congenital muscular dystrophy (CMD), characterised by severe brain malformations.[16] ## Diagnosis[edit] Medical diagnosis for the MEB usually involves the study of family history, measurement of serum CPK level, molecular testing, muscle biopsy and imaging study.[17] ### Physical examination[edit] People with MEB have distinctive facial dysmorphisms.[18] Rounded forehead, thin and drooping lip, micrognathia, midface retrusion, short nasal bridge are the possible indicative evidence for diagnosis.[2][18] Assessment of motor and mental development, visual ability also provide clues. ### Genetic test[edit] Genetic test can analyze the genome of infants for confirmation of the specific genetic mutation. Mutation in the POMGNT1 is the determinant in the diagnosis of MEB.[19] Several mutations like [c.1539+1G→A], [c.879+5G→T] are the prevalent nucleotide change found in affected people.[18][19] The commonly used practices collect fetal DNA by chronic villus sampling, followed by linkage analysis and direct sequencing to conclude the POMGNT1 gene sequence.[20] The genome determination helps to distinguish other congenital muscular dystrophies before and after birth. However, only some laboratories provide prenatal genetic test to screen for MEB.[2] ### Medical imaging[edit] A brain MRI showing lissencephaly (smooth brain) with ventriculomegaly. MEB can be diagnosed with medical imaging by the shared patterns of brain structural abnormalities. Common practice includes magnetic resonance imaging (MRI) and computerized tomography (CT). They can show the enlargement of ventricle, absence or degeneration of septum pellucidum, pachygyric symptoms, abnormalities in corpus collosum, lissencephaly.[21] Fetal MRI and ultrasound are used as a prenatal diagnostic tool if needed to screen for the disease. Observation like general structural malformation in the third trimester suggests congenital muscular dystrophy.[22] Further diagnostic test is required to make confirmation. Clinically, MRI is preferred over CT scan for its ability to reveal the neuron migration more precisely.[21] The result obtained from CT scan is limited to the size of ventricles and location of white matter whereas only MRI can provide information on cortical problems. ### Muscle biopsy[edit] Muscle biopsy is a means to investigate the muscle tissue. Morphology of muscle cells and other chemical parameters can be used to diagnoses muscle–eye–brian disease. The usage of biopsy includes: #### Histological analysis[edit] Direct examination of muscular tissues can proof muscle dystrophy, which can support the potential diagnosis of MEB. Patients are found to have myofibrils round in shape and in markedly various diameters, later nuclei, regenerating fibers and angulated fibers as a result from atrophy.[17][23] #### Enzymatic assay[edit] The mutation of MEB involves the malfunction of O-mannosyl ß-1,2-N-acetylgucosaminyltransfersase 1. By measuring the enzymatic activity of this protein, the presence of MEB can be affirmed.[17] Fibroblast and lymphoblasts are chosen to be the assayed participants.[24] #### Immunochemistry[edit] Western-blot (immunoblot) can be used to detect the O-mannosyl ß-1,2-N-acetylgucosaminyltransfersase 1 for diagnosis.[23][25] It helps to evaluate the glycosylation state of the protein which it supposed to do. ### Difficulties[edit] As a subtype of muscular dystrophy-dystroglycanopathy, MEB is often confused with other sub-type including Walker–Warburg syndrome and Fukuyama congenital muscular dystrophy.[17][26] All these 3 diseases share similar clinical presentation and are classified as the Type A(severe).[26] Overlapped findings contain clinical presentation and immunochemistry result.[27] The diagnosis has to make distinction among them. The decisive evidences for MEB are: MEB WWS FCMD Epidemiology[17] Finland Worldwide Japan Characteristic result of physical examination Ocular abnormalities[28] Progressive myopia with retinal degeneration Severe malformations Simple myopia and cataract without structural change Common contractures location [17] Elbow and knee Elbow Elbow, knee, ankle and hip Characteristic result of genetic test Major defected gene contributor [17] POMGNT1 POMT1, POMT2 FKTN Minor defected gene contributor[29][30][31] FKRP, FKTN FKRP, FCMD, LARGE, ISPD \-- Characteristic result of MRI Cerebral cortex[32] Diffused dysplasia Diffused cobblestone lissencephaly Frontal polymicrogyria White matter [32] Uneven T1 and T2 prolongation No myelin in cerebrum or cerebellum Delayed cerebral myelination Others Serum creatine kinase level[8][33][34] Normal to elevated Elevated to high level Elevated MEB: muscle–eye–brain disease WWS: Walker–Warburg syndrome FCMD: Fukuyama congenital muscular dystrophy ## Management[edit] There is no current curative treatment for any form of muscle dystrophies and only symptomatic care is available for the patients.[17] The corresponding supportive care to symptoms is:[33][34] Symptom Corresponding support treatment Contractures Physiological therapy and tendon-release surgery if needed Scoliosis Bracing, splinting and corrective surgery such as spinal fixation Muscle weakness Leg braces, wheelchair, occupation therapy Respiratory problem Regular monitoring by spirometry, noninvasive nighttime ventilation, tracheostomy, assisted coughing techniques Learning disabilities Specialized education programs Seizures Anti-seizures medication[35][better source needed] Vision problems Wear special eye glasses [7][35] Nutritional care Nasogastric tubes for short-term usage, gastrostomy for chronic need ## Prognosis[edit] MEB is a milder type of congenital muscle dystrophies, with a survival up to more than 70 years being possible.[34] The severity of MEB determines its prognosis. Though the prognosis is associated with the progression of symptoms, supportive care enhances the quality of life and also the life expectancy.[29] ## Epidemiology[edit] The majority of MEB occurrence is reported in the Finnish population. It is estimated to affect 1 in 50,000 newborns in Finland.[15] MEB is also identified outside of Finland, there were cases of suspected MEB in Japan and Korea.[10] However, worldwide distribution is unclear.[10] According to the European Union, the estimated prevalence of MEB in Europe is 0.12 per 100000.[41] Carrier rates [15] Ethnicity Detection Rate Carrier Frequency Finnish >99% 1 in 50 General Population 88% 1 in 500 The frequency of being a carrier of MEB is 1 in 50 in Finland, carriers for MEB commonly shows no signs or symptoms. However, their offsprings will have a higher chance to be affected by MEB.[15] ## History[edit] MEB was first discovered in Finland. In 1978, a patient from Finland showed symptoms including congenital muscular weakness, severe myopia, glaucoma, optical malformation, mental retardation, retinal hypoplasia, etc.[36] In 1980, 14 more people with similar symptoms were identified in Finland.[37] Similar cases were also published in 1989.[38] The disease was found in Dutch in 1992, 6 people were affected coming from 4 families.[39] After that, more cases were reported outside the Finnish population. MEB is phenotypically similar to the Walker–Warburg syndrome (WWS), both disorders are congenital muscular dystrophy. In 1990, Santavuori argued to distinct MEB from WWS, since MEB is specifically involving muscle weakness and there is a relatively long survival for MEB patients.[40] In the same year, Dobyns further examined the relation of WWS and MEB.[41] In 2001, the cause of MEB was first demonstrated as the mutations in the POMGNT1 gene, causing loss of its function.[42] ## References[edit] 1. ^ "Muscle eye brain disease \| Genetic and Rare Diseases Information Center (GARD) – an NCATS Program". rarediseases.info.nih.gov. Retrieved 27 October 2019. 2. ^ a b c d e f g h i j k l m n "Muscle eye brain disease \| Genetic and Rare Diseases Information Center (GARD) – an NCATS Program". rarediseases.info.nih.gov. Retrieved 2019-03-27. 3. ^ a b Fahnehjelm, Kristina Teär; Ygge, Jan; Engman, Mona-Lisa; Mosskin, Mikael; Santavuori, Pirkko; Malm, Gunilla (2001). "A child with Muscle-Eye-Brain disease". Acta Ophthalmologica Scandinavica. 79 (1): 72–75. doi:10.1034/j.1600-0420.2001.079001072.x. ISSN 1600-0420. PMID 11167293. 4. ^ a b c Haltia, M.; Leivo, I.; Somer, H.; Pihko, H.; Paetau, A.; Kivelä, T.; Tarkkanen, A.; Tomé, F.; Engvall, E. (1997). "Muscle—eye—brain disease: A neuropathological study". Annals of Neurology. 41 (2): 173–180. doi:10.1002/ana.410410208. ISSN 1531-8249. PMID 9029066. 5. ^ Shenoy, Anant M; Markowitz, Jennifer A; Bonnemann, Carsten G; Krishnamoorthy, Kalpathy; Bossler, Aaron D; Tseng, Brian S (March 2010). "Muscle–Eye–Brain Disease". Journal of Clinical Neuromuscular Disease. 11 (3): 124–126. doi:10.1097/CND.0b013e3181c5054d. ISSN 1522-0443. PMC 2925645. PMID 20215985. 6. ^ a b c d Diesen, C (2004-10-01). "POMGnT1 mutation and phenotypic spectrum in muscle–eye–brain disease". Journal of Medical Genetics. 41 (10): e115. doi:10.1136/jmg.2004.020701. ISSN 1468-6244. PMC 1735594. PMID 15466003. 7. ^ a b c Pihko, Helena; Lappi, Marjatta; Raitta, Christina; Sainio, Kimmo; Valanne, Leena; Somer, Hannu; Santavuori, Pirkko (January 1995). "Ocular findings in muscle–eye–brain (MEB) disease: a follow-up study". Brain and Development. 17 (1): 57–61. doi:10.1016/0387-7604(94)00101-3. ISSN 0387-7604. PMID 7762765. S2CID 33926340. 8. ^ a b c d Falsaperla, Raffaele; Praticò, Andrea D.; Ruggieri, Martino; Parano, Enrico; Rizzo, Renata; Corsello, Giovanni; Vitaliti, Giovanna; Pavone, Piero (2016-08-31). "Congenital muscular dystrophy: from muscle to brain". Italian Journal of Pediatrics. 42 (1): 78. doi:10.1186/s13052-016-0289-9. ISSN 1824-7288. PMC 5006267. PMID 27576556. 9. ^ "O52 Visual evoked potentials and electroretinography in brain-dead patients". Neurophysiologie Clinique/Clinical Neurophysiology. 20: 18s. August 1990. doi:10.1016/s0987-7053(05)80490-3. ISSN 0987-7053. 10. ^ a b c d e f g h Taniguchi, K. (2003-03-01). "Worldwide distribution and broader clinical spectrum of muscle–eye–brain disease". Human Molecular Genetics. 12 (5): 527–534. doi:10.1093/hmg/ddg043. ISSN 1460-2083. PMID 12588800. 11. ^ Shenoy, Anant M; Markowitz, Jennifer A; Bonnemann, Carsten G; Krishnamoorthy, Kalpathy; Bossler, Aaron D; Tseng, Brian S (March 2010). "Muscle–Eye–Brain Disease". Journal of Clinical Neuromuscular Disease. 11 (3): 124–126. doi:10.1097/CND.0b013e3181c5054d. ISSN 1522-0443. PMC 2925645. PMID 20215985. 12. ^ a b Raducu, Madalina; Cotarelo, Rocío P.; Simón, Rogelio; Camacho, Ana; Rubio-Fernández, Marcos; Hernández-Laín, Aurelio; Cruces, Jesús (February 2014). "Clinical Features and Molecular Characterization of a Patient with Muscle–Eye–Brain Disease: A Novel Mutation in the POMGNT1 Gene". Journal of Child Neurology. 29 (2): 289–294. doi:10.1177/0883073813509119. hdl:10261/124385. ISSN 0883-0738. PMID 24282183. S2CID 9209393. 13. ^ Santavuori, P.; Leisti, J.; Kruus, S. (1977). "Muscle, Eye and Brain Disease: A New Syndrome". Neuropediatrics. 8 (S 01): 553. doi:10.1055/s-0028-1091594. ISSN 0174-304X. 14. ^ a b c Reference, Genetics Home. "POMGNT1 gene". Genetics Home Reference. Retrieved 2019-03-27. 15. ^ a b c d "Muscle-eye brain disease - Gene : POMGNT1". GeneAware. Retrieved April 30, 2020. 16. ^ Strahl, Sabine; Lommel, Mark (2009-08-01). "Protein O-mannosylation: Conserved from bacteria to humans". Glycobiology. 19 (8): 816–828. doi:10.1093/glycob/cwp066. ISSN 0959-6658. PMID 19429925. 17. ^ a b c d e f g h S, Gosal Gurinder; H, Shah Hitesh (March 2011). "Muscle–Eye–Brain Disease; a Rare Form of Syndromic Congenital Muscular Dystrophy". Malaysian Orthopaedic Journal. 5 (1): 67–70. doi:10.5704/moj.1103.016. ISSN 1985-2533. 18. ^ a b c A, Diesen, C Saarinen, A Pihko, H Rosenlew, C Cormand, B Dobyns, W Dieguez, J Valanne, L Joensuu, T Lehesjoki (October 2004). POMGnT1 mutation and phenotypic spectrum in muscle–eye–brain disease. BMJ Group. OCLC 679802406. PMID 15466003. 19. ^ a b Saredi, S.; Ardissone, A.; Ruggieri, A.; Mottarelli, E.; Farina, L.; Rinaldi, R.; Silvestri, E.; Gandioli, C.; D'Arrigo, S. (July 2012). "Novel POMGNT1 point mutations and intragenic rearrangements associated with muscle–eye–brain disease". Journal of the Neurological Sciences. 318 (1–2): 45–50. doi:10.1016/j.jns.2012.04.008. ISSN 0022-510X. PMC 3405532. PMID 22554691. 20. ^ Balci, Burcu; Morris-Rosendahl, Deborah J.; Çelebi, Asli; Talim, Beril; Topalo??lu, Haluk; Dinçer, Pervin (2006). "Prenatal diagnosis of muscle–eye–brain disease". Prenatal Diagnosis. 27 (1): 51–54. doi:10.1002/pd.1622. ISSN 0197-3851. PMID 17154333. 21. ^ a b Valanne, L.; Pihko, H.; Katevuo, K.; Karttunen, P.; Somer, H.; Santavuori, P. (August 1994). "MRI of the brain in muscle–eye–brain (MEB) disease". Neuroradiology. 36 (6): 473–476. doi:10.1007/BF00593687. ISSN 0028-3940. PMID 7991095. S2CID 19829870. 22. ^ Millichap, J. J.; Nguyen, T.; Ryan, M. E. (2010-05-31). "Teaching NeuroImages: Prenatal MRI of muscle–eye–brain disease". Neurology. 74 (22): e101. doi:10.1212/wnl.0b013e3181e0f84b. ISSN 0028-3878. PMID 20513809. 23. ^ a b Raducu, Madalina; Cotarelo, Rocío P.; Simón, Rogelio; Camacho, Ana; Rubio-Fernández, Marcos; Hernández-Laín, Aurelio; Cruces, Jesús (2013-11-25). "Clinical Features and Molecular Characterization of a Patient with Muscle–Eye–Brain Disease" (PDF). Journal of Child Neurology. 29 (2): 289–294. doi:10.1177/0883073813509119. hdl:10261/124385. ISSN 0883-0738. PMID 24282183. S2CID 9209393. 24. ^ Vajsar, Jiri; Zhang, Wenli; Dobyns, William B.; Biggar, Doug; Holden, Kenton R.; Hawkins, Cynthia; Ray, Peter; Olney, Ann H.; Burson, Catherine M. (February 2006). "Carriers and patients with muscle–eye–brain disease can be rapidly diagnosed by enzymatic analysis of fibroblasts and lymphoblasts". Neuromuscular Disorders. 16 (2): 132–136. doi:10.1016/j.nmd.2005.11.012. ISSN 0960-8966. PMID 16427280. S2CID 21928381. 25. ^ Geis, Tobias; Marquard, Klaus; Rödl, Tanja; Reihle, Christof; Schirmer, Sophie; von Kalle, Thekla; Bornemann, Antje; Hehr, Ute; Blankenburg, Markus (2013-09-20). "Homozygous dystroglycan mutation associated with a novel muscle–eye–brain disease-like phenotype with multicystic leucodystrophy". Neurogenetics. 14 (3–4): 205–213. doi:10.1007/s10048-013-0374-9. ISSN 1364-6745. PMID 24052401. S2CID 15027740. 26. ^ a b Amberger, Joanna; Bocchini, Carol; Hamosh, Ada (2011-04-05). "A new face and new challenges for Online Mendelian Inheritance in Man (OMIM®)". Human Mutation. 32 (5): 564–567. doi:10.1002/humu.21466. ISSN 1059-7794. PMID 21472891. 27. ^ Bertini, Enrico; D'Amico, Adele; Gualandi, Francesca; Petrini, Stefania (December 2011). "Congenital Muscular Dystrophies: A Brief Review". Seminars in Pediatric Neurology. 18 (4): 277–288. doi:10.1016/j.spen.2011.10.010. PMC 3332154. PMID 22172424. 28. ^ Cormand, Bru; Avela, Kristiina; Pihko, Helena; Santavuori, Pirkko; Talim, Beril; Topaloglu, Haluk; de la Chapelle, Albert; Lehesjoki, Anna-Elina (January 1999). "Assignment of the Muscle–Eye–Brain Disease Gene to 1p32-p34 by Linkage Analysis and Homozygosity Mapping". The American Journal of Human Genetics. 64 (1): 126–135. doi:10.1086/302206. ISSN 0002-9297. PMC 1377710. PMID 9915951. 29. ^ a b Wang, Ching H.; Bonnemann, Carsten G.; Rutkowski, Anne; Sejersen, Thomas; Bellini, Jonathan; Battista, Vanessa; Florence, Julaine M.; Schara, Ulrike; Schuler, Pamela M. (December 2010). "Consensus Statement on Standard of Care for Congenital Muscular Dystrophies". Journal of Child Neurology. 25 (12): 1559–1581. doi:10.1177/0883073810381924. ISSN 0883-0738. PMC 5207780. PMID 21078917. 30. ^ Kang, P. B.; Morrison, L.; Iannaccone, S. T.; Graham, R. J.; Bonnemann, C. G.; Rutkowski, A.; Hornyak, J.; Wang, C. H.; North, K. (2015-03-31). "Evidence-based guideline summary: Evaluation, diagnosis, and management of congenital muscular dystrophy: Report of the Guideline Development Subcommittee of the American Academy of Neurology and the Practice Issues Review Panel of the American Association of Neuromuscular & Electrodiagnostic Medicine". Neurology. 84 (13): 1369–1378. doi:10.1212/WNL.0000000000001416. ISSN 0028-3878. PMC 4388744. PMID 25825463. 31. ^ Sparks, Susan E.; Quijano-Roy, Susana; Harper, Amy; Rutkowski, Anne; Gordon, Erynn; Hoffman, Eric P.; Pegoraro, Elena (1993). "Congenital Muscular Dystrophy Overview – ARCHIVED CHAPTER, FOR HISTORICAL REFERENCE ONLY". In Adam, Margaret P.; Ardinger, Holly H.; Pagon, Roberta A.; Wallace, Stephanie E. (eds.). Congenital Muscular Dystrophy Overview. GeneReviews®. University of Washington, Seattle. PMID 20301468. Retrieved 2019-03-27. 32. ^ a b Barkovich, A. J. (September 1998). "Neuroimaging manifestations and classification of congenital muscular dystrophies". AJNR. American Journal of Neuroradiology. 19 (8): 1389–1396. ISSN 0195-6108. PMID 9763366. 33. ^ a b Kirschner, Janbernd (2013), "Congenital muscular dystrophies", Pediatric Neurology Part III, Handbook of Clinical Neurology, 113, Elsevier, pp. 1377–1385, doi:10.1016/b978-0-444-59565-2.00008-3, ISBN 9780444595652, PMID 23622361, retrieved 2019-03-27 34. ^ a b c Horrocks, I.; Muntoni, F.; Longman, C.; Joseph, S. (2014-10-01). "G.P.315: Cases of normal to mildly elevated creatine kinase in muscle–eye–brain disease patients and delay in diagnosis". Neuromuscular Disorders. 24 (9): 916. doi:10.1016/j.nmd.2014.06.405. ISSN 0960-8966. S2CID 53300651. 35. ^ a b "https://myriadwomenshealth.com/2014/05/hello-world/". Myriad Women's Health. Retrieved 2019-03-27. External link in `\|title=` (help) 36. ^ RAITTA, CHRISTINA; LAMMINEN, MAIJA; SANTAVUORI, PIRKKO; LEISTI, JAAKKO (2009-05-27). "Ophthalmological Findings in a New Syndrome with Muscle, Eye and Brain Involvement". Acta Ophthalmologica. 56 (3): 465–472. doi:10.1111/j.1755-3768.1978.tb05700.x. ISSN 1755-375X. PMID 581135. 37. ^ W., Eriksson, Aldur (1980). Population structure and genetic disorders : Mariehamm, Åland Islands, Finland, August 1978. Academic Pr. ISBN 0122414500. OCLC 313921203. 38. ^ Santavuori, P.; Somer, H.; Sainio, K.; Rapola, J.; Kruus, S.; Nikitin, T.; Ketonen, L.; Leisti, J. (1989). "Muscle–eye–brain disease (MEB)". Brain & Development. 11 (3): 147–153. doi:10.1016/S0387-7604(89)80088-9. ISSN 0387-7604. PMID 2751061. S2CID 4702708. 39. ^ Leyten, Q. H.; Gabreëls, F. J.; Renier, W. O.; Renkawek, K.; ter Laak, H. J.; Mullaart, R. A. (December 1992). "Congenital muscular dystrophy with eye and brain malformations in six Dutch patients". Neuropediatrics. 23 (6): 316–320. doi:10.1055/s-2008-1071365. ISSN 0174-304X. PMID 1491751. 40. ^ Santavuori, P.; Pihko, H.; Sainio, K.; Lappi, M.; Somer, H.; Haltia, M.; Raitta, C.; Ketonen, L.; Leisti, J. (July 1990). "Muscle–eye–brain disease and Walker–Warburg syndrome". American Journal of Medical Genetics. 36 (3): 371–374. doi:10.1002/ajmg.1320360334. ISSN 0148-7299. PMID 2363444. 41. ^ Dobyns, William B.; Pagon, Roberta A.; Curry, Cynthia J. R.; Greenberg, Frank (July 1990). "Response to Santavuori et al. regarding Walker–Warburg syndrome and muscle–eye–brain disease". American Journal of Medical Genetics. 36 (3): 373–374. doi:10.1002/ajmg.1320360335. ISSN 0148-7299. 42. ^ Yoshida, A.; Kobayashi, K.; Manya, H.; Taniguchi, K.; Kano, H.; Mizuno, M.; Inazu, T.; Mitsuhashi, H.; Takahashi, S. (November 2001). "Muscular dystrophy and neuronal migration disorder caused by mutations in a glycosyltransferase, POMGnT1". Developmental Cell. 1 (5): 717–724. doi:10.1016/S1534-5807(01)00070-3. ISSN 1534-5807. PMID 11709191. 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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: "Hh blood group" – news · newspapers · books · scholar · JSTOR (October 2019) (Learn how and when to remove this template message) hh,[1] or the Bombay blood group, is a rare blood type. This blood phenotype was first discovered in Bombay, now known as Mumbai, in India, by Dr. Y. M. Bhende in 1952. It is mostly found in the Indian sub-continent (India, Bangladesh, Pakistan) and parts of the Middle East such as Iran. ## Contents * 1 Problems with blood transfusion * 2 Incidence * 3 Biochemistry * 4 Genetics * 5 Hemolytic disease of the newborn * 6 References * 7 External links ## Problems with blood transfusion[edit] The first person found to have the Bombay phenotype had a blood type that reacted to other blood types in a way never seen before. The serum contained antibodies that attacked all red blood cells of normal ABO phenotypes. The red blood cells appeared to lack all of the ABO blood group antigens and to have an additional antigen that was previously unknown. Individuals with the rare Bombay phenotype (hh) do not express H antigen (also called substance H), the antigen which is present in blood group O. As a result, they cannot make A antigen (also called substance A) or B antigen (substance B) on their red blood cells, whatever alleles they may have of the A and B blood-group genes, because A antigen and B antigen are made from H antigen. For this reason people who have Bombay phenotype can donate red blood cells to any member of the ABO blood group system (unless some other blood factor gene, such as Rh, is incompatible), but they cannot receive blood from any member of the ABO blood group system (which always contains one or more of A, B or H antigens), but only from other people who have Bombay phenotype. Receiving blood which contains an antigen which has never been in the patient's own blood causes an immune reaction due to the immune system of a hypothetical receiver producing immunoglobulins not only against antigen A and B, but also against H antigen. The most common immunoglobulins synthesized are IgM and IgG. This seems to have a very important role in the low frequency of hemolytic disease of the newborn among non-Bombay offspring of Bombay mothers. It is very important, in order to avoid any complications during a blood transfusion, to detect Bombay phenotype individuals, because the usual tests for ABO blood group system would show them as group O. Since anti-H immunoglobulins can activate the complement cascade, it will lead to the lysis of red blood cells while they are still in the circulation, provoking an acute hemolytic transfusion reaction. This, of course, cannot be prevented unless the lab technologist that is involved is aware of the existence of the Bombay blood group and has the means to test for it. ## Incidence[edit] This very rare phenotype is generally present in about 0.0004% (about 4 per million) of the human population, though in some places such as Mumbai (formerly Bombay) locals can have occurrences in as much as 0.01% (1 in 10,000) of inhabitants. Given that this condition is very rare, any person with this blood group who needs an urgent blood transfusion will probably be unable to get it, as no blood bank would have any in stock. Those anticipating the need for blood transfusion may bank blood for their own use, but of course this option is not available in cases of accidental injury. For example, by 2017 only one Colombian person was known to have this phenotype, and blood had to be imported from Brazil for a transfusion.[2] ## Biochemistry[edit] Biosynthesis of the H, A and B antigens involves a series of enzymes (glycosyl transferases) that transfer monosaccharides. The resulting antigens are oligosaccharide chains, which are attached to lipids and proteins that are anchored in the red blood cell membrane. The function of the H antigen, apart from being an intermediate substrate in the synthesis of ABO blood group antigens, is not known, although it may be involved in cell adhesion. People who lack the H antigen do not suffer from deleterious effects, and being H-deficient is only an issue if they need a blood transfusion, because they would need blood without the H antigen present on red blood cells. The specificity of the H antigen is determined by the sequence of oligosaccharides. More specifically, the minimum requirement for H antigenicity is the terminal disaccharide fucose-galactose, where the fucose has an alpha(1-2)linkage. This antigen is produced by a specific fucosyl transferase (Galactoside 2-alpha-L-fucosyltransferase 2) that catalyzes the final step in the synthesis of the molecule. Depending upon a person's ABO blood type, the H antigen is converted into either the A antigen, B antigen, or both. If a person has group O blood, the H antigen remains unmodified. Therefore, the H antigen is present more in blood type O and less in blood type AB. Hh antigen system \- diagram showing the molecular structure of the ABO(H) antigen system Two regions of the genome encode two enzymes with very similar substrate specificities: the H locus (FUT1) which encodes the Fucosyl transferase and the Se locus (FUT2) that instead indirectly encodes a soluble form of the H antigen, which is found in bodily secretions. Both genes are on chromosome 19 at q.13.3. - FUT1 and FUT2 are tightly linked, being only 35 kb apart. Because they are highly homologous, they are likely to have been the result of a gene duplication of a common gene ancestor. The H locus contains four exons that span more than 8 kb of genomic DNA. Both the Bombay and para-Bombay phenotypes are the result of point mutations in the FUT1 gene. At least one functioning copy of FUT1 needs to be present (H/H or H/h) for the H antigen to be produced on red blood cells. If both copies of FUT1 are inactive (h/h), the Bombay phenotype results. The classical Bombay phenotype is caused by a Tyr316Ter mutation in the coding region of FUT1. The mutation introduces a stop codon, leading to a truncated enzyme that lacks 50 amino acids at the C-terminal end, rendering the enzyme inactive. In Caucasians, the Bombay phenotype may be caused by a number of mutations. Likewise, a number of mutations have been reported to underlie the para-Bombay phenotype. The Se locus contains the FUT2 gene, which is expressed in secretory glands. Individuals who are "secretors" (Se/Se or Se/se) contain at least one copy of a functioning enzyme. They produce a soluble form of H antigen that is found in saliva and other bodily fluids. "Non-secretors" (se/se) do not produce soluble H antigen. The enzyme encoded by FUT2 is also involved in the synthesis of antigens of the Lewis blood group. ## Genetics[edit] Bombay phenotype occurs in individuals who have inherited two recessive alleles of the H gene (i.e.: their genotype is hh). These individuals do not produce the H carbohydrate that is the precursor to the A and B antigens, meaning that individuals may possess alleles for either or both of the A and B alleles without being able to express them. Because both parents must carry this recessive allele to transmit this blood type to their children, the condition mainly occurs in small closed-off communities where there is a good chance of both parents of a child either being of Bombay type, or being heterozygous for the h allele and so carrying the Bombay characteristic as recessive. Other examples may include noble families, which are inbred due to custom rather than local genetic variety. ## Hemolytic disease of the newborn[edit] In theory, the maternal production of anti-H during pregnancy might cause hemolytic disease in a fetus who did not inherit the mother's Bombay phenotype. In practice, cases of HDN caused in this way have not been described. This may be possible due to the rarity of the Bombay phenotype but also because of the IgM produced by the immune system of the mother. Since IgMs are not transported across the microscopic placental blood vessels (like IgG are) they cannot reach the blood stream of the fetus to provoke the expected acute hemolytic reaction. ## References[edit] 1. ^ Dean L. (2005). "6: The Hh blood group". Blood Groups and Red Cell Antigens. Bethesda, MD: National Center for Biotechnology Information (US) ll. Retrieved 2013-02-12. 2. ^ Colprensa (2017-07-13). "La primera importación de sangre salvó a una niña paisa" [The first import of blood saved a paisa girl]. El Colombiano (in Spanish). Medellín. Retrieved 2017-07-13. ## External links[edit] * Hh at BGMUT Blood Group Antigen Gene Mutation Database at NCBI, NIH * RMIT University The Bombay, para-Bombay and other H deficiencies * BombayBloodGroup.Org an initiative to connect individuals who donate and who are in need of Bombay blood group. * Genetics of the Bombay Phenotype * Bombay Blood Group * know more * v * t * e Blood transfusion and transfusion medicine Blood products * Whole blood * Platelets * Platelet transfusion * Red blood cells * Plasma * Fresh frozen plasma * PF24 * Cryoprecipitate * Cryosupernatant * White blood cells * Granulocyte transfusion * Blood substitutes General concepts * Blood donation * Methods * Apheresis (plasmapheresis, plateletpheresis, leukapheresis) * Exchange transfusion * Intraoperative blood salvage * Tests * Blood typing * Cross-matching * Coombs test * Blood bank * International Society of Blood Transfusion * ISBT 128 Transfusion reactions and adverse effects * Transfusion hemosiderosis * Transfusion related acute lung injury * Transfusion associated circulatory overload * Transfusion-associated graft versus host disease * Febrile non-hemolytic transfusion reaction * Hemolytic reaction * acute * delayed * Serum sickness * Transfusion transmitted infection Blood group systems * Blood types * ABO * Secretor status * Augustine * CD59 * Chido-Rodgers * Colton * Cromer * Diego * Dombrock * Duffy * Er * FORS * Gerbich * GIL * GLOB * Hh * Ii * Indian * JR * JMH * KANNO * Kell (Xk) * Kidd * Knops * Lan * Lewis * Lutheran * LW * MNS * OK * P * Raph * Rh and RHAG * Scianna * Sid * T-Tn * Vel * Xg * Yt * Other [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 inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors	hh blood group	c1859408	1,821	wikipedia	https://en.wikipedia.org/wiki/Hh_blood_group	2021-01-18T18:56:55	{"umls": ["C1859408"], "wikidata": ["Q545403"]}
This article is about the history of human immunodeficiency virus (HIV) and acquired immune deficiency syndrome (AIDS) in Australia. For a history of the disease worldwide, see AIDS pandemic. The history of HIV/AIDS in Australia is distinctive, as Australian government bodies recognised and responded to the AIDS pandemic relatively swiftly, with the implementation of effective disease prevention and public health programs, such as needle and syringe programs (NSPs). As a result, despite significant numbers of at-risk group members contracting the virus in the early period following its discovery, the country achieved and has maintained a low rate of HIV infection in comparison to the rest of the world. At the end of 2017, 27,545 people were estimated to be living with HIV in Australia. 20,922 infections were attributable to male‐to‐male sex exposure, 6,245 to heterosexual sex, 605 to injecting drug use, and 168 to ‘other’ exposures (vertical transmission to newborn, blood/tissue recipient, healthcare setting, haemophilia/coagulation disorder).[1] AIDS is no longer considered an epidemic or a public health issue in Australia, due to the success of anti-retroviral drugs and extremely low HIV-to-AIDS progression rates.[2] ## Contents * 1 Australian responses to HIV/AIDS * 2 HIV/AIDS and Australian law * 2.1 Deliberate or reckless transmission * 2.2 Discrimination * 2.3 Blood donations * 3 HIV/AIDS and Pregnant Australian Women * 3.1 Contracting HIV/AIDS * 3.2 Pregnant while HIV-positive * 3.3 Stigma associated towards Women with HIV/AIDS * 4 Ongoing research and awareness-raising * 5 HIV/AIDS in Australia since 2000 * 6 Infection rates in Australia * 6.1 XX International AIDS Conference (2014) * 7 Antiretroviral treatments * 8 See also * 9 Bibliography * 10 References * 11 External links Estimated AIDS diagnoses by year in Australia from data at avert.org The first Australian case was in 1981 and this was diagnosed retrospectively in 1994 in an article by Dr Paul Gerrard published in the Medical Journal of Australia (Australia's first case of AIDS?: Pneumocystis carinii pneumonia and HIV in 1981). Further cases of HIV/AIDS were in Sydney in October 1982, and the first Australian death from AIDS occurred in Melbourne in July 1983.[3][4][5] Spurred to action both by the emergence of the disease amongst their social networks and by public hysteria and vilification, gay, lesbian, drug user and sex worker communities and organisations were instrumental in the rapid creation of AIDS councils (though their names varied), sex worker organisations, drug user organisations and positive people's groups. The AIDS councils were formed in South Australia, Victoria and Western Australia in 1983, and in New South Wales, Queensland, Tasmania and the Australian Capital Territory in 1985.[3][6][7][8][9] The state and territory AIDS councils, along with the other national peak organisations representing at-risk groups Australian Injecting & Illicit Drug Users League (AIVL), National Association of People with HIV Australia (NAPWHA), Anwernekenhe National Aboriginal and Torres Strait Islander HIV/AIDS Alliance (ANA), the Scarlet Alliance, and the Australian Federation of AIDS Organisations, all contribute to Australia's response to HIV.[10] Non-governmental organisations formed swiftly and have remained prominent in addressing AIDS in Australia. The most notable include the AIDS Trust of Australia, formed in 1987,[11] The Victorian AIDS Council (VAC),[12] formed in July 1983, and the Bobby Goldsmith Foundation, founded in mid 1984. The Bobby Goldsmith Foundation is one of Australia's oldest HIV/AIDS charities.[13] The Foundation is named in honour of Bobby Goldsmith, one of Australia's early victims of the disease, who was an athlete and active gay community member, who won 17 medals in swimming at the first Gay Olympics, in San Francisco in 1982.[14] The Foundation had its origins in a network of friends who organised care for Goldsmith to allow him to live independently during his illness, until his death in June 1984. This approach to supporting care and independent living in the community is the basis of the Foundation's work, but is also an approach reflected in the activities and priorities of many HIV/AIDS organisations in Australia. In 1985, Eve van Grafhorst was ostracised since she had contracted HIV/AIDS caused by a transfusion of infected blood.[15] The family moved to New Zealand where she died at the age of 11. ## Australian responses to HIV/AIDS[edit] Estimated HIV diagnoses by year from avert.org The Australian health policy response to HIV/AIDS has been characterised as emerging from the grassroots rather than top-down, and as involving a high degree of partnership between government and non-government stakeholders.[16] The capacity of these groups to respond early and effectively was instrumental in lowering infection rates before government-funded prevention programs were operational.[17][18] The response of both governments and NGOs was also based on recognition that social action would be central to controlling the disease epidemic.[19] Grim reaper advertisement In 1987, a well-known advertising program was launched, including television advertisements that featured the grim reaper rolling a ten-pin bowling ball toward a group of people standing in the place of the pins. These advertisements garnered a lot of attention: controversial when released, and continuing to be regarded as effective as well as pioneering television advertising.[20][21] The willingness of the Australian government to use mainstream media to deliver a blunt message through advertising was credited as contributing to Australia's success in managing HIV.[22] However the campaign also contributed to stigma for those living with the disease,[23] particularly in the gay community, an impact one of the advertising scheme's architects later regretted.[24] Australian Governments began in the mid-1980s to pilot or support programs involving needle exchange for intravenous drug users. These remain occasionally controversial, but are reported to have been crucial in keeping the incidence of the disease low, as well as being extremely cost-effective.[25][26] HIV/AIDS quickly became a more severe problem for several countries in the region around Australia, notably Papua New Guinea and Thailand, than it was within Australia itself. This led Australian governments and non-government organisations to place an increasing emphasis on international initiatives, particularly aimed at limiting the spread of the disease. In 2000, the Australian government introduced a $200 million HIV/AIDS prevention program that was targeted at south-east Asia.[27] In 2004, this was increased to $600 million over the six years to 2010 for the government's international HIV/AIDS response program, called Meeting the Challenge.[28] Australian non-government organisations such as the AIDS Trust are also involved in international efforts to combat the illness.[29] ## HIV/AIDS and Australian law[edit] ### Deliberate or reckless transmission[edit] In response to the risks of HIV transmission, some governments (e.g. Denmark) passed legislation designed specifically to criminalise intentional transmission of HIV.[30] Australia has not enacted specific laws, there have been a small number of prosecutions under existing state laws, with four convictions recorded between 2004 and 2006.[31] The case of Andre Chad Parenzee, convicted in 2006 and unsuccessfully appealed in 2007, secured widespread media attention as a result of expert testimony given by a Western Australian medical physicist that HIV did not lead to AIDS.[31][32][33] In February 2008, Hector Smith, aged 41, a male prostitute in the Australian Capital Territory who is HIV-positive, pleaded guilty in the ACT Magistrates Court to providing a commercial sexual service while knowing he was infected with a sexually-transmitted disease (STD) and failing to register as a sex worker.[34] Under ACT law it is illegal to provide or receive commercial sexual services if the person knows, or could reasonably be expected to know, that he or she is infected with a sexually transmitted infection (STI). In January 2009 Melbourne man Michael Neal was jailed for 18 years (with a minimum term of thirteen years, nine months) for deliberately infecting and trying to infect sexual partners with HIV without their knowledge, despite multiple warnings from the Victorian Department of Human Services.[35] ### Discrimination[edit] Australian governments have made it illegal to discriminate against a person on the grounds of their health status, including having HIV/AIDS;[36] for example, see Disability Discrimination Act, 1992 (Cwlth). However HIV positive individuals may still be denied immigration visas on the grounds that their treatment takes up limited resources and is a burden for taxpayers.[37] To end HIV discrimination in Queensland and Australia in general, there is a plan to raise awareness and educate local people on HIV by 2020.[38] This program is supported by government, as well as by many educational and volunteer organizations. The main aim of the program is to educate people about HIV as it will help to prevent it and stop HIV discrimination in the area. ### Blood donations[edit] Main article: Men who have sex with men blood donor controversy Australia was one of the first countries to screen all blood donors for HIV antibodies,[3] with screening in place for all transfused blood since March 1985.[39] This was not before infection was spread through contaminated blood, resulting in legal cases in the 1980s around whether screening had been appropriately implemented. One issue highlighted in the course of those actions was the challenge of medical litigation under statutes of limitation. A medical condition such as HIV that can lie latent or undiagnosed for a long period of time may only emerge after the time period for litigation has elapsed, preventing examination of medical liability.[40] Concerns about the integrity of the blood supply resurfaced following a case of the contraction of HIV by transfusion in Victoria in 1999. This led to the introduction of new blood screening tests, which also improved screening in relation to Hepatitis C.[41] Gay men have sought to donate blood to help increase Australia's blood supply stock, saying this volunteering would, in turn, help reduce discrimination towards LGBT people.[42][43] The Australian Red Cross Blood Service have indicated their concern regarding the possible transmission of HIV and noting they are receptive to a reduction in the current deferral period from 12 to 6 months, but the Australian Therapeutic Goods Administration, has rejected their submission on this issue.[44] ## HIV/AIDS and Pregnant Australian Women[edit] By the end of 2017, there were estimated to be 3,349 women diagnosed with HIV comprising 13.8% of all infections.[1] In 2013, the median age of diagnosis for women is at 30 years of age. The reasons for acquiring the HIV blood test is spread across three circumstances. Firstly, 30.2% of people become physically ill, 17.1% of peoples partner had tested positive therefore they accessed medical assistance and thirdly, 12.9% of people acquired testing due to exposure to a large risk episode.[45] ### Contracting HIV/AIDS[edit] The most common form of transmissions of HIV is through blood, semen, pre-ejaculation, rectal mucus, vaginal fluids and breast milk. Therefore, women need to be extremely cautious when engaging in sexual activity as well as if and when falling pregnant.[46] Often, behaviours that lead to women contracting the HIV virus include engagement in sexual intercourse within a heterosexual relation with someone who already has HIV/AIDS, using drugs intravenously or receiving infected blood products.[45] ### Pregnant while HIV-positive[edit] Stages of pregnancy term[47] stage starts ends Preterm - at 37 weeks Early term 36 weeks 39 weeks Full term 39 weeks 41 weeks Late term 41 weeks 42 weeks Postterm 42 weeks - Risks of passing on the HIV virus to an unborn child is extremely high for women whom have been diagnosed with HIV/AIDS. In Australia, it is a part of routine antenatal testing that mothers undergo a blood test to check for HIV/AIDS.[48] HIV transmission to an unborn child is often called Perinatal HIV transmission, Vertical Transmission or Mother-To-Child-Transmission (MTCT).[49] There are three main ways a mother can risk passing on the HIV virus to her child and that is during the pregnancy via crossing of the placenta, during birth if the baby comes in contact with the mothers bodily fluids and through the practice of breastfeeding.[48][49] Therefore, when falling pregnant it is important for a mother to access additional Antenatal care. Visitation to an infectious disease physician, experienced obstetrician, paediatrician and midwife is recommended. As well as accessing additional psycho-social support such as a counselor and support worker.[49] To reduce the risks of MTCT the mother can start preparing prenatally with a series of anti-retroviral medications. Using other means of conception practices such as the method of 'sperm washing'. This is where the sperm cells are separated from the seminal fluid and used to fertilise a woman's eggs via the use of a catheter or in vitro fertilisation (IVF) methods.[46] Seeking additional medical checkups to observe clinical markers determining disease progression along with regular observations of baby's development can also help in monitoring the health of the baby.[45][48] Pregnant woman In addition, the postnatal care taken to reduce risks of MTCT include avoiding procedures where the baby's skin may be cut or electing to have a cesarean section to reduce the risk of contact with body fluids.[49] Ensuring the baby's eyes and head are cleaned, the umbilical cord is clamped as soon as possible and placing an absorption pack (towel or sponge) over the umbilical cord when cut to prevent blood spurting will also reduce the risk of the baby coming in contact with any contaminated fluids.[49] Bottle feeding the baby also removes any chance of coming in contact with infected body fluids.[46] Along with the mother taking anti-retroviral medication, giving the baby a course of this until it is 4–6 weeks of age also drastically reduces its risk of transmission.[48] Medical practitioners also require the infant undergo regular blood tests at 1 week, 6 weeks, 12 weeks, 6 months, 12 months and 18 months to test for any evidence of the HIV virus.[48] ### Stigma associated towards Women with HIV/AIDS[edit] Isolation due to Stigma Association with HIV/AIDS within Australia is largely absent from the mainstream population. Therefore, in 2009, 73.6% of women diagnosed with HIV/AIDS reported unwanted disclosure of their health status due to a lack of awareness and knowledge about the disease.[45] This was due to the large amount of stigma associated with a HIV diagnosis. The emotional and psychological problems for pregnant mothers within Australia are extremely high. 42% of women diagnosed with HIV/AIDS are also diagnosed with a mental health condition due to the harsh effects of the arising stigma around such circumstances.[50] The stigma associated with HIV diagnosis in women often involves evoked assumptions that these women are considered a part of the sex trade industry, are homosexual or are intravenous drug users.[51] These women are often viewed as contagious and are assumed to have devious traits and behaviours. In western society, socially specific roles expected of women, such as motherhood, create automatic discrimination when diagnosed with HIV/AIDS.[45] Those women diagnosed with HIV/AIDS who express the idea of wanting to become pregnant are often discriminated against as being selfish, inconsiderate, uncaring and immoral.[51] Healthcare professionals and practitioners are often reported as having negative attitudes towards women who openly identify with having HIV/AIDS and being pregnant or wanting to become pregnant.[51] ## Ongoing research and awareness-raising[edit] The Sydney Mardi Gras, one of the largest street parades and gay and lesbian events in the world,[52] has HIV/AIDS as a significant theme, and is one of a number of pathways through which the non-government sector in Australia continues to address the disease.[53] Australian researchers have been active in HIV/AIDS research since the early 1980s.[54] The most prominent research organisation is the Kirby Institute (formerly National Centre in HIV Epidemiology & Clinical Research), based at the University of New South Wales, regarded as a leading research institution internationally, and a recipient of one of the first grants of the Bill & Melinda Gates Foundation outside the United States.[55] The Centre focusses on epidemiology, clinical research and clinical trials.[56] It also prepares the annual national surveillance reports on the disease. In 2006 the Centre received just under A$4 million in Commonwealth government funding, as well as several million dollars of funding from both public and pharmaceutical industry sources.[57] Three other research centres are also directly Commonwealth funded to investigate different facets of HIV/AIDS: the National Centre in HIV Social Research (NCHSR); the Australian Centre for HIV and Hepatitis Virology Research (ACH2) (formerly the National Centre for HIV Virology Research); and the Australian Research Centre in Sex, Health and Society (ARCSHS). Research has identified anal mucus as a significant carrier of the HIV virus,[58] with the risk of HIV infection after one act of unprotected receptive anal sex being approximately 20 times greater than after one act of unprotected vaginal sex.[59] Anal sex, risk-reduction strategies have been identified and promoted to reduce the likelihood of transmission of HIV/AIDS.[60][61] ## HIV/AIDS in Australia since 2000[edit] While the spread of the disease has been limited with some success, HIV/AIDS continues to present challenges in Australia. The Bobby Goldsmith Foundation reports that nearly a third of people with HIV/AIDS in New South Wales (the state with the largest infected population) are living below the poverty line.[13] Living with HIV/AIDS is associated with significant changes in employment and accommodation circumstances.[62][63] Survival time for people with HIV has improved over time, in part through the introduction of antiretroviral drug treatments[64] with post-exposure prophylaxis treatments reducing the possibility of seroconversion and minimising the likelihood of HIV progression to AIDS. However, HIV does have its own health issues.[65][66] After the initial success in limiting the spread of HIV, infection rates began to rise again in Australia, though they remained low by global standards. After dropping to 656 new reported cases in 2000, the rate rose to 930 in 2005.[67] Transmission continued to be predominantly through sexual contact between men, in contrast to many high-prevalence countries in which it was increasingly spread through heterosexual sex.[67][68] Indeed, the majority of new Australian cases of HIV/AIDS resulting from heterosexual contact have arisen through contact with a partner from a high-prevalence country (particularly from sub-Saharan Africa or parts of south-east Asia).[69] The new trend toward an increase in HIV infections prompted the government to indicate it was considering a return to highly visible advertising.[70] Reflecting this concern with the rise in new cases, Australia's fifth National HIV/AIDS Strategy (for the period 2005–2008) was titled Revitalising Australia's Response, and placed an emphasis on education and the prevention of transmission.[71] On 19 October 2010, The Sydney Morning Herald reported that 21,171 Australians have HIV, with 1,050 new cases diagnosed in 2009. The Sydney Morning Herald also reported that 63% of Australians living with HIV were men who have sex with men (MSM), and 3% were injecting drug users.[72] ## Infection rates in Australia[edit] In 2017 it was estimated 27,545 people living with HIV in Australia. In 2017, 63% of HIV notifications were attributed to sexual contact between men. 25% of cases were attributed to heterosexual sex, 5% to a combination of sexual contact between men and injecting drug use, 3% to injecting drug use only, and 3% to other/unspecified.[73] The Australian Federation of Aids Organisations reports that there has been a consistent decline in new HIV infections among men who have sex with men (MSM).[74]After peaking at 1,084 new diagnosed cases in 2014, the rate has dropped each year to reach 833 in 2018.[74] They estimate 6.3% of all MSM in Australia are living with HIV. While there has been a dramatic decrease in MSM with an 23% decline between 2014 and 2018, this has been partially offset by a 19% increase in case attributed to heterosexual sex during the same period.[74][1] ### XX International AIDS Conference (2014)[edit] From 20 to 25 July 2014, Melbourne, Australia hosted the XX International AIDS Conference. Speakers included Michael Kirby, Richard Branson and Bill Clinton. Clinton's focus was HIV treatment and he called for a greater levels of treatment provision worldwide;[75][76] in an interview during the conference, Kirby focused on legal issues and their relationship to medication costs and vulnerable groups—Kirby concluded by calling for an international inquiry: > And what is needed, as the Global Commission on HIV and the Law pointed out, is a new inquiry at international level – inaugurated by the secretary-general of the United Nations – to investigate a reconciliation between the right to health and the right of authors to proper protection for their inventions. At the moment, all the eggs are in the basket of the authors, and it's not really a proportionate balance. And that's why the Global Commission suggested that there should be a high level of investigation.[76] Branson, Global Drug Commissioner at the time of the conference, stressed the importance of decriminalising illicit injecting drug use to the prevention of HIV and, speaking in global terms, stated that "we're using too much money and far too many precious resources on incarceration".[77] The Open Society Foundation launched the "To Protect and Serve How Police, Sex Workers, and People Who Use Drugs Are Joining Forces to Improve Health and Human Rights" report at the conference.[78] The International AIDS Society (IAS) confirmed that six passengers on board the Malaysia Airlines Flight 17 shot down over Ukraine were killed. The six delegates were acknowledged during the conference at the AIDS 2014 Candlelight Vigil event.[77][79] ## Antiretroviral treatments[edit] Main article: Management of HIV/AIDS HIV infection is now treatable for those with HIV expecting to live near-normal lifespans, providing they continue taking a regimen of antiretroviral drugs.[80] Post-exposure prophylaxis drugs are generally available in Australia at a subsidised cost through the Pharmaceutical Benefits Scheme (PBS).[81] 84% of (the 24,000[82]) HIV positive gay men were on antiretroviral treatments in 2014.[83] Pre-exposure prophylaxis (PrEP) drugs[84] are used as a means of reducing HIV risk for people who do not have HIV, with some advocates saying it will allow condomless safe-sex.[85] Previously it costs $750 per month to import the drug from overseas.[86] In Australia, PrEP drugs were available, at "about $1,200 per month",[87] following the May 2016 approval of the Therapeutic Goods Administration.[88] Despite the lobbying to have these PrEP drugs subsidised under the Pharmaceutical Benefits Scheme,[86][89] in August 2016 it was announced that the Pharmaceutical Benefits Advisory Committee had rejected the proposal for this drug to be PBS-subsidised.[87][90] On 9 February 2018, the Pharmaceutical Benefits Advisory Committee (PBAC) announced that PrEP will be subsidised by the Australian Government through the Pharmaceutical Benefit Scheme (PBS).[91] The PBS subsidy came into effect on 1 April 2018, reducing the cost of PrEP to around $40 a month for eligible recipients.[92] ## See also[edit] * LGBT portal * Australia portal * AIDS photo diary, 1986–1990 * Breastfeeding and HIV * Health care in Australia * HIV and men who have sex with men * HIV and pregnancy * HIV drug resistance * HIV Drug Resistance Database * HIV/AIDS research * Management of HIV/AIDS * Men who have sex with men * Pre-exposure prophylaxis * Post-exposure prophylaxis * Subtypes of HIV ## Bibliography[edit] * Altman, Dennis (2001). Global Sex. Chicago: University of Chicago Press. pp. 216. ISBN 0-226-01606-4. * Bowtell, William (May 2005). "Australia's Response to HIV/AIDS 1982–2005" (PDF; requires download). HIV/AIDS Project. Lowy Institute for International Policy. ## References[edit] 1. ^ a b c "HIV in Australia: Annual surveillance short report 2018" (PDF). Kirby Institute. 2. ^ Dalzell, Stephanie (10 July 2016). "AIDS epidemic no longer a public health issue in Australia, scientists say". ABC. Retrieved 10 July 2016. 3. ^ a b c "26 years of HIV/AIDS". World AIDS Day Australia. Archived from the original on 28 August 2007. Retrieved 9 December 2017. 4. ^ Bowtell 2005, p. 15. 5. ^ Ware, Cheryl. HIV survivors in Sydney : memories of the epidemic. Cham, Switzerland. ISBN 9783030051020. OCLC 1097183579. 6. ^ "Vision & History". Queensland Association for Healthy Communities. Archived from the original on 29 August 2007. Retrieved 9 December 2017. 7. ^ "ACSA History". AIDS Council of South Australia. Retrieved 9 December 2017. 8. ^ "History". Western Australian AIDS Council. Archived from the original on 31 August 2007. Retrieved 9 December 2017. 9. ^ "Welcome to TasCAHRD". Tasmanian Council on AIDS, Hepatitis and Related Diseases. Archived from the original on 4 March 2016. Retrieved 9 December 2017. 10. ^ "List of members". Australian Federation of AIDS Organisations. Archived from the original on 30 August 2007. Retrieved 9 December 2017. 11. ^ "About the Trust". AIDS Trust of Australia. Archived from the original on 20 August 2006. Retrieved 9 December 2017. 12. ^ "Under The Red Ribbon". Victorian AIDS Council (VAC/GMHC). Retrieved 9 December 2017. 13. ^ a b "Message from the President". Bobby Goldsmith Foundation. Archived from the original on 2 September 2007. Retrieved 9 December 2017. 14. ^ "Who was Bobby Goldsmith?". Bobby Goldsmith Foundation. Archived from the original on 2 September 2007. Retrieved 9 December 2017. 15. ^ Sendziuk, Paul. "Denying the Grim Reaper: Australian Responses to AIDS". Eureka Street. Archived from the original on 2 April 2016. Retrieved 9 December 2017. 16. ^ Bowtell 2005, p. 18, 21. 17. ^ Bowtell 2005, p. 31. 18. ^ Plummer, D; Irwin, L (December 2006). "Grassroots activities, national initiatives and HIV prevention: clues to explain Australia's dramatic early success in controlling the HIV epidemic". International Journal of STD & AIDS. 17 (12): 787–793. doi:10.1258/095646206779307612. PMID 17212850. 19. ^ Kippax, Susan; Connell, R. W.; Dowsett, G. W.; Crawford, June (1993). Sustaining safe sex: gay communities respond to AIDS. London: Routledge Falmer (Taylor & Francis). p. 1. 20. ^ "Top ads? The creators have their say". The Age. 6 October 2002. Retrieved 24 September 2007. 21. ^ Altman, D (1992). Timewell, E; Minichiello, V; Plummer, D (eds.). The most political of diseases. AIDS in Australia. Prentice Hall. 22. ^ "20 years after Grim Reaper ad, AIDS fight continues". ABC News. Australia. Retrieved 9 December 2017. 23. ^ "HIV and AIDS discrimination and stigma". AVERT. Retrieved 1 September 2007. 24. ^ "Grim Reaper's demonic impact on gay community". B&T. 1 October 2002. Archived from the original on 20 November 2008. Retrieved 9 December 2017. 25. ^ Bowtell 2005, p. 27. 26. ^ "Needle & Syringe Programs: a Review of the Evidence" (PDF). Australian National Council on AIDS, Hepatitis C and Related Diseases. 2000. Retrieved 29 August 2008. 27. ^ "Projecting Australia and its Values". Advancing the National Interest: Australia's Foreign and Trade Policy White Paper. Department of Foreign Affairs and Trade. 2003. Archived from the original on 30 August 2007. Retrieved 9 December 2017. 28. ^ Bowtell 2005, p. 10. 29. ^ "Our Projects: Hope For Children – Cambodia". The AIDS Trust. Archived from the original on 7 June 2008. Retrieved 9 December 2017. 30. ^ "Criminalisation of HIV transmission in Europe". The Global Network of People Living with HIV/AIDS Europe and The Terrence Higgins Trust. 2005. Archived from the original on 10 May 2007. Retrieved 9 December 2017. 31. ^ a b Cameron, Sally (2007). "HIV on Trial". HIV Australia. 5 (4). Archived from the original on 29 August 2007. Retrieved 21 September 2007. 32. ^ Roberts, Jeremy (1 February 2007). "HIV experts line up to refute denier". The Australian. Retrieved 24 September 2007. 33. ^ "NHMRC says link between HIV and AIDS "overwhelming"" (Press release). National Health and Medical Research Council (NHMRC). 4 May 2007. Archived from the original on 29 August 2007. Retrieved 11 September 2007. 34. ^ Corbett, Kate (7 February 2008). "An HIV-positive male prostitute has admitted to potentially spreading the deadly virus". News.com.au. Retrieved 10 February 2008. 35. ^ "Man jailed for trying to spread HIV". Yahoo! News. 6 January 2009. Archived from the original on 21 January 2009. Retrieved 19 January 2009. 36. ^ Bowtell 2005, p. 19. 37. ^ Sean Parnell (6 July 2012). "Sponsored workers bumping up HIV bill". The Australian. News Limited. Retrieved 24 February 2013. 38. ^ "HIV foundation:Australian context". HIVfoundation.org.au. May 2018. 39. ^ Victorian Department of Human Services, Hospitals, AIDS & you Archived 2 September 2007 at the Wayback Machine 40. ^ Dwan v. Farquhar, 1 Qd. R. 234, 1988 41. ^ "Health Ministers agree to new blood screening test" (Press release). Australian Health Ministers. 4 August 1999. Retrieved 29 August 2008. 42. ^ Stott, Rob (19 May 2014). "Blood donation rules continue to exclude healthy donors". News Ltd. Retrieved 20 May 2014. 43. ^ "Frequently Asked Questions". Australian Red Cross Blood Service. Retrieved 20 May 2014. 44. ^ "Fact Finder: Our response to news.com.au's gay blood donation article". Australian Red Cross Blood Service. 19 May 2014. Archived from the original on 8 June 2014. Retrieved 20 May 2014. 45. ^ a b c d e Koelmeyer, Rachel; McDonald, Karalyn; Grierson, Jeffery. "BEYOND THE DATA: HIV-POSITIVE WOMEN IN AUSTRALIA". Australian Federation of AIDS Organisations. Australian Federation of AIDS Organisations. Retrieved 28 April 2015. 46. ^ a b c "HIV and women having children" (PDF). Better Health Channel. State of Victoria. Retrieved 28 April 2015. 47. ^ World Health Organization (November 2013). "Preterm birth". who.int. Retrieved 19 September 2014. 48. ^ a b c d e "HIV and AIDS in pregnancy". BabyCenter. BabyCenter Australia Medical Advisory Board. Retrieved 28 April 2015. 49. ^ a b c d e "Human immunodeficiency virus (HIV) – perinatal". State Government Victoria. Retrieved 28 April 2015. 50. ^ "HIV STATISTICS IN AUSTRALIA: WOMEN". Australian Federation of AIDS Organisations. Australian Federation of AIDS Organisations. Retrieved 28 April 2015. 51. ^ a b c McDonald, Karalyn. "'You don't grow another head': The experience of stigma among HIV-positive women in Australia". HIV Australia. 9 (4): 14–17. 52. ^ "History". New Mardi Gras. Retrieved 9 December 2017. 53. ^ Altman 2001, p. 83. 54. ^ See for example the Publications List of participants in the National Centre in HIV Epidemiology & Clinical Research dating back to 1983. 55. ^ Lebihan, Rachel (16–17 April 2011). "Top class research fails to get local support". Weekend Australian Financial Review. p. 31. 56. ^ "National Centre in HIV Epidemiology & Clinical Research". Retrieved 11 September 2007. 57. ^ "Annual Report" (PDF). National Centre in HIV Epidemiology & Clinical Research. 2006. Retrieved 11 September 2007. 58. ^ "It's time to talk top: the risk of insertive, unprotected anal sex". Australian Federation of AIDS Organisations. November 2011. Archived from the original on 25 June 2014. Retrieved 13 June 2014. 59. ^ "Transmission, sexual acts". Bobby Goldsmith Foundation. 2012. Retrieved 21 July 2014. 60. ^ "Anal sex and risk reduction". Australian Federation of AIDS Organisations. 12 January 2011. Archived from the original on 2 July 2014. Retrieved 13 June 2014. 61. ^ "HIV and men – safe sex". Department of Health, Victoria. June 2012. Retrieved 13 June 2014. 62. ^ Ezzy, D; De Visser, R; Grubb, I; McConachy, D (1998). "Employment, accommodation, finances and combination therapy: the social consequences of living with HIV/AIDS in Australia". AIDS Care. 10 (2): 189–199. doi:10.1080/09540129850124299. PMID 9743740. 63. ^ Ezzy, D; De Visser, R; Bartos, M (1999). "Poverty, disease progression and employment among people living with HIV/AIDS in Australia". AIDS Care. 11 (4): 405–414. doi:10.1080/09540129947785. PMID 10533533. 64. ^ Li, Yueming; McDonald, Ann M; Dore, Gregory J; Kaldor, John M (2000). "Improving survival following AIDS in Australia, 1991–1996". AIDS. 14 (15): 2349–2354. doi:10.1097/00002030-200010200-00016. PMID 11089623. 65. ^ "HIV Fact Sheet". Victorian Aids Council. Archived from the original on 18 July 2014. Retrieved 16 June 2014. 66. ^ Lewis, Dyani (29 November 2013). "Living with HIV in 2013". ABC. Retrieved 16 June 2014. 67. ^ a b McDonald, Ann (2006). "HIV/AIDS, Viral Hepatitis & Sexually Transmissible Infections in Australia Annual Surveillance Report" (PDF). National Centre in HIV Epidemiology and Clinical Research. Archived from the original (PDF) on 3 September 2007. Retrieved 9 December 2017. 68. ^ Altman 2001, p. 78. 69. ^ McDonald, Ann (2007). "HIV infection attributed to heterosexual contact in Australia, 1996 – 2005". HIV Australia. 5 (4). Archived from the original on 29 August 2007. Retrieved 9 December 2017. 70. ^ "Govt considering funding AIDS campaign". The Sydney Morning Herald. AAP. 5 April 2007. Retrieved 9 December 2017. 71. ^ "The National HIV/AIDS Strategy 2005–2008: Revitalising Australia's Response". Department of Health and Ageing. Archived from the original on 22 July 2008. Retrieved 29 August 2008. 72. ^ Benson, Kate (19 October 2010). "HIV rate rising but other infections less common". The Sydney Morning Herald. Retrieved 19 October 2010. 73. ^ Paynter, Heath. "HIV Statistics". Australian Federation of AIDS Organisations. Retrieved 12 March 2020. 74. ^ a b c "HIV in Australia" (PDF). Australian Federation of AIDS Organisations. 2020. Retrieved 12 March 2020. 75. ^ Melissa Davey (23 July 2014). "Aids-free generation within reach if we boost HIV treatment, says Bill Clinton". The Guardian. Retrieved 23 July 2014. 76. ^ a b Michael Kirby (23 July 2014). "'The law can be an awful nuisance in the area of HIV/AIDS': Michael Kirby". The Conversation. Retrieved 23 July 2014. 77. ^ a b "Decriminalisation of drug use – key to ending HIV". Health24. Health24. 22 July 2014. Retrieved 23 July 2014. 78. ^ "To Protect and Serve". Open Society Foundations. Open Society Foundations. July 2014. Retrieved 23 July 2014. 79. ^ Australian Associated Press (19 July 2014). "MH17: AIDS conference organisers name six delegates killed in crash". The Guardian. Retrieved 23 July 2014. 80. ^ Haire, Bridget (14 September 2015). "Five reasons why HIV infections in Australia aren't falling". The Conversation. Retrieved 24 September 2015. 81. ^ "Treating HIV". Queensland Positive People. Retrieved 24 September 2015. 82. ^ "HIV statistics in Australia: men". Retrieved 25 September 2015. 83. ^ Akersten, Matt (14 September 2015). "New stats reveal how HIV treatments are changing sex lives". SameSame. Retrieved 24 September 2015. 84. ^ "Pre-Exposure Prophylaxis (PrEP)". Centers for Disease Control and Prevention. Retrieved 24 September 2015. 85. ^ "Melbourne posters saying gay men can "f*** raw" on PrEP follow report revealing record figures of condomless sex". 18 September 2015. 86. ^ a b Lewis, David. "PrEP: The blue pill being used to prevent HIV, Five perspectives on the drug awaiting approval in Australia". ABC News. Retrieved 24 September 2015. 87. ^ a b Spooner, Rania (19 August 2016). "HIV prevention drug Truvada won't be subsidised in Australia". Sydney Morning Herald. Retrieved 2 September 2016. 88. ^ [1] 89. ^ Riley, Benjamin (3 March 2015). "Prep access for HIV prevention in Australia a step closer as Gilead applies to TGA". Star Observer. Retrieved 24 September 2015. 90. ^ Power, Shannon (19 August 2016). "Outrage as prep drug Truvada denied access to PBS". Star Observer. Retrieved 2 September 2016. 91. ^ "Pre-Exposure Prophylaxis (PrEP)". Australian Federation of AIDS Organisations. Retrieved 24 February 2018. 92. ^ "TENOFOVIR + EMTRICITABINE". Pharmaceutical Benefits Scheme (PBS). Retrieved 22 January 2019. ## External links[edit] Australian government official information source on HIV/AIDS: * Australian Department of Health and Ageing resources on HIV/AIDS in Australia The national peak organisations representing people living with or affected by HIV: * National Association of People with HIV * Australian Injecting & Illicit Drug Users League * Scarlet Alliance, Australian Sex Workers Association The National Federation of AIDS organisations: * Australian Federation of AIDS Organisations The AIDS councils: * AIDS Action Council of the ACT * AIDS Council of New South Wales * Northern Territory AIDS and Hepatitis Council * Queensland Association for Healthy Communities * AIDS Council of South Australia * Tasmanian Council on AIDS, Hepatitis and Related Diseases * Victorian AIDS Council * Western Australian AIDS Council Commonwealth government-funded research centres: * The National Centre in HIV Social Research * The National Centre in HIV Epidemiology and Clinical Research (NCHECR) Other HIV/AIDS organisations: * Bobby Goldsmith Foundation * AIDS Trust of Australia * Positive Life NSW - the voice of people with HIV since 1988 * ASHM \| Supporting the HIV, Viral Hepatitis and Sexual Health Workforce HIV/AIDS initiatives in Australia: * Melbourne Declaration \| Action on HIV! * Implementing the United Nations Political Declaration on HIV/AIDS in Australia's HIV Domestic Response: Turning Political Will into Action[permanent dead link] * v * t * e HIV/AIDS 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 HIV/AIDS topics HIV/AIDS HIV * HIV * Lentivirus * structure and genome * subtypes * CDC classification * disease progression rates * HIV/AIDS * diagnosis * management * pathophysiology * prevention * research * vaccination * PrEP * WHO disease staging system for HIV infection and disease * Children * Teens / Adults * Countries by AIDS prevalence rate Conditions * Signs and symptoms * AIDS-defining clinical condition * Diffuse infiltrative lymphocytosis syndrome * Lipodystrophy * Nephropathy * Neurocognitive disorders * Pruritus * Superinfection * Tuberculosis co-infection * HIV Drug Resistance Database * Innate resistance to HIV * Serostatus * HIV-positive people * Nutrition * Pregnancy History * History * Epidemiology * Multiple sex partners * Timeline * AIDS Museum * Timothy Ray Brown * Women and HIV/AIDS Social * AIDS orphan * Catholic Church and HIV/AIDS * Circumcision and HIV * Criminal transmission * Discrimination against people * Economic impact * Cost of treatment * HIV-affected community * HIV/AIDS activism * HIV/AIDS denialism * Red ribbon * Safe sex * Sex education * List of HIV-positive people * People With AIDS Self-Empowerment Movement * HIV/AIDS in the porn industry Culture * Discredited HIV/AIDS origins theories * International AIDS Conference * International AIDS Society * Joint United Nations Programme on HIV/AIDS (UNAIDS) * Media portrayal of HIV/AIDS * Misconceptions about HIV/AIDS * President's Emergency Plan for AIDS Relief (PEPFAR) * The SING Campaign * Solidays * Treatment Action Campaign * World AIDS Day * YAA/Youthforce * "Free Me" * Larry Kramer * Gay Men's Health Crisis * ACT UP * Silence=Death Project HIV/AIDS pandemic by region / country Africa * Angola * Benin * Botswana * Democratic Republic of the Congo * Egypt * Eswatini * Ethiopia * Ghana * Guinea * Côte d'Ivoire (Ivory Coast) * Kenya * Lesotho * Madagascar * Malawi * Mali * Mozambique * Namibia * Niger * Nigeria * Rwanda * Senegal * Tanzania * 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 inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors	HIV/AIDS in Australia	None	1,822	wikipedia	https://en.wikipedia.org/wiki/HIV/AIDS_in_Australia	2021-01-18T18:34:48	{"wikidata": ["Q5629819"]}
Sinus venosus atrial septal defect ASD locations. (1: upper sinus venosus defect; 2: lower sinus venosus defect.) SpecialtyCardiac surgery A sinus venosus atrial septal defect is a type of atrial septal defect primarily associated with the sinus venosus. They represent 5% of atrial septal defects.[1] They can occur near the superior vena cava or inferior vena cava, but the former are more common.[2] They can be associated with anomalous pulmonary venous connection.[3] ## References[edit] 1. ^ Robbins and Cotran Pathologic Basis of Disease 8th Edition 2. ^ "Yale: Congenital Heart Disease: Sinus Venosus ASD". Retrieved 2009-01-09. 3. ^ Attenhofer Jost CH, Connolly HM, Danielson GK, et al. (September 2005). "Sinus venosus atrial septal defect: long-term postoperative outcome for 115 patients". Circulation. 112 (13): 1953–8. doi:10.1161/CIRCULATIONAHA.104.493775. PMID 16172274. ## External links[edit] Classification D * ICD-10: Q21.1 * ICD-9-CM: 745.8 * MeSH: C548009 C548009, C548009 * v * t * e Congenital heart defects Heart septal defect Aortopulmonary septal defect * Double outlet right ventricle * Taussig–Bing syndrome * Transposition of the great vessels * dextro * levo * Persistent truncus arteriosus * Aortopulmonary window Atrial septal defect * Sinus venosus atrial septal defect * Lutembacher's syndrome Ventricular septal defect * Tetralogy of Fallot Atrioventricular septal defect * Ostium primum Consequences * Cardiac shunt * Cyanotic heart disease * Eisenmenger syndrome Valvular heart disease Right * pulmonary valves * stenosis * insufficiency * absence * tricuspid valves * stenosis * atresia * Ebstein's anomaly Left * aortic valves * stenosis * insufficiency * bicuspid * mitral valves * stenosis * regurgitation Other * Underdeveloped heart chambers * right * left * Uhl anomaly * Dextrocardia * Levocardia * Cor triatriatum * Crisscross heart * Brugada syndrome * Coronary artery anomaly * Anomalous aortic origin of a coronary artery * Ventricular inversion [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 inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors	Sinus venosus atrial septal defect	c0344730	1,823	wikipedia	https://en.wikipedia.org/wiki/Sinus_venosus_atrial_septal_defect	2021-01-18T19:08:44	{"gard": ["10696"], "mesh": ["C548009"], "umls": ["C0344730"], "icd-9": ["745.8"], "icd-10": ["Q21.1"], "orphanet": ["99105"], "wikidata": ["Q7525206"]}
A number sign (#) is used with this entry because of evidence that Oliver-McFarlane syndrome (OMCS) is caused by compound heterozygous mutation in the PNPLA6 (603197) gene on chromosome 19p13. Description Oliver-McFarlane syndrome is a rare congenital disorder characterized by trichomegaly, severe chorioretinal atrophy and multiple pituitary hormone deficiencies, including growth hormone (GH; 139250), gonadotropins (see 118860), and thyroid-stimulating hormone (TSH; see 118850). Thyroid and GH abnormalities may be present at birth and, if untreated, result in intellectual impairment and profound short stature. Congenital hypogonadism occurs in half of patients, and nearly all have documented hypogonadotropic hypogonadism during puberty, with subsequent reproductive dysfunction. Chorioretinal atrophy is typically noted in the first 5 years of life. Half of reported cases have spinocerebellar involvement, including ataxia, spastic paraplegia, and peripheral neuropathy (summary by Hufnagel et al., 2015). Laurence-Moon syndrome (245800) is an allelic disorder with overlapping features. Clinical Features Oliver and McFarlane (1965) described an isolated case of a male child with low-birth weight dwarfism, very long eyelashes and eyebrows, mental retardation, and pigmentary degeneration of the retina. The karyotype was normal and the parents were not consanguineous. Corby et al. (1971) reported a case of the full syndrome. Delleman and Van Walbeek (1975) described a case in a 24-year-old man who had been under observation for 19 years. The retinal degeneration resembled choroideremia. Cryptorchidism, underdevelopment of the penis, frontal alopecia, and bulging of the occipital and frontal bones were noted. Partial trisomy of chromosome 13 was suggested by karyotyping. Patton et al. (1986) reported a Caucasian male with typical features of Oliver-McFarlane syndrome. He presented at 2 years of age with failure to thrive. At that time, he was noted to have long eyelashes (20 mm) with bushy eyebrows and sparse scalp hair. These features had been present at birth. He had a small penis and his testes were not palpable. Examination of his fundi showed extensive peripheral and central choroidoretinal degeneration with pallor of the optic discs. He attended a school for the visually handicapped and had an IQ of 89. At age 10 years he developed obesity and gynecomastia. At age 18, he remained hypogonadal with no secondary characteristics. Endocrine studies showed evidence of hypothyroidism, growth hormone deficiency, and hypogonadotropic hypogonadism. When examined at age 37, he gave a 2-year history of progressive gait ataxia, generalized clumsiness, and titubation of the head. Brain scan showed cerebellar atrophy and an empty sella. Nerve conduction studies showed small or absent sensory action potentials with preserved motor nerve conduction velocities, suggesting an axonal peripheral neuropathy. Sampson et al. (1989) presented a 25-year follow-up of a patient. The father and mother were aged 37 and 28 years, respectively, at the time of the patient's birth. At the age of 2 years, she showed horizontal nystagmus and bilateral choroidoretinal pigmentary degeneration. Ring heterochromia of the iris and trichomegaly were also noted. Alopecia became evident by age 3 and was almost complete by the early teens. Scalp biopsy showed a perifollicular lymphocyte infiltrate which was similar to that seen in alopecia areata. Distal muscle weakness and wasting, affecting particularly the lower limbs, progressed slowly during her first decade. An axonal peripheral neuropathy was found in this patient and in the adult reported by Patton et al. (1986). When the patient was seen at age 15 because of delayed puberty, she was found to have growth hormone deficiency and hypogonadotropic hypogonadism. Treatment with growth hormone resulted in a growth spurt with a final adult height of 153 cm. Zaun et al. (1984) reported a case. Kondoh et al. (2003) stated that 2 female and 5 male patients with this disorder had been reported. They described 2 unrelated boys with trichomegaly and mental retardation, but without pigmentary retinal degeneration. One of them also lacked growth retardation. Haimi and Gershoni-Baruch (2005) described a brother and sister, born of first-cousin Arab parents, who had retinitis pigmentosa, growth failure with mildly delayed cognitive function, long eyelashes, and sparse hair. Haimi and Gershoni-Baruch (2005) concluded that these sibs confirmed the existence of this autosomal recessive condition. Sonmez et al. (2008) described a 13-year-old boy with Oliver-McFarlane syndrome who had prominent early pituitary dysfunction. During the neonatal period he had episodes of recurrent hypoglycemia and was noted to have micropenis and bilateral undescended testes, and thyroid and growth hormone supplementation was initiated. Gross motor development was delayed, and he did not walk independently until 4 years of age; however, his gait was wide-based and unsteady, and he was found to have sensory axonal neuropathy with normal motor nerve findings. Four years later, his sensory nerve action potentials were completely absent, but motor nerve function remained normal. Within a year his walking deteriorated, and he reverted to commando crawling. In addition, at 5 years of age, he had difficulty seeing in low light, and ophthalmologic examination revealed bilateral decreased vision and dramatic choroidal and retinal atrophy associated with retinal pigmentation. At 13 years of age, he could crawl short distances but was otherwise wheelchair dependent, had a moderate degree of learning difficulties, and remained incontinent. He was in the 3rd centile for height and 50th centile for weight, and had long eyelashes, bushy eyebrows, and frontal bossing. He also had hypogonadotropic hypogonadism, and testosterone injections had been commenced to induce puberty. Sonmez et al. (2008) stated that of 12 previously reported cases of Oliver-McFarlane syndrome, the only consistent features in every case were trichomegaly, chorioretinopathy, and prenatal and postnatal growth restrictions. Regarding the progressive deterioration in motor function in their patient, which had been attributed to his severe peripheral neuropathy, the authors noted that peripheral neuropathy had been recognized in 6 earlier cases, and 2 patients also showed evidence of progressive cerebellar ataxia. Inheritance The transmission pattern of Oliver-McFarlane syndrome in the family reported by Haimi and Gershoni-Baruch (2005) was consistent with autosomal recessive inheritance. Molecular Genetics In 6 patients from 5 families with a clinical diagnosis of Oliver-McFarlane syndrome, Hufnagel et al. (2015) identified compound heterozygous mutations in the PNPLA6 gene (see, e.g., 603197.0013-603197.0016). The mutations were found in 3 families by exome-sequencing and in the other 2 families by Sanger sequencing. Familial carrier testing, which was possible in 3 families, showed segregation of the mutation with the phenotype. Hair \- Very long eyelashes and eyebrows \- Frontal alopecia Eyes \- Pigmentary retinal degeneration \- Ring iris heterochromia \- Nystagmus Growth \- Low-birth-weight dwarfism Neuro \- Mental retardation \- Axonal peripheral neuropathy Skull \- Bulging occipital and frontal bones Inheritance \- Autosomal recessive Endocrine \- Growth hormone deficiency \- Hypogonadotropic hypogonadism Muscle \- Distal muscle weakness and wasting GU \- Cryptorchidism \- Underdeveloped penis \- Delayed puberty ▲ 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 inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors	OLIVER-MCFARLANE SYNDROME	c1848745	1,824	omim	https://www.omim.org/entry/275400	2019-09-22T16:21:30	{"doid": ["0111271"], "mesh": ["C536554"], "omim": ["275400"], "orphanet": ["3363"], "synonyms": ["Alternative titles", "TRICHOMEGALY WITH MENTAL RETARDATION, DWARFISM, AND PIGMENTARY DEGENERATION OF RETINA", "EYELASHES, LONG, WITH MENTAL RETARDATION"], "genereviews": ["NBK247161"]}
A number sign (#) is used with this entry because primary ciliary dyskinesia-12 (CILD12) is caused by homozygous mutation in the RSPH9 gene (612648) on chromosome 6p21. For a phenotypic description and a discussion of genetic heterogeneity of primary ciliary dyskinesia, see CILD1 (244400). Clinical Features Castleman et al. (2009) reported 2 unrelated but consanguineous Bedouin families with primary ciliary dyskinesia. One family was from the United Arab Emirates (Emirati), and the other was from Israel. Clinical features included reduced exercise tolerance, chronic wet cough, recurrent respiratory infections, bronchiectasis, and nasal symptoms such as rhinorrhea, rhinitis, nasal blockage, and sinusitis. There was also ear obstruction with consequent hearing problems, low weight, and short stature. One patient had a collapsed lower pulmonary lobe. Electron microscopic studies of affected individuals in 1 family showed an unusual intermittent loss of the central pair of the cilia, such that cilia cross-sections showed a small proportion with 9 + 0 structure in addition to the normal 9 + 2 structure. In the other family, electron microscopy showed a normal axoneme ultrastructure. However, this family was included in the study because of respiratory symptoms, dysmotility of the respiratory cilia, and sperm dysmotility, all consistent with a diagnosis of CILD. Cilia-motility studies showed an abnormal circular movement with a close to normal beat velocity in both families. No patients had laterality defects. Mapping Bianchi et al. (1992) found linkage to the HLA locus on chromosome 6p21 in 2 Italian families, each with 2 sibs affected with CILD. All 4 affected sibs, a male and a female in one family and 2 females in the other, shared the HLA-DR7;DQw2 haplotype. Furthermore, linkage of an ICS susceptibility locus with 6p21 was suggested by the fact that the affected sibs were HLA-identical, whereas the healthy brother in the second family was HLA-different. By genomewide linkage analysis of an Israeli Bedouin family and an Emirati Bedouin family, both with primary ciliary dyskinesia, Castleman et al. (2009) defined a common 1.9-Mb region on chromosome 6p21.1 between markers D6S400 and rs3734693 (multipoint lod score of 6.7 across D6S1604 to D6S451). Molecular Genetics In all 7 affected members of the Israeli Bedouin and Emirati Bedouin families with CILD12, Castleman et al. (2009) identified a homozygous deletion in the RSPH9 gene (612648.0001). Kott et al. (2013) identified pathogenic homozygous mutations in the RSPH9 gene (see, e.g., 612647.0002 and 612647.0003) in 7 families with CILD12. None of the patients had situs inversus. RSPH9 mutations accounted for 8.3% (4 of 48 families) of cases with the specific CILD phenotype characterized by ciliary central microtubule complex and radial spoke defects. Population Genetics Reish et al. (2010) found only a small 1.9-Mb region of homozygosity that showed identity by descent at the chromosome 6p21.1 locus that was shared between the Israeli Bedouin and Emirati Bedouin families with CILD12 reported by Castleman et al. (2009). Haplotype analysis suggested that the most recent common ancestor carrying the mutation was less than 17 generations ago in the Emirati family and less than 95 generations ago in the Israeli family. If the mutations in the 2 families are identical by descent, the mutation probably arose about 150 generations ago. However, the population genetic analysis could not determine whether the mutation was descended from a common ancestor or occurred as 2 independent events. [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 inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors	CILIARY DYSKINESIA, PRIMARY, 12	c2675228	1,825	omim	https://www.omim.org/entry/612650	2019-09-22T16:00:57	{"doid": ["0110601"], "mesh": ["C567211"], "omim": ["612650", "244400"], "orphanet": ["244"], "synonyms": ["Alternative titles", "CILIARY DYSKINESIA, PRIMARY, 12, WITHOUT SITUS INVERSUS", "PCD"], "genereviews": ["NBK1122"]}
Condition characterized by large amounts of dilute urine and increased thirst Not to be confused with Diabetes. Diabetes insipidus Vasopressin Pronunciation * "Diabetes: /ˌdaɪ.əˈbiːtiːz/ or /ˌdaɪ.əˈbiːtɪs/ SpecialtyEndocrinology SymptomsLarge amounts of dilute urine, increased thirst[1] ComplicationsDehydration, seizures[1] Usual onsetAny age[2][3] TypesCentral, nephrogenic, dipsogenic, gestational[1] CausesDepends on the type[1] Diagnostic methodUrine tests, blood tests, fluid deprivation test[1] Differential diagnosisDiabetes mellitus[1] TreatmentDrinking sufficient fluids[1] MedicationDesmopressin, thiazides, aspirin[1] PrognosisGood with treatment[1] Frequency3 per 100,000 per year[4] Diabetes insipidus (DI) is a condition characterized by large amounts of dilute urine and increased thirst.[1] The amount of urine produced can be nearly 20 liters per day.[1] Reduction of fluid has little effect on the concentration of the urine.[1] Complications may include dehydration or seizures.[1] There are four types of DI, each with a different set of causes.[1] Central DI (CDI) is due to a lack of the hormone vasopressin (antidiuretic hormone).[1] This can be due to injury to the hypothalamus or pituitary gland or genetics.[1] Nephrogenic DI (NDI) occurs when the kidneys do not respond properly to vasopressin.[1] Dipsogenic DI is a result of excessive fluid intake due to damage to the hypothalamic thirst mechanism.[1] It occurs more often in those with certain psychiatric disorders or on certain medications.[1] Gestational DI occurs only during pregnancy.[1] Diagnosis is often based on urine tests, blood tests and the fluid deprivation test.[1] Diabetes insipidus is unrelated to diabetes mellitus and the conditions have a distinct mechanism, though both can result in the production of large amounts of urine.[1] Treatment involves drinking sufficient fluids to prevent dehydration.[1] Other treatments depend on the type.[1] In central and gestational DI, treatment is with desmopressin.[1] Nephrogenic DI may be treated by addressing the underlying cause or the use of a thiazide, aspirin or ibuprofen.[1] The number of new cases of diabetes insipidus each year is 3 in 100,000.[4] Central DI usually starts between the ages of 10 and 20 and occurs in males and females equally.[2] Nephrogenic DI can begin at any age.[3] The term "diabetes" is derived from the Greek word meaning siphon.[5] ## Contents * 1 Signs and symptoms * 2 Cause * 2.1 Central * 2.2 Nephrogenic * 2.3 Dipsogenic * 2.4 Gestational * 3 Pathophysiology * 4 Diagnosis * 5 Treatment * 5.1 Central * 5.2 Nephrogenic * 6 Etymology * 7 References * 8 External links ## Signs and symptoms[edit] Excessive urination and extreme thirst and increased fluid intake (especially for cold water and sometimes ice or ice water) are typical for DI.[6] The symptoms of excessive urination and extreme thirst are similar to what is seen in untreated diabetes mellitus, with the distinction that the urine does not contain glucose. Blurred vision is a rarity. Signs of dehydration may also appear in some individuals, since the body cannot conserve much (if any) of the water it takes in. Extreme urination continues throughout the day and the night. In children, DI can interfere with appetite, eating, weight gain and growth, as well. They may present with fever, vomiting or diarrhea. Adults with untreated DI may remain healthy for decades as long as enough water is consumed to offset the urinary losses. However, there is a continuous risk of dehydration and loss of potassium that may lead to hypokalemia. ## Cause[edit] The several forms of diabetes insipidus are: ### Central[edit] Main article: Neurogenic diabetes insipidus Central DI has many possible causes. According to the literature, the principal causes of central DI and their oft-cited approximate frequencies are as follows: * Idiopathic – 30% * Malignant or benign tumors of the brain or pituitary – 25% * Cranial surgery – 20% * Head trauma – 16% ### Nephrogenic[edit] Main article: Nephrogenic diabetes insipidus Nephrogenic diabetes insipidus is due to the inability of the kidney to respond normally to vasopressin. ### Dipsogenic[edit] Dipsogenic DI or primary polydipsia results from excessive intake of fluids as opposed to deficiency of arginine vasopressin. It may be due to a defect or damage to the thirst mechanism, located in the hypothalamus,[7] or due to mental illness. Treatment with desmopressin may lead to water intoxication. ### Gestational[edit] Gestational DI occurs only during pregnancy and the postpartum period. During pregnancy, women produce vasopressinase in the placenta, which breaks down antidiuretic hormone (ADH). Gestational DI is thought to occur with excessive production and/or impaired clearance of vasopressinase.[8] Most cases of gestational DI can be treated with desmopressin (DDAVP), but not vasopressin. In rare cases, however, an abnormality in the thirst mechanism causes gestational DI, and desmopressin should not be used. Diabetes insipidus is also associated with some serious diseases of pregnancy, including pre-eclampsia, HELLP syndrome and acute fatty liver of pregnancy. These cause DI by impairing hepatic clearance of circulating vasopressinase. It is important to consider these diseases if a woman presents with diabetes insipidus in pregnancy, because their treatments require delivery of the baby before the disease will improve. Failure to treat these diseases promptly can lead to maternal or perinatal mortality. ## Pathophysiology[edit] Electrolyte and volume homeostasis is a complex mechanism that balances the body's requirements for blood pressure and the main electrolytes sodium and potassium. In general, electrolyte regulation precedes volume regulation. When the volume is severely depleted, however, the body will retain water at the expense of deranging electrolyte levels. The regulation of urine production occurs in the hypothalamus, which produces ADH in the supraoptic and paraventricular nuclei. After synthesis, the hormone is transported in neurosecretory granules down the axon of the hypothalamic neuron to the posterior lobe of the pituitary gland, where it is stored for later release. In addition, the hypothalamus regulates the sensation of thirst in the ventromedial nucleus by sensing increases in serum osmolarity and relaying this information to the cortex. Neurogenic/central DI results from a lack of ADH; occasionally it can present with decreased thirst as regulation of thirst and ADH production occur in close proximity in the hypothalamus. It is encountered as a result of hypoxic encephalopathy, neurosurgery, autoimmunity or cancer, or sometimes without an underlying cause (idiopathic). The main effector organ for fluid homeostasis is the kidney. ADH acts by increasing water permeability in the collecting ducts and distal convoluted tubules; specifically, it acts on proteins called aquaporins and more specifically aquaporin 2 in the following cascade. When released, ADH binds to V2 G-protein coupled receptors within the distal convoluted tubules, increasing cyclic AMP, which couples with protein kinase A, stimulating translocation of the aquaporin 2 channel stored in the cytoplasm of the distal convoluted tubules and collecting ducts into the apical membrane. These transcribed channels allow water into the collecting duct cells. The increase in permeability allows for reabsorption of water into the bloodstream, thus concentrating the urine. Nephrogenic DI results from lack of aquaporin channels in the distal collecting duct (decreased surface expression and transcription). It is seen in lithium toxicity, hypercalcemia, hypokalemia, or release of ureteral obstruction. Therefore, a lack of ADH prevents water reabsorption and the osmolarity of the blood increases. With increased osmolarity, the osmoreceptors in the hypothalamus detect this change and stimulate thirst. With increased thirst, the person now experiences a polydipsia and polyuria cycle. Hereditary forms of diabetes insipidus account for less than 10% of the cases of diabetes insipidus seen in clinical practice.[9] ## Diagnosis[edit] To distinguish DI from other causes of excess urination, blood glucose levels, bicarbonate levels, and calcium levels need to be tested. Measurement of blood electrolytes can reveal a high sodium level (hypernatremia as dehydration develops). Urinalysis demonstrates a dilute urine with a low specific gravity. Urine osmolarity and electrolyte levels are typically low. A fluid deprivation test is another way of distinguishing DI from other causes of excessive urination. If there is no change in fluid loss, giving desmopressin can determine if DI is caused by: 1. a defect in ADH production 2. a defect in the kidneys' response to ADH This test measures the changes in body weight, urine output, and urine composition when fluids are withheld to induce dehydration. The body's normal response to dehydration is to conserve water by concentrating the urine. Those with DI continue to urinate large amounts of dilute urine in spite of water deprivation. In primary polydipsia, the urine osmolality should increase and stabilize at above 280 mOsm/kg with fluid restriction, while a stabilization at a lower level indicates diabetes insipidus.[10] Stabilization in this test means, more specifically, when the increase in urine osmolality is less than 30 Osm/kg per hour for at least three hours.[10] Sometimes measuring blood levels of ADH toward the end of this test is also necessary, but is more time consuming to perform.[10] To distinguish between the main forms, desmopressin stimulation is also used; desmopressin can be taken by injection, a nasal spray, or a tablet. While taking desmopressin, a person should drink fluids or water only when thirsty and not at other times, as this can lead to sudden fluid accumulation in the central nervous system. If desmopressin reduces urine output and increases urine osmolarity, the hypothalamic production of ADH is deficient, and the kidney responds normally to exogenous vasopressin (desmopressin). If the DI is due to kidney pathology, desmopressin does not change either urine output or osmolarity (since the endogenous vasopressin levels are already high).[medical citation needed] Whilst diabetes insipidus usually occurs with polydipsia, it can also rarely occur not only in the absence of polydipsia but in the presence of its opposite, adipsia (or hypodipsia). "Adipsic diabetes insipidus" is recognised[11] as a marked absence of thirst even in response to hyperosmolality.[12] In some cases of adipsic DI, the person may also fail to respond to desmopressin.[13] If central DI is suspected, testing of other hormones of the pituitary, as well as magnetic resonance imaging, particularly a pituitary MRI, is necessary to discover if a disease process (such as a prolactinoma, or histiocytosis, syphilis, tuberculosis or other tumor or granuloma) is affecting pituitary function. Most people with this form have either experienced past head trauma or have stopped ADH production for an unknown reason.[medical citation needed] Habit drinking (in its severest form termed psychogenic polydipsia) is the most common imitator of diabetes insipidus at all ages. While many adult cases in the medical literature are associated with mental disorders, most people with habit polydipsia have no other detectable disease. The distinction is made during the water deprivation test, as some degree of urinary concentration above isoosmolar is usually obtained before the person becomes dehydrated.[medical citation needed] ## Treatment[edit] Treatment involves drinking sufficient fluids to prevent dehydration.[1] Other treatments depend on the type.[1] In central and gestational DI treatment is with desmopressin.[1] Nephrogenic DI may be treated by addressing the underlying cause or the use of a thiazide, aspirin, or ibuprofen.[1] ### Central[edit] Central DI and gestational DI respond to desmopressin which is given as intranasal or oral tablets. Carbamazepine, an anticonvulsive medication, has also had some success in this type of DI. Also, gestational DI tends to abate on its own four to six weeks following labor, though some women may develop it again in subsequent pregnancies. In dipsogenic DI, desmopressin is not usually an option. ### Nephrogenic[edit] Desmopressin will be ineffective in nephrogenic DI which is treated by reversing the underlying cause (if possible) and replacing the free water deficit. A thiazide diuretic, such as chlorthalidone or hydrochlorothiazide, can be used to create mild hypovolemia which encourages salt and water uptake in proximal tubule and thus improve nephrogenic diabetes insipidus.[14] Amiloride has additional benefit of blocking Na uptake. Thiazide diuretics are sometimes combined with amiloride to prevent hypokalemia caused by the thiazides. It seems paradoxical to treat an extreme diuresis with a diuretic, and the exact mechanism of action is unknown but the thiazide diuretics will decrease distal convoluted tubule reabsorption of sodium and water, thereby causing diuresis. This decreases plasma volume, thus lowering the glomerular filtration rate and enhancing the absorption of sodium and water in the proximal nephron. Less fluid reaches the distal nephron, so overall fluid conservation is obtained.[15] Lithium-induced nephrogenic DI may be effectively managed with the administration of amiloride, a potassium-sparing diuretic often used in conjunction with thiazide or loop diuretics. Clinicians have been aware of lithium toxicity for many years, and traditionally have administered thiazide diuretics for lithium-induced polyuria and nephrogenic diabetes insipidus. However, amiloride has recently been shown to be a successful treatment for this condition.[16] ## Etymology[edit] The word "diabetes" (/ˌdaɪ.əˈbiːtiːz/ or /ˌdaɪ.əˈbiːtɪs/) comes from Latin diabētēs, which in turn comes from Ancient Greek διαβήτης (diabētēs) which literally means "a passer through; a siphon".[17] Ancient Greek physician Aretaeus of Cappadocia (fl. in the first century CE) used that word, with the intended meaning "excessive discharge of urine", as the name for the disease.[18][19] Ultimately, the word comes from Greek διαβαίνειν (diabainein), meaning "to pass through",[17] which is composed of δια- (dia-), meaning "through" and βαίνειν (bainein), meaning "to go".[18] The word "diabetes" is first recorded in English, in the form "diabete", in a medical text written around 1425. "Insipidus" comes from Latin language insipidus (tasteless), from Latin: in- "not" + sapidus "tasty" from sapere "have a taste" — the full meaning is "lacking flavor or zest; not tasty". Application of this name to DI arose from the fact that diabetes insipidus does not cause glycosuria (excretion of glucose into the urine). ## 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 "Diabetes Insipidus". National Institute of Diabetes and Digestive and Kidney Diseases. October 2015. Archived from the original on 13 May 2017. Retrieved 28 May 2017. 2. ^ a b "Central Diabetes Insipidus". NORD (National Organization for Rare Disorders). 2015. Archived from the original on 21 February 2017. Retrieved 28 May 2017. 3. ^ a b "Nephrogenic Diabetes Insipidus". NORD (National Organization for Rare Disorders). 2016. Archived from the original on 19 February 2017. Retrieved 28 May 2017. 4. ^ a b Saborio P, Tipton GA, Chan JC (2000). "Diabetes Insipidus". Pediatrics in Review. 21 (4): 122–129. doi:10.1542/pir.21-4-122. PMID 10756175. 5. ^ Rubin, Alan L. (2011). Diabetes For Dummies (3 ed.). John Wiley & Sons. p. 19. ISBN 9781118052488. Archived from the original on 2017-09-08. 6. ^ USE. "Diabetes insipidus - PubMed Health". Ncbi.nlm.nih.gov. Archived from the original on 2012-08-29. Retrieved 2012-05-28. 7. ^ Perkins RM, Yuan CM, Welch PG (March 2006). "Dipsogenic diabetes insipidus: report of a novel treatment strategy and literature review". Clin. Exp. Nephrol. 10 (1): 63–7. doi:10.1007/s10157-005-0397-0. PMID 16544179. S2CID 6874287. 8. ^ Kalelioglu I, Kubat Uzum A, Yildirim A, Ozkan T, Gungor F, Has R (2007). "Transient gestational diabetes insipidus diagnosed in successive pregnancies: review of pathophysiology, diagnosis, treatment, and management of delivery". Pituitary. 10 (1): 87–93. doi:10.1007/s11102-007-0006-1. PMID 17308961. S2CID 9493532. 9. ^ Fujiwara TM, Bichet DG (2005). "Molecular Biology of Hereditary Diabetes Insipidus". Journal of the American Society of Nephrology. 16 (10): 2836–2846. doi:10.1681/ASN.2005040371. PMID 16093448. 10. ^ a b c Elizabeth D Agabegi; Agabegi, Steven S. (2008). Step-Up to Medicine (Step-Up Series). Hagerstwon, MD: Lippincott Williams & Wilkins. ISBN 978-0-7817-7153-5. 11. ^ Crowley RK, Sherlock M, Agha A, Smith D, Thompson CJ (2007). "Clinical insights into adipsic diabetes insipidus: a large case series". Clin. Endocrinol. 66 (4): 475–82. doi:10.1111/j.1365-2265.2007.02754.x. PMID 17371462. 12. ^ Sinha A, Ball S, Jenkins A, Hale J, Cheetham T (2011). "Objective assessment of thirst recovery in patients with adipsic diabetes insipidus". Pituitary. 14 (4): 307–11. doi:10.1007/s11102-011-0294-3. PMID 21301966. S2CID 25062519. 13. ^ Smith D, McKenna K, Moore K, Tormey W, Finucane J, Phillips J, Baylis P, Thompson CJ (2002). "Baroregulation of vasopressin release in adipsic diabetes insipidus". J. Clin. Endocrinol. Metab. 87 (10): 4564–8. doi:10.1210/jc.2002-020090. PMID 12364435. 14. ^ Verbalis JG (May 2003). "Diabetes insipidus". Rev Endocr Metab Disord. 4 (2): 177–85. doi:10.1023/A:1022946220908. PMID 12766546. S2CID 33533827. 15. ^ Loffing J (November 2004). "Paradoxical antidiuretic effect of thiazides in diabetes insipidus: another piece in the puzzle". J. Am. Soc. Nephrol. 15 (11): 2948–50. doi:10.1097/01.ASN.0000146568.82353.04. PMID 15504949. 16. ^ Finch CK, Kelley KW, Williams RB (April 2003). "Treatment of lithium-induced diabetes insipidus with amiloride". Pharmacotherapy. 23 (4): 546–50. doi:10.1592/phco.23.4.546.32121. PMID 12680486. 17. ^ a b Oxford English Dictionary. diabetes. Retrieved 2011-06-10. 18. ^ a b Harper, Douglas (2001–2010). "Online Etymology Dictionary. diabetes.". Archived from the original on 2012-01-13. Retrieved 2011-06-10. 19. ^ Dallas, John (2011). "Royal College of Physicians of Edinburgh. Diabetes, Doctors and Dogs: An exhibition on Diabetes and Endocrinology by the College Library for the 43rd St. Andrew's Day Festival Symposium". Archived from the original on 2011-09-27. Retrieved 2019-01-14. ## External links[edit] Classification D * ICD-10: E23.2 N25.1 * ICD-9-CM: 253.5 588.1 * OMIM: 304800 * MeSH: D003919 * DiseasesDB: 3639 External resources * MedlinePlus: 000377 * eMedicine: med/543 ped/580 * Diabetes insipidus at Curlie * v * t * e Pituitary disease Hyperpituitarism Anterior * Acromegaly * Hyperprolactinaemia * Pituitary ACTH hypersecretion Posterior * SIADH General * Nelson's syndrome * Hypophysitis Hypopituitarism Anterior * Kallmann syndrome * Growth hormone deficiency * Hypoprolactinemia * ACTH deficiency/Secondary adrenal insufficiency * GnRH insensitivity * FSH insensitivity * LH/hCG insensitivity Posterior Neurogenic diabetes insipidus General * Empty sella syndrome * Pituitary apoplexy * Sheehan's syndrome * Lymphocytic hypophysitis * Pituitary adenoma * v * t * e Kidney disease Glomerular disease * See Template:Glomerular disease Tubules * Renal tubular acidosis * proximal * distal * Acute tubular necrosis * Genetic * Fanconi syndrome * Bartter syndrome * Gitelman syndrome * Liddle's syndrome Interstitium * Interstitial nephritis * Pyelonephritis * Balkan endemic nephropathy Vascular * Renal artery stenosis * Renal ischemia * Hypertensive nephropathy * Renovascular hypertension * Renal cortical necrosis General syndromes * Nephritis * Nephrosis * Renal failure * Acute renal failure * Chronic kidney disease * Uremia Other * Analgesic nephropathy * Renal osteodystrophy * Nephroptosis * Abderhalden–Kaufmann–Lignac syndrome * Diabetes insipidus * Nephrogenic * Renal papilla * Renal papillary necrosis * Major calyx/pelvis * Hydronephrosis * Pyonephrosis * Reflux nephropathy * v * t * e X-linked disorders X-linked recessive Immune * Chronic granulomatous disease (CYBB) * Wiskott–Aldrich syndrome * X-linked severe combined immunodeficiency * X-linked agammaglobulinemia * Hyper-IgM syndrome type 1 * IPEX * X-linked lymphoproliferative disease * Properdin deficiency Hematologic * Haemophilia A * Haemophilia B * X-linked sideroblastic anemia Endocrine * Androgen insensitivity syndrome/Spinal and bulbar muscular atrophy * KAL1 Kallmann syndrome * X-linked adrenal hypoplasia congenita Metabolic * Amino acid: Ornithine transcarbamylase deficiency * Oculocerebrorenal syndrome * Dyslipidemia: Adrenoleukodystrophy * Carbohydrate metabolism: Glucose-6-phosphate dehydrogenase deficiency * Pyruvate dehydrogenase deficiency * Danon disease/glycogen storage disease Type IIb * Lipid storage disorder: Fabry's disease * Mucopolysaccharidosis: Hunter syndrome * Purine–pyrimidine metabolism: Lesch–Nyhan syndrome * Mineral: Menkes disease/Occipital horn syndrome Nervous system * X-linked intellectual disability: Coffin–Lowry syndrome * MASA syndrome * Alpha-thalassemia mental retardation syndrome * Siderius X-linked mental retardation syndrome * Eye disorders: Color blindness (red and green, but not blue) * Ocular albinism (1) * Norrie disease * Choroideremia * Other: Charcot–Marie–Tooth disease (CMTX2-3) * Pelizaeus–Merzbacher disease * SMAX2 Skin and related tissue * Dyskeratosis congenita * Hypohidrotic ectodermal dysplasia (EDA) * X-linked ichthyosis * X-linked endothelial corneal dystrophy Neuromuscular * Becker's muscular dystrophy/Duchenne * Centronuclear myopathy (MTM1) * Conradi–Hünermann syndrome * Emery–Dreifuss muscular dystrophy 1 Urologic * Alport syndrome * Dent's disease * X-linked nephrogenic diabetes insipidus Bone/tooth * AMELX Amelogenesis imperfecta No primary system * Barth syndrome * McLeod syndrome * Smith–Fineman–Myers syndrome * Simpson–Golabi–Behmel syndrome * Mohr–Tranebjærg syndrome * Nasodigitoacoustic syndrome X-linked dominant * X-linked hypophosphatemia * Focal dermal hypoplasia * Fragile X syndrome * Aicardi syndrome * Incontinentia pigmenti * Rett syndrome * CHILD syndrome * Lujan–Fryns syndrome * Orofaciodigital syndrome 1 * Craniofrontonasal dysplasia [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 inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors	Diabetes insipidus	c0011848	1,826	wikipedia	https://en.wikipedia.org/wiki/Diabetes_insipidus	2021-01-18T18:49:48	{"gard": ["11934"], "mesh": ["D003919"], "umls": ["C0011848"], "wikidata": ["Q220551"]}
"Drool" redirects here. For the film, see Drool (film). Drooling Other namesSalivation, driveling, dribbling, slobbering, sialorrhea A drooling Malamute Drooling, or slobbering, is the flow of saliva outside the mouth. Drooling can be caused by excess production of saliva, inability to retain saliva within the mouth (incontinence of saliva), or problems with swallowing (dysphagia or odynophagia). There are some frequent and harmless cases of drooling. For instance, a numbed mouth from either Orajel, or when going to the dentist's office. Isolated drooling in healthy infants and toddlers is normal and may be associated with teething.[1] It is unlikely to be a sign of disease or complications. Drooling in infants and young children may be exacerbated by upper respiratory infections and nasal allergies. Some people with drooling problems are at increased risk of inhaling saliva, food, or fluids into the lungs, especially if drooling is secondary to a neurological problem. However, if the body's normal reflex mechanisms (such as gagging and coughing) are not impaired, this is not life-threatening. ## Contents * 1 Causes * 2 Treatment * 2.1 Home care * 3 Popular culture * 4 See also * 5 References * 6 External links ## Causes[edit] Drooling or sialorrhea can occur during sleep. It is often the result of open-mouth posture from CNS depressants intake or sleeping on one's side. Sometimes while sleeping, saliva does not build up at the back of the throat and does not trigger the normal swallow reflex, leading to the condition. Freud conjectured that drooling occurs during deep sleep, and within the first few hours of falling asleep, since those who are affected by the symptom suffer the most severe harm while napping, rather than during overnight sleep.[citation needed][2] A sudden onset of drooling may indicate poisoning – especially by pesticides or mercury – or reaction to snake or insect venom. Excess capsaicin can cause drooling as well, an example being the ingestion of particularly high Scoville Unit chili peppers. Some neurological problems cause drooling. Medication can cause drooling, either due to primary action or side-effects; for example the pain-relief medication Orajel can numb the mucosa. Causes include: * exercise, especially cardiovascular exercise[citation needed] * stroke and other neurological pathologies * intellectual disability * autism * adenoid hypertrophy * cerebral palsy[3] * amyotrophic lateral sclerosis * tumors of the upper aerodigestive tract * Parkinson's disease[4] * rabies * mercury poisoning Drooling associated with fever or trouble swallowing may be a sign of an infectious disease including: * retropharyngeal abscess * peritonsillar abscess * tonsilitis * mononucleosis * strep throat * obstructive diseases (tumors, stenosis) * inability to swallow due to neurodegenerative diseases (amyotrophic lateral sclerosis) ## Treatment[edit] A comprehensive treatment plan depends on the cause and incorporates several stages of care: Correction of reversible causes, behavior modification, medical treatment, and surgical procedures. Atropine sulfate tablets are used in some circumstances to reduce salivation. The same for anticholinergic drugs which can be also a benefit because they decrease the activity of the acetylcholine muscarinic receptors and can result in decreased salivation. They may be prescribed by doctors in conjunction with behavior modification strategies. Other drugs used are glycopyrrolate and botulinum toxin A – botox injection in salivary glands to diminish saliva production.[5][6][7] In general, surgical procedures are considered after clear diagnosis of the cause and evaluation of non-invasive treatment options. Severe cases can be sometimes be treated by surgical intervention – salivary duct relocalization, or in extreme cases resection of salivary glands. ### Home care[edit] Care for drooling due to teething includes good oral hygiene. Ice pops or other cold objects (e.g., frozen bagels) may be helpful. Care must be taken to avoid choking when a child uses any of these objects. Drooling is also common in children with neurological disorders or undiagnosed developmental delay. Excessive drooling seems to be due to: 1. lack of awareness of the build-up of saliva in the mouth 2. infrequent swallowing 3. inefficient swallowing Treatment of excessive drooling addresses its cause: 1. cultivating awareness of the mouth and its functions 2. increased frequency of swallowing 3. cultivating swallowing skill ## Popular culture[edit] The scope of the meaning of the term drool in popular use has expanded to include any occasion wherein someone highly desires something.[8][9] ## See also[edit] * Slobbers * Salivary microbiome ## References[edit] 1. ^ Common Baby Teething Symptoms & Signs Kute Keiki. Retrieved on 2019-12-05 2. ^ Almeida, Cristiana; Almeida, Isabel; Vasconcelos, Carlos (2015). "Quality of life in systemic sclerosis". Autoimmunity Reviews. 14 (12): 1087–1096. doi:10.1016/j.autrev.2015.07.012. PMID 26212726. 3. ^ Weiss-Lambrou, R.; Tetreault, S.; Dudley, J. (1989). "The relationship between oral sensation and drooling in persons with cerebral palsy". American Journal of Occupational Therapy. 43 (3): 155–161. doi:10.5014/ajot.43.3.155. PMID 2735376. Retrieved 2013-10-02. 4. ^ Kalf, J.G. (2009). "Prevalence and definition of drooling in Parkinson's disease: A systematic review". Journal of Neurology. 256 (9): 1391–1396. doi:10.1007/s00415-009-5098-2. PMC 2733191. PMID 19288042. 5. ^ Ellies Maik (2004). "Reduction of salivary flow with botulinum toxin: Extended report on 33 patients with drooling, salivary fistulas, and sialadenitis". The Laryngoscope. 114 (10): 1856–1860. doi:10.1097/00005537-200410000-00033. PMID 15454785. 6. ^ Lipp, A.; Trottenberg, T.; Schink, T.; Kupsch, A.; Arnold, G. (2003). "A randomized trial of botulinum toxin A for treatment of drooling". Neurology. 61 (9): 1279–1281. doi:10.1212/WNL.61.9.1279. PMID 14610139. S2CID 42377134. Retrieved 2013-10-02. 7. ^ Mier, Richard J.; Bachrach, Steven J.; Lakin, Ryan C.; Barker, Tara; Childs, Judith; Moran, Maria (2000). "Treatment of Sialorrhea With GlycopyrrolateA Double-blind, Dose-Ranging Study". Archives of Pediatrics & Adolescent Medicine. 154 (12): 1214–8. doi:10.1001/archpedi.154.12.1214. PMID 11115305. Retrieved 2013-10-02. 8. ^ "Definition of DROOL". www.merriam-webster.com. Retrieved 2020-06-13. 9. ^ "DROOL \| meaning in the Cambridge English Dictionary". dictionary.cambridge.org. Retrieved 2020-06-13. ## External links[edit] Classification D * ICD-10: K11.7 * ICD-9-CM: 527.7 * MeSH: D012798 * DiseasesDB: 20764 External resources * MedlinePlus: 003048 Look up drool in Wiktionary, the free dictionary. * NIH site on drooling * 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 inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors	Drooling	c0013132	1,827	wikipedia	https://en.wikipedia.org/wiki/Drooling	2021-01-18T18:58:53	{"mesh": ["D012798"], "wikidata": ["Q18206654"]}
A neurodegenerative disease characterized by progressive muscular paralysis reflecting degeneration of motor neurons in the primary motor cortex, corticospinal tracts, brainstem and spinal cord. ## Epidemiology Incidence (average around 1/50,000 per year) and prevalence (average around 1/20,000) are relatively uniform in Western countries, although foci of higher frequency have been reported in the Western Pacific. The mean age of onset for sporadic ALS is about 60 years. Overall, there is a slight male preponderance (male to female ratio of around 1.5:1). ## Clinical description Approximately two thirds of patients with typical ALS have a spinal form of the disease (limb onset) and present with symptoms related to focal muscle weakness and wasting, in which onset of symptoms may start either distally or proximally in the upper and lower limbs. Gradually, spasticity may develop in the weakened atrophic limbs, affecting manual dexterity and gait. Patients with bulbar onset ALS usually present with dysarthria and dysphagia for solids or liquids. Limb symptoms can develop almost simultaneously with bulbar symptoms, and in the vast majority of cases will occur within 1-2 years. Paralysis is progressive and leads to death due to respiratory failure within 2-3 years for bulbar onset cases and 3-5 years for limb onset ALS cases. ## Etiology Most ALS cases are sporadic but 5-10% of cases are familial, and of these 20% involve a mutation of the SOD1 gene (21q22.11), about 2-5% involve mutations of the TARDBP gene (1p36.22) encoding the TAR DNA-binding protein 43 (TDP-43) and 1-2% involve mutations of the VCP gene (9p13.3) coding for the Valosin Containing Protein. Two percent of apparently sporadic cases involve SOD1 mutations, and TARDBP mutations have also been identified in sporadic cases. ## Diagnostic methods The diagnosis is based on clinical history, examination, electromyography, and exclusion of 'ALS-mimics' (e.g. multifocal motor neuropathy, Kennedy's disease (seethese terms) and cervical spondylotic myelopathy) by appropriate investigations. The pathological hallmarks comprise loss of motor neurons with intraneuronal ubiquitin-immunoreactive inclusions in upper motor neurons and TDP-43 immunoreactive inclusions in degenerating lower motor neurons. Signs of upper motor neuron and lower motor neuron damage not explained by any other disease process are suggestive of ALS. ## Management and treatment The management of ALS is supportive, palliative, and multidisciplinary. Non-invasive ventilation prolongs survival and improves quality of life. Riluzole is the only drug that has been shown to extend survival. [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 inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors	Amyotrophic lateral sclerosis	c0002736	1,828	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=803	2021-01-23T18:12:31	{"gard": ["5786"], "mesh": ["D000690"], "omim": ["105400", "205250", "300857", "606070", "606640", "608030", "608031", "608627", "611895", "612069", "612577", "613435", "613954", "614696", "614808", "615426", "615515", "616208", "616437", "617839", "617892"], "umls": ["C0002736"], "icd-10": ["G12.2"], "synonyms": ["ALS", "Charcot disease", "Lou Gehrig disease"]}
Dyshidrosis Other namesAcute vesiculobullous hand eczema,[1] dyshidrotic dermatitis,[2] cheiropompholyx,[3] dyshidrotic eczema,[3] pompholyx,[3] podopompholyx[3] The characteristic vesicles of dyshidrosis on a finger Pronunciation * /ˌdɪshaɪˈdroʊsɪs/[4] SpecialtyDermatology SymptomsItchy blisters on the palms of the hands and bottoms of the feet[5] ComplicationsSkin thickening[6] Usual onsetOften recurrent[7] DurationHeal over 3 weeks[6][7] CausesUnknown[7] Diagnostic methodBased on symptoms[7] Differential diagnosisPustular psoriasis, scabies[6] TreatmentAvoiding triggers, barrier cream, steroid cream, antihistamines[6][7] Frequency~1 in 2,000 (Sweden)[6] Dyshidrosis is a type of dermatitis that is characterized by itchy blisters on the palms of the hands and bottoms of the feet.[5] Blisters are generally one to two millimeters in size and heal over three weeks.[6][7] However, they often recur.[7] Redness is not usually present.[6] Repeated attacks may result in fissures and skin thickening.[6] The cause is unknown.[7] Triggers may include allergens, physical or mental stress, frequent hand washing, or metals.[7] Diagnosis is typically based on what it looks like and the symptoms.[7] Allergy testing and culture may be done to rule out other problems.[7] Other conditions that produce similar symptoms include pustular psoriasis and scabies.[6] Avoiding triggers may be useful, as may a barrier cream.[6] Treatment is generally with steroid cream.[7] High strength steroid creams may be required for the first week or two.[6] Antihistamines may be used to help with the itch.[7] If this is not effective steroid pills, tacrolimus, or psoralen plus ultraviolet A (PUVA) may be tried.[6][7] About 1 in 2,000 people are affected in Sweden.[6] Males and females appear to be affected equally.[6] It explains about one in five cases of hand dermatitis.[8] The first description was in 1873.[6] The name comes from the word "dyshidrotic", meaning "difficult sweating", as problems with sweating was once believed to be the cause.[6] ## Contents * 1 Signs and symptoms * 2 Causes * 3 Diagnosis * 4 Treatment * 5 Epidemiology * 6 Synonyms * 7 See also * 8 References * 9 External links ## Signs and symptoms Dyshidrosis has been described as having the following characteristics: * Itchiness of the palms or soles, followed the a sudden development of intensely itchy small blisters on the sides of the fingers, the palms or the feet.[9] * These blisters are often described as having a "tapioca pudding" appearance.[10] * After a few weeks, the small blisters eventually disappear as the top layer of skin falls off.[6][11][12] * These eruptions do not occur elsewhere on the body.[6] * The eruptions may be symmetrical.[13] * Advanced stage of dyshidrosis on the fingers * Palmar dyshidrosis * Advanced stage of palmar dyshidrosis on the palm showing cracked and peeling skin * Advanced stage of dyshidrosis on the foot. * Rim of scale on the palmar surface of the thumb from a resolving dyshidrotic flare ## Causes The exact causes of dyshidrosis are unknown. Food allergens may be involved in certain cases.[11] Cases studies have implicated a wide range of foods including tuna, tomato, pineapple, chocolate, coffee, and spices among others.[11] A number of studies have implicated balsam of Peru.[11] A 2013 study found that dyshydrosis on the hands increased among those allergic to house dust mites, following inhalation of house dust mite allergen.[14] Id reaction and irritant contact dermatitis are possible causes.[8] ## Diagnosis Dyshidrosis is diagnosed clinically, by gathering a patient's history and making careful observations (see signs and symptoms section).[7] Severity of symptoms can also be assessed using the dyshidrotic eczema area and severity index (DASI).[15] The DASI has been designed for clinical trials and is not typically used in practice. ## Treatment There are many treatments available for dyshidrosis. However, few of them have been developed or tested specifically on the condition. * Barriers to moisture and irritants, including barrier creams and gloves.[13] * Topical steroids[16] – while useful, can be dangerous long-term due to the skin-thinning side-effects, which are particularly troublesome in the context of hand dyshidrosis, due to the amount of toxins and bacteria the hands typically come in contact with. * Potassium permanganate dilute solution soaks – also popular, and used to 'dry out' the vesicles,[17] and kill off superficial Staphylococcus aureus,[18] but it can also be very painful. Undiluted it may cause significant burning.[19] * Dapsone (diamino-diphenyl sulfone), an antibacterial, has been recommended for the treatment of dyshidrosis in some chronic cases.[20] * Antihistamines: Fexofenadine up to 180 mg per day.[21] * Alitretinoin (9-cis-retinoic acid) has been approved for prescription in the UK. It is specifically used for chronic hand and foot eczema.[22][23][24] It is made by Basilea of Switzerland (BAL 4079). * Systemic steroids can be taken orally to treat especially acute and severe cases of dyshidrosis.[13] ## Epidemiology About 1 in 2,000 people are affected in Sweden. Males and females appear to be affected equally.[6] ## Synonyms Dyshidrosis is also known as pompholyx,[25] a term originating from the Greek word for "bubble".[8] ## See also * Dermatitis herpetiformis – a similar condition caused by celiac and often mistaken for dyshidrosis. * Epidermolysis bullosa – a genetic disorder that causes similar, albeit more severe, symptoms to those of dyshidrosis. ## References 1. ^ James, William; Berger, Timothy; Elston, Dirk (2005). Andrews' Diseases of the Skin: Clinical Dermatology (10th ed.). Saunders. ISBN 0-7216-2921-0. 2. ^ "Pompholyx". Patient. 2014-02-26. Archived from the original on 3 August 2016. Retrieved 11 August 2016. 3. ^ a b c d Rapini, Ronald P.; Bolognia, Jean L.; Jorizzo, Joseph L. (2007). Dermatology: 2-Volume Set. St. Louis: Mosby. ISBN 978-1-4160-2999-1. 4. ^ "Dyshidrosis". Merriam-Webster Online. Merriam-Webster. 2014. Archived from the original on 15 April 2014. Retrieved 14 April 2014. 5. ^ a b "What Is Atopic Dermatitis? Fast Facts". NIAMS. November 2014. Archived from the original on 27 July 2016. Retrieved 11 August 2016. 6. ^ a b c d e f g h i j k l m n o p q r s Lofgren, SM; Warshaw, EM (December 2006). "Dyshidrosis: epidemiology, clinical characteristics, and therapy". Dermatitis : Contact, Atopic, Occupational, Drug. 17 (4): 165–81. doi:10.2310/6620.2006.05021. PMID 17150166. 7. ^ a b c d e f g h i j k l m n o Colomb-Lippa, D; Klingler, AM (July 2011). "Dyshidrosis". Journal of the American Academy of Physician Assistants. 24 (7): 54. PMID 21748961. 8. ^ a b c Fitzpatrick, James (2016). "8". Dermatology Secrets Plus. Elsevier. pp. 70–81. ISBN 978-0-323-31029-1. 9. ^ Shelley, W. B. (1953-09-01). "Dysidrosis (pompholyx)". AMA Archives of Dermatology and Syphilology. 68 (3): 314–319. doi:10.1001/archderm.1953.01540090076008. ISSN 0096-5979. PMID 13079297. 10. ^ Bielan, Barbara (1996-04-01). "Dyshidrotic eczema". Dermatology Nursing. 8 (2). Archived from the original on 2017-04-02. 11. ^ a b c d Veien, Niels K. (2009-07-01). "Acute and recurrent vesicular hand dermatitis". Dermatologic Clinics. 27 (3): 337–353, vii. doi:10.1016/j.det.2009.05.013. ISSN 1558-0520. PMID 19580928. 12. ^ Lofgren, Sabra M.; Warshaw, Erin M. (2006-12-01). "Dyshidrosis: epidemiology, clinical characteristics, and therapy". Dermatitis: Contact, Atopic, Occupational, Drug. 17 (4): 165–181. doi:10.2310/6620.2006.05021. ISSN 1710-3568. PMID 17150166. 13. ^ a b c Perry, Adam D.; Trafeli, John P. (2009-05-01). "Hand Dermatitis: Review of Etiology, Diagnosis, and Treatment". The Journal of the American Board of Family Medicine. 22 (3): 325–330. doi:10.3122/jabfm.2009.03.080118. ISSN 1557-2625. PMID 19429739. 14. ^ Schuttelaar ML, Coenraads PJ, Huizinga J, De Monchy JG, Vermeulen KM (2013). "Increase in vesicular hand eczema after house dust mite inhalation provocation: a double-blind, placebo-controlled, cross-over study" (PDF). Contact Dermatitis. 68 (2): 76–85. doi:10.1111/j.1600-0536.2012.02172.x. PMID 23046099. S2CID 4609200. 15. ^ Vocks, E.; Plötz, S. G.; Ring, J. (1999-01-01). "The Dyshidrotic Eczema Area and Severity Index – A score developed for the assessment of dyshidrotic eczema". Dermatology. 198 (3): 265–269. doi:10.1159/000018127. ISSN 1018-8665. PMID 10393450. S2CID 22978226. 16. ^ "eMedicine – Dyshidrotic Eczema : Article by Camila K Janniger". Archived from the original on 2007-07-07. Retrieved 2007-07-10. 17. ^ BIRT AR (March 1964). "Drugs for Eczema of Children". Can Med Assoc J. 90 (11): 693–4. PMC 1922428. PMID 14127384. 18. ^ Stalder JF, Fleury M, Sourisse M, et al. (1992). "Comparative effects of two topical antiseptics (chlorhexidine vs KMn04) on bacterial skin flora in atopic dermatitis". Acta Derm Venereol Suppl (Stockh). 176: 132–4. PMID 1476027. 19. ^ Baron S, Moss C (February 2003). "Caustic burn caused by potassium permanganate". Arch. Dis. Child. 88 (2): 96. doi:10.1136/adc.88.2.96. PMC 1719457. PMID 12538301. 20. ^ "Vesicular hand dermatitis". Archived from the original on 2010-03-30. Retrieved 2010-04-07. 21. ^ Diepgen, Thomas L.; Agner, Tove; Aberer, Werner; Berth-Jones, John; Cambazard, Frédéric; Elsner, Peter; McFadden, John; Coenraads, Pieter Jan (2007-10-01). "Management of chronic hand eczema". Contact Dermatitis. 57 (4): 203–210. doi:10.1111/j.1600-0536.2007.01179.x. ISSN 1600-0536. PMID 17868211. S2CID 34639884. 22. ^ Ruzicka T, Lynde CW, Jemec GB, Diepgen T, Berth-Jones J, Coenraads PJ, et al. (April 2008). "Efficacy and safety of oral alitretinoin (9-cis retinoic acid) in patients with severe chronic hand eczema refractory to topical corticosteroids: results of a randomized, double-blind, placebo-controlled, multicentre trial" (PDF). Br. J. Dermatol. 158 (4): 808–17. doi:10.1111/j.1365-2133.2008.08487.x. PMID 18294310. S2CID 205256947. 23. ^ Bollag W, Ott F (1999). "Successful treatment of chronic hand eczema with oral 9-cis-retinoic acid". Dermatology (Basel). 199 (4): 308–12. doi:10.1159/000018280. PMID 10640839. S2CID 35358182. 24. ^ Ruzicka T, Larsen FG, Galewicz D, Horváth A, Coenraads PJ, Thestrup-Pedersen K, Ortonne JP, Zouboulis CC, Harsch M, Brown TC, Zultak M (December 2004). "Oral alitretinoin (9-cis-retinoic acid) therapy for chronic hand dermatitis in patients refractory to standard therapy: results of a randomized, double-blind, placebo-controlled, multicenter trial". Arch Dermatol. 140 (12): 1453–9. doi:10.1001/archderm.140.12.1453. PMID 15611422. 25. ^ "ICD 11 Beta Draft". ## External links Classification D * ICD-10: L30.1 * ICD-9-CM: 705.81 * MeSH: D011146 * DiseasesDB: 10373 * SNOMED CT: 25560004 External resources * MedlinePlus: 000832 * eMedicine: derm/110 ped/1867 * Patient UK: Dyshidrosis Wikimedia Commons has media related to Dyshidrosis. * Images of dyshidrotic eczema at Skinsight * Pompholyx at DermNet NZ (New Zealand Dermatological Society Incorporated) * v * t * e Dermatitis and eczema Atopic dermatitis * Besnier's prurigo Seborrheic dermatitis * Pityriasis simplex capillitii * Cradle cap Contact dermatitis (allergic, irritant) * plants: Urushiol-induced contact dermatitis * African blackwood dermatitis * Tulip fingers * other: Abietic acid dermatitis * Diaper rash * Airbag dermatitis * Baboon syndrome * Contact stomatitis * Protein contact dermatitis Eczema * Autoimmune estrogen dermatitis * Autoimmune progesterone dermatitis * Breast eczema * Ear eczema * Eyelid dermatitis * Topical steroid addiction * Hand eczema * Chronic vesiculobullous hand eczema * Hyperkeratotic hand dermatitis * Autosensitization dermatitis/Id reaction * Candidid * Dermatophytid * Molluscum dermatitis * Circumostomy eczema * Dyshidrosis * Juvenile plantar dermatosis * Nummular eczema * Nutritional deficiency eczema * Sulzberger–Garbe syndrome * Xerotic eczema Pruritus/Itch/ Prurigo * Lichen simplex chronicus/Prurigo nodularis * by location: Pruritus ani * Pruritus scroti * Pruritus vulvae * Scalp pruritus * Drug-induced pruritus * Hydroxyethyl starch-induced pruritus * Senile pruritus * Aquagenic pruritus * Aquadynia * Adult blaschkitis * due to liver disease * Biliary pruritus * Cholestatic pruritus * Prion pruritus * Prurigo pigmentosa * Prurigo simplex * Puncta pruritica * Uremic pruritus Other * substances taken internally: Bromoderma * Fixed drug reaction * Nummular dermatitis * Pityriasis alba * Papuloerythroderma of Ofuji * v * t * e Disorders of skin appendages Nail * thickness: Onychogryphosis * Onychauxis * color: Beau's lines * Yellow nail syndrome * Leukonychia * Azure lunula * shape: Koilonychia * Nail clubbing * behavior: Onychotillomania * Onychophagia * other: Ingrown nail * Anonychia * ungrouped: Paronychia * Acute * Chronic * Chevron nail * Congenital onychodysplasia of the index fingers * Green nails * Half and half nails * Hangnail * Hapalonychia * Hook nail * Ingrown nail * Lichen planus of the nails * Longitudinal erythronychia * Malalignment of the nail plate * Median nail dystrophy * Mees' lines * Melanonychia * Muehrcke's lines * Nail–patella syndrome * Onychoatrophy * Onycholysis * Onychomadesis * Onychomatricoma * Onychomycosis * Onychophosis * Onychoptosis defluvium * Onychorrhexis * Onychoschizia * Platonychia * Pincer nails * Plummer's nail * Psoriatic nails * Pterygium inversum unguis * Pterygium unguis * Purpura of the nail bed * Racquet nail * Red lunulae * Shell nail syndrome * Splinter hemorrhage * Spotted lunulae * Staining of the nail plate * Stippled nails * Subungual hematoma * Terry's nails * Twenty-nail dystrophy Hair Hair loss/ Baldness * noncicatricial alopecia: Alopecia * areata * totalis * universalis * Ophiasis * Androgenic alopecia (male-pattern baldness) * Hypotrichosis * Telogen effluvium * Traction alopecia * Lichen planopilaris * Trichorrhexis nodosa * Alopecia neoplastica * Anagen effluvium * Alopecia mucinosa * cicatricial alopecia: Pseudopelade of Brocq * Central centrifugal cicatricial alopecia * Pressure alopecia * Traumatic alopecia * Tumor alopecia * Hot comb alopecia * Perifolliculitis capitis abscedens et suffodiens * Graham-Little syndrome * Folliculitis decalvans * ungrouped: Triangular alopecia * Frontal fibrosing alopecia * Marie Unna hereditary hypotrichosis Hypertrichosis * Hirsutism * Acquired * localised * generalised * patterned * Congenital * generalised * localised * X-linked * Prepubertal Acneiform eruption Acne * Acne vulgaris * Acne conglobata * Acne miliaris necrotica * Tropical acne * Infantile acne/Neonatal acne * Excoriated acne * Acne fulminans * Acne medicamentosa (e.g., steroid acne) * Halogen acne * Iododerma * Bromoderma * Chloracne * Oil acne * Tar acne * Acne cosmetica * Occupational acne * Acne aestivalis * Acne keloidalis nuchae * Acne mechanica * Acne with facial edema * Pomade acne * Acne necrotica * Blackhead * Lupus miliaris disseminatus faciei Rosacea * Perioral dermatitis * Granulomatous perioral dermatitis * Phymatous rosacea * Rhinophyma * Blepharophyma * Gnathophyma * Metophyma * Otophyma * Papulopustular rosacea * Lupoid rosacea * Erythrotelangiectatic rosacea * Glandular rosacea * Gram-negative rosacea * Steroid rosacea * Ocular rosacea * Persistent edema of rosacea * Rosacea conglobata * variants * Periorificial dermatitis * Pyoderma faciale Ungrouped * Granulomatous facial dermatitis * Idiopathic facial aseptic granuloma * Periorbital dermatitis * SAPHO syndrome Follicular cysts * "Sebaceous cyst" * Epidermoid cyst * Trichilemmal cyst * Steatocystoma * simplex * multiplex * Milia Inflammation * Folliculitis * Folliculitis nares perforans * Tufted folliculitis * Pseudofolliculitis barbae * Hidradenitis * Hidradenitis suppurativa * Recurrent palmoplantar hidradenitis * Neutrophilic eccrine hidradenitis Ungrouped * Acrokeratosis paraneoplastica of Bazex * Acroosteolysis * Bubble hair deformity * Disseminate and recurrent infundibulofolliculitis * Erosive pustular dermatitis of the scalp * Erythromelanosis follicularis faciei et colli * Hair casts * Hair follicle nevus * Intermittent hair–follicle dystrophy * Keratosis pilaris atropicans * Kinking hair * Koenen's tumor * Lichen planopilaris * Lichen spinulosus * Loose anagen syndrome * Menkes kinky hair syndrome * Monilethrix * Parakeratosis pustulosa * Pili (Pili annulati * Pili bifurcati * Pili multigemini * Pili pseudoannulati * Pili torti) * Pityriasis amiantacea * Plica neuropathica * Poliosis * Rubinstein–Taybi syndrome * Setleis syndrome * Traumatic anserine folliculosis * Trichomegaly * Trichomycosis axillaris * Trichorrhexis (Trichorrhexis invaginata * Trichorrhexis nodosa) * Trichostasis spinulosa * Uncombable hair syndrome * Wooly hair nevus Sweat glands Eccrine * Miliaria * Colloid milium * Miliaria crystalline * Miliaria profunda * Miliaria pustulosa * Miliaria rubra * Occlusion miliaria * Postmiliarial hypohidrosis * Granulosis rubra nasi * Ross’ syndrome * Anhidrosis * Hyperhidrosis * Generalized * Gustatory * Palmoplantar Apocrine * Body odor * Chromhidrosis * Fox–Fordyce disease Sebaceous * Sebaceous hyperplasia [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 inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors	Dyshidrosis	c0032633	1,829	wikipedia	https://en.wikipedia.org/wiki/Dyshidrosis	2021-01-18T18:59:42	{"mesh": ["D011146"], "umls": ["C0032633"], "icd-10": ["L30.1"], "wikidata": ["Q1269276"]}
A number sign (#) is used with this entry because of evidence that Galloway-Mowat syndrome-1 (GAMOS1) is caused by homozygous mutation in the WDR73 gene (616144) on chromosome 15q25. Description Galloway-Mowat syndrome is a rare autosomal recessive neurodegenerative disorder characterized by infantile onset of microcephaly and central nervous system abnormalities resulting in severely delayed psychomotor development. Brain imaging shows cerebellar atrophy and sometimes cerebral atrophy. More variable features include optic atrophy, movement disorders, seizures, and nephrotic syndrome (summary by Vodopiutz et al., 2015). ### Genetic Heterogeneity of Galloway-Mowat Syndrome See also GAMOS2 (301006), caused by mutation in the LAGE3 gene (300060) on chromosome Xq28; GAMOS3 (617729), caused by mutation in the OSGEP gene (610107) on chromosome 14q11; GAMOS4 (617730), caused by mutation in the TP53RK gene (608679) on chromosome 20q13; GAMOS5 (617731), caused by mutation in the TPRKB gene (608680) on chromosome 2p13; GAMOS6 (618347), caused by mutation in the WDR4 gene (605924) on chromosome 21q22; GAMOS7 (618348), caused by mutation in the NUP107 gene (607617) on chromosome 12q15; and GAMOS8 (618349), caused by mutation in the NUP133 gene (607613) on chromosome 1q42. Clinical Features Galloway and Mowat (1968) observed a brother and sister with microcephaly, hiatus hernia, and nephrotic syndrome. The sibs died from nephrosis at ages 20 and 28 months. Parental consanguinity could not be demonstrated. Shapiro et al. (1976) studied a family with affected brother and sister. The parents were unrelated and of different ethnic extraction. The ears were large and floppy. Albuminuria was present from birth. Microcystic dysplasia and focal glomerulosclerosis were found at autopsy. The hiatus hernia caused vomiting with the first oral feeding. The girl had failure of cleavage of the anterior chambers of both eyes. The sibs died at 14 days and 3 years of age, respectively. Roos et al. (1987) found reports of 12 cases and described 2 affected sons of nonconsanguineous parents. Cooperstone et al. (1993) described 3 additional patients, of whom 2 were brother and sister, and reviewed 16 reported cases. Every patient but one had died before age 5.5 years. This was probably the disorder described by Palm et al. (1986) in 2 male sibs (a boy aged 2 years 10 months at death and a male fetus aborted at 22 weeks of gestation). They had similar brain and kidney malformations, namely, paraventricular heterotopias, central canal abnormalities (including hydrocephalus due to aqueductal stenosis in the boy), and glomerular kidney disease with proteinuria. In the fetus the central canal of the spinal cord was represented by 2 or 3 separate tubes. The kidneys were of normal gross appearance but histologically showed several small cysts lying mainly at the corticomedullary junction, lined with rather high epithelium and containing eosinophilic fluid. The authors pointed to a report of a single case of nephrosis and abnormal neuronal migration (Robain and Deonna, 1983). The patient was female. Garty et al. (1994) described a family of Jewish North African origin in which 2 males and a female out of 8 sibs from an uncle-niece marriage had congenital nephrotic syndrome due to diffuse mesangial sclerosis, microcephaly, and psychomotor retardation. The kidneys showed deposits of IgG and C3 in the mesangium and glomerular basement membranes. All 3 children died before the age of 3 years. Garty et al. (1994) reported that of 19 published cases of children with congenital nephrotic syndrome and microcephaly, only 4 had histologic evidence of diffuse mesangial sclerosis and 2 of their sibs probably had the same disease. Hou and Wang (1995) described the cases of 2 unrelated Chinese female infants with microcephaly, apparent porencephaly or encephalomalacia, developmental delay, minor facial anomalies, and contractural arachnodactyly. In 1 patient, focal glomerulosclerosis was diagnosed histologically by percutaneous renal biopsy performed to investigate the proteinuria with hematuria. Congenital hypothyroidism, presenting with markedly low T3 and T4, was also present in this patient, who died at age 5 months. The second patient had a similar condition but less severe brain and kidney malformations. Kingo et al. (1997) described an infant with presumed Galloway-Mowat syndrome who died at the age of 32 days. The diagnosis was made on the basis of microcephaly, congenital nephrosis, and hiatus hernia. Most of the findings had previously been described in this syndrome; thyroid dysplasia and adrenal hypoplasia were found and considered likely components of the syndrome. Colin et al. (2014) reported 3 patients from 2 unrelated families with GAMOS. Two Moroccan sibs presented with progressive postnatal secondary microcephaly (-2.5 to -3 SD in the first years of life), peripheral and axial hypotonia, severe intellectual disability, and seizures; one also had nystagmus. An unrelated boy, born of consanguineous Turkish parents, had microcephaly, hypertonia, intellectual disability, and spasticity. All patients also had optic atrophy and facial dysmorphism. Brain imaging of all 3 children showed severe cerebellar atrophy, thin corpus callosum, and cortical atrophy. No apparent myelin or gyration defects were observed. Two of the unrelated patients developed nephrotic syndrome at ages 5 and 8 years, respectively; the third patient, who was a sib, had normal renal function and no proteinuria at age 7. One patient with nephrotic syndrome developed chronic renal insufficiency and died at age 5 years. Renal biopsy showed severe collapsing focal segmental glomerulosclerosis and hypertrophic podocytes, as well as interstitial fibrosis and tubular dilations. The other patient with nephrotic syndrome had normal renal function with no proteinuria at age 13 years, but renal biopsy showed mild focal segmental glomerulosclerosis, hypertrophic podocytes, and some tubulointerstitial lesions. Ben-Omran et al. (2015) reported 2 sisters, born of consanguineous Egyptian parents, with GAMOS. They presented in infancy with severe global developmental delay, intellectual disability with lack of speech, mild microcephaly, axial hypotonia and inability to walk, and spastic quadriplegia with limited joint mobility and talipes foot deformities. Dysmorphic facial features included hypertelorism, epicanthal folds, large nose with prominent nasal bridge and tip, wide mouth, and strabismus. Both girls had biochemical features consistent with nephrotic syndrome. Brain imaging showed ventricular dilatation, small brainstem, thin corpus callosum, delayed myelination, and cerebellar hypoplasia reminiscent of a Dandy-Walker malformation. Additional features included optic atrophy, epilepsy, and abnormal EEG. One patient had hypopigmented nonitchy skin patches on the face and trunk. Vodopiutz et al. (2015) reported 5 patients from 4 consanguineous families with GAMOS. One of the patients was a girl, born of consanguineous Turkish parents, previously reported by Steiss et al. (2005), who developed nephrotic syndrome at age 16 years. Common features of all patients included profound intellectual disability with poor or absent speech, axial hypotonia, microcephaly, feeding problems, and cerebellar atrophy. More variable features included short stature, seizures, ataxia, spasticity, dystonia, lack of mobility, optic atrophy, strabismus, retinopathy, and brain atrophy. One family had basal ganglia degeneration. Most patients had proteinuria; 2 died of renal failure at ages 2.5 and 17 years. However, Vodopiutz et al. (2015) emphasized the high inter- and intrafamilial variability concerning renal involvement with regard to age at onset and type of kidney disease, and noted that some patients may not even have renal disease. Jinks et al. (2015) reported 30 Amish patients, ranging in age from 1 to 28 years, with GAMOS. The patients presented in infancy with roving nystagmus, visual impairment associated with progressive optic atrophy, irritability, and microcephaly with severely delayed psychomotor development. Only 10% achieved independent sitting or ambulation. Most developed extrapyramidal movements with axial dystonia and limb chorea. About 40% of children developed seizures, and EEG showed background slowing, multifocal sharp and spike-wave discharges, and rare hypsarrhythmia. Brain imaging showed diffuse cerebral atrophy, thin corpus callosum, and progressive cerebellar atrophy; gyral abnormalities were not observed. In addition, more than half (57%) of patients developed steroid-resistant proteinuria and progressive renal failure during early childhood. Death in 14 (47%) patients was due to complications of renal failure in most cases. Neuropathologic examination of 2 patients showed small brains with small sclerotic cerebella, small hindbrain, and thin corpus callosum. The cerebral cortex showed normal lamination. There was loss of striatal cholinergic interneurons, optic atrophy, and delamination of the lateral geniculate nuclei. The cerebella showed granule cell depletion, Bergmann gliosis, and signs of Purkinje cell deafferentation with asteroid bodies and dysmorphic dendritic trees. The findings were consistent with a profound disruption of cerebellar feedback to the nervous system, affecting visual, sensorimotor, and cognitive systems. Renal pathology showed focal segmental glomerulosclerosis (FSGS), thickened basement membrane, effacement of podocyte foot processes, fibrosis, and tubular atrophy. ### Clinical Variability Megarbane et al. (2001) reported a large inbred Lebanese family in which 5 children had severe developmental delay, psychomotor retardation, proportionate short stature, cerebellar spastic ataxia, microcephaly, optic atrophy, speech defect, abnormal osmiophilic pattern of skin vessels, and cerebellar atrophy. No evidence of metabolic disease was identified, and analysis of respiratory chain complex abnormalities was unremarkable. The authors suggested that these patients represent a novel autosomal recessive disorder. Delague et al. (2002) stated that the peculiar inversion of the usual osmiophilic pattern of the vessels observed in skin biopsies of children affected by this disorder, which they called CAMOS, had never been described in association with autosomal recessive nonprogressive congenital ataxia. Although the biologic and clinical significance of this observation was not evident, it was thought possible that the abnormal ultrastructure of the vessels prevented normal exchange between the blood and surrounding tissues, thus decreasing vessel permeability and modifying the production and/or migration of neuronal cells at an early stage. In a follow-up of the family reported by Megarbane et al. (2001), Vodopiutz et al. (2015) noted that none of the 5 patients had developed renal involvement by 25 to 31 years of age. Inheritance The transmission pattern of CAMOS in the families reported by Megarbane et al. (2001) and of GAMOS in the families reported by Colin et al. (2014) was consistent with autosomal recessive inheritance. Mapping Using identity by descent and DNA pooling (i.e., homozygosity mapping) in the Lebanese family reported by Megarbane et al. (2001), Delague et al. (2002) mapped the CAMOS disease locus to a 3.6-cM interval on chromosome 15q24-q26. Molecular Genetics In 3 patients from 2 unrelated families with GAMOS, Colin et al. (2014) identified 2 different homozygous truncating mutations in the WDR73 gene (616144.0001 and 616144.0002). The mutation in the first family was found by autozygosity mapping and exome sequencing; the second mutation was found in a patient ascertained from a cohort of 30 unrelated individuals with a similar phenotype who underwent direct sequencing of the WDR73 gene. Colin et al. (2014) presented evidence that WDR73 plays a role in regulation of the microtubule network during the cell cycle and suggested that loss of WDR73 function leads to impaired neuronal growth and brain development, as well as impaired podocyte growth and maintenance in the kidney. In 2 sisters, born of consanguineous Arab parents, with GAMOS, Ben-Omran et al. (2015) identified a homozygous truncating mutation in the WDR73 gene (Q235X; 616144.0003). The mutation, which was found by whole-exome sequencing, segregated with the disorder in the family. Morpholino knockdown of the wdr73 gene in zebrafish resulted in brain growth and morphogenesis defects, and the Q235X mutation was unable to rescue the phenotype of wdr73-null zebrafish. The findings suggested that WDR73 has an important role in neural progenitor cell proliferation and differentiation, particularly during development. In 10 individuals from 5 families with GAMOS, Vodopiutz et al. (2015) identified 5 different novel homozygous mutations, 2 truncating and 3 missense, in the WDR73 gene (616144.0004-616144.0008). The mutation in the first family was found by a combination of homozygosity mapping and whole-exome sequencing. Overall, WDR73 mutations were found in 3 (5.9%) of 51 patients with cerebellar atrophy and variable brain anomalies, and in 2 (5%) of 40 patients with a clinical diagnosis of GAMOS. The mutations, which segregated with the disorder in the families, were either not found or found at a very low frequency in the Exome Sequencing Project and ExAC databases. Functional studies of the variants were not performed. Some of the patients had late-onset or no renal involvement, thus expanding the phenotypic spectrum of the disorder. One of the families (family 2) reported by Vodopiutz et al. (2015) had previously been reported by Megarbane et al. (2001) and Delague et al. (2002). In this family, Nicolas et al. (2010) identified a homozygous variant in the ZNF592 gene (G1046R; 613624.0001) that was initially thought to be causative of the disorder. Vodopiutz et al. (2015) concluded that the WDR73 mutation identified in this family (H347Y; 616144.0005) was responsible for the phenotype, but a contribution from the ZNF592 variant could not be excluded. In 27 Amish patients with GAMOS, Jinks et al. (2015) identified a homozygous truncating mutation in the WDR73 gene (616144.0009). The mutation, which was found by a combination of linkage analysis and exome sequencing, was confirmed by Sanger sequencing and segregated with the disorder in the families. Expression of WDR73 was weak and cytosolic in patient fibroblasts. Patient fibroblasts showed growth and proliferation defects with abnormal progression through the cell cycle and early senescence. None of the mutant cells were observed in any phase of the cell cycle outside of interphase, and this growth defect could be rescued by expression of wildtype WDR73. The truncated protein showed increased interaction with tubulins and heat-shock proteins compared to wildtype, suggesting that the overstabilization of these interactions may hinder normal WDR73 movement. The 3.9-Mb Amish autozygous block contained a second truncating variant in the WHAMM gene (612393), which may have contributed to the phenotype; additional studies of this variant were not performed. Animal Model Ben-Omran et al. (2015) found expression of wdr73 in the midbrain and hindbrain of zebrafish embryos. Morpholino knockdown of the wdr73 gene resulted in signs of developmental delay, such as curved and/or truncated tail, reduced head size, and brain morphology defects in the midbrain and cerebellum, including dilated ventricles and a reduction in progenitor cells. The remaining progenitor cells persisted abnormally in a proliferative state, suggesting a failure to exit the cell cycle, which was associated with a defect in neuronal differentiation. These neurodevelopmental defects could be rescued by wildtype wrd73. Mutant fish also showed hypopigmentation. INHERITANCE \- Autosomal recessive GROWTH Height \- Short stature Weight \- Low birth weight Other \- Intrauterine growth retardation (IUGR) HEAD & NECK Head \- Microcephaly, postnatal \- Sloping forehead \- Flat occiput Face \- Small midface \- Micrognathia Ears \- Large ears \- Low-set ears \- Floppy ears Eyes \- Microphthalmia \- Hypertelorism \- Epicanthal folds \- Ptosis \- Corneal opacities \- Cataracts \- Hypoplastic iris \- Strabismus \- Optic atrophy \- Nystagmus Nose \- Small, pinched nose \- Large nose Mouth \- High-arched palate \- Wide mouth ABDOMEN Gastrointestinal \- Hiatal hernia (in some patients) \- Feeding difficulties (in some patients) GENITOURINARY Kidneys \- Chronic renal insufficiency \- Nephrotic syndrome \- Proteinuria \- Microcystic dysplasia \- Focal glomerulosclerosis \- Diffuse mesangial sclerosis \- Hypertrophic podocytes \- Interstitial fibrosis SKELETAL \- Joint contractures Hands \- Clenched hands \- Camptodactyly \- Slender digits Feet \- Pes cavus \- Talipes equinovarus SKIN, NAILS, & HAIR Skin \- Hypopigmentation Nails \- Hypoplastic nails MUSCLE, SOFT TISSUES \- Hypotonia, axial NEUROLOGIC Central Nervous System \- Delayed psychomotor development \- Mental retardation \- Lack of speech or poor speech \- Seizures (in some patients) \- Spastic quadriplegia (in some patients) \- Ataxia (in some patients) \- Dystonia (in some patients) \- Hyperreflexia \- Dilated ventricles \- Cerebellar atrophy \- Thin corpus callosum (in some patients) \- Cerebral atrophy \- Dandy-Walker malformation (in some patients) \- Small brainstem \- Abnormal sulci (1 patient) \- Abnormal gyri (1 patient) \- Pachygyria (1 patient) \- Deficient myelination PRENATAL MANIFESTATIONS Amniotic Fluid \- Oligohydramnios LABORATORY ABNORMALITIES \- Hypoalbuminemia \- Proteinuria MISCELLANEOUS \- Variable features \- Not all patients have dysmorphic facial features \- Not all patients have renal involvement \- Onset in infancy \- Death in childhood may occur MOLECULAR BASIS \- Caused by mutation in the WD repeat-containing protein 73 gene (WDR73, 616144.0001 ) ▲ 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 inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors	GALLOWAY-MOWAT SYNDROME 1	c0795949	1,830	omim	https://www.omim.org/entry/251300	2019-09-22T16:25:10	{"doid": ["0060364"], "mesh": ["C537548"], "omim": ["251300"], "orphanet": ["2065"], "synonyms": ["Alternative titles", "MICROCEPHALY, HIATAL HERNIA, AND NEPHROTIC SYNDROME", "GALLOWAY SYNDROME", "NEPHROSIS-NEURONAL DYSMIGRATION SYNDROME", "NEPHROSIS-MICROCEPHALY SYNDROME", "CEREBELLAR ATAXIA WITH MENTAL RETARDATION, OPTIC ATROPHY, AND SKIN ABNORMALITIES", "SPINOCEREBELLAR ATAXIA, AUTOSOMAL RECESSIVE 5, FORMERLY"]}
Human and animal disease Botulism A 14-year-old with botulism, characterised by weakness of the eye muscles and the drooping eyelids shown in the left image, and dilated and non-moving pupils shown in the right image. This youth was fully conscious. Pronunciation * /ˈbɒtjʊlɪzəm/ SpecialtyInfectious disease, gastroenterology SymptomsWeakness, trouble seeing, feeling tired, trouble speaking[1] ComplicationsRespiratory failure[2] Usual onset12 to 72 hours[2] DurationVariable[2] CausesClostridium botulinum[1] Diagnostic methodFinding the bacteria or their toxin[1] Differential diagnosisMyasthenia gravis, Guillain–Barré syndrome, Amyotrophic lateral sclerosis, Lambert Eaton syndrome[3] PreventionProper food preparation, no honey for children younger than one[1] TreatmentAntitoxin, antibiotics, mechanical ventilation[1] Prognosis~7.5% risk of death[1] Botulism is a rare and potentially fatal illness caused by a toxin produced by the bacterium Clostridium botulinum.[1] The disease begins with weakness, blurred vision, feeling tired, and trouble speaking.[1] This may then be followed by weakness of the arms, chest muscles, and legs.[1] Vomiting, swelling of the abdomen, and diarrhea may also occur.[1] The disease does not usually affect consciousness or cause a fever.[1] Botulism can be spread in several ways.[1] The bacterial spores which cause it are common in both soil and water.[1] They produce the botulinum toxin when exposed to low oxygen levels and certain temperatures.[1] Foodborne botulism happens when food containing the toxin is eaten.[1] Infant botulism happens when the bacteria develops in the intestines and releases the toxin.[1] This typically only occurs in children less than six months old, as protective mechanisms develop after that time.[1] Wound botulism is found most often among those who inject street drugs.[1] In this situation, spores enter a wound, and in the absence of oxygen, release the toxin.[1] It is not passed directly between people.[1] The diagnosis is confirmed by finding the toxin or bacteria in the person in question.[1] Prevention is primarily by proper food preparation.[1] The toxin, though not the organism, is destroyed by heating it to more than 85 °C (185 °F) for longer than 5 minutes.[1] Honey can contain the organism, and for this reason, honey should not be fed to children under 12 months.[1] Treatment is with an antitoxin.[1] In those who lose their ability to breathe on their own, mechanical ventilation may be necessary for months.[1] Antibiotics may be used for wound botulism.[1] Death occurs in 5 to 10% of people.[1] Botulism also affects many other animals.[1] The word is from Latin botulus, meaning sausage.[4] Early descriptions of botulism date from at least as far back as 1793 in Germany.[5] ## Contents * 1 Signs and symptoms * 1.1 Infant botulism * 1.2 Complications * 2 Cause * 2.1 Colonization of the gut * 2.2 Food * 2.3 Wound * 2.4 Inhalation * 2.5 Injection * 3 Mechanism * 4 Diagnosis * 5 Prevention * 5.1 Vaccine * 6 Treatment * 6.1 Antitoxin * 7 Prognosis * 8 Epidemiology * 8.1 United States * 8.2 United Kingdom * 8.3 China * 8.3.1 Qapqal disease * 8.4 Canada * 8.5 Ukraine * 8.6 Vietnam * 9 Other susceptible species * 10 See also * 11 References * 12 External links ## Signs and symptoms[edit] The muscle weakness of botulism characteristically starts in the muscles supplied by the cranial nerves—a group of twelve nerves that control eye movements, the facial muscles and the muscles controlling chewing and swallowing. Double vision, drooping of both eyelids, loss of facial expression and swallowing problems may therefore occur. In addition to affecting the voluntary muscles, it can also cause disruptions in the autonomic nervous system. This is experienced as a dry mouth and throat (due to decreased production of saliva), postural hypotension (decreased blood pressure on standing, with resultant lightheadedness and risk of blackouts), and eventually constipation (due to decreased forward movement of intestinal contents).[6] Some of the toxins (B and E) also precipitate nausea, vomiting,[6] and difficulty with talking. The weakness then spreads to the arms (starting in the shoulders and proceeding to the forearms) and legs (again from the thighs down to the feet).[6] Severe botulism leads to reduced movement of the muscles of respiration, and hence problems with gas exchange. This may be experienced as dyspnea (difficulty breathing), but when severe can lead to respiratory failure, due to the buildup of unexhaled carbon dioxide and its resultant depressant effect on the brain. This may lead to respiratory compromise and death if untreated.[6] Clinicians frequently think of the symptoms of botulism in terms of a classic triad: bulbar palsy and descending paralysis, lack of fever, and clear senses and mental status ("clear sensorium").[7] ### Infant botulism[edit] An infant with botulismː despite not being asleep or sedated, he cannot open his eyes or move; he also has a weak cry. Infant botulism (also referred to as floppy baby syndrome) was first recognized in 1976, and is the most common form of botulism in the United States. Infants are susceptible to infant botulism in the first year of life, with more than 90% of cases occurring in infants younger than six months.[8] Infant botulism results from the ingestion of the C. botulinum spores, and subsequent colonization of the small intestine. The infant gut may be colonized when the composition of the intestinal microflora (normal flora) is insufficient to competitively inhibit the growth of C. botulinum and levels of bile acids (which normally inhibit clostridial growth) are lower than later in life.[9] The growth of the spores releases botulinum toxin, which is then absorbed into the bloodstream and taken throughout the body, causing paralysis by blocking the release of acetylcholine at the neuromuscular junction. Typical symptoms of infant botulism include constipation, lethargy, weakness, difficulty feeding and an altered cry, often progressing to a complete descending flaccid paralysis. Although constipation is usually the first symptom of infant botulism, it is commonly overlooked.[10] Honey is a known dietary reservoir of C. botulinum spores and has been linked to infant botulism. For this reason honey is not recommended for infants less than one year of age.[9] Most cases of infant botulism, however, are thought to be caused by acquiring the spores from the natural environment. Clostridium botulinum is a ubiquitous soil-dwelling bacterium. Many infant botulism patients have been demonstrated to live near a construction site or an area of soil disturbance.[11] Infant botulism has been reported in 49 of 50 US states (all save for Rhode Island),[8] and cases have been recognized in 26 countries on five continents.[12] ### Complications[edit] Infant botulism has no long-term side effects, but can be complicated by hospital-acquired infections. Botulism can result in death due to respiratory failure. However, in the past 50 years, the proportion of patients with botulism who die has fallen from about 50% to 7% due to improved supportive care. A patient with severe botulism may require mechanical ventilation (breathing support through a ventilator) as well as intensive medical and nursing care, sometimes for several months. The person may require rehabilitation therapy after leaving the hospital.[13] ## Cause[edit] A photomicrograph of Clostridium botulinum bacteria. Clostridium botulinum is an anaerobic, Gram positive, spore-forming rod. Botulinum toxin is one of the most powerful known toxins: about one microgram is lethal to humans when inhaled.[14] It acts by blocking nerve function (neuromuscular blockade) through inhibition of the excitatory neurotransmitter acetylcholine's release from the presynaptic membrane of neuromuscular junctions in the somatic nervous system. This causes paralysis. Advanced botulism can cause respiratory failure by paralysing the muscles of the chest; this can progress to respiratory arrest.[15] Furthermore, acetylcholine release from the presynaptic membranes of muscarinic nerve synapses is blocked. This can lead to a variety of autonomic signs and symptoms described above. In all cases, illness is caused by the botulinum toxin produced by the bacterium C. botulinum in anaerobic conditions and not by the bacterium itself. The pattern of damage occurs because the toxin affects nerves that fire (depolarize) at a higher frequency first.[16] Mechanisms of entry into the human body for botulinum toxin are described below. ### Colonization of the gut[edit] The most common form in Western countries is infant botulism. This occurs in infants who are colonized with the bacterium in the small intestine during the early stages of their lives. The bacterium then produces the toxin, which is absorbed into the bloodstream. The consumption of honey during the first year of life has been identified as a risk factor for infant botulism; it is a factor in a fifth of all cases.[6] The adult form of infant botulism is termed adult intestinal toxemia, and is exceedingly rare.[6] ### Food[edit] Toxin that is produced by the bacterium in containers of food that have been improperly preserved is the most common cause of food-borne botulism. Fish that has been pickled without the salinity or acidity of brine that contains acetic acid and high sodium levels, as well as smoked fish stored at too high a temperature, presents a risk, as does improperly canned food. Food-borne botulism results from contaminated food in which C. botulinum spores have been allowed to germinate in low-oxygen conditions. This typically occurs in improperly prepared home-canned food substances and fermented dishes without adequate salt or acidity.[17] Given that multiple people often consume food from the same source, it is common for more than a single person to be affected simultaneously. Symptoms usually appear 12–36 hours after eating, but can also appear within 6 hours to 10 days.[18] ### Wound[edit] Wound botulism results from the contamination of a wound with the bacteria, which then secrete the toxin into the bloodstream. This has become more common in intravenous drug users since the 1990s, especially people using black tar heroin and those injecting heroin into the skin rather than the veins.[6] Wound botulism accounts for 29% of cases. ### Inhalation[edit] Isolated cases of botulism have been described after inhalation by laboratory workers.[citation needed] ### Injection[edit] Symptoms of botulism may occur away from the injection site of botulinum toxin.[19] This may include loss of strength, blurred vision, change of voice, or trouble breathing which can result in death.[19] Onset can be hours to weeks after an injection.[19] This generally only occurs with inappropriate strengths of botulinum toxin for cosmetic use or due to the larger doses used to treat movement disorders.[6] Following a 2008 review the FDA added these concerns as a boxed warning.[20] ## Mechanism[edit] The toxin is the protein botulinum toxin produced under anaerobic conditions (where there is no oxygen) by the bacterium Clostridium botulinum. Clostridium botulinum is a large anaerobic Gram-positive bacillus that forms subterminal endospores.[21] There are eight serological varieties of the bacterium denoted by the letters A to H. The toxin from all of these acts in the same way and produces similar symptoms: the motor nerve endings are prevented from releasing acetylcholine, causing flaccid paralysis and symptoms of blurred vision, ptosis, nausea, vomiting, diarrhea or constipation, cramps, and respiratory difficulty. Botulinum toxin is broken into eight neurotoxins (labeled as types A, B, C [C1, C2], D, E, F, and G), which are antigenically and serologically distinct but structurally similar. Human botulism is caused mainly by types A, B, E, and (rarely) F. Types C and D cause toxicity only in other animals.[22] In October 2013, scientists released news of the discovery of type H, the first new botulism neurotoxin found in forty years. However, further studies showed type H to be a chimeric toxin composed of parts of types F and A (FA).[23] Some types produce a characteristic putrefactive smell and digest meat (types A and some of B and F); these are said to be proteolytic; type E and some types of B, C, D and F are nonproteolytic and can go undetected because there is no strong odor associated with them.[21] When the bacteria are under stress, they develop spores, which are inert. Their natural habitats are in the soil, in the silt that comprises the bottom sediment of streams, lakes and coastal waters and ocean, while some types are natural inhabitants of the intestinal tracts of mammals (e.g., horses, cattle, humans), and are present in their excreta. The spores can survive in their inert form for many years.[24] Toxin is produced by the bacteria when environmental conditions are favourable for the spores to replicate and grow, but the gene that encodes for the toxin protein is actually carried by a virus or phage that infects the bacteria. Unfortunately, little is known about the natural factors that control phage infection and replication within the bacteria.[25] The spores require warm temperatures, a protein source, an anaerobic environment, and moisture in order to become active and produce toxin. In the wild, decomposing vegetation and invertebrates combined with warm temperatures can provide ideal conditions for the botulism bacteria to activate and produce toxin that may affect feeding birds and other animals. Spores are not killed by boiling, but botulism is uncommon because special, rarely obtained conditions are necessary for botulinum toxin production from C. botulinum spores, including an anaerobic, low-salt, low-acid, low-sugar environment at ambient temperatures.[26] Botulinum inhibits the release within the nervous system of acetylcholine, a neurotransmitter, responsible for communication between motor neurons and muscle cells. All forms of botulism lead to paralysis that typically starts with the muscles of the face and then spreads towards the limbs.[6] In severe forms, botulism leads to paralysis of the breathing muscles and causes respiratory failure. In light of this life-threatening complication, all suspected cases of botulism are treated as medical emergencies, and public health officials are usually involved to identify the source and take steps to prevent further cases from occurring.[6] Botulinum toxin A, C, and E cleave the SNAP-25, ultimately leading to paralysis. ## Diagnosis[edit] For botulism in babies, diagnosis should be made on signs and symptoms. Confirmation of the diagnosis is made by testing of a stool or enema specimen with the mouse bioassay. In people whose history and physical examination suggest botulism, these clues are often not enough to allow a diagnosis. Other diseases such as Guillain–Barré syndrome, stroke, and myasthenia gravis can appear similar to botulism, and special tests may be needed to exclude these other conditions. These tests may include a brain scan, cerebrospinal fluid examination, nerve conduction test (electromyography, or EMG), and an edrophonium chloride (Tensilon) test for myasthenia gravis. A definite diagnosis can be made if botulinum toxin is identified in the food, stomach or intestinal contents, vomit or feces. The toxin is occasionally found in the blood in peracute cases. Botulinum toxin can be detected by a variety of techniques, including enzyme-linked immunosorbent assays (ELISAs), electrochemiluminescent (ECL) tests and mouse inoculation or feeding trials. The toxins can be typed with neutralization tests in mice. In toxicoinfectious botulism, the organism can be cultured from tissues. On egg yolk medium, toxin-producing colonies usually display surface iridescence that extends beyond the colony.[27] ## Prevention[edit] Although the vegetative form of the bacteria is destroyed by boiling,[28][29] the spore itself is not killed by the temperatures reached with normal sea-level-pressure boiling, leaving it free to grow and again produce the toxin when conditions are right.[30][31] A recommended prevention measure for infant botulism is to avoid giving honey to infants less than 12 months of age, as botulinum spores are often present. In older children and adults the normal intestinal bacteria suppress development of C. botulinum.[32] While commercially canned goods are required to undergo a "botulinum cook" in a pressure cooker at 121 °C (250 °F) for 3 minutes, and thus rarely cause botulism, there have been notable exceptions. Two were the 1978 Alaskan salmon outbreak and the 2007 Castleberry's Food Company outbreak. Foodborne botulism is the rarest form though, accounting for only around 15% of cases (US)[33] and has more frequently been from home-canned foods with low acid content, such as carrot juice, asparagus, green beans, beets, and corn. However, outbreaks of botulism have resulted from more unusual sources. In July 2002, fourteen Alaskans ate muktuk (whale meat) from a beached whale, and eight of them developed symptoms of botulism, two of them requiring mechanical ventilation.[34] Other, much rarer sources of infection (about every decade in the US[33]) include garlic or herbs[35] stored covered in oil without acidification,[36] chili peppers,[33] improperly handled baked potatoes wrapped in aluminum foil,[33] tomatoes,[33] and home-canned or fermented fish. When canning or preserving food at home, attention should be paid to hygiene, pressure, temperature, refrigeration and storage. When making home preserves, only acidic fruit such as apples, pears, stone fruits and berries should be bottled. Tropical fruit and tomatoes are low in acidity and must have some acidity added before they are bottled.[37] Low-acid foods have pH values higher than 4.6. They include red meats, seafood, poultry, milk, and all fresh vegetables except for most tomatoes. Most mixtures of low-acid and acid foods also have pH values above 4.6 unless their recipes include enough lemon juice, citric acid, or vinegar to make them acidic. Acid foods have a pH of 4.6 or lower. They include fruits, pickles, sauerkraut, jams, jellies, marmalades, and fruit butters.[38] Although tomatoes usually are considered an acid food, some are now known to have pH values slightly above 4.6. Figs also have pH values slightly above 4.6. Therefore, if they are to be canned as acid foods, these products must be acidified to a pH of 4.6 or lower with lemon juice or citric acid. Properly acidified tomatoes and figs are acid foods and can be safely processed in a boiling-water canner.[38] Oils infused with fresh garlic or herbs should be acidified and refrigerated. Potatoes which have been baked while wrapped in aluminum foil should be kept hot until served or refrigerated. Because the botulism toxin is destroyed by high temperatures, home-canned foods are best boiled for 10 minutes before eating.[39] Metal cans containing food in which bacteria are growing may bulge outwards due to gas production from bacterial growth; such cans should be discarded.[40] Any container of food which has been heat-treated and then assumed to be airtight which shows signs of not being so, e.g., metal cans with pinprick holes from rust or mechanical damage, should be discarded. Contamination of a canned food solely with C. botulinum may not cause any visual defects to the container, such as bulging, or the food. Only assurance of sufficient thermal processing during production, and absence of a route for subsequent contamination, should be used as indicators of food safety. The addition of nitrites and nitrates to processed meats such as ham, bacon, and sausages reduces growth and toxin production of C. botulinum.[41] ### Vaccine[edit] Vaccines are under development, but they have disadvantages, and in some cases there are concerns that they may revert to dangerous native activity.[1] As of 2017 work to develop a better vaccine was being carried out, but the US FDA had not approved any vaccine against botulism.[42][43] ## Treatment[edit] Botulism is generally treated with botulism antitoxin and supportive care.[1] Supportive care for botulism includes monitoring of respiratory function. Respiratory failure due to paralysis may require mechanical ventilation for 2 to 8 weeks, plus intensive medical and nursing care. After this time, paralysis generally improves as new neuromuscular connections are formed.[44] In some abdominal cases, physicians may try to remove contaminated food still in the digestive tract by inducing vomiting or using enemas. Wounds should be treated, usually surgically, to remove the source of the toxin-producing bacteria.[45] ### Antitoxin[edit] Botulinum antitoxin consists of antibodies that neutralize botulinum toxin in the circulatory system by passive immunization.[46] This prevents additional toxin from binding to the neuromuscular junction, but does not reverse any already inflicted paralysis.[46] In adults, a trivalent antitoxin containing antibodies raised against botulinum toxin types A, B, and E is used most commonly; however, a heptavalent botulism antitoxin has also been developed and was approved by the U.S. FDA in 2013.[15][47] In infants, horse-derived antitoxin is sometimes avoided for fear of infants developing serum sickness or lasting hypersensitivity to horse-derived proteins.[48] To avoid this, a human-derived antitoxin has been developed and approved by the U.S. FDA in 2003 for the treatment of infant botulism.[49] This human-derived antitoxin has been shown to be both safe and effective for the treatment of infant botulism.[49][50] However, the danger of equine-derived antitoxin to infants has not been clearly established, and one study showed the equine-derived antitoxin to be both safe and effective for the treatment of infant botulism.[48] Trivalent (A,B,E) botulinum antitoxin is derived from equine sources utilizing whole antibodies (Fab and Fc portions). In the United States, this antitoxin is available from the local health department via the CDC. The second antitoxin, heptavalent (A,B,C,D,E,F,G) botulinum antitoxin, is derived from "despeciated" equine IgG antibodies which have had the Fc portion cleaved off leaving the F(ab')2 portions. This less immunogenic antitoxin is effective against all known strains of botulism where not contraindicated.[51] ## Prognosis[edit] The paralysis caused by botulism can persist for 2 to 8 weeks, during which supportive care and ventilation may be necessary to keep the person alive.[44] Botulism is fatal in 5% to 10% of people who are affected.[1] However, if left untreated, botulism is fatal in 40% to 50% of cases.[50] Infant botulism typically has no long-term side effects but can be complicated by treatment-associated adverse events. The case fatality rate is less than 2% for hospitalized babies.[52] ## Epidemiology[edit] Globally, botulism is fairly rare,[1] with approximately 1,000 cases yearly.[53] ### United States[edit] In the United States an average of 145 cases are reported each year. Of these, roughly 65% are infant botulism, 20% are wound botulism, and 15% are foodborne.[54] Infant botulism is predominantly sporadic and not associated with epidemics, but great geographic variability exists. From 1974 to 1996, for example, 47% of all infant botulism cases reported in the U.S. occurred in California.[54] Between 1990 and 2000, the Centers for Disease Control and Prevention reported 263 individual foodborne cases from 160 botulism events in the United States with a case-fatality rate of 4%. Thirty-nine percent (103 cases and 58 events) occurred in Alaska, all of which were attributable to traditional Alaska aboriginal foods. In the lower 49 states, home-canned food was implicated in 70 events (~69%) with canned asparagus being the most numerous cause. Two restaurant-associated outbreaks affected 25 persons. The median number of cases per year was 23 (range 17–43), the median number of events per year was 14 (range 9–24). The highest incidence rates occurred in Alaska, Idaho, Washington, and Oregon. All other states had an incidence rate of 1 case per ten million people or less.[55] The number of cases of food borne and infant botulism has changed little in recent years, but wound botulism has increased because of the use of black tar heroin, especially in California.[56] All data regarding botulism antitoxin releases and laboratory confirmation of cases in the US are recorded annually by the Centers for Disease Control and Prevention and published on their website.[54] * On July 2, 1971, the U.S. Food and Drug Administration (FDA) released a public warning after learning that a New York man had died and his wife had become seriously ill due to botulism after eating a can of Bon Vivant vichyssoise soup. * Between March 31 and April 6, 1977, 59 individuals developed type B botulism. All ill persons had eaten at the same Mexican restaurant in Pontiac, Michigan and all had consumed a hot sauce made with improperly home-canned jalapeño peppers, either by adding it to their food, or by eating a nacho that had had hot sauce used in its preparation. The full clinical spectrum (mild symptomatology with neurologic findings through life-threatening ventilatory paralysis) of type B botulism was documented.[57] * In April 1994, the largest outbreak of botulism in the United States since 1978 occurred in El Paso, Texas. Thirty persons were affected; 4 required mechanical ventilation. All ate food from a Greek restaurant. The attack rate among persons who ate a potato-based dip was 86% (19/22) compared with 6% (11/176) among persons who did not eat the dip (relative risk [RR] = 13.8; 95% confidence interval [CI], 7.6–25.1). The attack rate among persons who ate an eggplant-based dip was 67% (6/9) compared with 13% (24/189) among persons who did not (RR = 5.2; 95% CI, 2.9–9.5). Botulism toxin type A was detected from patients and in both dips. Toxin formation resulted from holding aluminum foil-wrapped baked potatoes at room temperature, apparently for several days, before they were used in the dips. Food handlers should be informed of the potential hazards caused by holding foil-wrapped potatoes at ambient temperatures after cooking.[58] * In 2002, fourteen Alaskans ate muktuk (whale blubber) from a beached whale, resulting in eight of them developing botulism, with two of the affected requiring mechanical ventilation.[59] * Beginning in late June 2007, 8 people contracted botulism poisoning by eating canned food products produced by Castleberry's Food Company in its Augusta, Georgia plant. It was later identified that the Castleberry's plant had serious production problems on a specific line of retorts that had under-processed the cans of food. These issues included broken cooking alarms, leaking water valves and inaccurate temperature devices, all the result of poor management of the company. All of the victims were hospitalized and placed on mechanical ventilation. The Castleberry's Food Company outbreak was the first instance of botulism in commercial canned foods in the United States in over 30 years.[citation needed] * One person died, 21 cases were confirmed, and 10 more were suspected in Lancaster, Ohio when a botulism outbreak occurred after a church potluck in April 2015. The suspected source was a salad made from home-canned potatoes.[60] * A botulism outbreak occurred in Northern California in May 2017 after 10 people consumed nacho cheese dip served at a gas station in Sacramento County. One man died as a result of the outbreak.[61] ### United Kingdom[edit] The largest recorded outbreak of foodborne botulism in the United Kingdom occurred in June 1989. A total of 27 patients were affected; one patient died. Twenty-five of the patients had eaten one brand of hazelnut yogurt in the week before the onset of symptoms. Control measures included the cessation of all yogurt production by the implicated producer, the withdrawal of the firm's yogurts from sale, the recall of cans of the hazelnut conserve, and advice to the general public to avoid the consumption of all hazelnut yogurts.[62] ### China[edit] From 1958–1983 there were 986 outbreaks of botulism in China involving 4,377 people with 548 deaths.[63] #### Qapqal disease[edit] After the Chinese Communist Revolution in 1949, a mysterious plague (named Qapqal disease) was noticed to be affecting several Sibe villages in Qapqal Xibe Autonomous County. It was endemic with distinctive epidemic patterns, yet the underlying cause remained unknown for a long period of time.[64] It caused a number of deaths and forced some people to leave the place.[65] In 1958, a team of experts were sent to the area by the Ministry of Health to investigate the cases. The epidemic survey conducted proved that the disease was primarily type A botulism,[66] with several cases of type B.[64] The team also discovered that, the source of the botulinum was local fermented grain and beans as well as raw meat food called mi song hu hu.[65] They promoted the improvement of fermentation techniques among local residents, and thus eliminated the disease. ### Canada[edit] From 1985-2015 there was an outbreak of 91 confirmed cases of foodborne botulism in Canada, 85% of which were in Inuit communities, especially Nunavik and First Nations of the coast of British Columbia from eating traditionally prepared marine mammal and fish products.[67] ### Ukraine[edit] In 2017, there were 70 cases of botulism with 8 deaths in Ukraine. The previous year there were 115 cases with 12 deaths. Most cases were the result of dried fish, a common local drinking snack.[68] ### Vietnam[edit] In 2020, several cases of botulism were reported in Vietnam. All of them were related to a product containing contaminated vegetarian pâté. Some patients have been put on life support.[69][70] ## Other susceptible species[edit] Botulism can occur in many vertebrates and invertebrates. Botulism has been reported in rats, mice, chicken, frogs, toads, goldfish, aplysia, squid, crayfish, drosophila, leeches, etc.[71] Death from botulism is common in waterfowl; an estimated 10,000 to 100,000 birds die of botulism annually. The disease is commonly called "limberneck". In some large outbreaks, a million or more birds may die. Ducks appear to be affected most often. An enzootic form of duck botulism in Western USA and Canada is known as "western duck sickness".[72] Botulism also affects commercially raised poultry. In chickens, the mortality rate varies from a few birds to 40% of the flock. Botulism seems to be relatively uncommon in domestic mammals; however, in some parts of the world, epidemics with up to 65% mortality are seen in cattle. The prognosis is poor in large animals that are recumbent. In cattle, the symptoms may include drooling, restlessness, uncoordination, urine retention, dysphagia, and sternal recumbency. Laterally recumbent animals are usually very close to death. In sheep, the symptoms may include drooling, a serous nasal discharge, stiffness, and incoordination. Abdominal respiration may be observed and the tail may switch on the side. As the disease progresses, the limbs may become paralyzed and death may occur. Phosphorus-deficient cattle, especially in southern Africa, are inclined to ingest bones and carrion containing clostridial toxins and consequently suffer lame sickness or lamsiekte. A recent study has demonstrated an effective vaccine against cattle botulism associated with Clostridium botulinum serotypes C and D.[73] The clinical signs in horses are similar to cattle. The muscle paralysis is progressive; it usually begins at the hindquarters and gradually moves to the front limbs, neck, and head. Death generally occurs 24 to 72 hours after initial symptoms and results from respiratory paralysis. Some foals are found dead without other clinical signs. Clostridium botulinum type C toxin has been incriminated as the cause of grass sickness, a condition in horses which occurs in rainy and hot summers in Northern Europe. The main symptom is pharynx paralysis.[74] Domestic dogs may develop systemic toxemia after consuming C. botulinum type C exotoxin or spores within bird carcasses or other infected meat[75] but are generally resistant to the more severe effects of Clostridium botulinum type C. Symptoms include flaccid muscle paralysis; dogs with breathing difficulties will require more intensive care monitoring. Muscle paralysis can lead to death due to cardiac and respiratory arrest.[76] Pigs are relatively resistant to botulism. Reported symptoms include anorexia, refusal to drink, vomiting, pupillary dilation, and muscle paralysis.[77] In poultry and wild birds, flaccid paralysis is usually seen in the legs, wings, neck and eyelids. Broiler chickens with the toxicoinfectious form may also have diarrhea with excess urates. ## See also[edit] * List of foodborne illness outbreaks ## 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 "Fact sheets - Botulism". World Health Organization. 10 January 2018. Retrieved 23 March 2019. 2. ^ a b c "Consumers - Foodborne Illnesses: What You Need to Know". FDA. Retrieved 11 May 2018. 3. ^ Caterino JM, Kahan S (2003). In a Page: Emergency medicine. Lippincott Williams & Wilkins. p. 122. ISBN 9781405103572. 4. ^ Lewis CT, Short C. "bŏtŭlus". A Latin Dictionary. Archived from the original on 2014-08-14. Retrieved 2014-06-09. 5. ^ Truong D, Dressler D, Hallett M, Zachary C (2014). Manual of Botulinum Toxin Therapy (2 ed.). Cambridge University Press. p. 1. ISBN 9781107654334. Archived from the original on 2017-09-10. 6. ^ a b c d e f g h i j Sobel J (October 2005). "Botulism". Clinical Infectious Diseases. 41 (8): 1167–73. doi:10.1086/444507. PMID 16163636. 7. ^ "Botulism". OutbreakID.com. Archived from the original on 2 April 2012. 8. ^ a b Arnon SS (2004). "Infant Botulism" (PDF). In Feigin RD, Cherry JD, Demmler GJ, Kaplan SL (eds.). Textbook of Pediatric Infectious Diseases (5th ed.). Philadelphia: WB Saunders. pp. 1758–66. Archived (PDF) from the original on 2011-07-26. 9. ^ a b Caya JG, Agni R, Miller JE (June 2004). "Clostridium botulinum and the clinical laboratorian: a detailed review of botulism, including biological warfare ramifications of botulinum toxin". Archives of Pathology & Laboratory Medicine. 128 (6): 653–62. doi:10.1043/1543-2165(2004)128<653:CBATCL>2.0.CO;2 (inactive 2020-12-12). PMID 15163234.CS1 maint: DOI inactive as of December 2020 (link) 10. ^ "Infant Botulism". kidshealth.org. Archived from the original on 2016-10-07. Retrieved 2016-09-28. 11. ^ Domingo RM, Haller JS, Gruenthal M (November 2008). "Infant botulism: two recent cases and literature review". Journal of Child Neurology. 23 (11): 1336–46. doi:10.1177/0883073808318200. PMID 18984848. S2CID 37908365. 12. ^ Koepke R, Sobel J, Arnon SS (July 2008). "Global occurrence of infant botulism, 1976-2006". Pediatrics. 122 (1): e73-82. doi:10.1542/peds.2007-1827. PMID 18595978. S2CID 207160701. 13. ^ "Clostridium perfringens". U.S. Centers for Disease Control and Prevention. Archived from the original on 16 June 2016. Retrieved 14 June 2016. 14. ^ Emmeluth D (2010). Botulism. Infobase Publishing. p. 38. ISBN 978-1-60413-235-9. Archived from the original on 2017-01-01. 15. ^ a b Arnon SS, Schechter R, Inglesby TV, Henderson DA, Bartlett JG, Ascher MS, et al. (February 2001). "Botulinum toxin as a biological weapon: medical and public health management". JAMA. 285 (8): 1059–70. doi:10.1001/jama.285.8.1059. PMID 11209178. 16. ^ Oxford Textbook of Medicine, 4th Ed., Section 7.55 17. ^ "About Botulism". Centers for Disease Control and Prevention. Retrieved 2020-04-08. 18. ^ "Facts About Botulism". Emergency Preparedness and Response. Centers for Disease Control and Prevention. October 14, 2001. Archived from the original on July 5, 2011. Retrieved July 2, 2011. 19. ^ a b c "Botox" (PDF). Retrieved 6 December 2019. 20. ^ "Update of Safety Review of OnabotulinumtoxinA (marketed as Botox/Botox Cosmetic), AbobotulinumtoxinA (marketed as Dysport) and RimabotulinumtoxinB (marketed as Myobloc)". 15 November 2017. Archived from the original on 2017-11-15. Retrieved 29 December 2019. 21. ^ a b "ETOX 80E -Botulism". University of California, Santa Cruz. Archived from the original on 2013-05-09. Retrieved 2014-02-12. 22. ^ Botulinum Toxin at eMedicine 23. ^ Maslanka SE, Lúquez C, Dykes JK, Tepp WH, Pier CL, Pellett S, et al. (February 2016). "A Novel Botulinum Neurotoxin, Previously Reported as Serotype H, Has a Hybrid-Like Structure With Regions of Similarity to the Structures of Serotypes A and F and Is Neutralized With Serotype A Antitoxin". The Journal of Infectious Diseases. 213 (3): 379–85. doi:10.1093/infdis/jiv327. PMC 4704661. PMID 26068781. 24. ^ Ward BQ, Carroll BJ, Garrett ES, Reese GB (May 1967). "Survey of the U.S. Gulf Coast for the presence of Clostridium botulinum". Applied Microbiology. 15 (3): 629–36. doi:10.1128/aem.15.3.629-636.1967. PMC 546991. PMID 5340653. 25. ^ Franson JC, Friend M (1999). "38: Avian Botulism" (PDF). Field Manual of Wildlife Disease. U.S. Geological Survey. ISBN 978-0-607-88096-0. Archived (PDF) from the original on 9 August 2016. Retrieved 14 June 2016. 26. ^ International Commission on Microbiological Specifications for Foods (1996). "Clostridium botulinum". Microorganisms in Foods 5: Characteristics of Microbial Pathogens. Springer. pp. 66–111. ISBN 978-0-412-47350-0. quoted in Centers for Disease Control Prevention (CDC) (October 2012). "Botulism from drinking prison-made illicit alcohol - Utah 2011". MMWR. Morbidity and Mortality Weekly Report. 61 (39): 782–4. PMID 23034585. Archived from the original on 2017-06-06. 27. ^ Weber JT (1994). "Botulism". In Hpeprich PD (ed.). Infectious Diseases (5th ed.). J. B. Lippincott Company. pp. 1185–94. 28. ^ "Botulism". WHO. Archived from the original on 2014-02-16. Retrieved 2014-02-12. 29. ^ "Foodborne Botulism FAQ". Food Safety Authority of Ireland. November 15, 2011. Archived from the original on May 21, 2014. Retrieved 2014-05-20. 30. ^ Teotonio I (February 21, 2008). "Couple suing over tainted juice". Toronto Star. Archived from the original on March 4, 2016. 31. ^ "Guidance for Industry: Refrigerated Carrot Juice and Other Refrigerated Low-Acid Juices". FDA. June 2007. Archived from the original on 2015-09-24. 32. ^ Arnon SS, Midura TF, Damus K, Thompson B, Wood RM, Chin J (February 1979). "Honey and other environmental risk factors for infant botulism". The Journal of Pediatrics. 94 (2): 331–6. doi:10.1016/S0022-3476(79)80863-X. PMID 368301. 33. ^ a b c d e "Arctic Investigations Program – DPEI". Centers for Disease Control and Prevention (CDC). 2011-04-01. Archived from the original on 2010-10-16. Retrieved 2014-02-12. 34. ^ Centers for Disease Control Prevention (CDC) (January 2003). "Outbreak of botulism type E associated with eating a beached whale--Western Alaska, July 2002". MMWR. Morbidity and Mortality Weekly Report. 52 (2): 24–6. PMID 12608715. Archived from the original on 2017-06-25. 35. ^ "Oil Infusions and the Risk of Botulism". Safefood News. Colorado State University Cooperative Extension. 1998. Archived from the original on 4 April 2013. 36. ^ Centers for Disease Control (CDC) (October 1985). "Update: international outbreak of restaurant-associated botulism--Vancouver, British Columbia, Canada". MMWR. Morbidity and Mortality Weekly Report. 34 (41): 643. PMID 3930945. Archived from the original on 2017-06-25. 37. ^ "Botulism fact sheet". Department of Public Health, Western Australia. Archived from the original on 2013-12-30. Retrieved 2014-02-12. 38. ^ a b "Complete Guide to Home Canning; Guide 1: Principles of Home Canning" (PDF). United States Department of Agriculture. Archived (PDF) from the original on 2018-01-27. Retrieved 2018-08-15. 39. ^ U.S. Food and Drug Administration. "Bad Bug Book: Foodborne Pathogenic Microorganisms and Natural Toxins Handbook Clostridium botulinum". Archived from the original on 29 November 2012. Retrieved 12 January 2013. 40. ^ Schneider KR, Silverberg R, Chang A, Goodrich Schneider RM (9 January 2015). "Preventing Foodborne Illness: Clostridium botulinum". edis.ifas.ufl.edu. University of Florida IFAS Extension. Archived from the original on 8 February 2017. Retrieved 7 February 2017. 41. ^ Christiansen LN, Johnston RW, Kautter DA, Howard JW, Aunan WJ (March 1973). "Effect of nitrite and nitrate on toxin production by Clostridium botulinum and on nitrosamine formation in perishable canned comminuted cured meat". Applied Microbiology. 25 (3): 357–62. doi:10.1128/AEM.25.3.357-362.1973. PMC 380811. PMID 4572891. 42. ^ Webb RP, Smith LA (May 2013). "What next for botulism vaccine development?". Expert Review of Vaccines. 12 (5): 481–92. doi:10.1586/erv.13.37. PMID 23659297. S2CID 39973963. 43. ^ Sundeen G, Barbieri JT (September 2017). "Vaccines against Botulism". Toxins. 9 (9): 268. doi:10.3390/toxins9090268. PMC 5618201. PMID 28869493. 44. ^ a b "Botulism: Treatment Overview for Clinicians". U.S. Centers for Disease Control and Prevention (CDC). 2006. Archived from the original on 4 March 2016. Retrieved 13 January 2016. 45. ^ Brook I (2006). "Botulism: the challenge of diagnosis and treatment". Reviews in Neurological Diseases. 3 (4): 182–9. PMID 17224901. 46. ^ a b O'Horo JC, Harper EP, El Rafei A, Ali R, DeSimone DC, Sakusic A, et al. (2018). "Efficacy of Antitoxin Therapy in Treating Patients With Foodborne Botulism: A Systematic Review and Meta-analysis of Cases, 1923-2016". Clinical Infectious Diseases. 66 (suppl_1): S43–S56. doi:10.1093/cid/cix815. PMC 5850555. PMID 29293927. 47. ^ "FDA approves first Botulism Antitoxin for use in neutralizing all seven known botulinum nerve toxin serotypes". FDA News Release. U.S. FDA. 22 March 2013. Archived from the original on 1 January 2016. Retrieved 14 January 2016. 48. ^ a b Vanella de Cuetos EE, Fernandez RA, Bianco MI, Sartori OJ, Piovano ML, Lúquez C, de Jong LI (November 2011). "Equine botulinum antitoxin for the treatment of infant botulism". Clinical and Vaccine Immunology. 18 (11): 1845–9. doi:10.1128/CVI.05261-11. PMC 3209035. PMID 21918119. 49. ^ a b Arnon SS, Schechter R, Maslanka SE, Jewell NP, Hatheway CL (February 2006). "Human botulism immune globulin for the treatment of infant botulism". The New England Journal of Medicine. 354 (5): 462–71. doi:10.1056/NEJMoa051926. PMID 16452558. 50. ^ a b Chalk, Colin H.; Benstead, Tim J.; Pound, Joshua D.; Keezer, Mark R. (17 April 2019). "Medical treatment for botulism". The Cochrane Database of Systematic Reviews. 4: CD008123. doi:10.1002/14651858.CD008123.pub4. ISSN 1469-493X. PMC 6468196. PMID 30993666. 51. ^ Yu PA, Lin NH, Mahon BE, Sobel J, Yu Y, Mody RK, et al. (2018). "Safety and Improved Clinical Outcomes in Patients Treated With New Equine-Derived Heptavalent Botulinum Antitoxin". Clinical Infectious Diseases. 66 (suppl_1): S57–S64. doi:10.1093/cid/cix816. PMC 5866099. PMID 29293928. 52. ^ "Botulism Prognosis". Medical Life Sciences. 2009-12-02. Retrieved 8 February 2019. 53. ^ Care, Government of Ontario, Ministry of Health and Long-Term. "Botulism - Diseases and Conditions - Publications - Public Information - MOHLTC". www.health.gov.on.ca. Retrieved 2017-10-29. 54. ^ a b c "National Case Surveillance: National Botulism Surveillance \| CDC National Surveillance". Centers for Disease Control and Prevention. 2013-06-25. Archived from the original on 2014-01-30. Retrieved 2014-02-12. 55. ^ Sobel J, Tucker N, Sulka A, McLaughlin J, Maslanka S (September 2004). "Foodborne botulism in the United States, 1990-2000". Emerging Infectious Diseases. Centers for Disease Control. 10 (9): 1606–11. doi:10.3201/eid1009.030745. PMC 3320287. PMID 15498163. 56. ^ Passaro DJ, Werner SB, McGee J, Mac Kenzie WR, Vugia DJ (March 1998). "Wound botulism associated with black tar heroin among injecting drug users". JAMA. 279 (11): 859–63. doi:10.1001/jama.279.11.859. PMID 9516001. 57. ^ Terranova W, Breman JG, Locey RP, Speck S (August 1978). "Botulism type B: epidemiologic aspects of an extensive outbreak". American Journal of Epidemiology. 108 (2): 150–6. doi:10.1093/oxfordjournals.aje.a112599. PMID 707476. 58. ^ Angulo FJ, Getz J, Taylor JP, Hendricks KA, Hatheway CL, Barth SS, et al. (July 1998). "A large outbreak of botulism: the hazardous baked potato". The Journal of Infectious Diseases. 178 (1): 172–7. doi:10.1086/515615. PMID 9652437. 59. ^ "Outbreak of botulism type E associated with eating a beached whale--Western Alaska, July 2002". MMWR. Morbidity and Mortality Weekly Report. 52 (2): 24–6. January 2003. PMID 12608715. 60. ^ "1 dead in botulism outbreak linked to Ohio church potluck". CNNWIRE. CNN. 28 April 2015. Archived from the original on 22 July 2015. Retrieved 19 July 2015. 61. ^ "Man dies in Sacramento county botulism outbreak from nacho cheese". KCRA. 22 May 2017. Archived from the original on 23 May 2017. Retrieved 22 May 2017. 62. ^ O'Mahony M, Mitchell E, Gilbert RJ, Hutchinson DN, Begg NT, Rodhouse JC, Morris JE (June 1990). "An outbreak of foodborne botulism associated with contaminated hazelnut yoghurt". Epidemiology and Infection. 104 (3): 389–95. doi:10.1017/s0950268800047403. PMC 2271776. PMID 2347382. 63. ^ Ying S, Shuyan C (1986-11-01). "Botulism in China". Clinical Infectious Diseases. 8 (6): 984–990. doi:10.1093/clinids/8.6.984. ISSN 0162-0886. 64. ^ a b Wu CR, Lian EH, Chen WJ, Liu YZ (1958). "Botulism: A report for Qapqal disease". National Medical Journal of China. 44 (10): 932–942. 65. ^ a b Fu SW, Wang CH (August 2008). "An overview of type E botulism in China". Biomedical and Environmental Sciences. 21 (4): 353–6. doi:10.1016/S0895-3988(08)60054-9. PMID 18837301. 66. ^ Huang Beibei, ed. (2011-11-12). "The Xibe ethnic minority". People's Daily. Retrieved 2018-01-29. 67. ^ Leclair D, Fung J, Isaac-Renton JL, Proulx JF, May-Hadford J, Ellis A, et al. (June 2013). "Foodborne botulism in Canada, 1985-2005". Emerging Infectious Diseases. 19 (6): 961–8. doi:10.3201/eid1906.120873. PMC 3713816. PMID 23735780. 68. ^ "Eight Ukrainians died of botulism in 2017". LB.ua. Retrieved 2017-10-29. 69. ^ "Độc tố trong pate Minh Chay được phát hiện cách nào?". Retrieved September 4, 2020. 70. ^ "Lethal bacteria in vegan pate puts seven people on life support". Retrieved September 4, 2020. 71. ^ Humeau Y, Doussau F, Grant NJ, Poulain B (May 2000). "How botulinum and tetanus neurotoxins block neurotransmitter release". Biochimie. 82 (5): 427–46. doi:10.1016/S0300-9084(00)00216-9. PMID 10865130. 72. ^ W.B. Gross (1984), Botulism, in "Diseases of poultry", ed. by M.S. Hofstad, Iowa State University Press, Ames, Iowa, USA; ISBN 0-8138-0430-2, 8th ed., p. 257 73. ^ Cunha CE, Moreira GM, Salvarani FM, Neves MS, Lobato FC, Dellagostin OA, Conceição FR (January 2014). "Vaccination of cattle with a recombinant bivalent toxoid against botulism serotypes C and D". Vaccine. 32 (2): 214–6. doi:10.1016/j.vaccine.2013.11.025. PMID 24252701. 74. ^ Blood DC, Henderson JA, Radostits OM (1979). Veterinary Medicine (5th ed.). London: Baillière Tindall. pp. 1060 (Grass sickness). ISBN 978-0-7020-07-18-7. 75. ^ "Dogs / Botulism". Vet Book. 2012-08-12. Archived from the original on 2014-02-21. Retrieved 2013-08-23. 76. ^ "Overview of botulism in poultry". Merck Manuals. 2012-03-31. Archived from the original on 2014-02-04. Retrieved 2013-08-23. 77. ^ Aiello SE, Mays A, eds. (1988). "Botulism". Merck Veterinary Manual (8th ed.). Whitehouse Station, NJ: Merck and Co. pp. 442–44. ## External links[edit] Classification D * ICD-10: A05.1 * ICD-9-CM: 005.1,040.41,040.42 * MeSH: D001906 * DiseasesDB: 2811 External resources * MedlinePlus: 000598 * eMedicine: article/213311 * Patient UK: Botulism Wikipedia's health care articles can be viewed offline with the Medical Wikipedia app. * BOTULISM in the United States, 1889–1996. Handbook for Epidemiologists, Clinicians and Laboratory Technicians. Centers for Disease Control and Prevention. National Center for Infectious Diseases, Division of Bacterial and Mycotic Diseases 1998. * NHS choices * CDC Botulism: Control Measures Overview for Clinicians * University of California, Santa Cruz Environmental toxicology – Botulism * CDC Botulism FAQ * FDA Clostridium botulinum Bad Bug Book * USGS Avian Botulism * v * t * e * Firmicutes (low-G+C) Infectious diseases * Bacterial diseases: G+ Bacilli Lactobacillales (Cat-) Streptococcus α optochin susceptible * S. pneumoniae * Pneumococcal infection optochin resistant * Viridans streptococci: S. mitis * S. mutans * S. oralis * S. sanguinis * S. sobrinus * S. anginosus group β A * bacitracin susceptible: S. pyogenes * Group A streptococcal infection * Streptococcal pharyngitis * Scarlet fever * Erysipelas * Rheumatic fever B * bacitracin resistant, CAMP test+: S. agalactiae * Group B streptococcal infection ungrouped * Streptococcus iniae * Cutaneous Streptococcus iniae infection γ * D * BEA+: Streptococcus bovis Enterococcus * BEA+: Enterococcus faecalis * Urinary tract infection * Enterococcus faecium Bacillales (Cat+) Staphylococcus Cg+ * S. aureus * Staphylococcal scalded skin syndrome * Toxic shock syndrome * MRSA Cg- * novobiocin susceptible * S. epidermidis * novobiocin resistant * S. saprophyticus Bacillus * Bacillus anthracis * Anthrax * Bacillus cereus * Food poisoning Listeria * Listeria monocytogenes * Listeriosis Clostridia Clostridium (spore-forming) motile: * Clostridium difficile * Pseudomembranous colitis * Clostridium botulinum * Botulism * Clostridium tetani * Tetanus nonmotile: * Clostridium perfringens * Gas gangrene * Clostridial necrotizing enteritis Finegoldia (non-spore forming) * Finegoldia magna Mollicutes Mycoplasmataceae * Ureaplasma urealyticum * Ureaplasma infection * Mycoplasma genitalium * Mycoplasma pneumoniae * Mycoplasma pneumonia Anaeroplasmatales * Erysipelothrix rhusiopathiae * Erysipeloid * v * t * e Chicken * Rooster * Hen * Chick As poultry * Chicken as food * List of chicken dishes * Breeds * Capon * Poularde * Poussin * Pullet * Broiler Husbandry * Battery cage * Free range * Furnished cages * Yarding * Chicken tractor * Poultry farming * Broiler industry * Beak trimming * Hatchery * Chick sexing * Chick culling * Candling * Abnormal behaviour of birds in captivity * European Union Council Directive 1999/74/EC Culture * Chickens as pets * Cockatrice * Cockfighting * Kapparos * Sarimanok * Rooster Flag Diseases * Aspergillosis * Avian infectious laryngotracheitis * Avian influenza * Avian sarcoma leukosis virus * Histomoniasis (blackhead disease) * Botulism * Campylobacteriosis * Candidiasis * Coccidiosis * Colds * Dermanyssus gallinae * Egg binding * Erysipelas * Fatty liver hemorrhagic syndrome * Fowlpox * Gallid alphaherpesvirus 3 * Gapeworm * Infectious bursal disease * Infectious coryza in chickens * Marek's disease * Mycoplasmas * Newcastle disease * Omphalitis * Psittacosis * Pullorum * Scaly leg * Squamous cell carcinoma * Tibial dyschondroplasia * Toxoplasmosis * v * t * e Consumer food safety Adulterants, food contaminants * 3-MCPD * Aldicarb * Antibiotic use in livestock * Cyanide * Formaldehyde * HGH controversies * Lead poisoning * Melamine * Mercury in fish * Sudan I Flavorings * Monosodium glutamate (MSG) * Salt * Sugar * High-fructose corn syrup Intestinal parasites and parasitic disease * Amoebiasis * Anisakiasis * Cryptosporidiosis * Cyclosporiasis * Diphyllobothriasis * Enterobiasis * Fasciolopsiasis * Fasciolosis * Giardiasis * Gnathostomiasis * Paragonimiasis * Toxoplasmosis * Trichinosis * Trichuriasis Microorganisms * Botulism * Campylobacter jejuni * Clostridium perfringens * Cronobacter * Enterovirus * Escherichia coli O104:H4 * Escherichia coli O157:H7 * Hepatitis A * Hepatitis E * Listeria * Norovirus * Rotavirus * Salmonella * Vibrio cholerae Pesticides * Chlorpyrifos * DDT * Lindane * Malathion * Methamidophos Preservatives * Benzoic acid * Ethylenediaminetetraacetic acid (EDTA) * Sodium benzoate Sugar substitutes * Acesulfame potassium * Aspartame * Saccharin * Sodium cyclamate * Sorbitol * Sucralose Toxins, poisons, environment pollution * Aflatoxin * Arsenic contamination of groundwater * Benzene in soft drinks * Bisphenol A * Dieldrin * Diethylstilbestrol * Dioxin * Mycotoxins * Nonylphenol * Shellfish poisoning Food contamination incidents * Devon colic * Swill milk scandal * Esing Bakery incident * 1858 Bradford sweets poisoning * 1900 English beer poisoning * Morinaga Milk arsenic poisoning incident * Minamata disease * 1971 Iraq poison grain disaster * Toxic oil syndrome * 1985 diethylene glycol wine scandal * UK mad cow disease outbreak * 1993 Jack in the Box E. coli outbreak * 1996 Odwalla E. coli outbreak * 2006 North American E. coli outbreaks * ICA meat repackaging controversy * 2008 Canada listeriosis outbreak * 2008 Chinese milk scandal * 2008 Irish pork crisis * 2008 United States salmonellosis outbreak * 2011 Germany E. coli outbreak * 2011 United States listeriosis outbreak * 2013 Bihar school meal poisoning * 2013 horse meat scandal * 2015 Mozambique beer poisoning * 2017 Brazil weak meat scandal * 2017–18 South African listeriosis outbreak * 2018 Australian rockmelon listeriosis outbreak * 2018 Australian strawberry contamination * Food safety incidents in China * Food safety incidents in Taiwan * Food safety in Australia * Foodborne illness * outbreaks * death toll * United States Regulation, standards, watchdogs * Acceptable daily intake * E number * Food labeling regulations * Food libel laws * International Food Safety Network * ISO 22000 * Nutrition facts label * Organic certification * The Non-GMO Project * Quality Assurance International * Food Standards Agency Institutions * Institute for Food Safety and Health * European Food Safety Authority * International Food Safety Network * Spanish Agency for Food Safety and Nutrition * Food Information and Control Agency (Spain) * Centre for Food Safety (Hong Kong) * Ministry of Food and Drug Safety (South Korea) [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 inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors	Botulism	c0006057	1,831	wikipedia	https://en.wikipedia.org/wiki/Botulism	2021-01-18T18:57:11	{"gard": ["943"], "mesh": ["D001906"], "umls": ["C0006057"], "icd-9": ["040.41", "005.1", "040.42"], "orphanet": ["1267"], "wikidata": ["Q154865"]}
Pure hair-nail type ectodermal dysplasia Other namesHair-nail ectodermal dysplasia Pure hair-nail type ectodermal dysplasia is a genetic mutation in the "hair matrix and cuticle keratin KRTHB5 gene" that causes ectodermal dysplasia of hair and nail type.[1] Manifestations of this disorder include onychodystrophy and severe hypotrichosis. It represents as an autosomal dominant trait.[2] ## See also[edit] * List of cutaneous conditions ## References[edit] 1. ^ Naeem, M; Wajid, M; Lee, K; Leal, S. M; Ahmad, W (2005). "A mutation in the hair matrix and cuticle keratin KRTHB5 gene causes ectodermal dysplasia of hair and nail type". Journal of Medical Genetics. 43 (3): 274–279. doi:10.1136/jmg.2005.033381. PMC 2563238. PMID 16525032. 2. ^ "Ectodermal dysplasia, pure hair-nail type". Gfmer.ch. 2009-12-26. Archived from the original on 2011-02-27. Retrieved 2010-01-20. ## External links[edit] Classification D * OMIM: 602032 * MeSH: C566592 External resources * Orphanet: 69084 This genetic disorder 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 inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors	Pure hair-nail type ectodermal dysplasia	c1865951	1,832	wikipedia	https://en.wikipedia.org/wiki/Pure_hair-nail_type_ectodermal_dysplasia	2021-01-18T19:10:14	{"mesh": ["C566592"], "umls": ["C1865951"], "orphanet": ["69084"], "wikidata": ["Q7261148"]}
Melorheostosis SpecialtyRheumatology Melorheostosis is a medical developmental disorder and mesenchymal dysplasia in which the bony cortex widens and becomes hyperdense in a sclerotomal distribution. The condition begins in childhood and is characterized by thickening of the bones. Pain is a frequent symptom and the bone can have the appearance of dripping candle wax.[1] ## Contents * 1 Cause * 2 Diagnosis * 3 Treatment * 4 See also * 5 References * 6 External links ## Cause[edit] A randomly occurring somatic mutation of the MAP2K1 gene during fetal development is believed to be the cause.[2][3] It is not known if LEMD3 mutations can cause isolated melorheostosis in the absence of osteopoikilosis or Buschke–Ollendorff syndrome.[4] ## Diagnosis[edit] Melorheostosis is a mesenchymal dysplasia manifesting as regions of dripping wax appearance or flowing candle wax appearance.[5] The disorder can be detected by radiograph due to thickening of bony cortex resembling "dripping candle wax." It is included on the spectrum of developmental bone dysplasias including pycnodysostosis and osteopoikilosis.[6] The disorder tends to be unilateral and monostotic (i.e. affecting a single bone), with only one limb typically involved. Cases with involvement of multiple limbs, ribs, and bones in the spine have also been reported. There are no reported cases of involvement of skull or facial bones. Melorheostosis can be associated with pain, physical deformity, skin and circulation problems, contractures, and functional limitation. It is also associated with a benign inner ear dysplasia known as osteosclerosis.[7] ## Treatment[edit] The disorder is progressive, with the ultimate severity of symptoms often depending on age of onset. In severe cases amputation has been performed when conservative measures such as physical therapy and regional anesthetics have been ineffective.[8] ## See also[edit] * List of radiographic findings associated with cutaneous conditions ## References[edit] 1. ^ "Definition of Melorheostosis". Medicinenet.com. Retrieved 9 July 2018. 2. ^ "Melorheostosis \| Genetic and Rare Diseases Information Center (GARD) – an NCATS Program". rarediseases.info.nih.gov. Retrieved 2019-01-22. 3. ^ Kang H, Jha S, Deng Z, Fratzl-Zelman N, Cabral WA, Ivovic A, Meylan F, Hanson EP, Lange E, Katz J, Roschger P, Klaushofer K, Cowen EW, Siegel RM, Marini JC, Bhattacharyya T (April 2018). "Somatic activating mutations in MAP2K1 cause melorheostosis". Nature Communications. 9 (1): 1390. Bibcode:2018NatCo...9.1390K. doi:10.1038/s41467-018-03720-z. PMC 5895796. PMID 29643386. 4. ^ Zhang Y, Castori M, Ferranti G, Paradisi M, Wordsworth BP (June 2009). "Novel and recurrent germline LEMD3 mutations causing Buschke-Ollendorff syndrome and osteopoikilosis but not isolated melorheostosis". Clinical Genetics. 75 (6): 556–61. doi:10.1111/j.1399-0004.2009.01177.x. PMID 19438932. 5. ^ Salam, Hani. "Melorheostosis - Radiology Reference Article - Radiopaedia.org". Radiopaedia.org. Retrieved 9 July 2018. 6. ^ Azouz ME, Greenspan A. "Melorheostosis - Orpha.net" (PDF). 7. ^ Subhas N, Sundaram M, Bauer TW, Seitz WH, Recht MP (February 2008). "Glenoid labrum ossification and mechanical restriction of joint motion: extraosseous manifestations of melorheostosis". Skeletal Radiology. 37 (2): 177–81. doi:10.1007/s00256-007-0405-4. PMID 18030463. 8. ^ Graham LE, Parke RC (April 2005). "Melorheostosis--an unusual cause of amputation". Prosthetics and Orthotics International. 29 (1): 83–6. doi:10.1080/17461550500066808. PMID 16180380. ## External links[edit] * 01061 at CHORUS Classification D * ICD-10: M85.8 * ICD-9-CM: 733.99 * OMIM: 155950 * MeSH: D008557 * DiseasesDB: 29229 * 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 inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors	Melorheostosis	c3149631	1,833	wikipedia	https://en.wikipedia.org/wiki/Melorheostosis	2021-01-18T18:56:48	{"gard": ["9474"], "mesh": ["D008557"], "umls": ["C3149631"], "icd-9": ["733.99"], "icd-10": ["M85.8"], "orphanet": ["2485"], "wikidata": ["Q1127727"]}
A rare, genetic hemoglobinopathy characterized by anemia and erythrocyte abnormalities including anisocytosis, poikilocytosis, target cells, and irreversibly sickled cells. Clinical course is similar to sickle cell disease, including acute episodes of pain, splenic infarction and splenic sequestration crisis, vaso-occlusive crisis, acute chest syndrome, ischemic brain injury, osteomyelitis and avascular bone necrosis. [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 inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors	Sickle cell-hemoglobin D disease syndrome	c0272084	1,834	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=251370	2021-01-23T18:30:32	{"gard": ["12458"], "umls": ["C0272084"], "icd-10": ["D57.2"], "synonyms": ["HbSD disease"]}
For a general phenotypic description and a discussion of genetic heterogeneity of glioma, see GLM1 (137800). Mapping Working from the hypothesis that coinheritance of low-risk variants contributes to the 2-fold increased risk of glioma in relatives of individuals with primary brain tumors, Shete et al. (2009) conducted a metaanalysis of 2 glioma genomewide association studies by genotyping 550,000 tagged SNPs in a total of 1,878 cases and 3,670 controls, with validation in 3 additional independent series totaling 2,545 cases and 2,953 controls. They observed significant association of a single-nucleotide polymorphism (SNP), rs2736100 (OR = 1.27, 95% CI 1.19-1.37, combined P = 1.50 x 10(-17)) at chromosome 5p15.33 in intron 2 of the TERT gene (187270). TERT encodes the reverse transcriptase component of telomerase, essential for telomerase activity in maintaining telomeres and cell immortalization. [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 inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors	GLIOMA SUSCEPTIBILITY 8	c0017638	1,835	omim	https://www.omim.org/entry/613033	2019-09-22T15:59:55	{"mesh": ["D005910"], "omim": ["613033"], "orphanet": ["182067"]}
Tendon rupture is a condition in which a tendon separates in whole or in part from tissue to which it is attached, or is itself torn or otherwise divided in whole or in part.[1][2] Examples include: * Achilles tendon rupture * Biceps tendon rupture * Anterior cruciate ligament injury * Biceps femoris tendon rupture and Quadriceps tendon rupture * Cruciate ligament#Rupture * Patellar tendon rupture ## References[edit] 1. ^ Thomas, JR; Lawton, JN (February 2017). "Biceps and Triceps Ruptures in Athletes". Hand Clinics. 33 (1): 35–46. doi:10.1016/j.hcl.2016.08.019. PMID 27886838. 2. ^ Wu, Y; Lin, L; Li, H; Zhao, Y; Liu, L; Jia, Z; Wang, D; He, Q; Ruan, D (December 2016). "Is surgical intervention more effective than non-surgical treatment for acute Achilles tendon rupture? A systematic review of overlapping meta-analyses". International Journal of Surgery. 36 (Pt A): 305–311. doi:10.1016/j.ijsu.2016.11.014. PMID 27838385. [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 inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors	Tendon rupture	c0151937	1,836	wikipedia	https://en.wikipedia.org/wiki/Tendon_rupture	2021-01-18T18:57:05	{"umls": ["C0151937"], "wikidata": ["Q40889763"]}
Stuve-Wiedemann syndrome (STWS) is a congenital skeletal (bone) dysplasia characterized by small stature, bowing of the long bones, and other skeletal anomalies. Patients often present with serious complications such as breathing and feeding difficulties and episodes of hyperthermia (elevated body temperature). The condition is transmitted in an autosomal recessive fashion and appears to be caused by mutations in the leukemia inhibitory factor receptor gene (LIFR). STWS is often fatal during the neonatal period due to respiratory distress or hyperthermic episodes. However, some patients do survive to adolescence and beyond. Survivors may develop spinal deformities, spontaneous fractures, bowing of the lower limbs, prominent joints, and dysautonomia symptoms (including temperature instability). Treatment is mainly symptomatic and should include efforts to prevent choking, physical therapy and/or surgery to address bone abnormalities, efforts to prevent vision loss, and treatment for osteopenia or osteoporosis. Caution should be exercised when using anesthesia due to the predisposition to hyperthermia. [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 inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors	Stuve-Wiedemann syndrome	c0796176	1,837	gard	https://rarediseases.info.nih.gov/diseases/5045/stuve-wiedemann-syndrome	2021-01-18T17:57:30	{"mesh": ["C537502"], "omim": ["601559"], "umls": ["C0796176"], "orphanet": ["3206"], "synonyms": ["STWS", "Schwartz-Jampel syndrome type 2", "SJS2", "Schwartz-Jampel syndrome neonatal", "Stuve-Wiedemann/Schwartz-Jampel type 2 syndrome", "Neonatal Schwartz-Jampel syndrome type 2"]}
Hallermann-Streiff syndrome (HSS) is a rare condition with characteristic features that are present at birth and become more apparent over time. Signs and symptoms include an unusually shaped skull, distinctive facial features, thin skin and hair, and eye and dental abnormalities. Other features include poor vision, a small upper airway, and short stature. HSS is diagnosed based on a physical examination that identifies the specific signs and symptoms that have been described in this condition. The cause of HSS is unknown and is thought to be due to a random genetic change. HSS is not thought to be inherited in families. Because this condition is so rare, little is known about how HSS changes over time. Problems with airway management and premature aging have been reported. Most people with HSS have normal intelligence. Treatment for HSS is based on the specific symptoms and may involve multiple surgeries. [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 inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors	Hallermann-Streiff syndrome	c0018522	1,838	gard	https://rarediseases.info.nih.gov/diseases/288/hallermann-streiff-syndrome	2021-01-18T18:00:10	{"mesh": ["D006210"], "omim": ["234100"], "umls": ["C0018522"], "orphanet": ["2108"], "synonyms": ["Hallermann Streiff syndrome", "HSS", "Hallermann Streiff Francois syndrome", "Francois dyscephalic syndrome", "François dyscephalic syndrome", "Oculomandibulofacial syndrome"]}
## Summary ### Clinical characteristics. Arginase deficiency in untreated individuals is characterized by episodic hyperammonemia of variable degree that is infrequently severe enough to be life threatening or to cause death. Most commonly, birth and early childhood are normal. Untreated individuals have slowing of linear growth at age one to three years, followed by development of spasticity, plateauing of cognitive development, and subsequent loss of developmental milestones. If untreated, arginase deficiency usually progresses to severe spasticity, loss of ambulation, complete loss of bowel and bladder control, and severe intellectual disability. Seizures are common and are usually controlled easily. Individuals treated from birth, either as a result of newborn screening or having an affected older sib, appear to have minimal symptoms. ### Diagnosis/testing. The diagnosis of arginase deficiency is established in a proband with suggestive clinical and/or biochemical findings and confirmed by identification of biallelic pathogenic variants in ARG1 or, in limited instances, by failure to detect arginase enzyme activity (usually <1% of normal) in red blood cell extracts. ### Management. Treatment of manifestations: Management should closely mirror that for urea cycle disorders, except that individuals with arginase deficiency are not as likely to have episodes of hyperammonemia; if present, such episodes respond to conservative management (e.g., intravenous fluid administration). Treatment should involve a team coordinated by a metabolic specialist. Routine outpatient management includes restriction of dietary protein and consideration of oral nitrogen-scavenging drugs (in those who have chronic or recurrent hyperammonemia). Treatment of an acutely ill (comatose and encephalopathic) individual requires: rapid reduction of plasma ammonia concentration; use of pharmacologic agents (sodium benzoate and/or sodium phenylbutyrate/phenylacetate) to promote excretion of excess nitrogen through alternative pathways; and introduction of calories supplied by carbohydrates and fat to reduce catabolism and the amount of excess nitrogen in the diet while avoiding overhydration and resulting cerebral edema. Standard treatment for seizures, spasticity, developmental delay / intellectual disability, and joint contractures. In those with persistent hepatic synthetic function abnormalities, fresh-frozen plasma should be considered prior to surgical procedures. In the rare instance of progression to hepatic fibrosis and cirrhosis, liver transplantation can be considered. Prevention of primary manifestations: Maintenance of plasma arginine concentration as near normal as possible through restriction of dietary protein and use of oral nitrogen-scavenging drugs as necessary to treat hyperammonemia. Liver transplantation eliminates hyperargininemia and presumably the risk for hyperammonemia but is rarely necessary in arginase deficiency. Surveillance: Regular follow up at intervals determined by age and degree of metabolic stability. Assessment of metabolic control (plasma ammonia, amino acid profile, and nutritional labs) at least monthly for the first year of life and as determined by a metabolic specialist after the first year of life; guanidinoacetate and liver function tests every six to 12 months; monitoring of growth and developmental progress at each visit. Agents/circumstances to avoid: Valproic acid (exacerbates hyperammonemia). Evaluation of relatives at risk: Plasma quantitative amino acid analysis, molecular genetic testing (if the family-specific pathogenic variants are known), or enzymatic testing in all sibs (especially younger ones) of a proband to allow early diagnosis and treatment of those found to be affected. Pregnancy management: In general, affected pregnant women should continue dietary protein restriction and ammonia-scavenging medications (after an appropriate benefit/risk calculation) based on their clinical course before pregnancy. Other: Immunizations on the usual schedule; appropriate use of antipyretics as indicated (ibuprofen preferred over acetaminophen). ### Genetic counseling. Arginase deficiency 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. Heterozygotes (carriers) are asymptomatic. Carrier testing for at-risk relatives and prenatal testing for pregnancies at increased risk are possible if the ARG1 pathogenic variants in the family are known. ## Diagnosis ### Suggestive Findings Scenario 1. Abnormal newborn screening (NBS) result * NBS for arginase deficiency is primarily based on quantification of the analyte arginine on dried blood spots. * Arginine values above the cutoff reported by the screening laboratory are considered positive and require follow-up biochemical testing (see Preliminary laboratory findings below). * If these studies support the diagnosis of arginase deficiency, additional testing is required to establish the diagnosis (see Establishing the Diagnosis). Note: (1) Some infants with arginase deficiency may have follow-up arginine levels in the normal range, and thus infants who continue to have elevated arginine-to-ornithine ratios and arginine toward the upper limit of normal should undergo additional diagnostic testing (see Establishing the Diagnosis) [Author, personal observation]. (2) Arginase deficiency is currently a secondary condition on the Recommended Uniform Screening Panel. Thus, not all states will screen for and detect newborns with arginase deficiency. Scenario 2. Symptomatic individual with either atypical findings or untreated arginase deficiency resulting from any of the following: * NBS not performed * False negative NBS result * Caregivers not compliant with recommended treatment following a positive NBS result Supportive but nonspecific clinical findings and preliminary laboratory findings can include the following. Clinical findings * Slowing of linear growth at age one to three years * Development of spasticity in the lower extremities * Plateauing of cognitive development * Loss of developmental milestones * Seizures Preliminary laboratory findings * Plasma quantitative amino acid analysis. Elevation of plasma arginine concentration three- to fourfold the upper limit of normal is highly suggestive of the diagnosis. Plasma arginine elevation is the primary means of ascertainment. Note: Up to twofold the upper limit of normal may be seen in infants who do not have arginase deficiency and who are otherwise normal. * Plasma ammonia concentration. Elevation of plasma ammonia concentration may be intermittent. Acute hyperammonemia (plasma ammonia concentration >150 µmol/L) is uncommon. * Urinary orotic acid concentration. Although urinary orotic acid concentration is often elevated, it is not a primary screen for this disorder. Note: Because elevations of these metabolites individually are not entirely specific to arginase deficiency, follow-up testing is required to establish or rule out the diagnosis of arginase deficiency (see Establishing the Diagnosis). ### Establishing the Diagnosis The diagnosis of arginase deficiency is established in a proband with suggestive clinical and/or biochemical findings and confirmed by identification of biallelic pathogenic variants in ARG1 (see Table 1) or, in limited instances, by failure to detect arginase enzyme activity (usually <1% of normal) in red blood cell extracts. Because of its relatively high sensitivity, ARG1 molecular genetic testing is the preferred confirmatory test for arginase deficiency. Note: Enzyme assay can be helpful if two pathogenic variants are not found on molecular genetic testing. #### Molecular Genetic Testing Approaches Scenario 1. Abnormal newborn screening (NBS) result. When NBS results and other laboratory findings suggest the diagnosis of arginase deficiency, molecular genetic testing approaches can include single-gene testing or use of a multigene panel: * Single-gene testing. Sequence analysis of ARG1 detects small intragenic deletions/insertions and missense, nonsense, and splice site variants; depending on the method used, exon or whole-gene deletions/duplications may not be detected. Perform sequence analysis first. If only one or no pathogenic variant is found, perform gene-targeted deletion/duplication analysis to detect intragenic deletions or duplications. Note: In individuals of French Canadian ancestry, the c.57+1G>A founder variant may be tested for first. * A multigene panel that includes ARG1 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. Scenario 2. Symptomatic individual with atypical findings or untreated arginase deficiency (resulting from NBS not performed or false negative NBS result): * If arginase deficiency is suspected, single-gene testing or a multigene panel may be performed (see Scenario 1). * When the diagnosis of arginase deficiency has not been considered, comprehensive genomic testing (which does not require the clinician to determine which gene[s] are likely involved) is an 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 Arginase Deficiency View in own window Gene 1MethodProportion of Pathogenic Variants 2 Detectable by Method ARG1Sequence analysis 3>98% 4 Gene-targeted deletion/duplication analysis 5<2% 4, 6 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\. Diez-Fernandez et al [2018]; data derived from Human Gene Mutation Database [Stenson et al 2017] 5\. 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. 6\. Three single or multiexon deletions have been reported [Korman et al 2004, Wang et al 2012, Diez-Fernandez et al 2018]. #### Measurement of Red Blood Cell Arginase Enzyme Activity Most affected individuals have no detectable arginase enzyme activity (usually <1% of normal) in red blood cell extracts. Note: (1) Although arginase is stable, a control sample should be obtained and treated identically if the cells are to be shipped to a distant site. (2) Liver and red blood cell arginase activity correlate well; therefore, it is not necessary to perform a liver biopsy when enzyme activity can be measured from a blood sample. ## Clinical Characteristics ### Clinical Description To date, more than 260 individuals with arginase deficiency have been identified [Uchino et al 1995; De Deyn et al 1997; Crombez & Cederbaum 2005; Schlune et al 2015; Huemer et al 2016; Therrell et al 2017; Diez-Fernandez et al 2018; Chandra et al 2019; Author, personal observation]. The following description of the phenotypic features associated with this condition is based primarily on individuals with severe disease. It should be noted that a phenotypic spectrum exists, and mildly affected individuals exhibit less severe features. Individuals treated from birth (as a result either of newborn screening or of having an affected older sib) appear to have minimal symptoms [Cederbaum et al 2004]. Growth and feeding. Most commonly, growth at birth and through early childhood is normal. * At age one to three years, linear growth slows and eventually the majority of affected children demonstrate growth deficiency, which persists if arginase deficiency goes untreated. * Microcephaly is common and is congenital in some cases. * Feeding issues may develop, leading to inadequate nutrition. Some require a supplemental feeding tube. Cognitive development. Initially, cognitive development in infancy and early childhood is normal. * Starting at age one to three years, previously normal cognitive development slows or stops and the child begins to lose developmental milestones. * If untreated, arginase deficiency usually progresses to severe intellectual disability with accompanying neurologic findings (see Neurologic features below). * Full scale IQ in adults is in the 70s, and about half are able to live independently, though they experience significant memory and fine motor deficits [Waisbren et al 2016]. Mildly affected individuals and those treated early in life may be able to hold a job. * Some children are more severely affected cognitively, whereas others have more severe spasticity and secondary joint contractures. Neurologic features. In untreated individuals, progressive neurologic signs typically include the development of severe spasticity with loss of ambulation and complete loss of bowel and bladder control. * Spasticity. Between 80% and 90% of affected individuals develop spasticity of the lower extremities [Huemer et al 2016, Chandra et al 2019]. * Spastic diplegia typically appears between ages two and four years and is often misdiagnosed as cerebral palsy. * Severe spasticity can lead to joint contractures and lordosis. * Seizures occur in 60%-75% of affected individuals and are usually controlled easily by anti-seizure medication [Huemer et al 2016, Chandra et al 2019]. Generalized tonic-clonic seizures are the most common seizure type. * Brain imaging often reveals cortical atrophy. Other parts of the nervous system including basal ganglia, cerebellum, medulla, and spinal cord are largely spared [De Deyn et al 1997]. Hyperammonemia. Unlike the other eight primary urea cycle disorders (see Urea Cycle Disorders Overview), arginase deficiency rarely results in elevated plasma ammonia concentration in the newborn period. * Episodic hyperammonemia of variable degree may occur during illness but is rarely severe enough to be life threatening, although death has been reported. * Hyperammonemia presents with vomiting, lethargy, and altered mental status but in some cases is asymptomatic and only recognized if blood ammonia is obtained during an acute illness. * Older individuals may present with postoperative encephalopathy. Liver disease. Hepatic dysfunction, if present, is usually mild, manifesting as transaminitis, prolonged coagulation time, and in some cases hepatomegaly. Affected individuals typically do not have bleeding problems from prolonged coagulation time. Rarely, neonatal cholestatic jaundice has been reported [Braga et al 1997, Gomes Martins et al 2010], and cirrhosis can occur. Some adults have developed hepatocellular carcinoma. Other. Some affected females experience symptomatic hyperammonemia during menstrual cycles. These individuals may require abortive therapy (see Management, Prevention of Primary Manifestations). Prognosis. While data are not available, the vast majority of affected individuals appear to survive and live long (albeit handicapped) lives. ### Genotype-Phenotype Correlations Genotype-phenotype correlations indicate that the amount of residual enzyme activity modulates the phenotype [Diez-Fernandez et al 2018]. Severe disease is associated with: * Homozygosity or compound heterozygosity for predicted loss-of-function variants such as c.466-2A>G, c.77delA, c.263_266delAGAA, and c.647_648ins32; * Missense changes such as p.Ile8Lys or p.Gly106Arg when homozygous or in combination with another severe allele. ### Prevalence Arginase deficiency is one of the rarest urea cycle defects. Its incidence has been estimated at between 1:350,000 and 1:1,000,000; the true incidence in nonrelated populations is unknown. Arginase deficiency is pan ethnic but may be more common among French Canadians due to a pathogenic founder variant [Uchino et al 1995] (see Table 9). ## Differential Diagnosis Hyperammonemia. Arginase is the sixth and final enzyme of the eight known steps in the urea cycle. See Urea Cycle Disorders Overview for approaches to distinguish: * Other causes of hyperammonemia from a urea cycle disorder; and * The differences between the urea cycle disorders themselves. Spasticity. Arginase deficiency may be misdiagnosed as static spastic diplegia (cerebral palsy). See Hereditary Spastic Paraplegia Overview. It should be noted that arginase deficiency is one of the few treatable causes of spastic diplegia [Prasad et al 1997]. ARG2. A second arginase gene is known (ARG2), but no human deficiency state has been identified and it is not clear that elevated plasma arginine would be a part of such a deficiency. CAT-2. A new metabolic disorder in the human cationic amino acid transporter-2 has been proposed. The biochemical profile includes high levels of arginine, ornithine, and lysine in both blood and urine. The one described affected individual presented with an abnormal newborn screen for arginase deficiency [Yahyaoui et al 2019]. ## Management No consensus clinical management guidelines for arginase deficiency have been published. However, general guidelines for the management of urea cycle disorders are available [Häberle et al 2019]. ### Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with arginase deficiency, the following evaluations summarized in Table 2 (if not performed as part of the evaluation that led to the diagnosis) are recommended. ### Table 2. Recommended Evaluations Following Initial Diagnosis in Individuals with Arginase Deficiency View in own window EvaluationComment Obtain plasma ammonia, amino acid profile, guanidinoacetate, & liver function tests. 1Consultation w/metabolic physician / biochemical geneticist Gastroenterology / nutrition / feeding team eval * To incl eval of aspiration risk & nutritional status * Consultation w/metabolic dietitian * Consider eval for gastric tube placement in those unable to meet nutritional needs orally. Developmental assessmentConsider referral to developmental pediatrician. Neurologic evalConsider referral to neurologist if spasticity is present or seizures are suspected. Musculoskeletal evalTo assess for secondary joint contractures & lordosis. Consider referral to rehabilitation medicine. 1\. Albumin, bilirubin, aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase, prothrombin time (PT), and partial thromboplastin time (PTT). ### Treatment of Manifestations The management of individuals with arginase deficiency should closely mirror that described in the Urea Cycle Disorders Overview, with one caveat: individuals with arginase deficiency are less prone to episodes of hyperammonemia and when present, hyperammonemia is more likely to respond to conservative management such as intravenous fluid administration. However, the individual who is comatose and encephalopathic is at high risk for severe brain damage and should be treated accordingly. Arginine supplementation is obviously contraindicated. ### Table 3. Routine Outpatient Management in Individuals with Arginase Deficiency View in own window PrincipleTreatmentConsideration/Other Restriction of dietary protein 1 * At least half of dietary protein from natural (complete) sources * Supplementation w/arginine-free essential amino acid formula * Protein requirement varies by age. Ideally, affected person should be on the minimum protein intake needed to maintain protein biosynthetic function, growth, & normal plasma amino acid concentrations. * Dietary modification does not lead to normalization of plasma arginine concentration but does cause improvement of some clinical symptoms. Administration of oral nitrogen-scavenging drugsSodium benzoate * 250 mg/kg/day Sodium phenylbutyrate * ≤250 mg/kg/day if <20 kg * 5 g/m2/day if >20 kg * Medications to be taken in = amts w/each meal or feeding (i.e., 3-4x/day) 2 * Not all affected individuals require nitrogen scavengers. Use only for chronic or recurrent hyperammonemia. 1\. The goal should be maintenance of plasma arginine concentration as near normal as possible. 2\. Häberle et al [2019], Urea Cycle Disorders Consortium ### Table 4. Acute Outpatient Management in Individuals with Arginase Deficiency View in own window Manifestation/ConcernTreatmentConsideration/Other Mildly ↑ catabolism 1 * Carbohydrate supplementation orally or by feeding tube * ↓ natural protein intake 2 Trial of outpatient treatment at home for 12-48 hrs w/assessments for clinical changes 3 FeverAdministration of antipyretics (acetaminophen, ibuprofen) if temperatures rises >38.5°C Occasional vomitingAntiemetics 1\. Fever; vomiting, diarrhea, dehydration 2\. Some centers advocate reducing natural protein intake to zero or to 50% of the normal prescribed regimen for short periods (24-48 hours) in the outpatient setting during intercurrent illness. 3\. Alterations in mentation/alertness, fever, and enteral feeding tolerance with any new or evolving clinical features should be discussed with the designated center of expertise for inherited metabolic diseases. ### Table 5. Acute Inpatient Management in Individuals with Arginase Deficiency View in own window Manifestation/ConcernTreatmentConsideration/Other Hyperammonemia (mild to moderate)Increase caloric intake: * IV fluids w/≥10% dextrose at 1-1.5x maintenance rate 1 * Protein-free oral formula, e.g., Mead Johnson PFD or Ross Formula ProPhree® Complete restriction of protein should not exceed 24-48 hrs, as depletion of essential amino acids may result in endogenous protein catabolism & nitrogen release. Transition patients from parenteral to enteral feeds as soon as possible. Hyperammonemia (severe)Same as above, plus nitrogen scavengers: * Enteral: Sodium benzoate, sodium phenylbutyrate, or glycerol phenylbutyrate * IV: Sodium phenylacetate & sodium benzoate (Ammonul®) Consider intralipids for additional calories or TPN if affected person is unable to tolerate enteral feeds for > few days.If affected person is unable to hydrate orally, consider placement of NG tube. Avoid overhydration, which can result in cerebral edema. 2 Dialysis 3It is rare for persons w/arginase deficiency to require dialysis. The ammonia level & clinical status determine need for dialysis. TPN = total parenteral nutrition 1\. High parenteral glucose plus insulin can be used acutely to diminish catabolism. 2\. The duration of cerebral edema correlates with poor neurologic outcome. 3\. Treatment of choice to most rapidly decrease serum ammonia concentration. The method employed depends on the affected person's circumstances. ### Table 6. Management of Other Complications in Individuals with Arginase Deficiency View in own window Manifestation/ConcernTreatmentConsideration/Other SeizuresStandard AEDs depending on seizure type 1Referral to neurologist SpasticityConsider a trial of Botox®. Orthotics, walkers, wheelchairs, & other durable medical equipmentReferral to rehabilitation medicine Persistent hepatic synthetic function abnormalities 2 * In most cases, only clinical monitoring is necessary. * W/more severe coagulopathy, FFP is administered prior to surgical procedures. Referral to hematologist for severe cases Hepatic fibrosis & cirrhosisLiver transplantationThis is a rare complication. Joint contractures * Physical therapy * Tendon release procedures Referral to orthopedist if severe AEDs = antiepileptic drugs; FFP = fresh-frozen plasma 1\. Valproic acid should be avoided (see Agents/Circumstances to Avoid) 2\. Particularly elevated prothrombin time. 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. #### Developmental Disability / Intellectual Disability Management Issues Ages 0-3 years. Referral to an early intervention program is recommended for access to occupational, physical, speech, and feeding therapy. In the United States, early intervention is a federally funded program available in all states. Ages 3-5 years. In the United States, 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. Ages 5-21 years * In the US, an IEP based on the individual's level of function should be developed by the local public school district. Affected children are permitted to remain in the public school district until age 21. * Discussion about transition plans including financial, vocation/employment, and medical arrangements should begin at age 12 years. Developmental pediatricians can provide assistance with transition to adulthood. 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. * 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 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. ### Prevention of Primary Manifestations The treatment goal is maintenance of plasma arginine concentration as near normal as possible through restriction of dietary protein intake, supplementation with arginine-free essential amino acid formula, and use of nitrogen-scavenging drugs as needed to treat hyperammonemia. Liver transplantation eliminates hyperargininemia and presumably the risk for hyperammonemia but (in contrast to other urea cycle disorders) is rarely necessary in arginase deficiency; see also Table 3. ### Prevention of Secondary Complications ### Table 7. Prevention of Secondary Manifestations in Individuals with Arginase Deficiency View in own window Manifestation/ SituationPreventionConsiderations/Other Hyperammonemic episodesOngoing education of affected persons & caregivers re natural history, maintenance & emergency treatment, prognosis, & risks of acute encephalopathic crisesWritten protocols for maintenance & emergency treatment should be provided to parents, primary care providers/pediatricians, & teachers & school staff. 1, 2 Treatment protocols & provision of emergency letters or cards to incl guidance for care in the event of illnessEmergency letters/cards should be provided summarizing key information & principles of emergency treatment for arginase deficiency & containing contact information for the primary treating metabolic center. MedicAlert® bracelets/pendants, or car seat stickers Adequate supplies of specialized dietary products (protein-free formulas; medication required for maintenance & emergency treatment) should always be maintained at home.For any planned travel or vacations, consider contacting a center of expertise near the destination prior to travel dates. 1\. Essential information including written treatment protocols should be provided before inpatient emergency treatment may be needed. 2\. Parents or local hospitals should immediately inform the designated metabolic center if: (1) temperature is >38.5°C; (2) vomiting/diarrhea or other symptoms of intercurrent illness develop; or (3) new neurologic symptoms occur. ### Surveillance Regular follow up at intervals determined by age and degree of metabolic stability is recommended (see Table 8). ### Table 8. Recommended Surveillance for Individuals with Arginase Deficiency View in own window Manifestation/MonitoringEvaluationFrequency Assessment of metabolic controlPlasma ammonia, amino acid profile, & nutritional monitoring labsAt least monthly for 1st yr of life; thereafter per metabolic specialist GuanidinoacetateEvery 6-12 mos Poor growthMonitor growthAt each visit Developmental delayMonitor developmental milestonesAt each visit in those age <18 yrs Neuropsychological testing using age-appropriate standardized assessment batteriesAs needed Neurologic deterioration 1Neurologic evalAt each visit 2 Persistent hepatic synthetic function abnormalitiesLiver function tests 3Every 6-12 mos Quality of lifeStandardized quality of life assessment tools for affected persons & parents/caregiversAs needed 1\. Developmental stagnation and/or regression; seizures; spasticity; development of joint contractures 2\. Referral to neurologist, orthopedist, and/or physical therapist as indicated 3\. Albumin, bilirubin, aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase, prothrombin time (PT), and partial thromboplastin time (PTT). ### Agents/Circumstances to Avoid Valproic acid should be avoided as it exacerbates hyperammonemia in urea cycle defects and other inborn errors of metabolism [Scaglia & Lee 2006]. ### Evaluation of Relatives at Risk Because the age of onset of arginase deficiency is delayed beyond the newborn period and the manifestations can vary, the genetic status of all sibs of a proband (especially the younger ones) should be clarified so that morbidity can be reduced by early diagnosis and treatment in those who are affected. Testing methods can include any one of the following: * Plasma quantitative amino acid analysis * Molecular genetic testing (if the family-specific ARG1 pathogenic variants are known) * Analysis of enzymatic activity in red blood cells See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes. ### Pregnancy Management The authors are not aware of any instance in which pregnancy has been reported in a woman with arginase deficiency. #### Prior to and During Pregancy To achieve metabolic control that will enable normal fetal growth and development, affected pregnant women should generally continue dietary protein restriction and ammonia-scavenging medications (after an appropriate benefit/risk calculation) based on their clinical course before pregnancy. * Protein restriction during pregnancy is challenging given the complications that commonly arise during pregnancy (i.e., nausea, vomiting, anorexia). * Due to increased protein and energy requirements in pregnancy and, oftentimes, difficulty with compliance, weekly to every two-week monitoring of plasma amino acids and ammonia is recommended, especially in the first and third trimester, and close monitoring immediately after delivery. * Plasma amino acid levels can help guide quick adjustments to diet in order to achieve normal plasma amino acid profiles that prevent catabolism and hyperammonemia while allowing for normal fetal growth and development. #### Fetal Outcomes There are no well-controlled epidemiologic studies of the fetal effects of sodium benzoate, phenylacetate, or phenylbutyrate during human pregnancy, although there are several case reports. Redonnet-Vernhet et al [2000] reported a woman with symptomatic ornithine transcarbamylase (OTC) deficiency who was treated with sodium benzoate during the first 11 weeks of gestation and was subsequently transitioned to sodium phenylbutyrate for the remainder of pregnancy. She delivered a healthy female, who at age two years continued to do well. Lamb et al [2013] reported another woman with symptomatic OTC who was treated throughout pregnancy with sodium benzoate (4 g/4x/day), sodium phenylbutyrate (2 g/4x/day) and arginine (300 mg/4x/day) who delivered a healthy, unaffected male who was doing well at age six weeks. Ho et al [2019] are the first to document the use of sodium phenylbutyrate throughout two sequential pregnancies in a woman with HHH syndrome: * In the first pregnancy sodium phenylbutyrate (5.5 g/4x/day) was used as maintenance therapy. This resulted in the delivery of a healthy female who was noted to have typical growth and development at age five years. * In the second pregnancy, emergency treatment with Ammonul® (sodium phenylacetate/sodium benzoate) to manage hyperammonemic crisis (ammonia 295 µmol/L) was used in addition to maintenance therapy of sodium phenylbuterate (5 g/4x/day). Although the mother responded well to emergency treatment, the baby experienced intrauterine growth restriction and remained in the NICU due to prematurity and low birth weight. At age two years, the child exhibited speech delay and autism. How severe metabolic decompensation, elevated plasma ornithine, and/or side effects of sodium phenylbutyrate, phenylacetate, and/or benzoate may have contributed to the speech delay and/or autism is not known. * Ho et al [2019] prefer and recommend the use of sodium benzoate if deemed medically necessary during pregnancy, but did not advise switching maintenance medications during pregnancy #### Theoretic Concerns Sodium benzoate has been reported to lead to malformations and neurotoxicity/nephrotoxicity in zebrafish larvae [Tsay et al 2007]. As a known differentiating agent, sodium phenylbutyrate also functions as a histone deacetylase inhibitor with potential teratogenicity, given its ability to alter gene expression in fetal mice [Di Renzo et al 2007]. Theoretically, the use of benzoate/phenylacetate and in particular sodium phenylbutyrate should be avoided during pregnancy, especially during the first trimester. The use of these medications should be carefully evaluated for each individual (benefit/risk ratio) in consultation with a metabolic genetics specialist. See MotherToBaby for further information on medication use during pregnancy. ### Therapies Under Investigation A clinical trial for enzyme replacement therapy using pegylated synthetic human arginase I is currently under way (Clinical Trials Identifier NCT03921541). A variety of genomic therapies are under investigation including mRNA therapy [Asrani et al 2018, Truong et al 2019], ARG1 gene editing [Lee et al 2016, Sin et al 2017], and viral-mediated gene therapy [Cantero et al 2016]. 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. ### Other Immunizations can be provided on the usual schedule. Appropriate use of antipyretics is indicated. Ibuprofen is preferred over acetaminophen. [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 inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors	Arginase Deficiency	c0268548	1,839	gene_reviews	https://www.ncbi.nlm.nih.gov/books/NBK1159/	2021-01-18T21:42:52	{"mesh": ["D020162"], "synonyms": ["ARG1 Deficiency", "Arginase-1 Deficiency", "Hyperargininemia"]}
Eosinophilic gastroenteritis occurs when certain white blood cells known as eosinophils get into the digestive tract and cause damage. Symptoms of eosinophilic gastroenteritis usually start in adulthood and may include stomach pain, nausea, vomiting, and the inability to absorb nutrients from food. Sometimes, a blockage in the intestines occurs. In most people, symptoms occur from time to time and may go away completely with treatment. The exact cause of eosinophilic gastroenteritis is unknown, but it may be due to an abnormal response of the immune system to food allergies. Diagnosis is based on the symptoms, a clinical exam, laboratory tests, and by excluding other more common conditions. Treatment is focused on managing the symptoms and includes diet and medication. [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 inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors	Eosinophilic gastroenteritis	c1262481	1,840	gard	https://rarediseases.info.nih.gov/diseases/9142/eosinophilic-gastroenteritis	2021-01-18T18:00:41	{"mesh": ["C535952"], "orphanet": ["2070"], "synonyms": ["Eosinophilic gastritis", "Eosinophilic enteritis", "Eosinophilic gastroenteropathy", "Eosinophilic esophagitis", "EGE", "Eosinophilic gastroenterocolitis"]}
## Clinical Features Shaikh et al. (2005) reported 2 consanguineous Pakistani families with autosomal recessive deafness. All affected individuals exhibited prelingual bilateral profound hearing loss without obvious vestibular or ocular anomalies. Mapping By genomewide linkage analysis in a consanguineous Pakistani family with autosomal recessive deafness, Shaikh et al. (2005) found linkage of the disorder to a locus, termed DFNB51, within an 8.33-cM region on chromosome 11p13-p12 (maximum multipoint lod score of 3.8 at marker D11S4102). Linkage information from the second family refined the locus to a 5.06-cM interval between markers D11S4200 and D11S4102. Sequencing excluded mutations in the SLC1A2 (600300), TRAF6 (602355), and RAMP (regeneration-associated muscle protease) genes. INHERITANCE \- Autosomal recessive HEAD & NECK Ears \- Deafness, sensorineural, profound (prelingual onset) ▲ 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 inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors	DEAFNESS, AUTOSOMAL RECESSIVE 51	c1864968	1,841	omim	https://www.omim.org/entry/609941	2019-09-22T16:05:26	{"doid": ["0110508"], "mesh": ["C538202"], "omim": ["609941"], "orphanet": ["90636"], "synonyms": ["Autosomal recessive isolated neurosensory deafness type DFNB", "Autosomal recessive isolated sensorineural deafness type DFNB", "Autosomal recessive non-syndromic neurosensory deafness type DFNB"]}
Noneruption of teeth - maxillary hypoplasia - genu valgum is an extremely rare syndrome that is characterized by multiple unerupted permanent teeth, hypoplasia of the alveolar process and of the maxillo-zygomatic region, severe genu valgum and deformed ears. [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 inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors	Non-eruption of teeth-maxillary hypoplasia-genu valgum syndrome	c1848903	1,842	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=2972	2021-01-23T17:48:37	{"gard": ["5027"], "mesh": ["C536952", "C537496"], "omim": ["273050"], "umls": ["C1848903", "C2931509"], "synonyms": ["Stoelinga-de Koomen-Davis syndrome"]}
Spinocerebellar ataxia 4 (SCA4) is a very rare form of hereditary progressive movement disorder. Symptoms include muscle weakness (atrophy) and difficulty coordinating body movements (ataxia), most notably causing a jerky, unsteady walking style (gait) and difficulty speaking (dysarthria). A distinctive feature of SCA4 is the progressive loss of feeling or sensation in the hands and feet (peripheral neuropathy) and loss of reflexes. Degeneration of the area of the brain controlling balance and movement (cerebellar atrophy) causes symptoms to worsen over decades. The symptoms of SCA4 typically begin during the fourth or fifth decade of life, but can begin as early as the late teen years.. SCA4 is inherited in an autosomal dominant manner. Although SCA4 has been linked to a location on chromosome 16, (16q22.1), the gene which causes SCA4 when mutated has not been found. Diagnosis is based on symptoms consistent with the disease. Although there is no cure, treatment options may include physical therapy, assistive devices, and medications depending on the type and severity of symptoms present. [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 inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors	Spinocerebellar ataxia 4	c0752122	1,843	gard	https://rarediseases.info.nih.gov/diseases/9970/spinocerebellar-ataxia-4	2021-01-18T17:57:35	{"mesh": ["D020754"], "omim": ["600223"], "umls": ["C0752122"], "orphanet": ["98765"], "synonyms": ["SCA4", "Spinocerebellar ataxia type 4", "Spinocerebellar ataxia autosomal dominant with sensory axonal neuropathy"]}
A number sign (#) is used with this entry because isolated adrenocorticotropic hormone (ACTH) deficiency (IAD) can be caused by homozygous or compound heterozygous mutation in the TBX19 gene (604614) on chromosome 1q24. Description Congenital isolated adrenocorticotropic hormone deficiency is characterized by severe hypoglycemia in the neonatal period, associated with seizures in about half of cases; prolonged cholestatic jaundice; and very low plasma ACTH levels with no significant response to CRH (122560). Plasma cortisol levels are also extremely low (Vallette-Kasic et al., 2005). TBX19 is required for initiation of transcription of the POMC gene (176830), which produces the precursor peptide from which ACTH is derived (Lamolet et al., 2001). Clinical Features Hung and Migeon (1968) described a 34-month-old black boy with apparent isolated ACTH deficiency. The adrenal medulla was unresponsive to insulin-induced hypoglycemia. Treatment of the adrenocortical insufficiency restored responsiveness. The enzyme phenylethanolamine-N-methyl transferase (PNMT; 171190) is localized to the adrenal medulla and catalyzes the N-methylation of norepinephrine to epinephrine. The activity of this enzyme is controlled by glucocorticoids. Lucking and Willig (1975) and Malpuech et al. (1988) each described 2 affected sibs. The patients of Malpuech et al. (1988) were brother and sister. The first-born, the male, died; pathologic findings included bilateral adrenal hypoplasia. Plasma estriol levels were assayed during the mother's next pregnancy. Prenatal diagnosis allowed immediate and effective management of this second affected child. In the second infant, echograms showed small adrenals and from age 3 weeks she tolerated fasting poorly. The diagnosis was confirmed by reduced plasma cortisol levels, particularly during attacks of hypoglycemia. Ichiba and Goto (1983) reported 2 affected sisters. Nussey et al. (1993) investigated a female infant who presented with hypoglycemia in the neonatal period. When studied at 6 weeks of age, she was found to have no measurable ACTH even after injection of corticotropin releasing hormone (CRH; 122560). On the other hand, ACTH precursors were measurable and were stimulated by CRH and suppressed by glucocorticoid administration. By sequencing PCR products from the patient's genomic DNA, the entire coding region of the POMC gene was established to be normal. Nussey et al. (1993) interpreted these results as compatible with a cleavage enzyme defect. As reviewed by Funder and Smith (1993), POMC is cleaved in the anterior pituitary, by an enzyme termed PC1, to yield ACTH and beta-lipotropin. In the brain and pituitary intermediate lobe, the enzyme PC2 cleaves ACTH into products that yield alpha-MSH and CLIP (see 176830) and cleaves beta-LPH into gamma-LPH and beta-endorphin. The human pituitary gland appears to lack an intermediate lobe, except in utero and perhaps in pregnancy; on the other hand, PC2 is present in the human genome and is expressed in neuroendocrine tissues. Funder and Smith (1993) suggested that the patient of Nussey et al. (1993) was either expressing PC2 ectopically in her anterior pituitary or that her PC1 normally expressed in the anterior pituitary had mutated to show a PC2-like pattern of substrate specificity. They also suggested a third intriguing possibility, that of a chimeric gene, with its 5-prime end derived from the PC1 gene and its translated region derived in large part (or entirely) from PC2, giving the tissue localization (and presumably control) characteristic of PC1 and the enzymatic activity of PC2. The precedent they cited was glucocorticoid remediable aldosteronism, which reflects the expression of a chimeric gene (see 103900). Expanding on a previous report by Vallette-Kasic et al. (2005), Couture et al. (2012) reported 37 patients from 29 families with isolated ACTH deficiency. The patients presented with severe neonatal hypoglycemia, often associated with seizures, and prolonged cholestatic jaundice. Neonatal death occurred in 25% of the families. All patients had very low plasma ACTH and cortisol with normal pituitary imaging. Only 2 patients had partial and transient growth hormone deficiency. Molecular Genetics In 2 patients with isolated deficiency of pituitary ACTH, including the sister of a patient reported by Malpuech et al. (1988), Lamolet et al. (2001) identified mutations in the TBX19 gene (604614.0001-604614.0002). Expanding on a previous report by Vallette-Kasic et al. (2005), Couture et al. (2012) studied 91 patients with IAD and identified 21 mutations in the TBX19 gene (see, e.g., 604614.0005) in 37 patients from 29 families with neonatal-onset complete IAD. Although mutations were found throughout the gene, most occurred in the T box, resulting in DNA binding defects. Mutation types comprised missense, nonsense, splice site, frameshift, and small intragenic deletions, consistent with a loss of protein function. In vitro functional expression studies of 4 of the missense mutations showed significantly decreased or absent transcriptional activity. The patients with TBX19 mutations accounted for 65% of those with neonatal-onset complete IAD. No TBX19 mutations were identified in any of the 22 patients with juvenile-onset IAD. Heterogeneity In a brother and sister with congenital isolated adrenocorticotropic hormone deficiency, Kyllo et al. (1996) reported that 22 markers defining the chromosomal haplotype flanking CRH (122560) were compatible with linkage of the disorder to the immediate area of that gene on chromosome 8. The family included 2 unaffected sibs and unaffected, unrelated parents. There was no detectable mutation of the proopiomelanocortin gene (POMC; 176830), and tests for linkage using polymorphic di- and tetranucleotide simple sequence repeat markers flanking the respective genes excluded POMC and neuroendocrine convertases 1 (162150) and 2 (162151). Corticotropin (ACTH) is one of several peptides derived from the POMC gene. For this reason mutations in POMC were considered a possible cause of ACTH deficiency. While proopiomelanocortin deficiency (609734) resulting from mutations in POMC includes ACTH deficiency, proopiomelanocortin deficiency is characterized by a distinctive phenotype. Further, it is possible that there are other causes, such as deficiency of an enzyme involved in the proteolytic cleavage of POMC to produce ACTH. INHERITANCE \- Autosomal recessive ABDOMEN Liver \- Cholestasis SKIN, NAILS, & HAIR Skin \- Jaundice NEUROLOGIC Central Nervous System \- Normal development in patients who are treated and survive infancy \- Seizures (due to hypoglycemia, in some patients) \- Normal pituitary imaging METABOLIC FEATURES \- Fasting hypoglycemia ENDOCRINE FEATURES \- ACTH deficiency \- Cortisol deficiency LABORATORY ABNORMALITIES \- Low serum cortisol MISCELLANEOUS \- Onset in infancy \- Approximately 25% of patients die in infancy MOLECULAR BASIS \- Caused by mutation in the T-box 19 gene (TBX19, 604614.0001 ) ▲ 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 inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors	ACTH DEFICIENCY, ISOLATED	c0271583	1,844	omim	https://www.omim.org/entry/201400	2019-09-22T16:31:28	{"doid": ["0080150"], "mesh": ["C562707"], "omim": ["201400"], "orphanet": ["199296"], "synonyms": ["Alternative titles", "ADRENOCORTICOTROPIC HORMONE DEFICIENCY"]}
Chondroid lipoma SpecialtyDermatology Chondroid lipomas are deep-seated, firm, yellow tumors that characteristically occur on the legs of women. They exhibit a characteristic translocation t(11;16) with a resulting C11orf95-MKL2 fusion oncogene.[1]:625 [2] ## See also[edit] * Lipoma * Skin lesion * List of cutaneous conditions ## References[edit] 1. ^ James, William; Berger, Timothy; Elston, Dirk (2005). Andrews' Diseases of the Skin: Clinical Dermatology. (10th ed.). Saunders. ISBN 0-7216-2921-0. 2. ^ Genes Chromosomes Cancer. 2010 Sep;49(9):810-8. doi: 10.1002/gcc.20788. C11orf95-MKL2 is the resulting fusion oncogene of t(11;16)(q13;p13) in chondroid lipoma. Huang D1, Sumegi J, Dal Cin P, Reith JD, Yasuda T, Nelson M, Muirhead D, Bridge JA. ## External links[edit] Classification D * ICD-O: 8862/0 * v * t * e Connective/soft tissue tumors and sarcomas Not otherwise specified * Soft-tissue sarcoma * Desmoplastic small-round-cell tumor Connective tissue neoplasm Fibromatous Fibroma/fibrosarcoma: * Dermatofibrosarcoma protuberans * Desmoplastic fibroma Fibroma/fibromatosis: * Aggressive infantile fibromatosis * Aponeurotic fibroma * Collagenous fibroma * Diffuse infantile fibromatosis * Familial myxovascular fibromas * Fibroma of tendon sheath * Fibromatosis colli * Infantile digital fibromatosis * Juvenile hyaline fibromatosis * Plantar fibromatosis * Pleomorphic fibroma * Oral submucous fibrosis Histiocytoma/histiocytic sarcoma: * Benign fibrous histiocytoma * Malignant fibrous histiocytoma * Atypical fibroxanthoma * Solitary fibrous tumor Myxomatous * Myxoma/myxosarcoma * Cutaneous myxoma * Superficial acral fibromyxoma * Angiomyxoma * Ossifying fibromyxoid tumour Fibroepithelial * Brenner tumour * Fibroadenoma * Phyllodes tumor Synovial-like * Synovial sarcoma * Clear-cell sarcoma Lipomatous * Lipoma/liposarcoma * Myelolipoma * Myxoid liposarcoma * PEComa * Angiomyolipoma * Chondroid lipoma * Intradermal spindle cell lipoma * Pleomorphic lipoma * Lipoblastomatosis * Spindle cell lipoma * Hibernoma Myomatous general: * Myoma/myosarcoma smooth muscle: * Leiomyoma/leiomyosarcoma skeletal muscle: * Rhabdomyoma/rhabdomyosarcoma: Embryonal rhabdomyosarcoma * Sarcoma botryoides * Alveolar rhabdomyosarcoma * Leiomyoma * Angioleiomyoma * Angiolipoleiomyoma * Genital leiomyoma * Leiomyosarcoma * Multiple cutaneous and uterine leiomyomatosis syndrome * Multiple cutaneous leiomyoma * Neural fibrolipoma * Solitary cutaneous leiomyoma * STUMP Complex mixed and stromal * Adenomyoma * Pleomorphic adenoma * Mixed Müllerian tumor * Mesoblastic nephroma * Wilms' tumor * Malignant rhabdoid tumour * Clear-cell sarcoma of the kidney * Hepatoblastoma * Pancreatoblastoma * Carcinosarcoma Mesothelial * Mesothelioma * Adenomatoid tumor This Dermal and subcutaneous growths 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 inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors	Chondroid lipoma	c1266131	1,845	wikipedia	https://en.wikipedia.org/wiki/Chondroid_lipoma	2021-01-18T18:36:49	{"umls": ["C1266131"], "wikidata": ["Q5104526"]}
Ellis-Van Creveld syndrome is an inherited condition that affects bone growth. Affected people generally have short stature; short arms and legs (especially the forearm and lower leg); and a narrow chest with short ribs. Other signs and symptoms may include polydactyly; missing and/or malformed nails; dental abnormalities; and congenital heart defects. More than half of people affected by Ellis-van Creveld syndrome have changes (mutations) in the EVC or EVC2 genes; the cause of the remaining cases is unknown. The condition is inherited in an autosomal recessive manner. Treatment is based on the signs and symptoms present in each person. [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 inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors	Ellis-Van Creveld syndrome	c0013903	1,846	gard	https://rarediseases.info.nih.gov/diseases/1301/ellis-van-creveld-syndrome	2021-01-18T18:00:43	{"mesh": ["D004613"], "omim": ["225500"], "orphanet": ["289"], "synonyms": ["Chondroectodermal dysplasia", "Mesoectodermal dysplasia", "Ellis Van Creveld syndrome", "Mesodermic dysplasia"]}
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Find sources: "Trinucleotide repeat disorder" – news · newspapers · books · scholar · JSTOR (December 2011) (Learn how and when to remove this template message) Trinucleotide repeat disorder Other namesTrinucleotide repeat expansion disorders, Triplet repeat expansion disorders or Codon reiteration disorders Trinucleotide repeat disorders, also known as microsatellite expansion diseases, are a set of over 50 genetic disorders caused by trinucleotide repeat expansion, a kind of mutation in which repeats of three nucleotides (trinucleotide repeats) increase in copy numbers until they cross a threshold above which they become unstable.[1] Depending on its location, the unstable trinucleotide repeat may cause defects in a protein encoded by a gene; change the regulation of gene expression; produce a toxic RNA, or lead to chromosome instability. In general, the larger the expansion the faster the onset of disease, and the more severe the disease becomes.[1] Trinucleotide repeats are a subset of a larger class of unstable microsatellite repeats that occur throughout all genomes. The first trinucleotide repeat disease to be identified was fragile X syndrome, which has since been mapped to the long arm of the X chromosome. Patients carry from 230 to 4000 CGG repeats in the gene that causes fragile X syndrome, while unaffected individuals have up to 50 repeats and carriers of the disease have 60 to 230 repeats. The chromosomal instability resulting from this trinucleotide expansion presents clinically as intellectual disability, distinctive facial features, and macroorchidism in males. The second DNA-triplet repeat disease, fragile X-E syndrome, was also identified on the X chromosome, but was found to be the result of an expanded CCG repeat.[2] The discovery that trinucleotide repeats could expand during intergenerational transmission and could cause disease was the first evidence that not all disease-causing mutations are stably transmitted from parent to offspring.[1] There are several known categories of trinucleotide repeat disorder. Category I includes Huntington's disease (HD) and the spinocerebellar ataxias. These are caused by a CAG repeat expansion in protein-coding portions, or exons, of specific genes. Category II expansions are also found in exons, and tend to be more phenotypically diverse with heterogeneous expansions that are generally small in magnitude. Category III includes fragile X syndrome, myotonic dystrophy, two of the spinocerebellar ataxias, juvenile myoclonic epilepsy, and Friedreich's ataxia. These diseases are characterized by typically much larger repeat expansions than the first two groups, and the repeats are located in introns rather than exons.[citation needed] ## Contents * 1 Types * 1.1 Polyglutamine (PolyQ) diseases * 1.2 Non-polyglutamine diseases * 2 Symptoms * 3 Genetics * 3.1 Non-trinucleotide expansions * 4 Mechanism * 5 See also * 6 References * 7 External links ## Types[edit] This section is missing information about OMIM numbers. Please expand the section to include this information. Further details may exist on the talk page. (April 2014) Some of the problems in trinucleotide repeat syndromes result from causing alterations in the coding region of the gene, while others are caused by altered gene regulation.[1] In over half of these disorders, the repeated trinucleotide, or codon, is CAG. In a coding region, CAG codes for glutamine (Q), so CAG repeats result in a polyglutamine tract. These diseases are commonly referred to as polyglutamine (or polyQ) diseases. The repeated codons in the remaining disorders do not code for glutamine, and these are classified as non-polyglutamine diseases. ### Polyglutamine (PolyQ) diseases[edit] Type Gene Normal PolyQ repeats Pathogenic PolyQ repeats DRPLA (Dentatorubropallidoluysian atrophy) ATN1 or DRPLA 6 - 35 49 - 88 HD (Huntington's disease) HTT 6 - 35 36 - 250 SBMA (Spinal and bulbar muscular atrophy)[3] AR 4 - 34 35 - 72 SCA1 (Spinocerebellar ataxia Type 1) ATXN1 6 - 35 49 - 88 SCA2 (Spinocerebellar ataxia Type 2) ATXN2 14 - 32 33 - 77 SCA3 (Spinocerebellar ataxia Type 3 or Machado-Joseph disease) ATXN3 12 - 40 55 - 86 SCA6 (Spinocerebellar ataxia Type 6) CACNA1A 4 - 18 21 - 30 SCA7 (Spinocerebellar ataxia Type 7) ATXN7 7 - 17 38 - 120 SCA12 (Spinocerebellar ataxia Type 12)[4] PPP2R2B 7 - 41 43 - 51 SCA17 (Spinocerebellar ataxia Type 17) TBP 25 - 42 47 - 63 ### Non-polyglutamine diseases[edit] Type Gene Codon Normal Pathogenic Mechanism[1] FRAXA (Fragile X syndrome) FMR1 CGG (5' UTR) 6 - 53 230+ abnormal methylation FXTAS (Fragile X-associated tremor/ataxia syndrome) FMR1 CGG (5' UTR) 6 - 53 55-200 increased expression, and a novel polyglycine product[5] FRAXE (Fragile XE mental retardation) AFF2 CCG (5' UTR) 6 - 35 200+ abnormal methylation Baratela-Scott syndrome[6] XYLT1 GGC (5' UTR) 6 - 35 200+ abnormal methylation FRDA (Friedreich's ataxia) FXN GAA (Intron) 7 - 34 100+ impaired transcription DM1 (Myotonic dystrophy Type 1) DMPK CTG (3' UTR) 5 - 34 50+ RNA-based; unbalanced DMPK/ZNF9 expression levels SCA8 (Spinocerebellar ataxia Type 8) SCA8 CTG (RNA) 16 - 37 110 - 250 ? RNA ## Symptoms[edit] A common symptom of polyQ diseases is the progressive degeneration of nerve cells, usually affecting people later in life. Although these diseases share the same repeated codon (CAG) and some symptoms, the repeats are found in different, unrelated genes. In all cases, the expanded CAG repeats are translated into an uninterrupted sequence of glutamine residues, forming a polyQ tract, and the accumulation of polyQ proteins damages key cellular functions such as the ubiquitin-proteasome system. However different polyQ-containing proteins damage different subsets of neurons, leading to different symptoms.[7] As of 2017[update], ten neurological and neuromuscular disorders were known to be caused by an increased number of CAG repeats.[8] The non-PolyQ diseases do not share any specific symptoms and are unlike the PolyQ diseases. In some of these diseases, such as Fragile X syndrome, the pathology is caused by lack of the normal function of the protein encoded by the affected gene. In others, such as Monotonic Dystrophy Type 1, the pathology is caused by a change in protein expression or function mediated through changes in the messenger RNA produced by the expression of the affected gene.[1] In yet others, the pathology is caused by toxic assemblies of RNA in the nuclei of cells.[9] ## Genetics[edit] Classification of the trinucleotide repeat, and resulting disease status, depends on the number of CAG repeats in Huntington's disease[10] Repeat count Classification Disease status <28 Normal Unaffected 28–35 Intermediate Unaffected 36–40 Reduced-penetrance May be affected >40 Full-penetrance Affected Trinucleotide repeat disorders generally show genetic anticipation: their severity increases with each successive generation that inherits them. This is likely explained by the addition of CAG repeats in the affected gene as the gene is transmitted from parent to child. For example, Huntington's disease occurs when there are more than 35 CAG repeats on the gene coding for the protein HTT. A parent with 35 repeats would be considered normal and would not exhibit any symptoms of the disease.[10] However, that parent's offspring would be at an increased risk of developing Huntington's compared to the general population, as it would take only the addition of one more CAG codon to cause the production of mHTT (mutant HTT), the protein responsible for disease. Huntington's very rarely occurs spontaneously; it is almost always the result of inheriting the defective gene from an affected parent. However, sporadic cases of Huntington's in individuals who have no history of the disease in their families do occur. Among these sporadic cases, there is a higher frequency of individuals with a parent who already has a significant number of CAG repeats in their HTT gene, especially those whose repeats approach the number (36) required for the disease to manifest. Each successive generation in a Huntington's-affected family may add additional CAG repeats, and the higher the number of repeats, the more severe the disease and the earlier its onset.[10] As a result, families that have suffered from Huntington's for many generations show an earlier age of disease onset and faster disease progression.[10] ### Non-trinucleotide expansions[edit] The majority of diseases caused by expansions of simple DNA repeats involve trinucleotide repeats, but tetra-, penta- and dodecanucleotide repeat expansions are also known that cause disease. For any specific hereditary disorder, only one repeat expands in a particular gene.[11] ## Mechanism[edit] Triplet expansion is caused by slippage during DNA replication or during DNA repair synthesis.[12] Because the tandem repeats have identical sequence to one another, base pairing between two DNA strands can take place at multiple points along the sequence. This may lead to the formation of 'loop out' structures during DNA replication or DNA repair synthesis.[13] This may lead to repeated copying of the repeated sequence, expanding the number of repeats. Additional mechanisms involving hybrid RNA:DNA intermediates have been proposed.[14][15] ## See also[edit] * C9orf72 * RAN translation ## References[edit] 1. ^ a b c d e f Orr HT, Zoghbi HY (2007). "Trinucleotide repeat disorders". Annual Review of Neuroscience. 30 (1): 575–621. doi:10.1146/annurev.neuro.29.051605.113042. PMID 17417937. 2. ^ "Fragile XE syndrome". Genetic and Rare Diseases Information Center (GARD). Retrieved 14 September 2012. 3. ^ Laskaratos, Achilleas; Breza, Marianthi; Karadima, Georgia; Koutsis, Georgios (2020-06-22). "Wide range of reduced penetrance alleles in spinal and bulbar muscular atrophy: a model-based approach". Journal of Medical Genetics: jmedgenet–2020–106963. doi:10.1136/jmedgenet-2020-106963. ISSN 0022-2593. 4. ^ Srivastava, Achal K.; Takkar, Amit; Garg, Ajay; Faruq, Mohammed (2017). "Clinical behaviour of spinocerebellar ataxia type 12 and intermediate length abnormal CAG repeats in PPP2R2B". Brain: A Journal of Neurology. 140 (1): 27–36. doi:10.1093/brain/aww269. ISSN 1460-2156. PMID 27864267. 5. ^ Gao FB, Richter JD (January 2017). "Microsatellite Expansion Diseases: Repeat Toxicity Found in Translation". Neuron. 93 (2): 249–251. doi:10.1016/j.neuron.2017.01.001. PMID 28103472. 6. ^ LaCroix, Amy J.; Stabley, Deborah; Sahraoui, Rebecca; Adam, Margaret P.; Mehaffey, Michele; Kernan, Kelly; Myers, Candace T.; Fagerstrom, Carrie; Anadiotis, George; Akkari, Yassmine M.; Robbins, Katherine M.; Gripp, Karen W.; Baratela, Wagner A.R.; Bober, Michael B.; Duker, Angela L.; Doherty, Dan; Dempsey, Jennifer C.; Miller, Daniel G.; Kircher, Martin; Bamshad, Michael J.; Nickerson, Deborah A.; Mefford, Heather C.; Sol-Church, Katia (January 2019). "GGC Repeat Expansion and Exon 1 Methylation of XYLT1 Is a Common Pathogenic Variant in Baratela-Scott Syndrome". The American Journal of Human Genetics. 104 (1): 35–44. doi:10.1016/j.ajhg.2018.11.005. PMC 6323552. PMID 30554721. 7. ^ Fan, Hueng-Chuen; Ho, Li-Ing; Chi, Ching-Shiang; Chen, Shyi-Jou; Peng, Giia-Sheun; Chan, Tzu-Min; Lin, Shinn-Zong; Harn, Horng-Jyh (May 2014). "Polyglutamine (PolyQ) Diseases: Genetics to Treatments". Cell Transplantation. 23 (4–5): 441–458. doi:10.3727/096368914X678454. ISSN 0963-6897. PMID 24816443. 8. ^ Adegbuyiro A, Sedighi F, Pilkington AW, Groover S, Legleiter J (March 2017). "Proteins Containing Expanded Polyglutamine Tracts and Neurodegenerative Disease". Biochemistry. 56 (9): 1199–1217. doi:10.1021/acs.biochem.6b00936. PMC 5727916. PMID 28170216. 9. ^ Brangwynne, Clifford P.; Sanders, David W. (June 2017). "Neurodegenerative disease: RNA repeats put a freeze on cells". Nature. 546 (7657): 215–216. Bibcode:2017Natur.546..215S. doi:10.1038/nature22503. ISSN 1476-4687. PMID 28562583. 10. ^ a b c d Walker FO (January 2007). "Huntington's disease". Lancet. 369 (9557): 218–28. doi:10.1016/S0140-6736(07)60111-1. PMID 17240289. 11. ^ Mirkin, Sergei M. (June 2007). "Expandable DNA repeats and human disease". Nature. 447 (7147): 932–940. Bibcode:2007Natur.447..932M. doi:10.1038/nature05977. ISSN 0028-0836. PMID 17581576. 12. ^ Usdin K, House NC, Freudenreich CH (2015). "Repeat instability during DNA repair: Insights from model systems". Critical Reviews in Biochemistry and Molecular Biology. 50 (2): 142–67. doi:10.3109/10409238.2014.999192. PMC 4454471. PMID 25608779. 13. ^ Petruska J, Hartenstine MJ, Goodman MF (February 1998). "Analysis of strand slippage in DNA polymerase expansions of CAG/CTG triplet repeats associated with neurodegenerative disease". The Journal of Biological Chemistry. 273 (9): 5204–10. doi:10.1074/jbc.273.9.5204. PMID 9478975. 14. ^ McIvor EI, Polak U, Napierala M (2010). "New insights into repeat instability: role of RNA•DNA hybrids". RNA Biology. 7 (5): 551–8. doi:10.4161/rna.7.5.12745. PMC 3073251. PMID 20729633. 15. ^ Salinas-Rios V, Belotserkovskii BP, Hanawalt PC (September 2011). "DNA slip-outs cause RNA polymerase II arrest in vitro: potential implications for genetic instability". Nucleic Acids Research. 39 (17): 7444–54. doi:10.1093/nar/gkr429. PMC 3177194. PMID 21666257. ## External links[edit] * Trinucleotide+Repeat+Expansion at the US National Library of Medicine Medical Subject Headings (MeSH) * GeneReviews/NCBI/NIH/UW entry on DRPLA * National Institute of Neurological Disorders and Stroke * Genetics Home Reference * v * t * e Genetics: repeated sequence, transposon, gene duplication Repeatome Repeated sequence Tandem repeats * Satellite DNA * Variable number tandem repeat/Minisatellite * Short tandem repeat/Microsatellite (Trinucleotide repeat disorders) Interspersed repeat * Gene conversion * Retrotransposon * DNA transposon * Polinton * Helitron Other * Inverted repeat * Direct repeat Transposon Retrotransposon SINEs * Alu sequence * MIR LINEs * LINE1 * LINE2 LTRs * HERV * MER4 * retroposon DNA transposon * Academ * Crypton * Dada * EnSpm/CACTA * Ginger1 * Ginger2 * Harbinger * hAT * Helitron * IS3EU * ISL2EU * Kolobok * Tc1/mariner * Merlin * MuDR * Novosib * P element * PiggyBac * Polinton * Sola * Transib * Zator * Zisupton Gene duplication * Gene amplification * Tandemly arrayed genes * Ribosomal DNA * Gene family * Gene cluster * Pseudogene See also * Genomic island * Pathogenicity island * Symbiosis island * Low copy repeats * CRISPR * Telomere * v * t * e Non-Mendelian inheritance: anticipation Trinucleotide Polyglutamine (PolyQ), CAG * Dentatorubral-pallidoluysian atrophy * Huntington's disease * Kennedy disease * Spinocerebellar ataxia 1, 2, 3, 6, 7, 17 (Machado-Joseph disease) Non-polyglutamine * CGG (Fragile X syndrome) * GAA (Friedreich's ataxia) * CTG (Myotonic dystrophy type 1) * CTG (Spinocerebellar ataxia 8) * CAG (Spinocerebellar ataxia 12) Tetranucleotide * CCTG (Myotonic dystrophy type 2) Pentanucleotide * ATTCT (Spinocerebellar ataxia 10) [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 inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors	Trinucleotide repeat disorder	c0524894	1,847	wikipedia	https://en.wikipedia.org/wiki/Trinucleotide_repeat_disorder	2021-01-18T18:53:42	{"mesh": ["D019680"], "wikidata": ["Q356736"]}
Coats plus syndrome is a pleiotropic multisystem disorder characterized by retinal telangiectasia and exudates, intracranial calcification with leukoencephalopathy and brain cysts, osteopenia with predisposition to fractures, bone marrow suppression, gastrointestinal bleeding and portal hypertension. It is transmitted as an autosomal recessive 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 inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors	Coats plus syndrome	c2677299	1,848	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=313838	2021-01-23T18:17:23	{"mesh": ["C567401"], "omim": ["612199", "617341"], "umls": ["C2677299"], "icd-10": ["H35.0"], "synonyms": ["CRMCC", "Cerebroretinal microangiopathy with calcifications and cysts"]}
White-Sutton syndrome is a disorder that causes intellectual disability, specific facial features, and other signs and symptoms affecting various parts of the body. Most affected individuals have features of autism spectrum disorder (ASD), a varied condition characterized by impaired social skills, communication problems, and repetitive behaviors. However, in White-Sutton syndrome these features can occur along with other characteristics that are unusual in people with ASD, such as an overly friendly demeanor. People with White-Sutton syndrome have delayed development, with speech and language usually being more delayed than motor skills such as walking. Intellectual disability can range from borderline normal to severe. Most people with White-Sutton syndrome have mild abnormalities of the head and face, which can include an unusually small head (microcephaly); a wide, short skull (brachycephaly); wide-set eyes (hypertelorism); a flat or sunken appearance of the middle of the face (midface hypoplasia); and a small mouth with a thin upper lip. A wide variety of additional signs and symptoms can occur with White-Sutton syndrome. Among the more common are hyperactivity; sleeping difficulties; vision defects, especially farsightedness; gastrointestinal problems; obesity; and short stature. Some individuals with White-Sutton syndrome are born with a hole in the muscle that separates the abdomen from the chest cavity (the diaphragm), which is called a diaphragmatic hernia. ## Frequency The prevalence of White-Sutton syndrome is unknown. Researchers estimate that changes in the gene associated with White-Sutton syndrome may account for up to 1 in 700 cases of intellectual disability, autism spectrum disorder, or both. However, most of these affected individuals have not been diagnosed with White-Sutton syndrome and may not exhibit all the features of this disorder. ## Causes White-Sutton syndrome is caused by mutations in the POGZ gene. This gene provides instructions for making a protein that is found in the cell nucleus. The POGZ protein attaches (binds) to chromatin, which is the network of DNA and proteins that packages DNA into chromosomes. Binding of the POGZ protein is part of the process that changes the structure of chromatin (chromatin remodeling) to alter how tightly regions of DNA are packaged. Chromatin remodeling is one way gene activity (expression) is regulated; when DNA is tightly packed gene expression is lower than when DNA is loosely packed. Regulation of gene expression by the POGZ protein is thought to be important to brain development, but the specific function of POGZ in the brain is not well understood. POGZ gene mutations are thought to impair the ability of the POGZ protein to bind to chromatin, leading to abnormal gene expression that affects development of the brain and other body systems. However, little is known about the specific changes in gene expression and how they lead to the development of intellectual disability and other signs and symptoms of White-Sutton syndrome. ### Learn more about the gene associated with White-Sutton syndrome * POGZ ## Inheritance Pattern This condition is inherited in an autosomal dominant pattern, which means one copy of the altered gene in each cell is sufficient to cause the disorder. Most cases of this condition occur in people with no history of the disorder in their family, and result from new (de novo) mutations in the gene that occur during the formation of reproductive cells (eggs or sperm) or in early embryonic development. [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 inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors	White-Sutton syndrome	c4225351	1,849	medlineplus	https://medlineplus.gov/genetics/condition/white-sutton-syndrome/	2021-01-27T08:24:46	{"omim": ["616364"], "synonyms": []}
A number sign (#) is used with this entry because of evidence that Usher syndrome type IIIB (USH3B) is caused by homozygous mutation in the HARS gene (HARS1; 142810) on chromosome 5q31. Description Usher syndrome type III is characterized by postlingual, progressive hearing loss, variable vestibular dysfunction, and onset of retinitis pigmentosa symptoms, including nyctalopia, constriction of the visual fields, and loss of central visual acuity, usually by the second decade of life (Karjalainen et al., 1985; Pakarinen et al., 1995). For a discussion of genetic heterogeneity of type III Usher syndrome, see USH3A (276902). Clinical Features Puffenberger et al. (2012) studied Usher syndrome patients from Old Order Amish families in Pennsylvania. Growth and development were normal during infancy. Visual impairment became evident during early childhood with the emergence of fine horizontal nystagmus, light aversion, and optic pallor. Funduscopic changes included marked attenuation of retinal vessels, cellophane-like reflex that produces a 'bull's eye' macula, and diffuse pigmentary stippling of the peripheral retina, consistent with retinitis pigmentosa. Patients were typically blind by the second or third decade of life, but the pace of visual deterioration was highly variable. Although no auditory data were available from newborns, some auditory function was present during infancy and deteriorated during early childhood, with all evoked auditory waveforms being absent by age 5. Amplifiers or cochlear implants partially restored hearing. Patients had delayed gross motor development, hyperactive patellar tendon reflexes, mild truncal ataxia, and a wide-based gait, but upper limb coordination and reflexes, peripheral nerve function, strength, tone, and intelligence were normal. Puffenberger et al. (2012) stated that the condition was most consistent with the type III variant of Usher syndrome, characterized by progressive vision and hearing loss during early childhood. ### Charles Bonnet Syndrome Puffenberger et al. (2012) reported that the so-called 'Charles Bonnet syndrome,' involving decreased visual acuity and vivid visual hallucinations, occurred in some Usher syndrome patients from Old Order Amish families in Pennsylvania. The attacks, which were precipitated by infectious illnesses, began during early childhood and were sometimes accompanied by nonsensical speech, inappropriate laughter, repetitive eye blinking, or psychomotor agitation. In 1 case, acute psychosis merged into a deep catatonia that lasted several days. Hallucinations typically responded to antipsychotic medications and were sometimes associated with transient myopathy. Rarely, children died suddenly and unexpectedly during an illness, presumably from a cardiac event, but routine electrocardiogram and 24-hour Holter monitoring results were normal. Mapping In 2 patients with Usher syndrome type III from Old Order Amish families in Pennsylvania, Puffenberger et al. (2012) performed whole-exome sequencing and identified an 8.4-Mb region of homozygosity between SNPs rs2603014 and rs325229 on chromosome 5q. Molecular Genetics In 2 patients from Old Order Amish families in Pennsylvania with Usher syndrome type III mapping to chromosome 5q, Puffenberger et al. (2012) identified homozygosity for a missense mutation in the HARS gene (Y454S; 142810.0001); the mutation was also found in homozygosity in an Old Order Amish patient from an unrelated deme in Ontario, Canada, with an identical phenotype. The variant was not found in dbSNP 129 or the 1000 Genomes Project; it was, however, detected in 7 of 406 Old Order Amish alleles, for a population-specific allele frequency of 1.72%. (Puffenberger (2012) stated that the correct population-specific allele frequency data appear in Table 4; corresponding data in the text are incorrect.) INHERITANCE \- Autosomal recessive HEAD & NECK Ears \- Hearing loss, progressive, starting in infancy Eyes \- Visual impairment, progressive, starting early childhood \- Fine horizontal nystagmus \- Photophobia \- Optic disc pallor \- Attenuation of retinal vessels \- Bull's eye maculae \- Diffuse pigmentary stippling of peripheral retina \- Visual hallucinations precipitated by infectious illness (in some patients) \- Repetitive eye blinking accompanying visual hallucinations (in some patients) NEUROLOGIC Central Nervous System \- Delayed gross motor development \- Patellar tendon reflexes hyperactive \- Truncal ataxia, mild \- Gait wide-based Behavioral Psychiatric Manifestations \- Hallucinations, visual, precipitated by infectious illness (in some patients) \- Nonsensical speech accompanying visual hallucinations (in some patients) \- Inappropriate laughter accompanying visual hallucinations (in some patients) \- Psychomotor agitation accompanying visual hallucinations (in some patients) MISCELLANEOUS \- Patients are typically blind by second or third decade of life, but pace of visual deterioration is highly variable MOLECULAR BASIS \- Caused by mutation in the histidyl-tRNA synthetase 1 gene (HARS1, 142810.0001 ) ▲ 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 inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors	USHER SYNDROME, TYPE IIIB	c0271097	1,850	omim	https://www.omim.org/entry/614504	2019-09-22T15:55:06	{"doid": ["0110842"], "mesh": ["D052245"], "omim": ["614504"], "orphanet": ["886", "231183"]}
A number sign (#) is used with this entry because autosomal recessive spastic ataxia-3 (SPAX3) is caused by homozygous or compound heterozygous complex genomic rearrangements involving the MARS2 gene (609728) on chromosome 2q33. For a discussion of genetic heterogeneity of spastic ataxia, see SPAX1 (108600). Clinical Features Thiffault et al. (2006) reported 23 French Canadian individuals from 17 families with spastic ataxia and brain white matter changes. The transmission pattern was consistent with autosomal recessive inheritance. Age at onset ranged from 2 to 59 years with a mean age of 15 years. All patients had ataxic gait, spasticity, and hyperreflexia. Other variable features included urinary urgency (57%), dysarthria (74%), dystonic positioning (57%), mild horizontal nystagmus (44%), scoliosis (35%), and mild hearing impairment (13%). Ten (44%) seemed to have mild cognitive impairment, although formal testing was not performed. Fifty-two percent of individuals were wheelchair-bound at a mean age of 36.6 years. Neuroimaging studies showed cerebellar atrophy in all patients and cerebral atrophy in 43%. About half of patients had nonspecific focal white matter changes in periventricular and deep white matter regions. There was no evidence of a peripheral neuropathy in any patients. Inheritance The transmission pattern of SPAX3 in the families reported by Thiffault et al. (2006) was consistent with autosomal recessive inheritance. Mapping By genomewide linkage analysis of 3 French Canadian families with autosomal recessive spastic ataxia with leukoencephalopathy, Thiffault et al. (2006) identified a 11.62-cM candidate locus on chromosome 2q33-q34 between markers D2S273 and D2S2321 (maximum multipoint lod score of 5.95). Haplotype analysis delineated a 2.51-cM critical region between D2S1782 and D2S2274 and suggested a founder effect. Sequencing analysis excluded mutations in 4 known genes within the 2.51-cM critical region. Molecular Genetics In 54 patients from 38 French-Canadian families with autosomal recessive spastic ataxia-3, most of whom were originally reported by Thiffault et al. (2006), Bayat et al. (2012) identified complex duplication rearrangements of the MARS2 gene. Haplotype analysis indicated that 3 duplication events (609728.0001-609728.0003) involving the MARS2 gene had occurred in their SPAX3 cohort. All patients carried these rearrangements in homozygous or compound heterozygous state, and the rearrangements segregated with the disorders in the families; in addition, a Brazilian patient with a similar phenotype also carried a homozygous duplication. The rearrangements were found using PCR, array CGH, sequencing, and Southern blot analysis. These data suggested that homologies among repeat elements were responsible for complex rearrangements, and Bayat et al. (2012) hypothesized that the numerous repetitive elements present in this gene induced genomic instability and caused template switching during DNA replication, as well as recombination errors. Cultured patient cells showed reduced complex I activity, increased levels of reactive oxygen species, and decreased cell proliferation rates compared to controls. Patient cells had increased levels of MARS2 mRNA, but decreased protein levels. The paradoxical decrease in protein levels may be due to an RNAi-mediated mechanism. Knockdown of MARS2 in HEK293 cells using shRNA caused some decreases in mitochondrial translation, with significant decreases only when protein levels were reduced beyond a certain level. Genotype/phenotype correlation analysis showed that patients with the Dup/Del rearrangement (609728.0001) tended to have an earlier age at onset, as did patients who were homozygous for the Dup1 rearrangement (609728.0002). Animal Model Bayat et al. (2012) identified a Drosophila strain homozygous for mutations in the homolog of the human MARS2 gene. Mutant flies had age-dependent degeneration of photoreceptors in the eye, consistent with defects in neuronal function and survival. Other features of these flies included reduced life span, muscle degeneration with abnormal myofibrils and abnormal mitochondria, and impaired cell proliferation in epithelial tissues. Cellular studies of the mutant flies showed defects in oxidative phosphorylation, increased reactive oxygen species, and an upregulation of the mitochondrial unfolded protein response. INHERITANCE \- Autosomal recessive HEAD & NECK Ears \- Mild hearing impairment (13%) Eyes \- Nystagmus, horizontal, mild (44%) GENITOURINARY Bladder \- Urinary urgency (57%) SKELETAL Spine \- Scoliosis (35%) NEUROLOGIC Central Nervous System \- Cerebellar ataxia \- Ataxic gait \- Spasticity \- Hyperreflexia \- Dysarthria (74%) \- Dystonia (57%) \- Dysmetria \- Cognitive impairment, mild (44%) \- Cerebellar atrophy \- Cortical atrophy (43%) \- Nonspecific leukoencephalopathy (52%) MISCELLANEOUS \- Variable age at onset (range 2 to 59 years, mean 24 years) \- High intrafamilial and interfamilial variability \- High frequency among French-Canadians \- About 50% of patients become wheelchair-bound at an average age of 37 years MOLECULAR BASIS \- Caused by mutation in the methionyl-tRNA synthetase 2 gene (MARS2, 609728.0001 ) ▲ 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 inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors	SPASTIC ATAXIA 3, AUTOSOMAL RECESSIVE	c1969645	1,851	omim	https://www.omim.org/entry/611390	2019-09-22T16:03:21	{"doid": ["0050942"], "mesh": ["C566956"], "omim": ["611390"], "orphanet": ["314603"], "synonyms": ["Alternative titles", "AUTOSOMAL RECESSIVE SPASTIC ATAXIA WITH LEUKOENCEPHALOPATHY"]}
A form of axonal Charcot-Marie-Tooth disease, a peripheral sensorimotor neuropathy, characterized by a relatively late onset, pupillary abnormalities and deafness, in most patients, associated with distal weakness and muscle 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 inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors	Autosomal dominant Charcot-Marie-Tooth disease type 2J	c1843153	1,852	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=99943	2021-01-23T17:26:35	{"gard": ["9198"], "mesh": ["C535417"], "omim": ["607736"], "umls": ["C1843153"], "icd-10": ["G60.0"], "synonyms": ["CMT2J"]}
A parasitic disease caused by different species of the genus Leishmania, transmitted through the bite of hematophagous female phlebotomine sand flies. The clinical spectrum ranges from asymptomatic to clinically overt disease which can remain localized to the skin or disseminate to the upper oral and respiratory mucous membranes or throughout the reticulo-endothelial system. Three main clinical syndromes have been described: visceral (or Kala-Azar; with fever, weight loss, hepatosplenomegaly), cutaneous, and mucocutaneous leishmaniasis (cutaneous or mucocutaneous ulceration). [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 inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors	Leishmaniasis	c0023281	1,853	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=507	2021-01-23T18:08:52	{"gard": ["6881"], "mesh": ["D007896"], "omim": ["608207"], "umls": ["C0023281"], "icd-10": ["B55.0", "B55.1", "B55.2", "B55.9"]}
Shoulder arthritis can be one of three types of arthritis in the glenohumeral joint of the shoulder. The glenohumeral joint is a ball and socket joint, which relies on cartilage to move smoothly and to operate normally. ## Contents * 1 Forms * 2 Symptoms * 3 Diagnosis * 4 Treatment * 5 Cryotherapy * 6 References ## Forms[edit] Shoulder arthritis is a clinical condition in which the joint that connects the ball of the arm bone (humeral head) to the shoulder blade socket (glenoid) has damaged or worn out cartilage. Normally the ends of the bone are covered with hyaline articular cartilage, a surface so smooth that the friction at the joint is less than that of an ice skate on ice. In arthritis, this cartilage is progressively lost, exposing the bone beneath. Shoulder arthritis is characterized by pain, stiffness, and loss of function and often by a grinding on shoulder motion.[1] One of the three forms of shoulder arthritis is osteoarthritis. Osteoarthritis is the gradual wearing down of the joint cartilage that occurs predominantly in elderly people, and sometimes as the result of overuse in athletes. Post-traumatic arthritis happens after a significant trauma is sustained by the joint, ruining the cartilage. This could be the result of a car accident or after repeated trauma. Rheumatoid arthritis is a disease where the body attacks its own cartilage and destroys it. In each of these cases, cartilage is being destroyed. ## Symptoms[edit] The main symptom of shoulder arthritis is pain; this is due to the grinding of the bones against each other because of the lack of cartilage. Pain usually occurs in the front of the shoulder and is worse with motion. People with shoulder arthritis will also experience moderate to severe weakness, stiffness developing over many years, and the inability to sleep on the affected shoulder. ## Diagnosis[edit] Diagnosis is simple; usually a doctor can diagnose shoulder arthritis by symptoms, but they may ask for an x-ray or MRI for confirmation. ## Treatment[edit] Treatment of shoulder arthritis is usually aimed at reducing pain; there is no way to replace lost cartilage except through surgery. Pain medicines available over-the-counter can be prescribed by the doctor, but another form of treatment is cryotherapy, which is the use of cold compression. Some vitamin supplements have been found to prevent further deterioration; glucosamine sulfate is an effective preserver of cartilage. Another way to prevent the further loss of cartilage would be to maintain motion in the shoulder, because once it is lost, it's difficult to regain. Steps to reduce extreme pain in cases of bad shoulder arthritis can involve the doctor giving injections directly into the shoulder, usually consisting of a steroid mixed with an anesthetic, or even shoulder surgery.[citation needed] For patients with severe shoulder arthritis that does not respond to non-operative treatment, shoulder surgery can be very helpful. Depending on the condition of the shoulder and the specific expectations of the patient, surgical options include total shoulder joint replacement arthroplasty [1], ‘ream and run’ (humeral hemiarthroplasty with non prosthetic glenoid arthroplasty [2], and reverse (Delta) total shoulder joint replacement arthroplasty [3]. ## Cryotherapy[edit] Cryotherapy is a very old form of pain relief. It is the treatment of pain and inflammation by reducing the skin temperature, and it can also significantly reduce swelling. For shoulder arthritis, cryotherapy is a sling that would fit over the shoulder and, with the use of a hand pump to circulate water, would keep the affected area cool. ## References[edit] Causes of Shoulder Arthritis and Treatment 1. ^ http://www.orthop.washington.edu/roughshoulder [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 inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors	Shoulder arthritis	c1298682	1,854	wikipedia	https://en.wikipedia.org/wiki/Shoulder_arthritis	2021-01-18T18:30:42	{"wikidata": ["Q7502694"]}
Retinal migraine Other namesOphthalmic migraine, and Ocular migraine Connections with migraine SpecialtyNeurology CausesStress, smoking, high blood pressure, oral contraceptive pill, exercise, bending over, high altitude, dehydration, low blood sugar, excessive heat FrequencyVaries from person to person Migraines * Migraine * Prevention of migraines * Aura * Cortical spreading depression * ICHD classification and diagnosis of migraine * Retinal migraine * Familial hemiplegic migraine * Sporadic hemiplegic migraine * * * * v * t * e Retinal migraine is a retinal disease often accompanied by migraine headache and typically affects only one eye. It is caused by ischaemia or vascular spasm in or behind the affected eye. The terms "retinal migraine" and "ocular migraine" are often confused with "visual migraine", which is a far-more-common symptom of vision loss, resulting from the aura phase of migraine with aura. The aura phase of migraine can occur with or without a headache. Ocular or retinal migraines happen in the eye, so only affect the vision in that eye, while visual migraines occur in the brain, so affect the vision in both eyes together. Visual migraines result from cortical spreading depression and are also commonly termed scintillating scotoma. ## Contents * 1 Symptoms * 2 Causes * 3 Diagnosis * 4 Treatment * 5 Prognosis * 6 See also * 7 References * 8 External links ## Symptoms[edit] Retinal migraine is associated with transient monocular visual loss (scotoma) in one eye lasting less than one hour.[1] During some episodes, the visual loss may occur with no headache and at other times throbbing headache on the same side of the head as the visual loss may occur, accompanied by severe light sensitivity and/or nausea. Visual loss tends to affect the entire monocular visual field of one eye, not both eyes. After each episode, normal vision returns. It may be difficult to read and dangerous to drive a vehicle while retinal migraine symptoms are present. Retinal migraine is a different disease than scintillating scotoma, which is a visual anomaly caused by spreading depression in the occipital cortex at the back of the brain, not in the eyes nor any component thereof.[2] Unlike in retinal migraine, a scintillating scotoma involves repeated bouts of temporary diminished vision or blindness and affects vision from both eyes, upon which sufferers may see flashes of light, zigzagging patterns, blind spots, or shimmering spots or stars.[3] ## Causes[edit] Retinal migraine is caused by the blood vessels (that leads to the eye) suddenly narrowing (constricting), reducing blood flow to the eye, which causes aura in vision. It may be triggered by: * Stress * Smoking * High blood pressure * Oral contraceptive pill * Exercise * Bending over * High altitude * Dehydration * Low blood sugar * Excessive heat Afterwards, the blood vessels relax, blood flow resumes and sight returns. Usually there are no abnormalities within the eye and permanent damage to the eye is rare. Retinal migraine tends to be more common in: * Women * People aged under 40 * People with a personal or family history of migraines or other headaches * People with an underlying disease (lupus, hardening of the arteries, sickle cell disease, epilepsy, antiphospholipid syndrome, and giant cell arteritis)[4] ## Diagnosis[edit] The medical exam should rule out any underlying causes, such as blood clot, stroke, pituitary tumor, or detached retina. A normal retina exam is consistent with retinal migraine.[5] ## Treatment[edit] Treatment depends on identifying behavior that triggers migraine such as stress, sleep deprivation, skipped meals, food sensitivities, or specific activities. Medicines used to treat retinal migraines include aspirin, other NSAIDS, and medicines that reduce high blood pressure.[5] ## Prognosis[edit] In general, the prognosis for retinal migraine is similar to that of migraine headache with typical aura. As the true incidence of retinal migraine is unknown, it is uncertain whether there is a higher incidence of permanent neuroretinal injury. The visual field data suggests that there is a higher incidence of end arteriolar distribution infarction and a higher incidence of permanent visual field defects in retinal migraine than in clinically manifest cerebral infarctions in migraine with aura. One study suggests that more than half of reported recurrent cases of retinal migraine subsequently experienced permanent visual loss in that eye from infarcts,[1] but more recent studies suggest such loss is a relatively rare side effect.[6] ## See also[edit] * Entoptic phenomenon * Scintillating scotoma ## References[edit] 1. ^ a b Grosberg BM, Solomon S, Lipton RB (August 2005). "Retinal migraine". Curr Pain Headache Rep. 9 (4): 268–71. doi:10.1007/s11916-005-0035-2. PMID 16004843. 2. ^ "imigraine.net". Archived from the original on July 19, 2009. Retrieved 24 June 2015. 3. ^ "https://www.ohiohealth.com/theme_of_focus/clinical_focus_concept/ocular_migraine__when_to_seek_help/". Ohio Health. Retrieved 12 February 2015. External link in `\|title=` (help) 4. ^ "Retinal migraine - NHS". Retrieved 29 Nov 2019. 5. ^ a b "Ocular Migraines - All About Retinal and Ocular Migraines". About.com Headaches & Migraines. Retrieved 24 June 2015. 6. ^ Choices, NHS. "Retinal migraine - NHS Choices". www.nhs.uk. Retrieved 17 November 2016. ## External links[edit] Classification D * ICD-10: G43.81 * v * t * e Headache Primary ICHD 1 * Migraine * Familial hemiplegic * Retinal migraine ICHD 2 * Tension * Mixed tension migraine ICHD 3 * Cluster * Chronic paroxysmal hemicrania * SUNCT ICHD 4 * Hemicrania continua * Thunderclap headache * Sexual headache * New daily persistent headache * Hypnic headache Secondary ICHD 5 * Migralepsy ICHD 7 * Ictal headache * Post-dural-puncture headache ICHD 8 * Hangover * Medication overuse headache ICHD 13 * Trigeminal neuralgia * Occipital neuralgia * External compression headache * Cold-stimulus headache * Optic neuritis * Postherpetic neuralgia * Tolosa–Hunt syndrome Other * Vascular [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 inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors	Retinal migraine	c0270861	1,855	wikipedia	https://en.wikipedia.org/wiki/Retinal_migraine	2021-01-18T18:54:04	{"umls": ["C0270861"], "icd-10": ["G43.8"], "wikidata": ["Q2736368"]}
Senile osteoporosis Other namesOsteoporosis type II Senile osteoporosis has been recently recognized as a geriatric syndrome with a particular pathophysiology. There are different classification of osteoporosis: primary, in which bone loss is a result of aging and secondary, in which bone loss occurs from various clinical and lifestyle factors.[1] Primary, or involuntary osteoporosis, can further be classified into Type I or Type II.[1] Type I refers to postmenopausal osteoporosis and is caused by the deficiency of estrogen.[1] While senile osteoporosis is categorized as an involuntary, Type II, and primary osteoporosis, which affects both men and women over the age of 70 years. It is accompanied by vitamin D deficiency, body's failure to absorb calcium, and increased parathyroid hormone.[2][3] Research over the years has shown that senile osteoporosis is the product of a skeleton in an advanced stage of life and can be caused by a deficiency caused by calcium. However, physicians are also coming to the conclusion that multiple mechanisms in the development stages of the disease interact together resulting in an osteoporotic bone, regardless of age.[4] Still, elderly people make up the fastest growing population in the world. As bone mass declines with age, the risk of fractures increases. Annual incidence of osteoporotic fractures is more than 1.5 million in the US and notably 20% of people die during the first year after a hip fracture.[5] It costs the US health system around $17 billion annually, with the cost projecting to $50 billion by 2040.[5] These costs represent a higher burden compared to other disease states, such as breast cancer, stroke, diabetes, or chronic lung disease.[5] Although there are cost effective and well-tolerated treatments, 23% of the diagnosed are women over 67 have received either bone mineral density (BMD) tests or prescription for treatment after fracture.[6] The clinical and economic burdens indicate there should be more effort in assessment of risk, prevention, and early intervention when it comes to osteoporosis.[5] ## Contents * 1 Cause * 1.1 Risk factors * 1.1.1 Medical * 1.1.2 Medications * 1.1.3 Genetic * 1.1.4 Social and nutritional factors * 2 Diagnosis * 3 Treatment * 4 Complications * 4.1 Fall prevention * 5 References * 6 Further reading ## Cause[edit] Bone remodeling, or the absorption and resorption of bone, is a natural mechanism that occurs to repair and strengthen bones in the body. However, an imbalance between the resorption and formation of bone occurs as people age, contributing to the development of senile osteoporosis. The aging of cortical and trabecular bones in particular cause the decrease in bone density in the elderly population.[1] Although most of the etiologic considerations regarding senile osteoporosis are not very clear for physicians yet, risk factors of osteoporosis have been identified. These factors include gender, age, hormone imbalances, reduced bone quality, and compromised integrity of bone microarchitecture.[1] Based on the current evidence attached to clinical experimentation, there is some evidence that the pathogenesis of the disease is related to a deficiency of zinc.[7] Such deficiency is known to lead to an increment of endogenous heparin, which is most likely caused by mast cell degranulation, and an increase in the bone resorption (calcium discharge in the bones) reaction of prostaglandin E2, which constrain the formation of more bone mass, making bones more fragile. These co-factors are shown to play an important role in the pathogenetic process attached to senile osteoporosis as they enhance the action of the parathyroid hormone.[8] The intake of calcium in elder people is quite low, and this problem is worsened by a reduced capability to ingest it. This, attached to a decrease in the absorption of vitamin D concerning metabolism, are also factors that contributes to a diagnosis of osteoporosis type II. ### Risk factors[edit] While senile osteoporosis (type II) is mainly attributed to age, other risks include medical, pharmacological, genetic, and environmental factors. Peak bone mass is a major determinant of bone density, which starts in utero and is typically complete by the age 40.[5] #### Medical[edit] Though secondary osteoporosis is a separate category when it comes to osteoporosis diagnosis, it can still be a contributing factor to primary osteoporosis. Secondary osteoporosis can be present in pre- and post-menopausal women and in men and have found to be factors contributing to osteoporosis in both sexes (50-80% of men and 30% of post-menopausal women).[9] Therefore, when treating people over 70, it is important to exclude secondary causes of osteoporosis which include endocrine disorders (e.g. hyperthyroidism and diabetes mellitus), gastrointestinal, hepatic and nutritional disorders (e.g. celiac disease and inflammatory bowel disease), hematological disorders (e.g. systemic mastocytosis), renal disorders (e.g. chronic kidney disease), and autoimmune disorders (e.g. rheumatoid arthritis and systemic lupus erythematosus).[9] #### Medications[edit] Medications that can contribute to bone loss include aluminum (found in antacids), aromatase inhibitors, cyclosporine, depo-medroxyprogesterone (premenopausal), glucocorticoids, lithium, proton pump inhibitors, serotonin reuptake inhibitors, tacrolimus, and tamoxifen (premenopausal). These medications can contribute to bone loss and can increase risk for osteoporotic fractures.[10] #### Genetic[edit] Maternal body build, lifestyle, and vitamin D status are some of the genetic and epigenetic effects that have been found to affect the BMD, specifically the developmental plasticity.[11] Additionally, other studies have found that race (e.g. Black women have the lowest risk), age (i.e. older age), body mass (i.e. lower weight), and gender (female) play a role in contributing to the risk of osteoporosis. Although the incidence of developing osteoporosis and hip fractures vary between population groups, older age is consistently associated with a higher incidence of fractures due to osteoporosis.[5] #### Social and nutritional factors[edit] There are several environmental and social factors that can contribute to the risk of developing osteoporosis. Smoking tobacco can increase the risk by decreasing the ability of the intestine to absorb calcium. Caffeine intake and heavy alcohol were also correlated with the decrease in bone density in the elderly population.[5] Without proper intake of vitamin D and calcium, it can increase the risk of osteoporosis in the elderly. These vitamin deficiencies pose as a risk factor, as it can decrease bone mass, decrease calcium absorption, and increase in bone turnover. There are also various medications can that interfere with the absorption of calcium, such as anticonvulsants, diuretics, corticosteroids, immunosuppressive medications, some antibiotics, and NSAIDS.[5] ## Diagnosis[edit] Because the diagnosis of osteoporosis is made only after a pathologic fracture has occurred, it is best to take serial bone density (also known as bone mineral density or BMD) measurement scans for high risk individuals (elderly).[3] The World Health Organization (WHO) has established a diagnostic criteria for osteoporosis using BMD T-scores which describes an individual's BMD in terms of the number of SDs by which is differs from the mean peak value in young, healthy persons of the same sex—currently more than 2.5 SDs below the mean as the criterion for osteoporosis.[5] For osteopenia (low bone mass) the range is 1.0 SD to less than 2.5 SDs below the mean. However, T-scores were initially used as an estimation of the prevalence of osteoporosis across populations not to assess osteoporosis prevalence in specific individuals which lead to the National Osteoporosis Foundation and the International Society for Clinical Densitometry to consider using dual-energy X-ray absorptiometry (DXA) of the hip and/or spine as the preferred measurement diagnosis of osteoporosis.[5] ## Treatment[edit] Calcium and vitamin D3 intake from diet or supplementation are crucial in the ethiopathogenesis of this disease; therefore, the effective treatments should consist of non pharmacological methods (such as a modified diet with more calcium 1000–1500 mg/day and vitamin D3 intake of 600-800 IU/day, exercising, smoking cessation, and alcohol restriction), fall prevention, and individually chosen pharmacological intervention (antiresorptive agent like bisphosphonate or estrogen replacement therapy in women).[12][13] Given bone fracture (hip, vertebrae, and colles) is a devastating complication of osteoporosis, vitamin D3 combined with calcium are used as primary prevention, along with alendronate, residronate, strontrium and zoledronic acid which have proven efficacy in primary and secondary hip fracture prevention.[14] The Institute of Medicine recommends a daily allowance of 800 IU of Vitamin D for people 70 and over, to get to a level of serum 25-hydroxyvitamin D (25OHD) of at least 20 ng/ml (50 nmol/liter) in addition to a daily allowance of 1,200 mg of calcium.[15] One systematic review of pharmacological agents from 2008 on postmenopausal woman age 65 found bisphosphonates to be more efficacious in improvement of bone marrow density and reduction of vertebral fractures compared to placebo. This systematic review also found that parathyroid hormone and estrogen/progesterone therapy had significant improvements in bone marrow density compared to placebo.[16] In addition to bisphosphonates, pharmacological treatments for osteoporosis can include calcitonin, parathyroid hormone 1-34, hormone replacement therapy, and monoclonal antibody therapy.[6] Another systematic review published in the Journal of American Geriatrics Society from 2017 showed that among men with risk of osteoporotic fracture, bisphosphonates had significant reduction in fracture compared to placebo, while calcitonin and monoclonal antibody therapy did not show efficacy compared to placebo.[17] In post-menopausal older women, estrogen therapy (but not low-dose conjugated estrogens or ultra-low-dose estradiol) may reduce the incidence of new vertebral, non-vertebral, and hip fractures.[13] Selective estrogen-receptor modulators such as raloxifene have been FDA approved to treat osteoporosis as it inhibits bone resorption, slightly increases spine BMD but have not been proved efficacious in antifracture properties.[13] Even though more studies are necessary for an efficient evaluation of the role played by zinc in senile osteoporosis, some doctors may recommend a proper supplementation of dietary zinc in addition to calcium and vitamin D3.[7] ## Complications[edit] Because senile osteoporosis is caused by the loss of bone mass due to aging, the bones are more fragile and thus more prone to fractures and fracture-related complications. These complications can include a more than doubled risk increase for future fractures and a lower quality of life resulting from chronic pain or disability, sometimes needing long-term nursing care.[1] Depending on the site, pathologic fractures can also increase relative mortality risk. Hip fractures alone are particularly debilitating and have a nearly 20% higher mortality rate within one year of the fracture.[18] Other fractures are more subtle and can go undetected for some time. For example, vertebral compression fractures in the spine, often noticeable by a loss of vertical height, can occur even during routine motions like twisting, coughing, and reaching.[19] In addition to decreased bone mineral density, there are other factors that contribute to fracture risk such as advanced age, lower body mass index, fracture history, smoking, steroid use, high alcohol intake, and fall history.[1] Studies linking alcohol and fracture risk define high intake as three or more drinks per day.[20] High caffeine intake may also play a role in fracture risk.[21] Many healthcare organizations also utilize a Fracture Risk Assessment Tool (FRAX) that can estimate a 10-year probability of having an osteoporotic fracture based on an individual's health information and the criteria listed above.[22] ### Fall prevention[edit] Of the risks listed above, falls contribute most significantly to the incidence of osteoporotic fractures. Regular exercise has the strongest correlation in decreasing fall risk.[23] Back and posture exercises such as tai chi as well as weight-bearing exercises such as walking can slow bone loss, improve balance, and strengthen muscles.[24] There are also precautions that can be taken at home to reduce the risk of falling. These include anchoring rugs to the floor, minimizing clutter, improving overall lighting and visibility, and installing handrails in stairways and hallways.[1] ## References[edit] This article includes a list of general references, but it remains largely unverified because it lacks sufficient corresponding inline citations. Please help to improve this article by introducing more precise citations. (June 2009) (Learn how and when to remove this template message) 1. ^ a b c d e f g h Sözen T, Özışık L, Başaran NÇ (March 2017). "An overview and management of osteoporosis". European Journal of Rheumatology. 4 (1): 46–56. doi:10.5152/eurjrheum.2016.048. PMC 5335887. PMID 28293453. 2. ^ Sotorník I (2016). "[Osteoporosis - epidemiology and pathogenesis]". Vnitrni Lekarstvi. 62 Suppl 6: 84–87. PMID 28124937. 3. ^ a b Glaser DL, Kaplan FS (December 1997). "Osteoporosis. Definition and clinical presentation". Spine. 22 (24 Suppl): 12S–16S. doi:10.1097/00007632-199712151-00003. PMID 9431639. S2CID 40587551. 4. ^ An overview on Osteoarthritis MedicineNet. Retrieved on 2010-03-05 5. ^ a b c d e f g h i j Lane NE (February 2006). "Epidemiology, etiology, and diagnosis of osteoporosis". American Journal of Obstetrics and Gynecology. 194 (2 Suppl): S3-11. doi:10.1016/j.ajog.2005.08.047. PMID 16448873. 6. ^ a b Cosman F, de Beur SJ, LeBoff MS, Lewiecki EM, Tanner B, Randall S, Lindsay R (October 2014). "Clinician's Guide to Prevention and Treatment of Osteoporosis". Osteoporosis International. 25 (10): 2359–81. doi:10.1007/s00198-014-2794-2. PMC 4176573. PMID 25182228. 7. ^ a b Yamaguchi M (May 2010). "Role of nutritional zinc in the prevention of osteoporosis". Molecular and Cellular Biochemistry. 338 (1–2): 241–54. doi:10.1007/s11010-009-0358-0. PMID 20035439. S2CID 35574730. 8. ^ National Center for Biotechnology Information. "Etiology of senile osteoporosis" 2010-03-05. 9. ^ a b Mirza F, Canalis E (September 2015). "Management of endocrine disease: Secondary osteoporosis: pathophysiology and management". European Journal of Endocrinology. 173 (3): R131-51. doi:10.1530/EJE-15-0118. PMC 4534332. PMID 25971649. 10. ^ Russell LA (December 2018). "Management of difficult osteoporosis". Best Practice & Research. Clinical Rheumatology. Practical issues in the modern management of rheumatic disease. 32 (6): 835–847. doi:10.1016/j.berh.2019.04.002. PMID 31427058. 11. ^ Aspray TJ, Hill TR (2019). "Osteoporosis and the Ageing Skeleton". Sub-Cellular Biochemistry. 91: 453–476. doi:10.1007/978-981-13-3681-2_16. ISBN 978-981-13-3680-5. PMID 30888662. 12. ^ Wawrzyniak A, Horst-Sikorska W (2008). "[Senile osteoporosis]". Polskie Archiwum Medycyny Wewnetrznej. 118 Suppl: 59–62. PMID 19562973. 13. ^ a b c Black DM, Rosen CJ (January 2016). "Clinical Practice. Postmenopausal Osteoporosis". The New England Journal of Medicine. 374 (3): 254–62. doi:10.1056/NEJMcp1513724. PMID 26789873. 14. ^ Duque G, Demontiero O, Troen BR (February 2009). "Prevention and treatment of senile osteoporosis and hip fractures". Minerva Medica. 100 (1): 79–94. PMID 19277006. 15. ^ Ross AC, Manson JE, Abrams SA, Aloia JF, Brannon PM, Clinton SK, et al. (January 2011). "The 2011 report on dietary reference intakes for calcium and vitamin D from the Institute of Medicine: what clinicians need to know". The Journal of Clinical Endocrinology and Metabolism. 96 (1): 53–8. doi:10.1210/jc.2010-2704. PMC 3046611. PMID 21118827. 16. ^ Brandão CM, Lima MG, Silva AL, Silva GD, Guerra AA, Acúrcio F (2008). "Treatment of postmenopausal osteoporosis in women: a systematic review". Cadernos de Saude Publica. 24 Suppl 4: s592-606. doi:10.1590/S0102-311X2008001600011. PMID 18797733. 17. ^ Nayak S, Greenspan SL (March 2017). "Osteoporosis Treatment Efficacy for Men: A Systematic Review and Meta-Analysis". Journal of the American Geriatrics Society. 65 (3): 490–495. doi:10.1111/jgs.14668. PMC 5358515. PMID 28304090. 18. ^ Melton LJ, Achenbach SJ, Atkinson EJ, Therneau TM, Amin S (May 2013). "Long-term mortality following fractures at different skeletal sites: a population-based cohort study". Osteoporosis International. 24 (5): 1689–96. doi:10.1007/s00198-012-2225-1. PMC 3630278. PMID 23212281. 19. ^ "Osteoporosis and Spinal Fractures - OrthoInfo - AAOS". www.orthoinfo.org. Retrieved 2020-07-31. 20. ^ Kanis JA, Johansson H, Johnell O, Oden A, De Laet C, Eisman JA, et al. (July 2005). "Alcohol intake as a risk factor for fracture". Osteoporosis International. 16 (7): 737–42. doi:10.1007/s00198-004-1734-y. PMID 15455194. S2CID 10303026. 21. ^ Hallström H, Wolk A, Glynn A, Michaëlsson K (2006-06-06). "Coffee, tea and caffeine consumption in relation to osteoporotic fracture risk in a cohort of Swedish women". Osteoporosis International. 17 (7): 1055–64. doi:10.1007/s00198-006-0109-y. PMID 16758142. S2CID 19735422. 22. ^ "Fracture Risk Assessment Tool (FRAX®)". APTA. Retrieved 2020-07-31. 23. ^ Panel On Prevention Of Falls In Older Persons, American Geriatrics Society British Geriatrics Society (January 2011). "Summary of the Updated American Geriatrics Society/British Geriatrics Society clinical practice guideline for prevention of falls in older persons". Journal of the American Geriatrics Society. 59 (1): 148–57. doi:10.1111/j.1532-5415.2010.03234.x. hdl:2262/89919. PMID 21226685. 24. ^ Kelley GA, Kelley KS, Tran ZV (September 2002). "Exercise and lumbar spine bone mineral density in postmenopausal women: a meta-analysis of individual patient data". The Journals of Gerontology. Series A, Biological Sciences and Medical Sciences. 57 (9): M599-604. doi:10.1093/gerona/57.9.M599. PMID 12196498. ## Further reading[edit] * Duque G, Gustavo DP, eds. (2008). Osteoporosis in Older Persons: Pathophysiology and Therapeutic Approach. Berlin: Springer. ISBN 978-1-84628-515-8. OCLC 166372389. * Demontiero O, Duque G (2009). "Once-yearly zoledronic acid in hip fracture prevention". Clinical Interventions in Aging. 4 (1): 153–64. doi:10.2147/cia.s5065. PMC 2685236. PMID 19503777. * Elbaz A, Wu X, Rivas D, Gimble JM, Duque G (April 2010). "Inhibition of fatty acid biosynthesis prevents adipocyte lipotoxicity on human osteoblasts in vitro". Journal of Cellular and Molecular Medicine. 14 (4): 982–91. doi:10.1111/j.1582-4934.2009.00751.x. PMC 2891630. PMID 19382912. * Gasparrini M, Rivas D, Elbaz A, Duque G (September 2009). "Differential expression of cytokines in subcutaneous and marrow fat of aging C57BL/6J mice". Experimental Gerontology. 44 (9): 613–8. doi:10.1016/j.exger.2009.05.009. PMID 19501151. S2CID 26493082. * Elbaz A, Rivas D, Duque G (December 2009). "Effect of estrogens on bone marrow adipogenesis and Sirt1 in aging C57BL/6J mice". Biogerontology. 10 (6): 747–55. doi:10.1007/s10522-009-9221-7. PMID 19333775. S2CID 2735866. * Duque G, Demontiero O, Troen BR (February 2009). "Prevention and treatment of senile osteoporosis and hip fractures". Minerva Medica. 100 (1): 79–94. PMID 19277006. * Duque G, Huang DC, Macoritto M, Rivas D, Yang XF, Ste-Marie LG, Kremer R (March 2009). "Autocrine regulation of interferon gamma in mesenchymal stem cells plays a role in early osteoblastogenesis". Stem Cells. 27 (3): 550–8. doi:10.1634/stemcells.2008-0886. PMID 19096039. * Duque G, Rivas D, Li W, Li A, Henderson JE, Ferland G, Gaudreau P (March 2009). "Age-related bone loss in the LOU/c rat model of healthy ageing". Experimental Gerontology. 44 (3): 183–9. doi:10.1016/j.exger.2008.10.004. PMID 18992316. S2CID 8550188. * Akter R, Rivas D, Geneau G, Drissi H, Duque G (February 2009). "Effect of lamin A/C knockdown on osteoblast differentiation and function". Journal of Bone and Mineral Research. 24 (2): 283–93. doi:10.1359/jbmr.081010. PMID 18847334. * Duque G (July 2008). "Bone and fat connection in aging bone". Current Opinion in Rheumatology. 20 (4): 429–34. doi:10.1097/BOR.0b013e3283025e9c. PMID 18525356. S2CID 39428542. * Duque G, Troen BR (May 2008). "Understanding the mechanisms of senile osteoporosis: new facts for a major geriatric syndrome". Journal of the American Geriatrics Society. 56 (5): 935–41. doi:10.1111/j.1532-5415.2008.01764.x. PMID 18454751. * Duque G (2008). "Intravenous zoledronic acid reduced new clinical fractures and deaths in patients who had recent surgery for hip fracture". ACP Journal Club. 148 (2): 40. PMID 18311870. * Rivas D, Akter R, Duque G (2007). "Inhibition of Protein Farnesylation Arrests Adipogenesis and Affects PPARgamma Expression and Activation in Differentiating Mesenchymal Stem Cells". PPAR Research. 2007: 81654. doi:10.1155/2007/81654. PMC 2220071. PMID 18274630. * Duque G, Rivas D (October 2007). "Alendronate has an anabolic effect on bone through the differentiation of mesenchymal stem cells". Journal of Bone and Mineral Research. 22 (10): 1603–11. doi:10.1359/jbmr.070701. PMID 17605634. * Duque G, Mallet L, Roberts A, Gingrass S, Kremer R, Sainte-Marie LG, Kiel DP (September 2006). "To treat or not to treat, that is the question: proceedings of the Quebec Symposium for the Treatment of Osteoporosis in Long-term Care Institutions, Saint-Hyacinthe, Quebec, November 5, 2004". Journal of the American Medical Directors Association. 7 (7): 435–41. doi:10.1016/j.jamda.2006.05.006. PMID 16979088. * Retornaz F, Duque G (October 2006). "[Osteoporosis in the elderly]". Presse Médicale (in French). 35 (10 Pt 2): 1547–56. doi:10.1016/S0755-4982(06)74850-3. PMID 17028520. * Duque G (2006). "Dietetic assistants improved postoperative clinical outcomes in older women with hip fracture". ACP Journal Club. 145 (2): 40. PMID 16944860. * Duque G, Rivas D (April 2006). "Age-related changes in lamin A/C expression in the osteoarticular system: laminopathies as a potential new aging mechanism". Mechanisms of Ageing and Development. 127 (4): 378–83. doi:10.1016/j.mad.2005.12.007. PMID 16445967. S2CID 38041347. * Vecino-Vecino C, Gratton M, Kremer R, Rodriguez-Mañas L, Duque G (2006). "Seasonal variance in serum levels of vitamin d determines a compensatory response by parathyroid hormone: study in an ambulatory elderly population in Quebec". Gerontology. 52 (1): 33–9. doi:10.1159/000089823. PMID 16439822. S2CID 35669304. * Montero-Odasso M, Schapira M, Duque G, Soriano ER, Kaplan R, Camera LA (December 2005). "Gait disorders are associated with non-cardiovascular falls in elderly people: a preliminary study". BMC Geriatrics. 5: 15. doi:10.1186/1471-2318-5-15. PMC 1325027. PMID 16321159. [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 inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors	Senile osteoporosis	c0029459	1,856	wikipedia	https://en.wikipedia.org/wiki/Senile_osteoporosis	2021-01-18T18:37:05	{"mesh": ["D010024"], "umls": ["C0029459"], "wikidata": ["Q17152799"]}
Rhabdoid tumor (RT) is an aggressive pediatric soft tissue sarcoma that arises in the kidney, the liver, the peripheral nerves and all miscellaneous soft-parts throughout the body. RT involving the central nervous system (CNS) is called atypical teratoid rhabdoid tumor (ATRT; see this term). ## Epidemiology The United Kingdom registry estimated that the age-standardized annual incidence of extra-CNS RT is about 1/2,000,000 children, which might be underestimated. Altogether, in infants less than one year, RT may account for 20% of renal cancers, and 15% of soft-part tumors. In the same age range, ATRT may be the most frequent malignant tumor of the posterior fossa. ## Clinical description RT usually occurs in infancy or childhood (mostly affecting patients < 2 years, with a median of 20 months).In most cases, the first symptoms are linked to the compressive effects of a bulky tumor (such as respiratory distress, abdomen mass, peripheral nerve palsy). Subcutaneous nodular metastases are specifically seen in patients with neonatal tumors. Exceptional cases can occur in adolescents and adults. RT arises in the kidney, liver, peripheral nerve and miscellaneous soft parts. Hypercalcemia may be seen at diagnosis (<1/3 of cases). RT affecting the CNS is called ATRT and constitutes about half of all RTs. ## Etiology 90% of RT cases have biallelic inactivation of SMARCB1 (22q11.23), a tumor suppressor gene encoding a member of SWI/SNF chromatin remodeling complex which broadly regulates the expression of the genome. Rare cases are associated with a biallelic mutation of SMARCA4 (19p13.3) (encoding another SWI/SNF chromatin-remodeling complex member). ## Diagnostic methods Once a tumor is evidenced by imaging scans (magnetic resonance and computed tomography), the diagnosis relies on tumor biopsy. The tumor is composed of a diffuse proliferation of rounded or polygonal cells with eccentric nuclei, prominent nucleoli and glassy eosinophilic cytoplasm containing hyaline-like inclusion bodies, arranged in sheets and nests (rhabdoid cells). Tumor cells are usually positive to glypican-3 (50% of cases), vimentin, epithelial markers (keratins, epithelial membrane antigen) and mesenchymal markers (smooth muscle actin, muscle-specific actin, S100 protein). Diagnosis is confirmed by loss of nuclear staining of SMARCB1 (or SMARCA4, exceptionally) protein by immunohistochemistry. ## Differential diagnosis Differential diagnosis includes all undifferentiated sarcomas, peripheral primitive neuroectodermal tumor in children, epithelioid sarcoma (especially the proximal type) in older patients, extraskeletal myxoid chondrosarcoma, and undifferentiated chordomas (see these terms) in cases with clivus involvement. ## Genetic counseling In 25% of cases, RT is associated with a germline mutation of SMARCB1. Rarely, germline mutations are inherited from asymptomatic parents, either because of gonadal mosaicism or incomplete penetrant mutations (familial RT; see this term). Adult carriers may develop multiple schwannomas or meningiomas (see these terms). ## Management and treatment No standard care exists for RT although several prospective trials are now running throughout the world. Treatment includes resection of the tumor mass (as complete as possible), multimodal aggressive chemotherapy and radiotherapy whenever feasible. However, the young age of patients may limit use of radiotherapy. ## Prognosis The survival rate is low with a 5 year survival rate of 20%. Prognostic factors include metastases, young age at diagnosis (< 2years), and incomplete resection. [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 inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors	Rhabdoid tumor	c0206743	1,857	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=69077	2021-01-23T18:13:51	{"gard": ["7572"], "mesh": ["D018335"], "omim": ["609322", "613325"], "umls": ["C0206743"], "icd-10": ["C49.9"], "synonyms": ["Malignant rhabdoid tumor"]}
A rare ovarian germ cell tumor characterized by a unilateral large adnexal mass containing variable amounts of immature embryonal-type tissues (mostly in the form of neuroectodermal tubules and rosettes, sometimes with a component of cellular mitotically active glia), admixed with ectodermal and endodermal elements with varying degrees of maturation. Patients typically present in their first three decades of life with signs and symptoms related to mass effect. The tumor is often associated with the occurrence of innumerable miliary nodules of mature glia in the peritoneum (gliomatosis peritonei) and abdominal lymph nodes. [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 inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors	Malignant teratoma of ovary	c0346182	1,858	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=398987	2021-01-23T18:13:55	{"icd-10": ["C56"], "synonyms": ["Immature teratoma of ovary", "Ovarian immature teratoma", "Ovarian malignant teratoma"]}
A chordoma is a rare tumor that develops from cells of the notochord, a structure that is present in the developing embryo and is important for the development of the spine. The notochord usually disappears before birth, though a few cells may remain embedded in the bones of the spine or at the base of the skull. Chordomas typically present in adults between the ages of 40 and 70 and can occur anywhere along the spine. About half of all chordomas occur at the bottom of the spine (sacrum); about one third occur at the base of the skull. The remaining cases of chordomas form in the spine at the level of the neck, chest, or other parts of the lower back. Chordomas grow slowly, extending gradually into the surrounding bone and soft tissue. The actual symptoms depend on the location of the chordoma. A chordoma that occurs at the base of the spine may cause problems with bladder and bowel function. A chordoma at the base of the skull may lead to double vision and headaches. In many cases, the cause of the chordoma remains unknown. Recent studies have shown that changes in the T gene have been associated with chordomas in a small set of families. In these families an inherited duplication of the T gene is associated with an increased risk of developing a chordoma. Duplications of the T gene have also been identified in people with chordoma who have no history of the tumor in their family, but in these cases the changes occur only in the tumor cells and are not inherited. The current treatment is often the surgical removal of the tumor, followed by radiotherapy. [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 inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors	Chordoma	c0008487	1,859	gard	https://rarediseases.info.nih.gov/diseases/1303/chordoma	2021-01-18T18:01:27	{"mesh": ["D002817"], "omim": ["215400"], "umls": ["C0008487"], "orphanet": ["178"], "synonyms": []}
Lethal acantholytic epidermolysis bullosa is a suprabasal subtype of epidermolysis bullosa simplex (EBS, see this term) characterized by generalized oozing erosions, usually in the absence of blisters. ## Epidemiology Prevalence is unknown but 3 cases have been reported to date. ## Clinical description Onset of the disease is at birth. Erosions are associated with absent nails, universal alopecia, and, in one patient, neonatal teeth. Extracutaneous involvement is always present, involving erosions of the soft tissues of the oral cavity, and gastrointestinal, genitourinary and respiratory tract abnormalities. Cardiomyopathy has been reported in one case. ## Etiology This form of EBS is due to mutations in the DSP (6p24) gene encoding desmoplakin. A homozygous nonsense mutation in the JUP gene (17q21) has been reported in a patient with a very similar phenotype. ## Genetic counseling Transmission is autosomal recessive. ## Prognosis In reported cases, death occurred within the first month of life from multiorgan failure secondary to huge transcutaneous fluid loss or airway obstruction due to mucosal sloughing. [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 inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors	Lethal acantholytic epidermolysis bullosa	c1864826	1,860	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=158687	2021-01-23T18:24:48	{"gard": ["9910"], "mesh": ["C535493"], "omim": ["609638"], "umls": ["C1864826"], "icd-10": ["Q81.0"], "synonyms": ["LAEB"]}
Flynn–Aird syndrome Flynn–Aird syndrome has an autosomal dominant pattern of inheritance. Flynn–Aird syndrome is a rare, hereditary, neurological disease that is inherited in an autosomal dominant fashion. The syndrome involves defects in the nervous, auditory, skeletal, visual, and endocrine systems and encompasses numerous symptoms, bearing striking similarity to other known syndromes of neuroectodermal nature such as: Werner syndrome, Cockayne syndrome and Refsum syndrome.[1] The onset of Flynn–Aird syndrome typically occurs between ten and twenty years of age, however, the earliest case was diagnosed at age seven. As the syndrome progresses, initial symptoms tend to intensify and new symptoms become apparent. Unlike related syndromes and despite the intensity of symptoms in the disease progression, Flynn–Aird syndrome does not appear to shorten life expectancy. The disease is characterized by early-onset dementia, ataxia, muscle wasting, skin atrophy, and eye abnormalities. In addition, patients have the potential of developing a number of other related symptoms such as: cataracts, retinitis pigmentosa, myopia (nearsightedness), dental caries, peripheral neuropathy (peripheral nerve damage), deafness, and cystic bone changes. This syndrome was first discovered in the early 1950s by American neurologists P. Flynn and Robert B. Aird who analyzed one family lineage inheritance pattern of this disease.[1] ## Contents * 1 Symptoms * 2 Genetics * 3 Pathophysiology * 4 Diagnosis * 5 Treatment * 6 History * 7 Research * 8 References * 9 External links ## Symptoms[edit] Individuals with this syndrome typically develop normally until reaching the second decade of their lives but the onset of symptoms has been observed as early as age seven. The first defect observed in individuals who suffer from this condition affects the auditory system and is known as bilateral nerve deafness. Another early symptom is the development of myopia (nearsightedness). In addition to bilateral nerve deafness and myopia, other symptoms that plague infected individuals early in disease progression include ataxia, muscle wasting, severe peripheral neuritic pain sometimes accompanied by elevated spinal fluid protein, and joint stiffness.[1] The central nervous system (CNS) is affected with deficits in the cerebral cortex which indicate signs of mental retardation even though psychological observations appear relatively normal for individuals studied. Atypical epilepsy is also a common feature of CNS malfunctioning including aphasia expressions, blurred vision, and numbness of the face and limbs.[1] In the third decade of the condition, individuals develop further visual problems including retinitis pigmentosa, and bilateral cataracts. Sufferers endure the restriction of visual fields, night blindness, and eventually severe or complete blindness. Individuals with this syndrome exhibit many physical deformities including skeletal, epidermal, and subcutaneous abnormalities. The skeletal problems are characterized by scoliosis and muscle weakness indicative of the kyphoscoliotic type which follow muscle wasting and peripheral neuritis (nerve inflammation). Osteoporosis is also observed in many cases. Skin and subcutaneous atrophy is common as well as skin ulcerations due to inability of the skin to heal. One of the final manifestations of disease is baldness.[1] There is no evidence that the progression of Flynn–Aird syndrome shortens the patient's life-span, but the terrible conditions certainly increase morbidity.[1] ## Genetics[edit] One family of 68 individuals over 5 generations was studied and the prevalence of disease among the family members suggests that it is indicative of dominant inheritance that is not sexually linked. This is supported by the fact that the disease failed to skip generations even in the absence of intermarriages and that disease incidence was independent of sex. The current findings suggest that the cause of the disease could be narrowed down to one enzymatic defect that is involved in the development of neuroectodermal tissue, however the exact molecular mechanisms are currently unknown. The other symptoms that arise such as bone defects and diabetes may be secondary to this enzymatic defect.[1] ## Pathophysiology[edit] The exact pathophysiological mechanism of Flynn–Aird syndrome is unknown. However, several theories are in place with regards to the nature of this disease including the presence of a genetically defective enzyme involving a neuroectodermal tissue constituent. This explanation provides evidence for the late onset of the condition, the intricate findings, the varied nature of the disorder, as well as the genetic incidence. In addition, some aspects of the condition may be linked to a suppressing (S) gene due to the fact that only a small amount of stigmata appeared while the defects were still transmitted in the family studied. A suppressing gene down regulates the phenotypic expression of another gene, especially of a mutant gene. Other abnormalities may be due to endocrine system diseases.[1] ## Diagnosis[edit] This section is empty. You can help by adding to it. (August 2017) ## Treatment[edit] Only symptomatic treatment for the management of disturbances can be indicated for affected individuals. The genetic origin of this disease would indicate gene therapy holds the most promise for future development of a cure. But at this time no specific treatments for Flynn–Aird syndrome exist. ## History[edit] P. Flynn and Robert B. Aird observed this neuroectodermal syndrome after studying one family whose members suffered a number of neurological symptoms that were consistent from generation to generation. A number of the symptoms overlapped with several known neurological diseases such as Werner syndrome, Refsum syndrome, and Cockayne syndrome, which could be indicative of similar causative origins. However, these syndromes are recessively inherited as opposed to the dominant inheritance seen in the family studied by P. Flynn and Robert B. Aird. About 15% of family members exhibited full-blown symptoms characteristic of the disease while others showed some symptoms that overlapped with the general clinical manifestation of the syndrome.[1] ## Research[edit] Following the initial inquiry by P. Flynn and Robert B. Air, only two case studies have been published in Germany and Japan respectably but are not currently accessible. At this time there are no indication of further scientific investigation of Flynn–Aird syndrome. However, there is research on other, more common syndromes such as Werner syndrome, Cockayne syndrome and Refsum syndrome that may help better understand Flynn–Aird syndrome. ## References[edit] 1. ^ a b c d e f g h i Flynn P, Aird RB (1965). "A neuroectodermal syndrome of dominant inheritance". J. Neurol. Sci. 2 (2): 161–82. doi:10.1016/0022-510X(65)90078-X. PMID 5878601. ## External links[edit] Classification D * ICD-10: Q87.8 * OMIM: 136300 * MeSH: C537066 External resources * Orphanet: 2047 * Flynn–Aird syndrome at NIH's Office of Rare Diseases [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 inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors	Flynn–Aird syndrome	c0343108	1,861	wikipedia	https://en.wikipedia.org/wiki/Flynn%E2%80%93Aird_syndrome	2021-01-18T19:06:11	{"gard": ["2347"], "mesh": ["C537066"], "umls": ["C0343108"], "orphanet": ["2047"], "wikidata": ["Q5463653"]}
Familial hypertriglyceridemia Familial hypertriglyceridemia is inherited in autosomal dominant manner Familial hypertriglyceridemia (type IV familial dyslipidemia) is a genetic disorder characterized by the liver overproducing very-low-density lipoproteins (VLDL). As a result, an afflicted individual will have an excessive number of VLDL and triglycerides on a lipid profile. This genetic disorder usually follows an autosomal dominant inheritance pattern. The disorder presents clinically in patients with mild to moderate elevations in triglyceride levels. Familial hypertriglyceridemia is typically associated with other co-morbid conditions such as hypertension, obesity, and hyperglycemia. Individuals with the disorder are mostly heterozygous in an inactivating mutation of the gene encoding for lipoprotein lipase (LPL). This sole mutation can markedly elevate serum triglyceride levels. However, when combined with other medications or pathologies it can further elevate serum triglyceride levels to pathologic levels.[1] Substantial increases in serum triglyceride levels can lead to certain clinical signs and the development of acute pancreatitis. Familial hypertriglyceridemia falls in the Fredrickson-Levy and Lee’s (FLL) phenotypes. The phenotypes include types I, IIa, IIb, III, IV, and V dyslipidemias. Familial hypertriglyceridemia is considered a type IV familial dyslipidemia it is distinguished from other dyslipidemias based on the individual’s lipid profile. Familial hypertriglyceridemia separates itself from other dyslipidemias with significantly high triglycerides and low HDL levels. It is important to recognize that co-morbid conditions that often concomitantly exist with the disorder can further alter the lipid panel.[2] ## Contents * 1 Etiology * 2 Epidemiology * 3 Pathophysiology * 4 Treatment * 5 See also * 6 References * 7 External links ## Etiology[edit] Familial hypertriglyceridemia is considered to be inherited in an autosomal dominant manner. However, it is important to recognize that most cases have a polygenic inheritance distancing themselves from traditional Mendelian inheritance patterns.[3] One of the most common mutations implicated in the development of familial hypertriglyceridemia is a heterozygous inactivating mutation of the LPL gene. Inactivation of this gene leads to an individual’s inability to hydrolyze the triglycerides within the VLDL core. This inactivation of function leads to a considerable accumulation of triglycerides and VLDL in the bloodstream, which then contributes to several avenues of pathology. Individuals with insulin resistance can have even further elevated levels of hypertriglyceridemia due to the fact that insulin is a potent activator of LPL. Therefore, an individual who is resistant to the bioactivity of insulin will have decreased LPL activity and will therefore lead to further hypertriglyceridemia, helping push serum triglycerides to pathologic levels. Beyond the classic understanding of single-gene mutation leading to disease, hypertriglyceridemia is also linked to several different genetic loci permitting additional aberrant changes to other lipid levels in the body.[4] ## Epidemiology[edit] Familial hypertriglyceridemia can follow an autosomal dominant monogenic inheritance pattern. The frequency of heterozygous carriers of certain pathologic mutations in the LPL gene can range from 0.06% to 20%. It is important to note that dissimilar mutations can confer varying degrees of underlying pathology. However, most cases of familial hypertriglyceridemia follow a polygenic inheritance pattern involving mutations in multiple genetic foci.[5][6] ## Pathophysiology[edit] Inactivity of lipoprotein lipase (LPL) plays the predominant role in the development of familial hypertriglyceridemia. LPL plays a role in the metabolism of triglycerides within VLDL molecules. Inactivation mutations in LPL will create an environment with an increased concentration of VLDL molecules and therefore, triglycerides. The elevation of baseline triglyceride levels begins the cascade into other pathologies.[2] The most common acute manifestation of hypertriglyceridemia is the occurrence of pancreatitis. Pancreatitis is caused by the premature activation of exocrine pancreatic enzymes. Secreted zymogens are cleaved to active trypsin and play a central role in digestion of food in the duodenum. If there is premature activation of trypsin within the pancreatic tissues, there is an induction of autodigestion of local tissue which leads to the initial presentation of pancreatitis. Autodigestion of local tissues also leads to disruptions in pancreatic microvascular tissue which can cause an ischemia-reperfusion event at the pancreatic level. There are other varying secondary causes of pancreatitis that can further contribute to the primary scenario of pancreatitis related to familial hypertriglyceridemia.[7][8] ## Treatment[edit] Treatment for familial hypertriglyceridemia should focus primarily on reducing serum triglyceride levels. If an individual has co-morbid conditions, ensuring that they are adequately addressed will aid in obtaining a more normal baseline lipid panel. Current guidelines suggest that when evaluating individuals with familial hypertriglyceridemia there should be special attention paid to their risk of developing cardiovascular disease in individuals with mild to moderate hypertriglyceridemia. Individuals with severe hypertriglyceridemia should be promptly evaluated for the possibility of developing pancreatitis.[7] The initial treatment for severe hypertriglyceridemia consists of beginning an individual on fibrate therapy in an attempt to normalize triglyceride levels. Fibrates such as fenofibrate or gemfibrozil are considered first-line therapy for the disease. Adjunctive niacin therapy can be used for individuals who are unable to decrease triglyceride levels through fibrate monotherapy. Niacin is especially useful for individuals who have a high risk of getting pancreatitis. Fish oil supplement can also be used as it has been shown to incur a significant reduction to both triglyceride and VLDL levels.[9] If properly managed, individuals with familial hypertriglyceridemia have a fairly good prognosis. If therapy is successful, these individuals do not have uncontrolled severe triglycerides and VLDL. It is important to educate individuals on possible secondary causes of elevated lipid profiles. Proper management of the secondary causes provides a good prognosis for overall individual health. ## See also[edit] * Primary hyperlipoproteinemia * Familial apoprotein CII deficiency * Skin lesion ## References[edit] 1. ^ Ripatti P, Rämö JT, Mars NJ, Fu Y, Lin J, Söderlund S, et al. (April 2020). "Polygenic Hyperlipidemias and Coronary Artery Disease Risk". Circulation: Genomic and Precision Medicine. 13 (2): e002725. doi:10.1161/CIRCGEN.119.002725. PMC 7176338. PMID 32154731. 2. ^ a b Quispe R, Hendrani A, Baradaran-Noveiry B, Martin S, Brown E, Kulkarni K, et al. (2019). "Characterization of lipoprotein profiles in patients with hypertriglyceridemic Fredrickson-Levy and Lees dyslipidemia phenotypes: the Very Large Database of Lipids Studies 6 and 7". Archives of Medical Science. 15 (5): 1195–1202. doi:10.5114/aoms.2019.87207. PMC 6764300. PMID 31572464. S2CID 203620865. 3. ^ Hegele RA, Ban MR, Hsueh N, Kennedy BA, Cao H, Zou GY, et al. (1 November 2009). "A polygenic basis for four classical Fredrickson hyperlipoproteinemia phenotypes that are characterized by hypertriglyceridemia". Human Molecular Genetics. 18 (21): 4189–4194. doi:10.1093/hmg/ddp361. PMC 2758142. PMID 19656773. 4. ^ Johansen CT, Wang J, Lanktree MB, McIntyre AD, Ban MR, Martins RA, et al. (August 2011). "An Increased Burden of Common and Rare Lipid-Associated Risk Alleles Contributes to the Phenotypic Spectrum of Hypertriglyceridemia". Arteriosclerosis, Thrombosis, and Vascular Biology. 31 (8): 1916–1926. doi:10.1161/ATVBAHA.111.226365. PMC 3562702. PMID 21597005. S2CID 7920385. 5. ^ Triglyceride Coronary Disease Genetics Consortium Emerging Risk Factors Collaboration, Sarwar N, Sandhu MS, Ricketts SL, Butterworth AS, Di Angelantonio E, et al. (May 2010). "Triglyceride-mediated pathways and coronary disease: collaborative analysis of 101 studies". The Lancet. 375 (9726): 1634–1639. doi:10.1016/S0140-6736(10)60545-4. PMC 2867029. PMID 20452521. 6. ^ "Department of Error". The Lancet. 376 (9735): 90. July 2010. doi:10.1016/S0140-6736(10)61075-6. PMC 3081093. 7. ^ a b Berglund L, Brunzell JD, Goldberg AC, Goldberg IJ, Sacks F, Murad MH, et al. (1 September 2012). "Evaluation and Treatment of Hypertriglyceridemia: An Endocrine Society Clinical Practice Guideline". The Journal of Clinical Endocrinology & Metabolism. 97 (9): 2969–2989. doi:10.1210/jc.2011-3213. PMC 3431581. PMID 22962670. 8. ^ "Corrigenda". The Journal of Clinical Endocrinology & Metabolism. 100 (12): 4685. 1 December 2015. doi:10.1210/jc.2015-3649. PMC 5399508. PMID 26562756. 9. ^ Pradhan A, Bhandari M, Vishwakarma P, Sethi R (March 2020). "Triglycerides and Cardiovascular Outcomes—Can We REDUCE-IT ?". International Journal of Angiology. 29 (1): 002–011. doi:10.1055/s-0040-1701639. PMC 7054063. PMID 32132810. ## External links[edit] Classification D * OMIM: 145750 * v * t * e Inborn error of lipid metabolism: dyslipidemia Hyperlipidemia * Hypercholesterolemia/Hypertriglyceridemia * Lipoprotein lipase deficiency/Type Ia * Familial apoprotein CII deficiency/Type Ib * Familial hypercholesterolemia/Type IIa * Combined hyperlipidemia/Type IIb * Familial dysbetalipoproteinemia/Type III * Familial hypertriglyceridemia/Type IV * Xanthoma/Xanthomatosis Hypolipoproteinemia Hypoalphalipoproteinemia/HDL * Lecithin cholesterol acyltransferase deficiency * Tangier disease Hypobetalipoproteinemia/LDL * Abetalipoproteinemia * Apolipoprotein B deficiency * Chylomicron retention disease Lipodystrophy * Barraquer–Simons syndrome Other * Lipomatosis * Adiposis dolorosa * Lipoid proteinosis * APOA1 familial renal amyloidosis [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 inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors	Familial hypertriglyceridemia	c0020480	1,862	wikipedia	https://en.wikipedia.org/wiki/Familial_hypertriglyceridemia	2021-01-18T19:00:17	{"mesh": ["D006953"], "wikidata": ["Q5432941"]}
Lees et al. (1964) described a kindred in 5 generations of which 12 males and 3 females were affected with optic neuritis accompanied in some by neurologic manifestations resembling disseminated sclerosis. One had ataxia, right leg weakness and dysarthria. Another developed left hemiparesis during a 2-week period and then recovered partially. Went (1974) expressed the opinion that this kindred is an example of Leber optic atrophy (535000) and not a separate entity. Eyes \- Optic atrophy \- optic neuritis Neuro \- Demyelination \- Ataxia \- Dysarthria \- Hemiparesis Inheritance \- Autosomal dominant \- ? same as Leber optic atrophy (535000) ▲ 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 inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors	OPTIC ATROPHY WITH DEMYELINATING DISEASE OF CNS	c1833830	1,863	omim	https://www.omim.org/entry/165200	2019-09-22T16:37:07	{"mesh": ["C563496"], "omim": ["165200"], "orphanet": ["99718"], "synonyms": ["LHON plus disease"]}
Klumpke paralysis is a rare type of birth injury to the nerves around a newborn’s shoulder, known as the brachial plexus. Most types of brachial plexus injuries affect the shoulder and upper arm. Klumpke paralysis affects the movement of the lower arm and hand. Signs and symptoms include weakness and loss of movement of the lower arm and hand. Some babies experience drooping of the eyelid on the opposite side of the face as well. This symptom may also be referred to as Horner syndrome. Klumpke paralysis is caused by an injury to the nerves of the brachial plexus that which may result during birth due to a a difficult delivery. This injury can cause a stretch injury (neuropraxia), scarring, or tearing of the brachial plexus nerves. Tearing is called an "avulsion” when the tear is at the spine, and “rupture” when it is not. Diagnosis of Klumpke paralysis is made at birth by physical examination. Sometimes x-rays and other tests are done to determine the extent of the nerve damage. Most infants with Klumpke paralysis have the more mild form of injury (neuropraxia) and often recover within 6 months. Some infants will require surgery. Rarely, infants with Klumpke paralysis will have some permanent damage. [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 inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors	Klumpke paralysis	c0270898	1,864	gard	https://rarediseases.info.nih.gov/diseases/3123/klumpke-paralysis	2021-01-18T17:59:34	{"mesh": ["D020516"], "umls": ["C0270898"], "synonyms": ["Lower brachial plexus palsy", "Dejerine-Klumpke palsy", "Klumpke's palsy"]}
A subtype of type 2 von Willebrand disease characterized by a bleeding disorder associated with a marked decrease in the affinity of the Willebrand factor (VWF) for factor VIII (FVIII). Abnormal bleeding manifestations are less frequent in this VWD subtype than in other forms of the disease. The disease manifests mainly as soft tissue bleeding (haematoma, post-operative bleeding, etc.). [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 inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors	Von Willebrand disease type 2N	c1282975	1,865	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=166093	2021-01-23T19:12:49	{"mesh": ["D056728"], "omim": ["613554"], "umls": ["C1282975"], "icd-10": ["D68.0"]}
A number sign (#) is used with this entry because of evidence that the Davignon-Chauveau type of congenital muscular dystrophy (MDCDC) is caused by homozygous mutation in the TRIP4 gene (604501) on chromosome 15q22. One such family has been reported. Clinical Features Davignon et al. (2016) reported a large consanguineous family from eastern France in which 4 individuals had a severe form of congenital muscular dystrophy. One patient died of respiratory failure at age 16 months. The other patients, aged 25, 24, and 10 years, were wheelchair-bound and required full assistance for all daily life activities. The patients presented at birth with neonatal hypotonia, head lag, poor antigravity limb movements, severe respiratory insufficiency necessitating tracheostomy in 2, and feeding difficulties. None had congenital contractures. Motor development was severely delayed, and only 1 patient was able to achieve independent ambulation between ages 4 and 11 years. All had severe muscle weakness leading to poor head control, rigid cervical spine, and severe scoliosis. Other features included generalized joint laxity and dry skin with follicular hyperkeratosis. Two patients had learning difficulties. Serum creatine kinase was normal or slightly elevated, and EMG showed a myopathic pattern with normal nerve conduction velocities. Muscle biopsies showed fiber size variability, rounded fibers, adipose replacement, minicore lesions, centralized nuclei, angular fibers, and cap lesions, reminiscent of a myopathy. Electron microscopy showed subsarcolemmal accumulations of disorganized sarcomere components lacking thick filaments. Inheritance The transmission pattern of congenital muscular dystrophy in the family reported by Davignon et al. (2016) was consistent with autosomal recessive inheritance. Molecular Genetics In 4 patients from a consanguineous French family with congenital muscular dystrophy, Davignon et al. (2016) identified a homozygous truncating mutation in the TRIP4 gene (W297X; 604501.0003). The mutation, which was found by linkage analysis followed by candidate gene sequencing, segregated with the disorder in the family. Patient cells showed no detectable TRIP4 protein and significantly decreased mRNA, suggesting that the mutation results in nonsense-mediated mRNA decay. Cultured patient-derived muscle cells showed normal proliferation and fusion in early differentiation, but had abnormally thick branching myotubes. Knockdown of the Trip4 gene using siRNA in a murine myoblastic cell line (C2C12) affected late myogenic differentiation and/or myotube growth, manifest as reduced levels of the contractile protein myosin heavy chain, similar to patient cells. Early myogenic differentiation was not affected. The findings indicated that the TRIP4 gene plays a role in late myogenic differentiation and that defects in myotube growth likely contributed to the disorder. INHERITANCE \- Autosomal recessive HEAD & NECK Mouth \- High-arched palate (1 patient) Neck \- Neck muscle weakness RESPIRATORY \- Respiratory insufficiency due to muscle weakness CHEST External Features \- Pectus excavatum \- Flat thorax \- Funnel thorax ABDOMEN Gastrointestinal \- Feeding difficulties due to muscle weakness SKELETAL \- Joint hyperlaxity Spine \- Scoliosis \- Rigid spine SKIN, NAILS, & HAIR Skin \- Dry skin \- Hyperelasticity, mild \- Follicular hyperkeratosis MUSCLE, SOFT TISSUES \- Hypotonia, severe \- Muscle biopsy shows dystrophic changes \- Fiber size variability \- Rounded fibers \- Centralized nuclei \- Minicore lesions \- Angular fibers \- Cap lesions \- Myopathic features seen on EMG \- Fatty degeneration of muscles NEUROLOGIC Central Nervous System \- Delayed motor development, severe \- Learning difficulties (in 2 patients) MISCELLANEOUS \- Onset at birth \- Patients become wheelchair bound in the second decade \- One consanguineous family has been reported (last curated August 2016) MOLECULAR BASIS \- Caused by mutation in the thyroid hormone receptor interactor 4 gene (TRIP4, 604501.0003 ) ▲ 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 inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors	MUSCULAR DYSTROPHY, CONGENITAL, DAVIGNON-CHAUVEAU TYPE	c4310736	1,866	omim	https://www.omim.org/entry/617066	2019-09-22T15:46:58	{"omim": ["617066"], "orphanet": ["486815"], "synonyms": ["Congenital muscular dystrophy, Davignon-Chauveau type"]}
"Adrenal hyperplasia" redirects here. You may also be interested in primary aldosteronism or Cushing's syndrome. Congenital adrenal hyperplasia SpecialtyEndocrinology SymptomsExcessive urination of sodium, virilism, early, delayed, or absent puberty, hyperandrogenism Usual onsetBefore birth DurationLifetime CausesVariants in genes responsible the enzymes required for the synthesis of cortisol in the adrenal cortex Congenital adrenal hyperplasia (CAH) is a group of autosomal recessive disorders characterized by impaired cortisol synthesis.[1] It results from the deficiency of one of the five enzymes required for the synthesis of cortisol in the adrenal cortex.[2] Most of these disorders involve excessive or deficient production of such hormones as glucocorticoids, mineralocorticoids, or sex steroids, and can alter development of primary or secondary sex characteristics in some affected infants, children or adults.[3] It is one of the most common autosomal recessive disorders in humans.[4][5][6] ## Contents * 1 Forms * 1.1 Classic * 1.1.1 Salt-wasting * 1.1.2 Simple-virilizing * 1.2 Non-classic * 2 Signs and symptoms * 3 Genetics * 3.1 Expressivity * 4 Diagnosis * 4.1 Clinical evaluation * 4.2 Laboratory studies * 4.3 Classification * 5 Screening * 6 Treatment * 7 Epidemiology * 8 History * 8.1 Before 20th century * 8.2 20th and 21st century * 9 People with CAH * 10 See also * 11 References * 12 Further reading * 13 External links ## Forms[edit] CAH can be of various forms. The clinical presentation of each form is different and depends to a large extent on the underlying enzyme defect, it precursor retention and deficient products.[7] Classical forms appear in infancy, and non-classical forms appear in late childhood. The presentation in patients with classic CAH can be further subdivided into two forms: salt-wasting and simple-virilizing, depending on whether mineralocorticoid deficiency presents or absents, respectively.[8] However, this subtyping is often not clinically meaningful because all patients lose salt to some degree, and clinical presentations may overlap.[9] ### Classic[edit] #### Salt-wasting[edit] In 75% of cases of severe enzyme deficiency, insufficient aldosterone production can lead to salt wasting, failure to thrive, and potentially fatal hypovolemia and shock. The missed diagnosis of salt-loss CAH is related to the increased risk of early neonatal morbidity and death.[1] #### Simple-virilizing[edit] The main feature of CAH in newborn female is the abnormal development of the external genitalia, which has varying degrees of virilization. According to clinical practice guidelines, for newborns found to have bilateral inaccessible gonads, CAH evaluation should be considered. If virilizing CAH cannot be identified and treated, both boys and girls may undergo rapid postnatal growth and virilization.[1] ### Non-classic[edit] Main article: Late onset congenital adrenal hyperplasia In addition to the salt-wasting and simple-virilizing forms of CAH diagnosed in infancy, there is also a mild or "non-classic" form, which is characterized by varying degrees of postnatal androgen excess, but is sometimes asymptomatic.[1] The non-classic form may be noticed in late childhood and may lead to accelerated growth, premature sexual maturation,[8] acne and secondary polycystic ovary syndrome.[10] In adult males, early balding and infertility may suggest the diagnosis.[10] The non-classic form is characterized by mild subclinical impairment of cortisol synthesis;[1] serum cortisol concentration is usually normal.[10] ## Signs and symptoms[edit] The symptoms of CAH vary depending upon the form of CAH and the sex of the patient. Symptoms can include: Due to inadequate mineralocorticoids:[citation needed] * Vomiting due to salt-wasting, leading to dehydration and death Due to excess androgens: * In extreme virilization a elongated clitoris with a phallic like structure.[11][12][13] * Ambiguous genitalia, in some infants, such that it can be initially difficult to identify external genitalia as "male" or "female" * Early pubic hair and rapid growth in childhood * Precocious puberty or failure of puberty to occur (sexual infantilism: absent or delayed puberty) * Excessive facial hair, virilization, and/or menstrual irregularity in adolescence * Infertility due to anovulation * Clitoromegaly, enlarged clitoris and shallow vagina[14] Due to insufficient androgens and estrogens:[citation needed] * Undervirilization in XY males, which can result in apparently female external genitalia * In females, hypogonadism can cause sexual infantilism or abnormal pubertal development, infertility, and other reproductive system abnormalities ## Genetics[edit] CAH results from mutations of genes for enzymes mediating the biochemical steps of production of mineralocorticoids, glucocorticoids or sex steroids from cholesterol by the adrenal glands (steroidogenesis).[15] Each form of CAH is associated with a specific defective gene. The most common type (95% of cases)[1] involves the gene for 21-hydroxylase, which is found on 6p21.3 as part of the HLA complex. 21-hydroxylase deficiency results from a unique mutation with two highly homologous near-copies in series consisting of an active gene (CYP21A2) and an inactive pseudogene (CYP21A1P). Mutant alleles result from recombination between the active and pseudogenes (gene conversion).[16] About 5% of cases of CAH are due to defects in the gene encoding 11β-hydroxylase and consequent 11β-hydroxylase deficiency. Other, more rare forms of CAH are caused by mutations in genes including HSD3B2 (3β-hydroxysteroid dehydrogenase 2), CYP17A1 (17α-hydroxylase/17,20-lyase),[17] CYP11A1 (P450scc; cholesterol side-chain cleavage enzyme), STAR (steroidogenic acute regulatory protein; StAR), CYB5A (cytochrome b5), and CYPOR (cytochrome P450 oxidoreductase; POR).[citation needed] ### Expressivity[edit] Further variability is introduced by the degree of enzyme inefficiency produced by the specific alleles each patient has. Some alleles result in more severe degrees of enzyme inefficiency. In general, severe degrees of inefficiency produce changes in the fetus and problems in prenatal or perinatal life. Milder degrees of inefficiency are usually associated with excessive or deficient sex hormone effects in childhood or adolescence, while the mildest forms of CAH interfere with ovulation and fertility in adults.[citation needed] ## Diagnosis[edit] This section needs additional citations for verification. Please help improve this article by adding citations to reliable sources. Unsourced material may be challenged and removed. (October 2015) (Learn how and when to remove this template message) ### Clinical evaluation[edit] Female infants with classic CAH have ambiguous genitalia due to exposure to high concentrations of androgens in utero. CAH due to 21-hydroxylase deficiency is the most common cause of ambiguous genitalia in genotypically normal female infants (44+XX). Less severely affected females may present with early pubarche. Young women may present with symptoms of polycystic ovarian syndrome (oligomenorrhea, polycystic ovaries, hirsutism).[medical citation needed] Males with classic CAH generally have no signs of CAH at birth. Some may present with hyperpigmentation, due to co-secretion with melanocyte-stimulating hormone (MSH), and possible penile enlargement. Age of diagnosis of males with CAH varies and depends on the severity of aldosterone deficiency. Boys with salt-wasting disease present early with symptoms of hyponatremia and hypovolemia. Boys with non-salt-wasting disease present later with signs of virilization.[16] In rarer forms of CAH, males are undermasculinized[citation needed] and females generally have no signs or symptoms at birth.[medical citation needed] ### Laboratory studies[edit] Genetic analysis can be helpful to confirm a diagnosis of CAH but it is not necessary if classic clinical and laboratory findings are present. In classic 21-hydroxylase deficiency, laboratory studies will show: * Hypoglycemia (due to hypocortisolism) - One of cortisol's many functions is to increase blood glucose levels. This occurs via a combination of several mechanisms, including (a) the stimulation of gluconeogesis (i.e. the creation of new glucose) in the liver, (b) the promotion of glycogenolysis (i.e. the breakdown of glycogen into glucose), and (c) the prevention of glucose leaving the bloodstream via the downregulation of GLUT-4 receptors (which normally promote movement of glucose from the bloodstream into adipose and muscle tissues). Therefore, when cortisol is deficient, these processes (effectively) occur in the reverse direction. Although there are compensatory mechanisms that mitigate the impact of hypocortisolism, they are limited in their extent and the net effect is still hypoglycemia. * Hyponatremia (due to hypoaldosteronism) - Aldosterone is the end product of the renin-angiotensin-aldosterone system that regulates blood pressure via blood pressure surveillance in the Kidney Juxtaglomerular apparatus. Aldosterone normally functions to increase sodium retention (which brings water as well) in exchange for potassium. Thus, lack of aldosterone causes hyperkalemia and hyponatremia. In fact, this is a distinguishing point from 11-hydroxylase deficiency, in which one of the increased products is 11-deoxycorticosterone that has weak mineralocorticoid activity. In 11-hydroxylase deficiency, 11-deoxycorticosterone is produced in such excess that it acts to retain sodium at the expense of potassium. It is this reason that patients with 11-hydroxylase deficiency do not show salt wasting (although sometimes they do in infancy), and instead have hypertension/water retention and sometimes hypokalemia. * Hyperkalemia (due to hypoaldosteronism) * Elevated 17α-hydroxyprogesterone Classic 21-hydroxylase deficiency typically causes 17α-hydroxyprogesterone blood levels >242 nmol/L.[medical citation needed] (For comparison, a full-term infant at three days of age should have <3 nmol/L. Many neonatal screening programs have specific reference ranges by weight and gestational age because high levels may be seen in premature infants without CAH.) Salt-wasting patients tend to have higher 17α-hydroxyprogesterone levels than non-salt-wasting patients. In mild cases, 17α-hydroxyprogesterone may not be elevated in a particular random blood sample, but it will rise during a corticotropin stimulation test. ### Classification[edit] Cortisol is an adrenal steroid hormone that is required for normal endocrine function. Production begins in the second month of fetal life. Poor cortisol production is a hallmark of most forms of CAH. Inefficient cortisol production results in rising levels of ACTH, because cortisol feeds back to inhibit ACTH production, so loss of cortisol results in increased ACTH.[18] This increased ACTH stimulation induces overgrowth (hyperplasia) and overactivity of the steroid-producing cells of the adrenal cortex. The defects causing adrenal hyperplasia are congenital (i.e. present at birth). Steroidogenesis. The enzymes affected in CAH are represented by one red and four green bars on the top half of the diagram (for example, "21α-hydroxylase" is visible near the top center. "17α-hydroxylase" and "17,20 lyase" are carried out by a single enzyme).[19] Depending upon which enzyme is unavailable, there is a reduced production of androgens (lower left) or mineralocorticoids (upper right). This in turn can lead to increased production of other molecules, due to a buildup of precursors. Cortisol deficiency in CAH is usually partial, and not the most serious problem for an affected person. Synthesis of cortisol shares steps with synthesis of mineralocorticoids such as aldosterone, androgens such as testosterone, and estrogens such as estradiol. The resulting excessive or deficient production of these three classes of hormones produce the most important problems for people with CAH. Specific enzyme inefficiencies are associated with characteristic patterns of over- or underproduction of mineralocorticoids or sex steroids. Since the 1960s most endocrinologists have referred to the forms of CAH by the traditional names in the left column, which generally correspond to the deficient enzyme activity. As exact structures and genes for the enzymes were identified in the 1980s, most of the enzymes were found to be cytochrome P450 oxidases and were renamed to reflect this. In some cases, more than one enzyme was found to participate in a reaction, and in other cases a single enzyme mediated in more than one reaction. There was also variation in different tissues and mammalian species. In all its forms, congenital adrenal hyperplasia due to 21-hydroxylase deficiency accounts for about 95% of diagnosed cases of CAH.[1] Unless another specific enzyme is mentioned, "CAH" in nearly all contexts refers to 21-hydroxylase deficiency. (The terms "salt-wasting CAH", and "simple virilizing CAH" usually refer to subtypes of this condition.) CAH due to deficiencies of enzymes other than 21-hydroxylase present many of the same management challenges as 21-hydroxylase deficiency, but some involve mineralocorticoid excess or sex steroid deficiency. Common medical term % OMIM Enzyme(s) Locus Substrate(s) Product(s) Mineralocorticoids Androgens 21-Hydroxylase CAH 95%[1] 201910 P450c21 6p21.3 17-OH-Progesterone→ Progesterone→ 11-Deoxycortisol DOC ↓ ↑ 11β-Hydroxylase CAH 5% 202010 P450c11β 8q21-22 11-Deoxycortisol→ DOC→ Cortisol Corticosterone ↑ ↑ 3β-HSD CAH Very rare 201810 3βHSD2 1p13 Pregnenolone→ 17-OH-Pregnenolone→ DHEA→ Progesterone 17-OH-Progesterone Androstenedione ↓ ↓ 17α-Hydroxylase CAH Very rare 202110 CYP17A1 10q24.3 Pregnenolone→ Progesterone→ 17-OH-Pregnenolone→ 17-OH-Pregnenolone 17-OH-Progesterone DHEA ↑ ↓ Lipoid CAH (20,22-desmolase) Very rare 201710 StAR P450scc 8p11.2 15q23-q24 Transport of cholesterol Cholesterol→ Into mitochondria Pregnenolone ↓ ↓ ## Screening[edit] Currently, in the United States and over 40 other countries, every child born is screened for 21-hydroxylase CAH at birth. This test will detect elevated levels of 17α-hydroxyprogesterone (17-OHP). Detecting high levels of 17-OHP enables early detection of CAH. Newborns detected early enough can be placed on medication and live a relatively normal life.[citation needed] The screening process, however, is characterized by a high false positive rate. In one study,[20] CAH screening had the lowest positive predictive value (111 true-positive cases among 20,647 abnormal screening results in a 2-year period, or 0.53%, compared with 6.36% for biotinidase deficiency, 1.84% for congenital hypo-thyroidism, 0.56% for classic galactosemia, and 2.9% for phenylketonuria). According to this estimate, 200 unaffected newborns required clinical and laboratory follow-up for every true case of CAH.[non-primary source needed] ## Treatment[edit] Since the clinical manifestations of each form of CAH are unique and depend to a large extent on the underlying enzyme defects, their precursor retention and defective products, the therapeutic goal of CAH is to replenish insufficient adrenal hormones and suppress excess of precursors.[7] Treatment of all forms of CAH may include any of: 1. Supplying enough glucocorticoid to reduce hyperplasia and overproduction of androgens or mineralocorticoids[citation needed] 2. Providing replacement mineralocorticoid and extra salt if the person is deficient[1] 3. Providing replacement testosterone or estrogens at puberty if the person is deficient[citation needed] 4. Additional treatments to optimize growth by delaying puberty or delaying bone maturation[citation needed] If CAH is caused by the deficiency of the 21-hydroxylase enzyme, then treatment aims to normalize levels of main substrate of the enzyme - 17α-Hydroxyprogesterone.[1] See also: Congenital adrenal hyperplasia due to 21-hydroxylase deficiency § Treatment ## Epidemiology[edit] The incidence varies geographically. In the United States, congenital adrenal hyperplasia in its classic form is particularly common in Native Americans and Yupik Eskimos (incidence 1⁄280). Among American Caucasians, the incidence of the classic form is approximately 1⁄15,000).[16] Continued treatment and wellness is enhanced by education and follow up.[21] ## History[edit] ### Before 20th century[edit] An Italian anatomist, Luigi De Crecchio (1832-1894) provided the earliest known description of a case of probable CAH. > I propose in this narrative that it is sometimes extremely difficult and even impossible to determine sex during life. In one of the anatomical theaters of the hospital..., there arrived toward the end of January a cadaver which in life was the body of a certain Joseph Marzo... The general physiognomy was decidedly male in all respects. There were no feminine curves to the body. There was a heavy beard. There was some delicacy of structure with muscles that were not very well developed... The distribution of pubic hair was typical of the male. Perhaps the lower extremities were somewhat delicate, resembling the female, and were covered with hair... The penis was curved posteriorly and measured 6 cm, or with stretching, 10 cm. The corona was 3 cm long and 8 cm in circumference. There was an ample prepuce. There was a first grade hypospadias... There were two folds of skin coming from the top of the penis and encircling it on either side. These were somewhat loose and resembled labia majora. De Crecchio then described the internal organs, which included a normal vagina, uterus, fallopian tube, and ovaries. > It was of the greatest importance to determine the habits, tendencies, passions, and general character of this individual... I was determined to get as complete a story as possible, determined to get at the base of the facts and to avoid undue exaggeration which was rampant in the conversation of many of the people present at the time of the dissection. He interviewed many people and satisfied himself that Joseph Marzo "conducted himself within the sexual area exclusively as a male", even to the point of contracting the "French disease" on two occasions. The cause of death was another in a series of episodes of vomiting and diarrhea.[22] This account was translated by Alfred Bongiovanni from De Crecchio ("Sopra un caso di apparenzi virili in una donna". Morgagni 7:154–188, 1865) in 1963 for an article in The New England Journal of Medicine. ### 20th and 21st century[edit] The association of excessive sex steroid effects with diseases of the adrenal cortex have been recognized for over a century. The term adrenogenital syndrome was applied to both sex-steroid producing tumors and severe forms of CAH for much of the 20th century, before some of the forms of CAH were understood. Congenital adrenal hyperplasia, which also dates to the first half of the century, has become the preferred term to reduce ambiguity and to emphasize the underlying pathophysiology of the disorders. Much of our modern understanding and treatment of CAH comes from research conducted at Johns Hopkins Medical School in Baltimore in the middle of the 20th century. Lawson Wilkins, "founder" of pediatric endocrinology, worked out the apparently paradoxical pathophysiology: that hyperplasia and overproduction of adrenal androgens resulted from impaired capacity for making cortisol. He reported use of adrenal cortical extracts to treat children with CAH in 1950. Genital reconstructive surgery was also pioneered at Hopkins. After application of karyotyping to CAH and other intersex disorders in the 1950s, John Money, JL Hampson, and JG Hampson persuaded both the scientific community and the public[citation needed] that sex assignment should not be based on any single biological criterion, and gender identity was largely learned and has no simple relationship with chromosomes or hormones. See Intersex for a fuller history, including recent controversies over reconstructive surgery. Hydrocortisone, fludrocortisone, and prednisone were available by the late 1950s. By 1980 all of the relevant steroids could be measured in blood by reference laboratories for patient care. By 1990 nearly all specific genes and enzymes had been identified. However, the last decade has seen a number of new developments, discussed more extensively in congenital adrenal hyperplasia due to 21-hydroxylase deficiency: 1. Debate over the value of genital reconstructive surgery and changing standards 2. Debate over sex assignment of severely virilized XX infants 3. New treatments to improve height outcomes 4. Newborn screening programs to detect CAH at birth 5. Increasing attempts to treat CAH before birth ## People with CAH[edit] * Lisa Lee Dark[23] * Betsy Driver[24] * Casimir Pulaski, hypothesized based on examination of remains[25] ## See also[edit] * Congenital adrenal hyperplasia due to 21-hydroxylase deficiency * Congenital adrenal hyperplasia due to 3β-hydroxysteroid dehydrogenase deficiency * Congenital adrenal hyperplasia due to 11β-hydroxylase deficiency * Congenital adrenal hyperplasia due to 17α-hydroxylase deficiency * Disorders of sex development * Inborn errors of steroid metabolism * List of vaginal anomalies ## References[edit] 1. ^ a b c d e f g h i j Speiser PW, Arlt W, Auchus RJ, Baskin LS, Conway GS, Merke DP, Meyer-Bahlburg HFL, Miller WL, Murad MH, Oberfield SE, White PC (2018). "Congenital Adrenal Hyperplasia Due to Steroid 21-Hydroxylase Deficiency: An Endocrine Society Clinical Practice Guideline". The Journal of Clinical Endocrinology and Metabolism. 103 (11): 4043–4088. doi:10.1210/jc.2018-01865. PMC 6456929. PMID 30272171. 2. ^ Speiser PW, White PC (August 2003). "Congenital adrenal hyperplasia". The New England Journal of Medicine. 349 (8): 776–88. doi:10.1056/NEJMra021561. PMID 12930931. 3. ^ Aubrey Milunsky; Jeff Milunsky (29 January 2010). Genetic Disorders and the Fetus: Diagnosis, Prevention and Treatment. John Wiley and Sons. pp. 600–. ISBN 978-1-4051-9087-9. Retrieved 14 June 2010. 4. ^ Speiser PW, Dupont B, Rubinstein P, Piazza A, Kastelan A, New MI (July 1985). "High frequency of nonclassical steroid 21-hydroxylase deficiency". American Journal of Human Genetics. 37 (4): 650–67. PMC 1684620. PMID 9556656. 5. ^ Krone N, Arlt W (April 2009). "Genetics of congenital adrenal hyperplasia". Best Practice & Research. Clinical Endocrinology & Metabolism. 23 (2): 181–92. doi:10.1016/j.beem.2008.10.014. PMC 5576025. PMID 19500762. 6. ^ Turcu AF, Nanba AT, Chomic R, Upadhyay SK, Giordano TJ, Shields JJ, Merke DP, Rainey WE, Auchus RJ (May 2016). "Adrenal-derived 11-oxygenated 19-carbon steroids are the dominant androgens in classic 21-hydroxylase deficiency". European Journal of Endocrinology. 174 (5): 601–9. doi:10.1530/EJE-15-1181. PMC 4874183. PMID 26865584. 7. ^ a b Feingold KR, Anawalt B, Boyce A, Chrousos G, de Herder WW, Dungan K, Grossman A, Hershman JM, Hofland HJ, Kaltsas G, Koch C, Kopp P, Korbonits M, McLachlan R, Morley JE, New M, Purnell J, Singer F, Stratakis CA, Trence DL, Wilson DP, New M, Yau M, Lekarev O, Lin-Su K, Parsa A, Pina C, Yuen T, Khattab A (15 March 2017). Congenital Adrenal Hyperplasia. MDText.com, Inc. PMID 25905188. 8. ^ a b Dauber A, Kellogg M, Majzoub JA (2010). "Monitoring of therapy in congenital adrenal hyperplasia". Clinical Chemistry. 56 (8): 1245–51. doi:10.1373/clinchem.2010.146035. PMID 20558634. 9. ^ Merke DP, Auchus RJ (September 2020). "Congenital Adrenal Hyperplasia Due to 21-Hydroxylase Deficiency". The New England Journal of Medicine. 383 (13): 1248–1261. doi:10.1056/NEJMra1909786. PMID 32966723. 10. ^ a b c "Congenital Adrenal Hyperplasia: Diagnosis and Emergency Treatment". 11. ^ Philadelphia, The Children's Hospital of (19 November 2019). "Classic congenital Adrenal Hyperplasia Diagnosed in the Newborn Period". www.chop.edu. Retrieved 5 September 2020. 12. ^ New, Maria; Yau, Mabel; Lekarev, Oksana; Lin-Su, Karen; Parsa, Alan; Pina, Christian; Yuen, Tony; Khattab, Ahmed (15 March 2017). "Figure 2, [Different degrees of virilization according...]". www.ncbi.nlm.nih.gov. Retrieved 5 September 2020. 13. ^ "Genital Birth Defects - Children's Health Issues". Merck Manuals Consumer Version. Retrieved 5 September 2020. 14. ^ Richard D. McAnulty, M. Michele Burnette (2006) Sex and sexuality, Volume 1, Greenwood Publishing Group, p.165 15. ^ David A. Warrell (2005). Oxford textbook of medicine: Sections 18-33. Oxford University Press. pp. 261–. ISBN 978-0-19-856978-7. Retrieved 14 June 2010. 16. ^ a b c Mais, Daniel D. (2008). Quick compendium of clinical pathology (2nd ed.). Chicago: ASCP Press. ISBN 978-0891895671. 17. ^ Miller WL (January 2012). "The syndrome of 17,20 lyase deficiency". The Journal of Clinical Endocrinology and Metabolism. 97 (1): 59–67. doi:10.1210/jc.2011-2161. PMC 3251937. PMID 22072737. 18. ^ Kumar, Vinay; Abbas, Abul K.; Aster, Jon C. (2014). Robbins and Cotran pathologic basis of disease. Kumar, Vinay, 1944-, Abbas, Abul K.,, Aster, Jon C.,, Perkins, James A. (Ninth ed.). Philadelphia, PA. p. 1128. ISBN 9781455726134. OCLC 879416939. 19. ^ Häggström, Mikael; Richfield, David (2014). "Diagram of the pathways of human steroidogenesis". WikiJournal of Medicine. 1 (1). doi:10.15347/wjm/2014.005. ISSN 2002-4436. 20. ^ Kenneth A. Pass; Eurico Carmago Neto (2005). Update: Newborn Screening for Endocrinopathies (PDF). pp. 831–834. Archived from the original (PDF) on 1 January 2014. Retrieved 12 December 2013. 21. ^ Kruse, B.; Riepe, F. G.; Krone, N.; Bosinski, H. a. G.; Kloehn, S.; Partsch, C. J.; Sippell, W. G.; Mönig, H. (July 2004). "Congenital adrenal hyperplasia - how to improve the transition from adolescence to adult life". Experimental and Clinical Endocrinology & Diabetes. 112 (7): 343–355. doi:10.1055/s-2004-821013. ISSN 0947-7349. PMID 15239019. 22. ^ Bongiovanni AM, Root AW (1963). "The Adrenogenital Syndrome". The New England Journal of Medicine. 268 (23): 1283–9 contd. doi:10.1056/NEJM196306062682308. PMID 13968788. 23. ^ "BBC Radio 4 – Changing Sex". Retrieved 6 August 2008. 24. ^ "Mayor Betsy Driver is Promoting Intersex Visibility Through Activism and Politics". Yahoo. 23 August 2019. Retrieved 10 September 2019. 25. ^ Schoenberg, Nara. "'It's a woman. It's not Pulaski.': New documentary argues Revolutionary War hero was intersex". chicagotribune.com. Archived from the original on 2 November 2019. Retrieved 28 May 2020. ## Further reading[edit] * Han, Thang S.; Walker, Brian R.; Arlt, Wiebke; Ross, Richard J. (17 December 2013). "Treatment and health outcomes in adults with congenital adrenal hyperplasia". Nature Reviews Endocrinology. 10 (2): 115–124. doi:10.1038/nrendo.2013.239. PMID 24342885. S2CID 6090764Figure 2: The adrenal steroidogenesis pathway. ## External links[edit] Wikimedia Commons has media related to Congenital adrenal hyperplasia. * Congenital adrenal hyperplasia at Curlie Classification D * ICD-11: 5A71.01 * ICD-10: E25.0 * MeSH: D000312 * v * t * e Adrenal gland disorder Hyperfunction Aldosterone * Hyperaldosteronism * Primary aldosteronism * Conn syndrome * Bartter syndrome * Glucocorticoid remediable aldosteronism * AME * Liddle's syndrome * 17α CAH * Pseudohypoaldosteronism Cortisol * Cushing's syndrome * Pseudo-Cushing's syndrome * Steroid-induced osteoporosis Sex hormones * 21α CAH * 11β CAH Hypofunction Aldosterone * Hypoaldosteronism * 21α CAH * 11β CAH Cortisol * CAH * Lipoid * 3β * 11β * 17α * 21α Sex hormones * 17α CAH * Inborn errors of steroid metabolism Adrenal insufficiency * Adrenal crisis * Adrenalitis * Xanthogranulomatous * Addison's disease * Waterhouse–Friderichsen syndrome * v * t * e Inborn errors of steroid metabolism Mevalonate pathway * HMG-CoA lyase deficiency * Hyper-IgD syndrome * Mevalonate kinase deficiency To cholesterol * 7-Dehydrocholesterol path: Hydrops-ectopic calcification-moth-eaten skeletal dysplasia * CHILD syndrome * Conradi-Hünermann syndrome * Lathosterolosis * Smith–Lemli–Opitz syndrome * desmosterol path: Desmosterolosis Steroids Corticosteroid (including CAH) * aldosterone: Glucocorticoid remediable aldosteronism * cortisol/cortisone: CAH 17α-hydroxylase * CAH 11β-hydroxylase * both: CAH 3β-dehydrogenase * CAH 21-hydroxylase * Apparent mineralocorticoid excess syndrome/11β-dehydrogenase Sex steroid To androgens * 17α-Hydroxylase deficiency * 17,20-Lyase deficiency * Cytochrome b5 deficiency * 3β-Hydroxysteroid dehydrogenase deficiency * 17β-Hydroxysteroid dehydrogenase deficiency * 5α-Reductase deficiency * Pseudovaginal perineoscrotal hypospadias To estrogens * Aromatase deficiency * Aromatase excess syndrome Other * X-linked ichthyosis * Antley–Bixler 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 inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors	Congenital adrenal hyperplasia	c0701163	1,867	wikipedia	https://en.wikipedia.org/wiki/Congenital_adrenal_hyperplasia	2021-01-18T18:31:15	{"gard": ["1465", "1467"], "mesh": ["D000312"], "umls": ["C0701163"], "orphanet": ["418"], "wikidata": ["Q366868"]}
Glucose transporter type 1 deficiency syndrome (GLUT1 deficiency syndrome) is an inherited condition that affects the nervous system. Signs and symptoms generally develop within the first few months of life and may include recurrent seizures (epilepsy) and involuntary eye movements. Affected people may also have microcephaly (unusually small head size) that develops after birth, developmental delay, intellectual disability and other neurological problems such as spasticity, ataxia (difficulty coordinating movements), and dysarthria. Approximately 10% of affected people have the "non-epileptic" form of GLUT1 deficiency syndrome which is associated with all the typical symptoms of the condition without seizures. GLUT1 deficiency syndrome is caused by changes (mutations) in the SLC2A1 gene and is inherited in an autosomal dominant manner. Although there is currently no cure for GLUT1 deficiency syndrome, a special diet (called a ketogenic diet) may help alleviate 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 inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors	Glucose transporter type 1 deficiency syndrome	c1847501	1,868	gard	https://rarediseases.info.nih.gov/diseases/9265/glucose-transporter-type-1-deficiency-syndrome	2021-01-18T18:00:18	{"mesh": ["C536830"], "omim": ["606777"], "umls": ["C1847501"], "orphanet": ["71277"], "synonyms": ["GLUT1 deficiency syndrome", "Encephalopathy due to GLUT1 deficiency", "Glucose transport defect, blood-brain barrier", "De Vivo disease", "GLUT-1 deficiency syndrome", "Glucose transporter protein syndrome", "GLUT1 DS", "G1D"]}
White blood cell abnormality Alder–Reilly anomaly, or Alder anomaly, is an inherited abnormality of white blood cells associated with mucopolysaccharidosis. When blood smears and bone marrow preparations from patients with Alder–Reilly anomaly are stained and examined microscopically, large, coarse granules may be seen in their neutrophils, monocytes, and lymphocytes. The condition may be mistaken for toxic granulation, a type of abnormal granulation in neutrophils that occurs transiently in inflammatory conditions.[1][2]:477[3] In addition to mucopolysaccharidosis, Alder–Reilly anomaly may occur in lipofuscinosis[4]:32 and Tay–Sachs disease.[5]:124 While the anomaly is generally considered to exhibit autosomal recessive inheritance,[1][2]:477 it may also occur in carriers who are heterozygous for the Tay–Sachs mutation, although the inclusions are much less frequent than in homozygotes.[5]:124 Alder–Reilly anomaly is not diagnostic of any disorder and does not correlate with disease severity.[4]:32 Affected white blood cells function normally.[2]:477 Alder–Reilly inclusions stain appear violet when treated with Wright–Giemsa stain and, in mucopolysaccharidosis, stain metachromatically with toluidine blue. Metachromatic staining is not seen in Tay–Sachs disease. The granules tend to be round or comma-shaped and may be surrounded by a clearing in the cytoplasm.[5]:124 ## References[edit] 1. ^ a b John P. Greer; Daniel A. Arber; Bertil E. Glader; Alan F. List; Robert M. Means; George M. Rodgers (19 November 2018). "Chapter 59: Qualitative disorders of leukocytes". Wintrobe's Clinical Hematology (14th ed.). Wolters Kluwer Health. ISBN 978-1-4963-6713-6. 2. ^ a b c Elaine Keohane; Larry Smith; Jeanine Walenga (20 February 2015). Rodak's Hematology: Clinical Principles and Applications. Elsevier Health Sciences. ISBN 978-0-323-23906-6. 3. ^ American Association for Clinical Chemistry (2018-12-09). "Blood Smear". Lab Tests Online. Retrieved 2019-12-25. 4. ^ a b Lila Penchansky (6 December 2012). Pediatric Bone Marrow. Springer Science & Business Media. ISBN 978-3-642-18799-5. 5. ^ a b c Barbara J. Bain (11 November 2014). Blood Cells: A Practical Guide. Wiley. ISBN 978-1-118-81729-2. * v * t * e Blood film findings Red blood cells Size * Anisocytosis * Macrocytosis * Microcytosis Shape * Poikilocytosis * Membrane abnormalities * Acanthocyte * Codocyte * Elliptocyte * Hereditary elliptocytosis * Spherocyte * Hereditary spherocytosis * Dacrocyte * Echinocyte * Schistocyte * Degmacyte * Sickle cell/drepanocyte * Sickle cell disease * Stomatocyte * Hereditary stomatocytosis Colour * Anisochromia * Hypochromic anemia * Polychromasia Inclusion bodies * Developmental * Howell–Jolly body * Basophilic stippling * Pappenheimer bodies * Cabot rings * Hemoglobin precipitation * Heinz body Other * Red cell agglutination * Rouleaux White blood cells Lymphocytes * Reactive lymphocyte * Smudge cell * Russell bodies Granulocytes * Hypersegmented neutrophil * Arneth count * Pelger–Huët anomaly * Döhle bodies * Toxic granulation * Toxic vacuolation * Critical green inclusion * Alder–Reilly anomaly * Jordans' anomaly * Birbeck granules * Left shift Other * Auer rod This article related to pathology 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 inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors	Alder–Reilly anomaly	None	1,869	wikipedia	https://en.wikipedia.org/wiki/Alder%E2%80%93Reilly_anomaly	2021-01-18T18:43:48	{"wikidata": ["Q85740606"]}
A rare mild form of galactosemia characterized by early onset of cataract and an absence of the usual signs of classic galactosemia, i.e. feeding difficulties, poor weight gain and growth, lethargy, and jaundice. ## Epidemiology Prevalence of this form of galactosemia is not known but is estimated to be less than 1/ 100,000. ## Clinical description Patients with galactokinase deficiency generally have elevated plasma galactose and increased urinary excretion of galactitol. They develop cataracts during the first weeks or months of life as a result of accumulation of galactitol in the lens. Patients are otherwise healthy. ## Etiology Galactokinase deficiency is caused by mutations in the GALK1 gene (17q24) coding for the galactokinase enzyme. ## Genetic counseling The disorder is inherited in an autosomal recessive manner. ## Prognosis Development of cataracts appears to be fully preventable if diagnosis is made early and a galactose-restricted diet is implemented and strictly followed. [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 inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors	Galactokinase deficiency	c0268155	1,870	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=79237	2021-01-23T19:04:14	{"gard": ["2422"], "mesh": ["C535999", "D005693"], "omim": ["230200"], "umls": ["C0268155", "C0751158"], "icd-10": ["E74.2"], "synonyms": ["GALK deficiency", "GALK-D", "Galactokinase deficiency galactosemia", "Galactosemia type 2"]}
A number sign (#) is used with this entry because this disorder is caused by mutation in the gene encoding mitochondrial cytochrome b (MTCYB; 516020). Description Histiocytoid cardiomyopathy, which was initially described by Voth (1962), goes by various names, including infantile xanthomatous cardiomyopathy (MacMahon, 1971), focal lipid cardiomyopathy (Bove and Schwartz, 1973), oncocytic cardiomyopathy (Silver et al., 1980), infantile cardiomyopathy with histiocytoid change (Ferrans et al., 1976), and foamy myocardial transformation of infancy (Yatani et al., 1988). The disorder is a rare but distinctive entity of infancy and childhood characterized by the presence of characteristic pale granular foamy histiocyte-like cells within the myocardium. It usually affects children younger than 2 years of age, with a clear predominance of females over males. Infants present with dysrhythmia or cardiac arrest, and the clinical course is usually fulminant, sometimes simulating sudden infant death syndrome (Andreu et al., 2000). Clinical Features Malhotra et al. (1994) presented a table reviewing the 50 reported cases of histiocytoid cardiomyopathy and added 3 'new' cases. They commented on the high frequency of anomalies involving the nervous system and eyes and of oncocytic cells in various glands. Because of the large number of mitochondria present in the histiocytoid cells, they resemble oncocytes. Malhotra et al. (1994) concluded that the syndrome is likely caused by prenatal myocardial or systemic, possibly viral, injury. Andreu et al. (2000) stated that approximately 61 cases of histiocytoid cardiomyopathy have been reported. Molecular Genetics Andreu et al. (2000) restudied a patient with histiocytoid cardiomyopathy reported by Papadimitriou et al. (1984). The patient was an infant girl who died of cardiac arrest at age 4 weeks with typical clinical and pathologic features of histiocytoid cardiomyopathy, but who also had involvement of other organs, including liver (hepatic steatosis) and kidney (acute tubular necrosis). Biochemical studies of cardiac muscle showed isolated complex III deficiency and a marked defect of reducible cytochrome b, the only mtDNA-encoded subunit of complex III of the respiratory chain. Because mutations in the MTCYB gene are often sporadic and can arise during embryogenesis, affecting a limited number of cells and resulting in tissue-specific phenotypes, Andreu et al. (2000) studied the MTCYB gene of this patient and identified a point mutation (516020.0011). [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 inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors	CARDIOMYOPATHY, INFANTILE HISTIOCYTOID	c1708371	1,871	omim	https://www.omim.org/entry/500000	2019-09-22T16:16:59	{"doid": ["0080198"], "mesh": ["C535584"], "omim": ["500000"], "orphanet": ["137675"], "synonyms": ["Alternative titles", "CARDIOMYOPATHY, INFANTILE XANTHOMATOUS", "CARDIOMYOPATHY, FOCAL LIPID", "CARDIOMYOPATHY, ONCOCYTIC", "FOAMY MYOCARDIAL TRANSFORMATION OF INFANCY"]}
Poikiloderma vasculare atrophicans Other namesParapsoriasis variegata[1] or Parapsoriasis lichenoides[2] Typical skin changes and discoloration described as poikiloderma vasculare atrophicans SpecialtyDermatology Poikiloderma vasculare atrophicans (PVA), is a cutaneous condition (skin disease) characterized by hypo- or hyperpigmentation (diminished or heightened skin pigmentation, respectively), telangiectasia and skin atrophy.[3][4][5] Other names for the condition include prereticulotic poikiloderma and atrophic parapsoriasis.[6] The condition was first described by pioneer American pediatrician Abraham Jacobi in 1906.[7] PVA causes areas of affected skin to appear speckled red and inflamed, yellowish and/or brown, gray or grayish-black, with scaling and a thinness that may be described as "cigarette paper".[3] On the surface of the skin, these areas may range in size from small patches, to plaques (larger, raised areas), to neoplasms (spreading, tumor-like growths on the skin).[3][6] Mycosis fungoides, a type of skin lymphoma, may be a cause of PVA. The condition may also be caused by, associated with or accompany any of the following conditions or disorders: other skin lymphomas, dermatomyositis, lupus erythematosus, Rothmund–Thomson syndrome, Kindler syndrome, dyskeratosis congenita, and chronic radiodermatitis.[4] Rare causes include arsenic ingestion, and the condition can also be idiopathic.[1][3][5] PVA may be considered a rare variant of cutaneous T-cell lymphoma, a non-Hodgkin's form of lymphoma affecting the skin.[7] It may also be included among a number of similar conditions that are considered as precursors to mycosis fungoides. PVA is believed to be a syndrome closely associated with large-plaque parapsoriasis and its cohort retiform parapsoriasis; including PVA, all three conditions fit within an updated view of the once ambiguous classification scheme known as parapsoriasis.[5] ## Contents * 1 Presentation * 2 Cause * 3 Diagnosis * 3.1 Classification * 4 Management * 5 See also * 6 References * 7 External links ## Presentation[edit] The layers of the epidermis (left). Melanocytes (rlght), located in the bottom epidermal layer, produce melanin. PVA can be characterized by speckled, combined hyper- and hypopigmentation in the plaques or patches of affected skin.[5] Hyperpigmentation is excess coloration, or darkening of the skin,[8] while hypopigmentation is a diminished or pallid coloring to the skin. Pigmentation changes in PVA, apparent in the epidermal (outermost) skin layer, may be attributed to incontinence (leaking out) of melanin from melanocytes into the dermal skin layer below.[5] Inflammation of the skin and cutaneous tissue, common with PVA,[7] also contributes to color changes in the skin, typified by redness. Telangiectasia, the visible "vascular" element of PVA, is the dilation of small blood vessels near the skin surface.[5] Skin atrophy, a wasting-away of the tissue comprising the skin, is a prominent part of PVA and effects the dermal, and particularly the epidermal layer.[5] This, in part, is the result of degenerative liquefaction of the stratum basale (bottom cell-layer) of the epidermis.[5] Atrophy of the skin gives it a thin, dry and wrinkled appearance, which in PVA-affected individuals has been described as "cigarette paper".[7] Hyperkeratosis, a thickening of the stratum corneum (top cell-layer of the epidermis), has also been reported.[5][9] ## Cause[edit] PVA usually has an underlying cause, attributed to existing skin diseases and disorders associated with a cutaneous lymphoma or inflammation.[5] Mycosis fungoides is the common lymphoma believed to cause PVA, although it may be considered a precursor when the lymphoma is occult (hidden) and undiagnosed.[5] Large plaque parapsoriasis is another common causes of PVA.[5] Less common causes include autoimmune-related connective tissue diseases such as lupus, dermatomyositis and scleroderma.[5] Dermatoses and those that are genetically inspired, called genodermatoses, may also be an underlying cause of PVA. Among them, xeroderma pigmentosum and Rothmund–Thomson syndrome (poikiloderma congenita) are thought to be the most prominent.[5] Ingestion of substances containing arsenic, such as arsphenamine, has also been suggested as a least common cause.[5] PVA can also be idiopathic (of unknown cause), as seen in a small number of cases.[5] ## Diagnosis[edit] ### Classification[edit] Poikiloderma vasculare atrophicans, or PVA, indicates that extra or altered skin pigmentation ("poikiloderma")[10] is occurring, associated with heightened visibity of capillaries ("vasculare", referring to telangiectasia) under the skin, related to thinning and wasting away ("atrophicans") of the skin and its tissue. Telangiectasia is an enlargement of capillaries underneath the skin.[10] PVA also has common names that include parapsoriasis-related terminology (i.e. parapsoriasis variagata, or "variegated" parapsoriasis).[5] Parapsoriasis is a term first used by Brocq in 1902,[11] intended to represent a group comprising a number of uncommon skin disorders, under a once used, now antiquated classification scheme for all inflammatory dermatoses (skin diseases known to be associated with or cause inflammation).[5] Brocq chose the term "parapsoriasis" to illustrate that the dermatoses placed in this group had or would have commonalities with psoriasiasis, including appearance and chronicity (lifelong or indefinite duration).[5] This poorly designated grouping has led to confusion in establishing a nosology (a method of classifying diseases and disorders) that associated or distinguished these disorders, and through the years differing opinions and uses regarding parapsoriasis by both authors and physicians has caused further confusion.[5] In more recent times, after much discussion and growing consensus, parapsoriasis and its terminology has been revisited and re-examined often. Newer thought on parapsoriasis, such as by Sutton (1956)[12] all the way to that by Sehgal, et al. (2007)[13] has cleared much of the confusion and has sparked increased understanding of parapsoriasis and its constituents. PVA fits within this updated view of parapsoriasis as a syndrome often associated with large plaque parapsoriasis and, or including its variant form, retiform parapsoriasis.[5] Additionally, it may be considered a precursor or variant of the lymphomatous skin disorder mycosis fungoides, which is also associated with large plaque parapsoriasis.[5] Large plaque parapsoriasis consists of inflamed, oddly discolored (such as yellow or blue), web-patterned and scaling plaques on the skin, 10 cm (3.9 in) or larger in diameter.[5] When the condition of the skin encompassed by these plaques worsens and becomes atrophic, it is typically considered retiform parapsoriasis.[5] PVA can occur in either the large plaque or retiform stage, but it can only be considered PVA when its three constituents (poikiloderma, telangiectasia, atrophy) are present.[5] PVA is therefore considered an independent syndrome identified by its constituents, wherever it occurs.[5] In modern consideration and usage, the solitary term "poikiloderma" has also come to represent all three elements of PVA.[5] When skin diseases and disorders or skin conditions described as dermatoses contain the term poikiloderma in their assessment or diagnosis (such as with Bloom syndrome), this can sometimes be an erroneous usage of the term.[5] Discretion has been advised.[5] Usage of the entire term "poikiloderma vasculare atrophicans" may also be reserved to indicate it as the primary condition affecting the skin in cases where the disorder associated with it is secondary.[5] ## Management[edit] This section is empty. You can help by adding to it. (May 2018) ## See also[edit] * List of cutaneous conditions ## References[edit] 1. ^ a b Howard MS, Smoller BR (Jun 2000). "Mycosis fungoides: classic disease and variant presentations". Seminars in Cutaneous Medicine and Surgery. 19 (2): 91–99. doi:10.1016/S1085-5629(00)80005-X. PMID 10892710. 2. ^ Diseases Database (DDB): 10208 3. ^ a b c d Chapman, R. S.; Paul, C. J. (July 1975). "Poikiloderma atrophicans vasculare as a pointer to reticulosis of the skin". Postgraduate Medical Journal. 51 (597): 463–467. doi:10.1136/pgmj.51.597.463. PMC 2496068. PMID 1103107. 4. ^ a b Rapini, Ronald P.; Bolognia, Jean L.; Jorizzo, Joseph L. (2007). Dermatology: 2-Volume Set. St. Louis: Mosby. ISBN 978-1-4160-2999-1. 5. ^ 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 Lambert WC, Everett MA (Oct 1981). "The nosology of parapsoriasis". J. Am. Acad. Dermatol. 5 (4): 373–395. doi:10.1016/S0190-9622(81)70100-2. PMID 7026622. 6. ^ a b Bonvalet, D.; Colau-Gohm, K.; Belaïch, S.; Civatte, J.; Degos, R. (Jan 1977). "The difference forms of "parapsoriasis en plaques". A report of 90 cases (author's transl)". Annales de dermatologie et de vénéréologie. 104 (1): 18–25. PMID 843023. 7. ^ a b c d Kreuter A, Hoffmamm K, Altmeyer P (Apr 2005). "A case of poikiloderma vasculare atrophicans, a rare variant of cutaneous T-cell lymphoma, responding to extracorporeal photopheresis". Journal of the American Academy of Dermatology. 52 (4): 706–708. doi:10.1016/j.jaad.2004.10.877. PMID 15793532. 8. ^ "A definition of the term "hyperpigmentation" from Aocd.com". Retrieved Feb 6, 2010. 9. ^ "A definition of the term "hyperkeratosis" from Everydayhealth.com". Retrieved Feb 6, 2010. 10. ^ a b "A definition of the term "poikiloderma" from Medterms.com". Retrieved Dec 28, 2009. 11. ^ Brocq L (1902). "Les parapsoriasis". Ann Dermatol Syphiligr (Paris). 3: 433–468. 12. ^ Sutton RL (1956). Diseases of the skin. St. Louis, Mo.: The C. V. Mosby Co. pp. 936–941. 13. ^ Sehgal, V. N.; Srivastava, G.; Aggarwal, A. K. (Nov–Dec 2007). "Parapsoriasis: a complex issue". Skinmed. 6 (6): 280–286. doi:10.1111/j.1540-9740.2007.06490.x. PMID 17975354. ## External links[edit] Classification D * ICD-10: L94.5 * ICD-9-CM: 696.2 * DiseasesDB: 10208 * v * t * e Cutaneous keratosis, ulcer, atrophy, and necrobiosis Epidermal thickening * keratoderma: Keratoderma climactericum * Paraneoplastic keratoderma * Acrokeratosis paraneoplastica of Bazex * Aquagenic keratoderma * Drug-induced keratoderma * psoriasis * Keratoderma blennorrhagicum * keratosis: Seborrheic keratosis * Clonal seborrheic keratosis * Common seborrheic keratosis * Irritated seborrheic keratosis * Seborrheic keratosis with squamous atypia * Reticulated seborrheic keratosis * Dermatosis papulosa nigra * Keratosis punctata of the palmar creases * other hyperkeratosis: Acanthosis nigricans * Confluent and reticulated papillomatosis * Callus * Ichthyosis acquisita * Arsenical keratosis * Chronic scar keratosis * Hyperkeratosis lenticularis perstans * Hydrocarbon keratosis * Hyperkeratosis of the nipple and areola * Inverted follicular keratosis * Lichenoid keratosis * Multiple minute digitate hyperkeratosis * PUVA keratosis * Reactional keratosis * Stucco keratosis * Thermal keratosis * Viral keratosis * Warty dyskeratoma * Waxy keratosis of childhood * other hypertrophy: Keloid * Hypertrophic scar * Cutis verticis gyrata Necrobiosis/granuloma Necrobiotic/palisading * Granuloma annulare * Perforating * Generalized * Subcutaneous * Granuloma annulare in HIV disease * Localized granuloma annulare * Patch-type granuloma annulare * Necrobiosis lipoidica * Annular elastolytic giant-cell granuloma * Granuloma multiforme * Necrobiotic xanthogranuloma * Palisaded neutrophilic and granulomatous dermatitis * Rheumatoid nodulosis * Interstitial granulomatous dermatitis/Interstitial granulomatous drug reaction Foreign body granuloma * Beryllium granuloma * Mercury granuloma * Silica granuloma * Silicone granuloma * Zirconium granuloma * Soot tattoo * Tattoo * Carbon stain Other/ungrouped * eosinophilic dermatosis * Granuloma faciale Dermis/ localized CTD Cutaneous lupus erythematosus * chronic: Discoid * Panniculitis * subacute: Neonatal * ungrouped: Chilblain * Lupus erythematosus–lichen planus overlap syndrome * Tumid * Verrucous * Rowell's syndrome Scleroderma/ Morphea * Localized scleroderma * Localized morphea * Morphea–lichen sclerosus et atrophicus overlap * Generalized morphea * Atrophoderma of Pasini and Pierini * Pansclerotic morphea * Morphea profunda * Linear scleroderma Atrophic/ atrophoderma * Lichen sclerosus * Anetoderma * Schweninger–Buzzi anetoderma * Jadassohn–Pellizzari anetoderma * Atrophoderma of Pasini and Pierini * Acrodermatitis chronica atrophicans * Semicircular lipoatrophy * Follicular atrophoderma * Linear atrophoderma of Moulin Perforating * Kyrle disease * Reactive perforating collagenosis * Elastosis perforans serpiginosa * Perforating folliculitis * Acquired perforating dermatosis Skin ulcer * Pyoderma gangrenosum Other * Calcinosis cutis * Sclerodactyly * Poikiloderma vasculare atrophicans * Ainhum/Pseudo-ainhum [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 inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors	Poikiloderma vasculare atrophicans	c0263369	1,872	wikipedia	https://en.wikipedia.org/wiki/Poikiloderma_vasculare_atrophicans	2021-01-18T18:51:07	{"icd-9": ["696.2"], "icd-10": ["L94.5"], "wikidata": ["Q7207847"]}
Herbst (1936) described a kindred in which 18 persons in 4 generations had a median groove or split in the lower lip. The upper lip was fleshy and moderately everted but only 1 of the examined persons had a median cleft of the upper lip. The maxilla was narrow and the teeth crowded and irregularly aligned. Gorlin (1968) thought this may have been an example of lower lip pits (119300). Inheritance \- Autosomal dominant \- ? same as lower lip pits Mouth \- Median grooved or split lower lip \- Fleshy everted upper lip \- Median cleft of upper lip Facies \- Narrow maxilla Teeth \- Crowded irregularly aligned teeth ▲ 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 inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors	SPLIT LOWER LIP	c1866743	1,873	omim	https://www.omim.org/entry/183400	2019-09-22T16:34:28	{"omim": ["183400"]}
GMS syndrome describes an extremely rare syndrome involving goniodysgenesis, intellectual disability and short stature in addition to microcephaly, short nose, small hands and ears, and that has been seen in one family to date. There have been no further descriptions in the literature since 1992. [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 inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors	GMS syndrome	c1841854	1,874	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=2090	2021-01-23T18:10:44	{"gard": ["2523"], "mesh": ["C564214"], "omim": ["138770"], "umls": ["C1841854"], "icd-10": ["Q87.8"], "synonyms": ["Goniodysgenesis-intellectual disability-short stature syndrome"]}
For a general description and a discussion of genetic heterogeneity of inflammatory bowel disease (IBD), including Crohn disease (CD) and ulcerative colitis (UC), see IBD1 (266600). Mapping Kugathasan et al. (2008) carried out a genomewide association analysis in a cohort of 1,011 individuals with pediatric-onset IBD and 4,250 matched controls. They identified significantly associated loci at chromosome 20q13, rs2315008T and rs4809330A; P = 6.30 x 10(-8) and 6.95 x 10(-8), respectively, with an odds ratio of 0.74 for both. These signals were replicated in an independent cohort of 173 IBD cases and 3,481 controls collected according to the same definition as the discovery cohort, as well as in the IBD cohort from the Wellcome Trust Case Control Consortium (2007), which included individuals with CD. For the Wellcome Trust CD cohort, the odds ratio for each of these SNPs was 0.842 with a 95% confidence interval of 0.753 to 0.939; combined P values for both replication sets were 8.85 x 10(-15) for rs2315008 and 1.62 x 10(-14) for rs4809330. The linkage disequilibrium (LD) peak on chromosome 20q13 includes the gene TNFRSF6B (603361). Kugathasan et al. (2008) noted that the protein product for TNFRSF6B acts as a decoy receptor (DCR3) in preventing FasL (134638)-induced cell death, and resistance to FasL-dependent apoptosis had been shown for T lymphocytes in CD. Kugathasan et al. (2008) compared the serum DCR3 concentration in individuals with IBD and controls and, within the IBD group, in those with and without the identified at-risk variants captured by the TNFRSF6B-tagging SNPs. The mean +/- standard error of the mean (SEM) serum DCR3 concentration increased from 84 +/- 37 pg/ml in healthy controls to 4,333 +/- 1,637 pg/ml in individuals with IBD carrying the major allelic variants, and 11,793 +/- 2,452 pg/ml in individuals with IBD carrying the minor allelic variants, (P less than 0.05 for IBD vs control, and within IBD for major vs minor allelic variants). The UK IBD Genetics Consortium & the Wellcome Trust Case Control Consortium 2 (2009) performed a genomewide association scan in 2,361 ulcerative colitis (UC) cases and 5,417 controls followed by genotyping in an independent set of 2,321 UC cases and 4,818 controls, and found the strongest association (combined p = 8.5 x 10(-17)) at rs6017342, which maps within a recombination hotspot on 20q13 and is located 5 kb distal to the 3-prime UTR of the HNF4A gene (600281), within an expressed sequence tag (DB076868). [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 inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors	INFLAMMATORY BOWEL DISEASE 24	c2675509	1,875	omim	https://www.omim.org/entry/612566	2019-09-22T16:01:11	{"mesh": ["C567252"], "omim": ["612566"]}
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: "Bacillary dysentery" – news · newspapers · books · scholar · JSTOR (July 2018) (Learn how and when to remove this template message) This article possibly contains original research. Please improve it by verifying the claims made and adding inline citations. Statements consisting only of original research should be removed. (July 2018) (Learn how and when to remove this template message) (Learn how and when to remove this template message) Bacillary dysentery SpecialtyInfectious disease Bacillary dysentery is a type of dysentery, and is a severe form of shigellosis. Bacillary dysentery is associated with species of bacteria from the family Enterobacteriaceae.[1] The term is usually restricted to Shigella infections.[2] Shigellosis is caused by one of several types of Shigella bacteria.[3] Three species are associated with bacillary dysentery: Shigella sonnei, Shigella flexneri and Shigella dysenteriae.[4] A study in China indicated that Shigella flexneri 2a was the most common serotype.[5] Salmonellosis caused by Salmonella enterica (serovar Typhimurium) has also been described as a cause of bacillary dysentery,[citation needed] though this definition is less common. It is sometimes listed as an explicit differential diagnosis of bacillary dysentery, as opposed to a cause.[6] Bacillary dysentery should not be confused with diarrhea caused by other bacterial infections. One characteristic of bacillary dysentery is blood in stool,[7] which is the result of invasion of the mucosa by the pathogen. ## Contents * 1 Pathogenesis * 2 Diagnosis * 3 Treatment * 4 References * 5 External links ## Pathogenesis[edit] This Section 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: "Bacillary dysentery" – news · newspapers · books · scholar · JSTOR (July 2018) (Learn how and when to remove this template message) Transmission is fecal-oral and is remarkable for the small number of organisms that may cause disease (10 ingested organisms cause illness in 10% of volunteers, and 500 organisms cause disease in 50% of volunteers). Shigella bacteria invade the intestinal mucosal cells but do not usually go beyond the lamina propria. Dysentery is caused when the bacteria escape the epithelial cell phagolysosome, multiply within the cytoplasm, and destroy host cells. Shiga toxin causes hemorrhagic colitis and hemolytic-uremic syndrome by damaging endothelial cells in the microvasculature of the colon and the glomeruli, respectively. In addition, chronic arthritis secondary to S. flexneri infection, called reactive arthritis, may be caused by a bacterial antigen; the occurrence of this syndrome is strongly linked to HLA-B27 genotype, but the immunologic basis of this reaction is not understood.[citation needed] ## Diagnosis[edit] Specimen: Fresh stool is collected. Culture: Specimen is inoculated on selective media like MacConkey's agar, DCA, XLD agar. Selenite F broth(0.4%) is used as enrichment medium which permits the rapid growth of enteric pathogens while inhibiting the growth of normal flora like E. coli for 6–8 hours. Subculture is done on the solid media from selenite F broth. All the solid media are incubated at 37 degrees for 24 hours. Cultural characteristics: Colorless (NLF) colonies appear on MacConkey's agar which are further confirmed by gram staining, hanging drop preparation and biochemical reactions. ## Treatment[edit] Dysentery is initially managed by maintaining fluid intake using oral rehydration therapy. If this treatment cannot be adequately maintained due to vomiting or the profuseness of diarrhea, hospital admission may be required for intravenous fluid replacement. Ideally, no antimicrobial therapy should be administered until microbiological microscopy and culture studies have established the specific infection involved. When laboratory services are not available, it may be necessary to administer a combination of drugs, including an amoebicidal drug to kill the parasite and an antibiotic to treat any associated bacterial infection. Anyone with bloody diarrhea needs immediate medical help. Treatment often starts with an oral rehydrating solution—water mixed with salt and carbohydrates—to prevent dehydration. (Emergency relief services often distribute inexpensive packets of sugars and mineral salts that can be mixed with clean water and used to restore lifesaving fluids in dehydrated children gravely ill from dysentery.) If Shigella is suspected and it is not too severe, the doctor may recommend letting it run its course—usually less than a week. The patient will be advised to replace fluids lost through diarrhea. If the infection is severe, the doctor may prescribe antibiotics, such as ciprofloxacin or TMP-SMX (Bactrim). Unfortunately, many strains of Shigella are becoming resistant to common antibiotics, and effective medications are often in short supply in developing countries. If necessary, a doctor may have to reserve antibiotics for those at highest risk for death, including young children, people over 50, and anyone suffering from dehydration or malnutrition. No vaccine is available. There are several Shigella vaccine candidates in various stages of development that could reduce the incidence of dysentery in endemic countries, as well as in travelers suffering from traveler's diarrhea.[8] ## References[edit] 1. ^ Dysentery,+Bacillary at the US National Library of Medicine Medical Subject Headings (MeSH) 2. ^ "bacillary dysentery" at Dorland's Medical Dictionary 3. ^ Yang F, Yang J, Zhang X, et al. (2005). "Genome dynamics and diversity of Shigella species, the etiologic agents of bacillary dysentery". Nucleic Acids Res. 33 (19): 6445–58. doi:10.1093/nar/gki954. PMC 1278947. PMID 16275786. 4. ^ "WHO \| Diarrhoeal Diseases". Archived from the original on 15 December 2008. Retrieved 2008-12-19. 5. ^ Wang XY, Tao F, Xiao D, et al. (July 2006). "Trend and disease burden of bacillary dysentery in China (1991-2000)". Bull. World Health Organ. 84 (7): 561–8. doi:10.2471/BLT.05.023853. PMC 2627389. PMID 16878230. 6. ^ "Bacillary Dysentery". Archived from the original on 27 December 2008. Retrieved 2008-12-19. 7. ^ "Enterobacteriaceae, Vibrio, Campylobacter and Helicobacter". Archived from the original on 24 December 2008. Retrieved 2008-12-19. 8. ^ Girard MP, Steele D, Chaignat CL, Kieny MP (April 2006). "A review of vaccine research and development: human enteric infections". Vaccine. 24 (15): 2732–50. doi:10.1016/j.vaccine.2005.10.014. PMID 16483695. ## External links[edit] Classification D * ICD-10: A03.9 * ICD-9-CM: 004 * MeSH: D004405 * DiseasesDB: 12005 * SNOMED CT: 274081004 * 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 Diseases of the digestive system Upper GI tract Esophagus * Esophagitis * Candidal * Eosinophilic * Herpetiform * Rupture * Boerhaave syndrome * Mallory–Weiss syndrome * UES * Zenker's diverticulum * LES * Barrett's esophagus * Esophageal motility disorder * Nutcracker esophagus * Achalasia * Diffuse esophageal spasm * Gastroesophageal reflux disease (GERD) * Laryngopharyngeal reflux (LPR) * Esophageal stricture * Megaesophagus * Esophageal intramural pseudodiverticulosis Stomach * Gastritis * Atrophic * Ménétrier's disease * Gastroenteritis * Peptic (gastric) ulcer * Cushing ulcer * Dieulafoy's lesion * Dyspepsia * Pyloric stenosis * Achlorhydria * Gastroparesis * Gastroptosis * Portal hypertensive gastropathy * Gastric antral vascular ectasia * Gastric dumping syndrome * Gastric volvulus * Buried bumper syndrome * Gastrinoma * Zollinger–Ellison syndrome Lower GI tract Enteropathy Small intestine (Duodenum/Jejunum/Ileum) * Enteritis * Duodenitis * Jejunitis * Ileitis * Peptic (duodenal) ulcer * Curling's ulcer * Malabsorption: Coeliac * Tropical sprue * Blind loop syndrome * Small bowel bacterial overgrowth syndrome * Whipple's * Short bowel syndrome * Steatorrhea * Milroy disease * Bile acid malabsorption Large intestine (Appendix/Colon) * Appendicitis * Colitis * Pseudomembranous * Ulcerative * Ischemic * Microscopic * Collagenous * Lymphocytic * Functional colonic disease * IBS * Intestinal pseudoobstruction / Ogilvie syndrome * Megacolon / Toxic megacolon * Diverticulitis/Diverticulosis/SCAD Large and/or small * Enterocolitis * Necrotizing * Gastroenterocolitis * IBD * Crohn's disease * Vascular: Abdominal angina * Mesenteric ischemia * Angiodysplasia * Bowel obstruction: Ileus * Intussusception * Volvulus * Fecal impaction * Constipation * Diarrhea * Infectious * Intestinal adhesions Rectum * Proctitis * Radiation proctitis * Proctalgia fugax * Rectal prolapse * Anismus Anal canal * Anal fissure/Anal fistula * Anal abscess * Hemorrhoid * Anal dysplasia * Pruritus ani GI bleeding * Blood in stool * Upper * Hematemesis * Melena * Lower * Hematochezia Accessory Liver * Hepatitis * Viral hepatitis * Autoimmune hepatitis * Alcoholic hepatitis * Cirrhosis * PBC * Fatty liver * NASH * Vascular * Budd–Chiari syndrome * Hepatic veno-occlusive disease * Portal hypertension * Nutmeg liver * Alcoholic liver disease * Liver failure * Hepatic encephalopathy * Acute liver failure * Liver abscess * Pyogenic * Amoebic * Hepatorenal syndrome * Peliosis hepatis * Metabolic disorders * Wilson's disease * Hemochromatosis Gallbladder * Cholecystitis * Gallstone / Cholelithiasis * Cholesterolosis * Adenomyomatosis * Postcholecystectomy syndrome * Porcelain gallbladder Bile duct/ Other biliary tree * Cholangitis * Primary sclerosing cholangitis * Secondary sclerosing cholangitis * Ascending * Cholestasis/Mirizzi's syndrome * Biliary fistula * Haemobilia * Common bile duct * Choledocholithiasis * Biliary dyskinesia * Sphincter of Oddi dysfunction Pancreatic * Pancreatitis * Acute * Chronic * Hereditary * Pancreatic abscess * Pancreatic pseudocyst * Exocrine pancreatic insufficiency * Pancreatic fistula Other Hernia * Diaphragmatic * Congenital * Hiatus * Inguinal * Indirect * Direct * Umbilical * Femoral * Obturator * Spigelian * Lumbar * Petit's * Grynfeltt-Lesshaft * Undefined location * Incisional * Internal hernia * Richter's Peritoneal * Peritonitis * Spontaneous bacterial peritonitis * Hemoperitoneum * Pneumoperitoneum [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 inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors	Bacillary dysentery	c1527298	1,876	wikipedia	https://en.wikipedia.org/wiki/Bacillary_dysentery	2021-01-18T18:49:50	{"mesh": ["D004405"], "umls": ["C1527298"], "icd-9": ["004"], "icd-10": ["A03.9"], "wikidata": ["Q3778137"]}
Compression of umbilical cord A knotted cord on a newborn baby. SpecialtyObstetrics Umbilical cord compression is the obstruction of blood flow through the umbilical cord secondary to pressure from an external object or misalignment of the cord itself. Cord compression happens in about one in 10 deliveries.[1] ## Contents * 1 Causes * 2 Diagnosis * 3 Treatment * 4 References * 5 External links ## Causes[edit] * Nuchal cord, when the umbilical cord is (tightly) around the neck of the fetus[2] * Entanglement of the cord[2] * Knot in the cord[2] * Cord prolapse, where the umbilical cord exits the birth canal before the baby, which can cause cord compression.[3] * As a complication of oligohydramnios in which there is insufficient amniotic fluid * Compression during uterine contractions in childbirth ## Diagnosis[edit] On cardiotocography (CTG), umbilical cord compression can present with variable decelerations in fetal heart rate.[1] ## Treatment[edit] Umbilical cord compression may be relieved by the mother switching to another position. In persistent severe signs of fetal distress, Cesarean section may be needed. ## References[edit] 1. ^ a b Childbirth Complications at medicinenet.com. Last Editorial Review: 1/30/2005 2. ^ a b c P02.5 Fetus and newborn affected by other compression of umbilical cord in ICD-10, the International Statistical Classification of Diseases 3. ^ Holton, Tim. "How Umbilical Cord Complications Can Endanger A Baby's Life". www.holtonlaw.com. ## External links[edit] Classification D * ICD-10: P02.5 * ICD-9-CM: 762.5 [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 inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors	Umbilical cord compression	c0266798	1,877	wikipedia	https://en.wikipedia.org/wiki/Umbilical_cord_compression	2021-01-18T18:59:10	{"icd-9": ["762.5"], "icd-10": ["P02.5"], "wikidata": ["Q7881314"]}
A number sign (#) is used with this entry because bilateral perisylvian polymicrogyria with autosomal recessive inheritance is caused by homozygous deletion of one 15-bp tandem repeat in a regulatory region of exon 1m of the ADGRG1 gene (604110) on chromosome 16q21. Mutations in the ADGRG1 gene also cause bilateral frontoparietal polymicrogyria (606854). Description Autosomal recessive bilateral perisylvian polymicrogyria is characterized by strikingly restricted polymicrogyria limited to the cortex surrounding the Sylvian fissure. Affected individuals have intellectual and language difficulty and seizures, but no motor disability (Bae et al., 2014). Clinical Features Bae et al. (2014) examined more than 1,000 individuals with gyral abnormalities and identified 5 individuals from 3 families (1 Turkish and 2 Irish American) with strikingly restricted polymicrogyria limited to the cortex surrounding the Sylvian fissure, which suggested a rare, genetically distinctive condition. Affected individuals suffered intellectual and language difficulty, as well as refractory seizures with onset ranging from 7 months to 10 years, but had no motor disability. MRI and quantitative gyral analysis showed abnormal inferior and middle gyri in prefrontal and motor cortex, with mildly affected temporal lobes. Broca's area in the left hemisphere and the corresponding areas of the right hemisphere were most severely affected. Affected neocortical surface showed abnormally numerous, small gyral-like folds that fused in coarse, irregular patterns, with abnormal and highly irregular white matter protrusions, consistent with polymicrogyria, along with widening of the Sylvian fissure. Pedigree 1 consisted of female and male sibs from a consanguineous Turkish family. The daughter had intellectual disability with an IQ of 48 and mild delay, but she could read and write. She had left eye esotropia, nystagmus, and mild bilateral thenar atrophy. Her brother had intellectual disability with an IQ of 57 and received special education; he could not read. Additionally, he was obese. Pedigree 2 consisted of 2 sisters of an Irish American family in whom the parents were third cousins. One sister received special education in math but completed a regular school. The other girl was reported to have an 'odd component and manner of behaving' similar to that of her sib. Pedigree 3 consisted of unaffected consanguineous Irish American parents and a son with perisylvian polymicrogyria. The boy had no reported cognitive or motor development abnormalities, but did have generalized convulsions with tonic stiffening and vocalization. Molecular Genetics All 5 patients from the 3 families reported by Bae et al. (2014) were homozygous for a 15-bp deletion in a regulatory element of GPR56 noncoding exon 1m (604110.0009). The mutated element normally contains 2 copies of this 15-bp tandem repeat and is located just upstream of the noncoding exon 1m transcription start site. The deletion was heterozygous in parents of the affected individuals, who manifested no obvious clinical signs, and was absent from thousands of control chromosomes in the dbSNP and 1000 Genomes Project databases. The 2 Irish American families carried the mutation on the same chromosomal haplotype, reflecting a common founder. The Turkish family carried the same deletion on a distinct haplotype, indicating that the mutation arose independently. [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 inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors	POLYMICROGYRIA, BILATERAL PERISYLVIAN, AUTOSOMAL RECESSIVE	c1845668	1,878	omim	https://www.omim.org/entry/615752	2019-09-22T15:51:04	{"mesh": ["C536658"], "omim": ["615752"], "orphanet": ["268940", "98889"], "synonyms": ["Alternative titles", "PMGR"], "genereviews": ["NBK1329"]}
Isolated focal cortical dysplasia is a rare, genetic, non-syndromic cerebral malformation due to abnormal neuronal migration disorder characterized by variable-sized, focalized malformations located in any part(s) of the cerebral cortex, which manifests with drug-resistant epilepsy (usually leading to intellectual disability) and behavioral disturbances. Abnormal MRI findings (e.g. abnormal white and/or grey matter signal, blurred gray-white matter junction, localized volume loss, cortical thickening, abnormal gyral pattern, abnormal hippocampus) and variable histopathologic patterns are 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 inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors	Isolated focal cortical dysplasia	c1846385	1,879	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=65683	2021-01-23T18:41:16	{"mesh": ["C537067"], "omim": ["607341"], "umls": ["C1846385", "C2938983"], "icd-10": ["Q04.8"], "synonyms": ["Epilepsy due to FCD"]}
Kaler et al. (1992) described 2 Mennonite sisters with a syndrome of sparse hair, osteopenia, mental retardation, minor facial abnormalities, joint laxity, and hypotonia. Their asymptomatic consanguineous parents had 6 other offspring, 3 of whom died in infancy of type II osteogenesis imperfecta and 3 of whom were normal. No abnormality was detected in the collagen synthesized by cultured fibroblasts from these 2 sisters or their parents. Kaler et al. (1992) concluded that their disorder is a new autosomal recessive syndrome distinct from type II OI (166210). The family was derived from a 300-member Mennonite community in southern Maryland. They pictured 1 of the 3 sibs who died at the age of 7 weeks of a condition diagnosed as OI on clinical and radiographic grounds. Neuro \- Mental retardation Facies \- Minor facial abnormalities Inheritance \- Autosomal recessive Joints \- Joint laxity Hair \- Sparse hair Skel \- Osteopenia Muscle \- Hypotonia ▲ 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 inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors	OSTEOPENIA AND SPARSE HAIR	c1850140	1,880	omim	https://www.omim.org/entry/259690	2019-09-22T16:23:51	{"mesh": ["C537706"], "omim": ["259690"], "orphanet": ["2324"]}
A giant congenital nevus is a dark-colored, often hairy patch of skin that is present at birth (congenital). It grows proportionally to the child. A congenital pigmented nevus is considered giant if by adulthood it is larger than 20cm (about 8 inches) in diameter. Giant congenital nevi can occur in people of any racial or ethnic background and on any area of the body. They result from localized genetic changes in the fetus that lead to excessive growth of melanocytes, the cells in the skin that are responsible for skin color. People with giant congenital nevi may have no other symptoms or may have several symptoms such as fragile, dry, or itchy skin. In about 5% to 10% of the cases the giant congenital nevus is associated with neurocutaneous melanocytosis (excess pigment cells in the brain or spinal cord) and is characterized by neurological symptoms. They also have an increased risk of developing malignant melanoma, a type of skin cancer, especially if the nevus is localized in the vertebral column or when there are multiple associated lesions (satellites). Whenever possible, treatment includes surgery to remove the nevus. In other cases other treatment such as dermabrasion, shaving or facial excision, chemical peels and laser can be done. In most cases, when there are no neurological problems, the prognosis is good, but it is necessary for the lesions to be examined regularly. [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 inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors	Giant congenital nevus	c1318558	1,881	gard	https://rarediseases.info.nih.gov/diseases/2469/giant-congenital-nevus	2021-01-18T18:00:20	{"omim": ["137550"], "orphanet": ["626"], "synonyms": ["GPHN", "Giant pigmented hairy nevus", "Giant pigmented nevus", "Bathing trunk nevus", "Large congenital melanocytic nevus", "Congenital giant pigmented nevus", "Giant hairy nevus", "Congenital hairy nevus", "Giant congenital melanocytic nevus"]}
A number sign (#) is used with this entry because the autosomal recessive form of Kenny-Caffey syndrome (KCS1) is caused by mutation in the gene encoding tubulin-specific chaperone E (TBCE; 604934). Biallelic mutation in the TBCE gene can also cause Sanjad-Sakati syndrome (HRDS; 241410) and PEAMO (617207). Inheritance of Kenny-Caffey syndrome is most often autosomal dominant (KCS2; 127000) (Franceschini et al., 1992). Clinical Features Franceschini et al. (1992) suggested autosomal recessive inheritance of Kenny-Caffey syndrome in female and male sibs, born of normal consanguineous parents. The sister died at 10 days of age with generalized hypertonic seizures associated with hypocalcemia. The later-born brother had neonatal hypoparathyroidism; at 1 year of age, he was short but intelligent. Both infants showed characteristic cortical thickening and medullary stenosis. Franceschini et al. (1992) noted that recessive inheritance was also suggested by the parental consanguinity in a family with a single affected child (Bergada et al., 1988) and by the family with 2 affected infants with the same normal father and different normal mothers who were sisters (Sarria et al., 1980). Khan et al. (1997) reported 16 affected children in 6 unrelated sibships, born to healthy, consanguineous parents of Bedouin ancestry. They were able to assess clinically 11 of these 16 patients. All presented with marked growth retardation, craniofacial anomalies, small hands and feet, hypocalcemia, hypoparathyroidism, radiologic evidence of cortical thickening of long bones with medullary stenosis, and absent diploic space in the skull. There was a history of 6 other affected sibs dying in infancy with hypocalcemic convulsions. All cases had early psychomotor retardation and absence of macrocephaly. Mapping Using 8 consanguineous Kuwaiti kindreds, Diaz et al. (1998) performed a genomewide search for linkage to the gene causing the autosomal recessive form of KCS with polymorphic short tandem repeat markers. Significant linkage to a locus situated at 1q42-q43 with a maximum 2-point lod score of 13.30 with marker D1S2649 was obtained. Haplotype analysis of flanking markers identified recombination events defining the KCS1 locus to a region between markers D1S2800 on the centromeric boundary and D1S2850 on the telomeric boundary, an approximately 4-cM interval. All affected individuals in these unrelated kindreds were homozygous for identical alleles at D1S2649 and D1S235, suggesting a single ancestral mutation underlying the disease in these families. Haploinsufficiency at 22q11, reported in a consanguineous KCS kindred by Sabry et al. (1998), was not documented in these families. Sabry et al. (1998) had demonstrated an interstitial deletion at 22q11 by fluorescence in situ hybridization in 2 affected sibs and their unaffected mother. The clinical findings in affected individuals from 6 of the 8 pedigrees studied by Diaz et al. (1998) had previously been described by Khan et al. (1997). Molecular Genetics Parvari et al. (2002) demonstrated mutations in the TBCE gene in both Kenny-Caffey syndrome and Sanjad-Sakati syndrome (see 604934.0001). INHERITANCE \- Autosomal recessive GROWTH Height \- Short stature, proportionate \- Birth length <3rd percentile Weight \- Birth weight <2,500gm Other \- Intrauterine growth failure HEAD & NECK Head \- Delayed anterior fontanelle closure Face \- Broad cheeks Eyes \- Hypertelorism Teeth \- Dental caries CHEST Ribs Sternum Clavicles & Scapulae \- Thin, long clavicles \- Thin ribs SKELETAL \- Delayed bone age Skull \- Poorly ossified skull bones \- Absent diploic space \- Calvarial osteosclerosis Limbs \- Medullary stenosis of tubular bones \- Thin long bones \- Internal cortical thickening Hands \- Small hands Feet \- Small feet NEUROLOGIC Central Nervous System \- Tetany \- Hypocalcemic seizure ENDOCRINE FEATURES \- Neonatal hypoparathyroidism \- Low parathyroid hormone HEMATOLOGY \- Anemia IMMUNOLOGY \- Recurrent bacterial infections LABORATORY ABNORMALITIES \- Hypocalcemia \- Low to low-normal magnesium MISCELLANEOUS \- Allelic to hypoparathyroidism-retardation-dysmorphism syndrome ( 241410 ) MOLECULAR BASIS \- Caused by mutations in the tubulin-specific chaperone E gene (TBCE, 604934.0001 ) ▲ 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 inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors	KENNY-CAFFEY SYNDROME, TYPE 1	c0265291	1,882	omim	https://www.omim.org/entry/244460	2019-09-22T16:26:14	{"mesh": ["C537020"], "omim": ["244460"], "orphanet": ["2333", "93324"], "synonyms": ["Alternative titles", "KCS", "KENNY-CAFFEY SYNDROME, AUTOSOMAL RECESSIVE"]}
A number sign (#) is used with this entry because occipital horn syndrome (OHS) is caused by mutation in the gene encoding Cu(2+)-transporting ATPase, alpha polypeptide (ATP7A; 300011). Menkes syndrome (309400) is caused by mutation in the same gene. Description Occipital horn syndrome is a rare connective tissue disorder characterized by hyperelastic and bruisable skin, hernias, bladder diverticula, hyperextensible joints, varicosities, and multiple skeletal abnormalities. The disorder is sometimes accompanied by mild neurologic impairment, and bony abnormalities of the occiput are a common feature, giving rise to the name (summary by Das et al., 1995). Clinical Features Lazoff et al. (1975) described an unusual syndrome in an 11-year-old male and 2 maternal uncles. Bony 'horns,' symmetrically situated on each side of the foramen magnum and pointing caudad, were demonstrable radiographically. A lifelong history of frequent loose stools, obstructive uropathy requiring in 1 uncle ileal loop diversion, and mild mental retardation were other features. Some suspicion that a relative through the maternal grandfather had the same condition (which could not be confirmed because of lack of cooperation) meant that autosomal dominant inheritance with reduced penetrance could not be excluded. Byers et al. (1976) found deficiency of lysyl oxidase in affected males in a family with apparent X-linked cutis laxa. Three affected males were observed, each in a different sibship connected through females who as children showed joint laxity but outgrew it. Hooked nose and long philtrum typical of cutis laxa were described. In 1 case, pectus excavatum and carinatum were sufficiently severe to require surgical repair shortly after birth. Two cousins were brought to medical attention because of recurrent urinary tract infection due to multiple large diverticula of the bladder. MacFarlane et al. (1980) described 2 kindreds with an X-linked disorder that in general appeared to fall into the Ehlers-Danlos category but had some unusual features such as bladder diverticula, bladder neck obstruction, marked varicosities, and, by x-ray, occipital horns, short broad clavicles, and fused carpal bones. Hall (1980) found that the children studied with Byers et al. (1976) also had occipital horns, and diarrhea, a feature found in MacFarlane's families, was also present. Thus, these are probably the same disorder. The age at which the affected persons were studied may have been a factor in determining whether the disorder was labeled cutis laxa or EDS. Low levels of ceruloplasmin (117700) and serum copper were found in these cases, suggesting that, like Menkes syndrome, it may be a disorder of copper metabolism rather than a primary defect of lysyl oxidase. Hollister (1981) pointed out that the patients show hypermobility of the finger joints but limitation of extension of the elbows. Kuivaniemi et al. (1982) studied 2 brothers with bladder diverticula, inguinal hernias, slight skin laxity and hyperextensibility, and skeletal abnormalities, including occipital exostoses. Lysyl oxidase activity was low in the medium of cultured skin fibroblasts, and conversion of newly synthesized collagen into the insoluble form was reduced. Copper concentrations were markedly elevated in cultured skin fibroblasts but decreased in serum and hair. Serum ceruloplasmin levels were low. Kaitila et al. (1982) suggested that this disorder may be allelic to Menkes disease. Peltonen et al. (1983) found many similar abnormalities of copper and collagen metabolism in the cultured fibroblasts of 13 patients with Menkes syndrome and 2 patients with OHS (then called EDS IX). In both disorders, fibroblasts had markedly increased copper content and rate of incorporation of (64)Cu, and accumulation was in metallothionein or a metallothionein-like protein as previously established for Menkes cells. Histochemical staining showed that copper was distributed uniformly throughout the cytoplasm in both cell types, this location being consistent with accumulation in metallothionein. Both fibroblast types showed very low lysyl oxidase activity and increased extractability of newly synthesized collagen, but no abnormality in cell viability, duplication rate, prolyl 4-hydroxylase activity, or collagen synthesis rate. Skin biopsy specimens from one EDS IX patient showed the same abnormalities in lysyl oxidase activity and collagen extractability. Fibroblasts of the mother of EDS IX patients showed increased (64)Cu incorporation. Allelism of occipital horn syndrome and Menkes syndrome was demonstrated in a definitive way by Das et al. (1995) who identified hemizygosity for a mutation in the copper-transporting ATPase that is mutant in Menkes syndrome. One of the mild mottled mutants in the mouse, 'blotchy,' symbolized Mo-blo, exhibits connective tissue abnormalities reminiscent of those seen in OHS patients, including weak skin and bone abnormalities. In blotchy males, hindlegs are occasionally deformed, vibrissae are kinked at birth, crosslinking of skin collagen and aortic elastin is defective, and death frequently results from aortic rupture. Das et al. (1995) identified similar splicing mutations in both the blotchy mouse and cases of the occipital horn syndrome. Das et al. (1995) reported 2 OHS patients in each of whom there was a deletion of 1 exon in the ATP7A gene; one deletion was caused by an A-to-G transition at the -4 position of the splice acceptor site 5-prime of the skipped exon, and the other deletion was caused by a G-to-A transition at the +5 splice donor site following the skipped exon. The first patient had presented to a genetics clinic at the age of 14 years for evaluation of musculoskeletal abnormalities and recurrent bladder rupture. In the neonatal period, mild hypotonia and, on radiographs, cranial contour abnormalities and wormian bones had been observed. There had been numerous orthopedic interventions, including osteotomies for leg straightening and treatment for multiple compression fractures of the vertebrae. Recurrent bladder rupture, bladder diverticula, vesicular calcium stones, and atonic bladder required intermittent catheterization. Examination showed dolichocephaly, prominent and simple ears, downslanting palpebral fissures with bilateral ptosis, dental crowding, pectus carinatum, cutis laxa, and muscle wasting. Neurologic status, including cognition, was normal. Serum ceruloplasmin was slightly low. Radiographs demonstrated osteopenia, dislocated radial heads, and characteristic occipital horns. Radiocopper accumulation in fibroblasts was elevated. The second patient presented to a medical genetics clinic at the age of 15 years, at which time he was wheelchair-bound because of genu valgum and coxa vara deformities. He was mentally retarded. The skin had a cobblestone appearance with hyperelasticity at the elbows and without skin friability. There was laxity of the interphalangeal joints with contractures at the elbows and knees. Serum ceruloplasmin and copper determinations were normal. Radiographs showed bilateral occipital horns. The large diverticula of the bladder were demonstrated. X-rays of the skeleton showed osteoporosis, fusion anomalies in the wrist, and dysplasia of the radius and ulna, with dislocation of the radius at the elbow. That the occipital horn syndrome has ramifications beyond connective tissue is suggested by peculiarities of personality. Unlike patients with Menkes disease, most patients with OHS have mild mental retardation. Wakai et al. (1993) described the first Japanese case in a 34-year-old man who had psychomotor retardation and seizures since early childhood. At the time of study, he had severe mental retardation and generalized muscular atrophy, in addition to characteristic facial features, hyperelasticity of the skin, and joint subluxation. Laboratory studies demonstrated low serum copper and ceruloplasmin levels as well as intestinal nonabsorption of copper. Radiographic studies showed occipital exostoses, bladder diverticula, tortuosity of peripheral veins, and osteoporosis. Lysyl oxidase activity was decreased in skin. Tsukahara et al. (1994) described OHS in an 18-year-old Japanese boy. In addition to bilateral occipital exostosis, radiologic features were prominent mandibular angles, short and broad clavicles with 'hammer-shaped' distal ends, long bones with thin and undercalcified cortices, coalescence between the hamate and capitate bones and between the greater and lesser multiangular bones, and coxa valga. Since birth the patient had had chronic diarrhea (5-10 times/day) that did not respond to antidiarrheal drugs. Tsukahara et al. (1994) found reports of a total of 21 patients, all male. Mild manifestations were described in some of the mothers or aunts of patients (Herman et al., 1992). In a study of cultured cells from patients with EDS IX, Kuivaniemi et al. (1985) could not demonstrate that there was secreted into the medium or contained in the cell any significant amounts of copper-deficient, catalytically inactive lysyl oxidase protein. Although the rapid degradation of a mutant protein could not be excluded, the authors favored the idea that synthesis of the lysyl oxidase protein is impaired. Levinson et al. (1993) found a marked reduction in expression of a copper-transporting ATPase gene, which Vulpe et al. (1993) had designated Mc1 and proposed as a candidate gene for Menkes disease, in Northern blots of RNA extracted from fibroblasts of 2 unrelated males with X-linked cutis laxa. Blackston et al. (1987) studied copper storage and copper retention in females at risk of being heterozygous. In the mother of an affected male, they found in skin fibroblasts a level of total copper and a value for retention of copper that were outside the normal. The findings in a sister of the proband indicated that she was homozygous normal. Khakoo et al. (1997) reported 2 phenotypically similar patients with primary cutis laxa associated with deficiency of lysyl oxidase. Previous reports of congenital cutis laxa had concerned mainly the X-linked form of the disorder, which is characterized by typical occipital osseous projections and an abnormality of copper metabolism. The 2 patients reported by Khakoo et al. (1997) showed no occipital projections and had normal copper metabolism. Furthermore, they showed wormian bones, and the family pattern of inheritance was thought to be consistent with an autosomal recessive disorder. The first boy, 15 years old at the time of report, was born with unusually translucent wrinkled skin with prominent veins, generalized joint laxity, and a hooked nose. A large umbilical hernia was repaired at 3 months of age. Lysyl oxidase deficiency was demonstrated by study of cultured fibroblasts. Lax skin, generalized joint laxity, and blue sclerae were consistently noted. The ears were large with prominent lobes. At the age of 10, the skin had become thicker without residual translucency. Wormian bones were demonstrated in the lambdoid sutures and osteoporosis of the lumbar spine was found. The mother's lysyl oxidase levels were approximately half normal. The second boy was born to first-cousin parents of Pakistani origin. Again the skin was lax at birth and the nose hooked, the joints of the hands and feet were hypermobile, and wormian bones were demonstrated in the lambdoid sutures. There was an irreducible, translocated left hip. Lysyl oxidase activity was measured at 20% of normal. At 2 years of age, the patient developed acute renal failure, owing to a vesicoureteric obstruction causing gross bilateral hydroureters and hydronephrosis. Bladder atonicity was also present. The ears were large, and radiographs of the lumbar spine showed osteoporosis. Bilateral dislocatable shoulders were also present in this boy, who was 5 years old at the time of the report. Tang et al. (2006) described 2 brothers with occipital horn syndrome. The proband had occipital horns bilaterally at age 4 years, short broad clavicles, broad and flat ilia, and dislocated radial heads. Both brothers had genu valgum; the proband required bilateral tibial osteotomies. Both brothers had coarse hair and hyperelastic skin but no dysmorphic facial features. The mother, who carried the mutation present in her sons, had had clubfoot requiring multiple surgeries as a young child. She had coarse hair and mild hyperextensibility of the metacarpophalangeal and interphalangeal joints, which was marked in her sons. Molecular Genetics Kaler et al. (1994) reported a 15-year-old male with OHS who had an A-to-G change at base 2642 of the MNK locus, predicting a neutral glycine for serine substitution at nucleotide 833. Actually, this mutation at the -2 exonic position of a splice donor site caused exon skipping and activation of a cryptic splice acceptor site (300011.0002). The authors suggested that maintenance of some normal splicing could explain the relatively mild phenotype of this patient. In a patient with OHS, Levinson et al. (1996) identified a 98-bp deletion involving an upstream regulatory element of the MNK gene; see 300011. Tang et al. (2006) described 2 brothers with occipital horn syndrome who had a missense mutation (N1304S; 300011.0013) that had 33% residual copper transport activity. Serum copper level was low, and ceruloplasmin was at the low end of normal. Nomenclature MacFarlane et al. (1980) suggested the designation Ehlers-Danlos syndrome type IX. It was suggested at a workshop convened in Berlin by Beighton (1986) that this disorder be removed from the Ehlers-Danlos category (with the EDS IX number retired, as with MPS V and clotting factor IV) and instead be placed in a category of disorders with secondary changes in connective tissue due to a defect in copper metabolism. INHERITANCE \- X-linked recessive HEAD & NECK Head \- Persistent, open anterior fontanel Face \- Long, thin face \- High forehead \- Long philtrum Nose \- Hooked nose Mouth \- High-arched palate Neck \- Long neck CARDIOVASCULAR Vascular \- Orthostatic hypotension \- Elongated, tortuous carotid arteries \- Intracranial arterial narrowing CHEST External Features \- Narrow shoulders \- Narrow chest Ribs Sternum Clavicles & Scapulae \- Short, broad clavicles \- Pectus excavatum \- Pectus carinatum \- Short, broad ribs ABDOMEN Gastrointestinal \- Chronic diarrhea \- Hiatal hernia GENITOURINARY Kidneys \- Hydronephrosis Ureters \- Ureteral obstruction Bladder \- Bladder diverticula \- Bladder rupture SKELETAL \- Joint laxity \- Osteoporosis Skull \- Occipital horn exostoses Spine \- Kyphosis \- Mild platyspondyly Pelvis \- Coxa valga \- Pelvic exostoses Limbs \- Short humeri \- Genu valgum \- Limited elbow extension \- Limited knee extension Hands \- Capitate-hamate fusion Feet \- Pes planus SKIN, NAILS, & HAIR Skin \- Soft skin \- Mildly extensible skin \- Loose, redundant skin \- Easy bruisability Hair \- Coarse hair NEUROLOGIC Central Nervous System \- Low-normal IQ NEOPLASIA \- Bladder carcinoma LABORATORY ABNORMALITIES \- Decreased serum copper \- Decreased ceruloplasmin MOLECULAR BASIS \- Caused by mutation in the ATPase, Cu++ transporting, alpha polypeptide gene (ATP7A, 300011.0002 ) ▲ 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 inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors	OCCIPITAL HORN SYNDROME	c0268353	1,883	omim	https://www.omim.org/entry/304150	2019-09-22T16:18:28	{"doid": ["0111272"], "mesh": ["C537860"], "omim": ["304150"], "orphanet": ["198"], "synonyms": ["Alternative titles", "CUTIS LAXA, X-LINKED, FORMERLY", "EHLERS-DANLOS SYNDROME, OCCIPITAL HORN TYPE, FORMERLY", "EDS IX, FORMERLY", "EDS9, FORMERLY"], "genereviews": ["NBK1413"]}
Supracondylar humerus fracture An elbow X-ray showing a displaced supracondylar fracture in a young child SpecialtyOrthopedic A supracondylar humerus fracture is a fracture of the distal humerus just above the elbow joint. The fracture is usually transverse or oblique and above the medial and lateral condyles and epicondyles. This fracture pattern is relatively rare in adults, but is the most common type of elbow fracture in children. In children, many of these fractures are non-displaced and can be treated with casting. Some are angulated or displaced and are best treated with surgery. In children, most of these fractures can be treated effectively with expectation for full recovery.[1] Some of these injuries can be complicated by poor healing or by associated blood vessel or nerve injuries with serious complications. ## Contents * 1 Signs and symptoms * 1.1 Complications * 1.1.1 Volkmann's contracture * 1.1.2 Malunion * 2 Mechanism * 3 Diagnosis * 3.1 X-rays * 3.1.1 Anterior X-ray * 3.1.2 Lateral X-ray * 3.2 Classification * 4 Management * 4.1 Gartland type I * 4.2 Gartland type II * 4.3 Gartland type III and IV * 4.4 Percutaneous pinning * 4.5 Follow up * 4.6 Neurovascular complications * 5 Epidemiology * 6 References * 7 Bibliography * 8 External links ## Signs and symptoms[edit] A child will complain of pain and swelling over the elbow immediately post trauma with loss of function of affected upper limb. Late onset of pain (hours after injury) could be due to muscle ischaemia (reduced oxygen supply). This can lead to loss of muscle function.[2] It is important to check for viability of the affected limb post trauma. Clinical parameters such as temperature of the limb extremities (warm or cold), capillary refilling time, oxygen saturation of the affected limb, presence of distal pulses (radial and ulnar pulses), assessment of peripheral nerves (radial, median, and ulnar nerves), and any wounds which would indicate open fracture. Doppler ultrasonography should be performed to ascertain blood flow of the affected limb if the distal pulses are not palpable. Anterior interosseus branch of the median nerve most often injured in postero-lateral displacement of the distal humerus as the proximal fragment is displaced antero-medially. This is evidenced by the weakness of the hand with a weak "OK" sign on physical examination (Unable to do an "OK" sign; instead a pincer grasp is performed). Radial nerve would be injured if the distal humerus is displaced postero-medially. This is because the proximal fragment will be displaced antero-laterally. Ulnar nerve is most commonly injured in the flexion type of injury because it crosses the elbow below the medial epidcondyle of the humerus.[2] A puckered, dimple, or an ecchymosis of the skin just anterior to the distal humerus is a sign of difficult reduction because the proximal fragment may have already penetrated the brachialis muscle and the subcutaneous layer of the skin.[2] ### Complications[edit] #### Volkmann's contracture[edit] Main article: Volkmann's contracture Swelling and vascular injury following the fracture can lead to the development of the compartment syndrome which leads to long-term complication of Volkmann's contracture (fixed flexion of the elbow, pronation of the forearm, flexion at the wrist, and joint extension of the metacarpophalangeal joint ). Therefore, early surgical reduction is indicated to prevent this type of complication.[2] #### Malunion[edit] The distal humerus grows slowly post fracture (only contributes 10 to 20% of the longitudinal growth of the humerus), therefore, there is a high rate of malunion if the supracondylar fracture is not corrected appropriately. Such malunion can result in cubitus varus deformity.[citation needed] ## Mechanism[edit] Extension type of supracondylar humerus fractures typically result from a fall on to an outstretched hand, usually leading to a forced hyperextension of the elbow. The olecranon acts as a fulcrum which focuses the stress on distal humerus (supracondylar area), predisposing the distal humerus to fracture. The supracondylar area undergoes remodeling at the age of 6 to 7, making this area thin and prone to fractures. Important arteries and nerves (median nerve, radial nerve, brachial artery, and ulnar nerve) are located at the supracondylar area and can give rise to complications if these structures are injured. Most vulnerable structure to get damaged is Median Nerve.[2] Meanwhile, the flexion-type of supracondylar humerus fracture is less common. It occurs by falling on the point of the elbow, or falling with the arm twisted behind the back. This causes anterior dislocation of the proximal fragment of the humerus.[3] ## Diagnosis[edit] * There is pain and swelling about the elbow. Bleeding at the fracture results in a large effusion in the elbow joint.[citation needed] * Depending on the fracture displacement, there may be deformity. With severe displacement, there may be an anterior dimple from the proximal bone end trapped within the biceps muscle. * The skin is usually intact. If there is a laceration that communicates with the fracture site, it is an open fracture, which increases infection risk. For fractures with significant displacement, the bone end can be trapped within the biceps muscle with resulting tension producing an indentation to the skin, which is called a "pucker sign".[citation needed] * The vascular status must be assessed, including the warmth and perfusion of the hand, the time for capillary refill, and the presence of a palpable radial pulse. Limb vascular status is categorized as "normal," "pulseless with a (warm, pink) perfused hand," or "pulseless–pale (nonperfused)" (see "neurovascular complications" below). * The neurologic status must be assessed including the sensory and motor function of the radial, ulnar, and median nerves (see "neurovascular complications" below). Neurologic deficits are found in 10-20% of patients.[4] The mostly commonly injured nerve is the median nerve (specifically, the anterior interosseous portion of the median nerve). Injuries to the ulnar and radial nerves are less common. ### X-rays[edit] Diagnosis is confirmed by x-ray imaging. Antero-posterior (AP) and lateral view of the elbow joint should be obtained. Any other sites of pain, deformity, or tenderness should warrant an X-ray for that area too. X-ray of the forearm (AP and lateral) should also be obtained for because of the common association of supracondylar fractures with the fractures of the forearm. Ideally, splintage should be used to immobilise the elbow at 20 to 30 degrees flexion in order to prevent further injury of the blood vessels and nerves while doing X-rays. Splinting of fracture site with full flexion or extension of the elbow is not recommended as it can stretch the blood vessels and nerves over the bone fragments or can cause impingement of these structures into the fracture site.[2] Depending on the child's age, parts of the bone will still be developing and if not yet calcified, will not show up on the X-rays. The capitulum of the humerus is the first to ossify at the age of one year. Head of radius and medial epicondyle of the humerus starts to ossify at 4 to 5 years of age, followed by trochlea of humerus and olecranon of the ulna at 8 to 9 years of age, and lateral epicondyle of the humerus to ossify at 10 years of age.[2] #### Anterior X-ray[edit] Baumann's Angle Carrying angle can be evaluated through AP view of the elbow by looking at the Baumann’s angle.[2] There are two definitions of Bowmann's angle: The first definition of Baumann's angle is an angle between a line parallel to the longitudinal axis of the humeral shaft and a line drawn along the lateral epicondyle. The normal range is 70-75 degrees. Every 5 degrees change in Bowmann's angle can lead to 2 degrees change in carrying angle.[5] Another definition of Baumann's angle is also known as the humeral-capitellar angle. It is the angle between the line perpendicular to the long axis of the humerus and the growth plate of the lateral condyle. Reported normal values for Baumann's angle range between 9 and 26°.[6] An angle of more than 10° is regarded as acceptable.[6] #### Lateral X-ray[edit] On lateral view of the elbow, there are five radiological features should be looked for: tear drop sign, anterior humeral line, coronoid line, fish-tail sign, and fat pad sign/sail sign (anterior and posterior).[2][7] Tear drop sign \- Tear drop sign is seen on a normal radiograph, but is disturbed in supracondylar fracture.[7] Anterior humeral line \- It is a line drawn down along the front of the humerus on the lateral view and it should pass through the middle third of the capitulum of the humerus.[8] If it passes through the anterior third of the capitulum, it indicates the posterior displacement of distal fragment.[7] Fat pad sign/sail sign \- A non-displaced fracture can be difficult to identify and a fracture line may not be visible on the X-rays. However, the presence of a joint effusion is helpful in identifying a non-displaced fracture. Bleeding from the fracture expands the joint capsule and is visualized on the lateral view as a darker area anteriorly and posteriorly, and is known as the sail sign.[7] Coronoid line \- A line drawn along the anterior border of the coronoid process of the ulna should touch the anterior part of the lateral condyle of the humerus. If lateral condyle appears posterior to this line, it indicates the posterior displacement of lateral condyle.[7] Fish-tail sign \- The distal fragment is rotated away from the proximal fragment, thus the sharp ends of the proximal fragment looks like a shape of a fish-tail.[7] * Anterior and posterior sail sign in a child who has a subtle supracondylar fracture * Anterior humeral line (black line), with normal area passed on the capitulum of the humerus colored in green in a 4 year old child.[8] * The anterior humeral line is not reliable in children with sparse ossification of the capitulum, such as in this 6 months old child.[8] ### Classification[edit] Main article: Gartland classification Supracondylar fractures: Gartland classification Type Description[2] I Non-displaced II Angulated with intact posterior cortex IIA Angulation IIB Angulation with rotation III Complete displacement but have perisosteal (medial/lateral) contact IIIA Medial periosteal hinge intact. Distal fragment goes posteromedially IIIB Lateral periosteal hinge intact. Distal fragment goes posterolaterally IV Periostial disruption with instability in both flexion and extension ## Management[edit] ### Gartland type I[edit] Undisplaced or minimally displaced fractures can be treated by using an above elbow splint in 90 degrees flexion for 3 weeks. Orthopaedic cast and extreme flexion should be avoided to prevent compartment syndrome and vascular compromise. In case the varus of the fracture site is more than 10 degrees when compared to the normal elbow, closed reduction and percutaneous pinning using X-ray image intensifier inside operating theater is recommended. In one study, for those children who was done percutaneous pinning, immobilisation using a posterior splint and an arm sling has earlier resumption of activity when compared to immobilisation using collar and cuff sling. Both methods gives similar pain scores and activity level at two weeks of treatment.[2] ### Gartland type II[edit] Gartland Type II fractures requires closed reduction and casting at 90 degrees flexion. Percutaneous pinning is required if more than 90 degrees flexion is required to maintain the reduction. Closed reduction with percutaneous pinning has low complication rates. Closed reduction can be done by applying traction along the long axis of the humerus with elbow in slight flexion. Full extension of the elbow is not recommended because the neurovascular structures can hook around the proximal fragment of the humerus. If the proximal humerus is suspected to have pierced the brachialis muscle, gradual traction over the proximal humerus should be given instead. After that, reduction can be done through hyperflexion of the elbow can be done with the olecranon pushing anteriorly. If the distal fragment is internally rotated, reduction maneuver can be applied with extra stress applied over medial elbow with pronation of the forearm at the same time.[2] ### Gartland type III and IV[edit] Gartland III and IV are unstable and prone to neurovascular injury. Therefore, closed or open reduction together with percutaneous pinning within 24 hours is the preferred method of management with low complication rates. Straight arm lateral traction can be a safe method to deal with Gartland Type III fractures. Although Gartland Type III fractures with posteromedial displacement of distal fragment can be reduced with closed reduction and casting, those with posterolateral displacement should preferably be fixed by percutaneous pinning.[2] ### Percutaneous pinning[edit] Percutaneous pinning are usually inserted over the medial or lateral sides of the elbow under X-ray image intensifier guidance. There is 1.8 times higher risk of getting nerve injury when inserting both medial and lateral pins compared to lateral pin insertion alone. However, medial and lateral pins insertions are able to stabilise the fractures more properly than lateral pins alone. Therefore, medial and lateral pins insertion should be done with care to prevent nerve injuries around elbow region.[2] Percutaneous pinning should be done when close manipulation fails to achieve the reduction, unstable fracture after closed reduction, neurological deficits occurs during or after the manipulation of fracture, and surgical exploration is required to determine the integrity of the blood vessels and nerves. In open fractures, surgical wound debridement should be performed to prevent any infection into the elbow joint. All Type II and III fractures requiring elbow flexion of more than 90° to maintain the reduction needs to be fixed by percutaneous pinning. All Type IV fractures of supracondylar humerus are unstable; therefore, requires percutaneous pinning. Besides, any polytrauma with multiple fractures of the same side requiring surgical intervention is another indication for percutaneous pinning.[2] ### Follow up[edit] For routine displaced supracondylar fractures requiring percutaneous pinning, radiographic evaluation and clinical assessment can be delayed until the pin removal. Pins are only removed when there is no tenderness over the elbow region at 3 to 4 weeks. After pin removal, mobilisation of the elbow can begin.[2] ### Neurovascular complications[edit] Absence of radial pulse is reported in 6 to 20% of the supracondylar fracture cases. This is because brachial artery is frequently injured in Gartland Type II and Type III fractures, especially when the distal fragment is displaced postero-laterally (proximal fragment displaced antero-medially). Open/closed reduction with percutaneous pinning would the first line of management. However, if there is no improvement of pulse after the reduction, surgical exploration of brachial artery and nerves is indicated, especially when there is persistent pain at the fracture site (indicating limb ischaemia), neurological deficits (paresthesia, tingling, numbness), and additional signs of poor perfusion (prolonged capillary refilling time, and bluish discolouration of the fingers).[2] Meanwhile, for pink, pulseless hand (absent radial pulse but with good perfusion at extremities) after successful reduction and percutaneous pinning, the patient could still be observed until additional signs of ischaemia develops which warrants a surgical exploration.[9] Isolated neurological deficits occurred in 10 to 20% of the cases and can reach as high as 49% in Type III Gartland fractures. Neurapraxia (temporary neurological deficits due to blockage of nerve conduction) is the most common cause of the neurological deficits in supracondylar fractures. Such neurological deficits would resolve in two or three months. However, if the neurology is not resolved for this time frame, surgical exploration is indicated.[2] ## Epidemiology[edit] Supracondylar humerus fractures is commonly found in children between 5 and 7 years (90% of the cases), after the clavicle and forearm fractures. It is more often occurs in males, accounting of 16% of all pediatric fractures and 60% of all paediatric elbow fractures. The mechanism of injury is most commonly due to fall on an outstretch hand.[2] Extension type of injury (70% of all elbow fractures) is more common than the flexion type of injury (1% to 11% of all elbow injuries).[3] Injury often occurs on the non-dominant part of the limb. Flexion type of injury is more commonly found in older children. Open fractures can occur for up to 30% of the cases.[2] ## References[edit] 1. ^ "OrthoKids - Elbow Fractures". orthokids.org. Retrieved 2017-08-24. 2. ^ a b c d e f g h i j k l m n o p q r s t Vineet, Kumar; Ajai, Singh (1 December 2016). "Fracture Supracondylar Humerus: A Review". Journal of Clinical and Diagnostic Research. 10 (12): 1–6. doi:10.7860/JCDR/2016/21647.8942. PMC 5296534. PMID 28208961. 3. ^ a b Eira, Kuoppala; Roope, Parvianien; Tytti, Pokka; Minna, Serlo; Juha-Jaakko, Sinikumpu (11 May 2016). "Low incidence of flexion-type supracondylar humerus fractures but high rate of complications". Acta Orthopedica. 87 (4): 406–411. doi:10.1080/17453674.2016.1176825. PMC 4967285. PMID 27168001. 4. ^ Terry Canale, S.; Azar, Frederick M.; Beaty, James H. (2016-11-21). Campbell's operative orthopaedics. Azar, Frederick M.,, Canale, S. T. (S. Terry),, Beaty, James H.,, Preceded by: Campbell, Willis C. (Willis Cohoon), 1880-1941. (Thirteenth ed.). Philadelphia, PA. ISBN 978-0323374620. OCLC 962333989. 5. ^ Ravi Kumar, Biradar; Sharik Afsar, Khan (2017). "Intraoperative assessment of Baumann's angle and carrying angles are very good prognostic predictors in the treatment of type III supracondylar humerus fractures in children" (PDF). Al Ameen Journal of Medical Sciences. 10 (1): 64–70. Retrieved 15 April 2018. 6. ^ a b Page 1405 in: S. Terry Canale, James H. Beaty (2012). Campbell's Operative Orthopaedics (12 ed.). Elsevier Health Sciences. ISBN 9780323087186. 7. ^ a b c d e f John, Ebnezar; Rakesh, John (31 December 2016). Textbook of orthopaedics. JP Medical Ltd. p. 135. ISBN 9789386056689. Retrieved 15 April 2018. 8. ^ a b c Kilborn, Tracy; Moodley, Halvani; Mears, Stewart (2015). "Elbow your way into reporting paediatric elbow fractures – A simple approach". South African Journal of Radiology. 19 (2). doi:10.4102/sajr.v19i2.881. ISSN 2078-6778. 9. ^ Griffin, K.J.; Walsh, S.R.; Markar, S.; Tang, T.Y.; Boyle, J.R.; Hayes, P.D. (2008). "The Pink Pulseless Hand: A Review of the Literature Regarding Management of Vascular Complications of Supracondylar Humeral Fractures in Children". European Journal of Vascular and Endovascular Surgery. 36 (6): 697–702. doi:10.1016/j.ejvs.2008.08.013. PMID 18851922. ## Bibliography[edit] * De Pellegrin, M.; Fracassetti, D; Moharamzadeh, D; Origo, C; Catena, N. "Advantages and disadvantages of the prone position in the surgical treatment of supracondylar humerus fractures in children. A literature review". Injury. doi:10.1016/j.injury.2018.09.046. PMID 30286976. ## External links[edit] Classification D * ICD-10: S42.4 External resources * AO Foundation: 13-A2.3 * 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 inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors	Supracondylar humerus fracture	c0347788	1,884	wikipedia	https://en.wikipedia.org/wiki/Supracondylar_humerus_fracture	2021-01-18T19:08:00	{"umls": ["C0347788"], "icd-9": ["812.51", "812.41"], "icd-10": ["S42.4"], "wikidata": ["Q7644671"]}
Multifocal motor neuropathy (MMN) is a rare neuropathy characterized by progressive, asymmetric muscle weakness and atrophy (wasting). Signs and symptoms may include weakness in the hands and lower arms; cramping; involuntary contractions or twitching; wrist drop or foot drop, and atrophy of affected muscles. MMN is thought to be due to an abnormal immune response, but the underlying cause is not clear. Most people treated with intravenous immune globulin (IVIG) have rapid improvement in weakness, but maintenance IVIG is usually required for sustained improvement. Cyclophosphamide has also been effective in treating MMN. Physical and occupational therapy may be helpful for some people with MMN. [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 inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors	Multifocal motor neuropathy	c0393847	1,885	gard	https://rarediseases.info.nih.gov/diseases/11011/multifocal-motor-neuropathy	2021-01-18T17:58:55	{"orphanet": ["641"], "synonyms": ["MMN", "MMNCB", "Multifocal motor neuropathy with conduction block"]}
Dicarboxylic aminoaciduria is a rare metabolic disorder characterized by the excessive loss of aspartate and glutamate in urine. Symptoms have varied greatly among the few reported cases. Dicarboxylic aminoaciduria is caused by mutations in the SLC1A1 gene. It is inherited in an autosomal recessive fashion. [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 inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors	Dicarboxylic aminoaciduria	c1857253	1,886	gard	https://rarediseases.info.nih.gov/diseases/1855/dicarboxylic-aminoaciduria	2021-01-18T18:00:53	{"mesh": ["C536171"], "omim": ["222730"], "umls": ["C1857253"], "orphanet": ["2195"], "synonyms": ["Glutamate-aspartate transport defect", "Dicarboxylicaminoaciduria"]}
This article includes a list of general references, but it remains largely unverified because it lacks sufficient corresponding inline citations. Please help to improve this article by introducing more precise citations. (December 2015) (Learn how and when to remove this template message) Adams–Oliver syndrome Other namesCongenital scalp defects with distal limb anomalies[1] SpecialtyPediatrics, dermatology, orthopedic surgery Adams–Oliver syndrome (AOS) is a rare congenital disorder characterized by defects of the scalp and cranium (cutis aplasia congenita), transverse defects of the limbs, and mottling of the skin. ## Contents * 1 Signs and symptoms * 2 Genetics * 3 Mechanism * 4 Diagnosis * 5 Management * 6 Prognosis * 7 Epidemiology * 8 History * 9 Citations * 10 References * 11 External links ## Signs and symptoms[edit] Two key features of AOS are aplasia cutis congenita with or without underlying bony defects and terminal transverse limb defects.[2] Cutis aplasia congenita is defined as missing skin over any area of the body at birth; in AOS skin aplasia occurs at the vertex of the skull. The size of the lesion is variable and may range from solitary round hairless patches to complete exposure of the cranial contents. There are also varying degrees of terminal limb defects (for example, shortened digits) of the upper extremities, lower extremities, or both. Individuals with AOS may have mild growth deficiency, with height in the low-normal percentiles. The skin is frequently observed to have a mottled appearance (cutis marmorata telangiectatica congenita). Other congenital anomalies, including cardiovascular malformations, cleft lip and/or palate, abnormal renal system, and neurologic disorders manifesting as seizure disorders and developmental delay are sometimes observed. Variable defects in blood vessels have been described, including hypoplastic aortic arch, middle cerebral artery, pulmonary arteries. Other vascular abnormalities described in AOS include absent portal vein, portal sclerosis, arteriovenous malformations, abnormal umbilical veins, and dilated renal veins.[citation needed] ## Genetics[edit] AOS was initially described as having autosomal dominant inheritance due to the reports of families with multiple affected family members in more than one generation.[3] The severity of the condition can vary between family members, suggestive of variable expressivity and reduced penetrance of the disease-causing allele. Subsequently, it was reported that some cases of AOS appear to have autosomal recessive inheritance, perhaps with somewhat more severe phenotypic effects.[citation needed] Six AOS genes have been identified: ARHGAP31,[4] DOCK6,[5] RBPJ,[6] EOGT,[7][8] NOTCH1,[9][10] and DLL4.[11] ARHGAP31 and DOCK6 are both regulatory proteins that control members of the Rho family of GTPases and specifically regulate the activity of Cdc42 and Rac1. Autosomal dominant mutations in ARHGAP31 (a GTPase-activating protein) and autosomal recessive mutations in DOCK6 (a guanine nucleotide exchange factor) cause an accumulation of the inactive GTPase and lead to defects of the cytoskeleton.[citation needed] RBPJ, EOGT, NOTCH1 and DLL4 are all involved in the Notch signalling pathway. Mutations in EOGT are found in AOS with autosomal recessive inheritance;[7] the other three genes account for cases with autosomal dominant inheritance. ## Mechanism[edit] The precise mechanism underlying the congenital abnormalities observed in AOS is unknown. Similar terminal transverse limb anomalies and cardiovascular malformations are seen in animal models of hypoxic insults during the first trimester.[12][13] Combined with the common association of cardiac and vascular abnormalities in AOS, it has been hypothesized that the spectrum of defects observed in AOS could be due to a disorder of vasculogenesis.[citation needed] In rare cases, AOS can be associated with chromosomal translocations. A panel of candidate genes (including ALX4, ALX1, MSX1, MSX2, P63, RUNX2 and HOXD13) were tested but no disease-causing mutations were identified.[14][15] More recently, mutations in six genes have been identified, highlighting the Rho family of GTPases and the Notch signalling pathway as important factors in the pathogenesis of AOS.[citation needed] ## Diagnosis[edit] The diagnosis of AOS is a clinical diagnosis based on the specific features described above. A system of major and minor criteria was proposed.[16] Major features Minor features Terminal transverse limb defects Cutis marmorata Aplasia cutis congenita Congenital heart defect Family history of AOS Vascular anomaly The combination of two major criteria would be sufficient for the diagnosis of AOS, while a combination of one major and one minor feature would be suggestive of AOS. Genetic testing can be performed to test for the presence of mutation in one of the known genes, but these so far only account for an estimated 50% of patients with AOS. A definitive diagnosis may therefore not be achieved in all cases.[citation needed] ## Management[edit] Management of AOS is largely symptomatic and aimed at treating the various congenital anomalies present in the individual. When the scalp and/or cranial bone defects are severe, early surgical intervention with grafting is indicated.[citation needed] ## Prognosis[edit] The overall prognosis is excellent in most cases. Most children with Adams–Oliver syndrome can likely expect to have a normal life span. However, individuals with more severe scalp and cranial defects may experience complications such as hemorrhage and meningitis, leading to long-term disability.[citation needed] ## Epidemiology[edit] AOS is a rare genetic disorder and the annual incidence or overall prevalence of AOS is unknown. Approximately 100 individuals with this disorder have been reported in the medical literature. ## History[edit] AOS was first reported by the American pediatric cardiologist Forrest H. Adams and the clinical geneticist Clarence Paul Oliver in a family with eight affected members.[3] ## Citations[edit] 1. ^ RESERVED, INSERM US14-- ALL RIGHTS. "Orphanet: Adams Oliver syndrome". www.orpha.net. Retrieved 16 May 2019. 2. ^ Mašek, Jan; Andersson, Emma R. (2017-05-15). "The developmental biology of genetic Notch disorders". Development. 144 (10): 1743–1763. doi:10.1242/dev.148007. ISSN 0950-1991. PMID 28512196. 3. ^ a b Adams, Forrest H.; Oliver, C. P. (1945-01-01). "HEREDITARY DEFORMITIES IN MAN Due to Arrested Development". Journal of Heredity. 36 (1): 3–7. doi:10.1093/oxfordjournals.jhered.a105415. ISSN 0022-1503. 4. ^ Southgate, Laura; Machado, Rajiv D.; Snape, Katie M.; Primeau, Martin; Dafou, Dimitra; Ruddy, Deborah M.; Branney, Peter A.; Fisher, Malcolm; Lee, Grace J. (2011-05-13). "Gain-of-function mutations of ARHGAP31, a Cdc42/Rac1 GTPase regulator, cause syndromic cutis aplasia and limb anomalies". American Journal of Human Genetics. 88 (5): 574–585. doi:10.1016/j.ajhg.2011.04.013. ISSN 1537-6605. PMC 3146732. PMID 21565291. 5. ^ Shaheen, Ranad; Faqeih, Eissa; Sunker, Asma; Morsy, Heba; Al-Sheddi, Tarfa; Shamseldin, Hanan E.; Adly, Nouran; Hashem, Mais; Alkuraya, Fowzan S. (2011-08-12). "Recessive mutations in DOCK6, encoding the guanidine nucleotide exchange factor DOCK6, lead to abnormal actin cytoskeleton organization and Adams-Oliver syndrome". American Journal of Human Genetics. 89 (2): 328–333. doi:10.1016/j.ajhg.2011.07.009. ISSN 1537-6605. PMC 3155174. PMID 21820096. 6. ^ Hassed, Susan J.; Wiley, Graham B.; Wang, Shaofeng; Lee, Ji-Yun; Li, Shibo; Xu, Weihong; Zhao, Zhizhuang J.; Mulvihill, John J.; Robertson, James (2012-08-10). "RBPJ mutations identified in two families affected by Adams-Oliver syndrome". American Journal of Human Genetics. 91 (2): 391–395. doi:10.1016/j.ajhg.2012.07.005. ISSN 1537-6605. PMC 3415535. PMID 22883147. 7. ^ a b Shaheen, Ranad; Aglan, Mona; Keppler-Noreuil, Kim; Faqeih, Eissa; Ansari, Shinu; Horton, Kim; Ashour, Adel; Zaki, Maha S.; Al-Zahrani, Fatema (2013-04-04). "Mutations in EOGT confirm the genetic heterogeneity of autosomal-recessive Adams-Oliver syndrome". American Journal of Human Genetics. 92 (4): 598–604. doi:10.1016/j.ajhg.2013.02.012. ISSN 1537-6605. PMC 3617382. PMID 23522784. 8. ^ Cohen, Idan; Silberstein, Eldad; Perez, Yonatan; Landau, Daniella; Elbedour, Khalil; Langer, Yshaia; Kadir, Rotem; Volodarsky, Michael; Sivan, Sara (2014-03-01). "Autosomal recessive Adams-Oliver syndrome caused by homozygous mutation in EOGT, encoding an EGF domain-specific O-GlcNAc transferase". European Journal of Human Genetics. 22 (3): 374–378. doi:10.1038/ejhg.2013.159. ISSN 1476-5438. PMC 3925282. PMID 23860037. 9. ^ Stittrich, Anna-Barbara; Lehman, Anna; Bodian, Dale L.; Ashworth, Justin; Zong, Zheyuan; Li, Hong; Lam, Patricia; Khromykh, Alina; Iyer, Ramaswamy K. (2014-09-04). "Mutations in NOTCH1 cause Adams-Oliver syndrome". American Journal of Human Genetics. 95 (3): 275–284. doi:10.1016/j.ajhg.2014.07.011. ISSN 1537-6605. PMC 4157158. PMID 25132448. 10. ^ Southgate, Laura; Sukalo, Maja; Karountzos, Anastasios S. V.; Taylor, Edward J.; Collinson, Claire S.; Ruddy, Deborah; Snape, Katie M.; Dallapiccola, Bruno; Tolmie, John L. (2015-08-01). "Haploinsufficiency of the NOTCH1 Receptor as a Cause of Adams-Oliver Syndrome With Variable Cardiac Anomalies". Circulation: Cardiovascular Genetics. 8 (4): 572–581. doi:10.1161/CIRCGENETICS.115.001086. ISSN 1942-3268. PMC 4545518. PMID 25963545. 11. ^ Meester, Josephina A. N.; Southgate, Laura; Stittrich, Anna-Barbara; Venselaar, Hanka; Beekmans, Sander J. A.; den Hollander, Nicolette; Bijlsma, Emilia K.; Helderman-van den Enden, Appolonia; Verheij, Joke B. G. M. (2015-09-03). "Heterozygous Loss-of-Function Mutations in DLL4 Cause Adams-Oliver Syndrome". American Journal of Human Genetics. 97 (3): 475–482. doi:10.1016/j.ajhg.2015.07.015. ISSN 1537-6605. PMC 4564989. PMID 26299364. 12. ^ Webster, William S.; Abela, Dominique (2007-09-01). "The effect of hypoxia in development". Birth Defects Research Part C: Embryo Today: Reviews. 81 (3): 215–228. doi:10.1002/bdrc.20102. ISSN 1542-975X. PMID 17963271. 13. ^ Ghatpande, Satish K.; Billington, Charles J.; Rivkees, Scott A.; Wendler, Christopher C. (2008-03-01). "Hypoxia induces cardiac malformations via A1 adenosine receptor activation in chicken embryos". Birth Defects Research. Part A, Clinical and Molecular Teratology. 82 (3): 121–130. doi:10.1002/bdra.20438. ISSN 1542-0760. PMC 3752680. PMID 18186126. 14. ^ Verdyck, Pieter; Holder-Espinasse, Muriel; Hul, Wim Van; Wuyts, Wim (2003-06-01). "Clinical and molecular analysis of nine families with Adams-Oliver syndrome". European Journal of Human Genetics. 11 (6): 457–463. doi:10.1038/sj.ejhg.5200980. ISSN 1018-4813. PMID 12774039. 15. ^ Verdyck, P.; Blaumeiser, B.; Holder-Espinasse, M.; Van Hul, W.; Wuyts, W. (2006-01-01). "Adams-Oliver syndrome: clinical description of a four-generation family and exclusion of five candidate genes". Clinical Genetics. 69 (1): 86–92. doi:10.1111/j.1399-0004.2006.00552.x. ISSN 0009-9163. PMID 16451141. S2CID 29732072. 16. ^ Snape, Katie M. G.; Ruddy, Deborah; Zenker, Martin; Wuyts, Wim; Whiteford, Margo; Johnson, Diana; Lam, Wayne; Trembath, Richard C. (2009-08-01). "The spectra of clinical phenotypes in aplasia cutis congenita and terminal transverse limb defects". American Journal of Medical Genetics Part A. 149A (8): 1860–1881. doi:10.1002/ajmg.a.32708. ISSN 1552-4833. PMID 19610107. S2CID 36061071. ## References[edit] Jones, Kenneth L (1997). Smith's Recognizable Patterns of Human Malformation (5th ed.). Saunders. ISBN 0-7216-6115-7. James, William; Berger, Timothy; Elston, Dirk (2005). Andrews' Diseases of the Skin: Clinical Dermatology (10th ed.). Saunders. ISBN 0-7216-2921-0. Baskar S, Kulkarni ML, Kulkarni AM, Vittalrao S, Kulkarni PM (2009). "Adams–Oliver syndrome: Additions to the clinical features and possible role of BMP pathway". Am J Med Genet A. 149 (8): 1678–1684. doi:10.1002/ajmg.a.32938. PMID 19606482. S2CID 205311375. Bonafede RP, Beighton P (1979). "Autosomal dominant inheritance of scalp defects with ectrodactyly". Am J Med Genet. 3 (1): 35–41. doi:10.1002/ajmg.1320030109. PMID 474617. Maniscalco M, Zedda A, Faraone S, de Laurentiis G, Verde R, Molese V, Lapiccirella G, Sofia M (2005). "Association of Adams–Oliver syndrome with pulmonary arterio-venous malformation in the same family: a further support to the vascular hypothesis". Am J Med Genet A. 136 (3): 269–274. doi:10.1002/ajmg.a.30828. PMID 15948197. S2CID 3093562. McGoey RR, Lacassie Y (2008). "Adams–Oliver syndrome in siblings with central nervous system findings, epilepsy, and developmental delay: refining the features of a severe autosomal recessive variant". Am J Med Genet A. 146 (4): 488–491. doi:10.1002/ajmg.a.32163. PMID 18203152. S2CID 205308934. Whitley CB, Gorlin RJ (1991). "Adams–Oliver syndrome revisited". Am J Med Genet. 40 (3): 319–326. doi:10.1002/ajmg.1320400315. PMID 1951437. Zapata HH, Sletten LJ, Pierpont ME (1995). "Congenital cardiac malformations in Adams–Oliver syndrome". Clin Genet. 47 (2): 80–84. doi:10.1111/j.1399-0004.1995.tb03928.x. PMID 7606848. S2CID 13643644. ## External links[edit] Classification D * ICD-10: Q87.2 * OMIM: 100300 * MeSH: C538225 * DiseasesDB: 32741 External resources * Orphanet: 974 [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 inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors	Adams–Oliver syndrome	c0265268	1,887	wikipedia	https://en.wikipedia.org/wiki/Adams%E2%80%93Oliver_syndrome	2021-01-18T18:38:58	{"gard": ["5739"], "mesh": ["C538225"], "umls": ["C0265268"], "orphanet": ["974"], "wikidata": ["Q351708"]}
A slow virus is a virus, or a viruslike agent, etiologically associated with a slow virus disease. A slow virus disease is a disease that, after an extended period of latency, follows a slow, progressive course spanning months to years, frequently involves the central nervous system, and in most cases progresses to death. Examples of slow virus diseases include HIV/AIDS, caused by the HIV virus,[1] subacute sclerosing panencephalitis, the rare result of a measles virus infection,[2] and Paget's disease of bone (osteitis deformans), which seems to be associated with paramyxoviruses, especially the measles virus and the human respiratory syncytial virus.[3] ## Contents * 1 Characteristics * 2 Some examples of viral agents * 3 Prions: "atypical slow viruses" * 3.1 Cause * 3.2 Disease presentation * 3.3 Some examples of prion diseases * 4 See also * 5 References ## Characteristics[edit] Every infectious agent is different, but in general, slow viruses:[4] * Cause an asymptomatic primary infection * Have a long incubation period ranging from months to years * Follow a slow but relentless progressive course leading to death * Tend to have a genetic predisposition * Often re-emerge from latency if the host becomes immuno-compromised Additionally, the immune system seems to plays a limited role, or no role, in protection from many of these slow viruses. This may be due to the slow replication rates some of these agents exhibit,[5] preexisting immunosuppression (as in the cases of JC virus and BK virus),[6] or, in the case of prions, the identity of the agent involved.[7] ## Some examples of viral agents[edit] Virus Virus family Disease Typical latency Transmitted by JC virus Polyomavirus Progressive multifocal leukoencephalopathy Years to Life§ Unknown; possibly contaminated water[6] BK virus Polyomavirus BK nephropathy Years to life§ Unknown; possibly respiratory spread/urine; possibly contaminated water[6] Measles virus Paramyxovirus Subacute sclerosing panencephalitis 1–10 years Respiratory droplets[8] Rubella virus Togaviridae Progressive rubella panencephalitis 10–20 years Respiratory droplets[9] Rabies virus Rhabdoviridae Rabies 3–12 weeks Bite of an infected animal[10] §JC virus & BK virus only cause disease in immunocompromised patients ## Prions: "atypical slow viruses"[edit] Transmissible spongiform encephalopathies (TSEs), including kuru and Creutzfeldt–Jakob disease of humans, scrapie of sheep, and bovine spongiform encephalopathy (BSE) of cattle, were previously classified as slow virus diseases. However, TSEs are more correctly classified as prion diseases. Prions are misfolded proteins that are "infectious" because they can induce misfolding in other previously normal proteins; however, they do not contain DNA or RNA so they cannot be classified as viruses.[11] Before scientists knew the cause of spongiform encephalopathies, they hypothesized that small virus particles, which they termed virions, were to blame. Once it was discovered that prions were the real cause of TSEs and that prions contained no nucleic acid, the term virions was discarded and these particles were renamed prions. A minority of researchers still believe, however, that prion diseases are caused by an as-yet unidentified slow virus, although there is little evidence to support this finding, as Ma and colleagues have created a recombinant prion protein.[12] Prions are so named because they appear to contain only protein.[13] No evidence of nucleic acid has been found in any prion particle studied. Treatments that destroy protein, like denaturation, destroy prion infectivity, but treatments that destroy nucleic acids, like UV radiation, do not destroy prion infectivity. The prion protein is known as PrP and is a cell surface glycophosphatidylinositol(GPI)-anchored protein. Its normal function in the body is unknown, though presumably it serves, or served, some purpose because it is coded for by a host gene. The infectious form of PrP has the same amino acid sequence and the same post-translational modifications as the normal form, but it has a different tertiary conformation. The normal PrP contains many alpha-helices, whereas the disease-associated form contains many beta-pleated sheets. It is this conformational change from mostly alpha-helices to mostly beta-pleated sheets that gives the prion its infectious ability.[14] The disease-associated form of the prion protein is commonly referred to as PrPsc because it was first found in scrapie infections in sheep. The diseased form is also occasionally called PrPres because it is more resistant to protease than the normal, non-disease associated form. ### Cause[edit] In some cases, the cause of prion diseases is known. Ingestion of a copy of an abnormally folded, infectious PrP can induce a spongiform encephalopathy in the consumer. For example, kuru is passed through the ritual consumption of brain material in some tribal cultures, and bovine spongiform encephalopathy is thought to have developed from the use of prion-infected sheep protein in cattle feed. However, some cases of spongiform encephalopathies appear to be sporadic, and it is not known in these cases what causes the first prion protein to change its conformation and become infectious. Once one abnormal prion protein exists, however, it can induce the conformational change from predominantly α-helix to predominately β-pleated sheet in neighboring proteins. ### Disease presentation[edit] The clinical presentation of prion diseases will vary from patient to patient. However, some general characteristics of prion diseases are listed below. Prions: * cause diseases that are confined to the CNS * have a prolonged incubation period * follow a slow, progressive, fatal course of disease * produce a spongiform encephalopathy * characteristically result in vacuolation of neurons * can cause formation of fibrillar aggregates, which contain PrP and have amyloid-like characteristics[15] ### Some examples of prion diseases[edit] Disease Typical length of progression to death Species affected Kuru disease 30–50 years Humans[16] Fatal familial insomnia 8–75 months Humans[17] Bovine spongiform encephalopathy 1–3 years Cows, humans ## See also[edit] * Clinical latency * Virus latency ## References[edit] 1. ^ "About HIV/AIDS \| HIV Basics \| HIV/AIDS \| CDC". www.cdc.gov. 2019-02-28. Retrieved 2019-03-05. 2. ^ PubMed Health "Subacute Sclerosing Panencephalitis". Retrieved February 10, 2012. 3. ^ The Journal of Clinical Investigation "Paget's Disease of Bone". Retrieved February 2, 2018. 4. ^ Chapter 44 of Medical Microbiology by Warren Levinson "Slow Viruses & Prions". Retrieved February 2, 2018. 5. ^ The Journal of Virology "Underwhelming the Immune Response: Effect of Slow Virus Growth on CD8+-T-Lymphocyte Responses". Retrieved February 2, 2018. 6. ^ a b c The Journal of Infectious Disease "BK and JC virus: a review". Retrieved February 2, 2018. 7. ^ Viruses "Prion Disease and the Innate Immune System". Retrieved February 2, 2018. 8. ^ The Postgraduate Medical Journal "Subacute sclerosing panencephalitis". Retrieved February 2, 2018. 9. ^ Nihon Rinsho. Japanese Journal of Clinical Medicine "Progressive rubella panencephalitis". Retrieved February 2, 2018. 10. ^ Lancet Neurology "Human rabies: neuropathogenesis, diagnosis, and management.". Retrieved February 2, 2018. 11. ^ Centers for Disease Control and Prevention "Prion Diseases". Retrieved February 10, 2012 12. ^ Ma, Jiyan; Yuan, Chong-Gang; Wang, Xinhe; Wang, Fei (2010-02-26). "Generating a Prion with Bacterially Expressed Recombinant Prion Protein". Science. 327 (5969): 1132–1135. doi:10.1126/science.1183748. ISSN 0036-8075. PMC 2893558. PMID 20110469. 13. ^ Prusiner SB (1998). "Prions". Proc. Natl. Acad. Sci. U.S.A. 95 (23): 13363–83. doi:10.1073/pnas.95.23.13363. PMC 33918. PMID 9811807. 14. ^ Eghiaian F, Grosclaude J, Lesceu S, Debey P, Doublet B, Tréguer E, Rezaei H, Knossow M (2004). "Insight into the PrPC-->PrPSc conversion from the structures of antibody-bound ovine prion scrapie-susceptibility variants". Proc. Natl. Acad. Sci. U.S.A. 101 (28): 10254–9. doi:10.1073/pnas.0400014101. PMC 478560. PMID 15240887. 15. ^ Hunt, Margaret (October 2006). "Virology Chapter 23 — Slow Virus Diseases of the Nervous System". Microbiology and Immunology On-line. University of South Carolina School of Medicine. Retrieved 2012-02-10. 16. ^ The Lancet "Kuru in the 21st century—an acquired human prion disease with very long incubation periods". Retrieved February 2, 2018. 17. ^ Sleep Medicine Reviews "Fatal familial insomnia: a model disease in sleep physiopathology". Retrieved February 2, 2018. [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 inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors	Slow virus	c0037341	1,888	wikipedia	https://en.wikipedia.org/wiki/Slow_virus	2021-01-18T18:33:54	{"mesh": ["D012897"], "wikidata": ["Q7542129"]}
The features of pars planitis are vitritis with peripheral retinal vasculitis, snowbank exudates, and vitreous condensation over the inferior peripheral retina and pars plana, usually in both eyes. Familial pars planitis was first reported by Culbertson et al. (1983) who described 9 affected members of 4 families: twin sisters, a mother and daughter, 2 brothers, and a sister and 2 brothers. Malinowski et al. (1993) established an association between HLA-DR2 and pars planitis. In addition, they found that 5 of their HLA-DR2-positive pars planitis patients subsequently developed multiple sclerosis (MS; 126200). Raja et al. (1999) corroborated a relationship among pars planitis, HLA-DR2 (specifically the HLA-DR15 allele), and MS. Of their 37 patients with pars planitis, 6 (16%) developed MS. Oruc et al. (2001) investigated HLA class II suballeles in 28 pars planitis patients and 50 normal controls. Pars planitis was associated with increased frequencies of the HLA-DR2 suballeles HLA-DR15, -DR51, and -DR17. The authors suggested that there is an immunogenic predisposition to pars planitis. [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 inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors	PARS PLANITIS	c0030593	1,889	omim	https://www.omim.org/entry/606177	2019-09-22T16:10:35	{"doid": ["12731"], "mesh": ["D015868"], "omim": ["606177"], "icd-9": ["363.21"], "icd-10": ["H30.2"]}
A number sign (#) is used with this entry because of evidence that mitochondrial complex I deficiency nuclear type 31 (MC1DN31) is caused by homozygous mutation in the TIMMDC1 gene (615534) on chromosome 3q13. For a discussion of genetic heterogeneity of mitochondrial complex I deficiency, see 252010. Clinical Features Kremer et al. (2017) reported 3 unrelated patients (35791, 66744, and 96687) with mitochondrial complex I deficiency. All patients had severe neurologic dysfunction manifest as infantile-onset hypotonia, failure to thrive, and delayed or minimal psychomotor development. Additional more variable features included sensorineural deafness, dysmetria, dyskinetic movements, peripheral neuropathy, and nystagmus. One patient had brain imaging results consistent with Leigh syndrome, and another patient developed refractory seizures. Two patients died at ages 30 and 20 months; the third patient was alive at age 6 years, but had 2 older sibs who died young from a neurodegenerative disorder with severe epilepsy. The patients, from Greece, Northern Africa, and Germany, were of differing ethnic descent. Molecular Genetics In 3 unrelated patients (35791, 66744, and 96687) with mitochondrial complex I deficiency, Kremer et al. (2017) identified a homozygous mutation in the TIMMDC1 gene (615534.0001). INHERITANCE \- Autosomal recessive GROWTH Other \- Failure to thrive HEAD & NECK Ears \- Sensorineural deafness Eyes \- Nystagmus MUSCLE, SOFT TISSUES \- Hypotonia NEUROLOGIC Central Nervous System \- Global developmental delay \- Lack of developmental progress \- Neurologic deterioration \- Seizures \- Dysmetria \- Dyskinetic movements \- White matter abnormalities consistent with Leigh syndrome Peripheral Nervous System \- Peripheral neuropathy LABORATORY ABNORMALITIES \- Mitochondrial complex I deficiency in various tissues MISCELLANEOUS \- Onset in infancy \- Early death may occur \- Three unrelated families have been reported (last curated January 2019) MOLECULAR BASIS \- Caused by mutation in the translocase of inner mitochondrial membrane domain-containing protein 1 gene (TIMMDC1, 615534.0001 ) ▲ 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 inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors	MITOCHONDRIAL COMPLEX I DEFICIENCY, NUCLEAR TYPE 31	c2936907	1,890	omim	https://www.omim.org/entry/618251	2019-09-22T15:42:48	{"mesh": ["C537475"], "omim": ["618251"], "orphanet": ["2609"]}
## Clinical Features Le Ber et al. (2006) described 12 male patients from 8 unrelated families with dystonia and cerebellar atrophy. Mean age at onset was 27 years (range, 9 to 42). Eight patients had a similar phenotype with spasmodic dysphonia at onset and cerebellar atrophy on brain MRI. The 4 other patients had dystonia with less severe or no spasmodic dysphonia and cerebellar atrophy on brain MRI. All 12 patients had dystonia, variably affecting the upper limb, neck, face, or lower limb, and dysphagia was also reported. Cerebellar signs were slowly progressive and mainly included ataxic gait. The authors commented that the marked cerebellar atrophy on MRI contrasted with the relatively mild clinical cerebellar signs. Levodopa was not helpful in 8 patients who were treated. Le Ber et al. (2006) suggested the designation DYTCA, for dystonia with cerebellar atrophy, to describe this phenotype. ### Neuropathologic Findings Miyamoto et al. (2015) reported the neuropathologic findings of a 47-year-old man who had a history of adult-onset progressive dystonia, spasmodic dysphonia, and static ataxia, reminiscent of DYTCA. Brain imaging showed cerebellar atrophy, and postmortem examination showed a markedly atrophic cerebellum. Microscopic analysis showed diffuse cortical degeneration with thinning of the molecular layers, loss of Purkinje cells, Bergmann gliosis, rarefaction of the granular cell layers, and fibrillary gliosis in the white matter. There was also neuronal loss in the inferior olivary nucleus. Other areas of the brain, including the brainstem and thalamus, showed no abnormal changes. The findings were consistent with chronic neurodegeneration limited to the cerebelloolivary region. The patient showed a partial response of his severe dystonia to deep-brain stimulation of the globus pallidus, suggesting functional impairment in the basal ganglia. The patient's younger brother had mild truncal instability and mild cerebellar atrophy on brain imaging, but did not have limb ataxia, dysphonia, or dystonia. Inheritance Le Ber et al. (2006) noted that 4 families with 2 affected sibs supports autosomal recessive inheritance; however because all of the patients were male, X-linked inheritance could not be ruled out. INHERITANCE \- Autosomal recessive HEAD & NECK Face \- Facial dystonia Eyes \- Nystagmus, horizontal gaze-evoked Neck \- Torticollis RESPIRATORY Larynx \- Spasmodic dysphonia due to laryngeal spasm ABDOMEN Gastrointestinal \- Dysphagia NEUROLOGIC Central Nervous System \- Dystonia, focal (at onset) \- Dystonia may become generalized \- Dysarthria \- Brisk reflexes \- Cerebellar ataxia, slowly progressive \- Cerebellar atrophy MISCELLANEOUS \- Mean age at onset 27 years (range 9 to 42) \- Poor response to levodopa treatment \- X-linked inheritance could not be ruled out ▲ 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 inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors	DYSTONIA WITH CEREBELLAR ATROPHY	c2673697	1,891	omim	https://www.omim.org/entry/611694	2019-09-22T16:03:01	{"mesh": ["C567131"], "omim": ["611694"]}
Mosaic trisomy 5 is a rare chromosomal anomaly syndrome with a variable phenotype ranging from clinically normal to patients presenting intrauterine growth retardation, congenital heart anomalies (mainly ventricular septal defect), multiple dysmorphic features (e.g. hypertelorism, prominent nasal bridge) and other congenital anomalies (incl. eventration of diaphragm, agenesis of corpus callosum, cloverleaf skull, clinodactyly, anteriorly placed anus). Psychomotor development may be normal in spite of low growth parameters being 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 inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors	Mosaic trisomy 5	c2931603	1,892	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=96060	2021-01-23T17:17:48	{"mesh": ["C537762"], "icd-10": ["Q92.1"], "synonyms": ["Mosaic trisomy chromosome 5", "Trisomy 5 mosaicism"]}
Myxoid chondrosarcoma SpecialtyOncology Myxoid chondrosarcoma is a type of chondrosarcoma.[1] It has been associated with a t(9;22) (q22;q12) EWS/CHN gene fusion.[2] ## References[edit] 1. ^ Goh YW, Spagnolo DV, Platten M, et al. (November 2001). "Extraskeletal myxoid chondrosarcoma: a light microscopic, immunohistochemical, ultrastructural and immuno-ultrastructural study indicating neuroendocrine differentiation". Histopathology. 39 (5): 514–24. doi:10.1046/j.1365-2559.2001.01277.x. PMID 11737310. 2. ^ Brody RI, Ueda T, Hamelin A, et al. (March 1997). "Molecular analysis of the fusion of EWS to an orphan nuclear receptor gene in extraskeletal myxoid chondrosarcoma". Am. J. Pathol. 150 (3): 1049–58. PMC 1857890. PMID 9060841. ## External links[edit] Classification D * ICD-O: 9231/3 * v * t * e Tumours of bone and cartilage Diaphysis * Multiple myeloma * Epithelia * Adamantinoma * Primitive neuroectodermal tumor * Ewing family * Ewing's sarcoma Metaphysis Osteoblast * Osteoid osteoma * Osteoblastoma * Osteoma/osteosarcoma Chondroblast * Chondroma/ecchondroma/enchondroma * Enchondromatosis * Extraskeletal chondroma * Chondrosarcoma * Mesenchymal chondrosarcoma * Myxoid chondrosarcoma * Osteochondroma * Osteochondromatosis * Chondromyxoid fibroma Fibrous * Ossifying fibroma * Fibrosarcoma Epiphysis Chondroblast * Chondroblastoma Myeloid * Giant-cell tumor of bone Other Notochord * Chordoma [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 inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors	Myxoid chondrosarcoma	c0334551	1,893	wikipedia	https://en.wikipedia.org/wiki/Myxoid_chondrosarcoma	2021-01-18T18:56:05	{"umls": ["C0334551"], "wikidata": ["Q17047222"]}
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. (September 2017) Renal anaplastic sarcoma SpecialtyUrology, oncology Renal anaplastic sarcoma is a rare tumour of the kidney.[1][2] By 2017 about 25 cases have been reported.[3] This tumour occurs in children and young adults and is more common in females than males. Because of its rarity its natural history is not well understood. ## Contents * 1 Genetics * 2 Diagnosiss * 2.1 Histology * 3 Treatment * 4 History * 5 References ## Genetics[edit] An association with mutations in the DICER-1 gene has been reported.[4][5][6] ## Diagnosiss[edit] Aspiration cytology may be of use in making the diagnosis. CT scans of the abdomen and the rest of the body are normally done to assist in surgical planning. The age at diagnosis of this condition varies between 10 months to 41 years.[7] The male:female ratio is 2:3. The most common presentation is an asymptomatic abdominal mass. The tumour is more common on the right and it may metastise to lung, liver and bone. ### Histology[edit] On histology the tumours have a marked spindle cell component. Other cells may be bizarre in shape. Cartilage or bone tissue may be found. A cystic component may be present. The differential diagnosis includes * anaplastic Wilms’ tumor * renal synovial sarcomas * malignant mesenchymomas * ectomesenchymomas ## Treatment[edit] Because of the rarity of this tumour, optimal treatment is as yet unknown. It is usually treated by excision. Radiation and chemotherapy have also been used in addition to surgery. ## History[edit] This tumour was first described in 2007.[7] This lesion was recognised during a review of a series of 15,000 renal timours. ## References[edit] 1. ^ Watanabe N, Omagari D, Yamada T, Nemoto N, Furuya T, Sugito K, Koshinaga T, Yagasaki H, Sugitani M (2013) Anaplastic sarcoma of the kidney: case report and literature review. Pediatr Int 55(5):e129-132 2. ^ Labanaris A, Zugor V, Smiszek R, Nützel R, Kühn R (2009) Anaplastic sarcoma of the kidney. ScientificWorldJournal 9:97-101 3. ^ Arabi H, Al-Maghraby H, Yamani A, Yousef Y, Huwait H (2016) Anaplastic sarcoma of the kidney: A rare unique renal neoplasm. Int J Surg Pathol 24(6):556-561 4. ^ Wu MK, Vujanic GM, Fahiminiya S, Watanabe N, Thorner PS, O'Sullivan MJ, Fabian MR, Foulkes WD (2017) Anaplastic sarcomas of the kidney are characterized by DICER1 mutations. Mod Pathol 5. ^ Yoshida M, Hamanoue S, Seki M, Tanaka M, Yoshida K, Goto H, Ogawa S, Takita J, Tanaka Y (2016) Metachronous anaplastic sarcoma of the kidney and thyroid follicular carcinoma as manifestations of DICER1 abnormalities. Hum Pathol 61:205-209 6. ^ Wu MK, Cotter MB, Pears J, McDermott MB, Fabian MR, Foulkes WD, O'Sullivan MJ (2016) Tumor progression in DICER1-mutated cystic nephroma-witnessing the genesis of anaplastic sarcoma of the kidney. Hum Pathol 53:114-120 7. ^ a b Vujanić GM, Kelsey A, Perlman EJ, Sandstedt B, Beckwith JB (2007) Anaplastic sarcoma of the kidney: a clinicopathologic study of 20 cases of a new entity with polyphenotypic features. Am J Surg Pathol 31(10):1459-1468 [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 inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors	Renal anaplastic sarcoma	None	1,894	wikipedia	https://en.wikipedia.org/wiki/Renal_anaplastic_sarcoma	2021-01-18T18:49:43	{"umls": ["CL555408"], "wikidata": ["Q56291604"]}
Rolandic epilepsy (RE) is a focal childhood epilepsy characterized by seizures consisting of unilateral facial sensory-motor symptoms, with electroencephalogram (EEG) showing sharp biphasic waves over the rolandic region. It is an age-related epilepsy, with excellent outcome. ## Epidemiology RE is the most common childhood epilepsy and accounts for 8-25% of all childhood epilepsies. Its incidence has been estimated to be approximately 1/5,000 in children within 15 years. ## Clinical description Onset is between 3 and 12 years, in otherwise normal children (peak of onset is 5-8 years). Seizures typically occur during sleep or drowsy states; they are brief with unilateral sensorimotor (such as numbness, tingling, drooling) that involves pharynx, tongue, face, lips and sometimes hand. Speech arrest often occurs, while comprehension is preserved. Seizures may alternate from one side to the other and may become generalized. Longer attacks can be followed by post-ictal hemiplegia. Some children may have selective neuropsychological impairment affecting language, attention, visuomotor skills and behavior. They usually do not outlast the period of active seizures. Seizure remission occurs within 2-4 years from the onset. The majority of patients have <10 seizures and 10-20% have a single seizure. ## Etiology Etiology of RE is still unknown. There is probably a genetic predisposition: an increased rate of RE, febrile seizures, and epilepsy-aphasia spectrum disorders were found among relatives. Pathogenesis seems to be related with the critical and vulnerable phase of brain maturation. ## Diagnostic methods Diagnosis of RE relies on the clinical features and on EEG findings that show slow, diphasic, high voltage, centrotemporal spikes, activated by sleep. Brain magnetic resonance imaging (MRI) is normal. ## Differential diagnosis Differential diagnosis includes other idiopathic focal childhood epilepsies (benign childhood occipital epilepsy, Panayiotopoulos type and Gastaut type. Other etiologies causing similar symptoms are excluded with brain MRI. ## Genetic counseling Autosomal dominant transmission has been reported in some cases. ## Management and treatment The majority of patients, who have a single or few seizures, do not require treatment. Differently, patients with frequent seizures (10-20%) may need treatment for a short time. In such cases, carbamazepine or valproate are preferred even if, in rare cases, carbamazepine may have a paradoxical effect. ## Prognosis Prognosis of RE is favorable since nearly 90% of patients remit before puberty. In rare cases (<1%), RE may evolve to atypical RE with linguistic, behavioral and neuropsychological deficits. An aggressive treatment with steroids, in these cases might change the evolution of the disease and a remission of neuropsychological deficits might be seen. [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 inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors	Rolandic epilepsy	c0376532	1,895	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=1945	2021-01-23T19:05:44	{"gard": ["10287"], "mesh": ["D019305"], "omim": ["117100", "245570"], "umls": ["C0376532", "C2363129"], "icd-10": ["G40.0"], "synonyms": ["BECRS", "BECTS", "BRE", "Benign epilepsy of childhood with centrotemporal spikes", "Benign familial epilepsy of childhood with rolandic spikes", "Benign rolandic epilepsy", "Centrotemporal epilepsy"]}
Change in the action or side effects of a drug caused This article may need to be rewritten to comply with Wikipedia's quality standards. You can help. The talk page may contain suggestions. (February 2019) This article's tone or style may not reflect the encyclopedic tone used on Wikipedia. See Wikipedia's guide to writing better articles for suggestions. (February 2019) (Learn how and when to remove this template message) A drug interaction is a change in the action or side effects of a drug caused by concomitant administration with a food, beverage, supplement, or another drug.[1] A cause of a drug interaction involves one drug which alters the pharmacokinetics of another medical drug. Alternatively, drug interactions result from competition for a single receptor or signaling pathway. Both synergy and antagonism occur during different phases of the interaction between a drug, and an organism. For example, when synergy occurs at a cellular receptor level this is termed agonism, and the substances involved are termed agonists. On the other hand, in the case of antagonism, the substances involved are known as inverse agonists. The risk of a drug-drug interaction increases with the number of drugs used.[2] Over a third (36%) of the elderly in the U.S. regularly use five or more medications or supplements, and 15% are at risk of a significant drug-drug interaction.[3] ## Contents * 1 Pharmacodynamic interactions * 2 Pharmacokinetic interactions * 2.1 Absorption interactions * 2.1.1 Changes in motility * 2.2 Transport and distribution interactions * 2.3 Metabolism interactions * 2.3.1 CYP450 * 2.3.2 Enzymatic inhibition * 2.3.3 Enzymatic induction * 2.4 Excretion interactions * 2.4.1 Renal excretion * 2.4.2 Bile excretion * 3 Herb-drug interactions * 3.1 Examples * 3.2 Mechanisms * 4 Underlying factors * 5 Epidemiology * 6 See also * 7 Notes * 8 References * 9 Bibliography * 10 External links ## Pharmacodynamic interactions[edit] When two drugs are used together, their effects can be additive (the result is what you expect when you add together the effect of each drug taken independently), synergistic (combining the drugs leads to a larger effect than expected), or antagonistic (combining the drugs leads to a smaller effect than expected).[4] There is sometimes confusion on whether drugs are synergistic or additive, since the individual effects of each drug may vary from patient to patient.[5] A synergistic interaction may be beneficial for patients, but may also increase the risk of overdose. Both synergy and antagonism can occur during different phases of the interaction between a drug, and an organism. The different responses of a receptor to the action of a drug have resulted in a number of classifications, such as "partial agonist", "competitive agonist" etc. These concepts have fundamental applications in the pharmacodynamics of these interactions. The proliferation of existing classifications at this level, along with the fact that the exact reaction mechanisms for many drugs are not well-understood means that it is almost impossible to offer a clear classification for these concepts. It is even possible that many authors would misapply any given classification.[6] Direct interactions between drugs are also possible and may occur when two drugs are mixed prior to intravenous injection. For example, mixing thiopentone and suxamethonium in the same syringe can lead to the precipitation of thiopentone.[7] The change in an organism's response upon administration of a drug is an important factor in pharmacodynamic interactions. These changes are extraordinarily difficult to classify given the wide variety of modes of action that exist, and the fact that many drugs can cause their effect through a number of different mechanisms. This wide diversity also means that, in all but the most obvious cases it is important to investigate, and understand these mechanisms. The well-founded suspicion exists that there are more unknown interactions than known ones. Effects of the competitive inhibition of an agonist by increases in the concentration of an antagonist. A drugs potency can be affected (the response curve shifted to the right) by the presence of an antagonistic interaction.pA2 known as the Schild representation, a mathematical model of the agonist:antagonist relationship or vice versa. NB: the x-axis is incorrectly labelled and should reflect the agonist concentration, not antagonist concentration. Pharmacodynamic interactions can occur on: 1. Pharmacological receptors:[8] Receptor interactions are the most easily defined, but they are also the most common. From a pharmacodynamic perspective, two drugs can be considered to be: 1. Homodynamic, if they act on the same receptor. They, in turn can be: 1. Pure agonists, if they bind to the main locus of the receptor, causing a similar effect to that of the main drug. 2. Partial agonists if, on binding to one of the receptor's secondary sites, they have the same effect as the main drug, but with a lower intensity. 3. Antagonists, if they bind directly to the receptor's main locus but their effect is opposite to that of the main drug. These include: 1. Competitive antagonists, if they compete with the main drug to bind with the receptor. The amount of antagonist or main drug that binds with the receptor will depend on the concentrations of each one in the plasma. 2. Uncompetitive antagonists, when the antagonist binds to the receptor irreversibly and is not released until the receptor is saturated. In principle the quantity of antagonist and agonist that binds to the receptor will depend on their concentrations. However, the presence of the antagonist will cause the main drug to be released from the receptor regardless of the main drug's concentration, therefore all the receptors will eventually become occupied by the antagonist. 2. Heterodynamic competitors, if they act on distinct receptors. 2. Signal transduction mechanisms: these are molecular processes that commence after the interaction of the drug with the receptor.[9] For example, it is known that hypoglycaemia (low blood glucose) in an organism produces a release of catecholamines, which trigger compensation mechanisms thereby increasing blood glucose levels. The release of catecholamines also triggers a series of symptoms, which allows the organism to recognise what is happening and which act as a stimulant for preventative action (eating sugars). Should a patient be taking a drug such as insulin, which reduces glycaemia, and also be taking another drug such as certain beta-blockers for heart disease, then the beta-blockers will act to block the adrenaline receptors. This will block the reaction triggered by the catecholamines should a hypoglycaemic episode occur. Therefore, the body will not adopt corrective mechanisms and there will be an increased risk of a serious reaction resulting from the ingestion of both drugs at the same time. 3. Antagonic physiological systems:[9] Imagine a drug A that acts on a certain organ. This effect will increase with increasing concentrations of physiological substance S in the organism. Now imagine a drug B that acts on another organ, which increases the amount of substance S. If both drugs are taken simultaneously it is possible that drug A could cause an adverse reaction in the organism as its effect will be indirectly increased by the action of drug B. An actual example of this interaction is found in the concomitant use of digoxin and furosemide. The former acts on cardiac fibres and its effect is increased if there are low levels of potassium (K) in blood plasma. Furosemide is a diuretic that lowers arterial tension but favours the loss of K+. This could lead to hypokalemia (low levels of potassium in the blood), which could increase the toxicity of digoxin. ## Pharmacokinetic interactions[edit] Modifications in the effect of a drug are caused by differences in the absorption, transport, distribution, metabolism or excretion of one or both of the drugs compared with the expected behavior of each drug when taken individually. These changes are basically modifications in the concentration of the drugs. In this respect, two drugs can be homergic if they have the same effect in the organism and heterergic if their effects are different. ### Absorption interactions[edit] #### Changes in motility[edit] Some drugs, such as the prokinetic agents increase the speed with which a substance passes through the intestines. If a drug is present in the digestive tract's absorption zone for less time its blood concentration will decrease. The opposite will occur with drugs that decrease intestinal motility. * pH: Drugs can be present in either ionised or non-ionised form, depending on their pKa (pH at which the drug reaches equilibrium between its ionised and non-ionised form).[10] The non-ionized forms of drugs are usually easier to absorb, because they will not be repelled by the lipidic bylayer of the cell, most of them can be absorbed by passive diffusion, unless they are too big or too polarized (like glucose or vancomycin), in which case they may have or not have specific and non specific transporters distributed on the entire intestine internal surface, that carries drugs inside the body. Obviously increasing the absorption of a drug will increase its bioavailability, so, changing the drug's state between ionized or not, can be useful or not for certain drugs. Certain drugs require an acid stomach pH for absorption. Others require the basic pH of the intestines. Any modification in the pH could change this absorption. In the case of the antacids, an increase in pH can inhibit the absorption of other drugs such as zalcitabine (absorption can be decreased by 25%), tipranavir (25%) and amprenavir (up to 35%). However, this occurs less often than an increase in pH causes an increase in absorption. Such as occurs when cimetidine is taken with didanosine. In this case, a gap of two to four hours between taking the two drugs is usually sufficient to avoid the interaction.[11] * Drug solubility: The absorption of some drugs can be drastically reduced if they are administered together with food with a high fat content. This is the case for oral anticoagulants and avocado. * Formation of non-absorbable complexes: * Chelation: The presence of di- or trivalent cations can cause the chelation of certain drugs, making them harder to absorb. This interaction frequently occurs between drugs such as tetracycline or the fluoroquinolones and dairy products (due to the presence of Ca++). * Binding with proteins. Some drugs such as sucralfate binds to proteins, especially if they have a high bioavailability. For this reason its administration is contraindicated in enteral feeding.[12] * Finally, another possibility is that the drug is retained in the intestinal lumen forming large complexes that impede its absorption. This can occur with cholestyramine if it is associated with sulfamethoxazol, thyroxine, warfarin or digoxin. * Acting on the P-glycoprotein of the enterocytes: This appears to be one of the mechanisms promoted by the consumption of grapefruit juice in increasing the bioavailability of various drugs, regardless of its demonstrated inhibitory activity on first pass metabolism.[13] ### Transport and distribution interactions[edit] The main interaction mechanism is competition for plasma protein transport. In these cases the drug that arrives first binds with the plasma protein, leaving the other drug dissolved in the plasma, which modifies its concentration. The organism has mechanisms to counteract these situations (by, for example, increasing plasma clearance), which means that they are not usually clinically relevant. However, these situations should be taken into account if other associated problems are present such as when the method of excretion is affected.[14] ### Metabolism interactions[edit] Diagram of cytochrome P450 isoenzyme 2C9 with the haem group in the centre of the enzyme. Many drug interactions are due to alterations in drug metabolism.[15] Further, human drug-metabolizing enzymes are typically activated through the engagement of nuclear receptors.[15] One notable system involved in metabolic drug interactions is the enzyme system comprising the cytochrome P450 oxidases. #### CYP450[edit] Cytochrome P450 is a very large family of haemoproteins (hemoproteins) that are characterized by their enzymatic activity and their role in the metabolism of a large number of drugs.[16] Of the various families that are present in human beings the most interesting in this respect are the 1, 2 and 3, and the most important enzymes are CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP2E1 and CYP3A4.[17] The majority of the enzymes are also involved in the metabolism of endogenous substances, such as steroids or sex hormones, which is also important should there be interference with these substances. As a result of these interactions the function of the enzymes can either be stimulated (enzyme induction) or inhibited (enzyme inhibition). #### Enzymatic inhibition[edit] If drug A is metabolized by a cytochrome P450 enzyme and drug B inhibits or decreases the enzyme's activity, then drug A will remain with high levels in the plasma for longer as its inactivation is slower. As a result, enzymatic inhibition will cause an increase in the drug's effect. This can cause a wide range of adverse reactions. It is possible that this can occasionally lead to a paradoxical situation, where the enzymatic inhibition causes a decrease in the drug's effect: if the metabolism of drug A gives rise to product A2, which actually produces the effect of the drug. If the metabolism of drug A is inhibited by drug B the concentration of A2 that is present in the blood will decrease, as will the final effect of the drug. #### Enzymatic induction[edit] If drug A is metabolized by a cytochrome P450 enzyme and drug B induces or increases the enzyme's activity, then blood plasma concentrations of drug A will quickly fall as its inactivation will take place more rapidly. As a result, enzymatic induction will cause a decrease in the drug's effect. As in the previous case, it is possible to find paradoxical situations where an active metabolite causes the drug's effect. In this case, the increase in active metabolite A2 (following the previous example) produces an increase in the drug's effect. It can often occur that a patient is taking two drugs that are enzymatic inductors, one inductor and the other inhibitor or both inhibitors, which greatly complicates the control of an individual's medication and the avoidance of possible adverse reactions. An example of this is shown in the following table for the CYP1A2 enzyme, which is the most common enzyme found in the human liver. The table shows the substrates (drugs metabolized by this enzyme) and the inductors and inhibitors of its activity:[17] Drugs related to CYP1A2 Substrates Inhibitors Inductors * Caffeine * Theophylline * Phenacetin * Clomipramine * Clozapine * Thioridazine * Omeprazole * Nicotine * Cimetidine * Ciprofloxacin * Phenobarbital * Fluvoxamine * Venlafaxine * Ticlopidine Enzyme CYP3A4 is the enzyme that the greatest number of drugs use as a substrate. Over 100 drugs depend on its metabolism for their activity and many others act on the enzyme as inductors or inhibitors. Some foods also act as inductors or inhibitors of enzymatic activity. The following table shows the most common: Foods and their influence on drug metabolism[18],[12],[19] Food Mechanism Drugs affected * Avocado * Brassicas (brussel sprouts, broccoli, cabbage) Enzymatic inductor Acenocoumarol, warfarin Grapefruit juice Enzymatic inhibition * Calcium channel blockers: nifedipine, felodipine, nimodipine, amlodipine * Cyclosporine, tacrolimus * Terfenadine, astemizole * Cisapride, pimozide * Carbamazepine, saquinavir, midazolam, alprazolam, triazolam Main article: Grapefruit drug interactions Soya Enzymatic inhibition Clozapine, haloperidol, olanzapine, caffeine, NSAIDs, phenytoin, zafirlukast, warfarin Garlic Increases antiplatelet activity * Anticoagulants * NSAIDs, acetylsalicylic acid Ginseng To be determined Warfarin, heparin, aspirin and NSAIDs Ginkgo biloba Strong inhibitor of platelet aggregation factor Warfarin, aspirin and NSAIDs Hypericum perforatum (St John's wort) Enzymatic inductor (CYP450) Warfarin, digoxin, theophylline, cyclosporine, phenytoin and antiretrovirals Ephedra Receptor level agonist MAOI, central nervous system stimulants, alkaloids ergotamines and xanthines Kava (Piper methysticum) Unknown Levodopa Ginger Inhibits thromboxane synthetase (in vitro) Anticoagulants Chamomile Unknown Benzodiazepines, barbiturates and opioids Hawthorn Unknown Beta-adrenergic antagonists, cisapride, digoxin, quinidine Grapefruit juice can act as an enzyme inhibitor. Any study of pharmacological interactions between particular medicines should also discuss the likely interactions of some medicinal plants. The effects caused by medicinal plants should be considered in the same way as those of medicines as their interaction with the organism gives rise to a pharmacological response. Other drugs can modify this response and also the plants can give rise to changes in the effects of other active ingredients. There is little data available regarding interactions involving medicinal plants for the following reasons: St John's wort can act as an enzyme inductor. 1. False sense of security regarding medicinal plants. The interaction between a medicinal plant and a drug is usually overlooked due to a belief in the "safety of medicinal plants." 2. Variability of composition, both qualitative and quantitative. The composition of a plant-based drug is often subject to wide variations due to a number of factors such as seasonal differences in concentrations, soil type, climatic changes or the existence of different varieties or chemical races within the same plant species that have variable compositions of the active ingredient. On occasion, an interaction can be due to just one active ingredient, but this can be absent in some chemical varieties or it can be present in low concentrations, which will not cause an interaction. Counter interactions can even occur. This occurs, for instance, with ginseng, the Panax ginseng variety increases the Prothrombin time, while the Panax quinquefolius variety decreases it.[20] 3. Absence of use in at-risk groups, such as hospitalized and polypharmacy patients, who tend to have the majority of drug interactions. 4. Limited consumption of medicinal plants has given rise to a lack of interest in this area.[21] They are usually included in the category of foods as they are usually taken as a tea or food supplement. However, medicinal plants are increasingly being taken in a manner more often associated with conventional medicines: pills, tablets, capsules, etc. ### Excretion interactions[edit] #### Renal excretion[edit] Human kidney nephron. Only the free fraction of a drug that is dissolved in the blood plasma can be removed through the kidney. Therefore, drugs that are tightly bound to proteins are not available for renal excretion, as long as they are not metabolized when they may be eliminated as metabolites.[22] Creatinine clearance is used as a measure of kidney functioning but it is only useful in cases where the drug is excreted in an unaltered form in the urine. The excretion of drugs from the kidney's nephrons has the same properties as that of any other organic solute: passive filtration, reabsorption and active secretion. In the latter phase, the secretion of drugs is an active process that is subject to conditions relating to the saturability of the transported molecule and competition between substrates. Therefore, these are key sites where interactions between drugs could occur. Filtration depends on a number of factors including the pH of the urine, it having been shown that the drugs that act as weak bases are increasingly excreted as the pH of the urine becomes more acidic, and the inverse is true for weak acids. This mechanism is of great use when treating intoxications (by making the urine more acidic or more alkali) and it is also used by some drugs and herbal products to produce their interactive effect. Drugs that act as weak acids or bases Weak acids Weak bases * Acetylsalicylic acid * Furosemide * Ibuprofen * Levodopa * Acetazolamide * Sulfadiazine * Ampicillin * Chlorothiazide * Paracetamol * Chloropropamide * Cromoglicic acid * Ethacrynic acid * alpha-Methyldopamine * Phenobarbital * Warfarin * Theophylline * Phenytoin * Reserpine * Amphetamine * Procaine * Ephedrine * Atropine * Diazepam * Hydralazine * Pindolol * Propranolol * Salbutamol * Alprenolol * Terbutaline * Amiloride * Chlorpheniramine[23] #### Bile excretion[edit] Bile excretion is different from kidney excretion as it always involves energy expenditure in active transport across the epithelium of the bile duct against a concentration gradient. This transport system can also be saturated if the plasma concentrations of the drug are high. Bile excretion of drugs mainly takes place where their molecular weight is greater than 300 and they contain both polar and lipophilic groups. The glucuronidation of the drug in the kidney also facilitates bile excretion. Substances with similar physicochemical properties can block the receptor, which is important in assessing interactions. A drug excreted in the bile duct can occasionally be reabsorbed by the intestines (in the enterohepatic circuit), which can also lead to interactions with other drugs. ## Herb-drug interactions[edit] Herb-drug interactions are drug interactions that occur between herbal medicines and conventional drugs.[24] These types of interactions may be more common than drug-drug interactions because herbal medicines often contain multiple pharmacologically active ingredients, while conventional drugs typically contain only one.[24] Some such interactions are clinically significant,[25] although most herbal remedies are not associated with drug interactions causing serious consequences.[26] Most herb-drug interactions are moderate in severity.[27] The most commonly implicated conventional drugs in herb-drug interactions are warfarin, insulin, aspirin, digoxin, and ticlopidine, due to their narrow therapeutic indices.[27][28] The most commonly implicated herbs involved in such interactions are those containing St. John’s Wort, magnesium, calcium, iron, or ginkgo.[27] ### Examples[edit] Examples of herb-drug interactions include, but are not limited to: * St. John's wort affects the clearance of numerous drugs, including cyclosporin, SSRI antidepressants, digoxin, indinavir, and phenprocoumon.[24] It may also interact with the anti-cancer drugs irinotecan and imatinib.[29] * Salvia miltiorrhiza may enhance anticoagulation and bleeding among people taking warfarin.[25] * Allium sativum has been found to decrease the plasma concentration of saquinavir, and may cause hypoglycemia when taken with chlorpropamide.[25] * Ginkgo biloba can cause bleeding when combined with warfarin or aspirin.[25] * Concomitant ephedra and caffeine use has been reported to, in rare cases, cause fatalities.[30] ### Mechanisms[edit] The mechanisms underlying most herb-drug interactions are not fully understood.[31] Interactions between herbal medicines and anticancer drugs typically involve enzymes that metabolize cytochrome P450.[29] For example, St. John's Wort has been shown to induce CYP3A4 and P-glycoprotein in vitro and in vivo.[29] ## Underlying factors[edit] It is possible to take advantage of positive drug interactions. However, the negative interactions are usually of more interest because of their pathological significance, and also because they are often unexpected, and may even go undiagnosed. By studying the conditions that favor the appearance of interactions, it should be possible to prevent them, or at least diagnose them in time. The factors or conditions that predispose the appearance of interactions include:[6] * Old age: factors relating to how human physiology changes with age may affect the interaction of drugs. For example, liver metabolism, kidney function, nerve transmission or the functioning of bone marrow all decrease with age. In addition, in old age there is a sensory decrease that increases the chances of errors being made in the administration of drugs.[32] * Polypharmacy: The use of multiple drugs by a single patient, to treat one or more ailments. The more drugs a patient takes the more likely it will be that some of them will interact.[33] * Genetic factors: Genes synthesize enzymes that metabolize drugs. Some races have genotypic variations that could decrease or increase the activity of these enzymes. The consequence of this would, on occasions, be a greater predisposition towards drug interactions and therefore a greater predisposition for adverse effects to occur. This is seen in genotype variations in the isozymes of cytochrome P450. * Hepatic or renal diseases: The blood concentrations of drugs that are metabolized in the liver and/or eliminated by the kidneys may be altered if either of these organs is not functioning correctly. If this is the case an increase in blood concentration is normally seen.[33] * Serious diseases that could worsen if the dose of the medicine is reduced. * Drug dependent factors:[34] * Narrow therapeutic index: Where the difference between the effective dose and the toxic dose is small.[n. 1] The drug digoxin is an example of this type of drug. * Steep dose-response curve: Small changes in the dosage of a drug produce large changes in the drug's concentration in the patient's blood plasma. * Saturable hepatic metabolism: In addition to dose effects the capacity to metabolize the drug is greatly decreased ## Epidemiology[edit] Among US adults older than 55, 4% are taking medication and or supplements that put them at risk of a major drug interaction.[35] Potential drug-drug interactions have increased over time[36] and are more common in the low educated elderly even after controlling for age, sex, place of residence, and comorbidity.[37] ## See also[edit] * Deprescribing * Cytochrome P450 * Classification of Pharmaco-Therapeutic Referrals * Drug interactions can be checked for free online with interaction checkers (note that not all drug interaction checkers provide the same results, and only a drug information expert, such as a pharmacist, should interpret results or provide advice on managing drug interactions) * Multi-Drug Interaction Checker by Medscape [5] * Drug Interactions Checker by Drugs.com [6] ## Notes[edit] 1. ^ The term effective dose is generally understood to mean the minimum amount of a drug that is needed to produce the required effect. The toxic dose is the minimum amount of a drug that will produce a damaging effect. ## References[edit] 1. ^ "What is a Drug Interaction?". AIDSinfo. U.S. Department of Health and Human Services. Retrieved 15 June 2019. 2. ^ Tannenbaum C, Sheehan NL (July 2014). "Understanding and preventing drug-drug and drug-gene interactions". Expert Review of Clinical Pharmacology. 7 (4): 533–44. doi:10.1586/17512433.2014.910111. PMC 4894065. PMID 24745854. 3. ^ Qato DM, Wilder J, Schumm LP, Gillet V, Alexander GC (April 2016). "Changes in Prescription and Over-the-Counter Medication and Dietary Supplement Use Among Older Adults in the United States, 2005 vs 2011". JAMA Internal Medicine. 176 (4): 473–82. doi:10.1001/jamainternmed.2015.8581. PMC 5024734. PMID 26998708. 4. ^ Greco, W. R.; Bravo, G.; Parsons, J. C. (1995). "The search for synergy: a critical review from a response surface perspective". Pharmacological Reviews. 47 (2): 331–385. ISSN 0031-6997. PMID 7568331. 5. ^ Palmer, Adam C.; Sorger, Peter K. (2017-12-14). "Combination Cancer Therapy Can Confer Benefit via Patient-to-Patient Variability without Drug Additivity or Synergy". Cell. 171 (7): 1678–1691.e13. doi:10.1016/j.cell.2017.11.009. ISSN 1097-4172. PMC 5741091. PMID 29245013. 6. ^ a b Baños Díez, J. E.; March Pujol, M (2002). Farmacología ocular (in Spanish) (2da ed.). Edicions UPC. p. 87. ISBN 978-8483016473. Retrieved 23 May 2009. 7. ^ Khan, Shahab; Stannard, Naina; Greijn, Jeff (2011-07-12). "Precipitation of thiopental with muscle relaxants: a potential hazard". JRSM Short Reports. 2 (7): 58. doi:10.1258/shorts.2011.011031. ISSN 2042-5333. PMC 3147238. PMID 21847440. 8. ^ S Gonzalez. "Interacciones Farmacológicas" (in Spanish). Archived from the original on 2009-01-22. Retrieved 1 January 2009. 9. ^ a b Curso de Farmacología Clínica Aplicada, in El Médico Interactivo Archived 2009-08-31 at the Wayback Machine 10. ^ Malgor — Valsecia, Farmacología general: Farmacocinética.Cap. 2. en "Archived copy" (PDF). Archived from the original (PDF) on 2012-09-07. Retrieved 2012-03-20.CS1 maint: archived copy as title (link) Revised 25 September 2008 11. ^ Alicia Gutierrez Valanvia y Luis F. López-Cortés Interacciones farmacológicas entre fármacos antirretrovirales y fármacos usados para ciertos transtornos gastrointestinales. on [1] accessed 24 September 2008 12. ^ a b Marduga Sanz, Mariano. Interacciones de los alimentos con los medicamentos. on [2] Archived 2014-07-07 at the Wayback Machine 13. ^ Tatro, DS. Update: Drug interaction with grapefruit juice. Druglink, 2004. 8 (5), page 35ss 14. ^ Valsecia, Mabel en 15. ^ a b Elizabeth Lipp (2008-06-15). "Tackling Drug-Interaction Issues Early On". Genetic Engineering & Biotechnology News. Mary Ann Liebert, Inc. pp. 14, 16, 18, 20. Retrieved 2008-07-06. "(subtitle) Researchers explore a number of strategies to better predict drug responses in the clinic" 16. ^ IUPAC, Compendium of Chemical Terminology, 2nd ed. (the "Gold Book") (1997). Online corrected version: (2006–) "cytochrome P450". doi:10.1351/goldbook.CT06821 Danielson PB (December 2002). "The cytochrome P450 superfamily: biochemistry, evolution and drug metabolism in humans". Current Drug Metabolism. 3 (6): 561–97. doi:10.2174/1389200023337054. PMID 12369887. 17. ^ a b Nelson D (2003). Cytochrome P450s in humans Archived July 10, 2009, at the Wayback Machine. Consulted 9 May 2005. 18. ^ Bailey DG, Malcolm J, Arnold O, Spence JD (August 1998). "Grapefruit juice-drug interactions". British Journal of Clinical Pharmacology. 46 (2): 101–10. doi:10.1046/j.1365-2125.1998.00764.x. PMC 1873672. PMID 9723817. Comment in: Mouly S, Paine MF (August 2001). "Effect of grapefruit juice on the disposition of omeprazole". British Journal of Clinical Pharmacology. 52 (2): 216–7. doi:10.1111/j.1365-2125.1978.00999.pp.x. PMC 2014525. PMID 11488783.[permanent dead link] 19. ^ Covarrubias-Gómez, A.; et al. (January–March 2005). "¿Qué se auto-administra su paciente?: Interacciones farmacológicas de la medicina herbal". Revista Mexicana de Anestesiología. 28 (1): 32–42. Archived from the original on 2012-06-29. 20. ^ J. C. Tres Interacción entre fármacos y plantas medicinales. on Archived April 15, 2012, at the Wayback Machine 21. ^ Zaragozá F, Ladero M, Rabasco AM et al. Plantas Medicinales (Fitoterapia Práctica). Second Edition, 2001. 22. ^ Gago Bádenas, F. Curso de Farmacología General. Tema 6.- Excreción de los fármacos. en [3] 23. ^ , Farmacología general: Farmacocinética.Cap. 2. en "Archived copy" (PDF). Archived from the original (PDF) on 2012-09-07. Retrieved 2012-03-20.CS1 maint: archived copy as title (link) Revised 25 September 2008 24. ^ a b c Fugh-Berman, Adriane; Ernst, E. (20 December 2001). "Herb-drug interactions: Review and assessment of report reliability". British Journal of Clinical Pharmacology. 52 (5): 587–595. doi:10.1046/j.0306-5251.2001.01469.x. PMC 2014604. PMID 11736868. 25. ^ a b c d Hu, Z; Yang, X; Ho, PC; Chan, SY; Heng, PW; Chan, E; Duan, W; Koh, HL; Zhou, S (2005). "Herb-drug interactions: a literature review". Drugs. 65 (9): 1239–82. doi:10.2165/00003495-200565090-00005. PMID 15916450. 26. ^ Posadzki, Paul; Watson, Leala; Ernst, Edzard (May 2012). "Herb-drug interactions: an overview of systematic reviews". British Journal of Clinical Pharmacology. 75 (3): 603–618. doi:10.1111/j.1365-2125.2012.04350.x. PMC 3575928. PMID 22670731. 27. ^ a b c Tsai, HH; Lin, HW; Simon Pickard, A; Tsai, HY; Mahady, GB (November 2012). "Evaluation of documented drug interactions and contraindications associated with herbs and dietary supplements: a systematic literature review". International Journal of Clinical Practice. 66 (11): 1056–78. doi:10.1111/j.1742-1241.2012.03008.x. PMID 23067030. 28. ^ Na, Dong Hee; Ji, Hye Young; Park, Eun Ji; Kim, Myung Sun; Liu, Kwang-Hyeon; Lee, Hye Suk (3 December 2011). "Evaluation of metabolism-mediated herb-drug interactions". Archives of Pharmacal Research. 34 (11): 1829–1842. doi:10.1007/s12272-011-1105-0. PMID 22139684. 29. ^ a b c Meijerman, I.; Beijnen, J. H.; Schellens, J. H.M. (1 July 2006). "Herb-Drug Interactions in Oncology: Focus on Mechanisms of Induction". The Oncologist. 11 (7): 742–752. doi:10.1634/theoncologist.11-7-742. PMID 16880233. 30. ^ Ulbricht, C.; Chao, W.; Costa, D.; Rusie-Seamon, E.; Weissner, W.; Woods, J. (1 December 2008). "Clinical Evidence of Herb-Drug Interactions: A Systematic Review by the Natural Standard Research Collaboration". Current Drug Metabolism. 9 (10): 1063–1120. doi:10.2174/138920008786927785. PMID 19075623. 31. ^ Chen, XW; Sneed, KB; Pan, SY; Cao, C; Kanwar, JR; Chew, H; Zhou, SF (1 June 2012). "Herb-drug interactions and mechanistic and clinical considerations". Current Drug Metabolism. 13 (5): 640–51. doi:10.2174/1389200211209050640. PMID 22292789. 32. ^ Merle L, Laroche ML, Dantoine T, Charmes JP (2005). "Predicting and Preventing Adverse Drug Reactions in the Very Old". Drugs & Aging. 22 (5): 375–392. doi:10.2165/00002512-200522050-00003. PMID 15903351. 33. ^ a b García Morillo, J.S. Optimización del tratamiento de enfermos pluripatológicos en atención primaria UCAMI HHUU Virgen del Rocio. Sevilla. Spain. Available for members of SEMI at: ponencias de la II Reunión de Paciente Pluripatológico y Edad Avanzada Archived 2013-04-14 at Archive.today 34. ^ Castells Molina, S.; Castells, S. y Hernández Pérez, M. Farmacología en enfermería Published by Elsevier Spain, 2007 ISBN 84-8174-993-1, 9788481749939 Available from [4] 35. ^ Qato DM, Alexander GC, Conti RM, Johnson M, Schumm P, Lindau ST (December 2008). "Use of prescription and over-the-counter medications and dietary supplements among older adults in the United States". JAMA. 300 (24): 2867–78. doi:10.1001/jama.2008.892. PMC 2702513. PMID 19109115. 36. ^ Haider SI, Johnell K, Thorslund M, Fastbom J (December 2007). "Trends in polypharmacy and potential drug-drug interactions across educational groups in elderly patients in Sweden for the period 1992 - 2002". International Journal of Clinical Pharmacology and Therapeutics. 45 (12): 643–53. doi:10.5414/cpp45643. PMID 18184532. 37. ^ Haider SI, Johnell K, Weitoft GR, Thorslund M, Fastbom J (January 2009). "The influence of educational level on polypharmacy and inappropriate drug use: a register-based study of more than 600,000 older people". Journal of the American Geriatrics Society. 57 (1): 62–9. doi:10.1111/j.1532-5415.2008.02040.x. PMID 19054196. ## Bibliography[edit] MA Cos. Interacciones de fármacos y sus implicancias clínicas. In: Farmacología Humana. Chap. 10, pp. 165–176. (J. Flórez y col. Eds). Masson SA, Barcelona. 1997. ## External links[edit] * Drug Interactions: What You Should Know. U.S. Food and Drug Administration, Center for Drug Evaluation and Research, September 2013 Authority control * LCCN: sh85039701 * NDL: 00576253 * v * t * e Combined substance use and adulteration Combined substance use * Active metabolite * Codrug * Combination drug * Combined drug intoxication * Drug interaction * Poly drug use * Polypharmacy * Polysubstance dependence * Prodrug * Synergy Adulteration * Contamination * Clandestine chemistry * Cutting agent * Diluent * Impurity * Lacing * Mickey Finn Harm reduction * Pill testing * Reagent testing [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 inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors	Drug interaction	c0687133	1,896	wikipedia	https://en.wikipedia.org/wiki/Drug_interaction	2021-01-18T18:53:33	{"mesh": ["D004347"], "wikidata": ["Q718753"]}
A number sign (#) is used with this entry because of evidence that diaphragmatic hernia-3 (DIH3) is caused by heterozygous mutation in the ZFPM2 gene (603693) on chromosome 8q23. For a general phenotypic description and a discussion of genetic heterogeneity of congenital diaphragmatic hernia, see (142340). Clinical Features Temple et al. (1994) reported 2 unrelated girls with isolated unilateral congenital diaphragmatic hernia. One child had a left posterolateral diaphragmatic hernia and a balanced reciprocal translocation (8;13)(q22.3;q22) inherited from her unaffected mother. The second child had a right posterolateral diaphragmatic hernia and a de novo balanced reciprocal translocation (8;15)(q22.3;q15). Temple et al. (1994) suggested that 8q22.3 may harbor a gene involved in isolated congenital diaphragmatic hernia. Longoni et al. (2015) reported 13 patients with DIH3 associated with mutations in the ZFPM2 gene. All had isolated posterolateral congenital diaphragmatic hernia except 1 who also had craniofacial abnormalities, tetralogy of Fallot with an overriding aorta, a ventricular septal defect, and a narrow right ventricular outflow tract. The patient with additional features also had a 250-kb copy number gain of unknown significance on 8q24.21. Inheritance The transmission pattern of DIH3 in the families reported by Longoni et al. (2015) was consistent with autosomal dominant inheritance, with incomplete penetrance estimated at 37.5%. Cytogenetics Wat et al. (2011) identified 3 unrelated patients with congenital diaphragmatic hernia who had a heterozygous deletion of chromosome 8q involving the ZFPM2 gene, also known as FOG2. One patient had a 1.04-Mb deletion inherited from his unaffected father, and another had a 711-kb deletion also involving the OXR1 gene (605609) inherited from his unaffected mother. The third patient had a large 32.3-Mb deletion that also included the EXT1 (608177) and TRPS1 (604386) genes that are associated with Langer-Giedion syndrome (TRPS2; 150230); this infant had short extremities and died shortly after delivery. These patients were ascertained from a cohort of 45 patients with congenital diaphragmatic hernia. Molecular Genetics In a deceased child with diaphragmatic development defects and severe primary pulmonary hypoplasia (see 265430), Ackerman et al. (2005) identified a de novo heterozygous mutation in the ZFPM2 gene (603693.0003). Postmortem analysis showed incomplete lung fissures bilaterally and a deep posterior left diaphragmatic eventration. The heart was grossly normal. Ackerman et al. (2005) suggested that mutations in the ZFPM2 gene may result in primary pulmonary and diaphragmatic defects. In 2 of 96 patients with congenital diaphragmatic hernia, Bleyl et al. (2007) identified heterozygosity for novel sequence alterations in exon 7 of the ZFPM2 gene (603693.0004-603693.0005). Due to the lack of parental DNA, Bleyl et al. (2007) were unable to determine whether the changes were de novo. Longoni et al. (2015) identified potentially pathogenic heterozygous variants in the ZFPM2 gene (see, e.g., 603693.0002) in 13 (5%) of 275 patients with congenital diaphragmatic hernia. Most of the mutations were missense, but 2 were truncating. In addition, 2 multiplex families of European origin with DIH were found to carry either a heterozygous deletion or a truncating mutation in the ZFPM2 gene, respectively. Functional studies were not performed. [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 inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors	DIAPHRAGMATIC HERNIA 3	c0235833	1,897	omim	https://www.omim.org/entry/610187	2019-09-22T16:04:59	{"doid": ["3827"], "mesh": ["D065630"], "omim": ["610187"], "orphanet": ["2140"]}
Charcot-Marie-Tooth disease, type 2H (CMT2H, also referred to as CMT4C2) is an axonal CMT peripheral sensorimotor polyneuropathy associated with pyramidal involvement. ## Epidemiology So far, it has been described in 13 members of a large Tunisian family. ## Clinical description Onset occurred during the first decade of life with progressive distal atrophy involving both the upper and lower limbs, associated with a mild pyramidal syndrome (brisk patellar and upper limb reflexes, absent ankle reflexes and unattainable plantar reflexes). ## Etiology CMT2H is transmitted in an autosomal recessive manner and the disease-causing locus has been mapped to 8q13-21.1. This region contains the GDAP1 gene, which has been implicated in the demyelinating disease CMT4A, and in the axonal disease CMT4C4 or CMT2K (see these terms). [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 inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors	Charcot-Marie-Tooth disease type 2H	c1843173	1,898	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=101102	2021-01-23T18:11:59	{"gard": ["9196"], "mesh": ["C535415"], "omim": ["607731"], "umls": ["C1843173"], "icd-10": ["G60.0"], "synonyms": ["AR-CMT2C", "Autosomal recessive axonal CMT4C2", "Axonal Charcot-Marie-Tooth disease with pyramidal involvement", "CMT2H"]}
AIDS awareness sign in Rwanda Rwanda faces a generalized epidemic, with an HIV prevalence rate of 3.1 percent among adults ages 15 to 49. The prevalence rate has remained relatively stable, with an overall decline since the late 1990s, partly due to improved HIV surveillance methodology. In general, HIV prevalence is higher in urban areas than in rural areas, and women are at higher risk of HIV infection than men. Young women ages 15 to 24 are twice as likely to be infected with HIV as young men in the same age group. Populations at higher risk of HIV infection include people in prostitution and men attending clinics for sexually transmitted infections.[1] Rwanda is among the world's least developed countries, ranking 166 of 187 in the United Nations Development Program's 2011 Human Development Index. Some 60 percent of the population lives in poverty. During the three months of genocide in 1994, mass rape, sexual torture and psychological trauma were common. Massive population flows following the Rwandan genocide of 1994 have resulted in an increase in the urban population. The shortage of human resources throughout the health sector is a significant constraint. Of Rwandans killed or displaced during the genocide, a disproportionate number were highly skilled and educated members of society, including doctors, nurses and other health workers. Many health centers lack essential physical facilities, equipment and supplies. Electricity supply is erratic throughout Rwanda, affecting hospitals, health centers and laboratories. Blood safety, data management and drug storage are all impacted by the erratic electricity supply. While stigma continues to be a problem for people living with HIV/AIDS, the situation is slowly improving due to good information sharing at all levels about HIV/AIDS.[2] The President Paul Kagame has made many efforts in improving the situation, through different awareness raising initiatives.[1] ## Contents * 1 Overview * 1.1 History and emergence in Africa * 1.2 Emergence and prevalence of HIV in Rwanda * 2 National policy and programmatic responses to the HIV/AIDS epidemic * 2.1 History of Rwanda's HIV/AIDS response * 2.1.1 Early responses * 2.1.2 The 1990–1994 civil war and genocide * 2.1.3 Rebuilding after the civil War * 2.1.4 HIV/AIDS policies and programs in the past * 2.2 Current legal and policy framework * 2.2.1 Second National Strategic Plan on HIV and AIDS (National Strategic Plan 2013–2018)[16] * 2.2.2 Other relevant legislation and policy * 3 HIV interventions and achievements * 3.1 Prevention * 3.1.1 Testing and counseling programs * 3.1.2 Condom distribution * 3.1.3 Circumcision * 3.1.4 Prevention of mother to child transmission (PMTCT) * 3.2 Care, treatment, and support * 4 Current challenges in the HIV/AIDS response * 4.1 External donor funding * 4.2 Stigma * 4.3 Targeting subpopulations * 5 Financing for the national HIV response * 5.1 Key development partners * 5.2 Rwanda fiscal year 2011–2012 * 5.3 Rwanda fiscal year 2012–2013 * 6 See also * 7 References ## Overview[edit] ### History and emergence in Africa[edit] Acquired immune deficiency syndrome (AIDS) is a disease comprising associated conditions caused by a human immunodeficiency virus (HIV) infection. Despite myriad research studies, unresolved questions about origins and epidemic emergence of HIV/AIDS remain. At the beginning of the global AIDS epidemic in the early 1980s, HIV/AIDS was considered a disease exclusive to homosexual men and intravenous drug users, but in Africa, new HIV/AIDS cases were observed across numerous subpopulations. Proposed reasons for the emergence of HIV in Africa in the 20th century include, but are not limited to, rapid population growth, change in population structure, and clinical interventions that provided the opportunity for rapid human-to-human transmission. ### Emergence and prevalence of HIV in Rwanda[edit] The prevalence of HIV/AIDS is a major public health concern in Rwanda as HIV/AIDS-related mortality has substantial negative social and economic consequences for residents and the government. The first case of HIV infection in Rwanda was reported in 1983.[3] The estimated incidence rate for HIV in Rwanda is 0.11%; this is a stable rate.[4] According to the 2014–2015 Rwanda Demographic and Health Survey (RDHS), "In Rwanda, much of the information on national HIV prevalence is derived from the antenatal care (ANC) sentinel surveillance system. Although surveillance data do not provide estimates of HIV prevalence for the general population, they do provide results specific to women attending antenatal clinics. The inclusion of HIV testing in the 2005, 2010, and 2014–15 RDHS surveys offer[ed] the opportunity to better understand the magnitude and patterns of infection in the general population of reproductive age, including men age 15–59 who are not tested as part of antenatal sentinel surveillance. The 2014–15 RDHS is the third RDHS survey to anonymously link HIV testing results with key behavioral and sociodemographic characteristics of both male and female respondents, the first being the 2005 RDHS. These surveys provide national, population-based trend data on HIV prevalence among women age 15–49 and men age 15–59. In addition, for the first time, the 2014–15 RDHS included HIV testing of children age 0–14."[5] In Rwanda, HIV prevalence has been stable since 2005 and remains at 3% among adults age 15–49 (4% among women and 2% among men). The prevalence of HIV is higher in urban areas (6%) than rural areas (2%); HIV prevalence is 6% in the capital city of Kigali and 2–3% in each of the other provinces.[5] The HIV prevalence increases with age. Less than 1% of children (ages 0–14) are living with HIV. Across age groups, the highest HIV prevalence is observed among women age 40–44 (8%) and men age 45–49 (9%).[5] Regardless of sex, HIV prevalence is closely related to marital status. Fifteen percent of widows and 8% of those divorced or separated reported being HIV positive, as compared with only 3% of those who were married at the time of the survey.[5] By wealth, HIV prevalence is highest among both young women and young men in the highest wealth quintile. However, the relationship between HIV prevalence and household wealth quintile is not linear.[5] Among youth in Rwanda, HIV prevalence by educational attainment. Five percent of young women with no education are HIV-positive whereas 2% of young women with a primary education and 1% with a secondary education or higher are HIV-positive. Among young men, HIV prevalence is higher among those with any education than among those with none.[5] ## National policy and programmatic responses to the HIV/AIDS epidemic[edit] ### History of Rwanda's HIV/AIDS response[edit] #### Early responses[edit] Rwanda's HIV/AIDS surveillance efforts began in 1984 with the establishment of a national AIDS case reporting system in hospitals and health centers.[3] The country's early response to its HIV/AIDS epidemic was relatively rapid and sustained. In 1985, the Rwandan Ministry of Health and the Red Cross established one of the first and most effective blood donor screening programs in Africa.[6] In 1986, Rwanda was the first country in the world to conduct and report on a nationally representative HIV/AIDS seroprevalence survey.[7] In 1987, the National AIDS Program was established in collaboration with the World Health Organization (WHO).[7] #### The 1990–1994 civil war and genocide[edit] Rwanda's civil war began in 1990. Between April and July 1994, genocide claimed the lives of an estimated 800,000 Rwandese, displaced nearly four million people, and had a devastating impact on national health infrastructure. In addition to severe limitations being placed on the ability of the Rwandan government to prevent and treat HIV/AIDS during the genocide, the International Criminal Tribunal for Rwanda noted the use of 'genocidal rape' as a weapon of war during this time, with between 250,000 and 500,000 women and girls being subjected to rape.[8] Deliberate infection with HIV was observed as a pattern of warfare. The exact effect of these actions on HIV/AIDS prevalence is, however, not known. #### Rebuilding after the civil War[edit] After the civil war and the genocide, Rwanda's health system had been devastated, with life expectancy at just 30 years and four out of five children dying before their first birthday.[9] Between 1990 and 2002, the country recorded steadily increasing numbers of new AIDS cases with between 1,000 and 4,000 new case reports per year. This was followed more recently by dramatic increases in cases in 2003 and 2004 (over 6,000 and 12,000 cases reported, respectively).[7] Overall, HIV prevalence is thought to have stabilized since its peak in the early 1990s, partly also due to the effects of the genocide.[7] Rwanda adopted a community-based healthcare model (called Mutuelles de Santé, the insurance requires community members to pay a premium based on their income and a 10% upfront charge for each visit) to counter shortages in skilled professionals and prioritized national ownership of healthcare as a central aspect of its health reconstruction efforts after the war. Vision 2020, the national development plan which aims to make Rwanda a lower-middle income-country by 2020, includes health as a central aspect of development and guides the national allocation of resources.[10] Rwanda favors a multi-sectoral approach to health care, and, while funding for the health system is heavily dependent on donor aid, State ownership and control over policy is strong.[9] #### HIV/AIDS policies and programs in the past[edit] There has been growing availability of HIV testing, care, and treatment services in Rwanda since 2000. Anti-retroviral therapy (ART) was first introduced in 1999. The 2005–2009 Health Sector Strategic Plan names as one of its goals the curbing and reversal of the spread of HIV infection by 2015.[11] It also includes as goals increasing demand for HIV prophylaxis and treatment through the development of public education campaigns and 'gender-specific' implementation. In 2006, it was reported that voluntary testing and counseling was available at 226 sites. Large-scale Prevention of Mother to Child Transmission (PMTCT) and health promotion initiatives were also reported in at least 208 sites.[7] In 2009, Rwanda published its first National Strategic Plan on HIV and AIDS, outlining the overarching goals for the country's multi-sector response. "It is based on the most up-to-date understanding of the epidemic and the strengths and weaknesses of the systems and mechanisms that are used to respond." The Plan calls for "universal access to HIV and AIDS services".[12] In addition, it counts the reduction of infections, reduced morbidity and mortality and equal opportunities for persons living with HIV/AIDS as goals. The plan also targeted behavior change and risk reduction as important outcomes. In 2012, it was estimated that 80% of people in need of ART were able to access it through the community-based healthcare system.[13] The National Strategic Plan (2009–2012) was succeeded by the Second National Strategic Plan on HIV and AIDS (2013–2018). ### Current legal and policy framework[edit] HIV/AIDS is prioritized in several policy instruments, including Vision 2020 and the Economic Development and Poverty Reduction Strategy 2013–2018 (EDPRS II),[14] which includes a framework for multi-sectoral responses to HIV/AIDS. Each sector within EDPRS II has specific HIV mainstreaming strategies and targets, including education, health, labor, military, transport, gender, young people, agriculture, finance and social welfare. The third Health Sector Strategic Plan (HSSP-III)[15] is a framework document for the development and shaping of health policy in Rwanda. Among its goals are the reduction of HIV infections, reduction of HIV-related morbidity and mortality, strengthened management of HIV/AIDS and equal opportunities for people living with HIV. #### Second National Strategic Plan on HIV and AIDS (National Strategic Plan 2013–2018)[16][edit] The National Strategic Plan is a reference document for all sectors, institutions and partners involved in the fight against HIV and AIDS. The National Strategic Plan goals include: * Lowering the new infection rate by two thirds from an estimated 6,000 per year currently to 2,000; * Halving the number of HIV-related deaths from 5,000 to 2,500 per year; and * Ensuring that people living with HIV have the same opportunities as all others. The National Strategic Plan addresses issues of key populations and vulnerable groups. These include men who have sex with men, sex workers, mobile populations, persons in uniform, young people, women and girls and people with disabilities. Key settings such as prisons, schools and workplaces are also taken into account. Cross cutting issues related to human rights protection, stigma and discrimination, gender inequality, poverty and involvement of people living with HIV also feature in the National Strategic Plan. The National Strategic Plan outlines strategies such as creating public awareness of stigma and discrimination and addressing the legal barriers that prevent key populations from accessing and utilizing services. Due to the lack of a mid-term progress report, it is unclear if this objective has been met. Prevention of sexual transmission of HIV and sexually transmitted infections, prevention of mother to child transmission of HIV, counselling and testing and prevention of HIV in health care settings are stated priorities of the National Strategic Plan. In addition, the key drivers of HIV in Rwanda have been identified through the Mode of Transmission model. The strategies for prevention have since been revised and updated to be more consistent with new developments and technology. For example, male circumcision using Prepex is currently being rolled out in the Rwanda. According to the National Strategic Plan, priority interventions relating to HIV treatment include increasing access and enrolment on ART, providing treatment for TB/HIV co-infection and community and home-based palliative care. There has been a lot of progress in the area of treatment including more people being able to access ART, the adoption of the test and treat strategy for discordant couples, sex workers, and the adoption of the new WHO treatment guidelines and the availability of treatment for prisoners. However, challenges still remain with regard to pre-ART care, treatment for opportunistic infections and improving adherence. With regard to orphans and vulnerable children (OVC), the development of OVC standards of care has recently taken place. The National Strategic Plan focuses on strategic needs of OVC such as protecting their human rights and ensuring access to adequate food, shelter, education and health services, and protection from abuse. Major challenges include the continuous increase in OVC, poor data collection and lack of a national OVC database. The National Strategic Plan includes indicators and targets, making it possible to track progress and follow up on commitments made. It will be evaluated both at midterm and at the end of the cycle. Thus far, there have not been any mid-term reports published. #### Other relevant legislation and policy[edit] The Constitution of Rwanda[17] and the regulation regarding labor in Rwanda (N° 13/2009 of 27/05/2009)[18] prohibits discrimination within certain contexts. These are general laws with no specific reference to HIV and AIDS. With regard to the laws to reduce violence against women, the Law on Prevention and Punishment of Gender-Based Violence was enacted in 2008.[19] It outlaws gender-based violence which is defined broadly to include physical, sexual, economic and psychological violence. Read with the Penal Code, the Act criminalizes willful HIV transmission. This is due to the fact that the Act defines sexual abuse to include "the engagement of another person in sexual contact, whether married or not, which includes sexual conduct that abuses, humiliates or degrades the other person or otherwise violates another person's sexual integrity, or sexual contact by a person aware of being infected with HIV or any other sexually transmitted infection with another person without that other person being given prior information of the infection." ## HIV interventions and achievements[edit] ### Prevention[edit] Rwanda uses a number of HIV/AIDs prevention strategies. These include social and educational programs, condom distribution, volunteer medical male circumcision, and prevention of mother to child transmission. #### Testing and counseling programs[edit] HIV testing and counseling (HTC) services are provided free of charge in all public health facilities and accredited private clinics in Rwanda. Outreach HCT campaigns are regularly carried out to deliver services to areas with less access to the health system. These campaigns are conducted in partnership with community-based organizations, the private sector, non-governmental organizations (NGOs) and faith-based organizations. In 2013, Rwanda introduced testing using "finger prick" blood collection in all health facilities. The number of health facilities offering voluntary counseling and testing has increased from 15 in 2001 to 493 in 2013.[20] Special attention is given to the prevention of HIV among vulnerable groups. Of these vulnerable groups, female sex workers were identified as key in preventing the further spread of HIV. In 2010, the prevalence of HIV among sex workers was 51%.[21] To address female sex workers, national guidelines for HIV prevention in this vulnerable population were developed and disseminated as a part of the HIV National Strategic Plan 2013–2018. ROADS II, a USAID project, has been key in facilitating trainings, mentorships and peer groups to improve knowledge of HIV and prevention strategies, and condom distribution through peer education.[22] #### Condom distribution[edit] Rwanda has made gains in the distribution of condoms through social marketing and rapid sales outlets. The private sector has also been active in the uptake of condom use. From 2009 to 2013, 5 million more condoms have been distributed.[20] #### Circumcision[edit] In 2014, the prevalence of male circumcision was 30% between the ages of 15-49.[5] Voluntary medical male circumcision was added to the 2013–2018 National Strategic Plan of HIV. Surgical kit for voluntary medical male circumcision were provided to all facilities and two healthcare workers were trained per facility. These services are now regularly provided. #### Prevention of mother to child transmission (PMTCT)[edit] PMTCT services have been scaled up throughout the country with 97% of all facilities provide PMCTC services by 2013.[20] The national elimination of mother to child transmission strategy of 2011–2015 integrated PMTCT services into the regular healthcare system. Community health workers are also active in seeking out women who have missed follow-up appointments. Services for PMTCT provided during antenatal care visits include pre and post-test HIV counseling, blood draws for CD4, an appointment for CD4 results, partner testing, hemoglobin testing, WHO HIV clinical classification and enrolment in care, the initiation of ART, counseling on infant feeding and counseling on family planning. Option B+, an alternative PMTCT method, starts pregnant women on ARTs and continues treatment through pregnancy and life regardless of CD4 count. This treatment has been initiated in Rwanda and is being scaled to every health facility.[20] ### Care, treatment, and support[edit] Rwanda has been updated its management and protocols in accordance with 2013 WHO recommendations. New efforts include treatment as prevention for female sex workers and men who have sex with men and test and treat protocols for tuberculosis-HIV co-infection, hepatitis B virus-HIV co-infection, and hepatitis C virus-HIV co-infection. Over the course of the last ten years, treatment of HIV patients with ARTs has been considerably scaled up. In 2002, only four facilities delivered ARTs compared to 465 in 2013. Now 91% of cases receive care and treatment. ## Current challenges in the HIV/AIDS response[edit] ### External donor funding[edit] Continued, rapid decline in donor funding from external resources may affect targets set by the government "to reduce by 75% new HIV infections, reduce by 50% AIDS related deaths, and reach zero stigma and discriminations for people infected and affected by HIV, the government of Rwanda is putting in all efforts to takeover, however the reduction trend from external resources".[xxxvi] ### Stigma[edit] Widespread stigma and discrimination toward those living with HIV and AIDS can adversely impact willingness to be tested for HIV and compliance with ART. ### Targeting subpopulations[edit] Key populations – female workers, youth, and men with higher educational attainment – play an important role in the dynamic of HIV in Rwanda. ## Financing for the national HIV response[edit] Health expenditures on HIV are tracked through the Health Resource Tracking tool. All health sector actors, including Government institutions and Development Partners, are required to report annually their HIV expenditures for the previous fiscal year, as well as their budgets for the current fiscal year. Rwanda's Global AIDS Response Progress Report 2014 provides recent national HIV financing information for fiscal year 2011–2012 and fiscal year 2012–2013.[20] ### Key development partners[edit] Rwanda's key HIV development and funding partners include the Global Fund to Fight AIDS, Tuberculous and Malaria and PEPFAR. Additional development partners (including international foundations and NGOs, bilateral agencies, and the United Nations (UN)) provide financial and technical support and aid in Rwanda's process of HIV policy and program development.[20] Development partners work with the Rwandan Government to set and achieve targets outlined in the National Strategic Plan 2013–2018. Development partners conduct joint planning and coordination with the Government and submit annual reports and budgets to ensure the Government can monitor and maximize development partners' resources. Rwanda has a common monitoring and evaluation system managed by Rwanda Biomedical Center-HIV Division where development partners can utilize reporting tools. National and international partners are encouraged to work together to maximize time spent supporting beneficiaries and minimize the reporting burden.[20] ### Rwanda fiscal year 2011–2012[edit] Public and external funding sources for HIV/AIDS in Rwanda in fiscal year 2011–2012 totaled USD 234.6 million. Of the total funding, USD 17.7 million (7.6% of total HIV/AIDS spending) came from public funding, and USD 216.8 million (92.4% of total HIV/AIDS spending) came from external funding. This total funding excludes out-of-pocket and private sector contribution.[20] Among external HIV/AIDS funding sources in Rwanda, the Global Fund made up 48.8% of HIV/AIDS funding, followed by the U.S. government (39.3%), international NGOs (2.8%), and UN agencies (1.8%). Additional bilateral organizations played a smaller role, with the Government of Luxembourg and Swiss Development Cooperation combined contributing 0.2% of total HIV/AIDS funding. The only other multilateral agency contributing to the total funding included the World Bank, representing 0.01% of total HIV/AIDS funding.[20] ### Rwanda fiscal year 2012–2013[edit] Public and external funding sources for HIV/AIDS in Rwanda in fiscal year 2012–2013 totaled USD 243.6 million, a four percent increase from the previous fiscal year spending. Of the total funding, USD 20.0 million (8.2% of total HIV/AIDS spending) came from public funding, and USD 223.6 million (91.8% of total HIV/AIDS spending) came from external funding. This total funding excludes out-of-pocket and private sector contribution.[20] Among external HIV/AIDS funding sources in Rwanda, Global Fund for AIDS, Tuberculous and Malaria made up 54.7% of HIV/AIDS funding, followed by the U.S. government (34.6%), international NGOs (1.0%), and UN Agencies (1.0%). Additional bilateral organizations contributed less than 0.5% of total HIV/AIDS funding.[20] ## See also[edit] * AIDS pandemic * HIV/AIDS in Africa ## References[edit] 1. ^ a b " HIV/AIDS, Malaria and Other Diseases" UN in Rwanda (2014) Accessed May 20, 2016. 2. ^ "2008 Country Profile: Rwanda". U.S. Department of State (2008). Accessed August 25, 2008. This article incorporates text from this source, which is in the public domain. 3. ^ a b Van de Perre, P.; Rouvroy, D.; Lepage, P.; Bogaerts, J.; Kestelyn, P.; Kayihigi, J.; Hekker, A. C.; Butzler, J. P.; Clumeck, N. (1984-07-14). "Acquired immunodeficiency syndrome in Rwanda". Lancet. 2 (8394): 62–65. doi:10.1016/s0140-6736(84)90240-x. ISSN 0140-6736. PMID 6146008. 4. ^ UNAIDS. "HIV and AIDS estimates (2015)". 5. ^ a b c d e f g National Institute of Statistics of Rwanda; Ministry of Finance and Economic Planning; Ministry of Health; The DHS Program ICF International (2016). Rwanda Demographic and Health Survey, 2014-15 Final Report (PDF). Kigali, Rwanda and Rockville, Maryland. 6. ^ Allen, S.; Lindan, C.; Serufilira, A.; Van de Perre, P.; Rundle, A. C.; Nsengumuremyi, F.; Carael, M.; Schwalbe, J.; Hulley, S. (1991-09-25). "Human immunodeficiency virus infection in urban Rwanda. Demographic and behavioral correlates in a representative sample of childbearing women". JAMA. 266 (12): 1657–1663. doi:10.1001/jama.1991.03470120059033. ISSN 0098-7484. PMID 1886188. 7. ^ a b c d e Kayirangwa, E.; Hanson, J.; Munyakazi, L.; Kabeja, A. (2006-04-01). "Current trends in Rwanda's HIV/AIDS epidemic". Sexually Transmitted Infections. 82 Suppl 1: i27–31. doi:10.1136/sti.2006.019588. ISSN 1368-4973. PMC 2593071. PMID 16581756. 8. ^ Donovan, Paula (2002-12-01). "Rape and HIV/AIDS in Rwanda". Lancet. 360 Suppl: s17–18. doi:10.1016/s0140-6736(02)11804-6. ISSN 0140-6736. PMID 12504487. 9. ^ a b Emery, Neal. "Rwanda's Historic Health Recovery: What the U.S. Might Learn". Retrieved 2016-10-06. 10. ^ Republic of Rwanda Ministry of Finance and Economic Planning (2000). Rwanda Vision 2020 (PDF). 11. ^ Republic of Rwanda (2009). Health Sector Strategic Plan 2005-2009 (PDF). 12. ^ Republic of Rwanda (2009). Rwanda National Strategic Plan on HIV and AIDS 2009-2012 (PDF). 13. ^ Rosenberg, Tina. "In Rwanda, Health Care Coverage That Eludes the U.S." Retrieved 2016-10-06. 14. ^ "EDPRS-II" (PDF). 15. ^ "HSSP III" (PDF). 16. ^ Ministry of Health (2013). Rwanda HIV and AIDS National Strategic Plan 2013-2018 (PDF). Rwanda Biomedical Center. 17. ^ "Constitution of Rwanda". 18. ^ "LAW N° 13/2009 OF 27 MAY 2009 REGULATING LABOUR IN RWANDA". lip.alfa-xp.com. Retrieved 2016-10-06. 19. ^ Refugees, United Nations High Commissioner for. "Refworld \| Rwanda: Law No. 59/2008 of 2008 on Prevention and Punishment of Gender-Based Violence". Retrieved 2016-10-06. 20. ^ a b c d e f g h i j k Republic of Rwanda Ministry of Health (March 2014). Rwanda Global AIDS Response Progress Report (GARPR) 2014 (PDF). Rwanda Biomedical Center. 21. ^ Republic of Rwanda Ministry of Health (2010). Behavioral and Biological Surveillance Survey Among Female Sex Workers, Rwanda: Survey Report (PDF). Kigali, Rwanda. 22. ^ Family Health International (FHI 360) (2013). Roads to a Healthy Future (ROADS II) Project in Rwanda: Final Project Report. USAID. * v * t * e HIV/AIDS in Africa Sovereign states * Algeria * Angola * Benin * Botswana * Burkina Faso * Burundi * Cameroon * Cape Verde (Cabo Verde) * Central African Republic * Chad * Comoros * Democratic Republic of the Congo * Republic of the Congo * Djibouti * Egypt * Equatorial Guinea * Eritrea * Eswatini (Swaziland) * Ethiopia * Gabon * The Gambia * Ghana * Guinea * Guinea-Bissau * Ivory Coast (Côte d'Ivoire) * Kenya * Lesotho * Liberia * Libya * Madagascar * Malawi * Mali * Mauritania * Mauritius * Morocco * Mozambique * Namibia * Niger * Nigeria * Rwanda * São Tomé and Príncipe * Senegal * Seychelles * Sierra Leone * Somalia * South Africa * South Sudan * Sudan * Tanzania * Togo * Tunisia * Uganda * Zambia * Zimbabwe States with limited recognition * Sahrawi Arab Democratic Republic * Somaliland Dependencies and other territories * Canary Islands / Ceuta / Melilla (Spain) * Madeira (Portugal) * Mayotte / Réunion (France) * Saint Helena / Ascension Island / Tristan da Cunha (United Kingdom) * v * t * e HIV/AIDS topics HIV/AIDS HIV * HIV * Lentivirus * structure and genome * subtypes * CDC classification * disease progression rates * HIV/AIDS * diagnosis * management * pathophysiology * prevention * research * vaccination * PrEP * WHO disease staging system for HIV infection and disease * Children * Teens / Adults * Countries by AIDS prevalence rate Conditions * Signs and symptoms * AIDS-defining clinical condition * Diffuse infiltrative lymphocytosis syndrome * Lipodystrophy * Nephropathy * Neurocognitive disorders * Pruritus * Superinfection * Tuberculosis co-infection * HIV Drug Resistance Database * Innate resistance to HIV * Serostatus * HIV-positive people * Nutrition * Pregnancy History * History * Epidemiology * Multiple sex partners * Timeline * AIDS Museum * Timothy Ray Brown * Women and HIV/AIDS Social * AIDS orphan * Catholic Church and HIV/AIDS * Circumcision and HIV * Criminal transmission * Discrimination against people * Economic impact * Cost of treatment * HIV-affected community * HIV/AIDS activism * HIV/AIDS denialism * Red ribbon * Safe sex * Sex education * List of HIV-positive people * People With AIDS Self-Empowerment Movement * HIV/AIDS in the porn industry Culture * Discredited HIV/AIDS origins theories * International AIDS Conference * International AIDS Society * Joint United Nations Programme on HIV/AIDS (UNAIDS) * Media portrayal of HIV/AIDS * Misconceptions about HIV/AIDS * President's Emergency Plan for AIDS Relief (PEPFAR) * The SING Campaign * Solidays * Treatment Action Campaign * World AIDS Day * YAA/Youthforce * "Free Me" * Larry Kramer * Gay Men's Health Crisis * ACT UP * Silence=Death Project HIV/AIDS pandemic by region / country Africa * Angola * Benin * Botswana * Democratic Republic of the Congo * Egypt * Eswatini * Ethiopia * Ghana * Guinea * Côte d'Ivoire (Ivory Coast) * Kenya * Lesotho * Madagascar * Malawi * Mali * Mozambique * Namibia * Niger * Nigeria * Rwanda * Senegal * Tanzania * 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 inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors	HIV/AIDS in Rwanda	None	1,899	wikipedia	https://en.wikipedia.org/wiki/HIV/AIDS_in_Rwanda	2021-01-18T18:41:46	{"wikidata": ["Q11349126"]}

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