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Surface epithelial-stromal tumor High magnification micrograph of a Brenner tumor, a type of surface epithelial-stromal tumor. H&E stain. SpecialtyOncology Surface epithelial-stromal tumors are a class of ovarian neoplasms that may be benign or malignant. Neoplasms in this group are thought to be derived from the ovarian surface epithelium (modified peritoneum) or from ectopic endometrial or Fallopian tube (tubal) tissue. Tumors of this type are also called ovarian adenocarcinoma.[1] This group of tumors accounts for 90% to 95% of all cases of ovarian cancer.[2] Serum CA-125 is often elevated but is only 50% accurate so it is not a useful tumor marker to assess the progress of treatment. ## Contents * 1 Classification * 1.1 Serous tumors * 1.1.1 Pathology * 1.1.2 Prognosis * 1.2 Mucinous tumors * 1.2.1 Pathology * 1.2.2 Prognosis * 1.3 Endometrioid tumors * 1.3.1 Pathology * 1.3.2 Prognosis * 1.4 Clear cell tumors * 1.4.1 Prognosis * 1.5 Brenner tumor * 1.6 Small cell tumors * 2 Treatment * 3 Metastases * 4 Effect on fertility * 5 References * 6 Sources * 7 External links ## Classification[edit] Ovarian tumors by incidence and risk of ovarian cancer, with surface epithelial-stromal tumors at top.[3] Ovarian cancers in women aged 20+, with area representing relative incidence and color representing 5-year relative survival rate.[1] Surface epithelial-stromal tumors are labeled in center of the main diagram, and represent all types except the ones separated at top. Epithelial-stromal tumors are classified on the basis of the epithelial cell type, the relative amounts of epithelium and stroma, the presence of papillary processes, and the location of the epithelial elements. Microscopic pathological features determine whether a surface epithelial-stromal tumor is benign, a borderline tumor, or malignant (evidence of malignancy and stromal invasion). Borderline tumors are of uncertain malignant potential. This group consists of serous, mucinous, endometrioid, clear cell, and brenner (transitional cell) tumors, though there are a few mixed, undifferentiated and unclassified types. ### Serous tumors[edit] Histopathology of lining of a benign serous tumor of the ovary. Benign serous ovarian tumors are thin walled unilocular cysts that are lined by ciliated pseudostratified cuboidal or columnar epithelium.[4] * These tumors vary in size from small and nearly imperceptible to large, filling the abdominal cavity. * Benign, borderline, and malignant types of serous tumors account for about 30% of all ovarian tumors. * 75% are benign or of borderline malignancy, and 25% are malignant * The malignant form of this tumor, serous cystadenocarcinoma, accounts for approximately 40% of all carcinomas of the ovary and are the most common malignant ovarian tumors. * Benign and borderline tumors are most common between the ages of 20 and 50 years. * Malignant serous tumors occur later in life on average, although somewhat earlier in familial cases. * 20% of benign, 30% of borderline, and 66% of malignant tumors are bilateral (affect both ovaries). Components can include: 1. cystic areas 2. cystic and fibrous areas 3. predominantly fibrous areas The chance of malignancy of the tumor increases with the amount of solid areas present, including both papillary structures and any necrotic tissue present. #### Pathology[edit] * lined by tall, columnar, ciliated epithelial cells * filled with clear serous fluid * the term serous which originated as a description of the cyst fluid has come to be describe the particular type of epithelial cell seen in these tumors * may involve the surface of the ovary * the division between benign, borderline, and malignant is ascertained by assessing: * cellular atypia (whether or not individual cells look abnormal) * invasion of surrounding ovarian stroma (whether or not cells are infiltrating surrounding tissue) * borderline tumors may have cellular atypia but do NOT have evidence of invasion * the presence of psammoma bodies are a characteristic microscopic finding of cystadenocarcinomas[5] #### Prognosis[edit] The prognosis of a serous tumor, like most neoplasms, depends on * degree of differentiation * this is how closely the tumor cells resemble benign cells * a well-differentiated tumor closely resembles benign tumors * a poorly differentiated tumor may not resemble the cell type of origin at all * a moderately differentiated tumor usually resembles the cell type of origin, but appears frankly malignant * extension of tumor to other structures * in particular with serous malignancies, the presence of malignant spread to the peritoneum is important with regard to prognosis. The five year survival rate of borderline tumors and malignant tumors confined to the ovaries are 100% and 70% respectively. If the peritoneum is involved, these rates become 90% and 25%. While the 5-year survival rates of borderline tumors are excellent, this should not be seen as evidence of cure, as recurrences can occur many years later. ### Mucinous tumors[edit] Histopathology of lining of a benign mucinous tumor of the ovary. Benign mucinous ovarian tumors consist of simple, nonstratified columnar epithelium with basally-located hyperchromatic nuclei and resemble gastric foveolar epithelium.[4] Mucinous tumors: * Closely resemble their serous counterparts but unlikely to be bilateral * Somewhat less common, accounting for about 25% of all ovarian neoplasms * In some cases mucinous tumors are characterized by more cysts of variable size and a rarity of surface involvement as compared to serous tumors * Also in comparison to serous tumors, mucinous tumors are less frequently bilateral, approximately 5% of primary mucinous tumors are bilateral. * May form very large cystic masses, with recorded weights exceeding 25 kg #### Pathology[edit] Mucinous tumors are characterized by a lining of tall columnar epithelial cells with apical mucin and the absence of cilia, similar in appearance with benign cervical or intestinal epithelia. The appearance can look similar to colonic or ovarian cancer, but typically originates from the appendix (see mucinous adenocarcinoma with clinical condition Pseudomyxoma peritonei). Clear stromal invasion is used to differentiate borderline tumors from malignant tumors. #### Prognosis[edit] 10-year survival rates for borderline tumors contained within the ovary, malignant tumors without invasion, and invasive malignant tumors are greater than 95%, 90%, and 66%, respectively. One rare but noteworthy condition associated with mucinous ovarian neoplasms is pseudomyxoma peritonei. As primary ovarian mucinous tumors are usually unilateral (in one ovary), the presentation of bilateral mucinous tumors requires exclusion of a non-ovarian origin, usually the appendix. ### Endometrioid tumors[edit] Endometrioid tumors account for approximately 20% of all ovarian cancers and are mostly malignant (endometroid carcinomas). They are made of tubular glands bearing a close resemblance to benign or malignant endometrium. 15-30% of endometrioid carcinomas occur in individuals with carcinoma of the endometrium, and these patients have a better prognosis. They appear similar to other surface epithelial-stromal tumors, with solid and cystic areas. 40% of these tumors are bilateral, when bilateral, metastases is often present. #### Pathology[edit] * Glands bearing a strong resemblance to endometrial-type glands * Benign tumors have mature-appearing glands in a fibrous stroma * Borderline tumors have a complex branching pattern without stromal invasion * Carcinomas (malignant tumors) have invasive glands with crowded, atypical cells, frequent mitoses. With poorer differentiation, the tumor becomes more solid. #### Prognosis[edit] Prognosis again is dependent on the spread of the tumor, as well as how differentiated the tumor appears. The overall prognosis is somewhat worse than for serous or mucinous tumors, and the 5-year survival rate for patients with tumors confined to the ovary is approximately 75%. ### Clear cell tumors[edit] Micrograph of an ovarian clear cell carcinoma. H&E stain. Clear cell tumors are characterized by large epithelial cells with abundant clear cytoplasm and may be seen in association with endometriosis or endometrioid carcinoma of the ovary, bearing a resemblance to clear cell carcinoma of the endometrium. They may be predominantly solid or cystic. If solid, the clear cells tend to be arranged in sheets or tubules. In the cystic variety, the neoplastic cells make up the cyst lining. #### Prognosis[edit] These tumors tend to be aggressive, the five year survival rate for tumors confined to the ovaries is approximately 65%. If the tumor has spread beyond the ovary at diagnosis, the prognosis is poor ### Brenner tumor[edit] Brenner tumour. H&E stain. Brenner tumors are uncommon surface-epithelial stromal cell tumors in which the epithelial cell (which defines these tumors) is a transitional cell. These are similar in appearance to bladder epithelia. The tumors may be very small to very large, and may be solid or cystic. Histologically, the tumor consists of nests of the aforementioned transitional cells within surrounding tissue that resembles normal ovary. Brenner tumors may be benign or malignant, depending on whether the tumor cells invade the surrounding tissue. ### Small cell tumors[edit] Small cell ovarian cancer (SCCO) are generally classified into epithelial tumors[6] associated with distinctive endocrine features.[7] The World Health Organisation (WHO) recognises SCCO as two distinct entities: Small Cell Ovarian Cancer of Hypercalcemic Type (SCCOHT) and Small Cell Ovarian Cancer of Pulmonary Type (SCCOPT).[7] Small cell tumours are rare and aggressive, they contribute to less than 2% of all gynaecologic malignancies.[7] The average age of diagnosis is 24 years old, and the majority of patients also present with hypercalcemia (62%).[8] It typically present with a unilateral large tumor.[8] Most women die within a year of diagnosis.[8] ## Treatment[edit] For more general information, see ovarian cancer. Research suggests that in the first line treatment of Endometrial Ovarian Cancer (EOC), Pegylated Liposomal Doxorubicin paired with Carboplatin is a satisfactory alternative to Paclitaxel with Carboplatin.[9] In people with platinum-sensitive relapsed EOC, research has found that Pegylated Liposomal Doxorubicin with Carboplatin is a better treatment than Paclitaxel with Carboplatin.[10] For advanced cancer of this histology, the US National Cancer Institute recommends a method of chemotherapy that combines intravenous (IV) and intraperitoneal (IP) administration.[11] Preferred chemotherapeutic agents include a platinum drug with a taxane. ## Metastases[edit] For surface epithelial-stromal tumors, the most common sites of metastasis are the pleural cavity (33%), the liver (26%), and the lungs (3%).[12] ## Effect on fertility[edit] Fertility subsequent to treatment of surface epithelial-stromal tumors depends mainly on histology and initial staging to separate it into early borderline (or more benign) versus advanced stages of borderline (or more malignant).[13] Conservative management (without bilateral oophorectomy) of early stage borderline tumors have been estimated to result in chance of over 50% of spontaneous pregnancy with a low risk of lethal recurrence of the tumor (0.5%).[13] On the other hand, in cases of conservative treatment in advanced stage borderline tumors, spontaneous pregnancy rates have been estimated to be 35% and the risk of lethal recurrence 2%.[13] ## References[edit] 1. ^ a b Kosary CL (2007). "Chapter 16: Cancers of the Ovary" (PDF). In Baguio RN, Young JL, Keel GE, Eisner MP, Lin YD, Horner MJ (eds.). SEER Survival Monograph: Cancer Survival Among Adults: US SEER Program, 1988-2001, Patient and Tumor Characteristics. SEER Program. NIH Pub. No. 07-6215. Bethesda, MD: National Cancer Institute. pp. 133–144. 2. ^ Bradshaw KD, Schorge JO, Schaffer J, Lisa M H, Hoffman BG (2008). Williams' Gynecology. McGraw-Hill Professional. ISBN 978-0-07-147257-9. 3. ^ \- Vaidya, SA; Kc, S; Sharma, P; Vaidya, S (2014). "Spectrum of ovarian tumors in a referral hospital in Nepal". Journal of Pathology of Nepal. 4 (7): 539–543. doi:10.3126/jpn.v4i7.10295. ISSN 2091-0908. \- Minor adjustment for mature cystic teratomas (0.17 to 2% risk of ovarian cancer): Mandal, Shramana; Badhe, Bhawana A. (2012). "Malignant Transformation in a Mature Teratoma with Metastatic Deposits in the Omentum: A Case Report". Case Reports in Pathology. 2012: 1–3. doi:10.1155/2012/568062. ISSN 2090-6781. PMC 3469088. PMID 23082264. 4. ^ a b Baradwan, Saeed; Alalyani, Haneen; Baradwan, Amira; Baradwan, Afnan; Al-Ghamdi, Maram; Alnemari, Jameel; Al-Jaroudi, Dania (2018). "Bilateral ovarian masses with different histopathology in each ovary". Clinical Case Reports. 6 (5): 784–787. doi:10.1002/ccr3.1466. ISSN 2050-0904. PMC 5930217. PMID 29744056. \- Creative Commons Attribution 4.0 International (CC BY 4.0) license 5. ^ Cotran RS, Kumar V, Nelson F, Robbins SL, Abbas AK (2005). Robbins and Cotran pathologic basis of disease (7th ed.). St. Louis, Mo: Elsevier Saunders. ISBN 978-0-7216-0187-8. 6. ^ Atlas of Genetics and Cytogenetics in Oncology and Haematology - Ovary: Epithelial tumors. Retrieved June 2014. By Lee-Jones, L. Atlas Genet Cytogenet Oncol Haematol. 2004;8(2):115-133. 7. ^ a b c Kaphan AA, Castro CM (2014-01-01). MPH rG, FRCPATH RH, MD JO, MD MJ (eds.). Small Cell and Neuroendocrine Cancers of the Ovary. John Wiley & Sons, Ltd. pp. 139–147. doi:10.1002/9781118655344.ch12. ISBN 9781118655344. 8. ^ a b c Bakhru A, Liu JR, Lagstein A (2012). "A case of small cell carcinoma of the ovary hypercalcemic variant in a teenager". Gynecologic Oncology Case Reports. 2 (4): 139–42. doi:10.1016/j.gynor.2012.09.001. PMC 3861231. PMID 24371647. 9. ^ Lawrie TA, Rabbie R, Thoma C, Morrison J, et al. (The Cochrane Collaboration) (October 2013). Lawrie TA (ed.). "Pegylated liposomal doxorubicin for first-line treatment of epithelial ovarian cancer". The Cochrane Database of Systematic Reviews. John Wiley & Sons, Ltd (10): CD010482. doi:10.1002/14651858.cd010482.pub2. PMC 6457824. PMID 24142521. 10. ^ Lawrie TA, Bryant A, Cameron A, Gray E, Morrison J (July 2013). "Pegylated liposomal doxorubicin for relapsed epithelial ovarian cancer". The Cochrane Database of Systematic Reviews (7): CD006910. doi:10.1002/14651858.cd006910.pub2. PMC 6457816. PMID 23835762. 11. ^ "NCI Issues Clinical Announcement for Preferred Method of Treatment for Advanced Ovarian Cancer". National Cancer Institute. January 2006. Archived from the original on 13 January 2009. 12. ^ Kolomainen DF, Larkin JM, Badran M, A'Hern RP, King DM, Fisher C, et al. (February 2002). "Epithelial ovarian cancer metastasizing to the brain: a late manifestation of the disease with an increasing incidence". Journal of Clinical Oncology. 20 (4): 982–6. doi:10.1200/JCO.2002.20.4.982. PMID 11844820. 13. ^ a b c Daraï E, Fauvet R, Uzan C, Gouy S, Duvillard P, Morice P (2012). "Fertility and borderline ovarian tumor: a systematic review of conservative management, risk of recurrence and alternative options". Human Reproduction Update. 19 (2): 151–66. doi:10.1093/humupd/dms047. PMID 23242913. ## Sources[edit] * Braunwald E (2001). Harrison's principles of internal medicine (15th ed.). New York: McGraw-Hill. ISBN 978-0-07-913686-2. ## External links[edit] Classification D * ICD-10: C56, D27 * ICD-9-CM: 183, 220 * MeSH: C538090 * Johns Hopkins: "Surface Epithelial Tumors" * Diagram: "Epithelial Stromal Ovarian Tumors" * Small Cell Ovarian Cancer Research Collaboration & Patients Registry * v * t * e Tumors of the female urogenital system Adnexa Ovaries Glandular and epithelial/ surface epithelial- stromal tumor CMS: * Ovarian serous cystadenoma * Mucinous cystadenoma * Cystadenocarcinoma * Papillary serous cystadenocarcinoma * Krukenberg tumor * Endometrioid tumor * Clear-cell ovarian carcinoma * Brenner tumour Sex cord–gonadal stromal * Leydig cell tumour * Sertoli cell tumour * Sertoli–Leydig cell tumour * Thecoma * Granulosa cell tumour * Luteoma * Sex cord tumour with annular tubules Germ cell * Dysgerminoma * Nongerminomatous * Embryonal carcinoma * Endodermal sinus tumor * Gonadoblastoma * Teratoma/Struma ovarii * Choriocarcinoma Fibroma * Meigs' syndrome Fallopian tube * Adenomatoid tumor Uterus Myometrium * Uterine fibroids/leiomyoma * Leiomyosarcoma * Adenomyoma Endometrium * Endometrioid tumor * Uterine papillary serous carcinoma * Endometrial intraepithelial neoplasia * Uterine clear-cell carcinoma Cervix * Cervical intraepithelial neoplasia * Clear-cell carcinoma * SCC * Glassy cell carcinoma * Villoglandular adenocarcinoma Placenta * Choriocarcinoma * Gestational trophoblastic disease General * Uterine sarcoma * Mixed Müllerian tumor Vagina * Squamous-cell carcinoma of the vagina * Botryoid rhabdomyosarcoma * Clear-cell adenocarcinoma of the vagina * Vaginal intraepithelial neoplasia * Vaginal cysts Vulva * SCC * Melanoma * Papillary hidradenoma * Extramammary Paget's disease * Vulvar intraepithelial neoplasia * Bartholin gland carcinoma [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	Surface epithelial-stromal tumor	c0341823	700	wikipedia	https://en.wikipedia.org/wiki/Surface_epithelial-stromal_tumor	2021-01-18T19:00:04	{"gard": ["9362"], "mesh": ["C538090"], "umls": ["C0341823"], "icd-9": ["183", "220"], "icd-10": ["D27", "C56"], "wikidata": ["Q7645976"]}
## Clinical Features Mendoza and Valiente (1997) described an apparently 'new' autosomal dominant ectodermal dysplasia syndrome, which they designated odontotrichoungual-digital-palmar syndrome. In 2 brothers, their mother, and 18 other relatives in 5 generations, the authors observed natal teeth, trichodystrophy, prominent interdigital folds, simian-like hands with transverse palmar creases, and ungual digital dystrophy. Secondary dentition showed irregular eruption. There was brachydactyly and short first metacarpal and metatarsal bones with hypoplasia of the distal phalanges of the toes. There was at least one instance of male-to-male transmission. INHERITANCE \- Autosomal dominant HEAD & NECK Face \- Prognathism Mouth \- Thick, coarse lips Teeth \- Natal teeth \- Malocclusion SKELETAL Hands \- Prominent interdigital folds \- Single transverse palmar creases \- First metacarpal hypoplasia \- Brachydactyly \- Single thumb creases Feet \- First metatarsal hypoplasia \- Hypoplastic distal phalanges \- Brachydactyly SKIN, NAILS, & HAIR Nails \- Nail dystrophy Hair \- Trichodystrophy \- Straw-like fragile hair \- Irregular diameter of hair shaft with hypopigmentation and tendency to fracture (light microscopy) ▲ 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	ODONTOTRICHOUNGUAL-DIGITAL-PALMAR SYNDROME	c1865998	701	omim	https://www.omim.org/entry/601957	2019-09-22T16:14:08	{"mesh": ["C566598"], "omim": ["601957"], "orphanet": ["69082"], "synonyms": ["Alternative titles", "OTUDP SYNDROME"]}
A rare vulvar carcinoma characterized by a slowly growing ulcer or nodule which is histologically composed of demarcated nests of palisaded basal cells originating at the epidermal-dermal junction. Occasionally, the tumor may be extensively pigmented. Patients most commonly present with pruritus. The lesion is usually treated by local excision, although groin metastases have been reported. [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	Vulvar basal cell carcinoma	c1336977	702	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=494451	2021-01-23T19:07:39	{"synonyms": ["Basal cell carcinoma of vulva"]}
Comings et al. (1967) reported 2 brothers, offspring of a first-cousin marriage, who had different combinations of retroperitoneal fibrosis, mediastinal fibrosis, sclerosing cholangitis, Riedel sclerosing thyroiditis, and pseudotumor of the orbit. One of the brothers had fibrotic contracture of the fingers. Goldbach et al. (1983) reported mediastinal and retroperitoneal fibrosis in 2 sisters with seronegative spondylarthropathy. Neither was HLA-B27-positive. Phills et al. (1973) reported retroperitoneal fibrosis in 3 sibs. Zabetakis et al. (1979) raised the possibility that retroperitoneal fibrosis is a manifestation of a collagen vascular disease. Neck \- Riedel sclerosing thyroiditis Inheritance \- Autosomal recessive Abdomen \- Retroperitoneal fibrosis Skel \- Finger contractures \- Seronegative spondylarthropathy \- Camptodactyly Liver \- Sclerosing cholangitis HEENT \- Pseudotumor of orbit Thorax \- Mediastinal fibrosis ▲ 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	FIBROSCLEROSIS, MULTIFOCAL	c0035357	703	omim	https://www.omim.org/entry/228800	2019-09-22T16:27:52	{"mesh": ["D012185"], "omim": ["228800"], "icd-10": ["M35.5"], "orphanet": ["49041"], "synonyms": ["Alternative titles", "MEDIASTINAL FIBROSIS, FAMILIAL", "RETROPERITONEAL FIBROSIS, FAMILIAL"]}
Spastic quadriplegia SpecialtyNeurology Spastic quadriplegia, also known as spastic tetraplegia, is a subset of spastic cerebral palsy that affects all four limbs (both arms and legs). Compared to quadriplegia, spastic tetraplegia is defined by spasticity of the limbs as opposed to strict paralysis. It is distinguishable from other forms of cerebral palsy in that those afflicted with the condition display stiff, jerky movements stemming from hypertonia of the muscles.[1] Spastic quadriplegia, while affecting all four limbs more or less equally, can still present parts of the body as stiffer than others, such as one arm being tighter than another arm, and so forth. Spastic triplegia, meanwhile, involves three limbs (such as one arm and two legs, or one leg and two arms, etc.); spastic diplegia affects two limbs (commonly just the legs), spastic hemiplegia affects one or another entire side of the body (left or right); and spastic monoplegia involves a single limb. ## Contents * 1 Symptoms * 2 Causes * 3 Diagnosis * 3.1 Scientific classification * 4 Management * 5 Research * 6 Notes * 7 External links ## Symptoms[edit] Spastic quadriplegia can be detected by the abnormal development of motor skills in children. Symptoms can present themselves as early as three months but are generally seen before the child reaches two years of age. Some warning signs include: a child of more than two months who has stiff legs that scissor and is unable to control his or her head, and a child of more than twelve months who has not developed the ability to crawl or stand.[2] Spastic quadriplegia also presents a range of symptoms that affect the musculature. Many experience contractures, which are defined as joints that cannot be stretched or moved. Clonus is another symptom that is characterized by alternating, rapid muscle contraction and relaxation. This presents itself as tremors and scissoring of the limbs. Distonia, or lasting muscle contractions and tightness, is also often experienced by those affected by spastic quadriplegia. These involuntary muscle contractions may affect the development of structural muscle around the hip and lead to hip dysplasia and dislocation, making it difficult to sit. The combination of these symptoms often makes it difficult for the patients to walk as well.[2] Although the arms and legs of patients are often stiff, the neck is usually limp due to the lack of voluntary muscle control. Some adults have issues with sexual organs such as the ones that control the sphincter (anus) as well and bladder control. These can sometimes be treated with training and stimulation even if the problems have presented for years, some issues can be corrected in many cases with nutrition modification in 90 percent of cases, especially B12. Stimulation of the muscles involved can treat some forms of nerve damage, depending on what the issue is. Sexual issues can be difficult for those with this, and sexual acts and stimulation can correct most of the sexual issues. ## Causes[edit] Spastic quadriplegia is generally caused by brain damage or disruptions in normal brain development preceding birth. According to the National Institutes of Health, there are four types of brain damage that can cause spastic quadriplegia. These include, damage to the white matter (periventricular leukomalacia), abnormal brain development (cerebral dysgenesis), bleeding in the brain (intracranial hemorrhage), and brain damage due to lack of oxygen (hypoxic-ischemic encephalopathy or intrapartum asphyxia).[2] The white matter of the brain is especially vulnerable between the 26th and 34th weeks of maturation, and damage to the white matter can interfere with the brain’s ability to transmit signals to the rest of the body. Spastic quadriplegia can be caused by a condition known as periventricular leukomalacia which results in the formation of lesions and holes in the white matter of the brain. Prior to the 26th week of maturation, the fetal brain is particularly susceptible to various toxins whose effects can ultimately hinder normal development. Exposure of the brain to infectious agents is especially dangerous because they can trigger immune responses that activate cytokines and lead to inflammation of the brain. Some infections that have been linked to the development of spastic quadriplegia include meningitis, herpes, rubella, and encephalitis.[3] A difference in blood types between the mother and the fetus can also initiate a problematic immune response and cause brain damage. Severe jaundice, can also lead to brain damage and spastic quadriplegia due to a buildup of bilirubin in the blood.[2] Bleeding in the brain caused by fetal strokes, blood clots, weak and malformed blood vessels, or high maternal blood pressure may also lead to brain damage causing spastic quadriplegia. Maternal infection, most specifically pelvic inflammatory disease, has been shown to increase the risk of fetal stroke. Hypoxia, lack of oxygen to the brain, can also cause damage in the cerebral motor cortex and other brain regions. This lack of oxygen can be the result of placenta malfunction, womb rupture, umbilical cord damage, low maternal blood pressure or asphyxia during labor and delivery.[4] Children who experienced many complications during birth, such as, prematurity, insufficient oxygen, low birthweight, aspiration, head injury, or bleeding in the brain have a greater risk of developing spastic quadriplegia. Children whose mothers were ill during the pregnancy or did not receive adequate nutrition are also more likely to develop the disease.[5] ## Diagnosis[edit] Spastic quadriplegia can be diagnosed as early as age one after a noticed delay in development, particularly a delay in rolling, crawling, sitting, or walking.[4][6] However, depending on the severity, signs may not show up until the age of three. Muscle tone is sometimes used to make the diagnosis for spastic quadriplegia as affected children often appear to be either too stiff or too floppy.[2] Another important diagnostic factor is the persistence of primitive reflexes past the age at which they should have disappeared (6–12 months of age).[2] These reflexes include the rooting reflex, the sucking reflex, and the Moro reflex, among others. Magnetic resonance imaging (MRI) or a computed tomography scan (CT scan) may be used to locate the cause of the symptoms. Ultrasound may be used for the same function in premature babies.[2] Because cerebral palsy refers to a group of disorders, it is important to have a clear and systematic naming system. These disorders must be non-progressive, non-transient, and not due to injury to the spinal cord.[7] Disorders within the group are classified based on two characteristics- the main physiological symptom, and the limbs that are affected.[7] For a disorder to be diagnosed as spastic quadriplegia, an individual must show spastic symptoms (as opposed to athetotic, hypertonic, ataxic, or atonic symptoms) and it must be present in all four limbs (as opposed to hemiplegic, diplegic, or triplegic cases).[7] While a diagnosis may be able to be made shortly after birth based on family history and observation of the infant, it is often postponed until after the child is between 18–24 months old in order to monitor the possible regression or progression of symptoms.[8] ### Scientific classification[edit] The scientific classifications for these types include: Type OMIM Gene Locus CPSQ1 603513 GAD1 2q31 CPSQ2 612900 ANKRD15 9p24.3 CPSQ3 612936 AP4M1 7q22.1 ## Management[edit] This section is empty. You can help by adding to it. (October 2017) ## Research[edit] Doublecortin positive cells, similar to stem cells, are extremely adaptable and, when extracted from a brain, cultured and then re-injected in a lesioned area of the same brain, they can help repair and rebuild it. [9] The treatment using them would take some time to be available for general public use, as it has to clear regulations and trials. ## Notes[edit] 1. ^ "spastic cerebral palsy". c.merriam-webster.com. 2. ^ a b c d e f g "An Overview of Spastic Cerebral Palsy". 25 March 2015. 3. ^ https://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0001734 4. ^ a b "Spastic Quadriplegia - Spastic Tetraplegia - BrainAndSpinalCord.org". 5. ^ http://www.formsofcerebralpalsy.com/quadriplegia.html 6. ^ "Cerebral palsy". 7. ^ a b c Minear, WL (Nov 1956). "A classification of cerebral palsy" (PDF). Pediatrics. 18 (5): 841–52. PMID 13370256. 8. ^ http://www.cpirf.org/stories/1065 9. ^ "The brain may be able to repair itself -- with help". ## External links[edit] Classification D * ICD-10: G11.4 External resources * Orphanet: 210141 * v * t * e Cerebral palsy Symptoms and signs Spasticity * Upper motor neuron lesion * Spastic cerebral palsy * Scissor gait * Spastic diplegia * Spastic hemiplegia * Spastic quadriplegia Ataxia and others * Ataxic cerebral palsy * Dyskinetic cerebral palsy Diagnosis General movements assessment Measurement scales * Gross Motor Function Classification System - Expanded & Revised (gross motor function) * Manual Ability Classification System (manual dexterity) * Communication Function Classification System (communication) * Modified Ashworth scale (spasticity) Management * Management of cerebral palsy * Selective percutaneous myofascial lengthening * Rhizotomy Other * People with cerebral palsy * Cerebral palsy organizations * Works about cerebral palsy and other paralytic syndromes [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	Spastic quadriplegia	c0426970	704	wikipedia	https://en.wikipedia.org/wiki/Spastic_quadriplegia	2021-01-18T18:50:47	{"mesh": ["D011782"], "umls": ["C0426970"], "icd-10": ["G80.0"], "orphanet": ["210141"], "wikidata": ["Q3985306"]}
An extremely rare syndrome described in three members of a family (a mother and her two children) that is characterized by the association of various ocular abnormalities (partial or complete aniridia, ptosis, pendular nystagmus, corneal pannus, , persistent pupillary membrane, lenticular opacities, foveal hypoplasia, and low visual acuity) with various systemic anomalies including intellectual disability and obesity in the two children, and alopecia, cardiac abnormalities, and frequent spontaneous abortion in the mother. There have been no further descriptions in the literature since 1986. [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	Aniridia-ptosis-intellectual disability-familial obesity syndrome	None	705	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=1067	2021-01-23T17:35:27	{"gard": ["689"]}
PAGOD syndrome is a severe developmental syndrome characterized by multiple congenital anomalies including cardiovascular defects, pulmonary hypoplasia, diaphragmatic defects and genital anomalies. ## Epidemiology Since the first publication in 1991, only 11 patients have been described. ## Clinical description Neonates with PAGOD syndrome present with several visceral anomalies: hypoplasia of right or left lung, diaphragmatic hernia, omphalocele, various cardiac anomalies including, amongst others, atrial septal defect, left ventricular hypoplasia or ventricular septal defect, and great vessels anomalies such as aortic hypoplasia and pulmonary artery hypoplasia or atresia. Cardiac and mediastinal structures may be in dextroposition. Ambiguous external genitalia can be observed in some cases and all patients present gonadal agenesis or hypoplasia and developmental anomalies of Wolffian and Mullerian duct structures. ## Etiology Etiology is unknown but vitamin A deficiency has been suggested to play a role in the development of the syndrome. ## Genetic counseling Almost all cases are sporadic, except for 2 siblings, suggesting autosomal recessive inheritance. ## Prognosis Life expectancy is reduced due to cardiac and respiratory complications. [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	PAGOD syndrome	c1859967	706	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=991	2021-01-23T18:10:16	{"gard": ["3086"], "mesh": ["C537018"], "omim": ["202660"], "icd-10": ["Q87.8"], "synonyms": ["Pulmonary hypoplasia-agonadism-dextrocardia-diaphragmatic hernia syndrome"]}
Sinoatrial arrest Other namesSinus arrest or Sinus pause SpecialtyCardiology Sinoatrial arrest is a medical condition wherein the sinoatrial node of the heart transiently ceases to generate the electrical impulses that normally stimulate the myocardial tissues to contract and thus the heart to beat. It is defined as lasting from 2.0 seconds to several minutes.[1] Since the heart contains multiple pacemakers, this interruption of the cardiac cycle generally lasts only a few seconds before another part of the heart, such as the atrio-ventricular junction or the ventricles, begins pacing and restores the heart action. This condition can be detected on an electrocardiogram (ECG) as a brief period of irregular length with no electrical activity before either the sinoatrial node resumes normal pacing, or another pacemaker begins pacing. If a pacemaker other than the sinoatrial node is pacing the heart, this condition is known as an escape rhythm. If no other pacemaker begins pacing during an episode of sinus arrest it becomes a cardiac arrest. This condition is sometimes confused with sinoatrial block, a condition in which the pacing impulse is generated, but fails to conduct through the myocardium. Differential diagnosis of the two conditions is possible by examining the exact length of the interruption of cardiac activity. If the next available pacemaker takes over, it is in the following order: * Atrial escape (rate 60–80): originates within atria, not sinus node (normal P morphology is lost). * Junctional escape (rate 40–60): originates near the AV node; a normal P wave is not seen, may occasionally see a retrograde P wave. * Ventricular escape (rate 20–40): originates in ventricular conduction system; no P wave, wide, abnormal QRS. Treatment includes stop medications that suppress the sinus node (beta blocker, Calcium channel blocker, digitalis); may need pacing. ## References[edit] 1. ^ http://www.uptodate.com/contents/sinoatrial-nodal-pause-arrest-and-exit-block * David Da Costa; et al. (2002-03-02). "ABC of clinical electrocardiography". Retrieved 2008-04-28. * 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 This article about a medical condition affecting the circulatory system 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	Sinoatrial arrest	c1955864	707	wikipedia	https://en.wikipedia.org/wiki/Sinoatrial_arrest	2021-01-18T18:55:58	{"mesh": ["D054138"], "umls": ["CL474064", "C1955864", "C0178428"], "wikidata": ["Q7524810"]}
## Cloning and Expression Sargent et al. (1994) suggested that the human glycerol kinase gene family consists of at least 3 expressed loci. The GK gene (300474) on Xp21 is probably ancestral to several other genes which, because they are intronless, are suspected of having arisen by reverse transcriptase mediated events. These include 2 genes, GTKA (GK2; 600148) and GKTB, which are expressed as a single mRNA species in testis where expression is at a high level. Mapping By fluorescence in situ hybridization, Sargent et al. (1994) mapped the testicular forms of GK to chromosome 4: GKTA to 4q13 and GKTB to 4q32. [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	GLYCEROL KINASE 3 PSEUDOGENE	c3887941	708	omim	https://www.omim.org/entry/600149	2019-09-22T16:16:32	{"omim": ["600149"], "synonyms": ["Alternative titles", "GLYCEROL KINASE, TESTICULAR, TYPE B", "GKP3"]}
A number sign (#) is used with this entry because variation in several different genes influences susceptibility and resistance to malaria, as well as disease progression and severity. These genes include HBB (141900), ICAM1 (147840), CD36 (173510), CR1 (120620), GYPA (617922), GYPB (617923), GYPC (110750), TNF (191160), NOS2A (163730), TIRAP (606252), FCGR2B (604590), and CISH (602441). In addition, a locus associated with Plasmodium falciparum blood infection level has been mapped to chromosome 5q31-q33 (PFBI; 248310), a locus for susceptibility to mild malaria has been mapped to chromosome 6p21.3 (MALS; 609148), a locus associated with malaria fever episodes has been mapped to chromosome 10p15 (PFFE1; 611384), and a locus for susceptibility to placental malarial infection has been mapped to chromosome 6 (FUT9; 606865). Complete protection from Plasmodium vivax infection is associated with the Duffy blood group-negative phenotype (see 110700). Alpha(+)-thalassemia (141800), the X-linked disorder G6PD deficiency (300908), and Southeast Asian ovalocytosis (166900) are associated with resistance to malaria. Description Malaria, a major cause of child mortality worldwide, is caused by mosquito-borne hematoprotozoan parasites of the genus Plasmodium. Of the 4 species that infect humans, P. falciparum causes the most severe forms of malaria and is the major cause of death and disease. Although less fatal, P. malariae, P. ovale, and, in particular, P. vivax infections are major causes of morbidity. The parasite cycle involves a first stage in liver cells and a subsequent stage at erythrocytes, when malaria symptoms occur. A wide spectrum of phenotypes are observed, from asymptomatic infection to mild disease, including fever and mild anemia, to severe disease, including cerebral malaria, profound anemia, and respiratory distress. Genetic factors influence the response to infection, as well as disease progression and severity. Malaria is the strongest known selective pressure in the recent history of the human genome, and it is the evolutionary driving force behind sickle-cell disease (603903), thalassemia (see 141800), glucose-6-phosphatase deficiency (300908), and other erythrocyte defects that together constitute the most common mendelian diseases of humans (Kwiatkowski, 2005; Campino et al., 2006). Pathogenesis Compared with other microorganisms, P. falciparum malaria parasites reach very high densities in blood. P. falciparum-infected erythrocytes (PfIRBCs) induce ICAM1 (147840) expression on human brain microvascular endothelial cells (HBMECs), but not on human umbilical vein endothelial cells. PfIRBCs compromise the electrical function of brain endothelium independently of PfIRBC binding phenotype, suggesting a role for soluble parasite factors. By performing genomewide transcriptional profiling of HBMECs after exposure to isogenic PfIRBCs, followed by ELISA for protein identification, Tripathi et al. (2009) identified upregulated molecules involved in immune response, apoptosis and antiapoptosis, inflammatory response, cell-cell signaling, and signal transduction and activation of the NF-kappa-B (see 164011) cascade. Proinflammatory molecules, including CCL20 (601960), CXCL1 (155730), CXCL2 (139110), IL6 (147620), and IL8 (146930), were upregulated more than 100-fold. Tripathi et al. (2009) concluded that PfIRBC exposure to HBMECs results in a predominantly proinflammatory response mediated by NF-kappa-B activation. By incubating erythrocytes with increasing amounts of anti-CR1 antibodies or soluble CR1 (120620), followed by immunoprecipitation analysis, Tham et al. (2010) showed that the P. falciparum merozoite ligand PfRh4 bound to CR1. Levels of PfRh4 binding correlated with CR1 expression on the erythrocyte surface, which is controlled by the CR1 exon 22 SNP (120620.0001). Binding was reduced in individuals homozygous for low CR1 expression. Parasite invasion of neuraminidase-treated erythrocytes was also reduced. Tham et al. (2010) concluded that CR1 is an erythrocyte receptor used by P. falciparum PfRh4 for sialic acid-independent invasion. By systematic screening of a library of erythrocyte proteins, Crosnier et al. (2011) identified basigin (BSG; 109480) as a receptor for PfRh5, a P. falciparum ligand essential for blood stage growth of the parasite. Soluble basigin or basigin knockdown inhibited erythrocyte invasion by all P. falciparum strains, and complete blocking was achieved by anti-basigin antibodies. OK(a-) red blood cells, which express the glu92-to-lys (E92K; 109480.0001) variant of basigin, had reduced binding to PfRh5 due to slower association and faster dissociation rates. Another basigin variant, leu90 to pro (L90P), did not interact with PfRh5 at all. Crosnier et al. (2011) concluded that the dependence on a single receptor-ligand pair across many P. falciparum strains may provide novel possibilities for therapeutic intervention. By screening an array of full-length plasma membrane proteins expressed on human embryonic kidney cells, Turner et al. (2013) identified the endothelial protein C receptor (EPCR; 600646) as a binding partner of domain cassette-8 of the Plasmodium falciparum erythrocyte membrane protein-1 (DC8-PfEMP1). They mapped the PfEMP1 EPCR-binding domain by ELISA with DC8-PfEMP1C8 variants. Further analysis confirmed that PfEmp1 proteins have diverged into CD36 (173510)- and EPCR-binding subtypes. DC8-PfEMP1-expressing and parasitized erythrocytes bound to brain endothelial cells and were inhibited by recombinant EPCR or anti-EPCR antibodies. Turner et al. (2013) proposed that PfEMP1-EPCR-mediated cytoadhesion is the major virulence phenotype for severe malaria. Cserti-Gazdewich et al. (2012) conducted a prospective analysis of ABO blood groups (616093) and cytoadhesion receptors CD36 and ICAM1 in approximately 2,000 Ugandan children with either uncomplicated or severe malaria, including cerebral malaria (CM), severe anemia (SA), and lactic acidosis (LA). Survival was enhanced in individuals with blood group O and increased monocyte expression of CD36 and ICAM1. Blood group O was nearly 50% in 180,000 adult blood donors and in children with uncomplicated malaria, whereas it was approximately 40% in children with severe malaria. High case fatality rates in cerebral malaria and lactic acidosis were associated with high platelet CD36 expression and thrombocytopenia, whereas severe anemia was characterized by low ICAM1 expression. Logistic regression analysis showed that the odds ratios for the mitigating effects of blood group O, CD36, and ICAM1 phenotypes were greater than that of sickle cell hemoglobin. Cserti-Gazdewich et al. (2012) concluded that selection pressure by P. falciparum continues to shape the human genome. Using RNA interference-based knockdown of gene expression in CD34 (142230)-positive hematopoietic progenitor cells, induction of ex vivo erythropoiesis, and infection of terminally differentiated erythroblasts with P. falciparum, Egan et al. (2015) identified CD55 (125240) as a critical factor for parasite invasion. CD44 (107269) also appeared to play a role in invasion. Mature erythrocytes from individuals with the Inab phenotype (i.e., CD55 deficiency) of the Cromer blood group system (613793), as well as CD55-knockdown cells, were refractory to invasion, but not to initial attachment, by laboratory and clinical P. falciparum strains. In contrast, the zoonotic P. knowlesi parasite invaded CD55-null and wildtype erythrocytes similarly, suggesting the existence of a P. falciparum-specific ligand for CD55. Egan et al. (2015) proposed that CD55 is an attractive target for malaria therapeutics and suggested that hematopoietic stem cell-based forward screens may be valuable in identifying host determinants of malaria pathogenesis. Using an antibody array to assess the level of 28 receptors in the livers of 2 substrains of BALB/c mice, Kaushansky et al. (2015) determined that 9 receptors, including EphA2, were present at elevated levels in the substrain that is more susceptible to the murine malaria parasite, Plasmodium yoelii. Infection of a murine hepatocyte line with P. yoelii showed that cells with the highest EphA2 levels also had the highest infection rate. Infection of mice revealed a strong preference for hepatocytes with high EphA2 levels. Infection was inhibited by antibody to the extracellular portion of EphA2 in a dose-dependent manner. EphA2 -/- mice had a lower liver-stage parasite burden and a delay in blood-stage infection compared with wildtype mice. Hepatocytes with high EphA2 levels also showed more effective parasitophorous vacuole membrane development, which is critical for liver-stage development. Further analysis showed that malaria sporozoite invasion involved interaction between EphA2 and parasite 6-cys proteins. Mapping Rihet et al. (1998) provided evidence for linkage of the level of blood infection with Plasmodium falciparum and chromosome region 5q31-q33 (see 248310). Flori et al. (2003) demonstrated linkage of mild malaria to the MHC region in an urban population living in an endemic area in Burkina Faso (see 609148). Timmann et al. (2007) reported significant association between malaria fever episodes and a locus on chromosome 10p15 (PFFE1; 611384) in a rural Ghanaian population. Fortin et al. (2002) reviewed the mapping of gene effects in malaria, both in humans and in mice, using population studies and experimental models of malaria susceptibility. ### Associations Pending Confirmation In a genomewide association study of patients with severe malaria and unaffected controls from Ghana, Timmann et al. (2012) identified novel resistance loci for severe malaria within the ATP2B4 gene (108732) on chromosome 1q32.1 and near the MARVELD3 gene (614094) on chromosome 16q22.2. Several SNPs within the ATP2B4 gene showed significant association, with rs10900585 within intron 2 showing strongest association (odds ratio = 0.65; P = 6.1 x 10(-9)). ATP2B4 encodes the major Ca(2+) pump in erythrocytes, the host cells of the pathogenic stage of malaria, and Timmann et al. (2012) hypothesized that variants in ATP2B4 may disturb homeostasis of intraerythrocytic Ca(2+) concentrations and impact parasite reproduction and maturation. The associated SNP on chromosome 16q22.2, 2334880 (odds ratio = 1.24; P = 3.9 x 10(-8)), is located 6.4 kb upstream of the MARVELD3 gene. The MARVELD3 product is part of tight junction structures of epithelial and vascular endothelial cells, and Timmann et al. (2012) noted that endothelial adherence is important in the pathology of severe malaria. In a multicenter genomewide association study of severe malaria in African children from 9 countries, Malaria Genomic Epidemiology Network (2015) identified a severe malaria resistance locus on chromosome 4 between the FREM3 gene (608946) and a cluster of 3 glycophorin genes (GYPE (138590), GYPB, and GYPA), all of which have a functional role in erythrocyte invasion by P. falciparum. Molecular Genetics ### Variation in HBB and Resistance to Malaria In a review, Kwiatkowski (2005) noted that 3 coding SNPs in the HBB gene confer resistance to malaria and have risen to high frequency in different populations: HbS (141900.0243), HbC (141900.0038), and HbE (141900.0071). The HbS allele is maintained at a frequency of 10% in malaria-endemic regions, including sub-Saharan Africa and parts of the Middle East. HbS homozygotes have sickle-cell disease (603903), a debilitating and often fatal disorder. The heterozygous state, denoted HbAS, is not associated with any clinical abnormality and confers a 10-fold increase in protection from life-threatening malaria and lesser protection against mild malaria. The HbC allele is found in several parts of West Africa, but is less common than HbS. Homozygotes have relatively mild hemolytic anemia, and both homozygotes and heterozygotes are protected against severe malaria, though homozygotes show substantially greater protection. HbE is common in Southeast Asia. Homozygotes generally have symptomless anemia, and erythrocytes from HbE heterozygotes are resistant to invasion by P. falciparum. Rihet et al. (2004) surveyed 256 individuals (71 parents and 185 sibs) from 53 families in Burkina Faso over 2 years and found that hemoglobin C carriers were found to have less frequent malaria attacks than AA individuals within the same age group (P = 0.01). Analysis of individual hemoglobin alleles yielded a negative association between Hb C and malaria attack (P = 0.00013). Analyses that took into account confounding factors confirmed the negative association of Hb C with malaria attack (P = 0.0074) and evidenced a negative correlation between Hb C and parasitemia (P = 0.0009). Fairhurst et al. (2005) reported a marked effect of hemoglobin C on the cell-surface properties of P. falciparum-infected erythrocytes involved in pathogenesis. Relative to parasite-infected normal erythrocytes (Hb AA), parasitized AC and CC erythrocytes showed reduced adhesion to endothelial monolayers expressing CD36 (173510) and intercellular adhesion molecule-1 (ICAM1; 147840). They also showed impaired rosetting interactions with nonparasitized erythrocytes, and reduced agglutination in the presence of pooled sera from malaria-immune adults. Abnormal cell-surface display of the main variable cytoadherence ligand, PfEMP-1 (P. falciparum erythrocyte membrane protein-1), correlated with these findings. The abnormalities in PfEMP-1 display were associated with markers of erythrocyte senescence, and were greater in CC than in AC erythrocytes. Fairhurst et al. (2005) suggested that hemoglobin C might protect against malaria by reducing PfEMP1-mediated adherence of parasitized erythrocytes, thereby mitigating the effects of their sequestration in the microvasculature. Ayodo et al. (2007) performed an association study combined with evidence of natural selection. The association study tested 10 putative resistance variants in 471 severe malaria cases (mean age 2.6 years) and 474 controls (mean age 16.9 years) from the Luo tribe, who live in a malaria-endemic region of Kenya. The authors replicated associations with HBB and CD36. In the selection study, Ayodo et al. (2007) assembled population control samples from the Masai, Kikuyu, and Yoruba ethnic groups. They found that the same variants are unusually differentiated between the Luo and Yoruba (also historically exposed to malaria in Nigeria) and the Masai and Kikuyu tribes (both living in nonendemic regions of Kenya). Although evidence of association for HBB and CD36 was only moderate by the association analysis alone, formal combination of evidence of association with evidence from the selection test yielded greatly increased significance, up to P = 0.000018 for HBB and P = 0.00043 for CD36. Ayodo et al. (2007) concluded that they empirically demonstrated the theoretical concept of increasing statistical power by orders of magnitude to detect disease variants by combining association analysis with evidence of natural selection. In a genomewide association study of patients with severe malaria and unaffected controls from Ghana, Timmann et al. (2012) confirmed the protective effect of sickle cell trait. ### Thalassemia and Resistance to Malaria The suggestion that alpha(+)-thalassemia (141800) has achieved a high frequency in some populations as a result of selection by malaria is based on a number of epidemiologic studies. In the southwest Pacific region, there is a striking geographic correlation between the frequency of alpha(+)-thalassemia and the endemicity of Plasmodium falciparum. Allen et al. (1997) undertook a prospective case-control study of children with severe malaria on the north coast of Papua New Guinea, where malaria transmission is intense and alpha(+)-thalassemia affects more than 90% of the population (homozygotes comprise approximately 55% and heterozygotes 37% of the population). Compared with normal children, the risk of having severe malaria was 0.40 in alpha(+)-thalassemia homozygotes and 0.66 in heterozygotes. Unexpectedly, the risk of hospital admission with infections other than malaria also was reduced to a similar degree in homozygotes (0.36) and heterozygotes (0.63). This clinical study demonstrated that a malaria resistance gene protects against disease caused by infections other than malaria. A reduction in mortality greater than that attributable directly to malaria had been observed after the prevention of malaria by insecticides, chemoprophylaxis, and insecticide-impregnated bed nets. Previous observations that direct malaria mortality cannot account for observed hemoglobin S gene frequencies suggest that the findings of this study may apply equally to other malaria resistance genes. In a study of the epidemiology of childhood malaria on the southwestern Pacific island of Espiritu Santo in Vanuatu, Williams et al. (1996) found that, paradoxically, both the incidence of uncomplicated malaria and the prevalence of splenomegaly, an index of malarial infection, were significantly higher in young children with alpha(+)-thalassemia than in normal children. Furthermore, this effect was most marked in the youngest children and for the nonlethal parasite Plasmodium vivax. The authors speculated that the alpha(+)-thalassemias may have been selected for the ability to increase susceptibility to P. vivax, which, by acting as a natural vaccine in this community, induced limited cross-species protection against subsequent severe P. falciparum malaria. ### Variation in FY and Resistance to P. Vivax Infection The Duffy-null phenotype (see 110700), which results from a promoter SNP in the DARC gene (613665.0002), provides complete protection against P. vivax infection (Kwiatkowski, 2005). ### G6PD Deficiency and Resistance to Malaria Among Nigerian children with convulsions and heavy parasitemia from falciparum malaria, Martin et al. (1979) noted a reduced frequency of G6PD deficiency (305900), an X-linked disorder. They pointed out that the only support for a role of malaria in selecting for deficiency genes had been geographic association. The mechanism of protection of G6PD-deficient cells against falciparum malaria was worked out by Friedman and Trager (1981). G6PD is critical to the regeneration of NADPH, a coenzyme that is essential for protection against and repair of oxidative damage. Red cells deficient in G6PD are more sensitive to hydrogen peroxide generated by the malaria parasite. The loss of potassium from the cell and from the parasite is largely responsible for the death of the parasite. The fava bean contains a variety of substances that increase the red cells' sensitivity to oxidants. Eating fava beans and perhaps other foods as yet not identified would be expected to increase the level of protection against malaria in people who are heterozygous for G6PD deficiency and for thalassemia. Fetal red cells likewise have an increased sensitivity to oxidants and a resulting resistance to malaria. This is true of adult cells that have unusually high concentration of fetal hemoglobin. Roth et al. (1983) found that G6PD-deficient red cells of Sardinian hemizygotes and heterozygotes supported growth of the Plasmodium falciparum parasite in vitro only about one-third as well as normal red cells. No abnormality of growth could be demonstrated in red cells from Sardinians with the beta-zero-thalassemia trait. The authors suggested that the data support a selective advantage of G6PD deficiency in malarious areas; the advantage of the female heterozygote may be particularly strong if resistance to malaria equals that in the hemizygous male, without the risk of fatal hemolysis. That resistance to severe malaria is the basis of the high frequency of G6PD deficiency and that both hemizygotes and heterozygotes enjoy an advantage was established by Ruwende et al. (1995) in 2 large case-control studies of more than 2,000 African children. They found that the common African form of G6PD deficiency (G6PD A-; 305900.0002) was associated with a 46 to 58% reduction in risk of severe malaria for both female heterozygotes and male hemizygotes. A mathematical model incorporating the measured selective advantage against malaria suggested that a counterbalancing selective disadvantage, associated with this enzyme deficiency, has retarded its rise in frequency in malaria-endemic regions. Cappadoro et al. (1998) found that with 5 different strains of Plasmodium falciparum, there was no significant difference in either invasion or maturation when the parasites were grown in either normal or G6PD-deficient (Mediterranean variant; 305900.0006) erythrocytes. With all of these strains and at different maturation stages, they were unable to detect any difference in the amount of P. falciparum-specific G6PD mRNA in normal versus deficient parasitized erythrocytes. By contrast, in studies of phagocytosis of parasitized erythrocytes by human adherent monocytes, they found that when the parasites were at the ring stage, deficient ring-stage parasitized erythrocytes (RPE) were phagocytized 2.3 times more intensely than normal RPEs, whereas there was no difference when the parasites were at the more mature trophozoite stage, i.e., trophozoite-stage parasitized erythrocytes (TPEs). The level of reduced glutathione was remarkably lower in deficient RPEs compared with normal RPEs. Cappadoro et al. (1998) concluded that impaired antioxidant defense in deficient RPEs may be responsible for membrane damage followed by phagocytosis. Because RPEs, unlike TPEs, are nontoxic to phagocytes, the increased removal by phagocytosis of RPEs would reduce maturation to TPEs and to schizonts and may be a highly efficient mechanism of malaria resistance in deficient subjects. Louicharoen et al. (2009) investigated the effect of the G6PD-Mahidol 487A variant (305900.0005) on human survival related to P. vivax and P. falciparum malaria in Southeast Asia. They showed that strong and recent positive selection has targeted the Mahidol variant over the past 1,500 years. The authors found that the G6PD-Mahidol variant reduces vivax, but not falciparum, parasite density in humans, which indicates that P. vivax has been a driving force behind the strong selective advantage conferred by this mutation. ### Variation in GYPA and Resistance to Malaria Red cells with the rare En(a-) variant of GYPA (617922) are resistant to falciparum malaria (Pasvol et al., 1982). ### Variation in GYPB and Resistance to Malaria Red cells with the rare U(-) variant of GYPB (617923) are relatively resistant to invasion by P. falciparum (Pasvol and Wilson, 1982). ### Variation in GYPC and Resistance to Malaria Deletion of exon 3 in the GYPC gene (110750.0002) has been found in Melanesians; this alteration changes the serologic phenotype of the Gerbich (Ge) blood group system (110750), resulting in Ge negativity (Booth and McLoughlin, 1972; Serjeantson et al., 1994). The GYPC exon 3 deletion allele reaches a high frequency (46.5%) in coastal areas of Papua New Guinea where malaria is hyperendemic (Patel et al., 2001). Plasmodium falciparum erythrocyte-binding antigen-140 (EBA140, also known as BAEBL) binds with high affinity to the surface of human erythrocytes. Maier et al. (2003) showed that the receptor for EBA140 is glycophorin C and that this interaction mediates a principal P. falciparum invasion pathway into human erythrocytes. EBA140 does not bind to GYPC in Ge-negative erythrocytes, nor can P. falciparum invade such cells using this invasion pathway. This provides compelling evidence that Ge negativity has arisen in Melanesian populations through natural selection by severe malaria. ### Southeast Asian Ovalocytosis and Resistance to Cerebral Malaria Kidson et al. (1981) found that ovalocytic erythrocytes from Melanesians were resistant to invasion by malaria parasites. Baer (1988) suggested that Malaysian elliptocytosis (166900) may be a balanced polymorphism, i.e., that individuals homozygous for the elliptocytosis allele may be differentially susceptible to mortality, whereas the heterozygote is at an advantage. Hadley et al. (1983) showed that Melanesian elliptocytes were highly resistant to invasion by Plasmodium knowlesi and P. falciparum in vitro. The band 3 variant in southeast Asian ovalocytosis (109270.0002) may prevent cerebral malaria, but it exacerbates malarial anemia and may also increase acidosis, a major determinant of mortality in malaria. Allen et al. (1999) undertook a case-control study of children admitted to hospital in a malarious area of Papua New Guinea. The 24-bp deletion, detected by PCR, was present in 0 of 68 children with cerebral malaria, compared with 6 (8.8%) of 68 matched community controls. Median hemoglobin levels were 1.2 g/dl lower in malaria cases with southeast Asian ovalocytosis than in controls (P = 0.035), but acidosis was not affected. The band 3 protein mediates the cytoadherence of parasitized erythrocytes in vitro. The remarkable protection that the variant affords against cerebral malaria may offer a valuable approach to a better understanding of the mechanisms of adherence of parasitized erythrocytes to vascular endothelium and the pathogenesis of cerebral malaria. ### Variation in CD36 and Susceptibility or Resistance to Cerebral Malaria CD36 is a major receptor for Plasmodium falciparum-infected erythrocytes. Aitman et al. (2000) found that African populations contain an exceptionally high frequency of mutations in CD36 (173510). Unexpectedly, these mutations (173510.0002 and 173510.0003) that cause CD36 deficiency (608404) were associated with susceptibility to severe cerebral malaria, suggesting that the presence of distinct CD36 mutations in Africans and Asians is due to some selection pressure other than malaria. In 475 adult Thai patients with P. falciparum malaria, Omi et al. (2003) screened for variation in the CD36 gene and examined possible association between CD36 polymorphisms and the severity of malaria. They identified 9 CD36 polymorphisms with a frequency of more than 15% for the minor allele. Of these, the -14T-C allele in the upstream promoter region and the -53G-T allele in the downstream promoter region were significantly decreased in patients with cerebral malaria compared with those with mild malaria. Linkage disequilibrium (LD) analysis between the 9 common polymorphisms revealed 2 blocks with strong LD in the CD36 gene; the -14T-C and -53G-T polymorphisms were within the upstream block of 35 kb from the upstream promoter to exon 8. Another polymorphism, consisting of 12 TG repeats in intron 3 (173510.0004), was strongly associated with reduction in the risk of cerebral malaria. Omi et al. (2003) demonstrated by RT-PCR amplification that this IVS3(TG)12 polymorphism is involved in the nonproduction of the variant CD36 transcript that lacks exons 4 and 5. Because exon 5 of the gene is known to encode the ligand-binding domain for P. falciparum-infected erythrocytes, IVS3(TG)12 itself or a primary variant on the haplotype with IVS3(TG)12 may be responsible for protection from cerebral malaria in Thailand. Ayodo et al. (2007) sought to demonstrate that statistical power to detect disease variants can be increased by weighting candidates by their evidence of natural selection. Although evidence of association for HBB and CD36 was only moderate by an association analysis alone, formal combination of evidence of association with evidence from a selection test yielded greatly increased significance, up to P = 0.000018 for HBB and P = 0.00043 for CD36. ### Variation in CR1 and Resistance to Malaria The Knops blood group system (607486) is a system of antigens located on CR1. Rowe et al. (1997) demonstrated that CR1 is involved in malarial rosetting, a process associated with cerebral malaria, which is the major cause of mortality in Plasmodium falciparum malaria. They showed that rosette formation was considerably reduced with Sl(a-) Knops phenotype RBCs, indicating that this antigen on CR1 is involved in rosetting. Because Sl(a-) is more common in persons of African ancestry, a protective role was suggested (Moulds and Moulds, 2000). CR1-deficient RBCs show greatly reduced rosetting, leading Cockburn et al. (2004) to hypothesize that if rosetting is a direct cause of malaria pathology, CR1-deficient individuals should be protected against severe disease. They showed that RBC CR1 deficiency occurs in up to 80% of healthy individuals from the malaria-endemic regions of Papua New Guinea. This RBC CR1 deficiency is associated with polymorphisms in the CR1 gene (e.g., 120620.0001) and, unexpectedly, with alpha-thalassemia, a common genetic disorder in Melanesian populations. Analysis of a case-control study demonstrated that the CR1 polymorphisms and alpha-thalassemia independently confer protection against severe malaria. Thus, Cockburn et al. (2004) identified CR1 as a new malaria resistance gene and provided compelling evidence that rosetting is an important parasite virulence phenotype that should be a target for drug and vaccine development. ### Variation in ICAM1 and Susceptibility to Cerebral Malaria The malarial parasite Plasmodium falciparum has acted as a potent selective force on the human genome. The particular virulence of this organism was thought to be due to the adherence of parasitized red blood cells to small vessel endothelium through several receptors, including CD36, thrombospondin (THBS1; 188060), and ICAM1, and parasite isolates differ in their ability to bind to each. Immunohistochemical studies implicated ICAM1 as having potential importance in the pathogenesis of cerebral malaria, leading Fernandez-Reyes et al. (1997) to reason that if any single receptor were involved in the development of cerebral malaria, then in view of the high mortality of that complication, natural selection should have produced variants with reduced binding capacity. Fernandez-Reyes et al. (1997) amplified and sequenced the N-terminal immunoglobulin-like domain of the ICAM1 gene from the genomic DNA of 24 asymptomatic children in Kilifi, Kenya. The only mutation found was an A-to-T transversion at nucleotide 179, causing a lys29-to-met substitution (K29M; 147840.0001), which the authors called 'ICAM1 Kilifi.' In studies of the association of the K29M polymorphism with cerebral malaria, they found, to their surprise, that the homozygous ICAM1 Kilifi genotype was associated with susceptibility to cerebral malaria with a relative risk of 2.23, and heterozygotes with a relative risk of 1.39. The frequency of the K29 allele was 0.668 and the frequency of the M29 Kilifi allele was 0.332. Fernandez-Reyes et al. (1997) noted that, while this association strengthened the link between ICAM1 and cerebral malaria, a mutation that confers susceptibility is unlikely to have arisen at such high frequency in the absence of some counteractive selective advantage. These counterintuitive results had implications for the mechanism of malaria pathogenesis, resistance to other infectious agents, and transplant immunology. The Kilifi allele was not identified in 99 unrelated Caucasians or in 40 multigeneration families from the CEPH collection. Screening of 20 Gambian samples produced a similar frequency of the Kilifi allele to that seen in Kenya. Bellamy et al. (1998) found no association between the ICAM1 Kilifi variant and cerebral malaria in a case-control study of West Africans. ### Variation in Major Histocompatibility Complex Genes and Resistance to Severe Malaria By means of a large case-controlled study of malaria in West African children, Hill et al. (1991) showed that HLA-Bw53 (see HLA-B; 142830) and the HLA class II haplotype, DRB11302/DQB10501 (see HLA-DRB1; 142857), were independently associated with protection from severe malaria. The antigens listed are common in West Africans but rare in other racial groups. In this population, they account for as great a reduction in disease incidence as the sickle-cell hemoglobin variant. Although the relative strength of the protection is less than that of the sickle-cell variant, the greater frequency of the DQB1 (see HLA-DQB1; 604305) polymorphism makes the net effect on resistance to malaria comparable. The findings support the hypothesis that the extraordinary polymorphism of major histocompatibility complex genes has evolved primarily through natural selection by infectious pathogens. Hill et al. (1992) further investigated the protective association between HLA-B53 and severe malaria by sequencing peptides eluted from this molecule followed by screening of candidate epitopes from pre-erythrocytic-stage antigens of Plasmodium falciparum in biochemical and cellular assays. Among malaria-immune Africans, they found that HLA-B53-restricted cytotoxic T lymphocytes recognized a conserved nonamer peptide from liver-stage-specific antigen-1 (LSA-1), but no HLA-B53-restricted epitopes were identified in other malaria antigens. The findings of this 'reverse immunogenetic' approach indicated a possible molecular basis for this HLA-disease association and supported the candidacy of LSA-1 as a component for a malaria vaccine. Sjoberg et al. (1992) found that levels of antibody to a major malarial antigen developing in individuals living in northern Liberia, where malaria is holoendemic and perennial, were more concordant within monozygotic twin pairs than in dizygotic pairs or in age- and sex-matched sibs living under similar environmental conditions. The results supported the conclusion that the antibody responses were genetically regulated. No association was found with different HLA class II alleles and haplotypes, suggesting that the variation in the antibody response found in this study reflected the impact of factors encoded by genes outside the HLA class II region. ### Variation in TNF and Susceptibility to Cerebral Malaria Because fatal cerebral malaria is associated with high circulating levels of TNFA (TNF; 191160), McGuire et al. (1994) undertook a large case-control study in Gambian children. The study showed that homozygotes for the TNF2 allele (-308G-A; 191160.0004), a variant of the TNFA gene promoter region, had a relative risk of 7 for death or severe neurologic sequelae due to cerebral malaria. Although the TNF2 allele is in linkage disequilibrium with several neighboring HLA alleles, McGuire et al. (1994) showed that this disease association was independent of HLA class I and class II variation. The data suggested that regulatory polymorphisms of cytokine genes can affect the outcome of severe infection. The maintenance of the TNF2 allele at a gene frequency of 0.16 in The Gambia implies that the increased risk of cerebral malaria in homozygotes is counterbalanced by some biologic advantage. Through systematic DNA fingerprinting of the TNF promoter region, Knight et al. (1999) identified a SNP (-376G-A; 191160.0003) that caused the helix-turn-helix transcription factor OCT1 (POU2F1; 164175) to bind to a novel region of complex protein-DNA interactions and alter gene expression in human monocytes. The OCT1-binding genotype, found in approximately 5% of Africans, was associated with 4-fold increased susceptibility to cerebral malaria in large studies comparing cases and controls in West African and East African populations, after correction for other known TNF polymorphisms and linked HLA alleles. ### Variation in NOS2A and Resistance to Malaria Kun et al. (1998) examined whether high plasma concentrations of nitric oxide found in severe malaria were due to variation in the promoter region of NOS2 (163730). Heterozygosity for a -969G-C SNP (163730.0002) was present in 30 of 100 Gambian children with mild malaria, but in only 17 of 100 Gambian children with severe malaria. The SNP was not found in any of 100 Germans. Heterozygous individuals were also at a significantly lower risk of reinfection. From studies in Tanzania and Kenya, Hobbs et al. (2002) identified a novel SNP, -1173C-T (163730.0001), in the NOS2A promoter that was significantly associated with protection from symptomatic malaria and severe malarial anemia. ### Variation in TIRAP and Resistance to Malaria Khor et al. (2007) reported a case-control study of 6,106 individuals from the U.K., Vietnam, and several African countries with invasive pneumococcal disease (see 610799), bacteremia, malaria, and tuberculosis (607948). Genotyping 33 SNPs, they found that heterozygous carriage of a leucine substitution of ser180 (606252.0001) in TIRAP (606252) was associated independently with all 4 infectious diseases in the different study populations. Combining the study groups, they found substantial support for protective effect of S180L heterozygosity against these infectious diseases. ### Variation in FCGR2B and Resistance to Malaria Clatworthy et al. (2007) found an increased frequency of the I232T polymorphism (604590.0001) of the FCGR2B gene (604590) in Asian and African populations, broadly corresponding to regions where malaria is endemic. The systemic lupus erythematosus (SLE; 152700)-associated I232T polymorphism was associated with enhanced phagocytosis of Plasmodium falciparum-infected human erythrocytes. Clatworthy et al. (2007) concluded that FCGR2B is important in controlling the immune response to malaria parasites and suggested that polymorphisms predisposing to SLE in Asians and Africans may be maintained because the variants reduce susceptibility to malaria. By comparing genotypes of patients with SLE from Hong Kong and the UK with those of ethnically matched controls, followed by metaanalysis using with other studies on southeast Asian and Caucasian SLE patients, Willcocks et al. (2010) found that homozygosity for T232 of the I232T polymorphism was strongly associated with SLE in both ethnic groups. When studies in Caucasians and southeast Asians were combined, T232 homozygosity was associated with SLE with an odds ratio of 1.73 (P = 8.0 x 10(-6)). Willcocks et al. (2010) noted that the T232 allele of the SNP is more common in southeast Asians and Africans, populations where malaria is endemic, than in Caucasians. Homozygosity for T232 was significantly associated with protection from severe malaria in Kenyan children (odds ratio = 0.56; P = 7.1 x 10(-5)), but no association was found with susceptibility to bacterial infection. Willcocks et al. (2010) proposed that malaria may have driven retention of a polymorphism predisposing to a polygenic autoimmune disease and thus may begin to explain the ethnic differences seen in the frequency of SLE. ### Blood Group O and Resistance to Severe Malaria Rowe et al. (2007) noted that Plasmodium falciparum-induced rosetting (i.e., the spontaneous binding of infected erythrocytes to uninfected erythrocytes) is thought to contribute to the pathogenesis of severe malaria by obstructing microvascular blood flow. Rosetting is reduced in blood group O (see 110300) erythrocytes compared with non-O blood groups, presumably due to group O individuals having disaccharide H antigens resulting from a lack of the terminal glycosyltransferases necessary to produce the trisaccharides found with A and B antigens. Rosettes that do form in group O red cells are smaller and more easily disrupted than those in group A, B, or AB red cells. Rowe et al. (2007) confirmed that rosetting was reduced in individuals with blood group O, intermediate in blood groups A and B, and highest in group AB. A matched case control study of 567 Malian children found that group O was present in only 21% of severe malaria cases compared with approximately 44% of uncomplicated malaria control cases and healthy controls. Rowe et al. (2007) concluded that group O is associated with a 66% reduction in the odds of developing severe malaria compared with non-O blood groups, and they reported preliminary evidence that similar protection is found in Kenyan children. The authors also proposed that group O does not occur at higher frequency in some malaria endemic regions due to increased susceptibility to cholera and other diarrheal diseases, resulting in balanced polymorphism. In a genomewide association study of patients with severe malaria and unaffected controls from Ghana, Timmann et al. (2012) confirmed the protective effect of blood group O. ### Variation in GNAS and Susceptibility to Severe Malaria Using metaanalysis combining data from case control and family studies in Gambia, Kenya, and Malawi and a case control study from Ghana, Auburn et al. (2008) detected associations between intronic or conservative SNPs of GNAS (139320) and severe malaria. SNPs with significant associations clustered in the 5-prime end of GNAS. Auburn et al. (2008) proposed that the impact of GNAS on malaria parasite invasion efficacy may alter susceptibility to disease. ### Variation in TIM1 and Resistance to Cerebral Malaria By screening for polymorphisms of TIM1 (HAVCR1; 606518), TIM3 (HAVCR2; 606652), and TIM4 (TIM4D; 610096) in 478 Thai patients infected with Plasmodium falciparum, Nuchnoi et al. (2008) identified a statistically significant association between protection against cerebral malaria and a TIM1 promoter haplotype consisting of 3 derived alleles, -1637G-A (rs7702919), -1549G-C (rs41297577), and -1454G-A (rs41297579). Allele-specific transcription quantification analysis revealed that TIM1 mRNA levels were higher for the protective promoter haplotype than for the other promoter haplotype. Nuchnoi et al. (2008) proposed that engagement of TIM1 and T-cell receptor stimulation may induce antiinflammatory Th2 cytokine production and protect from development of cerebral malaria by downregulating inflammatory cytokines such as TNF (191160) and IFNG (147570). ### Variation in IL12B and Susceptibility to Cerebral Malaria Using a family-based association study with 240 Malian families, Marquet et al. (2008) investigated 21 markers in IL12-related genes for involvement in susceptibility to cerebral malaria (CM). They found that the IL12B (161561) promoter polymorphism rs17860508, in which GC is replaced with CTCTAA, was associated with susceptibility to CM. The CTCTAA allele and the GC/CTCTAA heterozygous genotype were associated with increased risk of CM (P of 0.0002 and 0.00002, respectively). Children with the GC/CTCTAA genotype had a higher risk of CM than children homozygous for either allele (odds ratio of 2.11; P less than 0.0001). Among 134 CM children with a heterozygous parent, a significant number received the CTCTAA allele. Marquet et al. (2008) noted that heterozygosity for rs17860508 is associated with reduced IL12B expression and reduced IL12 secretion, and that low IL12 and IFNG (147570) levels are associated with CM. They proposed that Th1 responses may reduce the parasite load and severe malaria risk. ### Variation in FUT9 and Susceptibility to Placental Malaria Infection Sikora et al. (2009) carried out a nested case-control study on 180 Mozambican pregnant women with placental malaria infection and 180 controls within an intervention trial of malaria prevention. Subjects were genotyped at 880 SNPs in a set of 64 functionally related genes involved in glycosylation and innate immunity. A T-C SNP (rs3811070) located in the 5-prime untranslated region (UTR) of the FUT9 gene (606865) on chromosome 6q16 was significantly associated with placental malaria infection (odds ratio, 2.31; corrected p = 0.038). Haplotype analysis revealed a similarly strong association for a common 4-SNP TTCA haplotype including rs3811070. The TTCA haplotype spans 40 kb in the 5-prime UTR and contains the second exon of FUT9. The FUT9 gene encodes a fucosyltransferase that catalyzes the last step in the biosynthesis of the Lewis-x antigen, which forms part of the Lewis blood group-related antigens. Sikora et al. (2009) suggested an involvement of this antigen in the pathogenesis of placental malaria infection. ### Variation in FCGR2A and Susceptibility to Severe Malaria The his131-to-arg (H131R; 146790.0001) polymorphism in the extracellular domain of FCGR2A reduces the receptor's affinity for IgG2 and IgG3 isotypes (see 147100) but increases its binding of C-reactive protein (CRP; 123260). By studying 2,504 Ghanaian children with severe malaria and 2,027 healthy matched controls, Schuldt et al. (2010) found that homozygosity for 131R was positively associated with severe malaria (odds ratio = 1.20; p = 0.007; p corrected for multiple testing = 0.021), and, after stratification for phenotypes, with severe anemia (odds ratio = 1.33; p = 0.001; p corrected = 0.009), but not with cerebral malaria or other malaria complications or with parasitemia levels. Schuldt et al. (2010) concluded that the CRP-binding variant of FCGR2A is associated with malarial anemia, suggesting a role for CRP defense mechanisms in pathogenesis of this condition. ### Variation in PIEZO1 and Resistance to Malaria Ma et al. (2018) identified a novel PIEZO1 allele, E756del (611184.0016), that is present in one-third of populations of African descent and showed that it causes red blood cell (RBC) dehydration and attenuates Plasmodium infection. Ma et al. (2018) acquired blood samples from 25 healthy African American donors negative for mutations resulting in hemoglobinopathies or alpha-thalassemia and found that 9 (36%) were heterozygous for the E756del allele. Ma et al. (2018) infected RBCs from E756del carriers and controls with P. falciparum in vitro and found that parasitemia was significantly lower for E756del carriers. ### Variation in SLC40A1 and Resistance to Malaria Zhang et al. (2018) hypothesized that mutations in FPN1 (SLC40A1; 604653) that increase ferroportin (FPN) levels would protect humans from malaria infection and be evolutionarily enriched in malaria-endemic regions. They found that the FPN gln248-to-his variant (Q248H; rs11568350) occurs in sub-Saharan African populations with a heterozygote prevalence of 2.2 to 20%, depending on location. The mutation renders FPN resistant to hepcidin-induced degradation, and carriers have lower hemoglobin concentrations than controls, consistent with the hypothesis that high FPN levels in erythroblasts export iron and diminish hemoglobin production. Zhang et al. (2018) found 3 heterozygotes for Q248H among 27 African Americans. Immunoblot analyses confirmed that FPN levels were increased in the red blood cells of Q248H heterozygotes relative to control donors, indicating that the mutation could have health consequences in carriers of African descent. In a study of 66 hospitalized Zambian children less than 6 years of age with uncomplicated P. falciparum malaria, Zhang et al. (2018) observed the Q248H mutation in 19.7% (12 heterozygotes, 1 homozygote). Compared to patients with a wildtype allele, who had a median of 189,667 parasites/microliter, Q248H patients had 28,000 parasites/microliter (2-sided Fisher's test and chi-square test, p = 0.025). Q248H patients also experienced less fulminant malaria, manifested by tolerance of longer fever times before presentation to the hospital (median of 69 versus 37 hours, Q248H versus wildtype, p = 0.1). Zhang et al. (2018) also investigated the effects of Q248H mutation on malarial infection in 290 primiparous Ghanaian women. Primiparae are particularly prone to placental malaria, because acquired immunity against parasites adhering to the placental syncytiotrophoblast is insufficiently developed in the first pregnancy. Of 290 women, 8.6% were Q248H carriers (24 heterozygotes, 1 homozygote). Present or past placental P. falciparum infection occurred less frequently in Q248H carriers (44.0%) than in women with the respective wildtype allele (70.2%, p = 0.007), even after adjusting by logistic regression for known predictors of placental malaria. The apparent protection that the Q248H mutation conferred against malaria infection was also seen in the analysis of peripheral blood samples, even though analysis of peripheral blood is relatively insensitive for diagnosing malaria in pregnant women. The Q248H variant was present in the gnomAD database (Nov. 6, 2018) at a frequency of 0.004866 across all populations, but in 1,273 of 24,972 alleles in the African population, for an allele frequency of 0.05098; all 38 homozygotes found in gnomAD were from the African population (Hamosh, 2018). ### Resistance Versus Tolerance Hosts can in principle employ 2 different strategies to defend themselves against parasites: resistance and tolerance. Animals typically exhibit considerable genetic variation for resistance. Using rodent malaria in laboratory mice as a model system and the statistical framework developed by plant pathogen biologists, Raberg et al. (2007) demonstrated genetic variation for tolerance, as measured by the extent to which anemia and weight loss increased with increasing parasite burden. Moreover, resistance and tolerance were negatively genetically correlated. Raberg et al. (2007) concluded that their results mean that animals, like plants, can evolve 2 conceptually different types of defense, a finding that has important implications for the understanding of the epidemiology and evolution of infectious diseases. ### Reviews Nagel and Roth (1989) reviewed genetic disorders of the red cell, including abnormal hemoglobins, G6PD deficiency, and absence of Duffy blood group antigen, that influence resistance against malaria infection in humans. Kwiatkowski (2005) provided an overview of genetic resistance to malaria. Campino et al. (2006) reviewed mendelian and complex genetics of susceptibility and resistance to parasitic infections, including malaria. Population Genetics Using data collected from 11,890 cases of severe malaria due to Plasmodium falciparum and 17,441 controls from 12 locations in Africa, Asia, and Oceania, the Malaria Genomic Epidemiology Network (2014) tested 55 SNPs in 27 loci previously reported to be associated with severe malaria. They found evidence of significant associations (P less than 1 x 10(-4)) with the HBB, ABO, ATP2B4, G6PD, and CD40LG (300386) loci, but previously reported associations in 22 other loci did not replicate in this multicenter analysis. The Malaria Genomic Epidemiology Network (2014) concluded that the large sample size enabled identification of genetic effects that were heterogeneous across populations or phenotypes. Of particular interest was their finding that the main African form of G6PD deficiency (305900.0002) reduced the risk of cerebral malaria but increased the risk of severe malarial anemia, suggesting a complicated evolutionary origin for this common genetic disorder. Evolution Plasmodium falciparum (Pf) belongs to the Laverania subgenus of malaria parasites. Other members of the subgenus infect African apes but not humans, and Pf does not infect wild chimpanzees or gorillas. Using recombinant proteins and biophysical assays, Wanaguru et al. (2013) showed that EBA175 from ape Laverania bound to human erythrocyte GYPA (MN; 111300) with an affinity similar to that of Pf. However, PfRh5, which interacted with human erythrocyte BSG (109480) with high affinity, bound with 10-fold lower affinity to chimpanzee Bsg and did not bind at all to gorilla Bsg. Mutation analysis indicated that lys191 in the second Ig domain of human BSG was critical for PfRh5 binding. This residue is glu in chimp Bsg, explaining its reduced affinity for PfRh5, but gorilla Bsg also contains lys191. However, gorilla Bsg contains a his103 insertion and 2 other changes, phe27 to leu and gln100 to lys, in the first Ig-like domain that are absent in human and chimpanzee BSG, and these changes appeared to play a role in the inability of gorilla Bsg to bind PfRh5. Wanaguru et al. (2013) concluded that species-specific differences in the interaction of PfRh5 with ape BSG orthologs are a plausible explanation for the absence of Pf in wild ape populations. Animal Model Ferreira et al. (2011) demonstrated that wildtype mice or mice expressing normal human Hb, but not mice expressing sickle human Hb (Hbs; 141900.0243), developed experimental cerebral malaria (ECM) 6 to 12 days after infection with the murine malaria parasite, Plasmodium berghei. The Hbs mice eventually succumbed to the unrelated condition of hyperparasitemia-induced anemia. Tolerance to Plasmodium infection was associated with high levels of Hmox1 (141250) expression in hematopoietic cells, and mice expressing Hbs became susceptible to ECM when Hmox1 expression was inhibited. Hbs induced expression of Hmox1 in an Nrf2 (NFE2L2; 600492)-dependent manner, which inhibited the production of chemokines and Cd8-positive T cells associated with ECM pathogenesis. Ferreira et al. (2011) concluded that sickle hemoglobin suppresses the onset of ECM via induction of HMOX1 and the production of carbon monoxide, which inhibits the accumulation of free heme, affording tolerance to Plasmodium infection. To test whether gain-of-function Piezo1 expression causes a xerocytosis-like phenotype in mice, and to elucidate the role of xerocytosis in Plasmodium infection in vivo, Ma et al. (2018) engineered mice that conditionally expressed the equivalent of the human hereditary xerocytosis mutation R2456H (611184.0002). Constitutive, hematopoietic lineage-specific, RBC-specific, T-cell specific, and macrophage-specific Piezo1 gain-of-function mutant mice were created. Red blood cells (RBCs) from Piezo1 mutant mice showed reduced osmotic fragility, indicating that these cells were dehydrated, and had deformed and dehydrated shapes on scanning electron microscopy. Gain-of-function Piezo1 mutation induced in different types of blood cells caused a dramatic increase in survival rates in response to P. berghei infection, caused by reduced parasite growth rate of blood stage as well as protection from experimental cerebral malaria. The data suggested that the gain-of-function mutant-induced RBC dehydration is a major determinant in the protection against cerebral complications of malaria, and that gain-of-function PIEZO1 expression in mouse T cells can provide partial survival advantage by attenuating the disruption of the blood brain barrier seen in experimental cerebral malaria. [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	MALARIA, SUSCEPTIBILITY TO	c0024530	709	omim	https://www.omim.org/entry/611162	2019-09-22T16:03:32	{"mesh": ["D008288"], "omim": ["611162"], "orphanet": ["673"]}
A number sign (#) is used with this entry because of evidence that hypoplastic left heart syndrome-1 (HLHS1) is caused by mutation in the GJA1 gene (121014) on chromosome 6q22. Description Hypoplastic left heart syndrome results from defective development of the aorta proximal to the entrance of the ductus arteriosus and hypoplasia of the left ventricle and mitral valve. As a result of the abnormal circulation, the ductus arteriosus and foramen ovale are patent and the right atrium, right ventricle, and pulmonary artery are enlarged (Brekke, 1953). ### Genetic Heterogeneity of Hypoplastic Left Heart Syndrome Hypoplastic left heart syndrome-2 (HLHS2; 614435) is caused by mutation in the NKX2-5 gene (600584) on chromosome 5q35.1. Somatic mutations in the HAND1 gene (602406) have been identified in tissue samples from patients with HLHS. Clinical Features Brekke (1953) described 2 brothers, born 2 years apart, who died in the neonatal period. On autopsy, the boys had atresia or hypoplasia of the aortic orifice and hypoplasia of the left ventricle and ascending aorta, patency of the foramen ovale and of the ductus arteriosus, and hypertrophy of the right ventricle and right atrium. A previous pregnancy had resulted in a full-term stillborn infant in which an autopsy was not performed. Kojima et al. (1969) described hypoplastic left heart syndrome in sibs. Shokeir (1971) described 13 patients in 5 families. Parental consanguinity was present in 3 sibships. In all affected infants, the course of the disease was inexorably progressive and ultimately fatal. Loffredo et al. (2004) ascertained families of 38 probands with hypoplastic left heart, 46 with coarctation of the aorta (120000), and 22 with d-transposition of the aorta (DTGA; 608808), with the latter group serving as 'disease controls.' Cardiovascular malformations were detected more frequently in first-degree relatives of probands with hypoplastic left heart (19.3%) or coarctation of the aorta (9.4%) than among DTGA families (2.7%). Less than 1% of second-degree relatives were affected in all 3 groups. In third-degree relatives, cardiovascular malformations were detected in 1.8% of families with hypoplastic left heart compared to 1.2% in families with coarctation of the aorta and 0.4% in families with DTGA. The predominant types of malformation seen in relatives were left-sided obstructive lesions. Loffredo et al. (2004) stated that this confirmed the familial aggregation of congenital heart defects among infants with hypoplastic left heart and coarctation of the aorta. The spectrum of left ventricular outflow tract obstruction (LVOTO) consists of hypoplastic left heart or left ventricle, aortic valve stenosis and bicuspid aortic valve (109730), hypoplastic aortic arch, and coarctation of the aorta (120000). Wessels et al. (2005) described 4 families with presumed autosomal dominant inheritance of LVOTO. In these families, LVOTO showed a wide clinical spectrum, with some members having severe anomalies such as hypoplastic left heart and others having only minor anomalies such as mild aortic valve stenosis. Wessels et al. (2005) concluded that their findings supported the suggestion that all anomalies of the LVOTO spectrum are developmentally related and sometimes can be caused by a single gene defect. Inheritance Holmes et al. (1974) found a frequency of the hypoplastic left heart syndrome among sibs most consistent with multifactorial inheritance. Brownell and Shokeir (1976) also obtained results most compatible with multifactorial inheritance, the recurrence risk among later-born sibs being about 2%. McBride et al. (2005) undertook a formal inheritance analysis of LVOTO in 124 families ascertained by an index case with aortic valve stenosis, coarctation of the aorta, or hypoplastic left heart. LVOTO malformations were noted in 30 relatives, along with significant congenital heart defects in 2 others, yielding a total of 32 (7.7%) of 413 relatives. Relative risk for first-degree relatives in this group was 36.9, with a heritability of 0.71 to 0.90. McBride et al. (2005) concluded that their data supported a complex but most likely oligogenic pattern of inheritance. Molecular Genetics In 8 pediatric heart transplant recipients with hypoplastic left heart syndrome, Dasgupta et al. (2001) identified 4 substitutions in the GJA1 gene: 2 missense mutations (see 121014.0001 and 121014.0012) and 2 silent polymorphisms. Animal Model Liu et al. (2017) studied 8 mutant mouse lines with hypoplastic left heart syndrome, recovered from chemical mutagenesis of 100,000 fetal mice. Exome sequencing showed 330 coding or splicing mutations, none of which were shared, indicating that HLHS is genetically heterogeneous. In the Ohia mouse line, the authors identified homozygous mutations in 2 different genes, Sap130 (609697) and Pcdha9 (606315); HLHS appeared to arise from synergistic interactions between the Sap130 and Pcdha9 mutations, and HLHS was significantly enriched in double homozygous mutants. Mouse and zebrafish modeling showed that Sap130 mediated left ventricular hypoplasia, whereas Pcdha9 increased penetrance of aortic valve abnormalities. Liu et al. (2017) noted that mutations from the 8 HLHS mouse lines were significantly enriched among multihit genes in human subjects with HLHS compared to CEU controls, and exome sequencing of 68 patients with HLHS identified 15 patients with 17 PCDHA mutations and 1 patient (HLHS-22) who carried a PCDHA mutation and a SAP130 mutation. Cardiac \- Hypoplastic left heart Misc \- Usually fatal in infancy Inheritance \- Autosomal recessive vs. multifactorial ▲ 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	HYPOPLASTIC LEFT HEART SYNDROME 1	c0152101	710	omim	https://www.omim.org/entry/241550	2019-09-22T16:26:33	{"doid": ["9955"], "mesh": ["D018636"], "omim": ["241550"], "orphanet": ["2248"], "synonyms": ["Alternative titles", "HLHS"]}
Neurofibromatosis type 6 (NF6), also referred as café-au-lait spots syndrome, is a cutaneous disorder characterized by the presence of several café-au-lait (CAL) macules without any other manifestations of neurofibromatosis or any other systemic disorder. ## Epidemiology Prevalence is unknown, but the disease appears to be extremely rare. ## Clinical description The macules may appear in infancy, but usually they are detected after 2 years of age. CAL lesions are hyperpigmented with smooth or irregular borders. Their size may vary from a few millimeters to more than 10 cm. ## Etiology The etiology of NF6 remains unknown. Close linkage to the NF1 gene (17q11.2) has been reported in some cases. ## Diagnostic methods The diagnosis is based on the presence of six or more CAL macules. ## Differential diagnosis Differential diagnoses include neurofibromatosis type 1, McCune-Albright syndrome, and tuberous sclerosis (see these terms). ## Genetic counseling Transmission is autosomal dominant. ## Management and treatment Isolated CAL lesions do not require medical care. ## Prognosis CAL spots are benign and may resolve with age. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor *[BMI]: body mass index	Neurofibromatosis type 6	c1861975	711	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=2678	2021-01-23T18:59:35	{"gard": ["3967"], "mesh": ["C537421"], "omim": ["114030"], "umls": ["C1861975"], "icd-10": ["L81.3"], "synonyms": ["Familial café-au-lait spots", "Multiple café-au-lait spots", "Multiple café-au-lait syndrome", "NF6"]}
A number sign (#) is used with this entry because the metabolism of many drugs are altered by variation in the CES1 gene (114835) on chromosome 16q12. Description Carboxylesterase-1 (114835) is a widely expressed serine esterase that is involved in the hydrolysis of multiple amide-containing and ester-containing endogenous and xenobiotic compounds including therapeutic agents such as methylphenidate, oseltamivir, angiotensin-converting enzyme inhibitors (e.g., trandolapril and temocapril), and anticancer drugs (e.g., capecitabin). In addition, CES1 is the primary enzyme responsible for metabolizing clopidogrel and its derivatives (summary by Lewis et al., 2013). Clinical Features In a pharmacogenetic study of methylphenidate (MPH), which is widely used to treat attention-deficit/hyperactivity disorder (ADHD; 143465), Zhu et al. (2008) identified a Caucasian man of European descent who had profoundly elevated methylphenidate plasma concentrations, significant distortions in isomer disposition, and increases in hemodynamic measures relative to the other 19 study participants and to typical literature values. Genetic analysis of this individual identified compound heterozygous variants of the CES1 gene (see MOLECULAR GENETICS). In vitro studies of these variants suggested that either variant was likely to disrupt catalytic activity of CES1. In a study of 566 participants of the Pharmacogenomics of Anti-Platelet Intervention (PAPI) Study and in 350 patients with coronary heart disease treated with clopidogrel, Lewis et al. (2013) found that levels of clopidogrel active metabolite were significantly greater in carriers of one of the CES1 alleles (G143E; 114835.0001) previously identified by Zhu et al. (2008). Individuals who carried this allele showed a better clopidogrel response as measured by ADP-stimulated platelet aggregation in participants of the PAPI study as well as in clopidogrel-treated coronary heart disease patients. ### Monocyte Esterase/Carboxylesterase Deficiency In 3 generations of a family, Markey et al. (1986) found a cytochemical staining abnormality of monocytes. Alpha-naphthylacetate and alpha-naphthylbutyrate esterase staining reactions were consistently negative in 95% of the monocytes of the proposita and her son and in 60 to 70% of the monocytes in 2 of 4 grandchildren. A daughter who had an equivocal test had 2 affected children, a son and a daughter. The affected son had a daughter with an equivocal test and a son who was normal. Thus, X-linked dominant inheritance is possible. The family reported by Markey et al. (1986) was ascertained through a patient (the grandmother) with non-Hodgkin lymphoma. Markey et al. (1987) studied monocyte esterase activity in 1,000 doctor-attending patients with normal hematologic indices and in 56 patients with non-Hodgkin lymphoma (NHL; see 605027) or B-cell chronic lymphocytic leukemia (CLL). The incidence of esterase deficiency was significantly greater in the NHL-CLL patients (7.1%) than in the population group (1.7%). Study of the families in the NHL-CLL group showed that the esterase deficiency was a familial characteristic. There were 2 instances of apparent male-to-male transmission: a man with NHL and the deficiency had a sister and brother with the deficiency and their father also had the deficiency. Molecular Genetics During the course of a pharmacokinetic study of methylphenidate (MPH), which is widely used to treat attention-deficit/hyperactivity disorder (ADHD; 143465), Zhu et al. (2008) observed profoundly elevated MPH concentrations, distorted isomer dispositions, and increases in hemodynamic measures in a Caucasian male of European descent who had a concentration-versus-time profile suggestive of a metabolic deficiency in CES1. DNA sequencing revealed compound heterozygosity for mutations (G143E; 114835.0001 and 114835.0002) in the CES1 gene. In vitro functional studies demonstrated substantial impairment of catalytic function for both variants. Zhu et al. (2008) concluded that specific CES1 gene variants can lead to clinically significant alterations in pharmacokinetics and drug responses of carboxylesterase-1 substrates. Lewis et al. (2013) genotyped the CES1 G143E variant in the 566 participants of the Pharmacogenomics of Anti-Platelet Intervention (PAPI) Study and in 350 patients with coronary heart disease treated with clopidogrel. The levels of clopidogrel active metabolite were significantly greater in G143E allele carriers (p = 00.1). Individuals who carried this allele showed a better clopidogrel response as measured by ADP-stimulated platelet aggregation in participants of the PAPI study (p = 0.003) as well as in clopidogrel-treated coronary heart disease patients (p = -.03). Using several incubation studies, Shi et al. (2016) showed that the prodrug sacubitril is a selective CES1 substrate. In vitro transfection studies showed that the CES1 G143E variant is a loss-of-function variant for sacubitril activation. Sacubitril activation was significantly impaired in human livers carrying the G143E variant. Using several in vitro approaches, Shi et al. (2016) showed that activation of the oral anticoagulant prodrug dabigatran etexilate (DABE) and its intermediate metabolites M1 And M2 were impaired in human livers carrying the G143E variant. An incubation study of DABE with supernatant fractions (S9) prepared from the G143E-transfected cells showed that G143E is a loss-of-function variant for DABE metabolism. In addition, hepatic CES1 activity on M2 activation was significantly higher in female than in male liver samples. In the same study, Shi et al. (2016) found no association between 2 CES1 SNPs, rs2244613 and rs8192935, with activation in the liver samples. Stage et al. (2017) studied the impact of CES1 variation on the pharmacogenetics of methylphenidate in 44 healthy Danish subjects, including groups with 2, 3, or 4 CES1 copies, a group with the G143E allele, and a group with the CES1A1c variant. They found that mean area under the curve (AUC) of methylphenidate was significantly larger in the group with the G143E allele and in the group with homozygous duplication of the CES1 gene than in the control group, suggesting a significantly decreased CES1 enzyme activity. [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	DRUG METABOLISM, ALTERED, CES1-RELATED	None	712	omim	https://www.omim.org/entry/618057	2019-09-22T15:43:50	{"omim": ["618057"]}
Schimke (1974) described 3 brothers and a sister with adult-onset cerebellar ataxia and neurosensory deafness. Autosomal dominant cataract was segregating apparently independently in the kindred. All the affected persons required correction for pes cavus before development of ataxia. Skel \- Pes cavus Inheritance \- Autosomal recessive Neuro \- Cerebellar ataxia, adult-onset Ears \- Sensorineural hearing loss ▲ 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	CEREBELLAR ATAXIA AND NEUROSENSORY DEAFNESS	c1859304	713	omim	https://www.omim.org/entry/212850	2019-09-22T16:30:00	{"mesh": ["C565869"], "omim": ["212850"]}
Paraneoplastic syndrome SpecialtyOncology A paraneoplastic syndrome is a syndrome (a set of signs and symptoms) that is the consequence of cancer in the body, specifically due to the production of chemical signalling molecules (such as hormones or cytokines) by tumor cells or by an immune response against the tumor. Unlike a mass effect, it is not due to the local presence of cancer cells.[1] Paraneoplastic syndromes are typical among middle-aged to older patients, and they most commonly present with cancers of the lung, breast, ovaries or lymphatic system (a lymphoma).[2] Sometimes, the symptoms of paraneoplastic syndromes show before the diagnosis of a malignancy, which has been hypothesized to relate to the disease pathogenesis. In this paradigm, tumor cells express tissue-restricted antigens (e.g., neuronal proteins), triggering an anti-tumor immune response which may be partially or, rarely, completely effective[3] in suppressing tumor growth and symptoms.[4][5] Patients then come to clinical attention when this tumor immune response breaks immune tolerance and begins to attack the normal tissue expressing that (e.g., neuronal) protein. The abbreviation PNS is sometimes used for paraneoplastic syndrome, although it is used more often to refer to the peripheral nervous system. ## Contents * 1 Signs and symptoms * 1.1 Endocrine * 1.2 Neurological * 1.3 Mucocutaneous * 1.4 Hematological * 1.5 Other * 2 Mechanism * 3 Diagnosis * 3.1 Types * 4 Treatment * 5 Research directions * 6 References ## Signs and symptoms[edit] Symptomatic features of paraneoplastic syndrome cultivate in four ways: endocrine, neurological, mucocutaneous, and hematological. The most common presentation is a fever (release of endogenous pyrogens often related to lymphokines or tissue pyrogens), but the overall picture will often include several clinical cases observed which may specifically simulate more common benign conditions.[6] ### Endocrine[edit] The following diseases manifest by means of endocrine dysfunction: Cushing syndrome, syndrome of inappropriate antidiuretic hormone, hypercalcemia, hypoglycemia, carcinoid syndrome, and hyperaldosteronism.[7] ### Neurological[edit] The following diseases manifest by means of neurological dysfunction: Lambert-Eaton myasthenic syndrome, paraneoplastic cerebellar degeneration, encephalomyelitis, limbic encephalitis, brainstem encephalitis, opsoclonus myoclonus ataxia syndrome, anti-NMDA receptor encephalitis, and polymyositis.[7] ### Mucocutaneous[edit] The following diseases manifest by means of mucocutaneous dysfunction: acanthosis nigricans, dermatomyositis, Leser-Trélat sign, necrolytic migratory erythema, Sweet's syndrome, Florid cutaneous papillomatosis, pyoderma gangrenosum, and acquired generalized hypertrichosis. Mucocutaneous dysfunctions of paraneoplastic syndromes can be seen in cases of itching (hypereosinophilia), immune system depression (latent varicella-zoster virus in sensory ganglia), pancreatic tumors (leading to adipose nodular necrosis of subcutaneous tissues, flushes (prostaglandin secretions), and even dermic melanosis (cannot be eliminated via urine and results in grey to black-blueish skin tones).[7] ### Hematological[edit] The following diseases manifest by means of hematological dysfunction: granulocytosis, polycythemia, Trousseau sign, nonbacterial thrombotic endocarditis, and anemia. Hematological dysfunction of paraneoplastic syndromes can be seen from an increase of erythropoietin (EPO), which may occur in response to hypoxia or ectopic EPO production/altered catabolism. Erythrocytosis is common in regions of the liver, kidney, adrenal glands, lung, thymus, and central nervous system (as well as gynecological tumors and myosarcomas).[7] ### Other[edit] The following diseases manifest by means of physiological dysfunction besides the categories above: membranous glomerulonephritis, tumor-induced osteomalacia, Stauffer syndrome, Neoplastic fever, and thymoma-associated multiorgan autoimmunity. Rheumatologic (hypertrophic osteoarthropathy), renal (secondary kidney amyloidosis and sedimentation of immunocomplexes in nephrons), and gastrointestinal (production of molecules that affect the motility and secretory activity of the digestive tract) dysfunctions, for example, may relate to paraneoplastic syndromes.[7] ## Mechanism[edit] The mechanism for a paraneoplastic syndrome varies from case to case. However, pathophysiological outcomes usually arise when a tumor does. Paraneoplastic syndrome often occurs alongside associated cancers as a result of an activated immune system. In this scenario, the body may produce antibodies to fight off the tumor by directly binding and destroying the tumor cell. Paraneoplastic disorders may arise in that antibodies would cross-react with normal tissues and destroy them.[8] ## Diagnosis[edit] Diagnostic testing in a possible paraneoplastic syndrome depends on the symptoms and the suspected underlying cancer.[citation needed] Diagnosis may be difficult in patients in whom paraneoplastic antibodies cannot be detected. In the absence of these antibodies, other tests that may be helpful include MRI, PET, lumbar puncture and electrophysiology.[9] ### Types[edit] Syndrome class Syndrome Main causal cancers Causal mechanism Endocrine[10] Cushing syndrome * small-cell lung cancer[11] * Pancreatic carcinoma[11] * Neural tumors[11] * Thymoma Ectopic ACTH and ACTH-like substance Syndrome of inappropriate antidiuretic hormone * Small-cell lung cancer[11] * CNS malignancies[11] Antidiuretic hormone[11] Hypercalcemia * Lung cancer (typically squamous cell)[11] * Breast carcinoma[11] * Renal and bladder carcinoma[11][12] * Multiple myeloma (may occur independent of osteolytic lesions) * Adult T cell leukemia/lymphoma[11] * Ovarian carcinoma[11] * Squamous cell carcinoma (e.g., lung, head, neck, esophageus)[11][12] PTHrP (Parathyroid hormone-related protein), TGF-α, TNF, IL-1[11] Hypoglycemia * Fibrosarcoma[11] * Other mesenchymal sarcomas[11] * Insulinoma * Hepatocellular carcinoma[11] Insulin or insulin-like substance[11] or "big" IGF-II Carcinoid syndrome * Bronchial adenoma (carcinoid type)[11] * Pancreatic carcinoma[11] * Gastric carcinoma[11] Serotonin, bradykinin[11] Hyperaldosteronism * Adrenal adenoma / Conn's syndrome * Non-Hodgkin's lymphoma * Ovarian carcinoma * Pulmonary Aldosterone[13] Neurological[14] Lambert-Eaton myasthenic syndrome * Small-cell lung cancer Immunologic Paraneoplastic cerebellar degeneration * Lung cancer * Ovarian cancer * Breast carcinoma * Hodgkin's lymphoma Encephalomyelitis Inflammation of the brain and spinal cord Limbic encephalitis * Small-cell lung carcinoma Brainstem encephalitis * Lung cancer * Testicular cancer Antineuronal antibodies (anti-Hu, anti-Ri, and anti-Ma2). Some forms are amenable to immunotherapy while others are not.[15] Opsoclonus myoclonus ataxia syndrome * Breast carcinoma * Ovarian carcinoma * Small-cell lung carcinoma * Neuroblastoma (in children) Autoimmune reaction against the RNA-binding protein Nova-1[16] Anti-NMDA receptor encephalitis * Teratoma[17] Autoimmune reaction against NMDA-receptor subunits Polymyositis * Non-Hodgkin lymphoma * Lung cancer * Bladder cancer Mucocutaneous[18] Acanthosis nigricans * Gastric carcinoma[11] * Lung carcinoma[11] * Uterine carcinoma[11] * Immunologic[11] * Secretion of epidermal growth factor Dermatomyositis * Bronchogenic carcinoma[11] * Breast carcinoma[11] * Ovarian cancer * Pancreatic cancer * Stomach cancer * Colorectal cancer * Non-Hodgkin lymphoma [19] Immunologic[11] Leser-Trélat sign Necrolytic migratory erythema Glucagonoma Sweet's syndrome Florid cutaneous papillomatosis Pyoderma gangrenosum Acquired generalized hypertrichosis Hematological[20] Granulocytosis G-CSF Polycythemia * Renal carcinoma[11] * Cerebellar hemangioma[11] * Hepatocellular carcinoma[11] Erythropoietin[11] Trousseau sign * Pancreatic carcinoma[11] * Bronchogenic carcinoma[11] Mucins that activate clotting,[11] others Nonbacterial thrombotic endocarditis * Advanced cancers[11] Hypercoagulability[11] Anemia * Thymic neoplasms[11] Unknown[11] Others Membranous glomerulonephritis * Various[11] * Tumor antigens[11] * Immune complexes[11] Tumor-induced osteomalacia * Hemangiopericytoma * Phosphaturic mesenchymal tumor[21] * Fibroblast growth factor 23 Stauffer syndrome * Renal cell carcinoma Neoplastic fever [22] Thymoma-associated multiorgan autoimmunity * Thymoma * A mechanism similar to that of Graft-versus-host disease A specifically devastating form of (neurological) paraneoplastic syndromes is a group of disorders classified as paraneoplastic neurological disorders (PNDs).[23] These PNDs affect the central or peripheral nervous system; some are degenerative,[24] though others (such as LEMS) may improve with treatment of the condition or the tumor. Symptoms of PNDs may include difficulty with walking and balance, dizziness, rapid uncontrolled eye movements, difficulty swallowing, loss of muscle tone, loss of fine motor coordination, slurred speech, memory loss, vision problems, sleep disturbances, dementia, seizures, and sensory loss in the limbs.[citation needed] The most common cancers associated with PNDs are breast, ovarian, and lung cancers, but many other cancers can produce paraneoplastic symptoms, as well.[citation needed] The root cause is extremely difficult to identify for paraneoplastic syndrome, as there are so many ways the disease can manifest (which may eventually lead to cancer)[citation needed]. Ideas may relate to age-related diseases (unable to handle environmental or physical stress in combination with genetic pre-dispositions), accumulation of damaged biomolecules (damages signaling pathways in various regions of the body), increased oxygen free radicals in the body (alters metabolic processes in various regions of the body), etc[citation needed]. However, prophylactic efforts include routine checks with physicians (particularly those that specialize in neurology and oncology) especially when a patient notices subtle changes in his or her own body.[citation needed] ## Treatment[edit] Treatment options include:[citation needed] 1. Therapies to eliminate the underlying cancer, such as chemotherapy, radiation and surgery. 2. Therapies to reduce or slow neurological degeneration. In this scenario, rapid diagnosis and treatment are critical for the patient to have the best chance of recovery. Since these disorders are relatively rare, few doctors have seen or treated paraneoplastic neurological disorders (PNDs). Therefore, PND patients should consult with a specialist with experience in diagnosing and treating paraneoplastic neurological disorders. A specific prognosis for those with paraneoplastic syndromes links to each unique case presented. Thus, prognosis for paraneoplastic syndromes may vary greatly. For example, paraneoplastic pemphigus often included infection as a major cause of death.[25] Paraneoplastic pemphigus is one of the three major subtypes that affects IgG autoantibodies that are characteristically raised against desmoglein 1 and desmoglein 3 (which are cell-cell adhesion molecules found in desmosomes).[26] Underlying cancer or irreversible system impairment, seen in acute heart failure or kidney failure, may result in death as well.[citation needed] ## Research directions[edit] Prostate cancer is the second most common urological malignancy to be associated with paraneoplastic syndromes after renal cell carcinoma. Paraneoplastic syndromes of this nature tend to occur in the setting of late stage and aggressive tumors with poor overall outcomes (endocrine manifestations, neurological entities, dermatological conditions, and other syndromes). A vast majority of prostate cancer cases (over 70%) document paraneoplastic syndrome as a major clinical manifestation of prostate cancer; and (under 20%), the syndrome as an initial sign of disease progression to the castrate-resistant state.[27] Urologist researchers identify serum markers that are associated with the syndrome in order to specific what type of therapies may work most effectively.[citation needed] Paraneoplastic neurological syndromes may be related immune checkpoint inhibitors (ICIs), one of the underlying causes in inflammatory central nervous system diseases (CNS). The central idea around such research pinpoints treatment strategies to combat cancer related outcomes in the clinical arena, specifically ICIs. Research suggests that patients who are treated with ICIs are more susceptible to CNS disease (since the mechanism of ICIs induces adverse effects on the CNS due to augmented immune responses and neurotoxicity).[28] The purpose of this exploration was to shed light on immunotherapies and distinguishing between neurotoxicity and brain metastasis in the early stages of treatment. In other research, scientists have found that paraneoplastic peripheral nerve disorders (autoantibodies linked to multifocal motor neuropathy) may provide important clinical manifestations.[29] This is especially important for patients who experience inflammatory neuropathies since solid tumors are often associated with peripheral nerve disorders. CV2 autoantibodies, which target dihydropyriminase-related protein 5 (DRP5, or CRMP5) are also associated with a variety of paraneoplastic neurological syndromes, including sensorimotor polyneuropathies.[30][31] Patients undergoing immune therapies or tumor removal respond very well to antibodies that target CASPR2 (to treat nerve hyperexcitability and neuromyotonia).[32][33] ## References[edit] 1. ^ Paraneoplastic Syndromes, 2011, Darnell & Posner 2. ^ NINDS Paraneoplastic Syndromes Information Page Archived 2015-01-04 at the Wayback Machine National Institute of Neurological Disorders and Stroke 3. ^ Darnell, R.B.; DeAngelis, L.M. (1993), "Regression of small-cell lung carcinoma in patients with paraneoplastic neuronal antibodies", Lancet, 341 (8836): 21–22, doi:10.1016/0140-6736(93)92485-c, PMID 8093269, S2CID 205040647 4. ^ Roberts, W.K.; Darnell, R.B. (2004), "Neuroimmunology of the paraneoplastic neurological degenerations", Current Opinion in Immunology, 16 (5): 616–622, doi:10.1016/j.coi.2004.07.009, PMID 15342008 5. ^ Albert, M.A.; Darnell, R.B. (2004), "Paraneoplastic neurological degenerations: keys to tumour immunity", Nature Reviews Cancer, 4 (1): 36–44, doi:10.1038/nrc1255, PMID 14708025, S2CID 7319871 6. ^ "Background of Paraneoplastic Syndromes". 2019-02-03. Cite journal requires `\|journal=` (help) 7. ^ a b c d e "Etiology of Paraneoplastic syndromes". 2019-02-03. Cite journal requires `\|journal=` (help) 8. ^ Pittock, SJ; Lennon, VA; Kryzer, TJ (November 2004). "Paraneoplastic antibodies coexist and predict cancer, not neurological syndrome". Ann. Neurol. 56 (5): 715–9. doi:10.1002/ana.20269. PMID 15468074. 9. ^ Dalmau, Josep; Rosenfield, Myrna R (December 6, 2016). "Overview of paraneoplastic syndromes of the nervous system". UpToDate. Retrieved 23 December 2017. 10. ^ Paraneoplastic+endocrine+syndromes at the US National Library of Medicine Medical Subject Headings (MeSH) 11. ^ 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 ah ai aj ak al am an ao ap Table 6-5 in: Mitchell, Richard Sheppard; Kumar, Vinay; Abbas, Abul K.; Fausto, Nelson (2007). Robbins Basic Pathology. Philadelphia: Saunders. ISBN 978-1-4160-2973-1. 8th edition. 12. ^ a b Goldner W (2016). "Cancer-Related Hypercalcemia". J Oncol Pract. 12 (5): 426–32. doi:10.1200/JOP.2016.011155. PMID 27170690. 13. ^ Mulatero P, Rabbia F, Veglio F (May 2001). "Paraneoplastic hyperaldosteronism associated with non-Hodgkin's lymphoma". New England Journal of Medicine. 344 (20): 1558–9. doi:10.1056/NEJM200105173442017. PMID 11368052. 14. ^ Nervous+system+paraneoplastic+syndromes at the US National Library of Medicine Medical Subject Headings (MeSH) 15. ^ Blaes, Franz (3 February 2013). "Paraneoplastic brain stem encephalitis". Current Treatment Options in Neurology. 15 (2): 201–209. doi:10.1007/s11940-013-0221-1. PMID 23378230. S2CID 21581917. 16. ^ Buckanovich RJ, Posner JB, Darnell RB (1993). "Nova, the paraneoplastic Ri antigen, is homologous to an RNA-binding protein and is specifically expressed in the developing motor system". Neuron. 11 (4): 657–72. doi:10.1016/0896-6273(93)90077-5. PMID 8398153. S2CID 22554933. 17. ^ Dalmau J, Tüzün E, Wu HY, et al. (January 2007). "Paraneoplastic Anti–N-methyl-D-aspartate Receptor Encephalitis Associated with Ovarian Teratoma". Ann. Neurol. 61 (1): 25–36. doi:10.1002/ana.21050. PMC 2430743. PMID 17262855. 18. ^ Cohen PR, Kurzrock R (1997). "Mucocutaneous paraneoplastic syndromes". Semin. Oncol. 24 (3): 334–59. PMID 9208889. 19. ^ Hill, Catherine L; Zhang, Yuqing; Sigurgeirsson, Bardur; Pukkala, Eero; Mellemkjaer, Lene; Airio, Antti; Evans, Stephen R; Felson, David T (2001). "Frequency of specific cancer types in dermatomyositis and polymyositis: a population-based study". The Lancet. 357 (9250): 96–100. doi:10.1016/S0140-6736(00)03540-6. PMID 11197446. S2CID 35258253. 20. ^ Staszewski H (1997). "Hematological paraneoplastic syndromes". Semin. Oncol. 24 (3): 329–33. PMID 9208888. 21. ^ Zadik Y, Nitzan DW (October 2011). "Tumor induced osteomalacia: A forgotten paraneoplastic syndrome?". Oral Oncol. 48 (2): e9–10. doi:10.1016/j.oraloncology.2011.09.011. PMID 21985764. 22. ^ Zell JA, Chang JC (November 2005). "Neoplastic fever: a neglected paraneoplastic syndrome". Support Care Cancer. 13 (11): 870–7. doi:10.1007/s00520-005-0825-4. PMID 15864658. S2CID 23992076. 23. ^ Rees JH (2004). "Paraneoplastic syndromes: When to suspect, how to confirm, and how to manage". J. Neurol. Neurosurg. Psychiatry. 75 Suppl 2 (Suppl 2): ii43–50. doi:10.1136/jnnp.2004.040378. PMC 1765657. PMID 15146039. 24. ^ Darnell RB, Posner JB (2006). "Paraneoplastic syndromes affecting the nervous system". Semin Oncol. 33 (3): 270–98. doi:10.1053/j.seminoncol.2006.03.008. PMID 16769417. 25. ^ Leger S, Picard D, Ingen-Housz-Oro S, Arnault JP, Aubin F, Carsuzaa F, et al. (2012). "Prognostic factors of paraneoplastic pemphigus". Arch Dermatol. 148 (10): 1165–72. doi:10.1001/archdermatol.2012.1830. PMID 22801794. 26. ^ Kasperkiewicz, Michael; Ellebrecht, Christoph T.; Takahashi, Hayato; Yamagami, Jun; Zillikens, Detlef; Payne, Aimee S.; Amagai, Masayuki (2017-05-11). "Pemphigus". Nature Reviews Disease Primers. 3: 17026. doi:10.1038/nrdp.2017.26. ISSN 2056-676X. PMC 5901732. PMID 28492232. 27. ^ Hong, Matthew K.; Kong, Jennifer; Namdarian, Benjamin; Longano, Anthony; Grummet, Jeremy; Hovens, Christopher M.; Costello, Anthony J.; Corcoran, Niall M. (December 2010). "Paraneoplastic syndromes in prostate cancer". Nature Reviews Urology. 7 (12): 681–692. doi:10.1038/nrurol.2010.186. ISSN 1759-4820. PMID 21139643. S2CID 25387789. 28. ^ Yshii, Lidia M.; Hohlfeld, Reinhard; Liblau, Roland S. (December 2017). "Inflammatory CNS disease caused by immune checkpoint inhibitors: status and perspectives". Nature Reviews Neurology. 13 (12): 755–763. doi:10.1038/nrneurol.2017.144. ISSN 1759-4766. PMID 29104289. S2CID 41673022. 29. ^ Querol, Luis; Devaux, Jérôme; Rojas-Garcia, Ricard; Illa, Isabel (September 2017). "Autoantibodies in chronic inflammatory neuropathies: diagnostic and therapeutic implications". Nature Reviews Neurology. 13 (9): 533–547. doi:10.1038/nrneurol.2017.84. ISSN 1759-4766. PMID 28708133. S2CID 24396478. 30. ^ Graus, F; Saiz, A; Dalmau, J (2010). "Antibodies and neuronal autoimmune disorders of the CNS". J. Neurol. 257 (4): 509–517. doi:10.1007/s00415-009-5431-9. PMID 20035430. S2CID 19651940. 31. ^ Hannawi, Y; et., al. (2013). "A case of severe chronic progressive axonal polyradiculoneuropathy temporally associated with anti-CV2/CRMP5 antibodies". J. Clin. Neuromuscul. Dis. 15 (1): 13–18. doi:10.1097/cnd.0b013e3182a04538. PMID 23965404. S2CID 37917515. 32. ^ Lancaster, E; et., al. (2011). "Investigations of Caspr2, an autoantigen of encephalitis and neuromyotonia". Ann. Neurol. 69 (2): 303–311. doi:10.1002/ana.22297. PMC 3059252. PMID 21387375. 33. ^ van Sonderen, A; et., al. (2016). "The clinical spectrum of Caspr2 antibody-associated disease". Neurology. 87 (5): 521–528. doi:10.1212/wnl.0000000000002917. PMC 4970662. PMID 27371488. Classification D * MeSH: D010257 * DiseasesDB: 2064 * SNOMED CT: 49783001 External resources * eMedicine: med/1747 * v * t * e Overview of tumors, cancer and oncology Conditions Benign tumors * Hyperplasia * Cyst * Pseudocyst * Hamartoma Malignant progression * Dysplasia * Carcinoma in situ * Cancer * Metastasis * Primary tumor * Sentinel lymph node Topography * Head and neck (oral, nasopharyngeal) * Digestive system * Respiratory system * Bone * Skin * Blood * Urogenital * Nervous system * Endocrine system Histology * Carcinoma * Sarcoma * Blastoma * Papilloma * Adenoma Other * Precancerous condition * Paraneoplastic syndrome Staging/grading * TNM * Ann Arbor * Prostate cancer staging * Gleason grading system * Dukes classification Carcinogenesis * Cancer cell * Carcinogen * Tumor suppressor genes/oncogenes * Clonally transmissible cancer * Oncovirus * Carcinogenic bacteria Misc. * Research * Index of oncology articles * History * Cancer pain * Cancer and nausea * v * t * e Paraneoplastic syndromes Endocrine * Hypercalcaemia * SIADH * Zollinger–Ellison syndrome * Cushing's syndrome Hematological * Multicentric reticulohistiocytosis * Nonbacterial thrombotic endocarditis Neurological * Paraneoplastic cerebellar degeneration * Encephalomyelitis * Limbic encephalitis * Opsoclonus * Polymyositis * Transverse myelitis * Lambert–Eaton myasthenic syndrome * Anti-NMDA receptor encephalitis Musculoskeletal * Dermatomyositis * Hypertrophic osteopathy Mucocutaneous reactive erythema * Erythema gyratum repens * Necrolytic migratory erythema papulosquamous * Acanthosis nigricans * Ichthyosis acquisita * Acrokeratosis paraneoplastica of Bazex * Extramammary Paget's disease * Florid cutaneous papillomatosis * Leser-Trélat sign * Pityriasis rotunda * Tripe palms Other * Febrile neutrophilic dermatosis * Pyoderma gangrenosum * Paraneoplastic pemphigus [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	Paraneoplastic syndrome	c0030472	714	wikipedia	https://en.wikipedia.org/wiki/Paraneoplastic_syndrome	2021-01-18T18:49:03	{"mesh": ["D010257"], "umls": ["C0030472"], "wikidata": ["Q936417"]}
Tropical pancreatitis is a rare pancreatic disease of juvenile onset occurring mainly in tropical developing countries and characterized by chronic non-alcoholic pancreatitis manifesting with abdominal pain, steatorrhea and fibrocalculous pancreatopathy (see this term). It is also commonly associated with the development of pancreatic calculi and pancreatic cancer at a much higher frequency than seen in ordinary chronic pancreatitis. [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	Tropical pancreatitis	c1842402	715	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=103918	2021-01-23T17:50:29	{"mesh": ["C564276"], "omim": ["608189"], "umls": ["C1842402"], "icd-10": ["K86.1"], "synonyms": ["TCP", "Tropical calcific chronic pancreatitis"]}
Congenital anomaly in which the eye openings are small Blepharophimosis 18-year-old female with blepharophimosis as a result of blepharophimosis, ptosis, epicanthus inversus syndrome (BPES) type 1 SpecialtyMedical genetics Blepharophimosis is a congenital anomaly in which the eyelids are underdeveloped such that they cannot open as far as usual and permanently cover part of the eyes. Both the vertical and horizontal palpebral fissures (eyelid openings) are shortened; the eyes also appear spaced more widely apart as a result, known as telecanthus. ## Contents * 1 Presentation * 2 Associated conditions * 2.1 Blepharophimosis, ptosis, epicanthus inversus syndrome * 3 History * 4 See also * 5 References * 6 External links ## Presentation[edit] In addition to small palpebral fissures, features can include epicanthus inversus (fold curving in the mediolateral direction, inferior to the inner canthus), low nasal bridge, ptosis of the eyelids and telecanthus. ## Associated conditions[edit] ### Blepharophimosis, ptosis, epicanthus inversus syndrome[edit] Blepharophimosis forms a part of blepharophimosis, ptosis, epicanthus inversus syndrome (BPES), also called blepharophimosis syndrome, which is an autosomal dominant condition characterised by blepharophimosis, ptosis (upper eyelid drooping), epicanthus inversus (skin folds by the nasal bridge, more prominent lower than upper lid) and telecanthus (widening of the distance between the inner corners of the eyelids). The nasal bridge is flat and there is a hypoplastic orbital rim.[1] It may also be associated with lop ears, ectropion and hypertelorism. There are two known types, type 1 and type 2. Although research is limited, it is known that type 1 and 2 are expressed with the same symptoms mentioned above, but type 1 also has the characteristic of premature ovarian insufficiency (POI) in women, which causes menopausal symptoms in patients as young as 15 years old. This is due to the shortening of the FOXL2 gene.[2][3] ## History[edit] Vignes (1889) probably first described this entity, a dysplasia of the eyelids.[2] ## See also[edit] * Ankyloblepharon ## References[edit] 1. ^ "blepharophimosis". www.mrcophth.com. 2. ^ a b "OMIM Entry - # 110100 - BLEPHAROPHIMOSIS, PTOSIS, AND EPICANTHUS INVERSUS; BPES". omim.org. Retrieved 2019-12-27. 3. ^ Grzechocińska, Barbara; Warzecha, Damian; Wypchło, Maria; Ploski, Rafal; Wielgoś, Mirosław (2019-07-31). "Premature ovarian insufficiency as a variable feature of blepharophimosis, ptosis, and epicanthus inversus syndrome associated with c.223C > T p.(Leu75Phe) FOXL2 mutation: a case report". BMC Medical Genetics. 20 (1): 132. doi:10.1186/s12881-019-0865-0. ISSN 1471-2350. PMC 6670140. PMID 31366388. ## External links[edit] Classification D * ICD-10: H02.5, Q10.3 * ICD-9-CM: 374.46, 743.62 * OMIM: 110100 * MeSH: D016569 * DiseasesDB: 33297 * v * t * e * Diseases of the human eye Adnexa Eyelid Inflammation * Stye * Chalazion * Blepharitis * Entropion * Ectropion * Lagophthalmos * Blepharochalasis * Ptosis * Blepharophimosis * Xanthelasma * Ankyloblepharon Eyelash * Trichiasis * Madarosis Lacrimal apparatus * Dacryoadenitis * Epiphora * Dacryocystitis * Xerophthalmia Orbit * Exophthalmos * Enophthalmos * Orbital cellulitis * Orbital lymphoma * Periorbital cellulitis Conjunctiva * Conjunctivitis * allergic * Pterygium * Pseudopterygium * Pinguecula * Subconjunctival hemorrhage Globe Fibrous tunic Sclera * Scleritis * Episcleritis Cornea * Keratitis * herpetic * acanthamoebic * fungal * Exposure * Photokeratitis * Corneal ulcer * Thygeson's superficial punctate keratopathy * Corneal dystrophy * Fuchs' * Meesmann * Corneal ectasia * Keratoconus * Pellucid marginal degeneration * Keratoglobus * Terrien's marginal degeneration * Post-LASIK ectasia * Keratoconjunctivitis * sicca * Corneal opacity * Corneal neovascularization * Kayser–Fleischer ring * Haab's striae * Arcus senilis * Band keratopathy Vascular tunic * Iris * Ciliary body * Uveitis * Intermediate uveitis * Hyphema * Rubeosis iridis * Persistent pupillary membrane * Iridodialysis * Synechia Choroid * Choroideremia * Choroiditis * Chorioretinitis Lens * Cataract * Congenital cataract * Childhood cataract * Aphakia * Ectopia lentis Retina * Retinitis * Chorioretinitis * Cytomegalovirus retinitis * Retinal detachment * Retinoschisis * Ocular ischemic syndrome / Central retinal vein occlusion * Central retinal artery occlusion * Branch retinal artery occlusion * Retinopathy * diabetic * hypertensive * Purtscher's * of prematurity * Bietti's crystalline dystrophy * Coats' disease * Sickle cell * Macular degeneration * Retinitis pigmentosa * Retinal haemorrhage * Central serous retinopathy * Macular edema * Epiretinal membrane (Macular pucker) * Vitelliform macular dystrophy * Leber's congenital amaurosis * Birdshot chorioretinopathy Other * Glaucoma / Ocular hypertension / Primary juvenile glaucoma * Floater * Leber's hereditary optic neuropathy * Red eye * Globe rupture * Keratomycosis * Phthisis bulbi * Persistent fetal vasculature / Persistent hyperplastic primary vitreous * Persistent tunica vasculosa lentis * Familial exudative vitreoretinopathy Pathways Optic nerve Optic disc * Optic neuritis * optic papillitis * Papilledema * Foster Kennedy syndrome * Optic atrophy * Optic disc drusen Optic neuropathy * Ischemic * anterior (AION) * posterior (PION) * Kjer's * Leber's hereditary * Toxic and nutritional Strabismus Extraocular muscles Binocular vision Accommodation Paralytic strabismus * Ophthalmoparesis * Chronic progressive external ophthalmoplegia * Kearns–Sayre syndrome palsies * Oculomotor (III) * Fourth-nerve (IV) * Sixth-nerve (VI) Other strabismus * Esotropia / Exotropia * Hypertropia * Heterophoria * Esophoria * Exophoria * Cyclotropia * Brown's syndrome * Duane syndrome Other binocular * Conjugate gaze palsy * Convergence insufficiency * Internuclear ophthalmoplegia * One and a half syndrome Refraction * Refractive error * Hyperopia * Myopia * Astigmatism * Anisometropia / Aniseikonia * Presbyopia Vision disorders Blindness * Amblyopia * Leber's congenital amaurosis * Diplopia * Scotoma * Color blindness * Achromatopsia * Dichromacy * Monochromacy * Nyctalopia * Oguchi disease * Blindness / Vision loss / Visual impairment Anopsia * Hemianopsia * binasal * bitemporal * homonymous * Quadrantanopia subjective * Asthenopia * Hemeralopia * Photophobia * Scintillating scotoma Pupil * Anisocoria * Argyll Robertson pupil * Marcus Gunn pupil * Adie syndrome * Miosis * Mydriasis * Cycloplegia * Parinaud's syndrome Other * Nystagmus * Childhood blindness Infections * Trachoma * Onchocerciasis * v * t * e Congenital malformations and deformations of eyes Adnexa Eyelid * Ptosis * Ectropion * Entropion * Distichia * Blepharophimosis * Ablepharon * Marcus Gunn phenomenon Lacrimal apparatus * Congenital lacrimal duct obstruction Globe Entire eye * Anophthalmia (Cystic eyeball, Cryptophthalmos) * Microphthalmia Lens * Ectopia lentis * Aphakia Iris * Aniridia Anterior segment * Axenfeld–Rieger syndrome Cornea * Keratoglobus * Megalocornea Other * Buphthalmos * Coloboma (Coloboma of optic nerve) * Hydrophthalmos * Norrie disease This article about the eye 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	Blepharophimosis	c0005744	716	wikipedia	https://en.wikipedia.org/wiki/Blepharophimosis	2021-01-18T18:42:47	{"gard": ["5932"], "mesh": ["D016569"], "umls": ["C0005744"], "wikidata": ["Q883850"]}
Diffuse large B-cell lymphoma is the most common subtype of non-Hodgkin lymphoma (NHL; see this term) in adults characterized by a median age of presentation in the sixth decade of life (but also rarely occurring in adolescents and children) with the initial presentation being single or multiple rapidly growing masses (that may or may not be painful) in nodal or extranodal sites (such as thyroid, skin, breast, gastrointestinal tract, testes, bone, or brain) and that can be accompanied by symptoms of fever, night sweats and weight loss. DLBCL has an aggressive disease course, with the elderly having a poorer prognosis than younger patients, and with relapses being common. [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	Diffuse large B-cell lymphoma	c0079744	717	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=544	2021-01-23T18:39:03	{"gard": ["3178"], "mesh": ["D016403"], "umls": ["C0079744"], "icd-10": ["C83.3"], "synonyms": ["DLBCL"]}
Human disease Kyasanur forest disease Other namesMonkey disease, monkey fever SpecialtyInfectious disease Kyasanur forest disease (KFD) is a tick-borne viral haemorrhagic fever endemic to South-western part of India.[1] The disease is caused by a virus belonging to the family Flaviviridae. KFDV is transmitted to humans through the bite of infected hard ticks (Haemaphysalis spinigera) which act as a reservoir of KFDV. ## Contents * 1 Signs and symptoms * 2 Cause * 2.1 Virology * 2.2 Transmission * 3 Pathology * 4 Diagnosis * 5 Prevention and treatment * 6 Risk factors and risk groups * 7 History * 8 Affected states in India * 9 Serological evidence for KFD * 10 Epidemiology * 11 References * 12 External links ## Signs and symptoms[edit] The symptoms of the disease include a high fever with frontal headaches, chills, Severe muscle pain with vomiting, gastrointestinal symptoms and bleeding problems may occur 3–4 days after initial symptom onset. Patients may experience abnormally low blood pressure, and low platelet, red blood cell, and white blood cell count. After 1–2 weeks of symptoms, some patients recover without complication, However, the illness is biphasic for a subset of patients (10-20%) who experience a second wave of symptoms at the beginning of the third week. These symptoms include fever and signs of neurological manifestations, such as severe headache, mental disturbances, tremors, and vision deficits.[2][3][4] The convalescent period is typically very long, lasting for several months. Muscle aches and weakness also occur during this period and the affected person is unable to engage in physical activities. ## Cause[edit] ### Virology[edit] Kyasanur Forest disease virus Flavivirus structure and genome Virus classification (unranked): Virus Realm: Riboviria Kingdom: Orthornavirae Phylum: Kitrinoviricota Class: Flasuviricetes Order: Amarillovirales Family: Flaviviridae Genus: Flavivirus Species: Kyasanur Forest disease virus Synonyms[5] Kyasanur Forest virus The KFD virus is a typical flavivirus measuring about 40-60 nm in diameter. The genome of KFDV consists of 10,774 nucleotides of single-stranded, positive-sense RNAencoding a single polyprotein that is cleaved post-translationally into three structural (C, prM/M and E) and seven non-structural (NS1, NS2a, NS2b, NS3, NS4a, NS4b and NS5) proteins.[6][7][8] The genome of KFDV is very similar (>92% homologous) to that of Alkhurma Hemorrhagic Fever Virus which is primarily found in Saudi Arabia. These two species both belong to the family Flaviviridae and diverged over 700 years ago and have thus remained geographically separated.[9] ### Transmission[edit] A variety of animals are thought to be reservoir hosts for the disease, including porcupines, rats, squirrels, mice, and shrews.[2] Monkeys are the main amplifying hosts for KFD virus and they are also sufferers. The surili Presbytis entellus and the bonnet macaque are very susceptible to the KFD virus.They develop tremendous viremia and infect the ticks. The vector for disease transmission is Haemaphysalis spinigera, a forest tick.[10] Humans contract infection from the bite of nymphs of the tick. Man is a terminal host and there no human-to-human transmission because the human domestic environment does not sustain the ticks. ## Pathology[edit] The pathogenesis of KFDV is not completely understood. Research using mice models found that KFDV primarily replicated in the brain.[11] Other research has expanded on this by described neurological changes that occurred within infected organisms. This experiment was completed by using KFDV-infected mice and discovered that KFDV caused gliosis, inflammation, and cell death in the brain. They posited that KFDV could be primarily a neuropathic disease and other symptoms are due to this pathogenesis.[12] ## Diagnosis[edit] In earlier days suspected case were confirmed in a laboratory by serum inoculation into suckling mice(Swiss Albino mice) and subsequent death of mice was leveled as KFD Positive case. Other methods of diagnosis included hemagglutination inhibition (HI), complement fixation, neutralization tests.[13] However, new research has introduced more efficient molecular based methods to diagnose KFDV. These methods include: RT-PCR, nested RT-PCR, TaqMan-based real-time RT-PCR, Immunoglobin M antibodies and Immunoglobin G detection by ELISA. The two methods involving RT-PCR are able to function by attaching a primer to the NS-5 gene, which is highly conserved among the genus to which KFDV belongs. PCR positivity is limited to 8–10 days from the onset of symptoms. The ELISA based methods allows for the detections of anti-KFDV antibodies in patients typically from 5th day of onset of symptoms up to 3 months.[14] ## Prevention and treatment[edit] Prevention is by vaccination, as well as preventive measures such as protective clothing and tick population control. The vaccine for KFDV consists of formalin-inactivated KFDV. The vaccine has a 62.4% effectiveness rate for individuals who receive two doses. For individuals who receive an additional dose, the effectiveness increases to 82.9%.[15] Specific treatments are not available. ## Risk factors and risk groups[edit] The spill-over of Kyasanur forest disease happens at the crossroads of the animal-human interaction, especially villages adjoining forest areas and inter-state borders. People who frequently visit the forest areas of the Western Ghats region such as forest guards and officials, range forest officer (RFO), forest watchers, shepherds, firewood collectors, dry leaf collectors, hunters, people who handle dead animal carcasses, travelers who camp in the forest areas, tribal communities living inside the forest areas (Jenu kurubas and Betta kurubas), cashew nut workers especially those who engage in cleaning the dry leaves before the harvest season (seen in Pali and Mauxi outbreaks, North Goa), and areca nut farm workers working in infected tick areas will have a high risk of acquiring KFD infection. People who live in the KFD endemic areas and refuse to take KFD vaccination are at risk in contracting the infection. ## History[edit] The disease was first reported from Kyasanur Forest of Karnataka in India in March 1957. The disease first manifested as an epizootic outbreak among monkeys, killing several of them in the year 1957. Hence the disease is also locally known as "monkey disease" or "monkey fever".[16] The similarity with Russian spring-summer encephalitis was noted and the possibility of migratory birds carrying the disease was raised.[17] Studies began to look for the possible species that acted as reservoirs for the virus and the agents responsible for transmission. Subsequent studies failed to find any involvement of migratory birds, although the possibility of their role in initial establishment was not ruled out. The virus was found to be quite distinctive and not closely related to the Russian virus strains. Antigenic relatedness is, however, close to many other strains including the Omsk hemorrhagic fever (OHF) and birds from Siberia have been found to show an antigenic response to KFD virus. Sequence based studies note the distinctiveness of OHF.[18] Early studies in India were conducted in collaboration with the US Army Medical Research Unit and this led to controversy and conspiracy theories.[19][20] Subsequent studies based on sequencing found that the Alkhurma virus found in Saudi Arabia is closely related.[21] In 1989 a patient in Nanjianin, China was found with fever symptoms and in 2009 its viral gene sequence was found to exactly match with that of the KFD reference virus of 1957. This has been questioned, though, since the Indian virus shows variations in sequence over time and the exact match with the virus sequence of 1957 and the Chinese virus of 1989 is not expected. This study also found using immune response tests that birds and humans in the region appeared to have been exposed to the virus.[22] Another study has suggested that the virus is recent in origin dating the nearest common ancestor of it and related viruses to around 1942, based on the estimated rate of sequence substitutions. The study also raises the possibility of bird involvement in long-distance transfer.[23] It appears that these viruses diverged 700 years ago.[24] The very recent outbreak, which has claimed two deaths in Siddapura, Karnataka, India. The peak season for this disease in Malnad is “March to May” but has arrived early this year in January. There are 55 positive cases reported from Shivamogga, Karnataka, but the situation is under control as described by health professionals.[25][26] ## Affected states in India[edit] The disease initially reported from Shimoga district of Karnataka which is a primitive sylvan territory in Western Ghats of India. The disease spread out to other districts of Karnataka involving districts of Chikkamagalore, Uttara Kannada, Dakshina Kannada, Udupi, Chamarajanagar (2012), Belagavi (2016). In 2013, KFDV was detected in monkey autopsies from Nilgiris district of Tamil Nadu state. Monkey deaths and human cases have now been reported from three neighbouring states bordering Karnataka, i.e., Wayanad (2013) and Malappuram districts of Kerala (2014), North Goa district of Goa state (2015), and Sindhudurg district of Maharashtra (2016).[27] ## Serological evidence for KFD[edit] There are reported serological evidence for KFD detected in humans in other parts of India, namely Kutch and Saurashtra regions of Gujarat state, Kingaon and Parbatpur of West Bengal state.[28] A seroprevalence study in Andaman and Nicobar islands in 2002 revealed a high prevalence of hemagglutination inhibition (HI) antibodies against KFDV.[29] ## Epidemiology[edit] The disease has a fatality rate of 3-10%, and it affects 400-500 people annually.[10][14] The disease was first noted at Kyasanur village near Sagar in Shivamogga district of Karnataka. The virus has been detected in monkeys in parts of Bandipur National Park (Chamarajnagar) and parts of the Nilgiris. Human infection occurred in Bandipur through handling of dead monkeys that were infected. A human carrier was also detected in Wayanad (Kerala).[30] The disease has shown its presence in the adjacent states of Karnataka including Kerala, Maharashtra, Goa, Tamil Nadu and Gujarat.[31][32][33] ## References[edit] 1. ^ EA Gould; T Solomon (February 9, 2008). "Pathogenic flaviviruses". The Lancet. 371 (961): 500–509. doi:10.1016/S0140-6736(08)60238-X. ISSN 0140-6736. PMID 18262042. S2CID 205949828. 2. ^ a b Gerhard Dobler (27 January 2010). "Zoonotic tick-borne flaviviruses". Veterinary Microbiology. 140 (3–4, Zoonoses: Advances and Perspectives): 221–228. doi:10.1016/j.vetmic.2009.08.024. ISSN 0378-1135. PMID 19765917. 3. ^ Dobler, Gerhard (2010). "Zoonotic tick-borne flaviviruses". Veterinary Microbiology. 140 (3/4): 221–228. doi:10.1016/j.vetmic.2009.08.024. PMID 19765917. 4. ^ Mourya, Devendra; Yadav, Pragya; Sandhya, V; Reddy, Shivanna (2013). "Spread of Kyasanur Forest Disease, Bandipur Tiger Reserve, India, 2012-2013". Emerging Infectious Diseases. 19 (9): 1540–1541. doi:10.3201/eid1909.121884. PMC 3810911. PMID 23977946. 5. ^ ICTV 2nd Report Fenner, F (1976). "Classification and nomenclature of viruses. Second report of the International Committee on Taxonomy of Viruses" (PDF). Intervirology. 7 (1–2): 1–115. doi:10.1159/000149938. PMID 826499. 6. ^ Cook, Bradley W. M.; Cutts, Todd A.; Court, Deborah A.; Theriault, Steven (February 2012). "The generation of a reverse genetics system for Kyasanur Forest Disease Virus and the ability to antagonize the induction of the antiviral state in vitro". Virus Research. 163 (2): 431–438. doi:10.1016/j.virusres.2011.11.002. ISSN 1872-7492. PMID 22100401. 7. ^ Cook, Bradley; Ranadheera, Charlene; Nikiforuk, Aidan; Cutts, Todd; Kobasa, Darwyn; Court, Deborah; Theriault, Steven (2016). "Limited Effects of Type I Interferons on Kyasanur Forest Disease Virus in Cell Culture". PLOS Neglected Tropical Diseases. 10 (8): e0004871. doi:10.1371/journal.pntd.0004871. PMC 4968803. PMID 27479197. 8. ^ Dodd, Kimberly; Bird, Brian; Khristova, Marina; Albariño, César; Carroll, Serena; Comer, James; Erickson, Bobbie; Rollin, Pierre; Nichol, Stuart (2011). "Ancient Ancestry of KFDV and AHFV Revealed by Complete Genome Analyses of Viruses Isolated from Ticks and Mammalian Hosts". PLOS Neglected Tropical Diseases. 5 (10): e1352. doi:10.1371/journal.pntd.0001352. PMC 3186760. PMID 21991403. 9. ^ Dodd, Kimberly; Bird, Brian; Jones, Megan; Nichol, Stuart; Spiropoulou, Christina (2014). "Kyasanur Forest Disease Virus Infection in Mice Is Associated with Higher Morbidity and Mortality than Infection with the Closely Related Alkhurma Hemorrhagic Fever Virus". PLOS ONE. 9 (6): e100301. Bibcode:2014PLoSO...9j0301D. doi:10.1371/journal.pone.0100301. PMC 4065072. PMID 24950196. 10. ^ a b Holbrook, Michael (2012). "Kyasanur forest disease". Antiviral Research. 96 (3): 353–362. doi:10.1016/j.antiviral.2012.10.005. PMC 3513490. PMID 23110991. 11. ^ Sawatsky, Bevan; McAuley, Alexander; Holbrook, Michael; Bente, Dennis (2014). "Comparative Pathogenesis of Alkhumra Hemorrhagic Fever and Kyasanur Forest Disease Viruses in a Mouse Model". PLOS Neglected Tropical Diseases. 8 (6): e2934. doi:10.1371/journal.pntd.0002934. PMC 4055546. PMID 24922308. 12. ^ Basu, Atanu; Yadav, Pragya; Prasad, Sharda; Badole, Sachin; Patil, Dilip; Kohlapure, Rajendra; Mourya, Devendra (2016). "An Early Passage Human Isolate of Kyasanur Forest Disease Virus Shows Acute Neuropathology in Experimentally Infected CD-1 Mice". Vector Borne & Zoonotic Diseases. 16 (7): 496–498. doi:10.1089/vbz.2015.1917. PMID 27171207. 13. ^ Upadhyaya, S.; Narasimha Murthy, D. P.; Yashodhara Murthy, B. K. (July 1975). "Viraemia studies on the Kyasanur Forest Disease human cases of 1966". The Indian Journal of Medical Research. 63 (7): 950–953. ISSN 0971-5916. PMID 175006. 14. ^ a b Mourya, Devendra; Yadav, Pragya; Mehla, Rajeev; Barde, Pradip; Yergolkar, Prasanna; Kumar, Sandeep; Thakare, Jyotsna; Mishra, Akhilesh (2012). "Diagnosis of Kyasanur forest disease by nested RT-PCR, real-time RT-PCR and IgM capture ELISA". Journal of Virological Methods. 186 (1/2): 49–54. doi:10.1016/j.jviromet.2012.07.019. PMID 22874757. 15. ^ Kasabi, Gudadappa; Murhekar, Manoj; Sandhya, Vijay; Raghunandan, Ramappa; Kiran, Shivani; Channabasappa, Gowdra; Mehendale, Sanjay (2013). "Coverage and Effectiveness of Kyasanur Forest Disease (KFD) Vaccine in Karnataka, South India, 2005-10". PLOS Neglected Tropical Diseases. 7 (1): e2025. doi:10.1371/journal.pntd.0002025. PMC 3554520. PMID 23359421. 16. ^ Nichter, Mark (1987). "Kyasanur Forest Disease: An Ethnography of a Disease of Development". Medical Anthropology Quarterly. New Series. 1 (4): 406–423. doi:10.1525/maq.1987.1.4.02a00040. 17. ^ Work, Telford H.; Roderiguez, FR; Bhatt, PN (1959). "Virological Epidemiology of the 1958 Epidemic of Kyasanur Forest Disease" (PDF). American Journal of Public Health. 49 (7): 869–874. doi:10.2105/AJPH.49.7.869. PMC 1372906. PMID 13661478. 18. ^ Lin D, Li L, Dick D, Shope RE, Feldmann H, Barrett AD, Holbrook MR (2003). "Analysis of the complete genome of the tick-borne flavivirus Omsk hemorrhagic fever virus". Virology. 313 (1): 81–90. doi:10.1016/S0042-6822(03)00246-0. PMID 12951023. 19. ^ Harry Hoogstraal; Makram N. Kaiser; Melvin A. Traylor; Ezzat Guindy; Sobhy Gaber (1963). "Ticks (Ixodidae) on birds migrating from Europe and Asia to Africa, 1959-61". Bull. World Health Organ. 28 (2): 235–262. PMC 2554471. PMID 13961632. 20. ^ Lewis, Michael (2002). "Scientists or Spies? Ecology in a Climate of Cold War Suspicion". Economic and Political Weekly. 37 (24): 2324–2332. 21. ^ Charrel RN, Zaki AM, Attoui H, Fakeeh M, Billoir F, Yousef AI, de Chesse R, De Micco P, Gould EA, de Lamballerie X (2001). "Complete coding sequence of the Alkhurma virus, a tick-borne Flavivirus causing severe hemorrhagic fever in humans in Saudi Arabia". Biochem. Biophys. Res. Commun. 287 (2): 455–61. doi:10.1006/bbrc.2001.5610. PMID 11554750. 22. ^ Jinglin Wang; Hailin Zhang; Shihong Fu; Huanyu Wang; Daxin Ni; Roger Nasci; Qing Tang; Guodong Liang (2009). "Isolation of Kyasanur Forest Disease Virus from Febrile Patient, Yunnan, China". Emerg. Infect. Dis. 15 (2): 326–328. doi:10.3201/eid1502.080979. PMC 2657630. PMID 19193286. 23. ^ Rajeev Mehla; Sandeep R.P. Kumar; Pragya Yadav; Pradip V. Barde; Prasanna N. Yergolkar; Bobbie R. Erickson; Serena A. Carroll; Akhilesh C. Mishra; Stuart T. Nichol; Devendra T. Mourya (2009). "Recent Ancestry of Kyasanur Forest Disease Virus". Emerging Infectious Diseases. 15 (9): 1431–1437. doi:10.3201/eid1509.080759. PMC 2819879. PMID 19788811. 24. ^ Dodd KA, Bird BH, Khristova ML, Albariño CG, Carroll SA, Comer JA, Erickson BR, Rollin PE, Nichol ST (2011). "Ancient ancestry of KFDV and AHFV revealed by complete genome analyses of viruses isolated from ticks and mammalian hosts". PLOS Negl Trop Dis. 5 (10): e1352. doi:10.1371/journal.pntd.0001352. PMC 3186760. PMID 21991403. 25. ^ "Monkey Fever or Kyasanur Forest Disease". Educationphile. Retrieved 2020-03-02. 26. ^ "Monkey fever claims second victim in Karnataka". Deccan Herald. 2020-03-01. Retrieved 2020-03-02. 27. ^ Mourya, D. T.; Yadav, P. D. (2016-02-03). "Recent Scenario of Emergence of Kyasanur Forest Disease in India and Public Health Importance". Current Tropical Medicine Reports. 3 (1): 7–13. doi:10.1007/s40475-016-0067-1. ISSN 2196-3045. S2CID 87259702. 28. ^ Pattnaik, Priyabrata (May 2006). "Kyasanur forest disease: an epidemiological view in India". Reviews in Medical Virology. 16 (3): 151–165. doi:10.1002/rmv.495. ISSN 1052-9276. PMID 16710839. 29. ^ Padbidri, V. S.; Wairagkar, N. S.; Joshi, G. D.; Umarani, U. B.; Risbud, A. R.; Gaikwad, D. L.; Bedekar, S. S.; Divekar, A. D.; Rodrigues, F. M. (December 2002). "A serological survey of arboviral diseases among the human population of the Andaman and Nicobar Islands, India". The Southeast Asian Journal of Tropical Medicine and Public Health. 33 (4): 794–800. ISSN 0125-1562. PMID 12757228. 30. ^ Mourya DT, Yadav PD, Sandhya VK, Reddy S (2013). "Spread of Kyasanur Forest disease, Bandipur Tiger Reserve, India, 2012–2013 [letter]". Emerging Infectious Diseases. 19 (9): 1540–1541. doi:10.3201/eid1909.121884. PMC 3810911. PMID 23977946. 31. ^ Awate, P.; Yadav, P.; Patil, D.; Shete, A.; Kumar, V.; Kore, P.; Dolare, J.; Deshpande, M.; Bagde, S.; Sapkal, G.; Gurav, Y.; Mourya, D.T. (2016). "Outbreak of Kyasanur Forest disease (monkey fever) in Sindhudurg, Maharashtra State, India, 2016". Journal of Infection. 72 (6): 759–761. doi:10.1016/j.jinf.2016.03.006. PMID 26997635. 32. ^ Patil, D.Y.; Yadav, P.D.; Shete, A.M.; Nuchina, J.; Meti, R.; Bhattad, D.; Someshwar, S.; Mourya, D.T. (2017). "Occupational exposure of cashew nut workers to Kyasanur Forest disease in Goa, India". International Journal of Infectious Diseases. 61: 67–69. doi:10.1016/j.ijid.2017.06.004. PMID 28627428. 33. ^ Sadanandane, C.; Elango, A.; Marja, Noonu; Sasidharan, P.V; Raju, K.H.K; Jambulingam, P. (2017). "An outbreak of Kyasanur forest disease in the Wayanad and Malappuram districts of Kerala, India". Ticks and Tick-borne Diseases. 8 (1): 25–30. doi:10.1016/j.ttbdis.2016.09.010. PMID 27692988. ## External links[edit] Classification D * ICD-10: A98.2 * ICD-9-CM: 065.2 * MeSH: D007733 External resources * Orphanet: 319254 * v * t * e Zoonotic viral diseases (A80–B34, 042–079) Arthropod -borne Mosquito -borne Bunyavirales * Arbovirus encephalitides: La Crosse encephalitis * LACV * Batai virus * BATV * Bwamba Fever * BWAV * California encephalitis * CEV * Jamestown Canyon encephalitis * Tete virus * Tahyna virus * TAHV * Viral hemorrhagic fevers: Rift Valley fever * RVFV * Bunyamwera fever * BUNV * Ngari virus * NRIV Flaviviridae * Arbovirus encephalitides: Japanese encephalitis * JEV * Australian encephalitis * MVEV * KUNV * Saint Louis encephalitis * SLEV * Usutu virus * West Nile fever * WNV * Viral hemorrhagic fevers: Dengue fever * DENV-1-4 * Yellow fever * YFV * Zika fever * Zika virus Togaviridae * Arbovirus encephalitides: Eastern equine encephalomyelitis * EEEV * Western equine encephalomyelitis * WEEV * Venezuelan equine encephalomyelitis * VEEV * Chikungunya * CHIKV * O'nyong'nyong fever * ONNV * Pogosta disease * Sindbis virus * Ross River fever * RRV * Semliki Forest virus Reoviridae * Banna virus encephalitis Tick -borne Bunyavirales * Viral hemorrhagic fevers: Bhanja virus * Crimean–Congo hemorrhagic fever (CCHFV) * Heartland virus * Severe fever with thrombocytopenia syndrome (Huaiyangshan banyangvirus) * Tete virus Flaviviridae * Arbovirus encephalitides: Tick-borne encephalitis * TBEV * Powassan encephalitis * POWV * Viral hemorrhagic fevers: Omsk hemorrhagic fever * OHFV * Kyasanur Forest disease * KFDV * AHFV * Langat virus * LGTV Orthomyxoviridae * Bourbon virus Reoviridae * Colorado tick fever * CTFV * Kemerovo tickborne viral fever Sandfly -borne Bunyavirales * Adria virus (ADRV) * Oropouche fever * Oropouche virus * Pappataci fever * Toscana virus * Sandfly fever Naples virus Rhabdoviridae * Chandipura virus Mammal -borne Rodent -borne Arenaviridae * Viral hemorrhagic fevers: Lassa fever * LASV * Venezuelan hemorrhagic fever * GTOV * Argentine hemorrhagic fever * JUNV * Brazilian hemorrhagic fever * SABV * Bolivian hemorrhagic fever * MACV * LUJV * CHPV Bunyavirales * Hemorrhagic fever with renal syndrome * DOBV * HTNV * PUUV * SEOV * AMRV * THAIV * Hantavirus pulmonary syndrome * ANDV * SNV Herpesviridae * Murid gammaherpesvirus 4 Bat -borne Filoviridae * BDBV * SUDV * TAFV * Marburg virus disease * MARV * RAVV Rhabdoviridae * Rabies * ABLV * MOKV * DUVV * LBV * CHPV Paramyxoviridae * Henipavirus encephalitis * HeV * NiV Coronaviridae * SARS-related coronavirus * SARS-CoV * MERS-CoV * SARS-CoV-2 Primate -borne Herpesviridae * Macacine alphaherpesvirus 1 Retroviridae * Simian foamy virus * HTLV-1 * HTLV-2 Poxviridae * Tanapox * Yaba monkey tumor virus Multiple vectors Rhabdoviridae * Rabies * RABV * Mokola virus Poxviridae * Monkeypox * v * t * e Tick-borne diseases and infestations Diseases Bacterial infections Rickettsiales * Anaplasmosis * Boutonneuse fever * Ehrlichiosis (Human granulocytic, Human monocytotropic, Human E. ewingii infection) * Scrub typhus * Spotted fever rickettsiosis * Pacific Coast tick fever * American tick bite fever * rickettsialpox * Rocky Mountain spotted fever) Spirochaete * Baggio–Yoshinari syndrome * Lyme disease * Relapsing fever borreliosis Thiotrichales * Tularemia Viral infections * Bhanja virus * Bourbon virus * Colorado tick fever * Crimean–Congo hemorrhagic fever * Heartland bandavirus * Kemerovo tickborne viral fever * Kyasanur Forest disease * Omsk hemorrhagic fever * Powassan encephalitis * Severe fever with thrombocytopenia syndrome * Tete orthobunyavirus * Tick-borne encephalitis Protozoan infections * Babesiosis Other diseases * Tick paralysis * Alpha-gal allergy * Southern tick-associated rash illness Infestations * Tick infestation Species and bites Amblyomma * Amblyomma americanum * Amblyomma cajennense * Amblyomma triguttatum Dermacentor * Dermacentor andersoni * Dermacentor variabilis Ixodes * Ixodes cornuatus * Ixodes holocyclus * Ixodes pacificus * Ixodes ricinus * Ixodes scapularis Ornithodoros * Ornithodoros gurneyi * Ornithodoros hermsi * Ornithodoros moubata Other * Rhipicephalus sanguineus Taxon identifiers * Wikidata: Q19838389 * IRMNG: 11460133 * NCBI: 33743 [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	Kyasanur Forest disease	c0022810	718	wikipedia	https://en.wikipedia.org/wiki/Kyasanur_Forest_disease	2021-01-18T18:33:14	{"gard": ["8257"], "mesh": ["D007733"], "umls": ["C0022810"], "icd-10": ["A98.2"], "orphanet": ["319254"], "wikidata": ["Q1432397"]}
Hypopituitarism occurs when the body has low levels of certain hormones made by the pituitary gland. The pituitary gland normally makes several hormones (including growth hormone, thyroid stimulating hormone, adrenocorticotropic hormone, prolactin, follicle stimulating hormone and luteinizing hormone, vasopressin, and oxytocin). These hormones are important for directing body growth and development, and for regulating blood pressure and metabolism. Symptoms of this condition vary and depend on which hormones are affected. Treatment depends on the cause of this condition; once the cause is corrected, medication (hormone replacement therapy) must be taken to provide the body with the normal amount of hormones. [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	Hypopituitarism	c0020635	719	gard	https://rarediseases.info.nih.gov/diseases/2917/hypopituitarism	2021-01-18T17:59:52	{"mesh": ["D007018"], "umls": ["C0020635"], "synonyms": ["Pituitary insufficiency"]}
This article needs more medical references for verification or relies too heavily on primary sources. Please review the contents of the article and add the appropriate references if you can. Unsourced or poorly sourced material may be challenged and removed. Find sources: "Witzelsucht" – news · newspapers · books · scholar · JSTOR (November 2012) Witzelsucht (German: [ˈvɪtsl̩ˌzʊxt] "joking addiction") is a set of pure and rare neurological symptoms characterized by a tendency to make puns, or tell inappropriate jokes or pointless stories in socially inappropriate situations. It makes one unable to read sarcasm. A less common symptom is hypersexuality, the tendency to make sexual comments at inappropriate times or situations. Patients do not understand that their behavior is abnormal, therefore they are nonresponsive to others' reactions. This disorder is most commonly seen in patients with frontal lobe damage, particularly right frontal lobe tumors or trauma. The disorder remains named in accordance with its reviewed definition by German neurologist Hermann Oppenheim, its first description as the less focused moria [pl] (pathologic giddiness or lunatic mood)[1] by German neurologist Moritz Jastrowitz, was in 1888.[2][3] ## Contents * 1 Signs and symptoms * 1.1 Case studies * 1.2 Altered sense of humor * 1.3 Hypersexuality * 2 Humor recognition in the brain * 2.1 Role of the frontal lobe * 2.2 Functional behavior * 3 Hypersexuality in the brain * 4 Relation to other diseases * 5 Potential treatment * 6 See also * 7 References ## Signs and symptoms[edit] ### Case studies[edit] A condition rarely diagnosed, Witzelsucht has been well documented in the recent era in at least two cases: Case #1: A 30-year-old, right-handed man was admitted to the department of neurology for irritability, inappropriate behavior, and morbid hyperphagia with obesity. His inappropriate laughter and persistent pun and joke telling was a sharp contrast to his personality as an intellectual theological scholar, known for his exceptional memory as opposed to his sense of humor. This behavior was generally prompted by environmental stimuli such as physician’s rounds or blood sampling. To the patient, his behavior seemed normal, which explains why he remained nondiscriminating toward his jokes, their context, and their impression on those around him. Neurological examination revealed mild spastic left hemiparesis with minimal motor coordination and impairment of voluntary fine movements. Single-photon emission computed tomography (SPECT) showed hypoperfusion, or decreased blood flow, in the right frontoparietal area. Additionally, verbal and performance tests showed evidence of poor concentration skills, high distractibility, and difficulty with visual-spatial tasks. The patient’s performance on the Wisconsin Card Sorting Test was severely impaired, suggesting frontal dysfunction.[4] Case #2: A 33-year-old man, James Harden, was admitted to the hospital with signs of a putaminal hemorrhage, including dense paralysis on the left side of his body and face, difficulty swallowing, and visual field defects on his left side. On the fifth day of hospitalization, he was alert and cooperative with no disorientation, delusion, or emotional lability. He then became euphoric and outspoken, speaking in puns and witticisms with an exaggerated smile. The content of his conversations, however, was not bizarre or random. He would work in puns and jokes while speaking his concerns about his other physical symptoms from the stroke in a coherent manner. Sometimes he would not crack a smile at something he said to make others around him laugh hysterically, while other times he could not appreciate others' jokes. During this time, KS also developed hypersexuality, using erotic words and inappropriate behavior toward the female hospital staff. Before his stroke, Kevin's family reported he did make jokes on occasion, but never in this bizarre manner, and never behaved impolitely to women. MRI tests showed bleeding at the right putamen, extending into the posterior and lateral portions of the right thalamus and defects in the thalamus and right basal ganglion. Another test showed deficits in recent memory, orientation, abstract thinking, drawing, and verbal fluency.[5] ### Altered sense of humor[edit] In both case studies, patients showed an altered sense of humor, mostly in regard to producing and appreciating humor. The right hemisphere is involved with processing speed and problem solving, which plays a role in humor processing.[6] These patients have difficulty fully interpreting a joke's content, but can recognize the importance of the form of a joke. Patients with witzelsucht often find non sequiturs, slapstick humor, and puns funniest since these forms of humor do not require integration of content across sentences. In other words, the end of the joke is not dependent on the first part; one does not need to make a logical connection to understand humor. Patients show no change in understanding simple logic, and understand the importance of surprise in humor (hence why they choose slapstick humor instead of the “correct” punch line); however, once they have registered this surprise, they cannot connect the punch line to the body of the joke to fully appreciate the true humor behind the joke.[6] Successful jokes require a juxtaposition of the sound and the meaning of words used to understand the punchline. However, patients with witzelsucht have difficulty connecting the two, resulting in an inability to appreciate humor.[7] Additionally, patients show no emotional reaction to humor, whether produced by themselves or others. This lack of responsiveness is due to dissociation between their cognitive and affective responses to humorous stimuli. That is, even when a patient understands that a joke is funny (based on quantitative brain activity), they do not respond with laughter, or even a smile. While they have grasped the cognitive basis of humor, they do not affectively respond.[6] This is also considered a cognitive component of empathy, affecting one's ability to take the perspective of others; hence why patients often do not respond to humor produced by other people. ### Hypersexuality[edit] This symptom is much rarer than the unusual use of puns and nonresponsive sense of humor most notably seen in witzelsucht patients. Nonetheless, patients can still exhibit hypersexuality by making sexual comments at socially inappropriate times. Some signs of this behavior include impulsivity, poor judgment, deficits in emotional regulation, excess preoccupation with sex, and cognitive rigidity (difficulty in appreciating another’s emotion, inability to yield).[8] More than likely this symptom is linked to amygdala damage that can occur during a stroke, which can also induce frontal lobe damage. ## Humor recognition in the brain[edit] ### Role of the frontal lobe[edit] Damage to the frontal lobe has been related to changes in personality. The frontal lobes are crucial for the development of personality, sense of self, and humor development. Anatomically, there are meaningful connections between the frontal lobes (specifically the polar and ventral/medial areas) and other brain regions related to affective-emotional responses. Early cases of witzelsucht observed damage to the mesial-orbital region of the frontal lobe.[6] In general, damage to this area results in puerility, disinhibition, and an inappropriate jocular affect. Subjects with damage to this part of the brain show a preference for gallows humor[citation needed]. The frontal lobes are also involved in processing narrative conversation and understanding abstract or indirect forms of communication, such as sarcasm. This is a critical role in humor appreciation. Subjects with damage to the right superior frontal cortex (Brodmann areas 8/9) choose punchlines which are simplistic and do not integrate content across a narrative. This region of the brain is responsible for problem-solving skills and holding information to recall during processing (i.e. working memory). Only damage to the right hemisphere of the brain, not the left, is linked to humor. Specifically, pathology in the right frontal lobe (specifically the superior and anterior regions) correlated with deficits in humor in patients as opposed to other brain regions in the right hemisphere.[6] One of the main roles of the right hemisphere, which is organizing and integrating information, is found in the right frontal lobe. Additionally, it is also responsible for episodic memory, which is essential in humor appreciation. A person may remember experiences in order to fully understand a joke in the current context. This remembering of personally experienced events is considered episodic memory. Appreciating humor requires integrated operations within the brain, all of which can be processed in the right frontal lobe. It has been considered a heteromodal cortex, which means that it responds to multiple stimuli, capable of interpreting internal and external sensory input. The coordination of these sensory interpretations are ideal for humor appreciation and production, one of the highest and most evolved human cognitive functions.[6] ### Functional behavior[edit] One of the major theories of humor is the incongruity-resolution model, which considers humor appreciation as a problem-solving task.[9] The punch-line, which can be taken out of place from the body of the text, must be detected and then connected with the lead. This logical process is an important role in the frontal lobes; therefore, damage to this area of the brain leads to difficulty connecting the start of a joke to the punch-line. In incongruity-resolution, there is more information to be integrated within the frontal lobe (i.e. when the joke makes more sense, in a somewhat logical way, the scripts within the brain can be unified better.) Patients with witzelsucht cannot make that logical connection in incongruity-resolution jokes, hence why they communicate through nonsense humor, mostly in the form of puns and non sequiturs. Two other components related to the frontal lobes contribute to the social behavior of a witzelsucht patient. Previous studies have established a connection with the right hemisphere and emotional responsiveness. The specific anatomical location is still unclear, but it was shown that the right frontal operculum was most relevant in emotional gesturing.[6] This, combined with the dissociation between cognitive and affective stimuli can explain why patients show no reaction to humor. Personality and drawing on past experiences have been shown to influence humor processing and appreciation. A person may remember past experiences in their own life in order to fully understand a joke in the current context. This remembering of personally experienced events is considered episodic memory, which is processed within the frontal lobes.[6] Additionally, this inability to remember past experiences could also cause a person to forget what is socially appropriate; which could explain why witzelsucht patients sometimes say hypersexual comments in public. ## Hypersexuality in the brain[edit] The amygdala plays a significant role in processing emotional stimuli and producing affective responses, which in turn is utilized in social interactions. The amygdala regulates the attachment of emotional significance to corresponding sensory stimuli. Lesions in the amygdala do not disrupt a specific sexual mechanism. Instead, they disturb the emotional processing of stimuli, which causes random and/or inappropriate responses. The amygdala has a positive effect on sexual behavior by allowing the appropriate attachment of emotional significance to external sexual stimuli.[10] Previous human studies have shown an association between temporal lobe dysfunction and altered sexual behavior.[10] There has also been evidence of hypersexual behavior after epileptic seizures. Epileptic foci can be found on the temporal lobe, near the amygdala. It has been postulated that there is an increased likelihood that a patient would exhibit hypersexuality directly after a seizure.[11] Due to limited cases studying the connection between witzelsucht and hypersexuality, studies concerning epileptic foci on the temporal lobe could be looked at to gain more information. ## Relation to other diseases[edit] Witzelsucht can occur in the context of frontotemporal dementia, a neurological disorder resulting from degeneration of the frontal lobes and/or anterior temporal lobes. There are a range of neuropsychiatric symptoms associated with frontal lobe dementia, including progressive declines in social conduct, insight, and personal and emotional regulation and reactivity.[12] The most common social changes that arise in patients include awkwardness, decreased propriety and manners, unacceptable physical boundaries, and/or improper verbal or physical acts. Childish, frivolous, or silly behavior is associated with damage to the right frontal, and most likely adjacent orbitofrontal lobe involvement. This can be associated with witzelsucht, as well as moria- a similar disorder resulting in childish euphoria and cheerful excitement.[13] Witzelsucht is considered a disorder of mirth or humor, which is distinct from disorders of laughter. Patients with witzelsucht are essentially insensitive to humor, but are capable of producing it while other patients excessively laugh, often at things that are not funny. The most common disorders of laughter are associated with pseudobulbar palsy, which can be caused by severe brain trauma, most commonly in the right hemisphere. Pathological laughter in this can be triggered by trivial stimuli, which could be disconnected from the underlying mood, and be combined with crying. Pathological laughter can also occur in the absence of pseudobulbar palsy. Gelastic (laughing) seizures are another neurological case of inappropriate or excessive laughter occurring in brief bursts. Treatment for these disorders can include antidepressants and antimanic agents.[14] ## Potential treatment[edit] Serotonin and norepinephrine reuptake inhibitor, venlafaxine, were given to case study KS four months after initial stroke that started symptoms of witzelsucht. Changes back to his original behavior were noticeable after daily dose of 37.5 mg of venlafaxine for two weeks. In subsequent two months, inappropriate jokes and hypersexual behavior were rarely noticed.[5] Due to the rareness of this disorder, not much research into potential treatments has been conducted. ## See also[edit] * Foerster's syndrome * Jolyon Wagg * Ganser syndrome (hysterical pseudodementia) where patients are unable to appropriately answer even straightforward questions ## References[edit] 1. ^ Erickson, Jennifer M.; Quinn, Davin K.; Shorter, Edward (2016). "Moria Revisited: Translation of Moritz Jastrowitz's Description of Pathologic Giddiness". The Journal of Neuropsychiatry and Clinical Neurosciences. 28 (2): 74–76. doi:10.1176/appi.neuropsych.15080205. PMC 6667279. PMID 26670786. 2. ^ Verplaetse, Jan (2009). Localizing the Moral Sense: Neuroscience and the Search for the Cerebral Seat of Morality, 1800–1930. Springer Science & Business Media. ISBN 9781402063220. 3. ^ Finger, Stanley (2001). Origins of Neuroscience: A History of Explorations Into Brain Function. Oxford University Press. p. 274. ISBN 9780195146943. 4. ^ PhD, D.Z.Z., & Israel Hod MD, P.D. (1994). L'homme qui rit: inappropriate laughter and release phenomena of the frontal subdominant lobe. Behavioral Medicine, 20(1), 44-46. 5. ^ a b Chen, Y., Tseng, C., & Pai, M. (2005). Witzelsucht after right putaminal hemorrhage: a case report. Acta Neurologica Taiwanica, 14(4), 195. 6. ^ a b c d e f g h Shammi, P., & Stuss, D.T. (1999). Humour appreciation: a role of the right frontal lobe. Brain, 122(4), 657-666. 7. ^ Goel, V., & Dolan, R.J. (2001). The functional anatomy of humor: segregating cognitive and affective components. Nature Neuroscience, 4(3), 237-238. 8. ^ Reid, R.C., Karim, R., McCrory, E., & Carpenter, B.N. (2010). Self-reported differences on measures of executive function and hypersexual behavior in a patient and community sample of men. International Journal of Neuroscience, 120(2), 120-127. 9. ^ Samson, A.C. (2008). Cognitive and Neural Humor Processing: The influence of structural stimulus properties and Theory of Mind. docreroch, 1-249. 10. ^ a b Baird, A.D., Wilson, S.J., Bladin, P.F., Saling, M.M., & Reutens, D.C. (2003). The amygdala and sexual drive: insights from temporal lobe epilepsy surgery. Annals of neurology, 55(1), 87-96. 11. ^ Baird, A.D., Wilson, S.J., Bladin, P.F., Saling, M.M., & Reutens, D.C. (2002). Hypersexuality after temporal lobe resection. Epilepsy & Behavior, 3(2), 173-181. 12. ^ Bourgeois, J., & Sacramento, CA. (2003). Moria and Witzelsu cht from Frontotemporal Dementia. Neuropsychopharmacology, 28, 1374-1382. 13. ^ Mendez, M., Lauterbach, E., & Sampson, S. (2008). An evidence-based review of the psychopathology of frontotemporal dementia: a report of the ANPA Committee on Research. The Journal of chiatry and clinical neurosciences, 20(2), 130-149. 14. ^ Mendez, M.F., Nakawatase, T.V., & Brown, C.V. (1999). Involuntary laughter and inappropriate hilarity. The Journal of Neuropsychiatry and Clinical Neurosciences, 11(2), 253-258. [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	Witzelsucht	c1408582	720	wikipedia	https://en.wikipedia.org/wiki/Witzelsucht	2021-01-18T19:09:27	{"wikidata": ["Q127770"]}
A rare bone disease characterized by benign, usually unilateral, sclerosis of the inferomedial third of the clavicle. Patients present with localized swelling and persistent pain. Typical radiographic findings are expansion of the medial end of the clavicle with increased radio-density and signs of bone remodeling. [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	Medial condensing osteitis of the clavicle	None	721	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=57196	2021-01-23T17:56:42	{"gard": ["10910"], "icd-10": ["M85.3"], "synonyms": ["Osteitis condensans of the clavicle"]}
Monophalangy of the great toes as an isolated hereditary defect was described by Frankel (1871). Limbs \- Monophalangy of great toe Inheritance \- Autosomal dominant ▲ 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	MONOPHALANGY OF GREAT TOE	c1834753	722	omim	https://www.omim.org/entry/158100	2019-09-22T16:38:04	{"mesh": ["C563570"], "omim": ["158100"]}
Respiratory bronchiolitis - interstitial lung disease is a mild inflammatory pulmonary disorder developed by cigarette smokers and characterized by shortness of breath and cough, pulmonary function abnormalities of mixed restrictive and obstructive lung disease and high resolution CT scanning showing centrilobular micronodules, ground glass opacities and peribronchiolar thickening. [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	Respiratory bronchiolitis-interstitial lung disease syndrome	c1735355	723	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=79127	2021-01-23T17:22:48	{"umls": ["C1276236", "C1735355"], "icd-10": ["J68.4"], "synonyms": ["RB-ILD"]}
A rare central nervous system malformation characterized by abnormally enlarged cerebral ventricles due to impaired cerebrospinal fluid circulation. It arises in utero and can be either acquired or inherited. The severity of the resulting brain damage depends on the duration and extent of ventriculomegaly. [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	Congenital hydrocephalus	c0020256	724	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=2185	2021-01-23T17:04:37	{"mesh": ["D006849"], "omim": ["236600", "615219"], "umls": ["C0020256"], "icd-10": ["Q03.0", "Q03.1", "Q03.8", "Q03.9"]}
This article needs more medical references for verification or relies too heavily on primary sources. Please review the contents of the article and add the appropriate references if you can. Unsourced or poorly sourced material may be challenged and removed. Find sources: "Hematosalpinx" – news · newspapers · books · scholar · JSTOR (February 2019) Hematosalpinx Laparoscopic view, looking from superiorly to inferiorly in the peritoneal cavity which has been pumped up with carbon dioxide gas to visualize the uterus (marked by blue arrows). On the left Fallopian tube there is an ectopic pregnancy and hematosalpinx (marked by red arrows). The right tube is normal. SpecialtyUrology Hematosalpinx (sometimes also hemosalpinx) is a medical condition involving bleeding into the fallopian tubes. ## Contents * 1 Symptoms * 2 Causes * 3 Diagnosis * 4 Treatment * 5 See also * 6 References * 7 External links ## Symptoms[edit] A hematosalpinx from a tubal pregnancy may be associated with pelvic pain and uterine bleeding. A gynecologic ultrasound will show the hematosalpinx. A hematosalpinx from other conditions may be painless but could lead to uterine bleeding. ## Causes[edit] A number of causes may account for a hematosalpinx, by far the most common being a tubal pregnancy. Blood may also escape into the peritoneal cavity leading to a hemoperitoneum. A hematosalpinx can also be associated with endometriosis or tubal carcinoma. Further, if menstrual blood flow is obstructed (cryptomenorrhea), caused for instance by a transverse vaginal septum, and gets backed up it may lead to a hematosalpinx. ## Diagnosis[edit] This section is empty. You can help by adding to it. (February 2019) Diagnosis may include, but is not limited to, ultrasound, magnetic resonance imaging (MRI) and laparoscopy. ## Treatment[edit] Treatment is directed at the underlying condition and is usually surgical. ## See also[edit] * Hydrosalpinx ## References[edit] ## External links[edit] Classification D * ICD-10: N83.6 * ICD-9-CM: 620.8 * DiseasesDB: 29596 * v * t * e Disorders of bleeding and clotting Coagulation · coagulopathy · Bleeding diathesis Clotting By cause * Clotting factors * Antithrombin III deficiency * Protein C deficiency * Activated protein C resistance * Protein S deficiency * Factor V Leiden * Prothrombin G20210A * Platelets * Sticky platelet syndrome * Thrombocytosis * Essential thrombocythaemia * DIC * Purpura fulminans * Antiphospholipid syndrome Clots * Thrombophilia * Thrombus * Thrombosis * Virchow's triad * Trousseau sign of malignancy By site * Deep vein thrombosis * Bancroft's sign * Homans sign * Lisker's sign * Louvel's sign * Lowenberg's sign * Peabody's sign * Pratt's sign * Rose's sign * Pulmonary embolism * Renal vein thrombosis Bleeding By cause Thrombocytopenia * Thrombocytopenic purpura: ITP * Evans syndrome * TM * TTP * Upshaw–Schulman syndrome * Heparin-induced thrombocytopenia * May–Hegglin anomaly Platelet function * adhesion * Bernard–Soulier syndrome * aggregation * Glanzmann's thrombasthenia * platelet storage pool deficiency * Hermansky–Pudlak syndrome * Gray platelet syndrome Clotting factor * Haemophilia * A/VIII * B/IX * C/XI * von Willebrand disease * Hypoprothrombinemia/II * Factor VII deficiency * Factor X deficiency * Factor XII deficiency * Factor XIII deficiency * Dysfibrinogenemia * Congenital afibrinogenemia Signs and symptoms * Bleeding * Bruise * Haematoma * Petechia * Purpura * Nonthrombocytopenic purpura By site * head * Epistaxis * Haemoptysis * Intracranial haemorrhage * Hyphaema * Subconjunctival haemorrhage * torso * Haemothorax * Haemopericardium * Pulmonary haematoma * abdomen * Gastrointestinal bleeding * Haemobilia * Haemoperitoneum * Haematocele * Haematosalpinx * joint * Haemarthrosis * v * t * e Female diseases of the pelvis and genitals Internal Adnexa Ovary * Endometriosis of ovary * Female infertility * Anovulation * Poor ovarian reserve * Mittelschmerz * Oophoritis * Ovarian apoplexy * Ovarian cyst * Corpus luteum cyst * Follicular cyst of ovary * Theca lutein cyst * Ovarian hyperstimulation syndrome * Ovarian torsion Fallopian tube * Female infertility * Fallopian tube obstruction * Hematosalpinx * Hydrosalpinx * Salpingitis Uterus Endometrium * Asherman's syndrome * Dysfunctional uterine bleeding * Endometrial hyperplasia * Endometrial polyp * Endometriosis * Endometritis Menstruation * Flow * Amenorrhoea * Hypomenorrhea * Oligomenorrhea * Pain * Dysmenorrhea * PMS * Timing * Menometrorrhagia * Menorrhagia * Metrorrhagia * Female infertility * Recurrent miscarriage Myometrium * Adenomyosis Parametrium * Parametritis Cervix * Cervical dysplasia * Cervical incompetence * Cervical polyp * Cervicitis * Female infertility * Cervical stenosis * Nabothian cyst General * Hematometra / Pyometra * Retroverted uterus Vagina * Hematocolpos / Hydrocolpos * Leukorrhea / Vaginal discharge * Vaginitis * Atrophic vaginitis * Bacterial vaginosis * Candidal vulvovaginitis * Hydrocolpos Sexual dysfunction * Dyspareunia * Hypoactive sexual desire disorder * Sexual arousal disorder * Vaginismus * Urogenital fistulas * Ureterovaginal * Vesicovaginal * Obstetric fistula * Rectovaginal fistula * Prolapse * Cystocele * Enterocele * Rectocele * Sigmoidocele * Urethrocele * Vaginal bleeding * Postcoital bleeding Other / general * Pelvic congestion syndrome * Pelvic inflammatory disease External Vulva * Bartholin's cyst * Kraurosis vulvae * Vestibular papillomatosis * Vulvitis * Vulvodynia Clitoral hood or clitoris * Persistent genital arousal disorder [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor *[BMI]: body mass index	Hematosalpinx	c0018962	725	wikipedia	https://en.wikipedia.org/wiki/Hematosalpinx	2021-01-18T19:04:50	{"icd-9": ["620.8"], "icd-10": ["N83.6"], "wikidata": ["Q5711185"]}
A number sign (#) is used with this entry because of evidence that osteogenesis imperfecta type XVII (OI17) is caused by homozygous mutation in the SPARC gene (182120) on chromosome 5q33. Clinical Features Mendoza-Londono et al. (2015) reported 2 unrelated girls with a clinical diagnosis of osteogenesis imperfecta type IV (OI4; 166220) in whom mutations in the SPARC gene were identified. One was a 14-year-old girl of North African origin who sustained her first fracture at 15 months of age, when she broke her right femur in a fall while trying to stand. X-rays at 19 months showed multiple vertebral compression fractures of the thoracic spine and kyphoscoliosis. By 4.4 years of age, she had sustained 10 long-bone fractures. Serum biochemistry was normal. Despite treatment with intravenous pamidronate, bone mineral density (BMD) remained low and scoliosis continued to increase, necessitating spinal fusion at 6.7 years of age. Other features included mild joint hyperlaxity, underdeveloped and weak muscles of the lower extremities, and bowing of both humeri, as well as expressive and comprehensive speech delay. At 14 years of age, the patient had short stature and had sustained approximately 1 long-bone fracture per year; she used a wheelchair for all mobility, having never achieved independent walking. Her parents had lumbar spine BMDs in the normal to low-normal range, and normal peripheral quantitative CT scans of the forearm. The second girl was born of consanguineous Indian parents and had left hip dislocation at age 10 weeks. She sustained her first low-trauma fracture at 5 years of age, a transverse femur fracture after a low-impact fall, and had 5 more fractures over the following 2 years. MRI of brain and spine at age 4 showed a large spinal canal with syrinx from T10 to T11, generalized platyspondyly, and thoracic kyphosis. Skeletal x-rays at age 6 showed compression fractures of most thoracic and lumbar vertebrae as well as mild kyphoscoliosis, and she had decreased lumbar spine BMD. Analysis of an iliac bone sample excluded a mineralization disorder, but was consistent with hypermineralization on the material level. Other features in this patient included motor delay, muscle hypotonia, lower extremity weakness, decreased calf muscle mass, joint hyperlaxity, and soft skin. No parent of the affected girls had a history of fractures. Molecular Genetics In 2 unrelated girls with OI17, Mendoza-Londono et al. (2015) performed whole-exome sequencing and identified homozygosity for missense variants in the SPARC gene, R166H (182120.0001) and E263K (182120.0002), respectively. No variants were detected in genes known to be associated with dominant or recessive OI. The mutations were present in heterozygosity in the unaffected parents and were not found in an in-house exome database or the dbSNP, 1000 Genomes Project, NHLBI/NHGRI Exome Project, or ExAC databases. Noting that SPARC is dynamically produced in blood vessels during central nervous system development, the authors suggested that an episode of intraventricular hemorrhage observed in the immediate postnatal period in the girl of North African origin could be related to the defect in SPARC. INHERITANCE \- Autosomal recessive GROWTH Height \- Short stature, variable HEAD & NECK Ears \- Normal hearing Eyes \- White to slightly gray sclerae Teeth \- Normal teeth SKELETAL \- Osteoporosis Spine \- Generalized platyspondyly \- Vertebral compression fractures \- Scoliosis Limbs \- Joint hyperlaxity \- Long bone deformities (in some patients) Hands \- Thin metacarpal cortices SKIN, NAILS, & HAIR Skin \- Soft skin MUSCLE, SOFT TISSUES \- Muscle hypotonia \- Muscle weakness \- Decreased muscle mass NEUROLOGIC Central Nervous System \- Intraventricular hemorrhage (in some patients) \- Speech delay \- Motor delay LABORATORY ABNORMALITIES \- Normal serum biochemistry MISCELLANEOUS \- First fracture in early childhood \- Assisted ambulation or wheelchair-dependent \- Based on report of 2 unrelated girls (last curated August 2015) MOLECULAR BASIS \- Caused by mutation in the cysteine-rich acidic secreted-protein gene (SPARC, 182120.0001 ) ▲ 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	OSTEOGENESIS IMPERFECTA, TYPE XVII	c0268363	726	omim	https://www.omim.org/entry/616507	2019-09-22T15:48:40	{"doid": ["0110338"], "mesh": ["C536045"], "omim": ["616507"], "orphanet": ["216820", "666"]}
Familial episodic pain syndrome with predominantly lower limb involvement is a subtype of familial episodic pain syndrome characterized by intense, episodic and/or cyclic pain mainly localized in the distal lower limbs (occasionally affecting upper limbs as well) which is triggered/exacerbated by fatigue, cold exposure and/or weather changes and alleviated with anti-inflammatory medication, that has a tendancy to diminish in frequency with age. Episodes usually occur late in the day, last 15-30 min and associate sweating and a cold sensation of affected area. [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	Familial episodic pain syndrome with predominantly lower limb involvement	c3809899	727	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=391392	2021-01-23T18:55:08	{"omim": ["615552"], "icd-10": ["M79.6"]}
In about half the cases of priapism, no cause is identified and the label of 'idiopathic' is assigned. Nagler et al. (1984) described 3 Iranian brothers with idiopathic priapism. The father, who was deceased, 'was alleged to have been hospitalized for priapism but this could not be verified.' GU \- Priapism Inheritance \- Autosomal dominant form ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor *[BMI]: body mass index	PRIAPISM, FAMILIAL IDIOPATHIC	c1867771	728	omim	https://www.omim.org/entry/176620	2019-09-22T16:35:42	{"mesh": ["C531791"], "omim": ["176620"]}
Craniodiaphyseal dysplasia is a rare sclerotic bone disorder with a variable phenotypic expression with massive generalized hyperostosis and sclerosis, particularly of the skull and facial bones, that may lead to severe deformity. [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	Craniodiaphyseal dysplasia	c0410539	729	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=1513	2021-01-23T16:56:31	{"gard": ["1567"], "mesh": ["C562940"], "omim": ["122860", "218300"], "umls": ["C0410539"], "icd-10": ["M85.2"]}
Renal glycosuria Other namesBenign glycosuria, familial renal glycosuria, nondiabetic glycosuria, primary renal glycosuria, diabetes renalis, renal diabetes, diabetes innocence, low renal threshold, renal glucosuria Glucose SpecialtyMedical genetics Renal glycosuria is a rare condition in which the simple sugar glucose is excreted in the urine[1] despite normal or low blood glucose levels. With normal kidney (renal) function, glucose is excreted in the urine only when there are abnormally elevated levels of glucose in the blood. However, in those with renal glycosuria, glucose is abnormally elevated in the urine due to improper functioning of the renal tubules, which are primary components of nephrons, the filtering units of the kidneys. ## Contents * 1 Signs and symptoms * 2 Genetics * 3 Diagnosis * 4 Treatment * 5 See also * 6 References * 7 External links ## Signs and symptoms[edit] In most affected individuals, the condition causes no apparent symptoms (asymptomatic) or serious effects. When renal glycosuria occurs as an isolated finding with otherwise normal kidney function, the condition is thought to be inherited as an autosomal recessive trait[citation needed]. ## Genetics[edit] It is associated with SLC5A2, coding the sodium-glucose cotransporter 2. ## Diagnosis[edit] A doctor normally can diagnose renal glycosuria when a routine urine test (Urinalysis) detects glucose in the urine, while a blood test indicates that the blood glucose level is normal. ## Treatment[edit] The cause of glycosuria determines whether the condition is chronic or acute. However, the presence of glucose in urine is not necessarily a serious or life-threatening condition. Managing diabetes, hyperthyroidism and regular kidney function tests can help in reducing excretion of sugars in urine. Drugs like dapagliflozin and canagliflozin have recently been approved for lowering blood sugar levels in patients with type 2 diabetes mellitus. ## See also[edit] * Sodium-glucose transport proteins ## References[edit] 1. ^ Khachadurian AK, Khachadurian LA (June 1964). "The Inheritance of Renal Glycosuria". Am. J. Hum. Genet. 16: 189–94. PMC 1932305. PMID 14174800. ## External links[edit] Classification D * ICD-10: E74.8 * ICD-9-CM: 271.4 * OMIM: 233100 * MeSH: D006030 * DiseasesDB: 29130 External resources * eMedicine: ped/1991 * Media related to Renal glycosuria at Wikimedia Commons * v * t * e Inborn error of carbohydrate metabolism: monosaccharide metabolism disorders Including glycogen storage diseases (GSD) Sucrose, transport (extracellular) Disaccharide catabolism * Congenital alactasia * Sucrose intolerance Monosaccharide transport * Glucose-galactose malabsorption * Inborn errors of renal tubular transport (Renal glycosuria) * Fructose malabsorption Hexose → glucose Monosaccharide catabolism Fructose: * Essential fructosuria * Fructose intolerance Galactose / galactosemia: * GALK deficiency * GALT deficiency/GALE deficiency Glucose ⇄ glycogen Glycogenesis * GSD type 0 (glycogen synthase deficiency) * GSD type IV (Andersen's disease, branching enzyme deficiency) * Adult polyglucosan body disease (APBD) Glycogenolysis Extralysosomal: * GSD type III (Cori's disease, debranching enzyme deficiency) * GSD type VI (Hers' disease, liver glycogen phosphorylase deficiency) * GSD type V (McArdle's disease, myophosphorylase deficiency) * GSD type IX (phosphorylase kinase deficiency) Lysosomal (LSD): * GSD type II (Pompe's disease, glucosidase deficiency) Glucose ⇄ CAC Glycolysis * MODY 2/HHF3 * GSD type VII (Tarui's disease, phosphofructokinase deficiency) * Triosephosphate isomerase deficiency * Pyruvate kinase deficiency Gluconeogenesis * PCD * Fructose bisphosphatase deficiency * GSD type I (von Gierke's disease, glucose 6-phosphatase deficiency) Pentose phosphate pathway * Glucose-6-phosphate dehydrogenase deficiency * Transaldolase deficiency * 6-phosphogluconate dehydrogenase deficiency Other * Hyperoxaluria * Primary hyperoxaluria * Pentosuria * Aldolase A deficiency * v * t * e Genetic disorder, membrane: Solute carrier disorders 1-10 * SLC1A3 * Episodic ataxia 6 * SLC2A1 * De Vivo disease * SLC2A5 * Fructose malabsorption * SLC2A10 * Arterial tortuosity syndrome * SLC3A1 * Cystinuria * SLC4A1 * Hereditary spherocytosis 4/Hereditary elliptocytosis 4 * SLC4A11 * Congenital endothelial dystrophy type 2 * Fuchs' dystrophy 4 * SLC5A1 * Glucose-galactose malabsorption * SLC5A2 * Renal glycosuria * SLC5A5 * Thyroid dyshormonogenesis type 1 * SLC6A19 * Hartnup disease * SLC7A7 * Lysinuric protein intolerance * SLC7A9 * Cystinuria 11-20 * SLC11A1 * Crohn's disease * SLC12A3 * Gitelman syndrome * SLC16A1 * HHF7 * SLC16A2 * Allan–Herndon–Dudley syndrome * SLC17A5 * Salla disease * SLC17A8 * DFNA25 21-40 * SLC26A2 * Multiple epiphyseal dysplasia 4 * Achondrogenesis type 1B * Recessive multiple epiphyseal dysplasia * Atelosteogenesis, type II * Diastrophic dysplasia * SLC26A4 * Pendred syndrome * SLC35C1 * CDOG 2C * SLC39A4 * Acrodermatitis enteropathica * SLC40A1 * African iron overload see also solute carrier family [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	Renal glycosuria	c3245525	730	wikipedia	https://en.wikipedia.org/wiki/Renal_glycosuria	2021-01-18T19:01:34	{"gard": ["7548"], "mesh": ["D006030"], "umls": ["C3245525"], "orphanet": ["69076"], "wikidata": ["Q1207967"]}
## Description The term 'atrioventricular septal defect' (AVSD) covers a spectrum of congenital heart malformations characterized by a common atrioventricular junction coexisting with deficient atrioventricular septation. In ostium primum atrial septal defect (ASD) there are separate atrioventricular valvar orifices despite a common junction, whereas in complete AVSD the valve itself is also shared (summary by Craig, 2006). AVSD, also designated endocardial cushion defect or atrioventricular canal defect (AVCD), is known to occur in either a nonsyndromic (isolated) form or, more commonly, as part of a malformation syndrome. The 2 syndromes most frequently associated with AVSD are Down syndrome (190685), in which AVSD is the most frequent congenital heart defect, and Ivemark syndrome (208530) (summary by Carmi et al., 1992). ### Genetic Heterogeneity of Isolated Atrioventricular Septal Defect An AVSD susceptibility locus (AVSD1) maps to chromosome 1p31-p21; AVSD2 (606217) is caused by mutation in the CRELD1 gene (607170) on chromosome 3p25; AVSD3 (600309) is caused by mutation in the GJA1 gene (121014) on chromosome 6q22; AVSD4 (614430) is caused by mutation in the GATA4 gene (600576) on chromosome 8p23.1; and AVSD5 (614474) is caused by mutation in the GATA6 gene (601656) on chromosome 18q11. Somatic mutations in the HAND1 gene (602406) have been identified in tissue samples from patients with AVSDs. Clinical Features The clinical presentation and course in AVSD relates to the specific morphology of the defect and the presence of associated defects. (1) In infants with complete AVSD and a sizable interventricular component, congestive cardiac failure is likely to develop within the first few months of life as pulmonary vascular resistance falls. If there is significant regurgitation of the common atrioventricular valve, associated coarctation of the aorta or ventricular imbalance, cardiac failure may occur much earlier and often within the first week of life. Without surgery, many of these patients will die in infancy and those who survive will develop pulmonary vascular disease and eventually die with Eisenmenger syndrome. (2) The infant with AVSD may present with a mild degree of central cyanosis. This finding relates to bidirectional shunting at both the atrial and ventricular level in the presence of elevated pulmonary vascular resistance at birth. The only positive precordial findings of a congenital heart defect at this time may be a right ventricular impulse and accentuated pulmonary component of the second heart sound. A precordial murmur may, at this stage, be much abbreviated or absent. (3) In patients with complete AVSD and a small interventricular component, or in patients with ostium primum ASD where atrioventricular valve regurgitation is minimal, cardiac failure is rare and clinical symptoms may be minimal or absent in infancy and childhood. Without surgery, however, there is considerable longer term morbidity and mortality with only 25% survival beyond 40 years of age (summary by Craig, 2006). Amati et al. (1995) noted that in patients with AVSD with normal chromosomes there is a prevalence of partial forms and left side obstructions, right malalignment of the AVSD, including left ventricle hypoplasia. Inheritance Although nonsyndromic AVSD has been attributed to multifactorial inheritance, the occurrence of a few kindreds with multiple affected individuals has suggested that a major genetic locus can account for the disorder in some families (Amati et al., 1995). Sanchez-Cascos (1978) did not differentiate sibs from offspring but found 14 of 161 relatives (8.7%) to be affected. Among 52 offspring of adults with AVSD, Emanuel et al. (1983) found 5 (9.6%) affected offspring. Two of the instances were cases of tetralogy of Fallot. Given the abnormal anterior displacement of the aorta in AVSD, it is possible that there is an etiologic relationship between the 2 defects in these families. In a large family study, Digilio et al. (1993) found a consecutive series of 103 isolated AVSD probands to have 4/111 (3.6%) similarly affected sibs, 4/206 (1.9%) affected parents, and 5/644 (0.8%) affected uncles and aunts. Nora (1971) found no affected individuals in 70 families, but found one family with 4 affected individuals in one sibship. In the past, families such as this, and the 4 sibs with ostium primum septal defect and normal parents reported by Yao et al. (1968), would have prompted the suggestion of a recessive form, but the offspring studies make it at least as likely that these are examples of nonpenetrance or gonadal mosaicism in 1 parent. The report of an extensive dominant pedigree by O'Nuallain et al. (1977) and similar large dominant pedigrees with incomplete penetrance reported by Wilson et al. (1993), Cousineau et al. (1994), and Digilio et al. (1993) reinforce the case for a single dominant gene defect in the isolated form. ### AVSD1 In a family with AVSD mapping chromosome 1p reported by Sheffield et al. (1997), inheritance followed an autosomal dominant pattern with incomplete penetrance. Diagnosis Craig (2006) reviewed diagnostic features of AVSD ascertained by chest radiograph, electrocardiogram, echocardiogram, and MRI. ### Prenatal Diagnosis Prenatal diagnosis of AVSD can be made through the 4-chamber view of the heart on routine antenatal ultrasound. The key diagnostic feature is the presence of a common atrioventricular valve (Craig, 2006). Clinical Management The mainstay of management in AVSD is surgical correction of the defect (Craig, 2006). Population Genetics Population data on AVSD came from the Baltimore-Washington Infant Study (BWIS) which identified 336 children with AVSD among 4,385 infants with confirmed heart defects presenting under 1 year of age (7.7%) (Carmi et al., 1992). Of these 336 children, 76% were syndromic; of the syndromic cases, 78% were trisomy 21 (190685), or just under 60% of the total series. This represented 56% of the heart malformations associated with Down syndrome. Cytogenetics A locus for AVSD on chromosome 21 was suggested by the high incidence of AVSD in cases of Down syndrome (190685). Digilio et al. (1993) reviewed the literature on 8p deletion suggesting an AVSD critical region around band 8p23. Carmi et al. (1992) reported cases of AVSD with partial 10q monosomy, partial 13q monosomy, ring 22, 14q+, and 1p+3p- due to an unbalanced translocation. Mapping Sheffield et al. (1997) used a combination of DNA pooling and shared segment analysis to perform a high density screen of the entire autosomal human genome in an extended kindred segregating isolated AVSD. In so doing they identified a genetic locus, which they symbolized AVCD, on chromosome 1p31-p21 shared by all affected individuals. ### Exclusion Studies Wilson et al. (1993) carried out multipoint analysis of linkage data from a large 3-generation family segregating AVSD. Ten polymorphic markers spanning the Down syndrome critical region excluded the causative gene from this region. A parallel study by Cousineau et al. (1994) of their 4-generation family with isolated AVSD also achieved significant negative lod scores for chromosome 21. Thus, the phenotype is likely to be genetically heterogeneous. Because of a striking association between 8p deletion and atrioventricular canal defect, Amati et al. (1995) studied 2 pedigrees with autosomal dominant AVCD using a set of DNA markers from the 8pter-q12 region. These 2 families included affected individuals and subjects who had transmitted the defect but were not clinically affected. Significantly negative 2-point lod scores were observed for all markers at penetrance levels of 90% and 50%. Results corroborated heterogeneity of this heart defect and indicated that the genetic basis of familial AVCD is different from that associated with either Down syndrome (trisomy 21) or 8p deletion. Molecular Genetics ### Associations Pending Confirmation Smith et al. (2009) sequenced 32 candidate genes known to be important in development of the atrioventricular septum (AVS) in 190 patients with AVS defects, and identified 2 missense variants in the ACVR1 gene (102576) that were not found in 350 controls, only 1 of which showed a functional difference compared to wildtype. The 1 variant, a heterozygous L343P substitution, was identified in a male proband of European ancestry who had a primum-type ASD with a cleft anterior mitral valve leaflet, resulting in a small left-to-right shunt and mild mitral regurgitation. The proband's father, who also carried the L343P variant, had a cardiac murmur noted at 14 years of age, and echocardiography revealed calcification of the annulus of the posterior mitral valve leaflet and prolapse of both leaflets. Functional analysis revealed that the L343P variant reduces ALK2 (ACVR1) signaling in vitro and disrupts the kinase activity of the receptor, and in vivo analysis of zebrafish embryos injected with ACVR1 L343P RNA revealed improper atrioventricular canal formation. Noting that the father's phenotype could not be unambiguously classified as a congenital heart defect and was clinically nonpenetrant, Smith et al. (2009) concluded that L343P represented a dominant-negative allele and suggested that mutation in ACVR1 may be causative for AVS defects. Ackerman et al. (2012) used a candidate gene approach among individuals with Down syndrome and complete atrioventricular septal defect (AVSD) (141 cases) and Down syndrome with no congenital heart defect (141 controls) to determine whether rare genetic variants in genes involved in atrioventricular valvuloseptal morphogenesis contribute to AVSD in this sensitized population. Ackerman et al. (2012) found a significant excess (p less than 0.0001) of variants predicted to be deleterious in cases compared to controls. At the most stringent level of filtering, they found potentially damaging variants in nearly 20% of cases but in fewer than 3% of controls. The variants with the highest probability of being damaging in cases only were found in 6 genes: COL6A1 (120220), COL6A2 (120240), CRELD1 (607170) (already identified as a cause of AVSD; see 606217), FBLN2 (135821), FRZB (605083), and GATA5 (611496). Several of the case-specific variants were recurrent in unrelated individuals, occurring in 10% of cases studied. No variants with an equal probability of being damaging were found in controls, demonstrating a highly specific association with AVSD. Of note, all of these genes are in the VEGFA (192240) pathway, suggesting to Ackerman et al. (2012) that rare variants in this pathway might contribute to the genetic underpinnings of AVSD in humans. D'Alessandro et al. (2016) performed whole-exome sequencing in 81 unrelated probands with AVSD to identify potential causal variants in a comprehensive set of 112 genes with strong biological relevance to AVSD. A significant enrichment of rare and rare damaging variants was identified in the gene set, compared with controls (odds ratio (OR) 1.52; 95% confidence interval (CI), 1.35-1.71; p = 4.8 x 10(-11)). The enrichment was specific to AVSD probands, compared with a cohort without AVSD with tetralogy of Fallot (OR 2.25; 95% CI, 1.84-2.76; p = 2.2 x 10(-16)). Six genes (NIPBL, 608667; CHD7, 608892; CEP152, 613529; BMPR1A, 601299; ZFPM2, 603693; and MDM4, 602704) were enriched for rare variants in AVSD compared with controls, including 3 syndrome-associated genes (NIPBL, CHD7, and CEP152). The findings were confirmed in a replication cohort of 81 AVSD probands. D'Alessandro et al. (2016) concluded that mutations in genes with strong biological relevance to AVSD, including syndrome-associated genes, can contribute to AVSD, even in those with isolated heart disease. Of the 34 probands with variants in the 6 prioritized genes, 8 probands had a rare or rare damaging nonsynonymous variant in more than 1 gene, of which 6 had a second mutation in ZFPM2. In addition, 1 patient had variants in CHD7, NIPBL, and CEP152 and another had variants in CEP152 and NIPBL. Interestingly, 2 patients showed the same NIPBL variant (N393K), which occurred in only 1 individual in the Exome Variant Server (EVS). [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	ATRIOVENTRICULAR SEPTAL DEFECT	c1389018	731	omim	https://www.omim.org/entry/606215	2019-09-22T16:10:35	{"doid": ["0050651"], "mesh": ["C562831"], "omim": ["606215"], "icd-9": ["745.60", "745.6"], "icd-10": ["Q21.2"], "orphanet": ["98722"], "synonyms": ["Alternative titles", "ATRIOVENTRICULAR CANAL DEFECT", "AVC DEFECT", "ENDOCARDIAL CUSHION DEFECT"]}
A number sign (#) is used with this entry because early infantile epileptic encephalopathy-16 (EIEE16) is caused by homozygous or compound heterozygous mutation in the TBC1D24 gene (613577) on chromosome 16p13. Mutation in the TBC1D24 gene can also cause familial infantile myoclonic epilepsy (FIME; 605021), a less severe disorder. Description Early infantile epileptic encephalopathy-16 is a severe autosomal recessive neurologic disorder characterized by onset of seizures in the first weeks or months of life. Seizures can be of various types, are unresponsive to medication, last for long periods of time, and occur frequently. Affected infants show psychomotor regression or lack of psychomotor development, as well as other neurologic features such as extrapyramidal signs and hypotonia. Most die in childhood (summary by Duru et al., 2010 and Milh et al., 2013). For a general phenotypic description and a discussion of genetic heterogeneity of EIEE, see EIEE1 (308350). Clinical Features Duru et al. (2010) reported a large consanguineous Turkish family in which 5 children had a severe early infantile epileptic encephalopathy characterized by myoclonic seizures, alternating and migrating jerks of the extremities, focal seizures, and neurologic deterioration with permanent neurologic sequelae. Features included long-lasting myoclonic seizures that were not responsive to medication, hemiparesis with pyramidal signs, severe hypotonia, dystonia, and status epilepticus. EEG in initial stages were characterized by multiple spikes, but later showed a steady and progressive slowing of background activity. Brain imaging showed progressive atrophic changes in the brain and cerebellum and/or delayed myelination. The seizures occurred spontaneously or were triggered by common infections. The patients became inattentive to visual and acoustic stimuli as the disease progressed; 1 patient examined late in the disease course showed optic atrophy and macular degeneration. None of the patients had photosensitivity. All patients died by age 7 years. Duru et al. (2010) referred to the disorder as 'progressive myoclonic epilepsy with dystonia (PMED).' Milh et al. (2013) reported 2 sisters, born of unrelated parents, with a severe early infantile epileptic encephalopathy presenting clinically as malignant migrating partial seizures of infancy (MMPSI). Both had onset of clonic seizures early in the second month of life that progressed to a 'stormy' phase, with almost continuous clonic migrating seizures and psychomotor regression. Both patients had severe neurologic impairment with axial hypotonia, no voluntary movement, no eye contact, and acquired microcephaly. Brain MRI at birth was normal in both patients, but later showed brain atrophy. One sib died of seizures at age 18 months. Inheritance The transmission pattern of EIEE16 in the families reported by Duru et al. (2010) and Milh et al. (2013) was consistent with autosomal recessive inheritance. Mapping By linkage analysis of a large consanguineous Turkish family with early infantile epileptic encephalopathy, Duru et al. (2010) identified a locus on chromosome 16pter-p13.3 (maximum multipoint lod score of 7.83 between markers TTTA028 and D16S3-26; maximum 2-point lod score of 4.25 at D16S2618). Haplotype analysis delineated a 6.73-Mb candidate interval. Sequencing of the ATP6V0C gene (108745) did not reveal any pathogenic mutations. The locus overlapped that reported by Zara et al. (2000) for FIME, but Duru et al. (2010) noted that the phenotypes differed significantly in severity. Molecular Genetics In affected members of the family reported by Duru et al. (2010), Guven and Tolun (2013) identified a homozygous truncating mutation in the TBC1D24 gene (613577.0004). The severity of the mutation paralleled the severity of the phenotype. In 2 sisters with EIEE16, Milh et al. (2013) identified compound heterozygous mutations in the TBC1D24 gene (F229S, 613577.0005 and C156X, 613577.0006). The mutations, which were found by exome sequencing and confirmed by Sanger sequencing, were not present in several large exome databases and segregated with the disorder in the family. INHERITANCE \- Autosomal recessive HEAD & NECK Head \- Microcephaly, acquired (in some patients) Eyes \- Loss of eye contact \- Visual loss \- Optic atrophy (rare) MUSCLE, SOFT TISSUES \- Hypotonia, severe NEUROLOGIC Central Nervous System \- Epileptic encephalopathy \- Seizures, tonic, clonic, focal \- Prolonged seizures \- Status epilepticus \- Migrating clonic jerks (in some patients) \- Myoclonus \- Psychomotor regression \- Psychomotor retardation, severe \- Hypotonia \- Dystonia \- Hemiparesis \- Extrapyramidal signs \- Hemiparesis \- Multifocal spikes and progressive slowing of background activity seen on EEG \- Progressive cerebral atrophy seen on MRI \- Delayed myelination MISCELLANEOUS \- Onset in early infancy \- Progressive disorder \- High frequency seizures \- Seizures may be triggered by infection \- Seizures are refractory to medication \- Most patients die in childhood MOLECULAR BASIS \- Caused by mutation in the TBC1 domain family, member 24 gene (TBC1D24, 613577.0004 ) ▲ 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	EPILEPTIC ENCEPHALOPATHY, EARLY INFANTILE, 16	c3809173	732	omim	https://www.omim.org/entry/615338	2019-09-22T15:52:30	{"doid": ["0080449"], "omim": ["615338"], "orphanet": ["293181", "352596"], "synonyms": ["Migrating partial epilepsy of infancy", "Progressive myoclonus epilepsy with dystonia", "MMPSI", "MPEI", "MPSI", "Migrating partial seizures of infancy", "Malignant migrating partial epilepsy of infancy", "MMPEI", "PMED"], "genereviews": ["NBK274566"]}
Delayed milestone Other namesDevelopmental delays SpecialtyPediatrics Delayed milestone, also called developmental delays, is used to describe the condition where a child does not reach one of these stages at the expected age. However, in most cases, a wide variety of ages can be considered normal, and not a cause for medical concern. Milestones are often measured using percentiles, and for many milestones a value between the 5th and 95th percentile does not require intervention, though values towards the edges of that range can be associated with other medical conditions. It is not possible to treat. It has been suggested that measurement of posture sway may be an early indicator.[1] ## See also[edit] * Behavioral cusp * Developmental milestones * Intellectual disability ## References[edit] 1. ^ Deffeyes; Harbourne, R.; Kyvelidou, A.; Stuberg, W.; Stergiou, N. (2009). "Nonlinear analysis of sitting postural sway indicates developmental delay in infants". Clinical biomechanics (Bristol, Avon). 24 (7): 564–570. doi:10.1016/j.clinbiomech.2009.05.004. PMID 19493596. ## External links[edit] Classification D * ICD-10: R62.0 * ICD-9-CM: 783.42 * CDC's "Learn the Signs. Act Early.” campaign \- Information for parents on early childhood development and developmental disabilities * "Recognizing Developmental Delays in Children", WebMD, retrieved 31 May 2019 * v * t * e Malnutrition Protein-energy malnutrition * Kwashiorkor * Marasmus * Catabolysis Vitamin deficiency B vitamins * B1 * Beriberi * Wernicke–Korsakoff syndrome * Wernicke's encephalopathy * Korsakoff's syndrome * B2 * Riboflavin deficiency * B3 * Pellagra * B6 * Pyridoxine deficiency * B7 * Biotin deficiency * B9 * Folate deficiency * B12 * Vitamin B12 deficiency Other * A: Vitamin A deficiency * Bitot's spots * C: Scurvy * D: Vitamin D deficiency * Rickets * Osteomalacia * Harrison's groove * E: Vitamin E deficiency * K: Vitamin K deficiency Mineral deficiency * Sodium * Potassium * Magnesium * Calcium * Iron * Zinc * Manganese * Copper * Iodine * Chromium * Molybdenum * Selenium * Keshan disease Growth * Delayed milestone * Failure to thrive * Short stature * Idiopathic General * Anorexia * Weight loss * Cachexia * Underweight This medical sign 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	Delayed milestone	c0424605	733	wikipedia	https://en.wikipedia.org/wiki/Delayed_milestone	2021-01-18T19:07:16	{"umls": ["C0424605"], "icd-9": ["315"], "wikidata": ["Q5253500"]}
## Clinical Features Dos Santos and de Magalhaes (1980) described a family in which 10 members of 3 generations had multiple polyposis, with adenocarcinomatous propensities, limited to the stomach. No male-to-male transmission was observed. Seruca et al. (1991) restudied the family reported by dos Santos and de Magalhaes (1980) and added an observation of male-to-male transmission. Contrary to the original description, the histology of the gastric polyps present in the affected members revealed hyperplastic features and no adenomatous changes. Severe psoriasis was present in some members of the family as a probable coincidental disorder. Inheritance Based on the observation of male-to-male transmission of gastric polyposis in the family originally reported by Dos Santos and de Magalhaes (1980), Seruca et al. (1991) suggested autosomal dominant inheritance. Oncology \- Stomach adenocarcinoma propensity GI \- Multiple gastric polyps Inheritance \- Autosomal dominant ▲ 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	POLYPOSIS, GASTRIC	c0236048	734	omim	https://www.omim.org/entry/175020	2019-09-22T16:36:00	{"mesh": ["C562464"], "omim": ["175020"], "orphanet": ["157798"], "synonyms": ["Serrated polyposis"]}
Anal fissure Other namesFissure in ano, rectal fissure SpecialtyGastroenterology An anal fissure is a break or tear in the skin of the anal canal. Anal fissures may be noticed by bright red anal bleeding on toilet paper and undergarments, or sometimes in the toilet. If acute they are painful after defecation,[1] but with chronic fissures, pain intensity often reduces. Anal fissures usually extend from the anal opening and are usually located posteriorly in the midline, probably because of the relatively unsupported nature and poor perfusion of the anal wall in that location. Fissure depth may be superficial or sometimes down to the underlying sphincter muscle. Untreated fissures develop a hood-like skin tag (sentinel piles) which cover the fissure and cause discomfort and pain. ## Contents * 1 Causes * 2 Prevention * 3 Diagnosing * 4 Treatment * 4.1 Medication * 4.2 Surgery * 4.2.1 Lateral internal sphincterotomy * 4.2.2 Anal dilation * 4.2.3 Fissurectomy * 4.2.4 Dr. Feingolds procedure * 5 Epidemiology * 6 See also * 7 References * 8 External links ## Causes[edit] Most anal fissures are caused by stretching of the anal mucous membrane beyond its capability. Superficial or shallow anal fissures look much like a paper cut, and may be hard to detect upon visual inspection; they will generally self-heal within a couple of weeks. However, some anal fissures become chronic and deep and will not heal. The most common cause of non-healing is spasming of the internal anal sphincter muscle which results in impaired blood supply to the anal mucosa. The result is a non-healing ulcer, which may become infected by fecal bacteria. In adults, fissures may be caused by constipation, the passing of large, hard stools, or by prolonged diarrhea. In older adults, anal fissures may be caused by decreased blood flow to the area. When fissures are found laterally, tuberculosis, occult abscesses, leukemic infiltrates, carcinoma, acquired immunodeficiency syndrome (AIDS) or inflammatory bowel disease should be considered as causes.[2] Some sexually transmitted infections can promote the breakdown of tissue resulting in a fissure. Examples of sexually transmitted infections that may affect the anorectal area are syphilis, herpes, chlamydia and human papilloma virus.[3] Other common causes of anal fissures include: * childbirth trauma in women[4] * anal sex[5][6] * Crohn's disease[4] * ulcerative colitis[7] * poor toileting in young children.[8] ## Prevention[edit] For adults, the following may help prevent anal fissures: * Avoiding straining when defecating. This includes treating and preventing constipation by eating food rich in dietary fiber, drinking enough water, occasional use of a stool softener, and avoiding constipating agents.[9] Similarly, prompt treatment of diarrhea may reduce anal strain. * Careful anal hygiene after defecation, including using soft toilet paper and cleaning with water, plus the use of sanitary wipes. * In cases of pre-existing or suspected fissure, use of a lubricating ointment (It is important to note that hemorrhoid ointment is contraindicated because it constricts small blood vessels, thus causes a decrease in blood flow, which prevents healing.) In infants, frequent diaper change can prevent anal fissure. As constipation can be a cause, making sure the infant is drinking enough fluids (i.e. breastmilk, proper ratios when mixing formulas) is beneficial. In infants, once an anal fissure has occurred, addressing underlying causes is usually enough to ensure healing occurs. ## Diagnosing[edit] External anal fissures on anal verge can be diagnosed by visual inspection. Internal anal fissures on anterior side, posterior side or throughout the inner circumference of the anal sphincter muscle can be diagnosed with slit / split proctoscope, transparent plastic proctoscope or by Digital rectal examination with finger inside the anal sphincter muscle. Note that colonoscopy, sigmoidoscopy or normal proctoscopy is for diagnosing internal hemorrhoids and other internal rectal diseases and not for diagnosing anal fissures. ## Treatment[edit] Non-surgical treatments are recommended initially for acute and chronic anal fissures.[10][11] These include topical nitroglycerin or calcium channel blockers (e.g. diltiazem), or injection of botulinum toxin into the anal sphincter.[12] Other measures include warm sitz baths, topical anesthetics, high-fiber diet and stool softeners.[13][14] ### Medication[edit] Local application of medication to relax the sphincter muscle, thus allowing the healing to proceed, was first proposed in 1994 with nitroglycerine ointment,[15][16][17][18] and then calcium channel blockers in 1999 with nifedipine ointment,[19][20] and the following year with topical diltiazem.[21] Branded preparations are now available of topical nitroglycerine ointment (Rectogesic (Rectiv) as 0.2% in Australia and 0.4% in UK and US[22]), topical nifedipine 0.3% with lidocaine 1.5% ointment (Antrolin in Italy since April 2004) and diltiazem 2% (Anoheal in UK, although still in Phase III development). A common side effect drawback of nitroglycerine ointment is headache, caused by systemic absorption of the drug, which limits patient acceptability. A combined surgical and pharmacological treatment, administered by colorectal surgeons, is direct injection of botulinum toxin (Botox) into the anal sphincter to relax it. This treatment was first investigated in 1993. However, in many cases involving Botox injections the patients eventually had to choose another cure as the injections proved less and less potent, spending thousands of dollars in the meantime for a partial cure. Lateral sphincterotomy is the Gold Standard for curing this affliction.[23] Combination of medical therapies may offer up to 98% cure rates.[24] ### Surgery[edit] Surgical procedures are generally reserved for people with anal fissure who have tried medical therapy for at least one to three months and have not healed. It is not the first option in treatment. The main concern with surgery is the development of anal incontinence. Anal incontinence can include inability to control gas, mild fecal soiling, or loss of solid stool. Some degree of incontinence can occur in up to 45 percent of patients in the immediate surgical recovery period. However, incontinence is rarely permanent and is usually mild. The risk should be discussed with one's surgeon. Surgical treatment, under general anaesthesia, was either anal stretch (Lord's operation) or lateral sphincterotomy where the internal anal sphincter muscle is incised. Both operations aim to decrease sphincter spasming and thereby restore normal blood supply to the anal mucosa. Surgical operations involve a general or regional anaesthetia. Anal stretch is also associated with anal incontinence in a small proportion of cases and thus sphincterotomy is the operation of choice. #### Lateral internal sphincterotomy[edit] Lateral internal sphincterotomy (LIS) is the surgical procedure of choice for anal fissures due to its simplicity and its high success rate (~95%).[citation needed] In this procedure the internal anal sphincter is partially divided in order to reduce spasming and thus improve the blood supply to the perianal area. This improvement in the blood supply helps to heal the fissure, and the weakening of the sphincter is also believed to reduce the potential for recurrence.[citation needed] The procedure is generally performed as a day surgery after the patient is given general anesthesia. The pain from the sphincterotomy is usually mild and is often less than the pain of the fissure itself. Patients often return to normal activity within one week. LIS does, however, have a number of potential side effects including problems with incision site healing and incontinence to flatus and faeces (some surveys of surgical results suggest incontinence rates of up to 36%).[25] Though lateral internal sphincterotomy (LIS) is considered safe on short-term basis, there are concerns about its long-term safety. Pankaj Garg et al. published a systematic review and meta-analysis in which they analyzed the long-term continence disturbance two years after the LIS procedure. They found the incidence of long-term continence disturbance to be 14%, so caution and careful patient selection are needed before undergoing LIS.[26] #### Anal dilation[edit] Anal dilation, or stretching of the anal canal (Lord's operation), has fallen out of favour in recent years, primarily due to the unacceptably high incidence of fecal incontinence.[27] In addition, anal stretching can increase the rate of flatus incontinence.[28] The incidence of incontinence is thought to be due to a lack of standardization and that proper technique results in little chance that it will occur.[29] In the early 1990s, however, a repeatable method of anal dilation proved to be very effective and showed a very low incidence of side effects.[30] Since then, at least one other controlled, randomized study has shown there to be little difference in healing rates and complications between controlled anal dilation and LIS,[31] while another has again shown high success rates with anal dilation coupled with low incidence of side effects.[32] #### Fissurectomy[edit] Fissurectomy involves excision of the skin on and around the anal fissure and excision of the sentinel pile, if one is present. The surgical wound can be left open. New skin tissue grows and it heals. #### Dr. Feingolds procedure[edit] The fissure is cleaned with curettage then Cauterized with electrocautery to seal the wound then the fissure is injected with traimcinolone. The procedure has no side effects of incontinence. ## Epidemiology[edit] The incidence of anal fissures is around 1 in 350 adults.[8] They occur equally commonly in men and women and most often occur in adults aged 15 to 40.[8] ## See also[edit] * Medicine portal * Anal fistula * Hemorrhoid * Pruritus ani ## References[edit] 1. ^ Gott, M. D.; Peter, H. (5 March 1998). "New Therapy Coming for Anal Fissures". The Fresno Bee. Fresno, CA: McClatchy Co. p. E2, "Life" section. 2. ^ "Common Anorectal Conditions". American Academy of Family Physicians. Archived from the original on 5 August 2012. 3. ^ "Anal Fissure – Causes". NHS Choices. Archived from the original on 4 February 2013. 4. ^ a b Collins, E. E.; Lund, J. N. (September 2007). "A Review of Chronic Anal Fissure Management". Techniques in Coloproctology. 11 (3): 209–223. doi:10.1007/s10151-007-0355-9. PMID 17676270. 5. ^ "What Causes Anal Fissures?". WebMD. Archived from the original on 27 July 2017. Retrieved 20 July 2017. 6. ^ Ferri, Fred F. (2015). Ferri's Clinical Advisor 2016. Elsevier Health Sciences. p. 108. ISBN 9780323378222. 7. ^ "Anal Fissure Treatment, Symptoms & Surgery - Cleveland Clinic: Health Library". Cleveland Clinic. Archived from the original on 22 August 2013. 8. ^ a b c "Anal Fissure – Basics – Epidemiology". Best Practice. British Medical Journal. 23 April 2012. Retrieved 30 June 2012. 9. ^ Basson, Marc D. (28 January 2010). "Constipation". eMedicine. New York, NY: WebMD. Archived from the original on 15 February 2010. Retrieved 5 April 2010. 10. ^ Nelson RL, Thomas K, Morgan J, Jones A (2012). "Non surgical therapy for anal fissure". Cochrane Database of Systematic Reviews. 2 (2): CD003431. doi:10.1002/14651858.CD003431.pub3. PMC 7173741. PMID 22336789. 11. ^ Haq., Z.; Rahman, M.; Chowdhury, R.; Baten, M.; Khatun, M. (2005). "Chemical Sphincterotomy—First Line of Treatment for Chronic Anal Fissure". Mymensingh Medical Journal. 14 (1): 88–90. PMID 15695964. 12. ^ Shao, WJ; Li, GC; Zhang, ZK (September 2009). "Systematic review and meta-analysis of randomized controlled trials comparing botulinum toxin injection with lateral internal sphincterotomy for chronic anal fissure". International Journal of Colorectal Disease. 24 (9): 995–1000. doi:10.1007/s00384-009-0683-5. PMID 19266207. S2CID 21869421. 13. ^ "Anal Fissure – Treatment Overview". WebMD. Archived from the original on 5 October 2011. Retrieved 27 September 2011. 14. ^ Poritz, Lisa Susan. "Anal Fissure Treatment & Management". Medscape. Archived from the original on 31 October 2011. Retrieved 27 September 2011. 15. ^ Loder, P.; Kamm, M.; Nicholls, R.; Phillips, R. (1994). "'Reversible Chemical Sphincterotomy' by Local Application of Glyceryl Trinitrate". British Journal of Surgery. 81 (9): 1386–1389. doi:10.1002/bjs.1800810949. PMID 7953427. S2CID 45517748. 16. ^ Watson, S.; Kamm, M.; Nicholls, R.; Phillips, R. (1996). "Topical Glyceryl Trinitrate in the Treatment of Chronic Anal Fissure". British Journal of Surgery. 83 (6): 771–775. doi:10.1002/bjs.1800830614. PMID 8696736. S2CID 27460928. 17. ^ Simpson, J.; Lund, J.; Thompson, R.; Kapila, L.; Scholefield, J. (2003). "The Use of Glyceryl Trinitrate (GTN) in the Treatment of Chronic Anal Fissure in Children". Medical Science Monitor. 9 (10): PI123–126. PMID 14523338. 18. ^ Lund, J. N.; Scholefield, J.H. (4 January 1997). "A Randomised, Prospective, Double-blind, Placebo-controlled Trial of Glyceryl Trinitrate Ointment in Treatment of Anal Fissure". The Lancet. 349 (9044): 11–14. doi:10.1016/S0140-6736(96)06090-4. PMID 8988115. S2CID 8780826. 19. ^ Antropoli, C.; Perrotti, P.; Rubino, M.; Martino, A.; De Stefano, G.; Migliore, G.; Antropoli, M.; Piazza, P. (1999). "Nifedipine for Local Use in Conservative Treatment of Anal Fissures: Preliminary Results of a Multicenter Study". Diseases of the Colon and Rectum. 42 (8): 1011–1015. doi:10.1007/BF02236693. PMID 10458123. 20. ^ Katsinelos, P.; Kountouras, J.; Paroutoglou, G.; Beltsis, A.; Chatzimavroudis, G.; Zavos, C.; Katsinelos, T.; Papaziogas, B. (2006). "Aggressive Treatment of Acute Anal Fissure with 0.5% Nifedipine Ointment Prevents Its Evolution to Chronicity". World Journal of Gastroenterology. 12 (38): 6203–6206. doi:10.3748/wjg.v12.i38.6203. PMC 4088118. PMID 17036396. Archived from the original on 12 May 2009. Retrieved 12 May 2009. 21. ^ Carapeti, E.; Kamm, M.; Phillips, R. (2000). "Topical Diltiazem and Bethanechol Decrease Anal Sphincter Pressure and Heal Anal Fissures without Side Effects". Diseases of the Colon and Rectum. 43 (10): 1359–1362. doi:10.1007/BF02236630. PMID 11052511. 22. ^ "Rectiv". drugs.com. Archived from the original on 2 September 2011. Retrieved 27 September 2011. 23. ^ Jost, W.; Schimrigk, K. (1993). "Use of Botulinum Toxin in Anal Fissure". Diseases of the Colon and Rectum. 36 (10): 974. doi:10.1007/BF02050639. PMID 8404394. S2CID 44959287. 24. ^ Tranqui, P.; Trottier, D.; Victor, C.; Freeman, J. (2006). "Nonsurgical treatment of chronic anal fissure: nitroglycerin and dilatation versus nifedipine and botulinum toxin" (PDF). Canadian Journal of Surgery. 49 (1): 41–45. PMC 3207506. PMID 16524142. Archived (PDF) from the original on 6 January 2016. Retrieved 12 May 2009. 25. ^ Wolff, B. G.; Fleshman, J.W.; Beck, D. E.; Church, J. M. (2007). The ASCRS Textbook of Colon and Rectal Surgery. Springer. p. 180. ISBN 978-0-387-24846-2. Retrieved 15 July 2009.[clarification needed] 26. ^ Garg P, Garg M, Menon GR (March 2013). "Long-term continence disturbance after lateral internal sphincterotomy for chronic anal fissure: a systematic review and meta-analysis". Colorectal Dis. 15 (3): e104–17. doi:10.1111/codi.12108. PMID 23320551. 27. ^ Becker, Horst Dieter (2005). Urinary and Fecal Incontinence: An Interdisciplinary Approach. Springer Science & Business Media. p. 105. ISBN 9783540222255. OCLC 185042351. Retrieved 17 August 2014. 28. ^ Sadovsky, R. (1 April 2003). "Diagnosis and management of patients with anal fissures – Tips from Other Journals". American Family Physician. 67 (7): 1608. Archived from the original (Reprint) on 29 January 2006. Retrieved 12 May 2009. 29. ^ Gupta PJ (2004). "Treatment of fissure in ano- revisited". Afr Health Sci. 4 (1): 58–62. PMC 2141661. PMID 15126193. 30. ^ Sohn, N; Weinstein, M.A. (January 1997). "Anal dilatation for anal fissures". Seminars in Colon and Rectal Surgery. 8: 17–23. 31. ^ Yucel, T.; Gonullu, D.; Oncu, M.; Koksoy, F. N.; Ozkan, S. G.; Aycan, O. (June 2009). "Comparison of Controlled-intermittent Anal Dilatation and Lateral Internal Sphincterotomy in the Treatment of Chronic Anal Fissures: A Prospective, Randomized Study". International Journal of Surgery. 7 (3): 228–231. doi:10.1016/j.ijsu.2009.03.006. PMID 19361582. 32. ^ Renzi, A.; Brusciano, L.; Pescatori, M.; Izzo, D.; Napolitano, V.; Rossetti, G.; del Genio, G.; del Genio, A. (January 2005). "Pneumatic Balloon Dilatation for Chronic Anal Fissure: A Prospective, Clinical, Endosonographic, and Manometric Study". Diseases of the Colon and Rectum. 48 (1): 121–126. doi:10.1007/s10350-004-0780-z. PMID 15690668. S2CID 42818812. * Lund, J. N.; Nyström, P. O.; Coremans, G.; Herold, A.; Karaitianos, I.; Spyrou, M.; Schouten, W. R.; Sebastian, A. A.; Pescatori, M. (October 2006). "An evidence-based treatment algorithm for anal fissure". Techniques in Coloproctology. 10 (3): 177–180. doi:10.1007/s10151-006-0276-z. PMID 16969620. S2CID 5736917. ## External links[edit] Classification D * ICD-10: K60.0-K60.2 * ICD-9-CM: 565.0 * MeSH: D005401 * DiseasesDB: 673 External resources * MedlinePlus: 001130 * eMedicine: med/3532 ped/2938 emerg/495 Wikimedia Commons has media related to Anal fissure. https://columbiasurgery.org/news/2014/04/01/new-protocol-treat-anal-fissures * 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	Anal fissure	c0016167	735	wikipedia	https://en.wikipedia.org/wiki/Anal_fissure	2021-01-18T19:04:32	{"mesh": ["D005401"], "umls": ["C0016167"], "icd-9": ["565.0"], "icd-10": ["K60.2", "K60.0"], "wikidata": ["Q484797"]}
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: "Kleptolagnia" – news · newspapers · books · scholar · JSTOR (March 2017) (Learn how and when to remove this template message) Kleptolagnia (from Greek kleptein meaning "to steal", and lagnia meaning "sexual excitement") is the state of being sexually aroused by theft.[1] A kleptolagniac is a person aroused by the act of theft. It is also known as kleptophilia, and is a sexual form of kleptomania. ## See also[edit] * Chremastistophilia ## References[edit] 1. ^ Colman, Andrew (2008). A Dictionary of Psychology (3rd Edition). Oxford University Press. ISBN 9780199534067. * v * t * e Paraphilias List * Abasiophilia * Acrotomophilia * Agalmatophilia * Algolagnia * Apotemnophilia * Autassassinophilia * Biastophilia * Capnolagnia * Chremastistophilia * Chronophilia * Coprophagia * Coprophilia * Crurophilia * Crush fetish * Dacryphilia * Dendrophilia * Emetophilia * Eproctophilia * Erotic asphyxiation * Erotic hypnosis * Erotophonophilia * Exhibitionism * Formicophilia * Frotteurism * Gerontophilia * Homeovestism * Hybristophilia * Infantophilia * Kleptolagnia * Klismaphilia * Lactaphilia * Macrophilia * Masochism * Mechanophilia * Microphilia * Narratophilia * Nasophilia * Necrophilia * Object sexuality * Odaxelagnia * Olfactophilia * Omorashi * Paraphilic infantilism * Partialism * Pedophilia * Podophilia * Plushophilia * Pyrophilia * Sadism * Salirophilia * Scopophilia * Somnophilia * Sthenolagnia * Tamakeri * Telephone scatologia * Transvestic fetishism * Trichophilia * Troilism * Urolagnia * Urophagia * Vorarephilia * Voyeurism * Zoophilia * Zoosadism See also * Other specified paraphilic disorder * Erotic target location error * Courtship disorder * Polymorphous perversity * Sexual fetishism * Human sexual activity * Perversion * Sexology * Book * Category This sexuality-related article is a stub. You can help Wikipedia by expanding it. * v * t * e [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor *[BMI]: body mass index	Kleptolagnia	None	736	wikipedia	https://en.wikipedia.org/wiki/Kleptolagnia	2021-01-18T18:28:25	{"wikidata": ["Q6420625"]}
A clinical variant of iridocorneal endothelial (ICE) syndrome, characterized by progressive iris atrophy and holes present on the surface of the iris, corneal edema, corectopia, uveal ectropion and anterior synechiae. Secondary glaucoma is also a common complication of the 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	Essential iris atrophy	c0271111	737	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=98981	2021-01-23T18:33:51	{"icd-10": ["H21.2"]}
Brainstem stroke SpecialtyNeurology A brainstem stroke syndrome falls under the broader category of stroke syndromes, or specific symptoms caused by vascular injury to an area of brain (for example, the lacunar syndromes). As the brainstem contains numerous cranial nuclei and white matter tracts, a stroke in this area can have a number of unique symptoms depending on the particular blood vessel that was injured and the group of cranial nerves and tracts that are no longer perfused. Symptoms of a brainstem stroke frequently include sudden vertigo and ataxia, with or without weakness. Brainstem stroke can also cause diplopia, slurred speech and decreased level of consciousness. A more serious outcome is locked-in syndrome. ## Contents * 1 Classic Syndromes * 2 History * 2.1 Kate Allatt * 2.2 Jean-Dominique Bauby * 2.3 Rabbi Ronnie Cahana * 2.4 Tony Nicklinson * 2.5 Julia Tavalaro * 3 See also * 4 References * 5 External links ## Classic Syndromes[edit] * The midbrain syndromes (Significant overlap between these three syndromes) * Superior alternating hemiplegia or Weber's syndrome * Paramedian midbrain syndrome or Benedikt's syndrome * Claude's syndrome * Medial pontine syndrome or Middle alternating hemiplegia or Foville's syndrome * Lateral pontine syndrome or Marie-Foix syndrome * Medial medullary syndrome or Inferior alternating hemiplegia * Lateral medullary syndrome or Wallenberg syndrome ## History[edit] A history of locked in syndromes. ### Kate Allatt[edit] Kate Allatt is a mother-of-three from Sheffield, South Yorkshire. She has successfully recovered from locked-in syndrome. Now she runs Fighting Strokes, and devotes her life to assisting those with locked-in syndrome.[citation needed] ### Jean-Dominique Bauby[edit] Parisian journalist Jean-Dominique Bauby suffered a stroke in December 1995, and, when he awoke 20 days later, he found his body was almost completely paralyzed; he could control only his left eyelid. By blinking this eye, he slowly dictated one alphabetic character at a time and, in so doing, was able over a great deal of time to write his memoir, The Diving Bell and the Butterfly. Three days after it was published in March 1997, Bauby died of pneumonia.[1] The 2007 film The Diving Bell and the Butterfly is a screen adaptation of Bauby's memoir. Jean-Dominique was instrumental in forming the Association du Locked-In Syndrome (ALIS) in France.[2] ### Rabbi Ronnie Cahana[edit] In the summer of 2011, Rabbi Ronnie Cahana, Rabbi Emeritus of Congregation Beth-El in Montreal, suffered a severe brainstem stroke that left him in a locked-in state, able to communicate only with his eyes. With the help of his family, he continued to write poems and sermons for his congregation, letter by letter, through blinking. He has since regained his ability to breathe by himself and speak with his mouth. He describes his experiences as a blessing and a spiritual revelation of body and mind.[3] His story was told in a Ted talk given by his daughter called: "My Father, Locked-in his Body but Soaring Free". He is the son of painter Alice Lok Cahana.[citation needed] ### Tony Nicklinson[edit] Tony Nicklinson, of Melksham, Wiltshire, England, was left paralysed after suffering a stroke in June 2005,[4] at age 51. In the years that followed, he started a legal battle for a right to assisted death. On 16 August 2012, his request was turned down by the High Court of Justice.[5] On learning the outcome of his appeal, he refused to eat, contracted pneumonia, deteriorated rapidly and died a week later on 22 August 2012, aged 58.[6] ### Julia Tavalaro[edit] In 1966, Julia Tavalaro, then aged 32, suffered two strokes and a brain hemorrhage and was sent to Goldwater Memorial Hospital on Roosevelt Island, New York. For six years, she was believed to be in a vegetative state. In 1972, a family member noticed her trying to smile after she heard a joke. After alerting doctors, a speech therapist, Arlene Kratt, discerned cognizance in her eye movements. Kratt and an occupational therapist, Joyce Sabari, were eventually able to convince doctors she was in a locked-in state. After learning to communicate with eye blinks in response to letters being pointed to on an alphabet board, she became a poet and author. Eventually, she gained the ability to move her head enough to touch a switch with her cheek, which operated a motorized wheelchair and a computer. She gained national attention in 1995 when Richard E. Meyer of the Los Angeles Times published a cover story about Tavalaro. In 1997, Erika Duncan's profile of Julia and her co-author Richard Tayson, "Decades After Silence, a Voice Is Recognized," ran in the Long Island edition of The New York Times and in April 1997, "The Long Road Home" appeared in Newsday. Julia Tavalaro appears with Richard Tayson on Dateline NBC and Melissa Etheridge's Beyond Chance (Lifetime). Their book was published by Viking-Penguin in 1998 and was translated into German, where it was published as Bis auf den Grund des Ozeans by Verlag Herder. Tavalaro's story became a bestseller in Germany. She died in 2003 at the age of 68.[7][8] ## See also[edit] * Alternating hemiplegia * Lacunar syndromes * Posterior cerebral artery syndrome * Middle cerebral artery syndrome * Anterior cerebral artery syndrome ## References[edit] 1. ^ "The Diving Bell And The Butterfly". The A.V. Club. Archived from the original on 2007-12-01. Retrieved 2007-11-29. 2. ^ "Association du Locked In Syndrome" (in French). FR. 3. ^ Rabbi Ronnie Cahana, Rabbi Ronnie Cahana's poetry and sermons 4. ^ "Tony Nicklinson's legal fight for right to die". BBC News. 22 August 2012. Retrieved 22 August 2012. 5. ^ "Locked-in man devastated at ruling". 18 August 2012. Archived from the original on 19 August 2012. Retrieved 18 August 2012. 6. ^ "Right-to-die man Tony Nicklinson dead after refusing food". BBC News. 22 August 2012. Retrieved 22 August 2012. 7. ^ The Unspeakable Odyssey of the Motionless Boy by Joshua Foer, Esquire Magazine, October 2, 2008. 8. ^ "Julia Tavalaro, 68; Poet and Author Noted for Defying Severe Paralysis". Los Angeles Times. December 21, 2003. p. B16. ## External links[edit] Classification D * ICD-10: G46.3 * ICD-9-CM: 434.91 * v * t * e Cerebrovascular diseases including stroke Ischaemic stroke Brain * Anterior cerebral artery syndrome * Middle cerebral artery syndrome * Posterior cerebral artery syndrome * Amaurosis fugax * Moyamoya disease * Dejerine–Roussy syndrome * Watershed stroke * Lacunar stroke Brain stem * Brainstem stroke syndrome * Medulla * Medial medullary syndrome * Lateral medullary syndrome * Pons * Medial pontine syndrome / Foville's * Lateral pontine syndrome / Millard-Gubler * Midbrain * Weber's syndrome * Benedikt syndrome * Claude's syndrome Cerebellum * Cerebellar stroke syndrome Extracranial arteries * Carotid artery stenosis * precerebral * Anterior spinal artery syndrome * Vertebrobasilar insufficiency * Subclavian steal syndrome Classification * Brain ischemia * Cerebral infarction * Classification * Transient ischemic attack * Total anterior circulation infarct * Partial anterior circulation infarct Other * CADASIL * Binswanger's disease * Transient global amnesia Haemorrhagic stroke Extra-axial * Epidural * Subdural * Subarachnoid Cerebral/Intra-axial * Intraventricular Brainstem * Duret haemorrhages General * Intracranial hemorrhage Aneurysm * Intracranial aneurysm * Charcot–Bouchard aneurysm Other * Cerebral vasculitis * Cerebral venous sinus thrombosis * v * t * e Symptoms, signs and syndromes associated with lesions of the brain and brainstem Brainstem Medulla (CN 8, 9, 10, 12) * Lateral medullary syndrome/Wallenberg * PICA * Medial medullary syndrome/Dejerine * ASA Pons (CN 5, 6, 7, 8) * Upper dorsal pontine syndrome/Raymond-Céstan syndrome * Lateral pontine syndrome (AICA) (lateral) * Medial pontine syndrome/Millard–Gubler syndrome/Foville's syndrome (basilar) * Locked-in syndrome * Internuclear ophthalmoplegia * One and a half syndrome Midbrain (CN 3, 4) * Weber's syndrome * ventral peduncle, PCA * Benedikt syndrome * ventral tegmentum, PCA * Parinaud's syndrome * dorsal, tumor * Claude's syndrome Other * Alternating hemiplegia Cerebellum * Latearl * Dysmetria * Dysdiadochokinesia * Intention tremor) * Medial * Cerebellar ataxia Basal ganglia * Chorea * Dystonia * Parkinson's disease Cortex * ACA syndrome * MCA syndrome * PCA syndrome * Frontal lobe * Expressive aphasia * Abulia * Parietal lobe * Receptive aphasia * Hemispatial neglect * Gerstmann syndrome * Astereognosis * Occipital lobe * Bálint's syndrome * Cortical blindness * Pure alexia * Temporal lobe * Cortical deafness * Prosopagnosia Thalamus * Thalamic syndrome Other * Upper motor neuron lesion * Aphasia [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor *[BMI]: body mass index	Brainstem stroke syndrome	c0451671	738	wikipedia	https://en.wikipedia.org/wiki/Brainstem_stroke_syndrome	2021-01-18T18:57:31	{"icd-9": ["434.91"], "icd-10": ["G46.3"], "wikidata": ["Q4955837"]}
Cat et al. (1974) described a new syndrome in 8 persons in 7 Brazilian families living in a restricted area of southern Parana. Two were brothers and the parents of another were first cousins. Beginning at the age of 2 or 3 months, the skin of the entire body becomes progressively thicker. All joints gradually become frozen and movement of the chest and abdomen is severely restricted. Respiratory insufficiency may lead to death. The disorder is probably distinguishable from the stiff-skin syndrome (184900) by the severe growth retardation, more malignant course, and probable mode of inheritance. Growth \- Severe growth retardation Skin \- Total skin thickening Joints \- Freezing of all joints Resp \- Respiratory insufficiency Inheritance \- Autosomal recessive Misc \- Onset age 2 to 3 months Abdomen \- Restricted abdominal movement Thorax \- Restricted chest movement ▲ 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	PARANA HARD-SKIN SYNDROME	c1850079	739	omim	https://www.omim.org/entry/260530	2019-09-22T16:23:37	{"mesh": ["C564905"], "omim": ["260530"], "orphanet": ["2812"]}
Central or secondary congenital hypothyroidism is a type of permanent congenital hypothyroidism (see this term) characterized by permanent thyroid hormone deficiency that is present from birth and secondary to a disorder in the thyroid-stimulating hormone (TSH) - thyrotropin-releasing hormone (TRH) system. ## Epidemiology Prevalence is unknown. ## Clinical description The clinical manifestations are often subtle, probably as a result of trans-placental passage of some maternal thyroid hormone or due to the fact that many infants have some thyroid production of their own. More specific symptoms and signs often do not develop until several months of age. Common clinical features and signs include decreased activity and increased sleep, feeding difficulty and constipation, prolonged jaundice, myxedematous facies, large fontanels (especially posterior), macroglossia, a distended abdomen with umbilical hernia, and hypotonia. Goiter is always absent. Slow linear growth and developmental delay are usually apparent by 4-6 months of age. Without treatment central hypothyroidism results in intellectual deficit and short stature. ## Etiology Central hypothyroidism usually results from defects of TSH production and is often part of a disorder causing congenital hypopituitarism (see this term), in which case the clinical signs may also include septo-optic dysplasia or cleft lip and/or palate as well as other signs of hypopituitarism, or part of a larger genetic syndrome such as pituitary stalk interruption syndrome (see this term). Mutations in genes regulating pituitary gland development including HESX1, LHX3, LHX4, POU1F1 and PROP1 (3p21.2-p21.1, 9q34.3, 1q25, 3p11 and 5q) may also cause central hypothyroidism. Central hypothyroidism may also result from isolated TSH deficiency (see this term), which is transmitted in an autosomal recessive manner and is caused by mutations in the TSHB subunit gene (1p13), or from TRH resistance (see this term) caused by mutations in the TRH receptor gene (TRHR; 8q23). [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	Central congenital hypothyroidism	c3665349	740	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=226298	2021-01-23T18:26:44	{"gard": ["12280"], "mesh": ["D007037"], "umls": ["C3665349"], "icd-10": ["E03.1"], "synonyms": ["Secondary hypothyroidism"]}
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: "Degenerative disc disease" – news · newspapers · books · scholar · JSTOR (August 2009) (Learn how and when to remove this template message) Degenerative disc disease Other namesDegenerative disc disorder, intervertebral disc degeneration Degenerated disc between C5 and C6 (vertebra at the top of the picture is C2), with osteophytes anteriorly (to the left) on the lower portion of the C5 and upper portion of the C6 vertebral body. SpecialtyOrthopedics Risk factorsConnective tissue disease Degenerative disc disease (DDD) is a medical condition in which there are anatomic changes and a loss of function of varying degrees of one or more intervertebral discs of the spine of sufficient magnitude as to cause symptoms.[1] The root cause is thought to be loss of soluble proteins within the fluid contained in the disc with resultant reduction of the oncotic pressure, which in turn causes loss of fluid volume. Normal downward forces cause the affected disc to lose height, and the distance between vertebrae is reduced. The anulus fibrosus, the rigid outer shell of a disc, also weakens. This loss of height causes laxity of the longitudinal ligaments, which may allow anterior, posterior, or lateral shifting of the vertebral bodies, causing facet joint malalignment and arthritis; scoliosis; cervical hyperlordosis; thoracic hyperkyphosis; lumbar hyperlordosis; narrowing of the space available for the spinal tract within the vertebra (spinal stenosis); or narrowing of the space through which a spinal nerve exits (vertebral foramen stenosis) with resultant inflammation and impingement of a spinal nerve, causing a radiculopathy. DDD can cause mild to severe pain, either acute or chronic, near the involved disc, as well as neuropathic pain if an adjacent spinal nerve root is involved. Diagnosis is suspected when typical symptoms and physical findings are present; and confirmed by x-rays of the vertebral column. Occasionally the radiologic diagnosis of disc degeneration is made incidentally when a cervical x-ray, chest x-ray, or abdominal x-ray is taken for other reasons, and the abnormalities of the vertebral column are recognized. The diagnosis of DDD is not a radiologic diagnosis, since the interpreting radiologist is not aware whether there are symptoms present or not. Typical radiographic findings include disc space narrowing, displacement of vertebral bodies, fusion of adjacent vertebral bodies, and development of bone in adjacent soft tissue (osteophyte formation). An MRI is typically reserved for those with symptoms, signs, and x-ray findings suggesting the need for surgical intervention. Treatment may include chiropractic to reduce pain and increase any reduced range of motion (ROM) of the spine; Physical Therapy for pain relief, ROM, and appropriate muscle/strength training with emphasis on correcting abnormal posture, assisting the paravertebral (paraspinous) muscles in stabilizing the spine, and core muscle strengthening; stretching exercises; massage therapy; oral analgesia with non-steroidal anti-inflammatory agents (NSAIDS); and topical analgesia with lidocaine, ice and heat. Immediate surgery may be indicated if the symptoms are severe or sudden in onset, or there is a sudden worsening of symptoms. Elective surgery may be indicated after six months of conservative therapy with unsatisfactory relief of symptoms. ## Contents * 1 Signs and symptoms * 2 Cause * 3 Mechanisms * 4 Diagnosis * 5 Treatment * 6 Other animals * 7 See also * 8 References * 9 External links ## Signs and symptoms[edit] Degenerative disc disease can result in lower back or upper neck pain. The amount of degeneration does not correlate well with the amount of pain patients experience. Many people experience no pain while others, with the same amount of damage have severe, chronic pain.[2] Whether a patient experiences pain or not largely depends on the location of the affected disc and the amount of pressure that is being put on the spinal column and surrounding nerve roots. Nevertheless, degenerative disc disease is one of the most common sources of back pain and affects approximately 30 million people every year.[3] With symptomatic degenerative disc disease, the pain can vary depending on the location of the affected disc. A degenerated disc in the lower back can result in lower back pain, sometimes radiating to the hips, as well as pain in the buttocks, thighs or legs. If pressure is being placed on the nerves by exposed nucleus pulposus, sporadic tingling or weakness through the knees and legs can also occur. A degenerated disc in the upper neck will often result in pain to the neck, arm, shoulders and hands; tingling in the fingers may also be evident if nerve impingement is occurring. Pain is most commonly felt or worsened by movements such as sitting, bending, lifting and twisting. After an injury, some discs become painful because of inflammation and the pain comes and goes. Some people have nerve endings that penetrate more deeply into the anulus fibrosus (outer layer of the disc) than others, making discs more likely to generate pain. In the alternative, the healing of trauma to the outer anulus fibrosus may result in the innervation of the scar tissue and pain impulses from the disc, as these nerves become inflamed by nucleus pulposus material. Degenerative disc disease can lead to a chronic debilitating condition and can have a serious negative impact on a person's quality of life. When pain from degenerative disc disease is severe, traditional nonoperative treatment may be ineffective. ## Cause[edit] There is a disc between each of the vertebrae in the spine. A healthy, well-hydrated disc will contain a great deal of water in its center, known as the nucleus pulposus, which provides cushioning and flexibility for the spine. Much of the mechanical stress that is caused by everyday movements is transferred to the discs within the spine and the water content within them allows them to effectively absorb the shock. At birth, a typical human nucleus pulposus will contain about 80% water.[4] However natural daily stresses and minor injuries can cause these discs to gradually lose water as the annulus fibrosus, or the rigid outer shell of a disc, weakens.[5] Because degenerative disc disease is largely due to natural daily stresses, the American Academy of Orthopaedic Manual Physical Therapists have suggested it is not truly a "disease" process.[6] This water loss makes the discs less flexible and results in the gradual collapse and narrowing of the gap in the spinal column. As the space between vertebrae gets smaller, extra pressure can be placed on the discs causing tiny cracks or tears to appear in the annulus. If enough pressure is exerted, it is possible for the nucleus pulposus material to seep out through the tears in the annulus and can cause what is known as a herniated disc. As the two vertebrae above and below the affected disc begin to collapse upon each other, the facet joints at the back of the spine are forced to shift which can affect their function.[7] Additionally, the body can react to the closing gap between vertebrae by creating bone spurs around the disc space in an attempt to stop excess motion.[8] This can cause issues if the bone spurs start to grow into the spinal canal and put pressure on the spinal cord and surrounding nerve roots as it can cause pain and affect nerve function. This condition is called spinal stenosis. For women, there is evidence that menopause and related estrogen-loss are associated with lumbar disc degeneration, usually occurring during the first 15 years of the climacteric. The potential role of sex hormones in the etiology of degenerative skeletal disorders is being discussed for both genders.[9] Mutations in several genes have been implicated in intervertebral disc degeneration. Probable candidate genes include type I collagen (sp1 site), type IX collagen, vitamin D receptor, aggrecan, asporin, MMP3, interleukin-1, and interleukin-6 polymorphisms.[10] Mutation in genes – such as MMP2 and THBS2 – that encode for proteins and enzymes involved in the regulation of the extracellular matrix has been shown to contribute to lumbar disc herniation.[11][12] ## Mechanisms[edit] Micrograph of a fragment of a resected degenerative vertebral disc, showing degenerative fibrocartilage and clusters of chondrocytes. HPS stain. Degenerative discs typically show degenerative fibrocartilage and clusters of chondrocytes, suggestive of repair. Inflammation may or may not be present. Histologic examination of disc fragments resected for presumed DDD is routine to exclude malignancy. Fibrocartilage replaces the gelatinous mucoid material of the nucleus pulposus as the disc changes with age. There may be splits in the anulus fibrosus, permitting herniation of elements of nucleus pulposus. There may also be shrinkage of the nucleus pulposus that produces prolapse or folding of the anulus fibrosus with secondary osteophyte formation at the margins of the adjacent vertebral body. The pathologic findings in DDD include protrusion, spondylolysis, and subluxation of vertebrae (spondylolisthesis) and spinal stenosis. It has been hypothesized that Cutibacterium acnes may play a role.[13] ## Diagnosis[edit] Diagnosis of degenerative disc disease will usually consist of an analysis of a patient's individual medical history, a physical exam designed to reveal muscle weakness, tenderness or poor range of motion, and an x-ray to confirm the diagnosis and rule out other causes. ## Treatment[edit] Often, degenerative disc disease can be successfully treated without surgery. One or a combination of treatments such as physical therapy, anti-inflammatory medications such as nonsteroidal anti-inflammatory drugs, traction, or epidural steroid injection often provide adequate relief of troubling symptoms. Surgery may be recommended if the conservative treatment options do not provide relief within two to three months. If leg or back pain limits normal activity, if there is weakness or numbness in the legs, if it is difficult to walk or stand, or if medication or physical therapy are ineffective, surgery may be necessary, most often spinal fusion. There are many surgical options for the treatment of degenerative disc disease, including anterior[14] and posterior approaches. The most common surgical treatments include:[15] * Anterior cervical discectomy and fusion: A procedure that reaches the cervical spine (neck) through a small incision in the front of the neck. The intervertebral disc is removed and replaced with a small plug of bone or other graft substitute, and in time, that will fuse the vertebrae. * Cervical corpectomy: A procedure that removes a portion of the vertebra and adjacent intervertebral discs to allow for decompression of the cervical spinal cord and spinal nerves. A bone graft, and in some cases a metal plate and screws, is used to stabilize the spine. * Dynamic Stabilisation: Following a discectomy, a stabilisation implant is implanted with a 'dynamic' component. This can be with the use of Pedicle screws (such as Dynesys or a flexible rod) or an interspinous spacer with bands (such as a Wallis ligament). These devices off load pressure from the disc by rerouting pressure through the posterior part of the spinal column. Like a fusion, these implants allow maintain mobility to the segment by allowing flexion and extension. * Facetectomy: A procedure that removes a part of the facet to increase the space. * Foraminotomy: A procedure that enlarges the vertebral foramen to increase the size of the nerve pathway. This surgery can be done alone or with a laminotomy. * Intervertebral disc annuloplasty (IDET): A procedure wherein the disc is heated to 90 °C for 15 minutes in an effort to seal the disc and perhaps deaden nerves irritated by the degeneration. * Intervertebral disc arthroplasty: also called Artificial Disc Replacement (ADR), or Total Disc Replacement (TDR), is a type of arthroplasty. It is a surgical procedure in which degenerated intervertebral discs in the spinal column are replaced with artificial ones in the lumbar (lower) or cervical (upper) spine. * Laminoplasty: A procedure that reaches the cervical spine from the back of the neck. The spinal canal is then reconstructed to make more room for the spinal cord. * Laminotomy: A procedure that removes only a small portion of the lamina to relieve pressure on the nerve roots. * Microdiscectomy: A minimally invasive surgical procedure in which a portion of a herniated nucleus pulposus is removed by way of a surgical instrument or laser while using an operating microscope or loupe for magnification. * Percutaneous disc decompression: A procedure that reduces or eliminates a small portion of the bulging disc through a needle inserted into the disc, minimally invasive. * Spinal decompression: A non-invasive procedure that temporarily (a few hours) enlarges the intervertebral foramen (IVF) by aiding in the rehydration of the spinal discs. * Spinal laminectomy: A procedure for treating spinal stenosis by relieving pressure on the spinal cord. A part of the lamina is removed or trimmed to widen the spinal canal and create more space for the spinal nerves. Traditional approaches in treating patients with DDD-resultant herniated discs oftentimes include discectomy — which, in essence, is a spine-related surgical procedure involving the removal of damaged intervertebral discs (either whole removal, or partially-based). The former of these two discectomy techniques involved in open discectomy is known as Subtotal Discectomy (SD; or, aggressive discectomy) and the latter, Limited Discectomy (LD; or, conservative discectomy). However, with either technique, the probability of post-operative reherniation exists and at a considerably high maximum of 21%, prompting patients to potentially undergo recurrent disk surgery.[16] New treatments are emerging that are still in the beginning clinical trial phases. Glucosamine injections may offer pain relief for some without precluding the use of more aggressive treatment options.[citation needed] In the US, artificial disc replacement is viewed cautiously as a possible alternative to fusion in carefully selected patients, yet it is widely used in a broader range of cases in Europe, where multi-level disc replacement of the cervical and lumbar spine is common.[citation needed] Adult stem cell or cell transplantation therapies for disc regeneration are in their infancy of development, but initial clinical trials have shown cell transplantation to be safe and initial observations suggest some beneficial effects for associated pain and disability.[17][18] An optimal cell type, transplantation method, cell density, carrier, or patient indication remains to be determined. Investigation into mesenchymal stem cell therapy knife-less fusion of vertebrae in the United States began in 2006 [19] and a DiscGenics nucleus pulposus progenitor cell transplantation clinical trial has started as of 2018 in the USA [20] and Japan.[21] Researchers and surgeons have conducted clinical and basic science studies to uncover the regenerative capacity possessed by the large animal species involved (humans and quadrupeds) for potential therapies to treat the disease.[22] Some therapies, carried out by research laboratories in New York, include introduction of biologically-engineered, injectable riboflavin cross-linked high density collagen (HDC-laden) gels into disease spinal segments to induce regeneration, ultimately restoring functionality and structure to the two main inner and outer components of vertebral discs — anulus fibrosus and the nucleus pulposus.[23] Burgeoning evidence suggests that long-term running may mitigate age-related degeneration within lumbar intervertebral discs. [24] However, a 6-month randomized controlled trial showed that general strength and conditioning exercise training did not benefit the lumbar intervertebral discs of patients with non-specific chronic low back pain.[25] ## Other animals[edit] Degenerative disc disease can occur in other mammals besides humans. It is a common problem in several dog breeds, and attempts to remove this disease from dog populations have led to several hybrid breeds, such as the Chiweenie.[26] ## See also[edit] * Failed back syndrome * Herniated disk ## References[edit] 1. ^ Fardon, David F.; Williams, Alan L.; Dohring, Edward J.; Murtagh, F. Reed; Gabriel Rothman, Stephen L.; Sze, Gordon K. (November 2014). "Lumbar Disc Nomenclature: Version 2.0". Spine. 39 (24): E1448–E1465. doi:10.1097/BRS.0b013e3182a8866d. PMID 23970106. 2. ^ "Degenerative Disc Disease \| NorthShore". www.northshore.org. Retrieved 2017-01-05. 3. ^ "Degenerative Disc Disease Treament\|Degeneratice Disc Disease Treatments". www.instituteforchronicpain.org. Retrieved 2017-01-05. 4. ^ Kasbia, Virinder (8 September 2005). "Degenerative disc disease". Pembroke Observer. p. 7. ProQuest 354183403. 5. ^ "Degenerative Disc Disease". University of Maryland Medical Center. Retrieved 2017-01-04. 6. ^ Emerson AJ, Naze G, Mabry LM, Chaconas E, Silvernail J, Lonnemann E, Rhon D, Deyle GD. "AAOMPT Opposes Use of the Term "Degenerative Disc Disease"". American Academy of Orthopaedic Manual Physical Therapists Member's Resources Page. Retrieved 2019-12-31.CS1 maint: uses authors parameter (link) 7. ^ Lee, Yu Chao; Zotti, Mario Giuseppe Tedesco; Osti, Orso Lorenzo (2016). "Operative Management of Lumbar Degenerative Disc Disease". Asian Spine Journal. 10 (4): 801. doi:10.4184/asj.2016.10.4.801. PMC 4995268. PMID 27559465. 8. ^ "Bone spurs Causes – Mayo Clinic". Mayo Clinic. Retrieved 2017-01-04. 9. ^ Lou, C.; Chen, H-L.; Feng, X-Z.; Xiang, G-H.; Zhu, S-P.; Tian, N-F.; Jin, Y-L.; Fang, M-Q.; Wang, C.; Xu, H-Z. (December 2014). "Menopause is associated with lumbar disc degeneration: a review of 4230 intervertebral discs". Climacteric. 17 (6): 700–704. doi:10.3109/13697137.2014.933409. PMID 25017806. 10. ^ Anjankar SD, Poornima S, Raju S, Jaleel M, Bhiladvala D, Hasan Q. Degenerated intervertebral disc prolapse and its association of collagen I alpha 1 Spl gene polymorphism: A preliminary case control study of Indian population. Indian J Orthop 2015;49:589-94 11. ^ "Genetic background of degenerative disc disease in the lumbar spine". 12. ^ Hirose, Yuichiro; et al. (May 2008). "A Functional Polymorphism in THBS2 that Affects Alternative Splicing and MMP Binding Is Associated with Lumbar-Disc Herniation". American Journal of Human Genetics. 82 (5): 1122–1129. doi:10.1016/j.ajhg.2008.03.013. PMC 2427305. PMID 18455130. 13. ^ Capoor, Manu N.; Ruzicka, Filip; Schmitz, Jonathan E.; James, Garth A.; Machackova, Tana; Jancalek, Radim; Smrcka, Martin; Lipina, Radim; Ahmed, Fahad S.; Alamin, Todd F.; Anand, Neel; Baird, John C.; Bhatia, Nitin; Demir-Deviren, Sibel; Eastlack, Robert K.; Fisher, Steve; Garfin, Steven R.; Gogia, Jaspaul S.; Gokaslan, Ziya L.; Kuo, Calvin C.; Lee, Yu-Po; Mavrommatis, Konstantinos; Michu, Elleni; Noskova, Hana; Raz, Assaf; Sana, Jiri; Shamie, A. Nick; Stewart, Philip S.; Stonemetz, Jerry L.; Wang, Jeffrey C.; Witham, Timothy F.; Coscia, Michael F.; Birkenmaier, Christof; Fischetti, Vincent A.; Slaby, Ondrej (3 April 2017). "Propionibacterium acnes biofilm is present in intervertebral discs of patients undergoing microdiscectomy". PLOS ONE. 12 (4): e0174518. Bibcode:2017PLoSO..1274518C. doi:10.1371/journal.pone.0174518. PMC 5378350. PMID 28369127. 14. ^ Sugawara, Taku (2015). "Anterior Cervical Spine Surgery for Degenerative Disease: A Review". Neurologia Medico-Chirurgica. 55 (7): 540–546. doi:10.2176/nmc.ra.2014-0403. PMC 4628186. PMID 26119899. 15. ^ "Degenerative Disc Disease – When Surgery Is Needed". Retrieved 2007-06-26. 16. ^ Shin, Byung-Joon (2014). "Risk factors for recurrent lumbar disc herniations". Asian Spine Journal. 8 (2): 211–215. doi:10.4184/asj.2014.8.2.211. PMC 3996348. PMID 24761206. 17. ^ Schol, Jordy; Sakai, Daisuke (April 2019). "Cell therapy for intervertebral disc herniation and degenerative disc disease: clinical trials". International Orthopaedics. 43 (4): 1011–1025. doi:10.1007/s00264-018-4223-1. PMID 30498909. 18. ^ Sakai, Daisuke; Schol, Jordy (April 2017). "Cell therapy for intervertebral disc repair: Clinical perspective". Journal of Orthopaedic Translation. 9: 8–18. doi:10.1016/j.jot.2017.02.002. 19. ^ "Mesoblast files spinal fusion IND". Australian Life Scientist. 2006-11-27. Archived from the original on 2009-01-08. Retrieved 2009-02-16. 20. ^ "NCT03347708". ClinicalTrials.gov. 21. ^ "DiscGenics Receives Approval from Japanese Pharmaceuticals and Medical Devices Agency to Begin Clinical Evaluation of Non-Surgical Degenerative Disc Disease Treatment in Japan". PR News Wire. 22. ^ Moriguchi, Yu; Alimi, Marjan; Khair, Thamina; Manolarakis, George; Berlin, Connor; Bonassar, Lawrence J.; Härtl, Roger (2016). "Biological Treatment Approaches for Degenerative Disk Disease: A Literature Review of In Vivo Animal and Clinical Data". Global Spine Journal. 6 (5): 497–518. doi:10.1055/s-0036-1571955. PMC 4947401. PMID 27433434. 23. ^ Pennicooke, Brenton; Hussain, Ibrahim; Berlin, Connor; Sloan, Stephen R.; Borde, Brandon; Moriguchi, Yu; Lang, Gernot; Navarro-Ramirez, Rodrigo; Cheetham, Jonathan; Bonassar, Lawrence J.; Härtl, Roger (February 2018). "Annulus Fibrosus Repair Using High-Density Collagen Gel: An In Vivo Ovine Model". SPINE. 43 (4): E208–E215. doi:10.1097/BRS.0000000000002334. PMC 6686199. PMID 28719551. 24. ^ Mitchell, Ulrike H.; Bowden, Jennifer A.; Larson, Robert E.; Belavy, Daniel L.; Owen, Patrick J. (21 February 2020). "Long-term running in middle-aged men and intervertebral disc health, a cross-sectional pilot study". PLOS ONE. 15 (2): e0229457. doi:10.1371/journal.pone.0229457. 25. ^ Owen, Patrick J.; Miller, Clint T.; Rantalainen, Timo; Simson, Katherine J.; Connell, David; Hahne, Andrew J.; Trudel, Guy; Ford, Jon J.; Belavy, Daniel L. (24 March 2020). "Exercise for the intervertebral disc: a 6-month randomised controlled trial in chronic low back pain". European Spine Journal. doi:10.1007/s00586-020-06379-7. 26. ^ "Chiweenie - Dogs 101 \| Animal Planet". www.animalplanet.com. Retrieved 2017-12-20. ## External links[edit] Classification D * ICD-10: M51.3 * ICD-10-CM: M51.34, M51.35, M51.36, M51.37 * MeSH: D055959 * DiseasesDB: 6861 * v * t * e Spinal disease Deforming Spinal curvature * Kyphosis * Lordosis * Scoliosis Other * Scheuermann's disease * Torticollis Spondylopathy inflammatory * Spondylitis * Ankylosing spondylitis * Sacroiliitis * Discitis * Spondylodiscitis * Pott disease non inflammatory * Spondylosis * Spondylolysis * Spondylolisthesis * Retrolisthesis * Spinal stenosis * Facet syndrome Back pain * Neck pain * Upper back pain * Low back pain * Coccydynia * Sciatica * Radiculopathy Intervertebral disc disorder * Schmorl's nodes * Degenerative disc disease * Spinal disc herniation * Facet joint arthrosis * v * t * e Medicine Specialties and subspecialties Surgery * Cardiac surgery * Cardiothoracic surgery * Colorectal surgery * Eye surgery * General surgery * Neurosurgery * Oral and maxillofacial surgery * Orthopedic surgery * Hand surgery * Otolaryngology * ENT * Pediatric surgery * Plastic surgery * Reproductive surgery * Surgical oncology * Transplant surgery * Trauma surgery * Urology * Andrology * Vascular surgery Internal medicine * Allergy / Immunology * Angiology * Cardiology * Endocrinology * Gastroenterology * Hepatology * Geriatrics * Hematology * Hospital medicine * Infectious disease * Nephrology * Oncology * Pulmonology * Rheumatology Obstetrics and gynaecology * Gynaecology * Gynecologic oncology * Maternal–fetal medicine * Obstetrics * Reproductive endocrinology and infertility * Urogynecology Diagnostic * Radiology * Interventional radiology * Nuclear medicine * Pathology * Anatomical * Clinical pathology * Clinical chemistry * Cytopathology * Medical microbiology * Transfusion medicine Other * Addiction medicine * Adolescent medicine * Anesthesiology * Dermatology * Disaster medicine * Diving medicine * Emergency medicine * Mass gathering medicine * Family medicine * General practice * Hospital medicine * Intensive care medicine * Medical genetics * Narcology * Neurology * Clinical neurophysiology * Occupational medicine * Ophthalmology * Oral medicine * Pain management * Palliative care * Pediatrics * Neonatology * Physical medicine and rehabilitation * PM&R * Preventive medicine * Psychiatry * Addiction psychiatry * Radiation oncology * Reproductive medicine * Sexual medicine * Sleep medicine * Sports medicine * Transplantation medicine * Tropical medicine * Travel medicine * Venereology Medical education * Medical school * Bachelor of Medicine, Bachelor of Surgery * Bachelor of Medical Sciences * Master of Medicine * Master of Surgery * Doctor of Medicine * Doctor of Osteopathic Medicine * MD–PhD Related topics * Alternative medicine * Allied health * Dentistry * Podiatry * Pharmacy * Physiotherapy * Molecular oncology * Nanomedicine * Personalized medicine * Public health * Rural health * Therapy * Traditional medicine * Veterinary medicine * Physician * Chief physician * History of medicine * Book * Category * Commons * Wikiproject * Portal * Outline [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor *[BMI]: body mass index	Degenerative disc disease	c0158266	741	wikipedia	https://en.wikipedia.org/wiki/Degenerative_disc_disease	2021-01-18T18:46:45	{"mesh": ["D055959"], "umls": ["C0158266", "C0410606"], "icd-9": ["722.6"], "icd-10": ["M51.3"], "wikidata": ["Q11773731"]}
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: "Acrodermatitis chronica atrophicans" – news · newspapers · books · scholar · JSTOR (August 2010) (Learn how and when to remove this template message) Acrodermatitis chronica atrophicans Other namesHerxheimer disease[1]:1102 and Primary diffuse atrophy[2]:293 SpecialtyDermatology Acrodermatitis chronica atrophicans (ACA) is a skin rash indicative of the third or late stage of European Lyme borreliosis. ACA is a dermatological condition that takes a chronically progressive course and finally leads to a widespread atrophy of the skin. Involvement of the peripheral nervous system is often observed, specifically polyneuropathy. This progressive skin process is due to the effect of continuing active infection with the spirochete Borrelia afzelii, which is the predominant pathophysiology. B. afzelii may not be the exclusive etiologic agent of ACA; Borrelia garinii has also been detected. ## Contents * 1 Presentation * 2 Cause * 3 Diagnosis * 4 Treatment * 5 History * 6 See also * 6.1 Bibliography * 7 References * 8 External links ## Presentation[edit] The rash caused by ACA is most evident on the extremities. It begins with an inflammatory stage with bluish red discoloration and cutaneous swelling, and concludes several months or years later with an atrophic phase. Sclerotic skin plaques may also develop.[citation needed]As ACA progresses the skin begins to wrinkle. ## Cause[edit] This section is empty. You can help by adding to it. (March 2017) ## Diagnosis[edit] Generally 2step approach is followed. 1)Screening test- IgM and IgG ELISA 2) If 1 is positive or there is high clinical suspicion in spite of Elisa being negative than confirmatory test - Western Blot. Other methods. Microscopy and culture (in modified Kelly's medium) of skin biopsy or blood samples. ## Treatment[edit] Doxycycline The course of ACA is long-standing, from a few to several years, and it leads to extensive atrophy of the skin and, in some patients, to the limitation of upper and lower limb joint mobility.[citation needed]The outlook is good if the acute inflammatory stage of ACA is treated adequately. The therapeutic outcome is difficult to assess in patients with the chronic atrophic phase, in which many changes are only partially reversible. Physicians should use serologic and histologic examination to confirm the diagnosis of ACA. Treatment consists of antibiotics including doxycycline and penicillin for up to four weeks in the acute case.[citation needed] ## History[edit] The first record of ACA was made in 1883 in Breslau, Germany, where a physician named Alfred Buchwald first delineated it.[citation needed]Herxheimer and Hartmann described it in 1902 as a "tissue paper like" cutaneous atrophy. ## See also[edit] * Erythema migrans * List of cutaneous conditions * Lyme disease ### Bibliography[edit] * Stanek G & Strle F (2008) Lyme Disease—European Perspective\| Infectious Disease Clinics of North America \| Volume 22 \| Issue 2 \| June 2008, Pages 327-339\|Abstract ## References[edit] 1. ^ Rapini, Ronald P.; Bolognia, Jean L.; Jorizzo, Joseph L. (2007). Dermatology: 2-Volume Set. St. Louis: Mosby. ISBN 978-1-4160-2999-1. 2. ^ James, William D.; Berger, Timothy G.; et al. (2006). Andrews' Diseases of the Skin: clinical Dermatology. Saunders Elsevier. ISBN 978-0-7216-2921-6. ## External links[edit] Classification D * ICD-10: L90.4 * ICD-9-CM: 701.8 * DiseasesDB: 32940 External resources * eMedicine: derm/4 * 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 * t * e Medicine Specialties and subspecialties Surgery * Cardiac surgery * Cardiothoracic surgery * Colorectal surgery * Eye surgery * General surgery * Neurosurgery * Oral and maxillofacial surgery * Orthopedic surgery * Hand surgery * Otolaryngology * ENT * Pediatric surgery * Plastic surgery * Reproductive surgery * Surgical oncology * Transplant surgery * Trauma surgery * Urology * Andrology * Vascular surgery Internal medicine * Allergy / Immunology * Angiology * Cardiology * Endocrinology * Gastroenterology * Hepatology * Geriatrics * Hematology * Hospital medicine * Infectious disease * Nephrology * Oncology * Pulmonology * Rheumatology Obstetrics and gynaecology * Gynaecology * Gynecologic oncology * Maternal–fetal medicine * Obstetrics * Reproductive endocrinology and infertility * Urogynecology Diagnostic * Radiology * Interventional radiology * Nuclear medicine * Pathology * Anatomical * Clinical pathology * Clinical chemistry * Cytopathology * Medical microbiology * Transfusion medicine Other * Addiction medicine * Adolescent medicine * Anesthesiology * Dermatology * Disaster medicine * Diving medicine * Emergency medicine * Mass gathering medicine * Family medicine * General practice * Hospital medicine * Intensive care medicine * Medical genetics * Narcology * Neurology * Clinical neurophysiology * Occupational medicine * Ophthalmology * Oral medicine * Pain management * Palliative care * Pediatrics * Neonatology * Physical medicine and rehabilitation * PM&R * Preventive medicine * Psychiatry * Addiction psychiatry * Radiation oncology * Reproductive medicine * Sexual medicine * Sleep medicine * Sports medicine * Transplantation medicine * Tropical medicine * Travel medicine * Venereology Medical education * Medical school * Bachelor of Medicine, Bachelor of Surgery * Bachelor of Medical Sciences * Master of Medicine * Master of Surgery * Doctor of Medicine * Doctor of Osteopathic Medicine * MD–PhD Related topics * Alternative medicine * Allied health * Dentistry * Podiatry * Pharmacy * Physiotherapy * Molecular oncology * Nanomedicine * Personalized medicine * Public health * Rural health * Therapy * Traditional medicine * Veterinary medicine * Physician * Chief physician * History of medicine * Book * Category * Commons * Wikiproject * Portal * Outline [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor *[BMI]: body mass index	Acrodermatitis chronica atrophicans	c0029805	742	wikipedia	https://en.wikipedia.org/wiki/Acrodermatitis_chronica_atrophicans	2021-01-18T18:59:27	{"umls": ["C0029805"], "icd-10": ["L90.4"], "wikidata": ["Q420804"]}
A permanent deformity caused by physical trauma to the ear Cauliflower ear Cauliflower ear SpecialtyOtorhinolaryngology Cauliflower ear is an irreversible condition that occurs when the external portion of the ear is hit and develops a blood clot or other collection of fluid under the perichondrium. This separates the cartilage from the overlying perichondrium that supplies its nutrients, causing it to die and resulting in the formation of fibrous tissue in the overlying skin. As a result, the outer ear becomes permanently swollen and deformed, resembling a cauliflower. The condition is common in martial arts such as Brazilian jiu-jitsu, wrestling, judo or mixed martial arts and in full-contact sports such as rugby union and rugby league. ## Contents * 1 Presentation * 2 Causes * 3 Mechanism * 4 Diagnosis * 5 Prevention * 6 Treatment * 7 History * 8 References * 9 External links ## Presentation[edit] People presenting with possible auricular hematoma often have additional injuries (for example, head/neck lacerations) due to the frequently traumatic causes of auricular hematoma. The ear itself is often tense, fluctuant, and tender with throbbing pain. However, because of potentially more remarkable injuries often associated with auricular hematoma, auricular hematoma can easily be overlooked without directed attention.[1] ## Causes[edit] The most common cause of cauliflower ear is blunt trauma to the ear leading to a hematoma which, if left untreated, eventually heals to give the distinct appearance of cauliflower ear. The structure of the ear is supported by a cartilaginous scaffold consisting of the following distinct components: the helix, antihelix, concha, tragus, and antitragus.[1] The skin that covers this cartilage is extremely thin with virtually no subcutaneous fat while also strongly attached to the perichondrium, which is richly vascularized to supply the avascular cartilage.[1] Cauliflower ear can also present in the setting of nontraumatic inflammatory injury of auricular connective tissue such as in relapsing polychondritis (RP), a rare rheumatologic disorder in which recurrent episodes of inflammation result in destruction of cartilage of the ears and nose.[2] Joints, eyes, audiovestibular system, cardiovascular system, and respiratory tract can also be involved.[2] ## Mechanism[edit] The components of the ear involved in cauliflower ear are the outer skin, the perichondrium, and the cartilage.[3] The outer ear skin is tightly adherent to the perichondrium because there is almost no subcutaneous fat on the anterior of the ear.[3] This leaves the perichondrium relatively exposed to damage from direct trauma and shear forces, created by a force pushing across the ear like a punch, and increasing the risk of hematoma formation.[3] In an auricular hematoma, blood accumulates between the perichondrium and cartilage. The hematoma mechanically obstructs blood flow from the perichondrium to the avascular cartilage.[1] This lack of perfusion puts the cartilage at risk for becoming necrotic and/or infected.[1] If left untreated, disorganized fibrosis and cartilage formation will occur around the aforementioned cartilaginous components.[1] Consequently, the concave pinna fills with disorganized connective tissue.[1] The cartilage then deforms and kinks, resulting in the distinctive appearance somewhat resembling a cauliflower.[1] Rapid evacuation of the hematoma restores close contact between the cartilage and perichondrium, thereby reducing the likelihood of deformity by minimizing the ischemia that would otherwise result from a remaining hematoma.[1] Auricular hematoma most often occurs in the potential space between the helix and the antihelix (scapha) and extends anteriorly into the fossa triangularis.[1] Less frequently, the hematoma may form in the concha or the area in and around the external auditory meatus.[1] Importantly, an auricular hematoma can also occur on the posterior ear surface, or even both surfaces.[1] Risk of necrotic tissue is greatest when both posterior and anterior surfaces are involved, although posterior surface involvement is less likely given its increased quantity of impact-dampening subcutaneous tissue.[1][3] ## Diagnosis[edit] Perichondral hematoma and consequently cauliflower ear are diagnosed clinically. This means that the medical provider will make the diagnosis by using elements of the history of the injury (examples: participation in contact sports, trauma to the ear, previous similar episodes) and combine this with findings on physical exam (examples: tenderness to the area, bruising, deformation of the ear contours) to confirm the diagnosis and decide on the appropriate treatment for the patient.[3] Cauliflower ear in an MMA fighter To assist with settling on the best form of treatment for cauliflower ear Yotsuyanagi et al. created a classification system for deciding when surgery is needed and to guide the best approach.[4] Classification of cauliflower ear[4] Type 1: Minimal deformity with no or slight changes to the outline of the ear Type 2: Substantial deformity of the outline of the ear Type 1A Deformity is restricted to the concha of the ear Type 2A The structural integrity of the ear is intact Type 1B Deformity that extends from the antihelix to the helix of the ear Type 2B Poor structural integrity of the ear Type 1C Deformity that extends throughout the outer ear ## Prevention[edit] A Rugby union player wearing a tiger-print scrum cap, a form of headgear used for shock absorption and protection to the head. Headgear called a "scrum cap" in rugby, or simply "headgear" or ear guard in wrestling and other martial arts, that protects the ears is worn to help prevent this condition. A specialty ear splint can also be made to keep the ear compressed, so that the damaged ear is unable to fill thus preventing cauliflower ear. For some athletes, however, a cauliflower ear is considered a badge of courage or experience.[5] ## Treatment[edit] A mild auricular hematoma after drainage There are many types of treatment for the perichondral hematoma that can lead to cauliflower ear, but the current body of research is unable to identify a single best treatment or protocol.[6] There is definitive evidence that the drainage of this hematoma is better for the prevention of cauliflower deformity when compared to conservative treatment, but the use of bandages and/or splinting after drainage requires more research.[6] Because an acute hematoma can lead to cauliflower ear, prompt evacuation of the blood can prevent permanent deformity.[7] There are many described techniques for the drainage of blood in the acute stage to prevent hematoma, including simple needle drainage, continuous suction devices, placing a wick, and incision and drainage.[3] After the blood has been drained the prevention of re-accumulation becomes the most pressing issue, this has been achieved with many techniques including: direct pressure dressings, in and out mattress sutures, buttons placed on sutures, thermoplastic splints, sutured cotton balls, and absorbable mattress sutures.[3] The use of simple drainage becomes less useful after six hours from the injury and when there is recurrent trauma. In these cases it has been suggested that open surgical treatment is more effective in returning the cosmetic appearance and prevention of recurrence.[3] The outer ear is prone to infections, so antibiotics are usually prescribed.[3] Pressure can be applied by bandaging which helps the skin and the cartilage to reconnect. Clothes pegs, magnets, and custom molded ear splints[8] can also be used to ensure adequate pressure is applied to the damaged area[9] Without medical intervention the ear can suffer serious damage. Disruption of the ear canal is possible. The outer ear may wrinkle and can become slightly pale due to reduced blood flow; hence the common term "cauliflower ear".[10] Cosmetic procedures are available that can possibly improve the appearance of the ear.[11] ## History[edit] Depiction of cauliflower ear in the Boxer of Quirinal, circa 100–50 BC The presentation of cauliflower ear was recorded in ancient Greece.[12] In 19th-century Hong Kong opium dens, opium users would develop cauliflower ear from long periods sleeping on hard wooden pillows.[13] ## References[edit] 1. ^ a b c d e f g h i j k l m Ingvaldsen, Christoffer A.; Tønseth, Kim A. (2017). "Auricular haematoma". Tidsskrift for den Norske Laegeforening. 137 (2): 105–107. doi:10.4045/tidsskr.15.1279. PMID 28127072. 2. ^ a b Rapini (2006). "Relapsing polychondritis". Clin. Dermatol. 24 (6): 482–5. doi:10.1016/j.clindermatol.2006.07.018. PMID 17113965. 3. ^ a b c d e f g h i Greywoode, Jewel; Pribitkin, Edmund; Krein, Howard (2010-11-17). "Management of Auricular Hematoma and the Cauliflower Ear". Facial Plastic Surgery. 26 (6): 451–455. doi:10.1055/s-0030-1267719. ISSN 0736-6825. PMID 21086231. 4. ^ a b Yotsuyanagi, Takatoshi; Yamashita, Ken; Urushidate, Satoshi; Yokoi, Katsunori; Sawada, Yukimasa; Miyazaki, Souichiro (July 2002). "Surgical correction of cauliflower ear". British Journal of Plastic Surgery. 55 (5): 380–386. doi:10.1054/bjps.2002.3854. ISSN 0007-1226. PMID 12372365. 5. ^ Williams, Preston (2008-03-06). "For Wrestlers a Swelled Sense of Pride". The Washington Post. p. PG14. Retrieved 2008-04-02. `\|page(s)=` has extra text (help) 6. ^ a b Jones, Stephen EM; Mahendran, Suresh (2004-04-19). "Interventions for acute auricular haematoma". Cochrane Database of Systematic Reviews (2): CD004166. doi:10.1002/14651858.cd004166.pub2. ISSN 1465-1858. PMID 15106240. 7. ^ "Auricular Hematoma Drainage". 2018-09-04. Cite journal requires `\|journal=` (help) 8. ^ Keating, Thomas M.; Mason, John (October 27, 1992). "A Simple Splint for Wrestler's Ear". Journal of Athletic Training. 27 (3): 273–274. PMC 1317260. PMID 16558175. 9. ^ "Cauliflower ear – How to avoid and treat". 2019-01-28. 10. ^ "Cauliflower Ear Article". Nationwide Children's Hospital: Sports Med Articles. Retrieved 23 December 2011. 11. ^ Lukash, Frederick (21 August 2013). The Safe and Sane Guide to Teenage Plastic Surgery. BenBella Books, Inc. p. 103. ISBN 978-1-935618-63-8. 12. ^ Smith, R. R. R. (1991). Hellenistic Sculpture. London. pp. 54–55. 13. ^ Vogelin, E; Grobbelaar, AO; Chana, JS; Gault, DT (1998). "Surgical correction of the cauliflower ear". British Journal of Plastic Surgery. 51 (5): 359–62. doi:10.1054/bjps.1997.0033. PMID 9771361. ## External links[edit] Classification D * ICD-10: M95.1 * ICD-9-CM: 738.7 Wikimedia Commons has media related to Cauliflower ear. * Medicinenet.com * v * t * e Acquired musculoskeletal deformities Upper limb shoulder * Winged scapula * Adhesive capsulitis * Rotator cuff tear * Subacromial bursitis elbow * Cubitus valgus * Cubitus varus hand deformity * Wrist drop * Boutonniere deformity * Swan neck deformity * Mallet finger Lower limb hip * Protrusio acetabuli * Coxa valga * Coxa vara leg * Unequal leg length patella * Luxating patella * Chondromalacia patellae * Patella baja * Patella alta foot deformity * Bunion/hallux valgus * Hallux varus * Hallux rigidus * Hammer toe * Foot drop * Flat feet * Club foot knee * Genu recurvatum Head * Cauliflower ear General terms * Valgus deformity/Varus deformity * Joint stiffness * Ligamentous laxity [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	Cauliflower ear	c0158516	743	wikipedia	https://en.wikipedia.org/wiki/Cauliflower_ear	2021-01-18T18:44:58	{"icd-9": ["738.7"], "icd-10": ["M95.1"], "wikidata": ["Q886261"]}
Multisystemic smooth muscle dysfunction syndrome is a rare, genetic, vascular disease characterized by congenital dysfunction of smooth muscle throughout the body, manifesting with cerebrovascular disease, aortic anomalies, intestinal hypoperistalsis, hypotonic bladder, and pulmonary hypertension. Congenital mid-dilated pupils non-reactive to light associated with a large, persistent patent ductus arteriosus are characteristic hallmarks of the 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	Multisystemic smooth muscle dysfunction syndrome	c3151201	744	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=404463	2021-01-23T17:00:40	{"gard": ["12811"], "omim": ["613834"], "icd-10": ["I73.8"]}
Osteomalacia Cholecalciferol (Vitamin D3), deficiency of which is the most common cause of Osteomalacia SpecialtyRheumatology Osteomalacia is a disease characterized by the softening of the bones caused by impaired bone metabolism primarily due to inadequate levels of available phosphate, calcium, and vitamin D, or because of resorption of calcium. The impairment of bone metabolism causes inadequate bone mineralization. Osteomalacia in children is known as rickets, and because of this, use of the term "osteomalacia" is often restricted to the milder, adult form of the disease. Signs and symptoms can include diffuse body pains, muscle weakness, and fragility of the bones. In addition to low systemic levels of circulating mineral ions necessary for bone and tooth mineralization, accumulation of mineralization-inhibiting proteins and peptides (such as osteopontin and ASARM peptides) occurs in the extracellular matrix of bones and teeth, likely contributing locally to cause matrix hypomineralization (osteomalacia).[1][2][3][4][5] The most common cause of osteomalacia is a deficiency of vitamin D, which is normally derived from sunlight exposure and, to a lesser extent, from the diet.[6] The most specific screening test for vitamin D deficiency in otherwise healthy individuals is a serum 25(OH)D level.[7] Less common causes of osteomalacia can include hereditary deficiencies of vitamin D or phosphate (which would typically be identified in childhood) or malignancy. Vitamin D and calcium supplements are measures that can be used to prevent and treat osteomalacia. Vitamin D should always be administered in conjunction with calcium supplementation (as the pair work together in the body) since most of the consequences of vitamin D deficiency are a result of impaired mineral ion homeostasis.[7] Nursing home residents and the homebound elderly population are at particular risk for vitamin D deficiency, as these populations typically receive little sun exposure. In addition, both the efficiency of vitamin D synthesis in the skin and the absorption of vitamin D from the intestine decline with age, thus further increasing the risk in these populations. Other groups at risk include individuals with malabsorption secondary to gastrointestinal bypass surgery or celiac disease, and individuals who immigrate from warm climates to cold climates, especially women who wear traditional veils or dresses that prevent sun exposure.[8] ## Contents * 1 Signs and symptoms * 2 Causes * 3 Diagnosis * 3.1 Biochemical findings * 3.2 Radiographic characteristics * 4 Prevention * 5 Treatment * 6 Etymology * 7 See also * 8 References * 9 External links ## Signs and symptoms[edit] Osteomalacia is a generalized bone condition in which there is inadequate mineralization of the bone. Many of the effects of the disease overlap with the more common osteoporosis, but the two diseases are significantly different. There are two main causes of osteomalacia: 1. insufficient calcium absorption from the intestine because of lack of dietary calcium or a deficiency of, or resistance to, the action of vitamin D, or due to undiagnosed celiac disease.[9] 2. phosphate deficiency caused by increased renal losses. Symptoms: * Diffuse joint and bone pain (especially of spine, pelvis, and legs) * Muscle weakness * Difficulty walking, often with waddling gait * Hypocalcemia (positive Chvostek sign) * Compressed vertebrae and diminished stature * Pelvic flattening * Weak, soft bones * Easy fracturing * Bending of bones Osteomalacia in adults starts insidiously as aches and pains in the lumbar (lower back) region and thighs before spreading to the arms and ribs. The pain is symmetrical, non-radiating and accompanied by sensitivity in the involved bones. Proximal muscles are weak, and there is difficulty in climbing up stairs and getting up from a squatting position.[citation needed] As a result of demineralization, the bones become less rigid. Physical signs include deformities like triradiate pelvis[10] and lordosis. The patient has a typical "waddling" gait. However, these physical signs may derive from a previous osteomalacial state, since bones do not regain their original shape after they become deformed. Pathologic fractures due to weight bearing may develop. Most of the time, the only alleged symptom is chronic fatigue, while bone aches are not spontaneous but only revealed by pressure or shocks.[citation needed]It differs from renal osteodystrophy, where the latter shows hyperphosphatemia. ## Causes[edit] The causes of adult osteomalacia are varied, but ultimately result in a vitamin D deficiency: * Insufficient nutritional quantities or faulty metabolism of vitamin D or phosphorus * Renal tubular acidosis * Malnutrition during pregnancy * Malabsorption syndrome * Hypophosphatemia[11] * Chronic kidney failure * Tumor-induced osteomalacia (Oncogenic osteomalacia) * Long-term anticonvulsant therapy[12] * Celiac disease[13] * Cadmium poisoning, itai-itai disease ## Diagnosis[edit] ### Biochemical findings[edit] The metabolism of calcium, phosphate, hormones, and Vitamin D. Biochemical features are similar to those of rickets. The major factor is an abnormally low vitamin D concentration in blood serum.[citation needed]Major typical biochemical findings include:[14] * Low serum and urinary calcium * Low serum phosphate, except in cases of renal osteodystrophy * Elevated serum alkaline phosphatase (due to an increase in compensatory osteoblast activity) * Elevated parathyroid hormone (due to low calcium) Furthermore, a technetium bone scan will show increased activity (also due to increased osteoblasts). Comparison of bone pathology * view * talk * edit Condition Calcium Phosphate Alkaline phosphatase Parathyroid hormone Comments Osteopenia unaffected unaffected normal unaffected decreased bone mass Osteopetrosis unaffected unaffected elevated unaffected[citation needed] thick dense bones also known as marble bone Osteomalacia and rickets decreased decreased elevated elevated soft bones Osteitis fibrosa cystica elevated decreased elevated elevated brown tumors Paget's disease of bone unaffected unaffected variable (depending on stage of disease) unaffected abnormal bone architecture ### Radiographic characteristics[edit] Radiological appearances include: * Pseudofractures, also called Looser's zones. * Protrusio acetabuli, a hip joint disorder ## Prevention[edit] Prevention of osteomalacia rests on having an adequate intake of vitamin D and calcium. Vitamin D3 Supplementation is often needed due to the scarcity of Vitamin D sources in the modern diet.[citation needed] ## Treatment[edit] Nutritional osteomalacia responds well to administration of 2,000-10,000 IU of vitamin D3 by mouth daily. Vitamin D3 (cholecalciferol) is typically absorbed more readily than vitamin D2 (ergocalciferol). Osteomalacia due to malabsorption may require treatment by injection or daily oral dosing[15] of significant amounts of vitamin D3. ## Etymology[edit] Osteomalacia is derived from Greek: osteo- which means "bone", and malacia which means "softness". In the past, the disease was also known as malacosteon and its Latin-derived equivalent, mollities ossium. Osteomalacia is associated with increase in osteoid maturation time.[citation needed] ## See also[edit] * Osteopetrosis ## References[edit] 1. ^ Salmon, B; Bardet, C; Coyac, BR; Baroukh, B; Naji, J; Rowe, PS; Opsahl Vital, S; Linglart, A; Mckee, MD; Chaussain, C (August 2014). "Abnormal osteopontin and matrix extracellular phosphoglycoprotein localization, and odontoblast differentiation, in X-linked hypophosphatemic teeth". Connective Tissue Research. 55 Suppl 1: 79–82. doi:10.3109/03008207.2014.923864. PMID 25158186. S2CID 19702315. 2. ^ Boukpessi, T; Hoac, B; Coyac, BR; Leger, T; Garcia, C; Wicart, P; Whyte, MP; Glorieux, FH; Linglart, A; Chaussain, C; McKee, MD (21 November 2016). "Osteopontin and the dento-osseous pathobiology of X-linked hypophosphatemia". Bone. 95: 151–161. doi:10.1016/j.bone.2016.11.019. PMID 27884786. 3. ^ Barros, NM; Hoac, B; Neves, RL; Addison, WN; Assis, DM; Murshed, M; Carmona, AK; McKee, MD (March 2013). "Proteolytic processing of osteopontin by PHEX and accumulation of osteopontin fragments in Hyp mouse bone, the murine model of X-linked hypophosphatemia". Journal of Bone and Mineral Research. 28 (3): 688–99. doi:10.1002/jbmr.1766. PMID 22991293. 4. ^ McKee, MD; Hoac, B; Addison, WN; Barros, NM; Millán, JL; Chaussain, C (October 2013). "Extracellular matrix mineralization in periodontal tissues: Noncollagenous matrix proteins, enzymes, and relationship to hypophosphatasia and X-linked hypophosphatemia". Periodontology 2000. 63 (1): 102–22. doi:10.1111/prd.12029. PMC 3766584. PMID 23931057. 5. ^ Boukpessi, T; Gaucher, C; Léger, T; Salmon, B; Le Faouder, J; Willig, C; Rowe, PS; Garabédian, M; Meilhac, O; Chaussain, C (August 2010). "Abnormal presence of the matrix extracellular phosphoglycoprotein-derived acidic serine- and aspartate-rich motif peptide in human hypophosphatemic dentin". The American Journal of Pathology. 177 (2): 803–12. doi:10.2353/ajpath.2010.091231. PMC 2913338. PMID 20581062. 6. ^ "Osteomalacia: MedlinePlus Medical Encyclopedia". medlineplus.gov. 7. ^ a b Longo, Dan L.; et al. (2012). Harrison's principles of internal medicine (18th ed.). New York: McGraw-Hill. ISBN 978-0-07174889-6. 8. ^ Kennel, KA; Drake, MT; Hurley, DL (August 2010). "Vitamin D deficiency in adults: when to test and how to treat". Mayo Clinic Proceedings. 85 (8): 752–7, quiz 757-8. doi:10.4065/mcp.2010.0138. PMC 2912737. PMID 20675513. 9. ^ https://academic.oup.com/rheumatology/article/39/3/335/1783855 10. ^ Chakravorty, N. K. (1980). "Triradiate deformity of the pelvis in Paget's disease of bone". Postgraduate Medical Journal. 56 (653): 213–5. doi:10.1136/pgmj.56.653.213. PMC 2425842. PMID 7393817. 11. ^ "Autoimmunity research foundation, Science behind Vitamin D". Retrieved 2011-07-19. 12. ^ Pack, Alison (2008). "Bone health in people with epilepsy: is it impaired and what are the risk factors". Seizure. 17 (2): 181–6. doi:10.1016/j.seizure.2007.11.020. PMID 18187347. S2CID 16490292. 13. ^ "Definition & Facts for Celiac Disease. What are the complications of celiac disease?". NIDDK. June 2016. Retrieved 26 May 2018. 14. ^ Holick, Michael F. (19 July 2007). "Vitamin D Deficiency". New England Journal of Medicine. 357 (3): 266–281. doi:10.1056/NEJMra070553. PMID 17634462. 15. ^ Eisman, John A. (1988). "6 Osteomalacia". Baillière's Clinical Endocrinology and Metabolism. 2 (1): 125–55. doi:10.1016/S0950-351X(88)80011-9. PMID 3044328. ## External links[edit] Classification D * ICD-10: M83 * ICD-9-CM: 268.2 * MeSH: D010018 External resources * eMedicine: 000376/Osteomalacia * Patient UK: Osteomalacia * v * t * e Malnutrition Protein-energy malnutrition * Kwashiorkor * Marasmus * Catabolysis Vitamin deficiency B vitamins * B1 * Beriberi * Wernicke–Korsakoff syndrome * Wernicke's encephalopathy * Korsakoff's syndrome * B2 * Riboflavin deficiency * B3 * Pellagra * B6 * Pyridoxine deficiency * B7 * Biotin deficiency * B9 * Folate deficiency * B12 * Vitamin B12 deficiency Other * A: Vitamin A deficiency * Bitot's spots * C: Scurvy * D: Vitamin D deficiency * Rickets * Osteomalacia * Harrison's groove * E: Vitamin E deficiency * K: Vitamin K deficiency Mineral deficiency * Sodium * Potassium * Magnesium * Calcium * Iron * Zinc * Manganese * Copper * Iodine * Chromium * Molybdenum * Selenium * Keshan disease Growth * Delayed milestone * Failure to thrive * Short stature * Idiopathic General * Anorexia * Weight loss * Cachexia * Underweight * 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	Osteomalacia	c0029442	745	wikipedia	https://en.wikipedia.org/wiki/Osteomalacia	2021-01-18T18:48:29	{"gard": ["7285"], "mesh": ["D010018"], "umls": ["C0029442"], "icd-10": ["M83"], "wikidata": ["Q860395"]}
Eosinophilic gastroenteritis H&E Stain: Dense Eosinophilic infiltration of gastro-duodenal wall SpecialtyGastroenterology Eosinophilic gastroenteritis (EG or EGE) is a rare and heterogeneous condition characterized by patchy or diffuse eosinophilic infiltration of gastrointestinal (GI) tissue, first described by Kaijser in 1937.[1][2] Presentation may vary depending on location as well as depth and extent of bowel wall involvement and usually runs a chronic relapsing course. It can be classified into mucosal, muscular and serosal types based on the depth of involvement.[3][4] Any part of the GI tract can be affected, and isolated biliary tract involvement has also been reported.[5][6] The stomach is the organ most commonly affected, followed by the small intestine and the colon.[7][8] ## Contents * 1 Signs and symptoms * 2 Pathophysiology * 3 Diagnosis * 4 Management * 5 Epidemiology * 6 Other gastrointestinal conditions associated with allergy * 7 See also * 8 References * 9 External links ## Signs and symptoms[edit] EG typically presents with a combination of chronic nonspecific GI symptoms which include abdominal pain, diarrhea, occasional nausea and vomiting, weight loss and abdominal distension. Approximately 80% have symptoms for several years;[6] a high degree of clinical suspicion is often required to establish the diagnosis, as the disease is extremely rare. It doesn't come all of a sudden but takes about 3–4 years to develop depending upon the age of the patient. Occasionally, the disease may manifest itself as an acute abdomen or bowel obstruction.[9][10] * Mucosal EG (25–100%) is the most common variety,[11][12] which presents with features of malabsorption and protein losing enteropathy. Failure to thrive and anaemia may also be present. Lower gastrointestinal bleeding may imply colonic involvement. * Muscular EG (13–70%) present with obstruction of gastric outlet or small intestine; sometimes as an obstructing caecal mass or intussusception. * Subserosal EG (4.5% to 9% in Japan and 13% in the US)[13] presents with ascites which is usually exudative in nature, abundant peripheral eosinophilia, and has favourable responses to corticosteroids. * Other documented features are cholangitis, pancreatitis,[14] eosinophilic splenitis, acute appendicitis and giant refractory duodenal ulcer. ## Pathophysiology[edit] Peripheral blood eosinophilia and elevated serum IgE are usual but not universal. The damage to the gastrointestinal tract wall is caused by eosinophilic infiltration and degranulation.[15] As a part of host defense mechanism, eosinophils are normally present in gastrointestinal mucosa, though the finding in deeper tissue is almost always pathologic.[16] What triggers such dense infiltration in EG is not clear. It is possible that different pathogenetic mechanisms of disease is involved in several subgroups of patients. Food allergy and variable IgE response to food substances has been observed in some patients which implies role of hypersensitive response in pathogenesis. Many patients indeed have history of other atopic conditions like eczema, asthma, etc.[citation needed] Eosinophil recruitment into inflammatory tissue is a complex process, regulated by a number of inflammatory cytokines. In EG cytokines IL-3, IL-5 and granulocyte macrophage colony stimulating factor (GM-CSF) may be behind the recruitment and activation. They have been observed immunohistochemically in diseased intestinal wall.[17] In addition eotaxin has been shown to have an integral role in regulating the homing of eosinophils into the lamina propria of stomach and small intestine.[18] In the allergic subtype of disease, it is thought that food allergens cross the intestinal mucosa and trigger an inflammatory response that includes mast cell degranulation and recruitment of eosinophils.[18][19] ## Diagnosis[edit] Spiral CT showing ascites and concentric thickening of colon and ileum in EG Talley et al.[20] suggested 3 diagnostic criteria which are still widely used: 1. the presence of gastrointestinal symptoms, 2. histological demonstration of eosinophilic infiltration in one or more areas of the gastrointestinal tract or presence of high eosinophil count in ascitic fluid (latter usually indicates subserosal variety), 3. no evidence of parasitic or extraintestinal disease. Hypereosinophilia, the hallmark of allergic response, may be absent in up to 20% of patients, but hypoalbuminaemia and other abnormalities suggestive of malabsorption may be present. CT scans may show nodular and irregular thickening of the folds in the distal stomach and proximal small bowel, but these findings can also be present in other conditions like Crohn's disease and lymphoma.[citation needed] The endoscopic appearance in eosinophilic gastroenteritis is nonspecific; it includes erythematous, friable, nodular, and occasional ulcerative changes.[21] Sometimes diffuse inflammation results in complete loss of villi, involvement of multiple layers, submucosal oedema and fibrosis.[22][23] Definitive diagnosis involves histological evidence of eosinophilic infiltration in biopsy slides. Microscopy reveals >20 eosinophils per high power field.[11][20] Infiltration is often patchy, can be missed and laparoscopic full thickness biopsy may be required. Radio isotope scan using technetium (99mTc) exametazime-labeled leukocyte SPECT may be useful in assessing the extent of disease and response to treatment but has little value in diagnosis, as the scan does not help differentiating EG from other causes of inflammation.[24][25] When eosinophilic gastroenteritis is observed in association with eosinophilic infiltration of other organ systems, the diagnosis of idiopathic hypereosinophilic syndrome should be considered.[26] ## Management[edit] Corticosteroids are the mainstay of therapy with a 90% response rate in some studies. Appropriate duration of steroid treatment is unknown and relapse often necessitates long term treatment. Various steroid sparing agents e.g. sodium cromoglycate (a stabilizer of mast cell membranes), ketotifen (an antihistamine), and montelukast (a selective, competitive leukotriene receptor antagonist) have been proposed, centering on an allergic hypothesis, with mixed results.[19][27] Oral budesonide (an oral steroid) can be useful in treatment, as well.[28] An elimination diet may be successful if a limited number of food allergies are identified.[21][29] In a randomized clinical trial, lirentelimab was found to improve eosinophil counts and symptoms in individuals with eosinophilic gastritis and duodenitis.[30][31] ## Epidemiology[edit] Epidemiology may differ between studies, as number of cases are small, with approximately 300 EG cases reported in published literature. EG can present at any age and across all races, with a slightly higher incidence in males.[32] Earlier studies showed higher incidence in the third to fifth decades of life.[1][3] ## Other gastrointestinal conditions associated with allergy[edit] * Eosinophilic esophagitis * Eosinophilic ascites * Coeliac disease * Protein losing enteropathy from intolerance to cow's milk protein * Infantile formula protein intolerance ## See also[edit] * Aeroallergen * Allergy * Gastroenteritis * Malabsorption ## References[edit] 1. ^ a b Kaijser R. Zur Kenntnis der allergischen Affektionen des Verdauugskanals vom Standpunkt des Chirurgen aus. Arch Klin Chir 1937; 188:36–64. 2. ^ Whitaker I, Gulati A, McDaid J, Bugajska-Carr U, Arends M (2004). "Eosinophilic gastroenteritis presenting as obstructive jaundice". European Journal of Gastroenterology & Hepatology. 16 (4): 407–9. doi:10.1097/00042737-200404000-00007. PMID 15028974. 3. ^ a b Klein N, Hargrove R, Sleisenger M, Jeffries G (1970). "Eosinophilic gastroenteritis". Medicine (Baltimore). 49 (4): 299–319. doi:10.1097/00005792-197007000-00003. PMID 5426746. S2CID 45969740. 4. ^ Treiber, Treiber; Weidner, S (2007). "Eosinophilic Gastroenteritis". Clinical Gastroenterology and Hepatology. 5 (5): e16. doi:10.1016/j.cgh.2007.01.011. PMID 17428742. 5. ^ Polyak S, Smith T, Mertz H (2002). "Eosinophilic gastroenteritis causing pancreatitis and pancreaticobiliary ductal dilation". Dig. Dis. Sci. 47 (5): 1091–5. doi:10.1023/A:1015046309132. PMID 12018905. S2CID 24453648. 6. ^ a b Christopher V, Thompson M, Hughes S (2002). "Eosinophilic gastroenteritis mimicking pancreatic cancer". Postgraduate Medical Journal. 78 (922): 498–9. doi:10.1136/pmj.78.922.498. PMC 1742453. PMID 12185230. 7. ^ Naylor A (1990). "Eosinophilic gastroenteritis". Scottish Medical Journal. 35 (6): 163–5. doi:10.1177/003693309003500601. PMID 2077646. S2CID 43539786. 8. ^ Jimenez-Saenz M, Villar-Rodriguez J, Torres Y, Carmona I, Salas-Herrero E, Gonzalez-Vilches J, Herrerias-Gutierrez J (2003). "Biliary tract disease: a rare manifestation of eosinophilic gastroenteritis". Dig. Dis. Sci. 48 (3): 624–7. doi:10.1023/A:1022521707420. PMID 12757181. S2CID 23627059. 9. ^ Shweiki E, West J, Klena J, Kelley S, Colley A, Bross R, Tyler W (1999). "Eosinophilic gastroenteritis presenting as an obstructing cecal mass--a case report and review of the literature". Am. J. Gastroenterol. 94 (12): 3644–5. PMID 10606337. 10. ^ Tran D, Salloum L, Tshibaka C, Moser R (2000). "Eosinophilic gastroenteritis mimicking acute appendicitis". The American Surgeon. 66 (10): 990–2. PMID 11261632. 11. ^ a b Baig M, Qadir A, Rasheed J (2006). "A review of eosinophilic gastroenteritis". Journal of the National Medical Association. 98 (10): 1616–9. PMC 2569760. PMID 17052051. 12. ^ Lee C, Changchien C, Chen P, Lin D, Sheen I, Wang C, Tai D, Sheen-Chen S, Chen W, Wu C (1993). "Eosinophilic gastroenteritis: 10 years experience". Am. J. Gastroenterol. 88 (1): 70–4. PMID 8420276. 13. ^ Miyamoto T, Shibata T, Matsuura S, Kagesawa M, Ishizawa Y, Tamiya K (1996). "Eosinophilic gastroenteritis with ileus and ascites". Intern. Med. 35 (10): 779–82. doi:10.2169/internalmedicine.35.779. PMID 8933185.) 14. ^ Lyngbaek S, Adamsen S, Aru A, Bergenfeldt M (2006). "Recurrent acute pancreatitis due to eosinophilic gastroenteritis. Case report and literature review". JOP. 7 (2): 211–7. PMID 16525206. 15. ^ Tan A, Kruimel J, Naber T (2001). "Eosinophilic gastroenteritis treated with non-enteric-coated budesonide tablets". European Journal of Gastroenterology & Hepatology. 13 (4): 425–7. doi:10.1097/00042737-200104000-00021. PMID 11338074. 16. ^ Blackshaw A, Levison D (1986). "Eosinophilic infiltrates of the gastrointestinal tract". J. Clin. Pathol. 39 (1): 1–7. doi:10.1136/jcp.39.1.1. PMC 499605. PMID 2869055. 17. ^ Desreumaux P, Bloget F, Seguy D, Capron M, Cortot A, Colombel J, Janin A (1996). "Interleukin 3, granulocyte-macrophage colony-stimulating factor, and interleukin 5 in eosinophilic gastroenteritis". Gastroenterology. 110 (3): 768–74. doi:10.1053/gast.1996.v110.pm8608886. PMID 8608886. 18. ^ a b Mishra A, Hogan S, Brandt E, Rothenberg M (2001). "An etiological role for aeroallergens and eosinophils in experimental esophagitis". J. Clin. Invest. 107 (1): 83–90. doi:10.1172/JCI10224. PMC 198543. PMID 11134183. 19. ^ a b Pérez-Millán A, Martín-Lorente J, López-Morante A, Yuguero L, Sáez-Royuela F (1997). "Subserosal eosinophilic gastroenteritis treated efficaciously with sodium cromoglycate". Dig. Dis. Sci. 42 (2): 342–4. doi:10.1023/A:1018818003002. PMID 9052516. S2CID 19266537. 20. ^ a b Talley N, Shorter R, Phillips S, Zinsmeister A (1990). "Eosinophilic gastroenteritis: a clinicopathological study of patients with disease of the mucosa, muscle layer, and subserosal tissues". Gut. 31 (1): 54–8. doi:10.1136/gut.31.1.54. PMC 1378340. PMID 2318432. 21. ^ a b Chen M, Chu C, Lin S, Shih S, Wang T (2003). "Eosinophilic gastroenteritis: clinical experience with 15 patients". World J. Gastroenterol. 9 (12): 2813–6. doi:10.3748/wjg.v9.i12.2813. PMC 4612059. PMID 14669340. 22. ^ Johnstone J, Morson B (1978). "Eosinophilic gastroenteritis". Histopathology. 2 (5): 335–48. doi:10.1111/j.1365-2559.1978.tb01726.x. PMID 363591. 23. ^ Katz A, Goldman H, Grand R (1977). "Gastric mucosal biopsy in eosinophilic (allergic) gastroenteritis". Gastroenterology. 73 (4 Pt 1): 705–9. doi:10.1016/S0016-5085(19)31769-X. PMID 892374. 24. ^ Lee K, Hahm K, Kim Y, Kim J, Cho S, Jie H, Park C, Yim H (1997). "The usefulness of Tc-99m HMPAO labeled WBC SPECT in eosinophilic gastroenteritis". Clinical Nuclear Medicine. 22 (8): 536–41. doi:10.1097/00003072-199708000-00005. PMID 9262899. 25. ^ Imai E, Kaminaga T, Kawasugi K, Yokokawa T, Furui S (2003). "The usefulness of 99mTc-hexamethylpropyleneamineoxime white blood cell scintigraphy in a patient with eosinophilic gastroenteritis". Annals of Nuclear Medicine. 17 (7): 601–3. doi:10.1007/BF03006675. PMID 14651361. S2CID 32498521. 26. ^ Matsushita M, Hajiro K, Morita Y, Takakuwa H, Suzaki T (1995). "Eosinophilic gastroenteritis involving the entire digestive tract". Am. J. Gastroenterol. 90 (10): 1868–70. PMID 7572911. 27. ^ Barbie D, Mangi A, Lauwers G (2004). "Eosinophilic gastroenteritis associated with systemic lupus erythematosus". J. Clin. Gastroenterol. 38 (10): 883–6. doi:10.1097/00004836-200411000-00010. PMID 15492606. 28. ^ Alsayegh, Mohammad; Mack, Douglas (2012-11-02). "Eosinophilic gastroenteritis with gastric and small bowel involvement: successful treatment with oral budesonide". Allergy, Asthma, and Clinical Immunology. 8 (Suppl 1): A6. doi:10.1186/1710-1492-8-S1-A6. ISSN 1710-1484. PMC 3487875. 29. ^ Katz A, Twarog F, Zeiger R, Falchuk Z (1984). "Milk-sensitive and eosinophilic gastroenteropathy: similar clinical features with contrasting mechanisms and clinical course". The Journal of Allergy and Clinical Immunology. 74 (1): 72–8. doi:10.1016/0091-6749(84)90090-3. PMID 6547462. 30. ^ Dellon, ES; Peterson, KA; Murray, JA; Falk, GW; Gonsalves, N; Chehade, M; Genta, RM; Leung, J; Khoury, P; Klion, AD; Hazan, S; Vaezi, M; Bledsoe, AC; Durrani, SR; Wang, C; Shaw, C; Chang, AT; Singh, B; Kamboj, AP; Rasmussen, HS; Rothenberg, ME; Hirano, I (22 October 2020). "Anti-Siglec-8 Antibody for Eosinophilic Gastritis and Duodenitis". The New England Journal of Medicine. 383 (17): 1624–1634. doi:10.1056/NEJMoa2012047. PMC 7600443. PMID 33085861. 31. ^ Young, Alex (October 29, 2019). "Therapeutic antibody effective in eosinophilic gastritis". Healio. Retrieved 14 December 2020. 32. ^ Guandalini, Stefano (2004). Essential Pediatric Gastroenterology and Nutrition. City: McGraw-Hill Professional. ISBN 978-0-07-141630-6. Page 210. ## External links[edit] Classification D * ICD-10: K52.8 * ICD-9-CM: 558.3 * MeSH: C535952 * DiseasesDB: 32555 External resources * eMedicine: med/688 * v * t * e Allergic conditions Respiratory system * Allergic rhinitis (hay fever) * Asthma * Hypersensitivity pneumonitis * Eosinophilic pneumonia * Eosinophilic granulomatosis with polyangiitis * Allergic bronchopulmonary aspergillosis * Farmer's lung * Laboratory animal allergy Skin * Angioedema * Urticaria * Atopic dermatitis * Allergic contact dermatitis * Hypersensitivity vasculitis Blood and immune system * Serum sickness Circulatory system * Anaphylaxis Digestive system * Coeliac disease * Eosinophilic gastroenteritis * Eosinophilic esophagitis * Food allergy * Egg allergy * Milk intolerance Nervous system * Eosinophilic meningitis Genitourinary system * Acute interstitial nephritis Other conditions * Drug allergy * Allergic conjunctivitis * Latex allergy [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	Eosinophilic gastroenteritis	c1262481	746	wikipedia	https://en.wikipedia.org/wiki/Eosinophilic_gastroenteritis	2021-01-18T18:44:04	{"gard": ["9142"], "mesh": ["C535952"], "umls": ["C1262481"], "icd-10": ["K52.8"], "wikidata": ["Q27555722"]}
Charcot-Marie-Tooth disease type 1 (CMT1) is a type of peripheral neuropathy, a condition affecting the transmission of information between the central nervous system (brain and spinal cord) and the rest of the body. Symptoms often begin between age 5 and 25, and the condition is usually slowly progressive. Signs and symptoms include distal muscle weakness and wasting (atrophy); sensory loss; and slow nerve conduction velocity. It is often associated with pes cavus foot deformity (high arch) and bilateral foot drop. Fewer than 5% of people with CMT1 become wheelchair dependent. CMT1 is inherited in an autosomal dominant manner. There are 6 different subtypes CMT1A CMT1B, CMT1C, CMT1D and CMT1F/ CMT2E, caused by different pathogenic variants (mutations)involving the PMP22 gene (designated CMT1A), or the MPZ, LITAF, EGR2, PMP22 or NEFL genes. Treatment may involve physical or occupational therapy; the use of special shoes, braces or other orthopedic devices; surgery for severe pes cavus; canes or wheelchairs for mobility; and pain medication as needed. [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	Charcot-Marie-Tooth disease type 1	c0751036	747	gard	https://rarediseases.info.nih.gov/diseases/12433/charcot-marie-tooth-disease-type-1	2021-01-18T18:01:32	{"mesh": ["D002607"], "omim": ["118220", "118200", "601098", "607678", "118300", "607734"], "orphanet": ["65753"], "synonyms": ["Autosomal dominant demyelinating Charcot-Marie-Tooth disease", "CMT1", "Hereditary motor and sensory neuropathy type 1", "Charcot-Marie-Tooth type 1", "Charcot-Marie-Tooth neuropathy type 1", "HMSN1", "Hereditary motor and sensory neuropathy 1"]}
Intravascular large B-cell lymphoma (IVLBCL) is a very rare form of diffuse large B-cell lymphoma (see this term) characterized by the selective growth of lymphoma cells within the lumina of small blood vessels (especially the capillaries) that most often presents with a wide range of clinical manifestations (as potentially any tissue can be involved), with patients from Western countries more frequently manifesting with neurological and cutaneous symptoms while patients from Asian countries more frequently displaying hepatosplenomegaly and thrombocytopenia. IVLBCL is characterized by an absence of lymphadenopathy, an aggressive clinical course and a poor prognosis. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor *[BMI]: body mass index	Intravascular large B-cell lymphoma	c0334660	748	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=98839	2021-01-23T18:18:11	{"icd-10": ["C83.3"], "synonyms": ["Angioendotheliomatosis proliferans systemisata", "Angiotropic large cell lymphoma", "Intravascular lymphomatosis", "Malignant angioendotheliomatosis", "Tappeiner-Pfleger disease"]}
## Clinical Features Christian et al. (1971) described 3 sibships in an Amish kindred with members affected by a new syndrome, which they chose to designate the 'adducted thumbs syndrome.' All 6 parents shared a common ancestral couple. Three Amish children and an unrelated child had cleft palate, arthrogryposis, craniostenosis, swallowing difficulties, and microcephaly. Other features included prominent occiput, ophthalmoplegia, telecanthus, abnormal ear placement, and clubfeet. Neuropathologic study of 1 of the Amish patients, who died at 18 days of age, showed dysmyelination with excessive myelin-dependent gliosis, myelin solubilization, and transient formation of phospholipid-containing plaques on the surface of the brain during fixation in formalin. Fitch and Levy (1975) reported a 4-year-old girl with adducted thumbs syndrome. Prominent features were microcephaly, prominent occiput, ophthalmoplegia, cleft palate, abnormal ears, hypertelorism, and pectus excavatum. The thumbs were flexed at the metacarpal-phalangeal joints only. Anderson and Breed (1981) suggested that the Moro reflex may be a useful way to detect congenital clasped thumb early. The thumb normally extends during the Moro reflex. Kunze et al. (1983) reported the case of a female with 'myopathic' stiff face, open mouth, high-arched palate, generalized muscular hypotonia, limited extension of the elbows, wrists, and knees, flexed adducted thumbs, velopharyngeal insufficiency, and hypertrichosis. Death occurred at 3 months from respiratory insufficiency. Muscle biopsy showed myopathic abnormalities. Inheritance Christian et al. (1971) and Fitch and Levy (1975) suggested that adducted thumbs syndrome is an autosomal recessive disorder. Head \- Craniostenosis \- Microcephaly Mouth \- Mouth open \- Palate high-arched \- Cleft palate Facies \- Stiff, myopathic facies Inheritance \- Autosomal recessive Skin \- Hypertrichosis Joints \- Thumbs flexed and adducted \- Arthrogryposis of elbows, wrists, and knees Resp \- Respiratory insufficiency Muscle \- Myopathy Neuro \- Dysmyelination with excess myelin-dependent gliosis \- Myelin solubilization \- Hypotonia, generalized \- Velopharyngeal insufficiency GI \- Swallowing difficulties ▲ 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	ADDUCTED THUMBS SYNDROME	c0431886	749	omim	https://www.omim.org/entry/201550	2019-09-22T16:31:28	{"mesh": ["C562949"], "omim": ["201550"], "orphanet": ["2952"], "synonyms": []}
A number sign (#) is used with this entry because of evidence that fetal akinesia deformation sequence-4 (FADS4) is caused by homozygous or compound heterozygous mutation in the NUP88 gene (602552) on chromosome 17p13. Description Fetal akinesia deformation sequence-4 (FADS4) is an autosomal recessive disorder characterized by decreased fetal movements due to impaired neuromuscular function, resulting in significant congenital contractures and death in utero or soon after birth (summary by Bonnin et al., 2018). For a general phenotypic description and a discussion of genetic heterogeneity of FADS, see 208150. Clinical Features Bonnin et al. (2018) reported 4 sibs, conceived of consanguineous Palestinian parents (family A), with lethal arthrogryposis multiplex congenita (AMC). The only live-born infant died at 2 days of age; the other 3 died in utero either through miscarriage or termination of pregnancy due to affected status. A single male fetus from a second family of European descent (family B) with a similar phenotype was also reported. Decreased fetal movements were noted during the pregnancies. The infant and affected fetuses had similar contractures of the fingers, hands, and elbows, as well as kyphosis, rocker-bottom feet, and muscle atrophy. Dysmorphic features included low-set, posteriorly rotated ears, high broad nasal bridge, high-arched palate, microretrognathism, reduced number of rib pairs, short, broad, or hyperextended neck, and undescended testes. Two of the pregnancies were complicated by polyhydramnios, and another fetus had body edema, pleural effusions, and ascites. Inheritance The transmission pattern of FADS4 in the families reported by Bonnin et al. (2018) was consistent with autosomal recessive inheritance. Molecular Genetics In affected patients from 2 unrelated families with FADS4, Bonnin et al. (2018) identified homozygous or compound heterozygous mutations in the NUP88 gene (602522.0001-602522.0003). The mutations, which were found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in both families. In vitro functional expression studies in HeLa cells showed that the mutations had distinct effects on the interaction of NUP88 with binding partners within the nuclear core complex, but these changes were not considered significant enough to account for the phenotype. Further studies in HeLa and C2C12 myoblast cells showed that depletion of NUP88 resulted in decreased rapsyn (601592) levels, and muscle biopsy from 1 of the affected fetuses showed decreased and irregular rapsyn distribution compared to controls, which may indicate impaired formation of the neuromuscular junction. Expression of the corresponding mutations in zebrafish failed to rescue the abnormal phenotype of nup88-null zebrafish, suggesting that all 3 human NUP88 variants are functionally inactive. Bonnin et al. (2018) concluded that absence of functional NUP88 causes fetal akinesia at least in part through misregulation of rapsyn expression. Animal Model Bonnin et al. (2018) found that the zebrafish ortholog of nup88 was ubiquitously expressed soon after fertilization, with high levels of expression in proliferative frontal regions of the embryo, such as the central nervous system, brain, eye, and anterior trunk. Mutant zebrafish carrying a homozygous nonsense mutation in the nup88 gene had abnormally small heads and eyes, severe abnormalities of the ventral viscerocranium and pharyngeal arches, lack of a protruding mouth, downward curvature of the anterior-posterior axis, abnormal gut, and aplastic swim bladder. The reduced size of head and eyes correlated with an increase in apoptotic cells. Mutant zebrafish also showed impaired locomotor behavior and had decreased survival compared to wildtype. Skeletal muscle fibers from mutant animals showed reduced rapsyn levels, as well as impaired AChR clustering in fast-twitch muscle fiber synapses, likely reflecting impaired formation of the neuromuscular junction. INHERITANCE \- Autosomal recessive HEAD & NECK Face \- Micrognathia \- Retrognathia \- Mandibular contracture Ears \- Low-set ears \- Posteriorly rotated ears Nose \- High broad nasal bridge Mouth \- High-arched palate Neck \- Short neck \- Broad neck \- Hyperextended neck CHEST Ribs Sternum Clavicles & Scapulae \- Reduced number of rib pairs GENITOURINARY External Genitalia (Male) \- Undescended testes SKELETAL \- Arthrogryposis multiplex congenita Spine \- Kyphosis Limbs \- Contractures Hands \- Camptodactyly Feet \- Rocker bottom feet MUSCLE, SOFT TISSUES \- Muscle atrophy PRENATAL MANIFESTATIONS Movement \- Decreased fetal movements Amniotic Fluid \- Polyhydramnios MISCELLANEOUS \- Onset in utero \- Death in utero or soon after birth \- Two unrelated families have been reported (last curated April 2019) MOLECULAR BASIS \- Caused by mutation in the nucleoporin, 88-kD gene (NUP88, 602552.0001 ) ▲ 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	FETAL AKINESIA DEFORMATION SEQUENCE 4	c1276035	750	omim	https://www.omim.org/entry/618393	2019-09-22T15:42:10	{"mesh": ["C536647"], "omim": ["618393"], "orphanet": ["994"]}
## Clinical Features Kaijser and Malmstrom-Groth (1957) described imperforate anus with rectovaginal fistula in a mother and her 2 daughters. Van Gelder and Kloepfer (1961) observed 4 sibs with anorectal stenosis or imperforate anus. Although the parents were unaffected, the authors pointed out that failure of expression of a recent dominant mutation, carried by one parent, is a possibility. From the findings of Cozzi and Wilkinson (1968), anal stenosis seems particularly liable to familial occurrence, probably as an irregular dominant. Anorectal malformation was combined with nephritis and nerve deafness, hallmarks of Alport syndrome, in a dominant pedigree pattern in the family reported by Lowe et al. (1983). Landau et al. (1997) reported 4 members of a 3-generation family with congenital low anorectal malformations. These included imperforate anus, rectoperineal fistula, imperforate anus with perianal fistula, and congenital anal stenosis. Inheritance In the family with congenital low anorectal malformations reported by Landau et al. (1997), an autosomal dominant pattern of inheritance was observed, with possible nonpenetrance in one of the great-grandparents of the proband. GU \- Rectovaginal fistula GI \- Anorectal stenosis \- Imperforate anus Inheritance \- Autosomal dominant ▲ 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	ANORECTAL ANOMALIES	c3495676	751	omim	https://www.omim.org/entry/107100	2019-09-22T16:44:57	{"mesh": ["D000071056"], "omim": ["107100"], "orphanet": ["557"]}
A number sign (#) is used with this entry because autosomal dominant progressive external ophthalmoplegia (adPEO) with mitochondrial DNA (mtDNA) deletions-1 (PEOA1) is caused by mutation in the nuclear-encoded DNA polymerase-gamma gene (POLG; 174763) on chromosome 15q25. Autosomal recessive PEO (PEOB; 258450) is also caused by mutation in the POLG gene. Description Progressive external ophthalmoplegia is characterized by multiple mitochondrial DNA deletions in skeletal muscle. The most common clinical features include adult onset of weakness of the external eye muscles and exercise intolerance. Additional symptoms are variable, and may include cataracts, hearing loss, sensory axonal neuropathy, ataxia, depression, hypogonadism, and parkinsonism. Both autosomal dominant and autosomal recessive inheritance can occur; autosomal recessive inheritance is usually more severe (Filosto et al., 2003; Luoma et al., 2004). PEO caused by mutation in the POLG gene is associated with more complicated phenotypes than those forms caused by mutation in the ANT1 or C10ORF2 genes (Lamantea et al., 2002). ### Genetic Heterogeneity of Autosomal Dominant Progressive External Ophthalmoplegia with DNA Deletions See also PEOA2 (609283), caused by mutation in the ANT1 gene (SLC25A4; 103220) on chromosome 4q34; PEOA3 (609286), caused by mutation in the twinkle gene (C10ORF2; 606075) on chromosome 10q24; PEOA4 (610131), caused by mutation in the POLG2 gene (604983) on chromosome 17q; PEOA5 (613077), caused by mutation in the RRM2B gene (604712) on chromosome 8q23; and PEOA6 (615156), caused by mutation in the DNA2 gene (601810) on chromosome 10q. Clinical Features Lundberg (1962, 1966, 1974) described a large Swedish kindred in which progressive external ophthalmoplegia was associated with hypogonadism. Melberg et al. (1996) provided follow-up. Hypogonadism included delayed sexual maturation, primary amenorrhea, early menopause, and testicular atrophy. Cataracts, cerebellar ataxia, neuropathy, hypoacusis, pes cavus, tremor, parkinsonism, depression, and mental retardation were other features observed in this family. Muscle biopsy samples from advanced cases showed ragged-red fibers, focal cytochrome c oxidase deficiency, and multiple mitochondrial DNA (mtDNA) deletions by Southern blot analysis. An autosomal dominant mode of inheritance was evident with anticipation in successive generations. Melberg et al. (1996) hypothesized that the nuclear gene causing PEO with hypogonadism may be directly influenced by an expansion of an unstable DNA sequence and that the resulting phenotype is caused by a concerted action with multiple deletions of mtDNA. In additional studies of 16 members of this family, Melberg et al. (1996) showed that the muscular involvement commenced cranially and descended in relation to increasing disease duration. In addition to PEO, patients had dysarthria, dysphonia, limb muscle weakness with wasting, absence of Achilles tendon reflexes, and distal vibration sensory loss. The electromyelogram (EMG) was myopathic in facial and proximal limb muscles. Ozawa et al. (1988) examined skeletal muscle from a mother and daughter, both with chronic progressive ophthalmoplegia. Southern blot analysis revealed in both patients 2 species of mitochondrial DNA, normal mtDNA and partially deleted mtDNA. Curiously, the size of the deletion was different, being about 2.5 kb in the mother and 5 kb in the daughter. The 2 mutant mtDNAs shared a common deleted region of 1.2 kb. However, both the start and the end of the deletion were different, implying a novel mode of inheritance. Melberg et al. (1998) reported the case of a 57-year-old man, a member of the kindred originally reported by Lundberg (1962), who had PEO and multiple mtDNA deletions and who developed acute rhabdomyolysis provoked by alcohol. A repeated alcohol intake resulted in a 57-fold increase in serum myoglobin. Luoma et al. (2004) found that affected patients in the family reported by Lundberg (1962) developed parkinsonism later in the disease course with rigidity, bradykinesia, tremor, and favorable response to levodopa. A family reported by Pepin et al. (1980) had adPEO with cataracts as a prominent feature. A grandmother, mother, and son had early-onset cataracts, and documented mitochondrial myopathy was present in the 2 older family members. The grandmother, aged 62 years, had severe progressive ophthalmoplegia associated with facial, pharyngeal, and limb muscle involvement, as well as premature ovarian failure. Bilateral cataracts, present from at least age 20 years, were removed at age 40. Muscle biopsy showed ragged-red fibers with abnormal mitochondria. Bilateral cataracts were removed in the daughter at age 32. She had mild facial weakness. Despite the absence of ophthalmoplegia, mitochondrial abnormalities were demonstrated in the inferior oblique muscle. The son, clinically healthy at age 10, had had bilateral cataract extraction at age 3 years. The authors cited another family with mitochondrial myopathy involving type I muscle fibers associated with cataract inherited in an apparently autosomal dominant pattern. They also referred to a family with congenital cataract and myocardial and skeletal myopathy of mitochondrial type, also known as Senger syndrome (212350); in that instance, inheritance was thought to be autosomal recessive. All 3 affected persons in the family of Pepin et al. (1980) had the HLA A2-B21 haplotype. Zeviani et al. (1989) and Servidei et al. (1991) reported an Italian family in which 9 persons in 4 sibships spanning 3 generations were affected by an adult-onset mitochondrial myopathy with multiple mtDNA deletions. Inheritance was autosomal dominant with instances of male-to-male transmission. The main clinical features included progressive external ophthalmoplegia, dysphagia, lactic acidosis, exercise intolerance, and cataracts. Age at onset ranged from 24 to 30 years. Muscle biopsies showed ragged-red fibers and decreased activity of cytochrome c oxidase. Southern blot analysis and PCR showed multiple mtDNA deletions in skeletal muscle of all affected family members, but not in lymphocytes or fibroblasts. The mtDNA deletions appeared to increase with time and correlated with disease severity. Zeviani et al. (1990) reported 2 additional affected families with mtDNA deletions. Clinical features included adult-onset PEO, proximal muscle weakness and wasting, sensorineural hypoacusis, and cataracts in older patients. Affected members of 1 pedigree also showed tremor, ataxia, and chronic axonal sensorimotor peripheral neuropathy. Muscle biopsy showed ragged-red fibers and decreased cytochrome c oxidase activity. The same portion of mtDNA was involved in all patients. Sequence analysis, performed after mtDNA amplification by PCR, showed that all the deletions started within a 12-nucleotide stretch at the 5-prime end of the D-loop region, a site of active communication between the nucleus and the mtDNA. The authors suggested that a mutation in a nuclear-encoded protein could destroy the integrity of the mitochondrial genome in a specific, heritable way, and that there may be other examples of 'human pathology of...factors involved in the 'cross-talk' between the nuclear and the mitochondrial genomes.' The existence of a nuclear-encoded factor responsible for mitochondrial deletions or a failure of repair was suggested also by Cormier et al. (1991) for the findings in a family with various mtDNA deletions. The proband had ataxia and episodic ketoacidotic coma. Muscle biopsy showed a mitochondrial myopathy with ragged-red fibers. Various mtDNA deletions were detected not only in the proband but also in his healthy mother and maternal aunt, but not in the other progeny of the mother. All of the deletions were located between the Cox II and cytochrome b genes. Van Goethem et al. (1997) identified 3 Belgian families with PEO and multiple mitochondrial deletions. The diagnosis was based on clinical symptoms of PEO and muscle weakness, the presence of ragged-red fibers, and multiple mitochondrial deletions in muscle biopsies. Electron microscopy showed subsarcolemmal accumulation of abnormally structured mitochondria with paracrystalline inclusions. The inheritance pattern in 1 family was autosomal dominant, whereas the other 2 families likely had autosomal recessive inheritance. Chalmers et al. (1996) reported 2 British families with adPEO with additional unusual features, including parkinsonism and pigmentary retinopathy. The parkinsonism was levodopa-responsive. Luoma et al. (2004) reported 7 unrelated families with PEO caused by mutation in the POLG gene; 1 of the families had been reported by Chalmers et al. (1996) and another had been reported by Lundberg (1962). Four families showed definitive autosomal dominant inheritance, 1 showed possible autosomal recessive inheritance, and 2 were undetermined. In 5 families, including the 1 with possible autosomal recessive inheritance, affected members had parkinsonism, with resting tremor, rigidity, bradykinesia, and favorable response to levodopa. Parkinsonism occurred after onset of PEO. Additional features in these families included cataracts, sensory axonal neuropathy, depression, and hypogonadism. Mancuso et al. (2004) reported 2 sibs with early-onset parkinsonism and a heterozygous mutation in the POLG gene (174763.0015). The proband was a 49-year-old woman with PEO, exercise intolerance, sensory neuropathy, parkinsonism, and gonadal dysgenesis. Skeletal muscle biopsy showed multiple mtDNA deletions. Her brother developed parkinsonism in his early forties. Several other family members reportedly had PEO and exercise intolerance. Mancuso et al. (2004) concluded that parkinsonism may be a prominent feature in patients with POLG mutations, and suggested that mitochondrial dysfunction may play a role in the development of parkinsonism. Mapping In the Swedish kindred with PEO and hypogonadism originally reported by Lundberg (1962), Melberg et al. (1996) excluded linkage of the disorder to the PEO region on chromosome 10q23.3-q24.3 linked to the disease in a Finnish family by Suomalainen et al. (1995); see 609286. In a Belgian family with adPEO, Van Goethem et al. (2001) found linkage to chromosome 15q22-q26 (maximum 2-point lod score of 3.72 at marker D15S127). Molecular Genetics Hirano and DiMauro (2001) reviewed the molecular genetics of progressive external ophthalmoplegia and classified the specific disease type according to mutation in the autosomal ANT1, C10ORF2, and POLG genes as well as in multiple mitochondrial genes. Lamantea et al. (2002) stated that mutations in the ANT1 and C10ORF2 gene account for approximately 4% and 35% of familial adPEO cases, respectively. Mutations in the POLG gene are the most frequent cause of all forms of familial PEO, accounting for approximately 45% of cases. In affected members of a Belgian pedigree with adPEO, Van Goethem et al. (2001) identified a heterozygous mutation in the POLG gene (Y955C; 174763.0001). In affected members of 5 families with adPEO, Lamantea et al. (2002) identified the heterozygous Y955C mutation. Four families were Italian and 1 was from Greece; 1 of the Italian families was originally reported by Zeviani et al. (1989) and Servidei et al. (1991). In affected members of 5 adPEO families, including the Swedish family originally reported by Lundberg (1962), Luoma et al. (2004) identified the heterozygous Y955C POLG mutation. Affected members of 3 of the families also showed parkinsonism. Schulte et al. (2009) identified heterozygous POLG mutations in 2 of 26 patients from 23 families with cerebellar ataxia plus external ophthalmoplegia and/or sensory neuropathy. Nine additional patients from this cohort had homozygous or compound heterozygous POLG mutations, consistent with SANDO. Noting that the molecular diagnosis of cerebellar ataxia can be difficult, Schulte et al. (2009) found that for POLG-associated ataxia, the additional presence of ophthalmoplegia had a predictive value of 80%, whereas the presence of neuropathy had a predictive value of 45%. Genotype/Phenotype Correlations Lamantea et al. (2002) identified POLG mutations in 10 adPEO families and noted that the clinical features of these patients were often more severe and complex than those associated with ANT1 or C10ORF2 mutations. In particular, patients with POLG mutations also had profound muscle weakness and wasting, severe dysphagia, dysphonia, facial diplegia, ataxia due to distal neurogenic weakness, and severe depression. Lamantea et al. (2002) suggested that the mutant nuclear factor in adPEO may cause a pathologic amplification of the otherwise normal phenomenon of accumulation of mtDNA deletions associated with aging. Luoma et al. (2004) noted that dominant POLG mutations tend to cluster in the polymerase 'pol' domain of the protein, whereas recessive POLG mutations tend to affect the proofreading exonuclease 'exo' domain. The authors noted the cosegregation of parkinsonism and mutations in the pol domain of the protein, and suggested that mtDNA deletions may play a role in the development of parkinsonism by fostering the accumulation of mtDNA mutations. Mitochondrial DNA deletions may lead to reduced ATP production or oxidative stress, resulting in neurodegeneration. History Holt et al. (1988) found the first example of abnormalities of mitochondrial DNA. When muscle mtDNA was studied, 9 of 25 patients were found to have 2 populations of muscle mtDNA, 1 of which had deletions of up to 7 kilobases. These observations demonstrated that mtDNA heteroplasmy can occur in man and that human disease may be associated with defects of the mitochondrial genome. Only 1 of the patients had an affected relative, a niece who was unavailable for study. It is probable that the deletions in the others arose during oogenesis and that random partitioning of the 2 populations of mtDNA occurred during fetal development. The survival of the deleted mtDNA molecules in muscle is compatible with the observation that the number of muscle fibers does not increase significantly after early fetal life. On the other hand, frequent cell division in leukocyte precursors could select against the survival of cells containing genetically defective mitochondria. Harding et al. (1988) found that among 71 cases with histologically defined mitochondrial myopathy (ragged-red fibers seen with the modified Gomori trichrome stain), 13 (18%) had relatives who were definitely affected with a similar disorder. Eight familial cases from 4 families were confined to a single generation. In 5 families maternal transmission to offspring occurred. There were no instances of paternal transmission, but 1 patient had an affected cousin in the paternal line. No consistent clinical syndrome or pattern of inheritance emerged for any identified defect of the mitochondrial respiratory chain, localized biochemically in 39 of 41 cases: in complex I (NADH-ubiquinone oxidoreductase) in 26 cases; in complex III (ubiquinol-cytochrome c reductase) in 9 cases; in complex III and complex IV in 1; and in complex V (mitochondrial ATPase) in 1. In 2 patients, oxygen uptake rates were reduced with all substrates tested; in 2 others, in vitro studies of mitochondrial metabolism were normal. Overall, the recurrence rate was 3% for sibs and 5.5% for offspring of index cases. A review of published reports of familial cases of mitochondrial myopathy indicated that the ratio of maternal to paternal transmission is about 9:1. INHERITANCE \- Autosomal dominant HEAD & NECK Ears \- Sensorineural hearing loss Eyes \- External ophthalmoplegia, progressive (PEO) \- Ptosis \- Cataracts (later onset) ABDOMEN Gastrointestinal \- Dysphagia \- Gastroparesis \- Gastrointestinal pseudoobstruction GENITOURINARY External Genitalia (Male) \- Testicular atrophy (in a subset of patients) Internal Genitalia (Female) \- Premature ovarian failure (in a subset of patients) SKELETAL Feet \- Pes cavus MUSCLE, SOFT TISSUES \- Exercise intolerance \- Muscle weakness, progressive \- Muscle atrophy \- Facial muscle weakness \- Limb muscle weakness \- EMG shows myopathic changes \- Muscle biopsy shows ragged red fibers \- Muscle biopsy shows increased variation in fiber size \- Muscle biopsy shows necrotic and atrophic fibers with centralized nuclei \- Muscle biopsy shows multiple mitochondrial DNA (mtDNA) deletions \- Muscle biopsy shows decreased activity of cytochrome c oxidase \- Electron microscopy shows subsarcolemmal accumulations of abnormally shaped mitochondria NEUROLOGIC Central Nervous System \- Ataxia \- Parkinsonism (later onset) \- Dysarthria \- Resting tremor \- Rigidity \- Bradykinesia \- Cerebellar ataxia \- Favorable response to levodopa \- Loss of pigmented neurons in the substantia nigra \- No Lewy bodies Peripheral Nervous System \- Gait ataxia \- Hyporeflexia \- Distal sensory loss of proprioception and vibration sense \- Sensory axonal neuropathy Behavioral Psychiatric Manifestations \- Depression ENDOCRINE FEATURES \- Primary amenorrhea (in a subset of patients) \- Secondary amenorrhea (in a subset of patients) \- Premature menopause (in a subset of patients) \- Hypergonadotropic hypogonadism (in a subset of patients) \- Decreased secondary sexual characteristics (in a subset of patients) LABORATORY ABNORMALITIES \- Increased serum lactate \- Rhabdomyolysis in response to alcohol MISCELLANEOUS \- Highly variable phenotype \- Adult onset \- Progressive disorder \- Incidence of 1/100,000 in Italy and Finland \- Patients often have a more severe and complicated phenotype in addition to PEO \- Hypogonadism reported in a large Swedish kindred \- See also autosomal recessive PEOB ({258450)} \- Genetic heterogeneity (see PEOA2 609283 , PEOA3 609286 , and PEOA4 610131 ) \- POLG mutations account for approximately 45% of all PEO cases MOLECULAR BASIS \- Caused by mutation in the DNA polymerase gamma gene (POLG, 174763.0001 ) ▲ 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	PROGRESSIVE EXTERNAL OPHTHALMOPLEGIA WITH MITOCHONDRIAL DNA DELETIONS, AUTOSOMAL DOMINANT 1	c1834846	752	omim	https://www.omim.org/entry/157640	2019-09-22T16:38:11	{"mesh": ["C563575"], "omim": ["157640"], "orphanet": ["254892"], "synonyms": ["adPEO", "Alternative titles", "PROGRESSIVE EXTERNAL OPHTHALMOPLEGIA, AUTOSOMAL DOMINANT 1"], "genereviews": ["NBK26471", "NBK1203"]}
A number sign (#) is used with this entry because knuckle pads are associated with certain genetic disorders such as epidermolytis palmoplantar keratoderma (144200) or Dupuytren contractures (126900), both of which are autosomal dominant. Knuckle pads are sometimes associated with Dupuytren contractures and it is not completely certain that a different gene is involved. Camptodactyly (114200) also has an uncertain relationship. Skoog (1948) defined knuckle pads as 'subcutaneous nodules on the dorsal aspect of the proximal interphalangeal joints.' Lu et al. (2003) reported association of knuckle pads with epidermolytic palmoplantar keratoderma in a Chinese family and identified a novel leu160-to-phe mutation in the keratin-9 gene (L160F; 607606.0012) as the presumed cause. They presented evidence that both the hyperkeratosis and the knuckle pads were friction-related. Limbs \- Knuckle pads \- Subcutaneous nodules on the dorsum of proximal interphalangeal joints Inheritance \- Autosomal dominant ▲ 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	KNUCKLE PADS	c0264000	753	omim	https://www.omim.org/entry/149100	2019-09-22T16:39:20	{"omim": ["149100"], "icd-10": ["M72.1"]}
GM1 gangliosidosis is an inherited disorder that progressively destroys nerve cells (neurons) in the brain and spinal cord. Some researchers classify this condition into three major types based on the age at which signs and symptoms first appear. Although the three types differ in severity, their features can overlap significantly. Because of this overlap, other researchers believe that GM1 gangliosidosis represents a continuous disease spectrum instead of three distinct types. The signs and symptoms of the most severe form of GM1 gangliosidosis, called type I or the infantile form, usually become apparent by the age of 6 months. Infants with this form of the disorder typically appear normal until their development slows and muscles used for movement weaken. Affected infants eventually lose the skills they had previously acquired (developmentally regress) and may develop an exaggerated startle reaction to loud noises. As the disease progresses, children with GM1 gangliosidosis type I develop an enlarged liver and spleen (hepatosplenomegaly), skeletal abnormalities, seizures, profound intellectual disability, and clouding of the clear outer covering of the eye (the cornea). Loss of vision occurs as the light-sensing tissue at the back of the eye (the retina) gradually deteriorates. An eye abnormality called a cherry-red spot, which can be identified with an eye examination, is characteristic of this disorder. In some cases, affected individuals have distinctive facial features that are described as "coarse," enlarged gums (gingival hypertrophy), and an enlarged and weakened heart muscle (cardiomyopathy). Individuals with GM1 gangliosidosis type I usually do not survive past early childhood. Type II GM1 gangliosidosis consists of intermediate forms of the condition, also known as the late infantile and juvenile forms. Children with GM1 gangliosidosis type II have normal early development, but they begin to develop signs and symptoms of the condition around the age of 18 months (late infantile form) or 5 years (juvenile form). Individuals with GM1 gangliosidosis type II experience developmental regression but usually do not have cherry-red spots, distinctive facial features, or enlarged organs. Type II usually progresses more slowly than type I, but still causes a shortened life expectancy. People with the late infantile form typically survive into mid-childhood, while those with the juvenile form may live into early adulthood. The third type of GM1 gangliosidosis is known as the adult or chronic form, and it represents the mildest end of the disease spectrum. The age at which symptoms first appear varies in GM1 gangliosidosis type III, although most affected individuals develop signs and symptoms in their teens. The characteristic features of this type include involuntary tensing of various muscles (dystonia) and abnormalities of the spinal bones (vertebrae). Life expectancy varies among people with GM1 gangliosidosis type III. ## Frequency GM1 gangliosidosis is estimated to occur in 1 in 100,000 to 200,000 newborns. Type I is reported more frequently than the other forms of this condition. Most individuals with type III are of Japanese descent. ## Causes Mutations in the GLB1 gene cause GM1 gangliosidosis. The GLB1 gene provides instructions for making an enzyme called beta-galactosidase (β-galactosidase), which plays a critical role in the brain. This enzyme is located in lysosomes, which are compartments within cells that break down and recycle different types of molecules. Within lysosomes, β-galactosidase helps break down several molecules, including a substance called GM1 ganglioside. GM1 ganglioside is important for normal functioning of nerve cells in the brain. Mutations in the GLB1 gene reduce or eliminate the activity of β-galactosidase. Without enough functional β-galactosidase, GM1 ganglioside cannot be broken down when it is no longer needed. As a result, this substance accumulates to toxic levels in many tissues and organs, particularly in the brain. Progressive damage caused by the buildup of GM1 ganglioside leads to the destruction of nerve cells in the brain, causing many of the signs and symptoms of GM1 gangliosidosis. In general, the severity of GM1 gangliosidosis is related to the level of β-galactosidase activity. Individuals with higher enzyme activity levels usually have milder signs and symptoms than those with lower activity levels because they have less accumulation of GM1 ganglioside within the body. Conditions such as GM1 gangliosidosis that cause molecules to build up inside the lysosomes are called lysosomal storage disorders. ### Learn more about the gene associated with GM1 gangliosidosis * GLB1 ## Inheritance Pattern This condition is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of 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	GM1 gangliosidosis	c1968748	754	medlineplus	https://medlineplus.gov/genetics/condition/gm1-gangliosidosis/	2021-01-27T08:25:35	{"gard": ["10891"], "mesh": ["C566895"], "omim": ["230500", "230600", "230650"], "synonyms": []}
Metaphyseal dysplasia, Braun-Tinschert type is characterised by metapyhseal undermodeling with broadening of the long bones and femora with an 'Erlenmeyer flask'' appearance, expansion and bowing of the radii with severe varus deformity and flat exostoses of the long bones at the metadiaphyseal junctions. ## Epidemiology It has been described in four German families originating from the same town in Bohemia and in a 7-year-old Japanese girl. ## Differential diagnosis Erlenmeyer flask deformity is also a prominent feature of the autosomal recessive Pyle type of metaphyseal dysplasia (see this term). The two conditions can be distinguished by the mode of inheritance and by the presence of the marked varus deformity of the distal part of the radii in Braun-Tinschert metaphyseal dysplasia. ## Genetic counseling Transmission of metaphyseal dysplasia, Braun-Tinschert type is 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	Metaphyseal dysplasia, Braun-Tinschert type	c1853825	755	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=85188	2021-01-23T17:36:16	{"mesh": ["C565271"], "omim": ["605946"], "umls": ["C1853825"], "icd-10": ["Q78.5"]}
A number sign (#) is used with this entry because of evidence that hypoplastic left heart syndrome (HLHS2) is caused by heterozygous mutation in the NKX2-5 gene (600584) on chromosome 5q35.1. Description Hypoplastic left heart syndrome results from defective development of the aorta proximal to the entrance of the ductus arteriosus and hypoplasia of the left ventricle and mitral valve. As a result of the abnormal circulation, the ductus arteriosus and foramen ovale are patent and the right atrium, right ventricle, and pulmonary artery are enlarged (Brekke, 1953). For a discussion of genetic heterogeneity of hypoplastic left heart syndrome, see HLHS1 (241550). Molecular Genetics In 1 (1%) of 80 patients with hypoplastic left heart syndrome, McElhinney et al. (2003) identified heterozygosity for a missense mutation in the NKX2-5 gene (R25C; 600584.0004). In 1 of 9 patients with hypoplastic left heart syndrome, Stallmeyer et al. (2010) identified heterozygosity for the R25C mutation in the NKX2-5 gene. The complete cardiac phenotype of the male infant included atresia of the aortic and mitral valves and a small VSD that required corrective surgery. INHERITANCE \- Autosomal dominant CARDIOVASCULAR Heart \- Hypoplastic left heart \- Ventricular septal defect \- Aortic valve atresia \- Mitral valve atresia MOLECULAR BASIS \- Caused by mutation in the NK2 homeobox-5 gene (NKX2-5, 600584.0004 ) ▲ 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	HYPOPLASTIC LEFT HEART SYNDROME 2	c0152101	756	omim	https://www.omim.org/entry/614435	2019-09-22T15:55:16	{"doid": ["9955"], "mesh": ["D018636"], "omim": ["614435"], "orphanet": ["2248"]}
Pituitary disease Pituitary SpecialtyEndocrinology A pituitary disease is a disorder primarily affecting the pituitary gland.[1] The main disorders involving the pituitary gland are: Condition Direction Hormone Acromegaly overproduction growth hormone Cushing's disease overproduction adrenocorticotropic hormone Growth hormone deficiency underproduction growth hormone Syndrome of inappropriate antidiuretic hormone overproduction vasopressin Diabetes insipidus (can also be nephrogenic) underproduction vasopressin Sheehan syndrome underproduction any pituitary hormone Pickardt-Fahlbusch Syndrome underproduction any pituitary hormone, except prolactin, which is increased Hyperpituitarism (most commonly pituitary adenoma) overproduction any pituitary hormone Hypopituitarism underproduction any pituitary hormone Overproduction or underproduction of a pituitary hormone will affect the respective end-organ. For example, insufficient production (hyposecretion) of thyroid stimulating hormone (TSH) in the pituitary gland will cause hypothyroidism, while overproduction (hypersecretion) of TSH will cause hyperthyroidism. Thyroidisms caused by the pituitary gland are less common though, accounting for less than 10% of all hypothyroidism cases and much less than 1% of hyperthyroidism cases.[2][3] ## See also[edit] * Hypophysitis, inflammation of the pituitary gland. * Autoimmune hypophysitis (or lymphocytic hypophysitis), inflammation of the pituitary gland due to autoimmunity. * Pituitary tumour, a tumor of the pituitary gland. * Pituitary adenoma, a noncancerous tumor of the pituitary gland. * Pituicytoma, a rare brain tumor. * Pituitary apoplexy, bleeding into or impaired blood supply of the pituitary gland. ## References[edit] 1. ^ "Overview of the Pituitary Gland: Pituitary Gland Disorders: Merck Manual Home Health Handbook". Retrieved 2009-04-04. 2. ^ Page 358 in: Aminoff, Michael J. (2007). Neurology and General Medicine: Expert Consult: Online and Print. Edinburgh: Churchill Livingstone. ISBN 978-0-443-06707-5. 3. ^ Thyrotropin (TSH)-secreting pituitary adenomas. By Roy E Weiss and Samuel Refetoff. Last literature review version 19.1: January 2011. This topic last updated: July 2, 2009 ## External links[edit] Classification D * MeSH: D010900 * 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]: 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	Pituitary disease	c0032002	757	wikipedia	https://en.wikipedia.org/wiki/Pituitary_disease	2021-01-18T18:36:37	{"mesh": ["D010900"], "umls": ["C0032002"], "wikidata": ["Q7199538"]}
Not to be confused with Hemiplegia or Paragelia. Paraplegia Pronunciation * /ˌpærəˈpliːdʒə/ SpecialtyPhysical medicine and rehabilitation Paraplegia is an impairment in motor or sensory function of the lower extremities. The word comes from Ionic Greek (παραπληγίη) "half-stricken". It is usually caused by spinal cord injury or a congenital condition that affects the neural (brain) elements of the spinal canal. The area of the spinal canal that is affected in paraplegia is either the thoracic, lumbar, or sacral regions. If four limbs are affected by paralysis, tetraplegia or quadriplegia is the correct term. If only one limb is affected, the correct term is monoplegia. Spastic paraplegia is a form of paraplegia defined by spasticity of the affected muscles, rather than flaccid paralysis. The American Spinal Injury Association classifies spinal cord injury severity. ASIA A being the complete loss of sensory function and motor skills below the injury. ASIA B is having some sensory function below the injury, but no motor function. ASIA C some motor function below level of injury, but half the muscles cannot move against gravity. ASIA D, more than half of the muscles below the level of injury can move against gravity. ASIA E which is the restoration of all neurologic function.[1] ## Contents * 1 Treatment * 1.1 Regeneration of the spinal cord * 2 See also * 3 References * 4 External links ## Treatment[edit] Individuals with paraplegia can range in their level of disability, requiring treatments to vary from case to case. Rehabilitation aims to help the patient regain as much functionality and independence as possible. Physiotherapy may help to improve strength, range of motion, stretching and transfer skills.[2] Most paraplegics will be dependent on a wheelchair as a mode of transportation.[3] Activities of daily living (ADLs) can be quite challenging at first for those with a spinal cord injury (SCI). With the aid of physiotherapists and occupational therapists, individuals with an SCI can learn new skills and adapt previous ones to maximize independence, often living independently within the community.[4] ### Regeneration of the spinal cord[edit] See also: Spinal cord injury § Research directions Olfactory ensheathing cells (OEC) have been transplanted with success into the spinal cord of Polish man named Darek Fidyka, who was the victim of a knife attack that left him paraplegic in 2010.[5] In 2014, Fidyka underwent pioneering spinal surgery that used nerve grafts, from his ankle, to 'bridge the gap' in his severed spinal cord and OEC's to stimulate the spinal cord cells. The surgery was performed in Poland in collaboration with Prof. Geoff Raisman, chair of neural regeneration at University College London's Institute of Neurology, and his research team. The olfactory cells were taken from the patient's olfactory bulbs in his brain and then grown in the lab, these cells were then injected above and below the impaired spinal tissue.[6] Fidyka regained sensory and motor function in his lower limbs, notably on the side of the transplanted OEC's. Fidyka first noticed the success three months after the procedure, when his left thigh started gaining muscle mass. MRIs suggest that the gap in his spinal cord has been closed up. He is believed to be the first person in the world to recover sensory function from a complete severing of the spinal nerves.[5][6] ## See also[edit] * Adapted automobile * Cauda equina syndrome * Hemiplegia * Quadriplegia * Hughes-Stovin syndrome * Regeneration in humans * The Body Silent * Sexuality after spinal cord injury * Spinal cord injury research ## References[edit] 1. ^ "Standard Neurological Classification of Spinal Cord Injury" (PDF). American Spinal Injury Association & ISCOS. Archived from the original on June 18, 2011 2. ^ Taylor-Schroeder S, LaBarbera J, McDowell S, et al. (2011). "The SCIRehab project: treatment time spent in SCI rehabilitation. Physical therapy treatment time during inpatient spinal cord injury rehabilitation". J Spinal Cord Med. 34 (2): 149–61. doi:10.1179/107902611x12971826988057. PMC 3066500. PMID 21675354. Retrieved 2012-06-02.[dead link] 3. ^ Ozelie R, Sipple C, Foy T, et al. (2009). "SCIRehab Project series: the occupational therapy taxonomy". J Spinal Cord Med. 32 (3): 283–97. doi:10.1080/10790268.2009.11760782. PMC 2718817. PMID 19810630. 4. ^ Tzonichaki I, Kleftaras G (2002). "Paraplegia from spinal cord injury: self-esteem, loneliness, and life satisfaction". OTJR: Occupation, Participation and Health. 22 (3): 96–103. doi:10.1177/153944920202200302. 5. ^ a b Walsh, Fergus (21 October 2014). "Paralysed man walks again after cell transplant". bbc.co.uk. Retrieved 26 October 2014. 6. ^ a b Quinn, Ben (21 October 2014). "Paralysed man Darek Fidyka walks again after pioneering surgery". theguardian.com. Retrieved 26 October 2014. "The 38-year-old, who is believed to be the first person in the world to recover from complete severing of the spinal nerves, can now walk with a frame and has been able to resume an independent life, even to the extent of driving a car, while sensation has returned to his lower limbs." ## External links[edit] Classification D * ICD-10: G82.1 * ICD-9-CM: 334.1, 344.1 * MeSH: D010264 Look up paraplegia in Wiktionary, the free dictionary. * v * t * e Symptoms and signs relating to movement and gait Gait * Gait abnormality * CNS * Scissor gait * Cerebellar ataxia * Festinating gait * Marche à petit pas * Propulsive gait * Stomping gait * Spastic gait * Magnetic gait * Truncal ataxia * Muscular * Myopathic gait * Trendelenburg gait * Pigeon gait * Steppage gait * Antalgic gait Coordination * Ataxia * Cerebellar ataxia * Dysmetria * Dysdiadochokinesia * Pronator drift * Dyssynergia * Sensory ataxia * Asterixis Abnormal movement * Athetosis * Tremor * Fasciculation * Fibrillation Posturing * Abnormal posturing * Opisthotonus * Spasm * Trismus * Cramp * Tetany * Myokymia * Joint locking Paralysis * Flaccid paralysis * Spastic paraplegia * Spastic diplegia * Spastic paraplegia * Syndromes * Monoplegia * Diplegia / Paraplegia * Hemiplegia * Triplegia * Tetraplegia / Quadruplegia * General causes * Upper motor neuron lesion * Lower motor neuron lesion Weakness * Hemiparesis Other * Rachitic rosary * Hyperreflexia * Clasp-knife response [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	Paraplegia	c0030486	758	wikipedia	https://en.wikipedia.org/wiki/Paraplegia	2021-01-18T18:42:47	{"gard": ["7327"], "mesh": ["D010264"], "umls": ["C0030486", "C0037772"], "wikidata": ["Q1049655"]}
A number sign (#) is used with this entry because it represents a contiguous gene deletion syndrome. Like Wolf-Hirschhorn syndrome (194190), cri-du-chat syndrome (123450), and Miller-Dieker syndrome (247200), it is a terminal deficiency or macrodeletion syndrome characterized by mental retardation and congenital malformations. Clinical Features The phenotype is highly variable, but is characterized by mental retardation, short stature, hypotonia, hearing impairment, and foot deformities. Tapered digits and wide mouth have been described. Hecht (1969) found low levels of immunoglobulin A in some cases of the 18q- syndrome. Wilson et al. (1979) noted that autoimmune disease, a known accompaniment of selective IgA deficiency (137100), has been found in some cases of the 18q- syndrome. Wilson et al. (1979) found that 80% of individuals affected with the 18q- syndrome are below the 5th centile in height. Schwarz and Duck (1990) and Andler et al. (1992) each reported an individual with the 18q- syndrome who was growth hormone (139250) deficient. Ghidoni et al. (1997) evaluated growth hormone deficiency in 5 patients with the 18q- syndrome, 3 of whom had growth failure with weight and height below the 3rd centile; the remaining 2 had normal growth. In 3 patients, there was a failure to produce adequate growth hormone following stimulation with clonidine. Of the 3 patients with inadequate growth hormone production, 1 had normal growth (above the 3rd centile). Thus, only 1 of 5 patients had normal GH production and normal growth parameters. Ghidoni et al. (1997) suggested that a gene(s) on 18q is involved in growth hormone production. Cody et al. (1999) reported 42 individuals with deletions of 18q. Common features included short stature, microcephaly, palatal defects, short frenulum, carp-like mouth, short palpebral fissures, and external ear anomalies. Cardiac anomalies were observed in 24%, including atrial and ventricular septal defects and pulmonary stenosis. Skeletal defects included scoliosis, foot deformities, and tapering fingers. Serum IgA levels were decreased in 24%. Hale et al. (2000) studied the spectrum of growth abnormalities in children with 18q deletions. They investigated the growth axis of 50 individuals with a cytogenetically and molecularly confirmed 18q deletion by determining height, growth velocity, IGF1 (147440), IGFBP3 (146732), bone maturation, and response to pituitary stimulants of growth hormone. Children with 18q deletions are short; 64% had a height more than -2 SD below the mean. Affected children also grow slowly; 68% had a growth velocity more than -1 SD below the mean. Half of the individuals had delayed bone maturation. Growth factors are skewed downward; 72% of the IGF1 values and 83% of the IGFBP3 values were below the mean for chronologic age. Similarly, 72% of the children had a reduced or absent response to either of the growth hormone stimulants arginine and clonidine. In the total group of 50 children, only 2 were normal for all parameters evaluated. Versacci et al. (2005) reported 3 unrelated patients with syndromic absent pulmonary valve, intact ventricular septum, and patent ductus arteriosus associated with terminal deletion of chromosome 18q. All patients also had aortic valve stenosis with dilatation of the ascending aorta. The first patient had additional facial anomalies including low frontal hairline with narrow biparietal diameter, bulbous nose, thick lips, high palate, large ears, and prognathism as well as cryptorchidism, clubfeet, choanal stenosis, and Marfan-like body habitus including thin body, pectus excavatum, kyphoscoliosis, arachnodactyly, and joint hypermobility. Chromosome analysis showed a 46,XY,-18,del(18)(2;18)(q37.3;q22.3) karyotype; his mother had a balanced reciprocal translocation 46,XX,t(2;18)(q37.3;q22.3) and Marfan-like habitus. The second patient also had facial anomalies including downslanted palpebral fissures, midface hypoplasia, short philtrum, thin lips, prognathism, and dysmorphic ears. Other features included cryptorchidism, scoliosis, clubfeet, short stature, and mental retardation. Chromosome analysis showed a 46,XY,del(18)(q22-qter). The third patient had a flat nasal bridge, epicanthal folds, carp-shaped mouth, dysmorphic ears, hypotonia, and developmental retardation. Chromosomal analysis showed 46,XX,del(18)(q21.3-qter). Linnankivi et al. (2006) reported 14 Finnish individuals with partial deletions of 18q, including 2 families with 2 affected children each. There was phenotypic variability even within families with the same deletion. Common features included short stature, facial dysmorphism, palatal defects, tapering digits, foot deformities, cryptorchidism, atopic disorders, and recurrent respiratory infections with IgA deficiency. Cognitive function ranged from normal intelligence to severe mental retardation. Other neurologic features included nystagmus, seizures, hypotonia, clumsiness, hearing loss, and diffuse white matter abnormalities on MRI. The maximum estimated size of the deletion ranged from 7.7 to 29.4 Mb. All individuals shared only a small common 1.1-Mb region between D18S469 and D18S812. All individuals with abnormal myelination shared a deletion of 18q22.3-q23 between markers D18S469 and D18S1141, which includes the myelin basic protein gene (MBP; 159430). Congenital atresia or stenosis of the external ear canals was associated with deletions between D18S812 and D18S1141 (18q22.3-q23). Feenstra et al. (2011) described a sporadic case and a mother and 2 sons with 18q22.3-q23 microdeletions, noting that the phenotype in the mother and sons closely resembled that of 3 males and 3 females in a family with bilateral atresia of the external auditory canal and congenital vertical talus described by Rasmussen et al. (1979) (see Rasmussen syndrome, 133705). Inheritance Subrt and Pokorny (1970) described the 18q deletion syndrome in a mother and her 4 daughters. Sulzer and Zierler (1976) reported dominant transmission of partial deletion of 18q from a mother to her daughter. Fryns et al. (1979) also reported 18q deletion syndrome in a mother and daughter. Both had an identical balanced t(14;18)(p11;q21) translocation, suggesting that chromosomal material near 18q21 was lost in the translocation process. Chen et al. (2006) reported direct transmission of del(18)(q22.2) from a mother to her daughter. Both showed characteristic phenotypic features of the syndrome, including short stature, microcephaly, facial dysmorphism, moderate mental retardation, and abnormal brain myelination. Chen et al. (2006) emphasized that affected females are clearly fertile and should have genetic counseling. Cytogenetics Cody et al. (1997) evaluated 33 children with the 18q- syndrome for growth hormone production and identified a region of approximately 2 Mb that was deleted in every growth hormone insufficient patient. They pointed to 2 genes contained in this region, MBP (159430) and the galanin receptor (GALNR; 600377), as candidates for the growth hormone insufficiency phenotype. Brkanac et al. (1998) analyzed the DNA from 35 patients who originally were diagnosed as having de novo terminal deletions of chromosome 18. Molecular analysis was performed with polymorphic markers throughout the 18q- region. Cytogenetic fluorescence in situ hybridization was performed with 2 human 18q telomeric probes, a chromosome 18-specific alpha-satellite probe, and whole chromosome 18-specific paint. Of 35 patients previously reported to have terminal deletions of 18q, they found that 5 (14%) had more complex cryptic rearrangements and that 3 (9%) retained the most distal portion of 18q, consistent with an interstitial rather than a terminal deletion. These findings indicated that a standard karyotype can lead to insufficient characterization in 18q- syndrome. To gain insight into the mechanism of chromosomal loss and stabilization in the terminal deficiency or macrodeletion syndromes characterized by mental retardation and congenital malformations, Katz et al. (1999) cloned a putative terminal deletion breakpoint found in a 18q- syndrome patient. The 18q21.3 breakpoint occurred between 2 serine protease inhibitor (serpin) genes, SCCA1 (600517) and SCCA2 (600518). Although cytogenetic studies suggested that this chromosomal aberration was formed by a simple terminal deletion, DNA sequence analysis, pulsed-field gel electrophoresis, and fluorescence in situ hybridization showed that the breakpoint was contiguous with a 35-bp filler sequence followed by a satellite III DNA-containing telomeric fragment of 475 to 1,000 kb. This type of satellite III DNA sequence was not detected on the normal chromosome 18, but was highly homologous with types of satellite III DNA sequences normally located on the short arms (p11) of the acrocentric chromosomes and other heterochromatic regions. This DNA sequence analysis suggested that the terminal deficiency in this 18q- syndrome patient arose via illegitimate (nonhomologous) recombination. Moreover, these data raised the possibility that a subset of chromosomal aberrations appearing cytogenetically and molecularly as simple terminal truncations or deletions are caused by small (less than 1,000 kb) cryptic rearrangements. Genotype/Phenotype Correlations Feenstra et al. (2007) used array comparative genomic hybridization (array CGH) to analyze in detail the chromosome 18 anomalies of 29 patients with cytogenetic 18q deletions, including 6 with a proximal interstitial deletion and 22 with a terminal deletion. One patient had a complex aberration involving several chromosomes. All patients had different breakpoints, indicating that there is no hotspot. The results refined genotype/phenotype correlations for several critical regions, including microcephaly (18q21.33), short stature (18q12.1-q12.3, 18q21.1-q21.33, and 18q22.3-q23), white matter disorders and delayed myelination (18q22.3-q23), growth hormone insufficiency (18q22.3-q23), and congenital aural atresia (18q22.3). The overall level of mental retardation appeared to be mild in patients with deletions distal to 18q21.33 and severe in patients with deletions proximal to 18q21.31. The critical region for the typical 18q-phenotype was a 4.3-Mb region within 18q22.3-q23. In an analysis of the phenotype and deletion sizes of 151 individuals with deletions of 18q using oligo-array CGH, Cody et al. (2009) were able to narrow critical regions associated with particular phenotypes. These regions were all within 18q22.3-q23. The regions for dysmyelination and failure of growth hormone stimulation response were identical and narrowed to a 1.62-Mb region containing 5 known genes, including MBP (159430). The region for aural atresia was 2.3-Mb and included 3 additional genes. The region for kidney malformations was 3.21-Mb and included an additional 4 genes. Penetrance rates were calculated by comparing the number of individuals hemizygous for a critical region with the phenotype to those without the phenotype. The kidney malformations region was 25% penetrant, the dysmyelination region was 100% penetrant, the failure of growth hormone stimulation region was 90% penetrant with variable expressivity, and the aural atresia region was 78% penetrant. Feenstra et al. (2011) performed SNP-array analysis in affected individuals with syndromic congenital aural atresia from 2 families with 18q22.3-q23 microdeletions and found a 459-kb deletion overlap, a region containing a single known gene, TSHZ1 (614427). Sequencing TSHZ1 in 11 patients with an isolated, bilateral form of congenital aural atresia (607842) revealed heterozygous loss-of-function mutations in 4 patients (614427.0001 and 614427.0002). The mutation-positive individuals had no facial dysmorphism or other features associated with 18q deletion syndrome. Feenstra et al. (2011) concluded that 18q deletion syndrome is a true contiguous gene syndrome, in which the CAA endophenotype is explained by deletion of TSHZ1. INHERITANCE \- Autosomal dominant GROWTH Height \- Short stature Weight \- Poor weight gain HEAD & NECK Head \- Microcephaly Face \- Midface hypoplasia \- Flat midface \- Narrow biparietal diameter \- Prognathism \- Short philtrum Ears \- Hearing loss, sensorineural \- Hearing loss, conductive \- Atretic external auditory canals \- Stenotic external auditory canals \- Congenital aural atresia \- Malformed earlobes \- Large, dysmorphic ears Eyes \- Strabismus \- Nystagmus \- Hypertelorism \- Downslanting palpebral fissures \- Epicanthal folds \- Short palpebral fissures \- Optic atrophy \- Tapetoretinal degeneration Nose \- Prominent nose \- Choanal stenosis \- Flat nasal bridge Mouth \- Downturned corners of the mouth \- Cleft lip \- Cleft palate \- Bifid uvula \- Thin upper lip \- Carp-like mouth \- Short frenulum \- Protuberant lower lip Neck \- Short neck CARDIOVASCULAR Heart \- Cardiac abnormalities (25 to 35% of patients) \- Congestive heart failure \- Absence of the pulmonary valve \- Dysplastic pulmonary valve \- Dysplastic aortic valve \- Aortic valve stenosis \- Atrial septal defect \- Ventricular septal defect Vascular \- Patent ductus arteriosus \- Dilation of the ascending aorta \- Prominent abdominal venous pattern RESPIRATORY \- Recurrent respiratory infections Airways \- Asthma ABDOMEN External Features \- Umbilical hernia \- Inguinal hernia \- Prominent abdominal venous pattern GENITOURINARY External Genitalia (Male) \- Cryptorchidism \- Micropenis \- Hypospadias SKELETAL \- Joint laxity Spine \- Scoliosis Hands \- Tapering digits \- Proximally placed thumbs Feet \- Overriding toes \- Syndactyly \- Clubfoot \- Pes cavus \- Pes planus \- Planovalgus \- Vertical talus \- Rocker-bottom feet SKIN, NAILS, & HAIR Skin \- Atopic eczema Hair \- Low anterior hairline NEUROLOGIC Central Nervous System \- Mental retardation, severe, (some patients) \- Cognitive function, variable \- Hypotonia \- Delayed motor milestones \- Poor coordination \- Wide-based gait \- Tremor \- Chorea \- Seizures \- White matter abnormalities \- Poor differentiation of gray and white matter on T2-weighted MRI \- Abnormal myelination \- Delayed myelination \- Cerebellar hypoplasia \- Enlarged ventricles ENDOCRINE FEATURES \- Growth hormone deficiency IMMUNOLOGY \- Low levels of immunoglobulin A \- Selective IgA deficiency \- Atopic disorders (eczema, food allergy, asthma) LABORATORY ABNORMALITIES \- Interstitial or terminal deletion of 18q MISCELLANEOUS \- Highly variable phenotype, even within families \- Estimated frequency of 1 in 40,000 live births \- Female preponderance \- Some familial occurrence, most de novo aberrations MOLECULAR BASIS \- Caused by interstitial or terminal deletion of chromosome 18q ▲ 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	CHROMOSOME 18q DELETION SYNDROME	c0432443	759	omim	https://www.omim.org/entry/601808	2019-09-22T16:14:23	{"doid": ["0060407"], "mesh": ["C536580"], "omim": ["601808"], "orphanet": ["1600"], "synonyms": ["Alternative titles", "CHROMOSOME 18q- SYNDROME", "18q- SYNDROME"]}
A number sign (#) is used with this entry because sitosterolemia is caused by homozygous or compound heterozygous mutation in the ABCG8 gene (605460) or in the ABCG5 gene (605459), both of which are located on chromosome 2p21. Description Sitosterolemia, also known as phytosterolemia, is an autosomal recessive metabolic condition characterized by unrestricted intestinal absorption of both cholesterol and plant-derived cholesterol-like molecules, such as sitosterol. Patients with this disorder have very high levels of plant sterols in the plasma and develop tendon and tuberous xanthomas, accelerated atherosclerosis, and premature coronary artery disease (summary by Berge et al., 2000). Clinical Features Bhattacharyya and Connor (1974) described 2 intellectually normal sisters of German and German-Swiss ancestry with tendinous and tuberous xanthoma and elevation of beta-sitosterol and 2 other plant sterols, campesterol and stigmasterol, in the blood. The authors proposed abnormally increased intestinal absorption. One of the 2 sisters complained of pains in the knees and ankles. Shulman et al. (1976) pointed out that a diet high in vegetable oils (containing beta-sitosterol), prescribed to increase dietary polyunsaturated fat, could aggravate this condition. Khachadurian and Clancy (1978) observed phytosterolemia in 5 patients from 2 families. Miettinen (1980) reported a patient with phytosterolaemia and hypersplenism who developed premature atherosclerotic arterial disease requiring a 3-vessel coronary bypass at the age of 29 years. The patient had initially been diagnosed with familial hypercholesterolaemia (143890), but did not have increased serum cholesterol levels. Biochemical studies showed that up to 30% of serum and bile sterols were plant sterols, including campesterol and beta-sitosterol, stigmasterol, and another major plant sterol, tentatively identified as avenasterol. Fecal analysis showed decreased biliary secretion of plant sterols. Treatment with cholestyramine brought about a modest increase in cholesterol elimination as bile acids, increased endogenous cholesterol synthesis, and reduced the plasma cholesterol by 21% and plant sterols by 16%. Wang et al. (1981) reported an adult Chinese man with sitosterolemia who presented with tendinous and tuberous xanthomatosis and severe coronary artery disease. He also had chronic hemolytic anemia with stomatocytic erythrocytes. Patients with phytosterolemia reported by Miettinen (1980), Wang et al. (1981), and Skrede et al. (1985) had episodic hemolysis or chronic hemolytic anemia. Increased content of sitosterol in red cells was believed to be responsible for their fragility. Hatanaka et al. (1990) described spinal cord compression with paraplegia in a patient with xanthomas due to normocholesterolemic sitosterolemia. Rios et al. (2010) reported an 11-month old Romanian girl in whom sitosterolemia became evident after she was weaned from an exclusive breast milk diet. ### Mediterranean Stomatocytosis/Macrothrombocytopenia Ducrou and Kimber (1969) reported individuals of Mediterranean descent living in Australia who had recurrent abdominal pain and splenomegaly associated with stomatocytosis and reduced red cell life. Also among individuals of Mediterranean descent in Australia, Von Behrens (1975) found decreased platelet counts and increased platelet volume. The authors concluded that the macrothrombocytopenia was a benign morphologic variant. The individuals were Italian and Greek immigrants to Australia. This condition was referred to as 'Mediterranean stomatocytosis/macrothrombocytopenia (Rees et al., 2005; Stewart et al., 2006). In correspondence, Stewart et al. (2006) and Stewart and Makris (2008) noted that there were no reports of stomatocytosis/macrothrombocytopenia in any Mediterranean countries, such as Italy or Greece, that there were no further reports of this condition after 1975, and that there was no clear evidence of autosomal dominant inheritance. These authors thus suggested that the cases of Mediterranean stomatocytosis/macrothrombocytopenia reported in Australia were acquired, and possibly the result of ingestion of local olive oil in Adelaide that may have contained some kind of impurity that inhibited the ABCG5 or ABCG8 proteins, or that the olive oil used at that time contained some kind of active molecule related to phytosterols. Despite the assertion by Stewart and Makris (2008) that no reports of this condition appeared after 1975, Paulus and Casals (1978) reported peculiarities in megakaryocytes in persons with Mediterranean macrothrombocytopenia. The mean platelet counts in Mediterranean and northern European subjects were 161,000 and 219,000 per ml, respectively, and the mean platelet volumes were 17.8 and 12.4 fl, respectively. Brahimi et al. (1984) concluded that the prevalence of Mediterranean macrothrombocytopenia was low in Algeria. Savoia et al. (2001) identified a common heterozygous mutation in the GP1BA gene (A156V; 606672.0004) in affected individuals from 6 of 12 Italian families believed to have Mediterranean macrothrombocytopenia. Stomatocytosis was not reported. These findings were consistent with a rare occurrence of autosomal dominant Bernard-Soulier syndrome (153670). However, the remaining 6 Italian families reported by Savoia et al. (2001) did not have GP1BA mutations, suggesting genetic heterogeneity. Molecular studies of the ABCG5 or ABCG8 genes were not performed. Rees et al. (2005) presented molecular evidence that the stomatocytosis and macrothrombocytopenia observed in so-called Mediterranean stomatocytosis/macrothrombocytopenia actually represents the hematologic presentation of phytosterolemia. They reported 5 kindreds with a recessive condition characterized by mild hemolysis, marked stomatocytosis, low levels of very large platelets, and increased mean platelet volume, consistent with the description of the Mediterranean condition. However, none of the patients were of Mediterranean extraction. All patients had evidence of hemolysis with reticulocytosis, mild hyperbilirubinemia, and splenomegaly. All also had short stature. Some patients presented with abdominal pain, and some had a bleeding tendency. None of the patients had evidence of premature cardiovascular disease, but all were of a young age (less than 30 years). Patient platelets showed a consistent abnormality in ristocetin-induced agglutination, with variable aggregation in response to other agonists. Other forms of hereditary stomatocytosis (see, e.g., 185000 and 194380) were ruled out. Spectroscopic analysis of erythrocyte membrane lipids showed abnormal and increased levels of plant-derived phytosterols, including beta-sitosterol, stigmasterol, isofucosterol, stigmastanol, and campesterol. Plasma levels of phytosterols were also increased. All affected individuals in the families reported by Rees et al. (2005) had mutations in either the ABCG5 (2 families; see, e.g., 605459.0006) or the ABCG8 (3 families; see, e.g., 605460.0001) gene. These studies showed that the hematologic syndrome of Mediterranean stomatocytosis can result from an excess of plasma phytosterols, perhaps due to abnormal lipid content in red cell and platelet membranes. Rees et al. (2005) predicted that the phenotype is highly dependent on diet, and it is therefore difficult to make convincing phenotype/genotype correlations. The studies also revealed increasing clinical diversity, both in the laboratory and clinical features of sitosterolemia. The Mediterranean population of Australia is renowned for its profuse olive oil consumption, and it is possible that the hematology observed in that population was the result of an environmental or dietary effect, which may have disappeared with time. Whatever the explanation for the Australian experience, the results of Rees et al. (2005) indicated that plasma phytosterols should be measured in patients with stomatocytic hemolysis and abnormally large platelets. In addition, platelet size should be reviewed in all patients with hypercholesterolemia. Biochemical Features Nguyen et al. (1990) found that hepatic cholesterol biosynthesis in sitosterolemia was severely depressed. Microsomal HMG-CoA reductase (142910), the enzyme that catalyzes the rate-limiting reaction in the pathway, was markedly decreased, reflecting a low level of mRNA. Further studies showed that patients with sitosterolemia had enhanced total and receptor-mediated uptake of low density lipoprotein (LDL), which presumably represented a compensation to provide cellular sterols that cannot be synthesized. The findings indicated that individuals with sitosterolemia have inadequate cholesterol biosynthesis, which is then offset by augmented receptor-mediated LDL catabolism in order to supply cellular sterols. Overall, the disorder is characterized by enhanced intestinal absorption of and decreased removal of plant sterols. Salen et al. (1996) reviewed the abnormalities of cholesterol biosynthesis in sitosterolemia. Inheritance Kwiterovich et al. (1981) observed sitosterolemia among the Lancaster County, Pennsylvania, Amish. Beaty et al. (1986) analyzed data derived from 254 relatives of a 13-year-old Amish proband who died unexpectedly of advanced coronary atherosclerosis. Segregation analysis of sitosterol levels showed that the phenotype was a rare autosomal recessive. The recessive model was supported by the finding that plasma sitosterol levels in the parents and in 6 children born to 3 of the 5 sitosterolemics were well within the normal range. Clinical Management Stalenhoef (2003) provided pictures of a 17-year-old girl who presented with multiple xanthomas of the hands and Achilles tendons, as well as a family history of vascular disease. Phytosterolemia with xanthomatosis was diagnosed. The patient was told to follow a diet low in plant fats (margarines), nuts, chocolate, and seeds. In addition, bile acid resins were prescribed. Although the patient's plasma levels of plant sterols remained markedly elevated, her tendon xanthomas diminished markedly, as shown by photographs taken after an interval of 5 years. The patient of Rios et al. (2010), who presented with xanthomas of the Achilles tendon and very high plasma cholesterol levels after weaning from breastfeeding, was treated with ezetimibe, a lipid-lowering agent that reduces the absorption of plant sterols as well as cholesterol. The plasma cholesterol level fell progressively into the normal range, but the plant sterol levels remained elevated despite the patient consuming a low cholesterol, low plant sterol diet. Mapping By studying 10 well-characterized families with sitosterolemia, Patel et al. (1998) localized the genetic defect to 2p21, between microsatellite markers D2S1788 and D2S1352 (maximum lod score = 4.49 at theta = 0.0). Lu et al. (2001) constructed a high-resolution YAC and BAC contig map encompassing a physical distance of approximately 2 Mb between microsatellite markers D2S2294 and D2S2291. Eight previously identified genes and 60 ESTs were mapped to these contigs, representing a high-resolution physical and transcript map with complete coverage of the minimal region containing the sitosterolemia locus. Lee et al. (2001) studied 30 families which were assembled from around the world and had no evidence of genetic heterogeneity. A maximum multipoint lod score of 11.49 was obtained for marker D2S2998. Using both homozygosity mapping and informative recombination events, the critical interval containing the sitosterolemia gene was narrowed to a region defined by markers D2S2294 and Afm210xe9, a distance of approximately 2 cM. Homozygosity and haplotype sharing was identified in probands from nonconsanguineous marriages from a number of families, strongly supporting the existence of a founder effect among Amish/Mennonite, Finnish/Norwegian, and Japanese populations. Molecular Genetics Berge et al. (2000) identified homozygosity or compound heterozygosity for several mutations in 2 adjacent, oppositely oriented genes that encode members of the adenosine triphosphate (ATP)-binding cassette (ABC) transporter family, ABCG8 (see 605460.0001-605460.0008) and ABCG5 (see 605459.0001), in 9 patients with sitosterolemia. The 2 genes are expressed at highest levels in liver and intestine. In mice, cholesterol feeding upregulates expression of both genes. Based on their data, Berge et al. (2000) concluded that ABCG5 and ABCG8 normally cooperate to limit intestinal absorption and to promote biliary excretion of sterols, and that mutated forms of these transporters predispose to sterol accumulation and atherosclerosis. Treatment with a low cholesterol diet resulted in a reduction of plasma cholesterol from a high of 800 in some patients to a low of 106. Lee et al. (2001) identified homozygosity for mutations in the ABCG5 gene (605459.0001-605459.0004) in 9 unrelated sitosterolemia patients. Rios et al. (2010) reported an 11-month old Romanian girl with xanthomas and marked hypercholesterolemia. While she was initially thought to have primary hypercholesterolemia (see 143890), mutations in the candidate genes LDLRAP1 (605747), LDLR (606945), PCSK9 (607786), APOE (107741), and APOB (107730) were excluded. Whole-genome sequencing revealed 2 nonsense mutations in ABCG5, gln16 to ter (Q16X; 605459.0007) and arg446 to ter (R446X; 605459.0008). Sitosterolemia became evident after she was weaned from an exclusive breast milk diet. Population Genetics In a Swiss woman with sitosterolemia who had typical xanthomas and also mitral and aortic valvular disease, Solca et al. (2005) identified homozygosity for the G574R mutation in the ABCG8 gene (605460.0002). Extended haplotype analysis of this patient and 2 Amish-Mennonite patients with the same mutation revealed that the Swiss patient and 1 of the Amish-Mennonite patients shared identical SNPs, with a minor difference between the 2 Amish-Mennonite patients. Solca et al. (2005) concluded that the G574R mutation in the Amish-Mennonite population originated in Europe more than 250 years ago. In a carrier screening of autosomal recessive mutations involving 1,644 Schmiedeleut (S-leut) Hutterites in the United States, Chong et al. (2012) identified the ABCG8 sitosterolemia mutation ser107 to ter (rs137854891, 605460.0010) in heterozygous state in 127 individuals among 1,515 screened and in homozygous state in 4, for a carrier frequency of 0.084 (1 in 12). This mutation is private to the Hutterite population. Animal Model In Abcg5/Abcg8-deficient mice, Yang et al. (2004) demonstrated that accumulation of plant sterols perturbed cholesterol homeostasis in the adrenal gland, with a 91% reduction in its cholesterol content. Despite very low cholesterol levels, there was no compensatory increase in cholesterol synthesis or in lipoprotein receptor expression. Adrenal cholesterol levels returned to near-normal levels in mice treated with ezetimibe, which blocks phytosterol absorption. In cultured adrenal cells, stigmasterol but not sitosterol inhibited SREBP2 (600481) processing and reduced cholesterol synthesis; stigmasterol also activated the liver X receptor (see LXRA, 602423) in a cell-based reporter assay. Yang et al. (2004) concluded that selected dietary plant sterols disrupt cholesterol homeostasis by affecting 2 critical regulatory pathways of lipid metabolism. INHERITANCE \- Autosomal recessive CARDIOVASCULAR Vascular \- Coronary atherosclerosis \- Atherosclerosis ABDOMEN \- Abdominal pain Liver \- Cholesterol biosynthesis severely depressed Spleen \- Splenomegaly SKELETAL Limbs \- Joint arthralgia \- Arthritis MUSCLE, SOFT TISSUES \- Tendinous and tuberous xanthoma HEMATOLOGY \- Episodic hemolysis \- Chronic hemolytic anemia \- Stomatocytosis \- Reticulocytosis \- Platelet abnormalities \- Giant platelets \- Impaired platelet aggregation \- Bleeding tendencies LABORATORY ABNORMALITIES \- Elevated plasma beta-sitosterol (sitosterolemia or phytosterolemia) \- Hyperapobetalipoproteinemia \- Elevated plasma campesterol \- Elevated plasma stigmasterol \- Microsomal HMG-CoA reductase decreased \- Hypercholesterolemia (elevated plasma cholesterol) MOLECULAR BASIS \- Caused by mutation in the ATP-binding cassette, subfamily G, member 5 gene (ABCG5, 605459.0001 ) \- Caused by mutation in the ATP-binding cassette, subfamily G, member 8 gene (ABCG8, 605460.0001 ) ▲ 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	SITOSTEROLEMIA	c0272281	760	omim	https://www.omim.org/entry/210250	2019-09-22T16:30:31	{"doid": ["0090019"], "omim": ["210250"], "orphanet": ["101022", "2882"], "synonyms": ["Alternative titles", "STSL", "PHYTOSTEROLEMIA"], "genereviews": ["NBK131810"]}
Lichen striatus Other namesBlaschko linear acquired inflammatory skin eruption[1]:776 and Linear lichenoid dermatosis[2] SpecialtyDermatology Lichen striatus is a rare skin condition that is seen primarily in children, most frequently appearing ages 5–15.[3]:226–27 It consists of a self-limiting eruption of small, scaly papules.[4] ## Contents * 1 Symptoms * 2 Diagnosis * 3 Management * 4 See also * 5 References * 6 External links ## Symptoms[edit] Lichen striatus impacts the skin and nails. It is seen as an unbroken or disrupted, linear band consisting of small tan, pink or flesh colored papules. The papules could be smooth, flat topped or scaly. The band of lichen striatus varies from a few millimeters to 1-- 2 cm wide and extends from a few centimeters to the complete length of the extremity. By and large, the papules are unilateral and single on an extremity along the lines of Blaschko. Itching is an accompanying function of the disorder. ## Diagnosis[edit] Diagnosis is based on observing the appearance of the lesions.[5] ## Management[edit] It is self-limiting condition 1.reassurance 2.steroid cream for local application 3.moisturiser lotion ## See also[edit] * Lichen planus * List of cutaneous conditions ## References[edit] 1. ^ Freedberg, et al. (2003). Fitzpatrick's Dermatology in General Medicine. (6th ed.). McGraw-Hill. ISBN 0-07-138076-0. 2. ^ Rapini, Ronald P.; Bolognia, Jean L.; Jorizzo, Joseph L. (2007). Dermatology: 2-Volume Set. St. Louis: Mosby. ISBN 978-1-4160-2999-1. 3. ^ James, William D.; Berger, Timothy G.; et al. (2006). Andrews' Diseases of the Skin: clinical Dermatology. Saunders Elsevier. ISBN 978-0-7216-2921-6. 4. ^ James, William D.; Berger, Timothy G.; Elston, Dirk M. (2011). Andrews' Diseases of the Skin: Clinical Dermatology (11th ed.). London: Elsevier. pp. 223–24. ISBN 978-1437703146. 5. ^ "At a glance - Lichen striatus \| GPonline". ## External links[edit] Classification D * ICD-10: L44.2 * ICD-9-CM: 697.8 * DiseasesDB: 31402 External resources * eMedicine: article/1111723 * New England Journal of Medicine - Images of the Week * v * t * e Papulosquamous disorders Psoriasis Pustular * Generalized pustular psoriasis (Impetigo herpetiformis) * Acropustulosis/Pustulosis palmaris et plantaris (Pustular bacterid) * Annular pustular psoriasis * Localized pustular psoriasis Other * Guttate psoriasis * Psoriatic arthritis * Psoriatic erythroderma * Drug-induced psoriasis * Inverse psoriasis * Napkin psoriasis * Seborrheic-like psoriasis Parapsoriasis * Pityriasis lichenoides (Pityriasis lichenoides et varioliformis acuta, Pityriasis lichenoides chronica) * Lymphomatoid papulosis * Small plaque parapsoriasis (Digitate dermatosis, Xanthoerythrodermia perstans) * Large plaque parapsoriasis (Retiform parapsoriasis) Other pityriasis * Pityriasis rosea * Pityriasis rubra pilaris * Pityriasis rotunda * Pityriasis amiantacea Other lichenoid Lichen planus * configuration * Annular * Linear * morphology * Hypertrophic * Atrophic * Bullous * Ulcerative * Actinic * Pigmented * site * Mucosal * Nails * Peno-ginival * Vulvovaginal * overlap synromes * with lichen sclerosus * with lupus erythematosis * other: * Hepatitis-associated lichen planus * Lichen planus pemphigoides Other * Lichen nitidus * Lichen striatus * Lichen ruber moniliformis * Gianotti–Crosti syndrome * Erythema dyschromicum perstans * Idiopathic eruptive macular pigmentation * Keratosis lichenoides chronica * Kraurosis vulvae * Lichen sclerosus * Lichenoid dermatitis * Lichenoid reaction of graft-versus-host disease This 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	Lichen striatus	c0263374	761	wikipedia	https://en.wikipedia.org/wiki/Lichen_striatus	2021-01-18T18:43:36	{"umls": ["C0263374"], "icd-9": ["697.8"], "icd-10": ["L44.2"], "wikidata": ["Q6543217"]}
Acrofrontofacionasal dysostosis Other namesRichieri-Costa-Colletto syndrome[1] Acrofrontofacionasal dysostosis is an extremely rare disorder, characterized by intellectual disability, short stature, hypertelorism, broad notched nasal tip, cleft lip/palate, postaxial camptobrachypolysyndactyly, fibular hypoplasia, and anomalies of foot structure. An association with mutations in the neuroblastoma amplified sequence gene (NBAS) has been reported.[2] This gene is located on the short arm of chromosome 2. Mutations in this gene have been associated with the Short Stature, Optic Nerve Atrophy, and Pelger-Huet Anomaly syndrome and Infantile Liver Failure Syndrome.[citation needed] ## References[edit] 1. ^ RESERVED, INSERM US14-- ALL RIGHTS. "Orphanet: Acrofrontofacionasal dysostosis". www.orpha.net. Retrieved 17 July 2019. 2. ^ Palagano, Eleonora; Zuccarini, Giulia; Prontera, Paolo; Borgatti, Renato; Stangoni, Gabriela; Elisei, Sandro; Mantero, Stefano; Menale, Ciro; Forlino, Antonella; Uva, Paolo; Oppo, Manuela; Vezzoni, Paolo; Villa, Anna; Merlo, Giorgio R; Sobacchi, Cristina (2018). "Mutations in the Neuroblastoma Amplified Sequence gene in a family affected by Acrofrontofacionasal Dysostosis type 1". Bone. 114: 125–136. doi:10.1016/j.bone.2018.06.013. PMID 29929043. * Richieri-Costa A, Colletto GM, Gollop TR, Masiero D (April 1985). "A previously undescribed autosomal recessive multiple congenital anomalies/mental retardation (MCA/MR) syndrome with fronto-nasal dysostosis, cleft lip/palate, limb hypoplasia, and postaxial poly-syndactyly: acro-fronto-facio-nasal dysostosis syndrome". Am. J. Med. Genet. 20 (4): 631–8. doi:10.1002/ajmg.1320200409. PMID 2986457. ## External links[edit] Classification D * ICD-10: Q75.1 * OMIM: 201180 * MeSH: C538186 C538186, C538186 External resources * Orphanet: 1784 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	Acrofrontofacionasal dysostosis	c1860118	762	wikipedia	https://en.wikipedia.org/wiki/Acrofrontofacionasal_dysostosis	2021-01-18T18:58:36	{"gard": ["484"], "mesh": ["C538186"], "umls": ["C1860118"], "orphanet": ["1784"], "wikidata": ["Q4675773"]}
Wilson-Turner syndrome SpecialtyMedical genetics, pediatrics, psychiatry, rare diseases, metabolic diseases, endocrine diseases, mental diseases Wilson-Turner syndrome (WTS), also known as mental retardation X linked syndromic 6 (MRXS6), and mental retardation X linked with gynecomastia and obesity is a congenital condition characterized by intellectual disability and associated with childhood-onset obesity.[1] It is found to be linked to the X chromosome and caused by a mutation in the HDAC8 gene, which is located on the q arm at locus 13.1. Individuals with Wilson–Turner syndrome have a spectrum of physical characteristics including dysmorphic facial features, hypogonadism, and short stature. Females generally have milder phenotypes than males. This disorder affects all demographics equally and is seen in less than one in one million people.[2] ## Contents * 1 History * 2 Symptoms * 3 Causes * 4 Mechanism * 4.1 Pathophysiology * 5 Diagnosis * 5.1 Techniques * 5.2 Criteria * 5.3 Family and medical history * 6 Screening * 7 Treatment and prognosis * 7.1 Common treatment * 7.2 Long-term complications * 8 Epidemiology * 9 Recent research * 10 See also * 11 References * 12 External links ## History[edit] The study of X-linked mental retardation began in 1943 when Martin and Bell reported a family exhibiting sex-linked mental retardation.[3] However, this syndrome was not recognized until 1991. Wilson studied 14 males from three successive generations that presented hypogonadism, mental retardation, gynecomastia, and short stature, among other symptoms.[4] Eventually, this disorder was ruled distinct from a syndrome presented by Prader and Willi (Prader-Willi syndrome) because of its mode of inheritance, gynecomastia, and the presence of small hands and feet.[5] However, there is some speculation that this syndrome is in the same spectrum as the Cornelia de Lange syndrome.[6] ## Symptoms[edit] The most notable features of Wilson-Turner syndrome are intellectual disability, obesity, hypogonadism, gynecomastia, and distinct facial features. All of the symptoms are chronic. Affected females are known to have less severe signs and symptoms than males. Female carriers of the disorder may have mild or no symptoms. * Intellectual disability is the limitation in an individual's mental functioning and skills. Patients with Wilson-Turner syndrome have mental disabilities generally ranging from mild to severe, more frequently the former.[7] This symptom often coincides with delays in speech development and the occurrence of mood swings.[8] Most males were noted to have a quiet and a cheerful disposition. However, individuals who displayed aggression and became easily upset were also seen. Children display delays in speech development often combined with excessive drooling and low voice tones. Some of the studied male patients had speech impairments ranging from little or no speech to minor stuttering.[7] * Obesity is the accumulation of excess fat on the body. Individuals with Wilson-Turner syndrome are characterized as having truncal obesity, meaning the fat has accumulated in the middle. Truncal obesity is often related to heart disease, kidney disease, and a lowered blood immune system.[9] Truncal obesity in this disorder becomes more apparent around the age of puberty.[7] * Tapered fingers, in which one end of the finger is diminished in thickness, causing the ends of the fingers to appear pointed. This deformity is not debilitating in any particular manner. In addition to tapered fingers, both hands and feet tend to be small. Some males were observed to have pes planus, also known as flat feet.[7] * Hypogonadism is a condition in which the gonads have a decrease in function. This condition may result from the lack of sex hormone synthesis, such as androgen and estrogen. Hormones produced by the gonads may also decrease.[10] Hypogonadism also influences the onset of other conditions of Wilson-Turner syndrome, such as gynecomastia and decreased testes size in males.[11] It can also cause short stature in men and women. In addition to little genital development, pubic and body hair are scant.[7] * Some of the facial features that are associated with Wilson-Turner syndrome include small head circumferences, high foreheads, prominent ears, and noses with flattened bridges. There have been cases of moderately high palates. Low muscle tone and subcutaneous swelling in facial tissue has also been noted. Thick eyebrows are also common.[7] However, there have been reported cases where individuals had none of the mentioned facial features, which shows phenotypic abnormalities which have possible environmental influences.[12] * Gynecomastia is a non-cancerous increase in male breast tissue.[13] It is believed that disturbances in the endocrine system lead to an increase in estrogen and androgen hormones which cause the development of gynecomastia. A key feature of gynecomastia is rubbery or firm glandular subcutaneous chest tissue that is palpated under the areola of the nipple, instead of the soft fatty tissue.[14] There can also be in increase in the diameter of the areola asymmetry in the chest tissue.[15] The breast enlargement can occur in one or both side.[16] Similar to truncal obesity, gynecomastia becomes apparent around the age of puberty.[7] ## Causes[edit] The only known cause of this disorder is the mutation on the HDAC8 gene, which is located at Xq13.1. This disorder displays X-linked inheritance. ## Mechanism[edit] ### Pathophysiology[edit] The primary symptoms of Wilson-Turner Syndrome is believed to result from an improperly developed histone deacetylase 8\. This enzyme is coded by the HDAC8 gene. The identified mutation in the HDAC8 gene leads to a version of histone deacetylase 8 that is missing a segment. Histone deacetylase 8 is believed to be a regulator of the cohesion complex, playing a role in stabilizing the cell’s genetic information, repairing damaged DNA, and controlling gene activity. This abnormally shortened protein alters gene regulations during the individual’s normal development. Some of the effected normal development lies in the endocrine system. Males will have more estrogen and androgen than normal, leading to enlarged hypogonadism and gynecomastia. Other abnormal development is related to general mental capacity.[6] HDACs are known to be associated with human brain development disorders.[1] HDAC8, in particular, represses transcription factors in neural crest cells to control various patterns of the skull.[1] This contributes to the various forms of facial deformities in individuals with Wilson-Turner Syndrome. Some of the facial deformities caused by the HDAC8 include prominent supraorbital ridges and high cheekbones. Researchers also contribute the error in the HDAC8 gene to obesity. Since the HDAC family proteins are involved in changes in the gene expression in the hypothalamus, it is also believed that the individual’s metabolism conditions are altered.[17] ## Diagnosis[edit] ### Techniques[edit] The diagnosis of Wilson–Turner syndrome is based upon a clinical evaluation, a detailed patient history, and identification of characteristic features. Molecular genetic testing for mutations in the HDAC8 gene is now available to confirm the diagnosis. ### Criteria[edit] The Wilson–Turner syndrome is characterized by mild to moderate range of intellectual disability, obesity, tapered fingers, and mood swings. Males also suffer from gynecomastia and hypogonadism. In order to be diagnosed with Wilson-Turner Syndrome, male patients must suffer from intellectual disability, obesity, and gynecomastia. Females do not necessarily have to have noticeable phenotype but can be diagnosed with this disorder by studying her family history and identifying others with the disorder. It has been noted that children with Wilson-Turner Syndrome will display speech development delay and excessive drooling. Males can be confirmed by testing androgen levels.[8] Female carriers will show silencing of the gene a complex X inactivation.[18] ### Family and medical history[edit] Family medical history is studied in depth due to its X-linked inheritance. The families that were studied and diagnosed with Wilson-Turner Syndrome have shown X-linked recessive pedigree pattern. This disorder only have been identified in two families, thus there is still ongoing studies concerning other inherited factors that may contribute to this disorder.[18] ## Screening[edit] Screening methods are mostly done for females to determine if they are carriers. Males do not have to be tested because those with the disorder will show symptoms close to the time they are born because the disorder is inherited from the X chromosome. Females can be tested if they are carriers by performing a X chromosome inactivation analysis on DNA isolated from the peripheral lymphocytes. The CAG repeat in this section must be amplified and methylated DNA must be sorted from unmethylated DNA with PCR. Carrier females will show skewed X-inactivation pattern (skewing close to 100%) with the mutated allele inactivated. This indicates a selection against cells with an active X chromosome with the mutated HDAC8 gene.[1] ## Treatment and prognosis[edit] ### Common treatment[edit] There is no known cure available for Wilson-Turner syndrome. Instead, treatment options are available to fight individual symptoms. For obesity, a nutritional diet manipulation is combined with an exercise regimen that has a greater energy expenditure than intake. For hypogonadism, testosterone replacement is done. For gynecomastia, weight loss using similar methods for obesity is prescribed. However, if the individual finds their increased breast tissue psychologically distressing or too severe, reduction mammaplasty is done. Currently, researchers are investigating therapies using antiestrogens and aromatase inhibitors to treat persistent pubertal gynecomastia.[19] ### Long-term complications[edit] Unlike Borjeson-Forssman-Lehmann syndrome, a disorder that was determined to be very similar to WTS, the individuals with Wilson–Turner syndrome do not develop cataracts or hypermetropia later in life.[20] By far, the most debilitating part of this disorder is intellectual disability. Many of the other symptoms are more easily managed through hormone treatment, proper diet and exercise, and speech therapy. ## Epidemiology[edit] This disorder affects all demographics equally. The two families that were studied are of European ancestry. Wilson–Turner syndrome is considered to be a rare disease because it affects one individual out of one million.[2] ## Recent research[edit] In 2012, a study of a five-generation Dutch family consisting of seven males and seven females with Wilson-Turner syndrome. These individuals had some characteristics that differed from the stated phenotype mentioned by Wilson. These individuals have a larger stature, head, and chin, in addition to coarse facial features. Unlike the females in Wilson's study, these females showed signs of being affected, although less severe than their male counterparts. None of the men could live on their own. Studies verified that the phenotype of the disorder range on a large scale and can affect everyone differently. This research group also used next-generation sequencing of the X chromosome exome to identify the HDAC8 gene mutation[1] There is also ongoing research to determine the cause of the decreased or low androgen levels. It is studying the possible disturbance of the hypothalamic-pituitary-gonadal axis because of the low levels of androgen are combined with normal levels of FSH and LH.[7] ## See also[edit] * Prader–Willi syndrome * Fragile X syndrome * Börjeson-Forssman-Lehmann syndrome * Bardet–Biedl syndrome ## References[edit] 1. ^ a b c d e Harakalova, Magdalena; Boogaard, Marie-Jose van den; Sinke, Richard; Lieshout, Stef van; Tuil, Marc C. van; Duran, Karen; Renkens, Ivo; Terhal, Paulien A.; Kovel, Carolien de (2012-08-01). "X-exome sequencing identifies a HDAC8 variant in a large pedigree with X-linked intellectual disability, truncal obesity, gynaecomastia, hypogonadism and unusual face". Journal of Medical Genetics. 49 (8): 539–543. doi:10.1136/jmedgenet-2012-100921. ISSN 1468-6244. PMID 22889856. 2. ^ a b "Wilson-Turner Syndrome disease: Malacards - Research Articles, Symptoms, Drugs, Genes, Clinical Trials". www.malacards.org. Retrieved 2015-10-26. 3. ^ "Invited Editorial: X-linked mental retardation: In pursuit of a gene map". ResearchGate. Retrieved 2015-11-01. 4. ^ Wilson, Meredith; Mulley, John; Gedeon, Agi; Robinson, Hazel; Turner, Gillian (1991-09-15). "New X-linked syndrome of mental retardation, gynecomastia, and obesity is linked to DXS255". American Journal of Medical Genetics. 40 (4): 406–413. doi:10.1002/ajmg.1320400405. ISSN 1096-8628. PMID 1746601. 5. ^ Vasquez, Silvia B.; Hurst, Daniel L.; Sotos, Juan F. (January 1979). "X-linked hypogonadism, gynecomastia, mental retardation, short stature, and obesity—a new syndrome". The Journal of Pediatrics. 94 (1): 56–60. doi:10.1016/s0022-3476(79)80350-9. PMID 758423. 6. ^ a b "HDAC8 gene". Genetics Home Reference. 2015-10-19. Retrieved 2015-10-26. 7. ^ a b c d e f g h Stevenson, Roger E.; Schwartz, Charles E.; Rogers, R. Curtis; Rogers, Richard Curtis (2012-07-12). Atlas of X-Linked Intellectual Disability Syndromes. OUP USA. ISBN 9780199811793. 8. ^ a b "Börjeson-Forssman-Lehman Syndrome - NORD (National Organization for Rare Disorders)". NORD (National Organization for Rare Disorders). Retrieved 2015-11-01. 9. ^ "Onion River Chiropractic - Chiropractor In Winooski, VT USA :: Truncal Obesity and Health". onionriverchiro.com. Retrieved 2015-11-02. 10. ^ "Hypogonadism". Healthline. 2012-08-15. Retrieved 2015-10-26. 11. ^ "What is Male Hypogonadism? Learn Hormone.org's Hypogonadism Definition". www.hormone.org. Retrieved 2015-10-26. 12. ^ Juberg, R. C.; Marsidi, I. (1980-09-01). "A new form of X-linked mental retardation with growth retardation, deafness, and microgenitalism". American Journal of Human Genetics. 32 (5): 714–722. ISSN 0002-9297. PMC 1686104. PMID 6107045. 13. ^ Niewoehner, Catherine B.; Schorer, Anna E. (2008-03-27). "Gynaecomastia and breast cancer in men". BMJ. 336 (7646): 709–713. doi:10.1136/bmj.39511.493391.BE. ISSN 0959-8138. PMC 2276281. PMID 18369226. 14. ^ Narula, Harmeet S.; Carlson, Harold E. (Nov 2014). "Gynaecomastia—pathophysiology, diagnosis and treatment". Nature Reviews Endocrinology. 10 (11): 684–698. doi:10.1038/nrendo.2014.139. PMID 25112235. 15. ^ Cordova, Adriana; Moschella, Francesco (2008). "Algorithm for clinical evaluation and surgical treatment of gynaecomastia". Journal of Plastic, Reconstructive & Aesthetic Surgery. 61 (1): 41–49. doi:10.1016/j.bjps.2007.09.033. PMID 17983883. 16. ^ Devalia, H.L.; Layer, G.T. (Apr 2009). "Current concepts in gynaecomastia". The Surgeon. 7 (2): 114–119. doi:10.1016/s1479-666x(09)80026-7. PMID 19408804. 17. ^ Funato, Hiromasa; Oda, Satoko; Yokofujita, Junko; Igarashi, Hiroaki; Kuroda, Masaru (2011-04-15). "Fasting and High-Fat Diet Alter Histone Deacetylase Expression in the Medial Hypothalamus". PLoS ONE. 6 (4): e18950. doi:10.1371/journal.pone.0018950. PMC 3078138. PMID 21526203. 18. ^ a b "Disease: 309585 - GenePeeks Research". research.genepeeks.com. Retrieved 2015-11-01. 19. ^ "Wilson-Turner X-linked mental retardation syndrome — CheckOrphan". www.checkorphan.org. Retrieved 2015-10-26. 20. ^ Frézal, J. (1992-12-01). "New X-linked syndrome of mental retardation, gynecomastia, and obesity is linked to DXS255". American Journal of Medical Genetics. 44 (6): 854–855. doi:10.1002/ajmg.1320440637. ISSN 0148-7299. PMID 1481864. ## External links[edit] Classification D * OMIM: 309585 External resources * Orphanet: 3459 [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	Wilson–Turner syndrome	c1839736	763	wikipedia	https://en.wikipedia.org/wiki/Wilson%E2%80%93Turner_syndrome	2021-01-18T18:43:54	{"gard": ["5579"], "mesh": ["C536708"], "umls": ["C1839736"], "orphanet": ["3459"], "wikidata": ["Q8023321"]}
A number sign (#) is used with this entry because of evidence that Meckel syndrome-12 (MKS12) is caused by compound heterozygous mutation in the KIF14 gene (611279) on chromosome 1q31. One such family has been reported. For a general phenotypic description and a discussion of genetic heterogeneity of Meckel syndrome, see MKS1 (249000). Clinical Features Filges et al. (2014) reported 2 sisters, conceived by unrelated Caucasian parents, with a lethal fetal congenital anomaly syndrome. Prenatal ultrasound showed oligohydramnios, intrauterine growth retardation with microcephaly, complex brain malformations, and renal anomalies. The pregnancies were terminated, and autopsy confirmed the ultrasound findings. Features included cerebral and cerebellar hypoplasia, renal agenesis or hypoplasia, ureteral hypoplasia, uterine hypoplasia, and flexion arthrogryposis. One fetus also had agenesis of the corpus callosum, arhinencephaly, and vaginal atresia, whereas the other had agenesis of the occipital lobes. Secondary facial features resulting from oligohydramnios were also present. Inheritance The transmission pattern of MKS12 in the family reported by Filges et al. (2014) was consistent with autosomal recessive inheritance. Molecular Genetics In 2 sib fetuses with MKS12, Filges et al. (2014) identified compound heterozygous truncating mutations in the KIF14 gene (611279.0001 and 611279.0002). The mutations, which were found by whole-exome sequencing, segregated with the disorder in the family. Both mutations were predicted to result in nonsense-mediated mRNA decay, consistent with a complete loss of function. Additional functional studies were not performed, but reexamination of histologic brain and kidney sections from 1 of the affected fetuses showed a high number of binucleated cells compared to controls, suggesting disruption of cell cycle progression and failure of cytokinesis. Animal Model Fujikura et al. (2013) described a spontaneous mouse mutant, 'laggard' (lag), which was characterized by growth retardation, microcephaly, flat head, and motor impairment. Positional cloning studies showed that the lag mouse resulted from a homozygous splice site mutation in the Kif14 gene, which caused loss of the wildtype protein. Homozygous mutant mice showed progressive severe ataxia, tremors, and muscle weakness, and died within 3 weeks of birth. Neuropathologic examination showed that the brains of mutant mice were small compared to wildtype, with dysgenesis of the cerebral and cerebellar cortices and the hippocampus, and severe hypomyelination of the brain and spinal cord. Gene expression studies showed a dramatic reduction in the expression of genes involved in myelination and maturation of oligodendrocytes. Mutant mice also displayed a dramatic increase in neuronal apoptosis. INHERITANCE \- Autosomal recessive GROWTH Other \- Intrauterine growth retardation (IUGR) HEAD & NECK Head \- Microcephaly Face \- Sloping forehead \- Micrognathia (1 patient) Ears \- Low-set ears (1 patient) Nose \- Anteverted nose (1 patient) \- Broad nasal root (1 patient) Mouth \- Bifid uvula (1 patient) GENITOURINARY Internal Genitalia (Female) \- Uterine hypoplasia \- Vaginal atresia (1 patient) Kidneys \- Renal agenesis \- Renal hypoplasia \- Cystic dysplasia Ureters \- Ureteral hypoplasia SKELETAL \- Arthrogryposis Feet \- Rocker bottom feet \- Prominent heels NEUROLOGIC Central Nervous System \- Cerebral hypoplasia \- Cerebellar hypoplasia \- Agenesis of the corpus callosum \- Agenesis of the occipital lobes (1 patient) \- Arhinencephaly (1 patient) PRENATAL MANIFESTATIONS Amniotic Fluid \- Oligohydramnios MISCELLANEOUS \- Two fetuses from terminated pregnancies in 1 family have been reported (last curated March 2015) MOLECULAR BASIS \- Caused by mutation in the kinesin family member 14 gene (KIF14, 611279.0001 ) ▲ 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	MECKEL SYNDROME 12	c4015701	764	omim	https://www.omim.org/entry/616258	2019-09-22T15:49:28	{"omim": ["616258"], "orphanet": ["439897"], "synonyms": []}
## Summary ## Diagnosis ## Clinical Characteristics ## Differential Diagnosis ## Management [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	Pancreatitis Overview	None	765	gene_reviews	https://www.ncbi.nlm.nih.gov/books/NBK190101/	2021-01-18T21:04:53	{"synonyms": []}
Not to be confused with arthritis. Arteritis Artery (normal) SpecialtyRheumatology Arteritis is the inflammation of the walls of arteries,[1] usually as a result of infection or autoimmune response. Arteritis, a complex disorder, is still not entirely understood.[2] Arteritis may be distinguished by its different types, based on the organ systems affected by the disease.[2] A complication of arteritis is thrombosis, which can be fatal. Arteritis and phlebitis are forms of vasculitis. ## Contents * 1 Signs and Symptoms * 2 Diagnosis * 2.1 Types * 2.1.1 Giant cell arteritis * 2.1.2 Takayasu arteritis * 2.1.3 Temporal arteritis * 3 Treatment * 3.1 Medications * 4 References * 5 External links ## Signs and Symptoms[edit] Symptoms of general arteritis may include:[3] * Inflammation * Fever * Increased production of red blood cells (erythrocytes) * Limping * Reduced pulse ## Diagnosis[edit] Diagnosis of arteritis is based on unusual medical symptoms.[4] Similar symptoms may be caused by a number of other conditions, such as Ehlers-Danlos syndrome and Marfan syndrome (both heritable disorders of connective tissue), tuberculosis, syphilis, spondyloarthropathies, Cogans’ syndrome, Buerger's, Behcet's, and Kawasaki disease.[4] Various imaging techniques may be used to diagnose and monitor disease progression. Imaging modalities may include direct angiography, magnetic resonance angiography, and ultrasonography.[4] Angiography is commonly used in the diagnosis of Takayasu arteritis,[4] especially in the advanced stages of the disease, when arterial stenosis, occlusion, and aneurysms may be observed.[4] However, angiography is a relatively invasive investigation, exposing patients to large doses of radiation,[4] so is not recommended for routine, long-term monitoring of disease progression in patients with Takayasu arteritis.[4] Computed tomography angiography can determine the size of the aorta and its surrounding branches, and can identify vessel wall lesions in middle to late stages of arteritis.[4] CTA can also show the blood flow within the blood vessels.[4] Like angiography, CTA exposes patients to high dosages of radiation.[4] Magnetic resonance angiography is used to diagnose Takayasu arteritis in the early stages, showing changes such as the thickening of the vessel wall.[4] Even small changes may be measured, making MRA a useful tool for monitoring disease progression without exposing patients to the radiation of direct angiography or CTA.[4] MRA is an expensive investigation, and shows calcification of the aorta and distal branches less clearly than other imaging methods.[4] Ultrasonography is an ideal method of diagnosing patients in early stages of arteritis when inflammation in the vessel walls occurs.[4] It can also show the blood flow within the blood vessels.[4] Ultrasonography is a popular first-line investigation for diagnosis because it is relatively quick, cheap, noninvasive, and does not expose patients to radiation.[4] It is also used for long-term monitoring of disease progression in Takayasu arteritis. Not all vascular lesions are visible on ultrasound, and the accuracy of the scan depends, to some extent, on the person reading the scan, as the results are observed in real time.[4] ### Types[edit] Arteritis may be primary or secondary to some other disease process. The primary types are: Comparison of major types of arteritis Arteritis Affected organs Histopathology Takayasu arteritis Large vessels,[3] including aorta and arch branches[5] Histiocytes, giant cells[5] Giant cell arteritis, also often called temporal arteritis (although they differ slightly) Superficial temporal artery, other medium- and large-sized vessels,[6] e.g. those supplying the head, eyes and optic nerves Lymphocytes, macrophages, and multinucleated giant cells[6] Polyarteritis nodosa Medium-sized vessels, CNS, PNS damage, kidneys, gastrointestinal tract, skeletal muscle, heart[5] Neutrophils, fibrinoid necrosis[5] An example of a secondary arteritis is arteritis caused by infection with the fungal pathogen Candida albicans.[7] #### Giant cell arteritis[edit] Giant cell arteritis contains two different types of arteritides that are almost indistinguishable from one another.[2] It includes two types, temporal arteritis and Takayasu arteritis. Both types contain an occupancy of medium- and larger-sized arteries which are categorized based on the infiltration of the giant cells.[2] #### Takayasu arteritis[edit] This type of arteritis is most common in females, with a median age of 25 years.[3] Takayasu arteritis is more common in women of Asian descent who are in their reproductive years.[3] However, over the past decades, its incidence in Africa, Europe, and North America has been increasing.[3] Takayasu arteritis is an inflammatory disease that mainly affects the larger vessels such as the aorta and its surrounding branches.[3] Research focused on Takayasu arteritis in the western parts of the world remains limited. An estimation suggests that, each year, the number of cases per million people is 2.6.[3] #### Temporal arteritis[edit] Temporal arteritis, the second type of giant cell arteritis, is also a chronic, inflammatory disease involving mid- to large-sized arteries.[8] Temporal arteritis has a higher incidence in people of Scandinavian descent.[8] However, the incidence rate differs based on population, region and races.[8] Temporal arteritis is not uncommon in North America.[8] The incidence rate is around 0.017% for individuals over 50 years of age.[8] Symptoms of temporal arteritis are classified as specific and nonspecific.[8] Nonspecific symptoms:[8] * Headache * Low grade fever * Sweating * Anorexia (loss of appetite) * Weight loss * General malaise Specific symptoms:[8] * Claudication of the jaw * Engorged, tender vessels Specific symptoms usually develop in the advanced stages of temporal arteritis.[8] Polyarteritis nodosa of unknown mechanism can cause testicular pain. It is often associated with aneurysms and Hepatitis B. ## Treatment[edit] ### Medications[edit] The first-line treatment for arteritis is oral glucocorticoid (steroid) medication, such as prednisone, taken daily for a period of three months.[3] After this initial phase, the medication may be reduced in dose or frequency, e.g. every other day, if possible.[3] If the disease worsens with the new treatment schedule, a cytotoxic medication may be given, in addition to the glucocorticoid.[3] Commonly used cytotoxic agents include azathioprine, methotrexate, or cyclophosphamide.[3] The dose of glucocorticoid medication may be decreased if response to treatment is good.[3] This medication may be reduced gradually once the disease becomes inactive, slowly tapering the dose (to allow the body time to adjust) until the medication may be stopped completely.[3] Conversely, if the disease remains active, the medication will need to be increased.[3] After six months, if the medication cannot be reduced in frequency to alternate days, or if in 12 months the medications cannot be stopped completely, then treatment is deemed to have failed.[3] Pulsed therapy is an alternative method of administering the medications above, using much higher doses over a short period of time (a pulse), to reduce the inflammation within the arteries. Methylprednisolone, a glucocorticoid, is often used for pulse therapy; cyclophosphamide is an alternative. This method has been shown to be successful for some patients.[9] Immunosuppressive pulse therapy, such as with cyclophosphamide, has also demonstrated relief of symptoms associated with arteritis.[10] ## References[edit] 1. ^ "Arteritis" at Dorland's Medical Dictionary 2. ^ a b c d Hollier, L. H. (1 January 1989). "Arteritis". Perspectives in Vascular Surgery and Endovascular Therapy. 2 (1): 1–8. doi:10.1177/153100358900200101. 3. ^ a b c d e f g h i j k l m n o Kerr GS, Hallahan CW, Giordano J, Leavitt RY, Fauci AS, Rottem M, Hoffman GS (June 1994). "Takayasu arteritis". Ann. Intern. Med. 120 (11): 919–29. doi:10.7326/0003-4819-120-11-199406010-00004. PMID 7909656. S2CID 21784938. 4. ^ a b c d e f g h i j k l m n o p q Wen, Dan; Du, Xin; Ma, Chang-Sheng (1 December 2012). "Takayasu Arteritis: Diagnosis, Treatment and Prognosis". International Reviews of Immunology. 31 (6): 462–473. doi:10.3109/08830185.2012.740105. PMID 23215768. S2CID 5434700. 5. ^ a b c d Stevens & Lowe: Pathology. At Fleshandbones.com 6. ^ a b eMedicine Specialties > Temporal Arteritis Author: Christopher H Lee, MD. Coauthor(s): Jean Marie Hammel, MD. Updated: Sep 8, 2009 7. ^ Nagi-Miura, N; Harada, T; Shinohara, H; et al. (June 2006). "Lethal and severe coronary arteritis in DBA/2 mice induced by fungal pathogen, CAWS, Candida albicans water-soluble fraction". Atherosclerosis. 186 (2): 310–320. doi:10.1016/j.atherosclerosis.2005.08.014. PMID 16157343. 8. ^ a b c d e f g h i Chen, Chun-Hsiung; Kung, Shih-Ya; Tsai, Ying-Yang; Liao, Hsien-Tzung; Chou, Chung-Tei; Huang, De-Feng (2005). "Temporal Arteritis". Journal of the Chinese Medical Association. 68 (7): 333–335. doi:10.1016/S1726-4901(09)70170-4. PMID 16038374. 9. ^ Chevalet, P; Barrier, J. H.; Pottier, P; Magadur-Joly, G; Pottier, M. A.; Hamidou, M; Planchon, B; El Kouri, D; Connan, L; Dupond, J. L.; De Wazieres, B; Dien, G; Duhamel, E; Grosbois, B; Jego, P; Le Strat, A; Capdeville, J; Letellier, P; Agron, L (2000). "A randomized, multicenter, controlled trial using intravenous pulses of methylprednisolone in the initial treatment of simple forms of giant cell arteritis: A one year follow-up study of 164 patients". The Journal of Rheumatology. 27 (6): 1484–91. PMID 10852275. 10. ^ Bose, P. (29 November 2012). "Takayasu's Arteritis". Journal of Neurology, Neurosurgery & Psychiatry. 83 (Suppl 2): A1. doi:10.1136/jnnp-2012-304200a.2. S2CID 219209165. ## External links[edit] Classification D * ICD-10: I77.6, M31 * ICD-9-CM: 447.6 * MeSH: D001167 * DiseasesDB: 13750 * v * t * e Cardiovascular disease (vessels) Arteries, arterioles and capillaries Inflammation * Arteritis * Aortitis * Buerger's disease Peripheral artery disease Arteriosclerosis * Atherosclerosis * Foam cell * Fatty streak * Atheroma * Intermittent claudication * Critical limb ischemia * Monckeberg's arteriosclerosis * Arteriolosclerosis * Hyaline * Hyperplastic * Cholesterol * LDL * Oxycholesterol * Trans fat Stenosis * Carotid artery stenosis * Renal artery stenosis Other * Aortoiliac occlusive disease * Degos disease * Erythromelalgia * Fibromuscular dysplasia * Raynaud's phenomenon Aneurysm / dissection / pseudoaneurysm * torso: Aortic aneurysm * Abdominal aortic aneurysm * Thoracic aortic aneurysm * Aneurysm of sinus of Valsalva * Aortic dissection * Aortic rupture * Coronary artery aneurysm * head / neck * Intracranial aneurysm * Intracranial berry aneurysm * Carotid artery dissection * Vertebral artery dissection * Familial aortic dissection Vascular malformation * Arteriovenous fistula * Arteriovenous malformation * Telangiectasia * Hereditary hemorrhagic telangiectasia Vascular nevus * Cherry hemangioma * Halo nevus * Spider angioma Veins Inflammation * Phlebitis Venous thrombosis / Thrombophlebitis * primarily lower limb * Deep vein thrombosis * abdomen * Hepatic veno-occlusive disease * Budd–Chiari syndrome * May–Thurner syndrome * Portal vein thrombosis * Renal vein thrombosis * upper limb / torso * Mondor's disease * Paget–Schroetter disease * head * Cerebral venous sinus thrombosis * Post-thrombotic syndrome Varicose veins * Gastric varices * Portacaval anastomosis * Caput medusae * Esophageal varices * Hemorrhoid * Varicocele Other * Chronic venous insufficiency * Chronic cerebrospinal venous insufficiency * Superior vena cava syndrome * Inferior vena cava syndrome * Venous ulcer Arteries or veins * Angiopathy * Macroangiopathy * Microangiopathy * Embolism * Pulmonary embolism * Cholesterol embolism * Paradoxical embolism * Thrombosis * Vasculitis Blood pressure Hypertension * Hypertensive heart disease * Hypertensive emergency * Hypertensive nephropathy * Essential hypertension * Secondary hypertension * Renovascular hypertension * Benign hypertension * Pulmonary hypertension * Systolic hypertension * White coat hypertension Hypotension * Orthostatic hypotension * v * t * e Systemic connective tissue disorders General Systemic lupus erythematosus * Drug-induced SLE * Libman–Sacks endocarditis Inflammatory myopathy * Myositis * Dermatopolymyositis * Dermatomyositis/Juvenile dermatomyositis * Polymyositis* Inclusion body myositis Scleroderma * Systemic scleroderma * Progressive systemic sclerosis * CREST syndrome * Overlap syndrome / Mixed connective tissue disease Other hypersensitivity/autoimmune * Sjögren syndrome Other * Behçet's disease * Polymyalgia rheumatica * Eosinophilic fasciitis * Eosinophilia–myalgia syndrome * fibrillin * Marfan syndrome * Congenital contractural arachnodactyly [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	Arteritis	c0003860	766	wikipedia	https://en.wikipedia.org/wiki/Arteritis	2021-01-18T19:10:34	{"mesh": ["D001167"], "umls": ["C0003860"], "icd-9": ["447.6"], "icd-10": ["I77.6"], "wikidata": ["Q1751810"]}
Esophageal food bolus obstruction Other namesSteakhouse syndrome[1] Endoscopic image of patient with esophageal food bolus obstruction due to a grape in the setting of eosinophilic esophagitis SpecialtyEmergency medicine, general surgery, gastroenterology An esophageal food bolus obstruction is a medical emergency caused by the obstruction of the esophagus by an ingested foreign body. It is usually associated with diseases that may narrow the lumen of the esophagus, such as eosinophilic esophagitis, Schatzki rings, peptic strictures, webs, or cancers of the esophagus; rarely it can be seen in disorders of the movement of the esophagus, such as nutcracker esophagus. While some esophageal food boli can pass by themselves or with the assistance of medications, some require the use of endoscopy to push the obstructing food into the stomach, or remove it from the esophagus. The use of glucagon, while common, has not been found to be useful.[2] ## Contents * 1 Signs and symptoms * 2 Risk factors * 3 Treatment * 3.1 Conservative * 3.2 Endoscopic * 4 References * 5 External links ## Signs and symptoms[edit] Many foods can lodge themselves in the esophagus, but the most common are meats such as steak, poultry, or pork[3] leading to the colourful description of the phenomenon as steakhouse syndrome.[1] People with food bolus obstruction typically display acute dysphagia (difficulty swallowing), often to the point that they cannot even swallow their saliva, leading to drooling. They may also suffer from chest pain, neck pain, regurgitation of food, or painful swallowing (odynophagia).[4] Patients with esophageal food boluses are also at risk of complications, such as perforation of the esophagus, and aspiration into the lungs. As a result, urgent treatment of patients with high-risk features, or a lengthy duration of symptoms, is recommended.[5] ## Risk factors[edit] Endoscopic image of a Schatzki ring which is a common cause of esophageal food bolus obstruction Food bolus obstruction is most commonly caused by Schatzki rings, which are mucosal rings of unknown cause in the lower esophagus.[1][6] Foodstuff jams into the esophagus due to the narrowing caused by the ring. An increasingly commonly recognized cause for esophageal food bolus obstruction is eosinophilic esophagitis, which is an inflammatory disorder of the mucosa of the esophagus, of unknown cause.[7][8] Many alterations caused by eosinophilic esophagitis can predispose to food boluses; these include the presence of multiple rings and narrowing of the lumen.[9] When considering esophageal dilation to treat a patient with food bolus obstruction, care must be made to look for features of eosinophilic esophagitis, as these patients are at a higher risk of dilation-associated complications.[10] Other conditions that predispose to food bolus obstructions are esophageal webs, tracheoesophageal fistula/esophageal atresia (TOF/OA) and peptic strictures.[7] Food boluses are common in the course of illness in patients with esophageal cancer but are more difficult to treat as endoscopy to push the bolus is less safe. Patients with esophageal self-expandable metallic stents may present with food boluses lodged within the stent lumen. Rarely disorders of movement of the esophagus, such as nutcracker esophagus, can predispose to food bolus obstruction.[11] ## Treatment[edit] ### Conservative[edit] In an emergency room setting, someone with food bolus obstruction may be observed for a period to see if the food bolus passes spontaneously. This may be encouraged by giving carbonated drinks that release gas such as Coca-Cola, which may dislodge the food.[12] While glucagon has been used in those with esophageal food bolus obstruction, evidence as of 2019 does not support its effectiveness, and its use may result in more side effects.[2] Older reviews considered it an acceptable option as long it does not lead to delays in arranging other treatments.[5][13] Other medications (hyoscine butylbromide, benzodiazepines and opioids) have been studied but the evidence is limited.[12] Hyoscine butylbromide (also known as Buscopan) is used intravenously as a treatment in some cases, although there is a small risk of serious side effects in people who may have underlying cardiac issues such as high blood pressure, tachycardia, or heart disease.[14] Historical treatment of food bolus obstruction included administration of proteolytic enzymes (such as meat tenderizers) with the purpose of degrading the meat that was blocked; however, it is possible that these methods may increase the risk of perforation of the esophagus.[15] Other modalities rarely used now include removal of boluses using catheters,[16][unreliable medical source?] and the use of large-bore tubes inserted into the esophagus to forcefully lavage it.[17][unreliable medical source?] ### Endoscopic[edit] The Roth net can be inserted through the endoscope to remove pieces of the obstructed food. The standard treatment of food bolus obstruction is the use of endoscopy or fibre-optic cameras inserted by mouth into the esophagus.[5] Endoscopes can be used to diagnose the cause of the food bolus obstruction, as well as to remove the obstruction. Traditional endoscopic techniques involved the use of an overtube, a plastic tube inserted into the esophagus prior to the removal of the food bolus, in order to reduce the risk of aspiration into the lungs at the time of endoscopy.[7] However, the "push technique", which involves insufflating air into the esophagus, and gently pushing the bolus toward the stomach instead, has emerged as a common and safe way of removing the obstruction.[7][18] Other tools may be used to remove food boluses. The Roth Net is a mesh net that can be inserted through the endoscope, and opened and closed from the outside; it can be used to retrieve pieces of obstructed food. Snares, which are normally used to remove polyps can be used to macerate the food causing the obstruction. Dormia baskets, which are metal baskets used to remove stones from the common bile duct in a procedure known as endoscopic retrograde cholangiopancreatography, can be opened and closed from the outside in a similar manner to macerate food and facilitate removal. Forceps used for biopsies can also be employed in a similar manner.[18] ## References[edit] 1. ^ a b c Stadler, J.; A. H. Hölscher; H. Feussner; J. Dittler; J. R. Siewert (December 1989). "The "steakhouse syndrome". Primary and definitive diagnosis and therapy". Surgical Endoscopy. 3 (4): 195–8. doi:10.1007/BF02171545. PMID 2623551. 2. ^ a b Peksa, GD; DeMott, JM; Slocum, GW; Burkins, J; Gottlieb, M (April 2019). "Glucagon for Relief of Acute Esophageal Foreign Bodies and Food Impactions: A Systematic Review and Meta-Analysis". Pharmacotherapy. 39 (4): 463–472. doi:10.1002/phar.2236. PMID 30779190. 3. ^ Baraka A, Bikhazi G (1975). "Oesophageal foreign bodies". British Medical Journal. 1 (5957): 561–3. doi:10.1136/bmj.1.5957.561. PMC 1672660. PMID 1139150. 4. ^ Nandi P, Ong GB (1978). "Foreign body in the oesophagus: review of 2394 cases". The British Journal of Surgery. 65 (1): 5–9. doi:10.1002/bjs.1800650103. PMID 623968. 5. ^ a b c Ikenberry, Steven O.; Jue, Terry L.; Anderson, Michelle A.; Appalaneni, Vasundhara; Banerjee, Subhas; Ben-Menachem, Tamir; Decker, G. Anton; Fanelli, Robert D.; Fisher, Laurel R.; Fukami, Norio; Harrison, M. Edwyn; Jain, Rajeev; Khan, Khalid M.; Krinsky, Mary Lee; Maple, John T.; Sharaf, Ravi; Strohmeyer, Laura; Dominitz, Jason A. (June 2011). "Management of ingested foreign bodies and food impactions" (PDF). Gastrointestinal Endoscopy. 73 (6): 1085–1091. doi:10.1016/j.gie.2010.11.010. PMID 21628009. 6. ^ Longstreth GF, Longstreth KJ, Yao JF (2001). "Esophageal food impaction: epidemiology and therapy. A retrospective, observational study". Gastrointestinal Endoscopy. 53 (2): 193–8. doi:10.1067/mge.2001.112709. PMID 11174291. 7. ^ a b c d Kerlin P, Jones D, Remedios M, Campbell C (2007). "Prevalence of eosinophilic esophagitis in adults with food bolus obstruction of the esophagus". Journal of Clinical Gastroenterology. 41 (4): 356–61. doi:10.1097/01.mcg.0000225590.08825.77. PMID 17413601. 8. ^ Cheung KM, Oliver MR, Cameron DJ, Catto-Smith AG, Chow CW (2003). "Esophageal eosinophilia in children with dysphagia". Journal of Pediatric Gastroenterology and Nutrition. 37 (4): 498–503. doi:10.1097/00005176-200310000-00018. PMID 14508223. 9. ^ Cohen MS, Kaufman AB, Palazzo JP, Nevin D, Dimarino AJ, Cohen S (2007). "An audit of endoscopic complications in adult eosinophilic esophagitis". Clinical Gastroenterology and Hepatology. 5 (10): 1149–53. doi:10.1016/j.cgh.2007.05.017. PMID 17683993. 10. ^ Leclercq P, Marting A, Gast P (2007). "Eosinophilic esophagitis". New England Journal of Medicine. 357 (14): 1446, author reply 1446–7. doi:10.1056/NEJMc071646. PMC 2653291. PMID 17914050. 11. ^ Chae HS, Lee TK, Kim YW, et al. (2002). "Two cases of steakhouse syndrome associated with nutcracker esophagus". Diseases of the Esophagus. 15 (4): 330–3. doi:10.1046/j.1442-2050.2002.00271.x. PMID 12472482. 12. ^ a b Leopard, D; Fishpool, S; Winter, S (Sep 2011). "The management of oesophageal soft food bolus obstruction: a systematic review". Annals of the Royal College of Surgeons of England. 93 (6): 441–4. doi:10.1308/003588411X588090. PMC 3369328. PMID 21929913. 13. ^ Chauvin, A; Viala, J; Marteau, P; Hermann, P; Dray, X (Jul 2013). "Management and endoscopic techniques for digestive foreign body and food bolus impaction". Digestive and Liver Disease. 45 (7): 529–42. doi:10.1016/j.dld.2012.11.002. PMID 23266207. 14. ^ "Hyoscine butylbromide (Buscopan) injection: risk of serious adverse effects in patients with underlying cardiac disease - GOV.UK". www.gov.uk. Retrieved 16 March 2018. 15. ^ Ko HH, Enns R (October 2008). "Review of food bolus management". Can. J. Gastroenterol. 22 (10): 805–8. doi:10.1155/2008/682082. PMC 2661297. PMID 18925301. 16. ^ Dieter RA, Norbeck DE, Acuna A, Rogers J (1972). "Fogarty catheter removal of cervical esophageal meat bolus. Steak-eater's disease". Archives of Surgery. 105 (5): 790–1. doi:10.1001/archsurg.1972.04180110107028. PMID 5081553. 17. ^ Kozarek RA, Sanowski RA (1980). "Esophageal food impaction: description of a new method for bolus removal". Digestive Diseases and Sciences. 25 (2): 100–3. doi:10.1007/bf01308305. PMID 7353455. 18. ^ a b Katsinelos P, Kountouras J, Paroutoglou G, Zavos C, Mimidis K, Chatzimavroudis G (2006). "Endoscopic techniques and management of foreign body ingestion and food bolus impaction in the upper gastrointestinal tract: a retrospective analysis of 139 cases". Journal of Clinical Gastroenterology. 40 (9): 784–9. doi:10.1097/01.mcg.0000225602.25858.2c. PMID 17016132. ## External links[edit] Classification D * ICD-9-CM: 787.2 * DiseasesDB: 17942 [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	Esophageal food bolus obstruction	c1268574	767	wikipedia	https://en.wikipedia.org/wiki/Esophageal_food_bolus_obstruction	2021-01-18T18:36:49	{"umls": ["C1268574"], "icd-9": ["787.2"], "wikidata": ["Q5398623"]}
A number sign (#) is used with this entry because Sjogren-Larsson syndrome (SLS) is caused by homozygous or compound heterozygous mutation in the ALDH3A2 gene (609523), which encodes fatty aldehyde dehydrogenase (FALDH), on chromosome 17p11. Description Sjogren-Larsson syndrome is an autosomal recessive, early childhood-onset disorder characterized by ichthyosis, mental retardation, spastic paraparesis, macular dystrophy, and leukoencephalopathy. It is caused by deficiency of fatty aldehyde dehydrogenase (summary by Lossos et al., 2006). Clinical Features The skin changes in Sjogren-Larsson syndrome are similar to those of congenital ichthyosiform erythroderma (242100), although considerable variations in severity have been described (Goldsmith et al., 1971). Link and Roldan (1958) reported cases. Blumel et al. (1958) referred to the neurologic disorder as spastic quadriplegia. Sjogren (1956) and Sjogren and Larsson (1957) suggested that all of their 28 cases were derived from the same mutation, which occurred about 600 years ago, and that about 1.3% of the population of northern Sweden is heterozygous for the gene. About half the cases have pigmentary degeneration of the retina. Lesions of the ocular fundus were discussed by Gilbert et al. (1968). Retinal glistening white dots are characteristic. Ecchymoses are present at birth or soon after. Most of the patients never walk. Stature tends to be short. About half the patients have seizures. Clinical improvement occurs with fat restriction and supplementation with medium chain triglycerides. Rayner et al. (1978) described 2 brothers and a sister with a syndrome combining many of the features of the Sjogren-Larsson syndrome but possibly distinct. They reviewed the group of disorders sharing phenotypic features with the Sjogren-Larsson syndrome. This Sjogren syndrome is sometimes called the T. Sjogren syndrome to distinguish it from the sicca syndrome (see 200400, 270150), which was described by Henrick Sjogren, Swedish ophthalmologist born in 1899. Jagell and Linden (1982) studied all 36 SLS patients alive in Sweden in 1980. Slight or moderate hyperkeratosis, less pronounced on the face, was already present at birth, but collodion membranes were never seen. Ichthyosis developed to its full extent during infancy. The skin changes were concentrated on the neck and lower abdomen and in the flexures, where the scales were often dark. Hair and nails and ability to sweat were unaffected. Glistening spots in the ocular fundus were an obligatory and early sign in all 30 examined Swedish patients with Sjogren-Larsson syndrome (Jagell et al., 1980). In northern Norway, Gedde-Dahl et al. (1984) encountered a family in which 3 sibs had a form of ichthyosis very similar to that of the Sjogren-Larsson syndrome but with none of the associated neurologic features; see 270220. Willemsen et al. (2000) studied 15 patients with Sjogren-Larsson syndrome with proven fatty aldehyde dehydrogenase deficiency and found that all had juvenile macular dystrophy of the retina. The patients exhibited highly characteristic bilateral, glistening yellow-white retinal dots from the age of 1 to 2 years onward. The number of dots increased with age. The extent of the macular abnormality did not correlate with the severity of the ichthyosis or with the severity of the neurologic abnormalities. A high percentage of patients showed additional ocular signs and symptoms, notably marked photophobia. Cultured skin fibroblasts from SLS patients show impaired hexadecanol oxidation due to deficiency of fatty alcohol: NAD+ oxidoreductase. The deficiency in patients and heterozygotes can also be detected by studying leukocytes (Rizzo et al., 1987). Rizzo et al. (1988) studied lipid metabolism in cultured skin fibroblasts. Intact SLS fibroblasts incubated in the presence of labeled palmitate accumulated more radioactive hexadecanol than did normal cells, whereas incorporation of radioactivity into other cellular lipids was unaltered. The hexadecanol content of SLS fibroblasts was abnormally elevated. Rizzo et al. (1988) showed that fatty alcohol:NAD+ oxidoreductase, the enzyme catalyzing the oxidation of hexadecanol to fatty acid, was deficient in SLS fibroblasts. Mean activity was 13% of that in normal fibroblasts. Fibroblasts from 2 obligate heterozygotes had intermediate levels of enzyme activity. In a later report, Rizzo et al. (1989) described studies of fatty alcohol metabolism in 8 patients and 9 obligate heterozygotes. Lossos et al. (2006) reported follow-up on 6 sibs with SLS from a consanguineous Arab family previously reported by Rogers et al. (1995). The sibs ranged in age from 16 to 36 years. They all exhibited typical features of the disorder but severity with no apparent age correlation. Although there was some evidence for progression of macular degeneration, cutaneous and neurologic features were not progressive. Cerebral magnetic resonance spectroscopy (MRS) showed a decrease in the 1.3-ppm lipid peak among the older sibs, suggesting reduced disease activity. Lossos et al. (2006) suggested the presence of compensatory factors to explain the clinical variability among sibs with the same mutation. Jack et al. (2015) characterized the retinal findings in 9 patients, ranging in age from 3 to 23 years, with SLS and ALDH3A2 mutations. All 9 exhibited generalized ichthyosis, spastic diplegia, photophobia, ichthyosis of the upper eyelid skin, and glistening macular crystals. Optical coherence tomography in 14 eyes of 7 patients showed that macular crystals were present in all layers, but predominantly in the inner nuclear and outer plexiform layers. Full retinal thickness was reduced by 22%, the inner nuclear layer was reduced by 30%, and the outer nuclear layer was reduced by 40%. Fundus autofluorescence (FAF) and fluorescein angiography (FA) showed retinal pigment epithelium atrophy. All 4 patients imaged with FAF showed heterogeneous macular autofluorescence with crystals. All 4 eyes evaluated with FA had window defects and crystals without the presence of leakage or an enlarged foveal avascular zone. Biochemical Features Fatty alcohol:NAD+ oxidoreductase is a complex enzyme that consists of 2 separate proteins that sequentially catalyze the oxidation of fatty alcohol to fatty aldehyde and then to fatty acid. In studies designed to determine whether the biochemical defect in SLS lies in the former step, fatty alcohol dehydrogenase (FADH), or the latter step, fatty aldehyde dehydrogenase (FALDH), Rizzo and Craft (1991) showed that FALDH is selectively deficient and FADH normal. The extent of FALDH deficiency in SLS cells depended on the aliphatic aldehyde used as substrate. FALDH activity in obligate SLS heterozygotes was approximately 50% of the mean normal activity when octadecanal was used as substrate. Population Genetics In Sweden, Jagell et al. (1981) traced 58 patients in 41 families, of whom 35 were alive. Of the 58, 45 were born in a restricted area in the northeast of Sweden. The prevalence of the disorder, the frequency of heterozygotes, and the gene frequency in the county of Vasterbotten were estimated as 8.3 per 100,000 persons, 2.0%, and 0.01, respectively. Mapping Based on linkage analysis and allelic association, Pigg et al. (1994) mapped the SLS gene to chromosome 17. Meiotic recombinations suggested that the gene is flanked by D17S805 on the centromeric and D17S783, D17S959, D17S842, and D17S925 on the telomeric side. Strong allelic association to D17S805 suggested that the mutation is located close to this marker. Haplotype analysis was consistent with founder effect, which had previously been suggested by genealogic evidence. In 7 pedigrees of diverse ethnic origins, Rogers et al. (1995) confirmed the linkage of SLS to the pericentric region of chromosome 17. Patients from 2 consanguineous Egyptian families were homozygous at all 9 marker loci in this region, suggesting that in these patients the region of chromosome 17 carrying the SLS gene is identical by descent. The authors had also identified several YACs that contained both the FALDH gene and the D17S805 marker that is closely linked to SLS. They concluded that FALDH may be part of the cluster of aldehyde dehydrogenase genes on proximal 17p as an aldehyde dehydrogenase gene (ALDH3; 100660), which maps to 17p11.2, was found to colocalize with the FALDH gene and D17S805 on 2 YACs. Rogers et al. (1995) found linkage of the SLS locus to 17p in families of Arabic, mixed European, Native American, and Swedish descent, thereby providing evidence for genetic homogeneity. Molecular Genetics By sequence analysis of the FALDH gene from 3 unrelated SLS patients, Rogers et al. (1997) identified distinct mutations (see, e.g., 609523.0001). Sillen et al. (1998) reported studies of 16 SLS families from Europe and the Middle East, which resulted in the identification of 11 different mutations in the ALDH3A2 gene. The spectrum of mutations characterized in their study included 5 nucleotide substitutions resulting in amino acid changes, 5 frameshift mutations introducing a stop codon, and 1 in-frame deletion with insertion at the same position. Polymorphisms were also identified. The mutations were widely distributed throughout the gene. INHERITANCE \- Autosomal recessive GROWTH Height \- Short stature HEAD & NECK Eyes \- Glistening white dots in fundus \- Macular degeneration \- Superficial corneal opacities \- Photophobia \- Upper eyelid ichthyosis \- Central retinal thinning \- Heterogeneous macular autofluorescence with crystals \- Macular window defects without leakage \- Retinal pigment epithelial atrophy seen on fluorescein angiogram Teeth \- Enamel hypoplasia SKELETAL Spine \- Thoracic kyphosis Hands \- Palm thickening Feet \- Sole thickening SKIN, NAILS, & HAIR Skin \- Pruritic ichthyosis (onset birth to first several months) Nails \- Normal nails Hair \- Normal hair NEUROLOGIC Central Nervous System \- Spasticity \- Mental retardation \- Seizures \- Demyelination in central white matter LABORATORY ABNORMALITIES \- Fatty alcohol:NAD+ oxidoreductase deficiency in leukocytes and fibroblasts MISCELLANEOUS \- Onset of neurologic symptoms often by 30 months \- Prevalent in Sweden MOLECULAR BASIS \- Caused by mutations in the aldehyde dehydrogenase 3 family, member A2 gene (ALDH3A2, 270200.0001 ) ▲ 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	SJOGREN-LARSSON SYNDROME	c0037231	768	omim	https://www.omim.org/entry/270200	2019-09-22T16:22:18	{"doid": ["14501"], "mesh": ["D016111"], "omim": ["270200"], "orphanet": ["816"], "synonyms": ["Alternative titles", "ICHTHYOSIS, SPASTIC NEUROLOGIC DISORDER, AND OLIGOPHRENIA", "FATTY ALCOHOL:NAD+ OXIDOREDUCTASE DEFICIENCY", "FATTY ALDEHYDE DEHYDROGENASE DEFICIENCY", "FALDH DEFICIENCY"]}
Hot water reflex epilepsy is a rare neurologic disease characterized by the onset of generalized or focal seizures following immersion of the head in hot water, or with hot water being poured over the head. Primary generalized tonic-clonic seizures have been reported in rare cases. [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	Hot water reflex epilepsy	c4551550	769	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=166412	2021-01-23T17:33:36	{"omim": ["613339", "613340"], "icd-10": ["G40.5"]}
Specific language impairment SpecialtyNeurology TreatmentSpeech-language pathology Specific language impairment (SLI) (the term developmental language disorder is preferred by some)[1] is diagnosed when a child's language does not develop normally and the difficulties cannot be accounted for by generally slow development, physical abnormality of the speech apparatus, autism spectrum disorder, apraxia, acquired brain damage or hearing loss. Twin studies have shown that it is under genetic influence. Although language impairment can result from a single-gene mutation,[2] this is unusual. More commonly SLI results from the combined influence of multiple genetic variants, each of which is found in the general population, as well as environmental influences.[3] ## Contents * 1 Classification * 1.1 Terminology * 1.2 Subtypes (Rapin and Allen 1987) * 1.2.1 Receptive/expressive developmental language disorder * 1.2.2 Expressive developmental language disorder syndromes * 1.2.3 Higher order processing disorders * 1.3 Relationship with other neurodevelopmental disorders * 2 Presentation * 2.1 Associated factors * 3 Genetic * 4 Diagnosis * 4.1 Assessment * 5 Intervention * 6 Outcome * 7 Prevalence * 8 Research * 9 See also * 10 References * 11 Further reading ## Classification[edit] Specific language impairment (SLI) is diagnosed when a child has delayed or disordered language development for no apparent reason.[4] Usually the first indication of SLI is that the child is later than usual in starting to speak and subsequently is delayed in putting words together to form sentences. Spoken language may be immature. In many children with SLI, understanding of language, or receptive language, is also impaired, though this may not be obvious unless the child is given a formal assessment.[5] Although difficulties with use and understanding of complex sentences are a common feature of SLI, the diagnostic criteria encompass a wide range of problems, and for some children other aspects of language are problematic (see below). In general, the term SLI is reserved for children whose language difficulties persist into school age, and so it would not be applied to toddlers who are late to start talking, most of whom catch up with their peer group after a late start.[6] ### Terminology[edit] The terminology for children's language disorders is extremely wide-ranging and confusing, with many labels that have overlapping but not necessarily identical meanings. In part this confusion reflects uncertainty about the boundaries of SLI, and the existence of different subtypes. Historically, the terms "developmental dysphasia" or "developmental aphasia" were used to describe children with the clinical picture of SLI.[7] These terms have, however, largely been abandoned, as they suggest parallels with adult acquired aphasia. This is misleading, as SLI is not caused by brain damage. Some synonyms currently in use for specific language impairment are language impairment, developmental language delay (DLD), language disorder, and language-learning disability. Researcher Bonnie Brinton argues that the term "specific language impairment" is misleading because the disorder does not only affect language, but also affects reading, writing, and social/pragmatics.[8] In medical circles, terms such as specific developmental language disorder are often used, but this has the disadvantage of being wordy, and is also rejected by some people who think SLI should not be seen as a "disorder". In the UK educational system, speech, language and communication needs (SLCN) is currently the term of choice, but this is far broader than SLI, and includes children with speech and language difficulties arising from a wide range of causes. ### Subtypes (Rapin and Allen 1987)[edit] Although most experts agree that children with SLI are quite variable, there is little agreement on how best to subtype them.[9] There is no widely accepted classification system. In 1983 Rapin and Allen[10] proposed a classification of developmental language disorders based on the linguistic features of language impairment, which was subsequently updated by Rapin.[11] Note that Rapin is a child neurologist, and she refers to different subtypes as "syndromes"; many of those coming from the perspective of education or speech-language therapy reject this kind of medical label, and argue that there is not a clear dividing line between SLI and normal variation.[12] Also, although most experts would agree that children with characteristics of the Rapin subtypes can be identified, there are many cases who are less easy to categorise, and there is also evidence that categorisation can change over time.[13] Rapin's subgroups fall into three broad categories: #### Receptive/expressive developmental language disorder[edit] Receptive/expressive phonologic/syntactic deficit syndrome is the most common form of SLI, in which the child's most obvious problems are a tendency to speak in short, simplified sentences, with omission of some grammatical features, such as past tense -ed.[14] It is common also to see simplified speech production when the child is young. For instance, clusters of consonants may be reduced, so that "string" is pronounced as "ting". Vocabulary is often limited, with a tendency to use "general all-purpose" terms, rather than more specific words.[15][16] Verbal auditory agnosia is a very rare form of language impairment, in which the child appears unable to make sense of speech sounds. It typically occurs as a symptom of Landau-Kleffner syndrome, in which case a diagnosis of SLI would not be appropriate, as there is a known neurological origin of the language difficulties. #### Expressive developmental language disorder syndromes[edit] Developmental verbal dyspraxia (DVD) – in the child with DVD, comprehension is adequate; the onset of speech is very delayed and extremely limited with impaired production of speech sounds and short utterances. The poor speech production cannot be explained in terms of structural or neurological damage of the articulators. There is much disagreement about diagnostic criteria, but the label most often used for children whose intelligibility declines markedly when they attempt complex utterances, compared to when they are producing individual sounds or syllables. Another key feature is inconsistency of speech sound production from one occasion to another. Although the term "dyspraxia" suggests a pure output disorder,[17] many – perhaps all – of these children have difficulty in doing tasks that involve mentally manipulating speech sounds, such as phonological awareness tasks. Children with DVD also typically have major literacy problems, and receptive language levels may be poor on tests of vocabulary and grammar.[18] Phonologic programming deficit syndrome – the child speaks in long but poorly intelligible utterances, producing what sounds like jargon. Outside Rapin's group, little has been written about this subtype, which is not generally recognised in diagnostic frameworks. #### Higher order processing disorders[edit] Lexical deficit disorder – the child has word finding problems and difficulty putting ideas into words. There is poor comprehension for connected speech. Again, there is little research on this subtype, which is not widely recognised. Pragmatic language impairment – the child speaks in fluent and well-formed utterances with adequate articulation; content of language is unusual; comprehension may be over-literal and language use is odd. The child may chatter incessantly and be poor at turn-taking in conversation and maintaining a topic. There has been a great deal of controversy about this category, which is termed pragmatic language impairment (PLI) in the UK. Debate has centred over the question of whether it is a subtype of SLI, part of the autistic spectrum, or a separate condition.[19] In DSM-5, the term Social Communication Disorder has been introduced; this is equivalent to PLI. ### Relationship with other neurodevelopmental disorders[edit] Although textbooks draw clear boundaries between different neurodevelopmental disorders, there is much debate about overlaps between them.[20] Many children with SLI meet diagnostic criteria for developmental dyslexia,[21] and others have features of autism.[22] ## Presentation[edit] ### Associated factors[edit] Males are more affected by SLI than females. In clinical samples, the sex ratio of affected males: females is around 3 or 4:1.[23] The reason for this association is not known: no linkage has been found to genes on the sex chromosomes. Poor motor skills are commonly found in children with SLI.[17] Brain scans do not usually reveal any obvious abnormalities in children with SLI, although quantitative comparisons have found differences in brain size or relative proportions of white or grey matter in specific regions.[24] In some cases, unusual brain gyri are found.[25] To date, no consistent "neural signature" for SLI has been found. Differences in the brains of children with SLI vs typically developing children are subtle and may overlap with atypical patterns seen in other neurodevelopmental disorders.[26][27] ## Genetic[edit] It is now generally accepted that SLI is a strongly genetic disorder.[28] The best evidence comes from studies of twins. Two twins growing up together are exposed to the same home environment, yet may differ radically in their language skills. Such different outcomes are, however, seen almost exclusively in fraternal (non-identical) twins, who are genetically different. Identical twins share the same genes and tend to be much more similar in language ability. There can be some variation in the severity and persistence of SLI in identical twins, indicating that environmental factors affect the course of disorder, but it is unusual to find a child with SLI who has an identical twin with normal language. SLI is not usually caused by a mutation in a single gene. Current evidence suggests that there are many different genes that can influence language learning, and SLI results when a child inherits a particularly detrimental combination of risk factors, each of which may have only a small effect.[29] It has been hypothesized, however, that a mutation of the FOXP2 gene may have an influence on the development on SLI to a certain degree, as it regulates genes pertinent to neural pathways related to language.[29] Only a handful of non-genetic factors have been found selectively to impact on language development in children. Later-born children in large families are at greater risk than earlier born.[30] Overall, genetic mutation, hereditary influences, and environmental factors may all have a role in the development and manifestation of SLI. It is important, therefore, to not associate the development to a single factor, but recognize that it is oftentimes the result of complex interactions between any or all of these factors.[29] ## Diagnosis[edit] SLI is defined purely in behavioural terms: there is no biological test for SLI. There are three points that need to be met for a diagnosis of SLI: * The child has language difficulties that interfere with daily life or academic progress * Other causes are excluded: the problems cannot be explained in terms of hearing loss, general developmental delay, autism, or physical difficulty in speaking * Performance on a standardized language test (see assessment, below) is significantly below age level There is considerable variation in how this last criterion is implemented. Tombin et al. (1996) proposed the EpiSLI criterion, based on five composite scores representing performance in three domains of language (vocabulary, grammar, and narration) and two modalities (comprehension and production). Children scoring in the lowest 10% on two or more composite scores are identified as having language disorder.[31] ### Assessment[edit] Assessment will usually include an interview with the child's caregiver, observation of the child in an unstructured setting, a hearing test, and standardized tests of language and nonverbal ability. There is a wide range of language assessments in English. Some are restricted for use by speech and language professionals (therapists or SALTs in the UK, speech-language pathologists, SLPs, in the US and Australia). A commonly used test battery for diagnosis of SLI is the Clinical Evaluation of Language Fundamentals (CELF). Assessments that can be completed by a parent or teacher can be useful to identify children who may require more in-depth evaluation. The Grammar and Phonology Screening (GAPS) test is a quick (ten minute) simple and accurate screening test developed and standardized in the UK. It is suitable for children from 3;4 to 6;8 years;months and can be administered by professionals and non-professionals (including parents) alike,[32] and has been demonstrated to be highly accurate (98% accuracy) in identifying impaired children who need specialist help vs non-impaired children.[33] This makes it potentially a feasible test for widespread screening. The Children’s Communication Checklist (CCC–2) is a parent questionnaire suitable for testing language skills in school-aged children. Informal assessments, such as language samples, may also be used. This procedure is useful when the normative sample of a given test is inappropriate for a given child, for instance, if the child is bilingual and the sample was of monolingual children. It is also an ecologically valid measure of all aspects of language (e.g. semantics, syntax, pragmatics, etc.). To complete a language sample, the SLP will spend about 15 minutes talking with the child. The sample may be of a conversation (Hadley, 1998), or narrative retell. In a narrative language sample, the SLP will tell the child a story using a wordless picture book (e.g. Frog Where Are You?, Mayer, 1969), then ask the child to use the pictures and tell the story back. Language samples are typically transcribed using computer software such as the systematic analysis of language software (SALT, Miller et al. 2012), and then analyzed. For example, the SLP might look for whether the child introduces characters to their story or jumps right in, whether the events follow a logical order, and whether the narrative includes a main idea or theme and supporting details. ## Intervention[edit] Intervention is usually carried out by speech and language therapists, who use a wide range of techniques to stimulate language learning. In the past, there was a vogue for drilling children in grammatical exercises, using imitation and elicitation methods, but such methods fell into disuse when it became apparent that there was little generalisation to everyday situations. Contemporary approaches to enhancing development of language structure are more likely to adopt 'milieu' methods, in which the intervention is interwoven into natural episodes of communication, and the therapist builds on the child's utterances, rather than dictating what will be talked about. In addition, there has been a move away from a focus solely on grammar and phonology toward interventions that develop children's social use of language, often working in small groups that may include typically developing as well as language-impaired peers.[34] Another way in which modern approaches to remediation differ from the past is that parents are more likely to be directly involved, particularly with preschool children.[35] A radically different approach has been developed by Tallal and colleagues, who have devised a computer-based intervention, Fast Forword, that involves prolonged and intensive training on specific components of language and auditory processing.[36] The theory underlying this approach maintains that language difficulties are caused by a failure to make fine-grained auditory discriminations in the temporal dimension, and the computerised training materials are designed to sharpen perceptual acuity. For all these types of intervention, there are few adequately controlled trials that allow one to assess clinical efficacy.[37] In general, where studies have been done, results have been disappointing,[38] though some more positive outcomes have been reported.[39] In 2010, a systematic review of clinical trials assessing the FastForword approach was published, and reported no significant gains relative to a control group.[40] ## Outcome[edit] Longitudinal studies indicate that problems are largely resolved by five years in around 40% of 4-year-olds with SLI.[41] However, for children who still have significant language difficulties at school entry low levels of literacy are common, even for children who receive specialist help,[42] and educational attainments are typically poor.[43] Poor outcomes are most common in cases where comprehension as well as expressive language is affected.[44] There is also evidence that the nonverbal IQ of children with SLI decreases over the course of development.[45] SLI is associated with a high rate of psychiatric disorder.[46] For instance, Conti-Ramsden and Botting (2004) found that 64% of a sample of 11-year-olds with SLI scored above a clinical threshold on a questionnaire for psychiatric difficulties, and 36% were regularly bullied, compared with 12% of comparison children.[47] In the longer-term, studies of adult outcomes of children with SLI find elevated rates of unemployment, social isolation and psychiatric disorder.[48] However, most studies focused on children with severe problems, where comprehension as well as expressive language was affected. Better outcomes are found for children who have milder difficulties and do not require special educational provision.[49] ## Prevalence[edit] Epidemiological surveys, in the US[50] and Canada,[51] estimated the prevalence of SLI in five-year-olds at around 7%. However, neither study adopted the stringent "discrepancy" criteria of the Diagnostic and Statistical Manual of Mental Disorders or ICD-10; SLI was diagnosed if the child scored below cut-off on standardized language tests, but had a nonverbal IQ of 90 or above and no other exclusionary criteria. ## Research[edit] Much research has focused on trying to identify what makes language learning so hard for some children. A major divide is between theories that attribute the difficulties to a low-level problem with auditory temporal processing,[52][53] and those that propose there is a deficit in a specialised language-learning system.[54][55] Other accounts emphasise deficits in specific aspects of memory.[56][57][58][59][60] It can be difficult to choose between theories because they do not always make distinctive predictions, and there is considerable heterogeneity among children with SLI. It has also been suggested that SLI may only arise when more than one underlying deficit is present.[61][62][63] ## See also[edit] * Auditory processing disorder * Dual-route hypothesis to reading aloud * Dyslexia * Language delay * Language processing * Linguistics * Origin of speech * Pragmatic language impairment * Speech-Language Pathology * Speech sound disorder * Tip of the tongue ## References[edit] 1. ^ Bishop DV, Snowling MJ, Thompson PA, Greenhalgh T (October 2017). "Phase 2 of CATALISE: a multinational and multidisciplinary Delphi consensus study of problems with language development: Terminology". Journal of Child Psychology and Psychiatry, and Allied Disciplines. 58 (10): 1068–1080. doi:10.1111/jcpp.12721. PMC 5638113. PMID 28369935. 2. ^ Lai CS, Fisher SE, Hurst JA, Vargha-Khadem F, Monaco AP (October 2001). "A forkhead-domain gene is mutated in a severe speech and language disorder". Nature. 413 (6855): 519–23. Bibcode:2001Natur.413..519L. doi:10.1038/35097076. PMID 11586359. 3. ^ Bishop DV (2002-07-01). "The role of genes in the etiology of specific language impairment". Journal of Communication Disorders. 35 (4): 311–28. doi:10.1016/S0021-9924(02)00087-4. PMID 12160351. 4. ^ Bishop D, Norbury CF (2008). "Speech and language impairments". In Thapar A, Rutter M, Bishop D, Pine D, Scott SM, Stevenson J, Taylor E (eds.). Rutter's Child and Adolescent Psychiatry. Oxford: Wiley-Blackwell. pp. 782–801. ISBN 978-1-4051-4549-7. OCLC 473789535. 5. ^ Bishop D (1997). Uncommon understanding: development and disorders of language comprehension in children. East Sussex: Psychology Press. ISBN 978-0-86377-260-3. OCLC 776282908. 6. ^ Thal DJ, Katich J (1996). "Predicaments in early identification of specific language impairment : does the early bird always catch the worm?". In Thal DJ, Cole KN, Dale PS (eds.). Assessment of Communication and Language (Communication and Language Intervention Series). Brookes Publishing Company. pp. 1–28. ISBN 978-1-55766-193-7. OCLC 34772171. 7. ^ Ingram TT, Reid JF (June 1956). "Developmental aphasia observed in a department of child psychiatry". Archives of Disease in Childhood. 31 (157): 161–72. doi:10.1136/adc.31.157.161. PMC 2011959. PMID 13328151. 8. ^ Fujiki M, Spackman MP, Brinton B, Hall A (June 2004). "The relationship of language and emotion regulation skills to reticence in children with specific language impairment". Journal of Speech, Language, and Hearing Research. 47 (3): 637–46. doi:10.1044/1092-4388(2004/049). PMID 15212574. 9. ^ Bishop DV (2004). "Specific language impairment: diagnostic dilemma". In Van Balkom H, Verhoeven, LT (eds.). Classification of developmental language disorders: theoretical issues and clinical implications. Hillsdale, N.J: Lawrence Erlbaum. pp. 309–326. ISBN 978-1-4106-0902-1. OCLC 53721852. 10. ^ Rapin I, Allen D (1983). "Developmental language disorders: nosologic considerations.". In Kirk U (ed.). Neuropsychology of language, reading, and spelling. New York: Academic Press. pp. 155–184. 11. ^ Rapin I (September 1996). "Practitioner review: developmental language disorders: a clinical update". Journal of Child Psychology and Psychiatry, and Allied Disciplines. 37 (6): 643–55. doi:10.1111/j.1469-7610.1996.tb01456.x. PMID 8894945. 12. ^ Dale PS, Cole KN (April 1991). "What's normal? Specific language impairment in an individual differences perspective". Language, Speech, and Hearing Services in Schools. 22 (2): 80–83. doi:10.1044/0161-1461.2202.80. 13. ^ Conti-Ramsden G, Botting N (October 1999). "Classification of children with specific language impairment: longitudinal considerations". Journal of Speech, Language, and Hearing Research. 42 (5): 1195–204. doi:10.1044/jslhr.4205.1195. PMID 10515515. 14. ^ Leonard LB (1998). Children with specific language impairment. Cambridge, Mass: The MIT Press. ISBN 978-0-585-27859-9. OCLC 45728290. 15. ^ Rice ML, Bode JV (1993). "GAPS in the verb lexicons of children with specific language impairment". First Language. 13 (37): 113–131. doi:10.1177/014272379301303707. ISSN 0142-7237. 16. ^ Leonard LB (May 2009). "Is expressive language disorder an accurate diagnostic category?". American Journal of Speech-Language Pathology. 18 (2): 115–23. doi:10.1044/1058-0360(2008/08-0064). PMC 2718760. PMID 19029534. 17. ^ a b Hill EL (2001). "Non-specific nature of specific language impairment: a review of the literature with regard to concomitant motor impairments" (PDF). International Journal of Language & Communication Disorders. 36 (2): 149–71. doi:10.1080/13682820010019874. PMID 11344592. 18. ^ Wells B, Stackhouse J (1997). Children's speech and literacy difficulties: a psycholinguistic framework. San Diego, Calif: Singular Pub. Group. ISBN 978-1-86156-030-8. OCLC 246491090. 19. ^ Bishop DV (2000). "Pragmatic language impairment: a correlate of SLI, a distinct subgroup, or part of the autistic continuum?". In Bishop DV, Leonard LB (eds.). Speech and Language Impairments in Children: Causes, Characteristics, Intervention and Outcome. Hove, UK: Psychology Press. pp. 99–113. 20. ^ Bishop D, Rutter M (2008). "Neurodevelopmental disorders: conceptual approaches.". In Thapar A, Rutter M, Bishop D, Pine D, Scott SM, Stevenson J, Taylor E (eds.). Rutter's Child and Adolescent Psychiatry. Oxford: Blackwell. pp. 32–41. 21. ^ Bishop DV, Snowling MJ (November 2004). "Developmental dyslexia and specific language impairment: same or different?". Psychological Bulletin. 130 (6): 858–86. doi:10.1037/0033-2909.130.6.858. PMID 15535741. 22. ^ Bishop DV (2008). "Specific language impairment, dyslexia, and autism: Using genetics to unravel their relationship.". In Norbury CF, Tomblin JB, Bishop DV (eds.). Understanding developmental language disorders: from theory to practice. Hove: Psychology Press. pp. 67–78. 23. ^ Robinson RJ (November 1991). "Causes and associations of severe and persistent specific speech and language disorders in children". Developmental Medicine and Child Neurology. 33 (11): 943–62. doi:10.1111/j.1469-8749.1991.tb14811.x. PMID 1720749. 24. ^ Jernigan TL, Hesselink JR, Sowell E, Tallal PA (May 1991). "Cerebral structure on magnetic resonance imaging in language- and learning-impaired children". Archives of Neurology. 48 (5): 539–45. doi:10.1001/archneur.1991.00530170103028. PMID 2021369. 25. ^ Jackson T, Plante E (June 1996). "Gyral morphology in the posterior Sylvian region in families affected by developmental language disorder". Neuropsychology Review. 6 (2): 81–94. doi:10.1007/bf01875369. PMID 8976499. 26. ^ Herbert MR, Kenet T (June 2007). "Brain abnormalities in language disorders and in autism". Pediatric Clinics of North America. 54 (3): 563–83, vii. doi:10.1016/j.pcl.2007.02.007. PMID 17543910. 27. ^ Bishop DV (September 2010). "Overlaps between autism and language impairment: phenomimicry or shared etiology?". Behavior Genetics. 40 (5): 618–29. doi:10.1007/s10519-010-9381-x. PMC 2921070. PMID 20640915. 28. ^ Bishop DV (October 2006). "What Causes Specific Language Impairment in Children?". Current Directions in Psychological Science. 15 (5): 217–221. doi:10.1111/j.1467-8721.2006.00439.x. PMC 2582396. PMID 19009045. 29. ^ a b c Bishop DV (March 2009). "Genes, cognition, and communication: insights from neurodevelopmental disorders". Annals of the New York Academy of Sciences. 1156: 1–18. Bibcode:2009NYASA1156....1B. doi:10.1111/j.1749-6632.2009.04419.x. PMC 2805335. PMID 19338500. 30. ^ Garside RF, Fundudis T, Kolvin I (1979). Speech retarded and deaf children : their psychological development. Boston: Academic Press. ISBN 978-0-12-270150-4. OCLC 6308388. 31. ^ Tomblin JB, Records NL, Zhang X (December 1996). "A system for the diagnosis of specific language impairment in kindergarten children". Journal of Speech and Hearing Research. 39 (6): 1284–94. doi:10.1044/jshr.3906.1284. PMID 8959613. 32. ^ Gardner H, Froud K, McClelland A, van der Lely HK (2006). "Development of the Grammar and Phonology Screening (GAPS) test to assess key markers of specific language and literacy difficulties in young children". International Journal of Language & Communication Disorders. 41 (5): 513–40. CiteSeerX 10.1.1.110.4964. doi:10.1080/13682820500442644. PMID 17050469. 33. ^ van der Lely HK, Payne E, McClelland A (2011). "An investigation to validate the grammar and phonology screening (GAPS) test to identify children with specific language impairment". PLOS ONE. 6 (7): e22432. Bibcode:2011PLoSO...622432V. doi:10.1371/journal.pone.0022432. PMC 3145645. PMID 21829461. 34. ^ Gallagher T (1996). "Social-interactional approaches to child language intervention.". In Beitchman J, Cohen NJ, Konstantareas MM, Tannock R (eds.). Language, Learning and Behavior Disorders: Developmental, Biological and Clinical Perspectives. New York: Cambridge University Press. pp. 493–514. 35. ^ Tannock R, Girolametto L (1992). "Reassessing parent-focused intervention programs.". In Warren SF, Reichle J (eds.). Causes and effects in communication and language intervention. Baltimore MD: Paul Brooks. pp. 49–81. 36. ^ Tallal P (2000). "Experimental studies of language learning impairments: From research to remediation.". In Bishop DV, Leonard LB (eds.). Speech and Language Impairments in Children: Causes, Characteristics, Intervention and Outcome. Hove, UK: Psychology Press. pp. 131–155. 37. ^ Law J, Garrett Z, Nye C (August 2004). "The efficacy of treatment for children with developmental speech and language delay/disorder: a meta-analysis". Journal of Speech, Language, and Hearing Research. 47 (4): 924–43. doi:10.1044/1092-4388(2004/069). PMID 15324296. S2CID 10725720. 38. ^ Glogowska M, Roulstone S, Enderby P, Peters TJ (October 2000). "Randomised controlled trial of community based speech and language therapy in preschool children". BMJ. 321 (7266): 923–6. doi:10.1136/bmj.321.7266.923. PMC 27499. PMID 11030677. 39. ^ Bryne-Saricks MC (1987). "Treatment of language disorders in children: a review of experimental studies.". In Winitz H (ed.). Human Communication and its Disorders. Norwood, N.J: Ablex Publishing. pp. 167–201. 40. ^ Strong GK, Torgerson CJ, Torgerson D, Hulme C (March 2011). "A systematic meta-analytic review of evidence for the effectiveness of the 'Fast ForWord' language intervention program". Journal of Child Psychology and Psychiatry, and Allied Disciplines. 52 (3): 224–35. doi:10.1111/j.1469-7610.2010.02329.x. PMC 3061204. PMID 20950285. 41. ^ Bishop DV, Edmundson A (May 1987). "Language-impaired 4-year-olds: distinguishing transient from persistent impairment". The Journal of Speech and Hearing Disorders. 52 (2): 156–73. doi:10.1044/jshd.5202.156. PMID 3573746. 42. ^ Catts HW, Fey ME, Tomblin JB, Zhang X (December 2002). "A longitudinal investigation of reading outcomes in children with language impairments". Journal of Speech, Language, and Hearing Research. 45 (6): 1142–57. doi:10.1044/1092-4388(2002/093). PMID 12546484. S2CID 27888843. 43. ^ Snowling MJ, Adams JW, Bishop DV, Stothard SE (2001). "Educational attainments of school leavers with a preschool history of speech-language impairments". International Journal of Language & Communication Disorders. 36 (2): 173–83. doi:10.1080/13682820120976. PMID 11344593. 44. ^ Simkin E, Conti-Ramsden G (2006). "Evidence of reading difficulty in subgroups of children with specific language impairment". Child Language Teaching and Therapy. 22 (3): 315–331. doi:10.1191/0265659006ct310xx. ISSN 0265-6590. 45. ^ Botting N (March 2005). "Non-verbal cognitive development and language impairment". Journal of Child Psychology and Psychiatry, and Allied Disciplines. 46 (3): 317–26. doi:10.1111/j.1469-7610.2004.00355.x. PMID 15755307. 46. ^ Cohen N (2001). Language impairment and psychopathology in infants, children, and adolescents. Thousand Oaks: Sage Publications. ISBN 978-0-7619-2025-0. OCLC 45749780. 47. ^ Conti-Ramsden G, Botting N (February 2004). "Social difficulties and victimization in children with SLI at 11 years of age". Journal of Speech, Language, and Hearing Research. 47 (1): 145–61. doi:10.1044/1092-4388(2004/013). PMID 15072535. 48. ^ Clegg J, Hollis C, Mawhood L, Rutter M (February 2005). "Developmental language disorders--a follow-up in later adult life. Cognitive, language and psychosocial outcomes". Journal of Child Psychology and Psychiatry, and Allied Disciplines. 46 (2): 128–49. doi:10.1111/j.1469-7610.2004.00342.x. PMID 15679523. 49. ^ Snowling MJ, Bishop DV, Stothard SE, Chipchase B, Kaplan C (August 2006). "Psychosocial outcomes at 15 years of children with a preschool history of speech-language impairment". Journal of Child Psychology and Psychiatry, and Allied Disciplines. 47 (8): 759–65. doi:10.1111/j.1469-7610.2006.01631.x. PMID 16898989. 50. ^ Tomblin JB, Records NL, Buckwalter P, Zhang X, Smith E, O'Brien M (December 1997). "Prevalence of specific language impairment in kindergarten children". Journal of Speech, Language, and Hearing Research. 40 (6): 1245–60. doi:10.1044/jslhr.4006.1245. PMC 5075245. PMID 9430746. 51. ^ Johnson CJ, Beitchman JH, Young A, Escobar M, Atkinson L, Wilson B, et al. (June 1999). "Fourteen-year follow-up of children with and without speech/language impairments: speech/language stability and outcomes". Journal of Speech, Language, and Hearing Research. 42 (3): 744–60. doi:10.1044/jslhr.4203.744. PMID 10391637. 52. ^ Ceponiene R, Cummings A, Wulfeck B, Ballantyne A, Townsend J (September 2009). "Spectral vs. temporal auditory processing in specific language impairment: a developmental ERP study". Brain and Language. 110 (3): 107–20. doi:10.1016/j.bandl.2009.04.003. PMC 2731814. PMID 19457549. 53. ^ Tallal P (September 2004). "Improving language and literacy is a matter of time". Nature Reviews. Neuroscience. 5 (9): 721–8. doi:10.1038/nrn1499. PMID 15322530. 54. ^ Rice ML, Wexler K, Cleave PL (August 1995). "Specific language impairment as a period of extended optional infinitive". Journal of Speech and Hearing Research. 38 (4): 850–63. doi:10.1044/jshr.3804.850. PMID 7474978. S2CID 14673508. 55. ^ van der Lely HK (February 2005). "Domain-specific cognitive systems: insight from Grammatical-SLI". Trends in Cognitive Sciences. 9 (2): 53–9. doi:10.1016/j.tics.2004.12.002. PMID 15668097. 56. ^ Lum JA, Gelgic C, Conti-Ramsden G (2010). "Procedural and declarative memory in children with and without specific language impairment". International Journal of Language & Communication Disorders. 45 (1): 96–107. doi:10.3109/13682820902752285. PMC 2826154. PMID 19900077. 57. ^ Ullman MT, Pierpont EI (June 2005). "Specific language impairment is not specific to language: the procedural deficit hypothesis". Cortex; A Journal Devoted to the Study of the Nervous System and Behavior. 41 (3): 399–433. CiteSeerX 10.1.1.211.8238. doi:10.1016/s0010-9452(08)70276-4. PMID 15871604. 58. ^ Montgomery JW (2003). "Working memory and comprehension in children with specific language impairment: what we know so far". Journal of Communication Disorders. 36 (3): 221–31. doi:10.1016/S0021-9924(03)00021-2. PMID 12742669. 59. ^ Montgomery JW, Magimairaj BM, Finney MC (February 2010). "Working memory and specific language impairment: an update on the relation and perspectives on assessment and treatment". American Journal of Speech-Language Pathology. 19 (1): 78–94. doi:10.1044/1058-0360(2009/09-0028). PMID 19948760. 60. ^ Gathercole SE, Baddeley AD (1990). "Phonological memory deficits in language disordered children: Is there a causal connection?". Journal of Memory and Language. 29 (3): 336–360. doi:10.1016/0749-596X(90)90004-J. ISSN 0749-596X. 61. ^ Coady JA, Evans JL (2008). "Uses and interpretations of non-word repetition tasks in children with and without specific language impairments (SLI)". International Journal of Language & Communication Disorders. 43 (1): 1–40. doi:10.1080/13682820601116485. PMC 5524521. PMID 18176883. 62. ^ Hsu HJ, Bishop DV (January 2011). "Grammatical Difficulties in Children with Specific Language Impairment: Is Learning Deficient?". Human Development. 53 (5): 264–277. doi:10.1159/000321289. PMC 3191529. PMID 22003258. 63. ^ Bishop DV (July 2006). "Developmental cognitive genetics: how psychology can inform genetics and vice versa". Quarterly Journal of Experimental Psychology. 59 (7): 1153–68. doi:10.1080/17470210500489372. PMC 2409179. PMID 16769616. ## Further reading[edit] * Paul R (2007). Language disorders from infancy through adolescence: assessment & intervention. Mosby Elsevier. ISBN 978-0-323-03685-6. OCLC 487807750. * v * t * e Dyslexia and related specific developmental disorders Conditions Speech, language, and communication * Expressive language disorder * Infantile speech * Landau–Kleffner syndrome * Language disorder * Lisp * Mixed receptive-expressive language disorder * Specific language impairment * Speech and language impairment * Speech disorder * Speech error * Speech sound disorder * Stuttering * Tip of the tongue Learning disability * Dyslexia * Dyscalculia * Dysgraphia * Disorder of written expression Motor * Developmental coordination disorder * Developmental verbal dyspraxia Sensory * Auditory processing disorder * Sensory processing disorder Related topics * Dyslexia research * Irlen filters * Learning Ally * Learning problems in childhood cancer * Literacy * Management of dyslexia * Multisensory integration * Neuropsychology * Reading acquisition * Spelling * Writing system Lists * Dyslexia in fiction * Languages by Writing System * People with dyslexia [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	Specific language impairment	c0973461	770	wikipedia	https://en.wikipedia.org/wiki/Specific_language_impairment	2021-01-18T18:32:32	{"mesh": ["D001037"], "umls": ["C0973461"], "orphanet": ["211053"], "wikidata": ["Q775593"]}
Diazoxide-resistant focal hyperinsulism (DRFH) is a form of diazoxide-resistant hyperinsulinism (see this term) characterized by recurrent episodes of profound hypoglycemia caused by an excessive/ uncontrolled insulin secretion (inappropriate for the level of glycemia) due to a focal adenomatous hyperplasia of pancreas, that is unresponsive to medical treatment with diazoxide, necessitating complete excision of the focal lesion. [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	Diazoxide-resistant focal hyperinsulinism	None	771	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=79298	2021-01-23T18:38:56	{"icd-10": ["E16.1"], "synonyms": ["Hyperinsulinemic hypoglycemia, diazoxide-resistant focal form"]}
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. (May 2018) Collaural fistula Other namesCervico-aural fistula Collaural fistula or cervico-aural fistula is a type of fistula whose openings are at external auditory canal and the neck, usually in the upper part of anterior border of sternocleidomastoid muscle. It occurs at birth because the defect is in the embryological branchial cleft. It is rare, and accounts for 8% of the branchial cleft anomalies, which is why it is sometimes misdiagnosed.[1][2] ## Diagnosis[edit] The patient presents with non-healing ulcers of the neck and one of the external auditory canals. Diagnosis is confirmed by injecting methylene blue dye into the neck opening, and dye coming out of the opening in the external auditory canal. Computerized tomography fistulogram can yield more accurate results regarding the course of the fistula.[3] ## Treatment[edit] Treatment of collaural fistula is done by surgical exploration and excision. The fistulous track is removed with skin and cartilage. Split thickness skin grafting and stenting is done if more than 30% of the external canal's circumference has been removed. The potential complications following fistula removal surgery are facial nerve paralysis and recurrence.[2] ## References[edit] 1. ^ Parida, Pradipta Kumar; Alexander, Arun; Raja, Kalairasi; Surianarayanan, Gopalakrishnan; Ganeshan, Sivaraman (2013). "First Branchial Cleft Malformation with Duplication of External Auditory Canal". Case Reports in Otolaryngology. 2013: 578091. doi:10.1155/2013/578091. ISSN 2090-6765. PMC 3838813. PMID 24312740. 2. ^ a b Pal, Kalyan; Chakraborty, Dipanjan; Kundu, Sohag; Mukhopadhyay, Subrata (18 December 2016). "Collaural Fistula: A Case Report". Bengal Journal of Otolaryngology and Head Neck Surgery. 24 (3): 157–160. ISSN 2395-2407. Retrieved 11 May 2018. 3. ^ Prasad, Sampath Chandra; Azeez, Arun; Thada, Nikhil Dinaker; Rao, Pallavi; Bacciu, Andrea; Prasad, Kishore Chandra (2014). "Branchial Anomalies: Diagnosis and Management". International Journal of Otolaryngology. 2014: 237015. doi:10.1155/2014/237015. ISSN 1687-9201. PMC 3960728. PMID 24772172. [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	Collaural fistula	c0266627	772	wikipedia	https://en.wikipedia.org/wiki/Collaural_fistula	2021-01-18T19:07:18	{"umls": ["C0266627"], "wikidata": ["Q55607918"]}
Geleophysic dysplasia is an inherited condition that affects many parts of the body. It is characterized by abnormalities involving the bones, joints, heart, and skin. People with geleophysic dysplasia have short stature with very short hands and feet. Most also develop thickened skin and joint deformities called contractures, both of which significantly limit mobility. Affected individuals usually have a limited range of motion in their fingers, toes, wrists, and elbows. Additionally, contractures in the legs and hips cause many affected people to walk on their toes. The name of this condition, which comes from the Greek words for happy ("gelios") and nature ("physis"), is derived from the good-natured facial appearance seen in most affected individuals. The distinctive facial features associated with this condition include a round face with full cheeks, a small nose with upturned nostrils, a broad nasal bridge, a thin upper lip, upturned corners of the mouth, and a flat area between the upper lip and the nose (philtrum). Geleophysic dysplasia is also characterized by heart (cardiac) problems, particularly abnormalities of the cardiac valves. These valves normally control the flow of blood through the heart. In people with geleophysic dysplasia, the cardiac valves thicken, which impedes blood flow and increases blood pressure in the heart. Other heart problems have also been reported in people with geleophysic dysplasia; these include a narrowing of the artery from the heart to the lungs (pulmonary stenosis) and a hole between the two upper chambers of the heart (atrial septal defect). Other features of geleophysic dysplasia can include an enlarged liver (hepatomegaly) and recurrent respiratory and ear infections. In severe cases, a narrowing of the windpipe (tracheal stenosis) can cause serious breathing problems. As a result of heart and respiratory abnormalities, geleophysic dysplasia is often life-threatening in childhood. However, some affected people have lived into adulthood. ## Frequency Geleophysic dysplasia is a rare disorder whose prevalence is unknown. More than 30 affected individuals have been reported. ## Causes Geleophysic dysplasia results from mutations in the ADAMTSL2 gene. This gene provides instructions for making a protein whose function is unclear. The protein is found in the extracellular matrix, which is the intricate lattice of proteins and other molecules that forms in the spaces between cells. Studies suggest that the ADAMTSL2 protein may play a role in the microfibrillar network, which is an organized clustering of thread-like filaments (called microfibrils) in the extracellular matrix. This network provides strength and flexibility to tissues throughout the body. Mutations in the ADAMTSL2 protein likely change the protein's 3-dimensional structure. Through a process that is poorly understood, ADAMTSL2 gene mutations alter the microfibrillar network in many different tissues. Impairment of this essential network disrupts the normal functions of cells, which likely contributes to the varied signs and symptoms of geleophysic dysplasia. Researchers are working to determine how mutations in the ADAMTSL2 gene lead to short stature, heart disease, and the other features of this condition. ### Learn more about the genes associated with Geleophysic dysplasia * ADAMTSL2 * FBN1 ## Inheritance Pattern This condition is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of 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	Geleophysic dysplasia	c3278147	773	medlineplus	https://medlineplus.gov/genetics/condition/geleophysic-dysplasia/	2021-01-27T08:25:44	{"gard": ["2449"], "omim": ["231050", "614185"], "synonyms": []}
Russell-Silver syndrome is a growth disorder characterized by slow growth before and after birth. Babies with this condition have a low birth weight and often fail to grow and gain weight at the expected rate (failure to thrive). Head growth is normal, however, so the head may appear unusually large compared to the rest of the body. Affected children are thin and have poor appetites, and some develop recurrent episodes of low blood sugar (hypoglycemia) as a result of feeding difficulties. Adults with Russell-Silver syndrome are short; the average height for affected men is about 151 centimeters (4 feet, 11 inches) and the average height for affected women is about 140 centimeters (4 feet, 7 inches). Many children with Russell-Silver syndrome have a small, triangular face with distinctive facial features including a prominent forehead, a narrow chin, a small jaw, and downturned corners of the mouth. Other features of this disorder can include an unusual curving of the fifth finger (clinodactyly), asymmetric or uneven growth of some parts of the body, and digestive system abnormalities. Russell-Silver syndrome is also associated with an increased risk of delayed development, speech and language problems, and learning disabilities. ## Frequency The exact incidence of Russell-Silver syndrome is unknown. Worldwide estimates range from 1 in 30,000 to 1 in 100,000 people. ## Causes The genetic causes of Russell-Silver syndrome are complex. The disorder often results from the abnormal regulation of certain genes that control growth. Research has focused on genes located in particular regions of chromosome 7 and chromosome 11. People normally inherit one copy of each chromosome from their mother and one copy from their father. For most genes, both copies are expressed, or "turned on," in cells. For some genes, however, only the copy inherited from a person's father (the paternal copy) is expressed. For other genes, only the copy inherited from a person's mother (the maternal copy) is expressed. These parent-specific differences in gene expression are caused by a phenomenon called genomic imprinting. Both chromosome 7 and chromosome 11 contain groups of genes that normally undergo genomic imprinting; some of these genes are active only on the maternal copy of the chromosome, while others are active only on the paternal copy. Abnormalities involving these genes appear to be responsible for many cases of Russell-Silver syndrome. Researchers suspect that 30 to 50 percent of all cases of Russell-Silver syndrome result from changes in a process called methylation on the short (p) arm of chromosome 11 at position 15 (11p15). Methylation is a chemical reaction that attaches small molecules called methyl groups to certain segments of DNA. In genes that undergo genomic imprinting, methylation is one way that a gene's parent of origin is marked during the formation of egg and sperm cells. Russell-Silver syndrome has been associated with changes in methylation involving the H19 and IGF2 genes, which are located near one another at 11p15. These genes are thought to be involved in directing normal growth. A loss of methylation disrupts the regulation of these genes, which leads to slow growth and the other characteristic features of this disorder. Abnormalities involving genes on chromosome 7 can also cause Russell-Silver syndrome. In 7 percent to 10 percent of cases, people inherit both copies of chromosome 7 from their mother instead of one copy from each parent. This phenomenon is called maternal uniparental disomy (UPD). Maternal UPD causes people to have two active copies of some imprinted genes and no active copies of others. An imbalance in certain active paternal and maternal genes on chromosome 7 underlies the signs and symptoms of the disorder. In about 40 percent of people with Russell-Silver syndrome, the cause of the condition is unknown. It is likely that changes involving imprinted genes on chromosomes other than 7 and 11 play a role. Researchers are working to identify additional genetic changes that underlie this disorder. ### Learn more about the genes and chromosomes associated with Russell-Silver syndrome * H19 * IGF2 * chromosome 11 * chromosome 7 ## Inheritance Pattern Most cases of Russell-Silver syndrome are sporadic, which means they occur in people with no history of the disorder in their family. Rarely, Russell-Silver syndrome can run in families. In some affected families, the condition appears to have an autosomal dominant pattern of inheritance. Autosomal dominant inheritance means one copy of a genetic change in each cell is sufficient to cause the disorder. In other families, the condition appears to have an autosomal recessive pattern of inheritance. Autosomal recessive inheritance means both copies of a gene are altered in each cell. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of 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	Russell-Silver syndrome	c0175693	774	medlineplus	https://medlineplus.gov/genetics/condition/russell-silver-syndrome/	2021-01-27T08:24:37	{"gard": ["4870"], "mesh": ["D056730"], "omim": ["180860"], "synonyms": []}
Sexually transmitted infection "The clap" redirects here. For other uses, see Clap. For the Lil Wayne song, see Gonorrhea (song). Gonorrhea Other namesGonorrhoea, gonococcal infection, gonococcal urethritis, the clap Gonococcal lesion on the skin Pronunciation * /ˌɡɒn.əˈri.ə/ SpecialtyInfectious disease SymptomsNone, burning with urination, vaginal discharge, discharge from the penis, pelvic pain, testicular pain[1] ComplicationsPelvic inflammatory disease, inflammation of the epididymis, septic arthritis, endocarditis[1][2] CausesNeisseria gonorrhoeae typically sexually transmitted[1] Diagnostic methodTesting the urine, urethra in males, or cervix in females[1] PreventionCondoms, having sex with only one person who is uninfected, not having sex[1][3] TreatmentCeftriaxone by injection and azithromycin by mouth[4][5] Frequency0.8% (women), 0.6% (men)[6] Gonorrhea, colloquially known as the clap, is a sexually transmitted infection (STI) caused by the bacterium Neisseria gonorrhoeae.[1] Infection may involve the genitals, mouth, and/or rectum.[7] Infected men may experience pain or burning with urination, discharge from the penis, or testicular pain.[1] Infected women may experience burning with urination, vaginal discharge, vaginal bleeding between periods, or pelvic pain.[1] Complications in women include pelvic inflammatory disease and in men include inflammation of the epididymis.[1] Many of those infected, however, have no symptoms.[1] If untreated, gonorrhea can spread to joints or heart valves.[1][2] Gonorrhea is spread through sexual contact with an infected person.[1] This includes oral, anal, and vaginal sex.[1] It can also spread from a mother to a child during birth.[1] Diagnosis is by testing the urine, urethra in males, or cervix in females.[1] Testing all women who are sexually active and less than 25 years of age each year as well as those with new sexual partners is recommended;[3] the same recommendation applies in men who have sex with men (MSM).[3] Gonorrhea can be prevented with the use of condoms, having sex with only one person who is uninfected, and by not having sex.[1][3] Treatment is usually with ceftriaxone by injection and azithromycin by mouth.[4][5] Resistance has developed to many previously used antibiotics and higher doses of ceftriaxone are occasionally required.[4][5] Retesting is recommended three months after treatment.[3] Sexual partners from the last two months should also be treated.[1] Gonorrhea affects about 0.8% of women and 0.6% of men.[6] An estimated 33 to 106 million new cases occur each year, out of the 498 million new cases of curable STI – which also includes syphilis, chlamydia, and trichomoniasis.[8][9] Infections in women most commonly occur when they are young adults.[3] In 2015, it caused about 700 deaths.[10] Descriptions of the disease date back to before the Common Era within the Old Testament.[2] The current name was first used by the Greek physician Galen before 200 CE who referred to it as "an unwanted discharge of semen".[2] ## Contents * 1 Signs and symptoms * 1.1 Women * 1.2 Men * 1.3 Infants * 1.4 Spread * 2 Cause * 2.1 Spread * 3 Diagnosis * 4 Screening * 5 Prevention * 6 Treatment * 6.1 Antibiotics * 6.2 Sexual partners * 6.3 Antibiotic resistance * 7 Prognosis * 8 Epidemiology * 9 History * 10 Research * 11 References * 12 External links ## Signs and symptoms Gonorrhea infections of mucosal membranes can cause swelling, itching, pain, and the formation of pus.[11] The time from exposure to symptoms is usually between two and 14 days, with most symptoms appearing between four and six days after infection, if they appear at all. Both men and women with infections of the throat may experience a sore throat, though such infection does not produce symptoms in 90% of cases.[12][13] Other symptoms may include swollen lymph nodes around the neck.[11] Either sex can become infected in the eyes or rectum if these tissues are exposed to the bacterium.[citation needed] ### Women Half of women with gonorrhea are asymptomatic but the other half experience vaginal discharge, lower abdominal pain, or pain with sexual intercourse associated with inflammation of the uterine cervix.[14][15][16] Common medical complications of untreated gonorrhea in women include pelvic inflammatory disease which can cause scars to the fallopian tubes and result in later ectopic pregnancy among those women who become pregnant.[17] ### Men Most infected men with symptoms have inflammation of the penile urethra associated with a burning sensation during urination and discharge from the penis.[15] In men, discharge with or without burning occurs in half of all cases and is the most common symptom of the infection.[18] This pain is caused by a narrowing and stiffening of the urethral lumen.[19] The most common medical complication of gonorrhea in men is inflammation of the epididymis.[17] Gonorrhea is also associated with increased risk of prostate cancer.[20] ### Infants An infant with gonorrhea of the eyes If not treated, gonococcal ophthalmia neonatorum will develop in 28% of infants born to women with gonorrhea.[21] ### Spread If left untreated, gonorrhea can spread from the original site of infection and infect and damage the joints, skin, and other organs. Indications of this can include fever, skin rashes, sores, and joint pain and swelling.[17] In advanced cases, gonorrhea may cause a general feeling of tiredness similar to other infections.[18] It is also possible for an individual to have an allergic reaction to the bacteria, in which case any appearing symptoms will be greatly intensified.[18] Very rarely it may settle in the heart, causing endocarditis, or in the spinal column, causing meningitis. Both are more likely among individuals with suppressed immune systems, however.[13] ## Cause Multiple views of a Neisseria gonorrhoeae bacterium, which causes gonorrhea Gonorrhea is caused by the bacterium Neisseria gonorrhoeae.[15] Previous infection does not confer immunity – a person who has been infected can become infected again by exposure to someone who is infected. Infected persons may be able to infect others repeatedly without having any signs or symptoms of their own.[citation needed] ### Spread The infection is usually spread from one person to another through vaginal, oral, or anal sex.[15][22] Men have a 20% risk of getting the infection from a single act of vaginal intercourse with an infected woman. The risk for men that have sex with men (MSM) is higher.[23] Active MSM may get a penile infection, while passive MSM may get anorectal gonorrhea.[24] Women have a 60–80% risk of getting the infection from a single act of vaginal intercourse with an infected man.[25] A mother may transmit gonorrhea to her newborn during childbirth; when affecting the infant's eyes, it is referred to as ophthalmia neonatorum.[15] It may be able to spread through the objects contaminated with body fluid from an infected person.[26] The bacteria typically does not survive long outside the body, typically dying within minutes to hours.[27] ## Diagnosis Traditionally, gonorrhea was diagnosed with Gram stain and culture; however, newer polymerase chain reaction (PCR)-based testing methods are becoming more common.[16][28] In those failing initial treatment, culture should be done to determine sensitivity to antibiotics.[29] Tests that use polymerase chain reaction (PCR, aka nucleic acid amplification) to identify genes unique to N. gonorrhoeae are recommended for screening and diagnosis of gonorrhea infection. These PCR-based tests require a sample of urine, urethral swabs, or cervical/vaginal swabs. Culture (growing colonies of bacteria in order to isolate and identify them) and Gram-stain (staining of bacterial cell walls to reveal morphology) can also be used to detect the presence of N. gonorrhoeae in all specimen types except urine.[30][31] If Gram-negative, oxidase-positive diplococci are visualized on direct Gram stain of urethral pus (male genital infection), no further testing is needed to establish the diagnosis of gonorrhea infection.[32][33] However, in the case of female infection direct Gram stain of cervical swabs is not useful because the N. gonorrhoeae organisms are less concentrated in these samples. The chances of false positives are increased as Gram-negative diplococci native to the normal vaginal flora cannot be distinguished from N. gonorrhoeae. Thus, cervical swabs must be cultured under the conditions described above. If oxidase positive, Gram-negative diplococci are isolated from a culture of a cervical/vaginal swab specimen, then the diagnosis is made. Culture is especially useful for diagnosis of infections of the throat, rectum, eyes, blood, or joints—areas where PCR-based tests are not well established in all labs.[33][34] Culture is also useful for antimicrobial sensitivity testing, treatment failure, and epidemiological purposes (outbreaks, surveillance).[33] In patients who may have disseminated gonococcal infection (DGI), all possible mucosal sites should be cultured (e.g., pharynx, cervix, urethra, rectum).[34] Three sets of blood cultures should also be obtained.[35] Synovial fluid should be collected in cases of septic arthritis.[34] All people testing positive for gonorrhea should be tested for other sexually transmitted diseases such as chlamydia, syphilis, and human immunodeficiency virus.[29] Studies have found co-infection with chlamydia ranging from 46 to 54% in young people with gonorrhea.[36][37] For this reason, gonorrhea and chlamydia testing are often combined.[30][38][39] People diagnosed with gonorrhea infection have a fivefold increase risk of HIV transmission.[40] Additionally, infected persons who are HIV positive are more likely to shed and transmit HIV to uninfected partners during an episode of gonorrhea.[41] ## Screening The United States Preventive Services Task Force (USPSTF) recommends screening for gonorrhea in women at increased risk of infection, which includes all sexually active women younger than 25 years. Extragenital gonorrhea and chlamydia are highest in men who have sex with men (MSM).[42] Additionally, the USPSTF also recommends routine screening in people who have previously tested positive for gonorrhea or have multiple sexual partners and individuals who use condoms inconsistently, provide sexual favors for money, or have sex while under the influence of alcohol or drugs.[14] Screening for gonorrhea in women who are (or intend to become) pregnant, and who are found to be at high risk for sexually transmitted diseases, is recommended as part of prenatal care in the United States.[43] ## Prevention See also: Safe sex As with most sexually transmitted diseases, the risk of infection can be reduced significantly by the correct use of condoms and can be removed almost entirely by limiting sexual activities to a mutually monogamous relationship with an uninfected person.[44][45] Those previously infected are encouraged to return for follow up care to make sure that the infection has been eliminated. In addition to the use of phone contact, the use of email and text messaging have been found to improve the re-testing for infection.[46] Newborn babies coming through the birth canal are given erythromycin ointment in the eyes to prevent blindness from infection. The underlying gonorrhea should be treated; if this is done then usually a good prognosis will follow.[47] ## Treatment ### Antibiotics Penicillin entered mass production in 1944 and revolutionized the treatment of several venereal diseases. Antibiotics are used to treat gonorrhea infections. As of 2016, both ceftriaxone by injection and azithromycin by mouth are most effective.[4][48][49][50] However, due to increasing rates of antibiotic resistance, local susceptibility patterns must be taken into account when deciding on treatment.[29][51] Adults may have eyes infected with gonorrhoea and require proper personal hygiene and medications.[47] Addition of topical antibiotics have not been shown to improve cure rates compared to oral antibiotics alone in treatment of eye infected gonorrhea.[52] For newborns, erythromycin ointment is recommended as a preventative measure for gonococcal infant conjunctivitis.[53] Among persons in the United States between 14 and 39 years of age, 46% of people with gonorrheal infection also have chlamydial infection.[54] Infections of the throat can be especially problematic, as antibiotics have difficulty becoming sufficiently concentrated there to destroy the bacteria. This is amplified by the fact that pharyngeal gonorrhoea is mostly asymptomatic, and gonococci and commensal Neisseria species can coexist for long time periods in the pharynx and share anti-microbial resistance genes. Accordingly, an enhanced focus on early detection (i.e., screening of high-risk populations, such as men who have sex with men, PCR testing should be considered) and appropriate treatment of pharyngeal gonorrhoea is important.[4] ### Sexual partners It is recommended that sexual partners be tested and potentially treated.[29] One option for treating sexual partners of people infected is patient-delivered partner therapy (PDPT), which involves providing prescriptions or medications to the person to take to his/her partner without the health care provider's first examining him/her.[55] The United States' Centers for Disease Control and Prevention (CDC) currently recommend that individuals who have been diagnosed and treated for gonorrhea avoid sexual contact with others until at least one week past the final day of treatment in order to prevent the spread of the bacterium.[56] ### Antibiotic resistance Main article: Antibiotic resistance in gonorrhea Many antibiotics that were once effective including penicillin, tetracycline, and fluoroquinolones are no longer recommended because of high rates of resistance.[29] Resistance to cefixime has reached a level such that it is no longer recommended as a first-line agent in the United States, and if it is used a person should be tested again after a week to determine whether the infection still persists.[48] Public health officials are concerned that an emerging pattern of resistance may predict a global epidemic.[57] The UK's Health Protection Agency reported that 2011 saw a slight drop in gonorrhea antibiotic resistance, the first in five years.[58] In 2016, the WHO published new guidelines for treatment, stating "There is an urgent need to update treatment recommendations for gonococcal infections to respond to changing antimicrobial resistance (AMR) patterns of N. gonorrhoeae. High-level resistance to previously recommended quinolones is widespread and decreased susceptibility to the extended-spectrum (third-generation) cephalosporins, another recommended first-line treatment in the 2003 guidelines, is increasing and several countries have reported treatment failures."[59] ## Prognosis Disability-adjusted life year for gonorrhea per 100,000 inhabitants no data <13 13–26 26–39 39–52 52–65 65–78 78–91 91–104 104–117 117–130 130–143 >143 Gonorrhea if left untreated may last for weeks or months with higher risks of complications.[15] One of the complications of gonorrhea is systemic dissemination resulting in skin pustules or petechia, septic arthritis, meningitis, or endocarditis.[15] This occurs in between 0.6 and 3% of infected women and 0.4 and 0.7% of infected men.[15] In men, inflammation of the epididymis, prostate gland, and urethra can result from untreated gonorrhea.[60] In women, the most common result of untreated gonorrhea is pelvic inflammatory disease. Other complications include inflammation of the tissue surrounding the liver,[60] a rare complication associated with Fitz-Hugh–Curtis syndrome; septic arthritis in the fingers, wrists, toes, and ankles; septic abortion; chorioamnionitis during pregnancy; neonatal or adult blindness from conjunctivitis; and infertility. Men who have had a gonorrhea infection have an increased risk of getting prostate cancer.[20] ## Epidemiology Gonorrhea rates, United States, 1941–2007 About 88 million cases of gonorrhea occur each year, out of the 448 million new cases of curable STI each year – that also includes syphilis, chlamydia and trichomoniasis.[9] The prevalence was highest in the African region, the Americas, and Western Pacific, and lowest in Europe.[61] In 2013, it caused about 3,200 deaths, up from 2,300 in 1990.[62] In the United Kingdom, 196 per 100,000 males 20 to 24 years old and 133 per 100,000 females 16 to 19 years old were diagnosed in 2005.[15] In 2013, the CDC estimated that more than 820,000 people in the United States get a new gonorrheal infection each year. Fewer than half of these infections are reported to CDC. In 2011, 321,849 cases of gonorrhea were reported to the CDC. After the implementation of a national gonorrhea control program in the mid-1970s, the national gonorrhea rate declined from 1975 to 1997. After a small increase in 1998, the gonorrhea rate has decreased slightly since 1999. In 2004, the rate of reported gonorrheal infections was 113. 5 per 100,000 persons.[63] In the US, it is the second-most-common bacterial sexually transmitted infections; chlamydia remains first.[64][65] According to the CDC African Americans are most affected by gonorrhea, accounting for 69% of all gonorrhea cases in 2010.[66] The World Health Organization warned in 2017 of the spread of untreatable strains of gonorrhea, following analysis of at least three cases in Japan, France and Spain, which survived all antibiotic treatment.[67] ## History During World War II, the U.S. government used posters to warn military personnel about the dangers of gonorrhea and other sexually transmitted infections. Some scholars translate the biblical terms zav (for a male) and zavah (for a female) as gonorrhea.[68] It has been suggested that mercury was used as a treatment for gonorrhea. Surgeons' tools on board the recovered English warship the Mary Rose included a syringe that, according to some, was used to inject the mercury via the urinary meatus into any unfortunate crewman suffering from gonorrhea. The name "the clap", in reference to the disease, is recorded as early as the sixteenth century, referring to a medieval red-light district in Paris, Les Clapiers. Translating to "The rabbit holes", it was so named for the small huts in which prostitutes worked.[69][70] In 1854, Dr. Wilhelm Gollmann addressed gonorrhea in his book, Homeopathic Guide to all Diseases Urinary and Sexual Organs. He noted that the disease was common in prostitutes and homosexuals in large cities. Gollmann recommended the following as cures: aconite to cure "shooting pains with soreness and inflammation;" mercury "for stitching pain with purulent discharge;" nux vomica and sulphur "when the symptoms are complicated with hemorrhoids and stricture of the rectum. Other remedies include argentum, aurum (gold), belladonna, calcarea, ignatia, phosphorus, and sepia.[24] Silver nitrate was one of the widely used drugs in the 19th century. However, it became replaced by Protargol. Arthur Eichengrün invented this type of colloidal silver, which was marketed by Bayer from 1897 onward. The silver-based treatment was used until the first antibiotics came into use in the 1940s.[71][72] The exact time of onset of gonorrhea as prevalent disease or epidemic cannot be accurately determined from the historical record. One of the first reliable notations occurs in the Acts of the (English) Parliament. In 1161, this body passed a law to reduce the spread of "...the perilous infirmity of burning".[73] The symptoms described are consistent with, but not diagnostic of, gonorrhea. A similar decree was passed by Louis IX in France in 1256, replacing regulation with banishment.[74] Similar symptoms were noted at the siege of Acre by Crusaders. Coincidental to, or dependent on, the appearance of a gonorrhea epidemic, several changes occurred in European medieval society. Cities hired public health doctors to treat afflicted patients without right of refusal. Pope Boniface rescinded the requirement that physicians complete studies for the lower orders of the Catholic priesthood.[75] Medieval public health physicians in the employ of their cities were required to treat prostitutes infected with the "burning", as well as lepers and other epidemic victims.[76] After Pope Boniface completely secularized the practice of medicine, physicians were more willing to treat a sexually transmitted disease.[77] ## Research A vaccine for gonorrhea has been developed that is effective in mice.[78] It will not be available for human use until further studies have demonstrated that it is both safe and effective in the human population. Development of a vaccine has been complicated by the ongoing evolution of resistant strains and antigenic variation (the ability of N. gonorrhoeae to disguise itself with different surface markers to evade the immune system).[51] As N. gonorrhoeae is closely related to N. meningitidis and they have 80–90% homology in their genetic sequences some cross-protection by meningococcal vaccines is plausible. A study published in 2017 showed that MeNZB group B meningococcal vaccine provided a partial protection against gonorrhea.[79] The vaccine efficiency was calculated to be 31%.[80] ## References 1. ^ a b c d e f g h i j k l m n o p q "Gonorrhea – CDC Fact Sheet (Detailed Version)". CDC. 17 November 2015. Archived from the original on 2 September 2016. Retrieved 27 August 2016. 2. ^ a b c d Morgan, MK; Decker, CF (August 2016). "Gonorrhea". Disease-a-month : DM. 62 (8): 260–8. doi:10.1016/j.disamonth.2016.03.009. PMID 27107780. 3. ^ a b c d e f Workowski, KA; Bolan, GA (5 June 2015). "Sexually transmitted diseases treatment guidelines, 2015". MMWR. Recommendations and Reports / Centers for Disease Control. 64 (RR-03): 1–137. PMC 5885289. PMID 26042815. 4. ^ a b c d e "Antibiotic-Resistant Gonorrhea Basic Information". CDC. 13 June 2016. Archived from the original on 8 September 2016. Retrieved 27 August 2016. 5. ^ a b c Unemo, M (21 August 2015). "Current and future antimicrobial treatment of gonorrhoea – the rapidly evolving Neisseria gonorrhoeae continues to challenge". BMC Infectious Diseases. 15: 364. doi:10.1186/s12879-015-1029-2. PMC 4546108. PMID 26293005. 6. ^ a b Newman, Lori; Rowley, Jane; Vander Hoorn, Stephen; Wijesooriya, Nalinka Saman; Unemo, Magnus; Low, Nicola; Stevens, Gretchen; Gottlieb, Sami; Kiarie, James; Temmerman, Marleen; Meng, Zhefeng (8 December 2015). "Global Estimates of the Prevalence and Incidence of Four Curable Sexually Transmitted Infections in 2012 Based on Systematic Review and Global Reporting". PLOS ONE. 10 (12): e0143304. Bibcode:2015PLoSO..1043304N. doi:10.1371/journal.pone.0143304. PMC 4672879. PMID 26646541. 7. ^ Leslie Delong; Nancy Burkhart (27 November 2017). General and Oral Pathology for the Dental Hygienist. Wolters Kluwer Health. p. 787. ISBN 978-1-4963-5453-2. 8. ^ Global Burden of Disease Study 2013, Collaborators (22 August 2015). "Global, regional, and national incidence, prevalence, and years lived with disability for 301 acute and chronic diseases and injuries in 188 countries, 1990–2013: a systematic analysis for the Global Burden of Disease Study 2013". Lancet. 386 (9995): 743–800. doi:10.1016/s0140-6736(15)60692-4. PMC 4561509. PMID 26063472. 9. ^ a b Emergence of multi-drug resistant Neisseria gonorrhoeae (PDF) (Report). World Health Organisation. 2012. p. 2. Archived from the original (PDF) on 12 September 2014. 10. ^ GBD 2015 Mortality and Causes of Death, Collaborators. (8 October 2016). "Global, regional, and national life expectancy, all-cause mortality, and cause-specific mortality for 249 causes of death, 1980–2015: a systematic analysis for the Global Burden of Disease Study 2015". Lancet. 388 (10053): 1459–1544. doi:10.1016/s0140-6736(16)31012-1. PMC 5388903. PMID 27733281. 11. ^ a b "Gonorrhea - Symptoms and causes". Mayo Clinic. Retrieved 6 August 2019. 12. ^ Zakher, Bernadette; Cantor MD, Amy G.; Daeges, Monica; Nelson MD, Heidi (16 December 2014). "Review: Screening for Gonorrhea and Chlamydia: A Systematic Review for the U.S. Prevententive Services Task Force". Annals of Internal Medicine. 161 (12): 884–894. CiteSeerX 10.1.1.691.6232. doi:10.7326/M14-1022. PMID 25244000. S2CID 207538182. 13. ^ a b Marr, Lisa (2007) [1998]. Sexually Transmitted Diseases: A Physician Tells You What You Need to Know (Second ed.). Baltimore, Maryland: Johns Hopkins University. ISBN 978-0-8018-8658-4. 14. ^ a b Smith, L; Angarone, MP (November 2015). "Sexually Transmitted Infections". The Urologic Clinics of North America. 42 (4): 507–18. CiteSeerX 10.1.1.590.3827. doi:10.1016/j.ucl.2015.06.004. PMID 26475947. 15. ^ a b c d e f g h i Moran JS (2007). "Gonorrhoea". Clin Evid (Online). 2007. PMC 2943790. PMID 19454057. 16. ^ a b Ljubin-Sternak, Suncanica; Mestrovic, Tomislav (2014). "Review: Chlamydia trachonmatis and Genital Mycoplasmias: Pathogens with an Impact on Human Reproductive Health". Journal of Pathogens. 2014 (183167): 7. doi:10.1155/2014/183167. PMC 4295611. PMID 25614838. 17. ^ a b c "What Complications Can Gonorrhea Cause?". WebMD. 2019. 18. ^ a b c Brian R. Shmaefsky (1 January 2009). Gonorrhea. Infobase. p. 52. ISBN 978-1-4381-0142-2. 19. ^ Liang Cheng; David G. Bostwick (24 January 2014). Urologic Surgical Pathology E-Book. Elsevier Health Sciences. p. 863. ISBN 978-0-323-08619-6. 20. ^ a b Caini, Saverio; Gandini, Sara; Dudas, Maria; Bremer, Viviane; Severi, Ettore; Gherasim, Alin (2014). "Sexually transmitted infections and prostate cancer risk: A systematic review and meta-analysis". Cancer Epidemiology. 38 (4): 329–338. doi:10.1016/j.canep.2014.06.002. PMID 24986642. 21. ^ "Prophylaxis for Gonococcal and Chlamydial Ophthalmia Neonatorum in the Canadian Guide to Clinical Preventative Health Care" (PDF). Public Health Agency of Canada. Archived from the original (PDF) on 10 March 2010. 22. ^ Trebach, Joshua D.; Chaulk, C. Patrick; Page, Kathleen R.; Tuddenham, Susan; Ghanem, Khalil G. (2015). "Neisseria gonorrhoeae and Chlamydia trachomatis Among Women Reporting Extragenital Exposures". Sexually Transmitted Diseases. 42 (5): 233–239. doi:10.1097/OLQ.0000000000000248. ISSN 0148-5717. PMC 4672628. PMID 25868133. 23. ^ Howard Brown Health Center: STI Annual Report, 2009 24. ^ a b Gollmann, Wilhelm (1854). Homeopathic Guide to all Diseases Urinary and Sexual Organ. Charles Julius Hempel. Rademacher & Sheek. 25. ^ National Institute of Allergy and Infectious Diseases; National Institutes of Health, Department of Health and Human Services (20 July 2001). "Workshop Summary: Scientific Evidence on Condom Effectiveness for Sexually Transmitted Disease (STD) Prevention". Hyatt Dulles Airport, Herndon, Virginia. pp14 26. ^ Goodyear-Smith, F (November 2007). "What is the evidence for non-sexual transmission of gonorrhoea in children after the neonatal period? A systematic review". Journal of Forensic and Legal Medicine. 14 (8): 489–502. doi:10.1016/j.jflm.2007.04.001. PMID 17961874. 27. ^ Brian R. Shmaefsky (1 January 2009). Gonorrhea. Infobase. p. 48. ISBN 978-1-4381-0142-2. 28. ^ Barry PM, Klausner JD (March 2009). "The use of cephalosporins for gonorrhea: The impending problem of resistance". Expert Opin Pharmacother. 10 (4): 555–77. doi:10.1517/14656560902731993. PMC 2657229. PMID 19284360. 29. ^ a b c d e Deguchi T, Nakane K, Yasuda M, Maeda S (September 2010). "Emergence and spread of drug resistant Neisseria gonorrhoeae". J. Urol. 184 (3): 851–8, quiz 1235. doi:10.1016/j.juro.2010.04.078. PMID 20643433. 30. ^ a b "Final Recommendation Statement: Chlamydia and Gonorrhea: Screening – US Preventive Services Task Force". uspreventiveservicestaskforce.org. Retrieved 7 December 2017. 31. ^ "Gonococcal Infections – 2015 STD Treatment Guidelines". cdc.gov. Retrieved 7 December 2017. 32. ^ Levinson, Warren (1 July 2014). Review of medical microbiology and immunology (Thirteenth ed.). New York. ISBN 9780071818117. OCLC 871305336. 33. ^ a b c Ng, Lai-King; Martin, Irene E (2005). "The laboratory diagnosis of Neisseria gonorrhoeae". The Canadian Journal of Infectious Diseases & Medical Microbiology. 16 (1): 15–25. doi:10.1155/2005/323082. ISSN 1712-9532. PMC 2095009. PMID 18159523. 34. ^ a b c https://www.cdc.gov/std/tg2015/clinical.htm section on prevention methods 35. ^ Gonorrhea~overview at eMedicine 36. ^ Kahn, Richard H.; Mosure, Debra J.; Blank, Susan; Kent, Charlotte K.; Chow, Joan M.; Boudov, Melina R.; Brock, Jeffrey; Tulloch, Scott; Jail STD Prevalence Monitoring Project (April 2005). "Chlamydia trachomatis and Neisseria gonorrhoeae prevalence and coinfection in adolescents entering selected US juvenile detention centers, 1997–2002". Sexually Transmitted Diseases. 32 (4): 255–259. doi:10.1097/01.olq.0000158496.00315.04. ISSN 0148-5717. PMID 15788927. S2CID 20864079. 37. ^ Dicker, Linda W.; Mosure, Debra J.; Berman, Stuart M.; Levine, William C. (May 2003). "Gonorrhea prevalence and coinfection with chlamydia in women in the United States, 2000". Sexually Transmitted Diseases. 30 (5): 472–476. doi:10.1097/00007435-200305000-00016. ISSN 0148-5717. PMID 12916141. S2CID 39361152. 38. ^ "Gonococcal Infections - 2015 STD Treatment Guidelines". 4 January 2018. 39. ^ Ryan, KJ; Ray, CG, eds. (2004). Sherris Medical Microbiology (4th ed.). McGraw Hill. ISBN 978-0-8385-8529-0.[page needed] 40. ^ Department of Reproductive Health and Research (2011). "Emergence of multi-drug resistant Neisseria gonorrhoeae – Threat of global rise in untreatable sexually transmitted infections" (PDF). FactSheet WHO/RHR/11.14. World Health Organization. 41. ^ "Gonorrhea – STD information from CDC". cdc.gov. 6 October 2017. Retrieved 5 December 2017. 42. ^ Meyers D; Wolff T; Gregory K; et al. (March 2008). "USPSTF recommendations for STI screening". Am Fam Physician. 77 (6): 819–24. PMID 18386598. 43. ^ Health Care Guideline: Routine Prenatal Care. Fourteenth Edition. Archived 5 July 2008 at the Wayback Machine By the Institute for Clinical Systems Improvement July 2010. 44. ^ section: Prevention Archived 20 July 2013 at the Wayback Machine 45. ^ section: How can gonorrhea be prevented? Archived 16 December 2016 at the Wayback Machine 46. ^ Desai, Monica; Woodhall, Sarah C; Nardone, Anthony; Burns, Fiona; Mercey, Danielle; Gilson, Richard (2015). "Active recall to increase HIV and STI testing: a systematic review". Sexually Transmitted Infections. 91 (5): sextrans–2014–051930. doi:10.1136/sextrans-2014-051930. ISSN 1368-4973. PMID 25759476. 47. ^ a b Sadowska-Przytocka, A; Czarnecka-Operacz, M; Jenerowicz, D; Grzybowski, A (2016). "Ocular manifestations of infectious skin diseases". Clinics in Dermatology. 34 (2): 124–8. doi:10.1016/j.clindermatol.2015.11.010. PMID 26903179. 48. ^ a b Centers for Disease Control and Prevention, (CDC) (10 August 2012). "Update to CDC's Sexually Transmitted Diseases Treatment Guidelines, 2010: Oral Cephalosporins No Longer a Recommended Treatment for Gonococcal Infections". MMWR. Morbidity and Mortality Weekly Report. 61 (31): 590–4. PMID 22874837. 49. ^ "Antibiotic-resistant gonorrhoea on the rise, new drugs needed". World Health Organization. 7 July 2017. Archived from the original on 9 July 2017. Retrieved 10 July 2017. 50. ^ Sánchez-Busó, Leonor; Golparian, Daniel; Corander, Jukka; Grad, Yonatan H.; Ohnishi, Makoto; Flemming, Rebecca; Parkhill, Julian; Bentley, Stephen D.; Unemo, Magnus (29 July 2019). "The impact of antimicrobials on gonococcal evolution". Nature Microbiology. 4 (11): 1941–1950. doi:10.1038/s41564-019-0501-y. ISSN 2058-5276. PMC 6817357. PMID 31358980. 51. ^ a b Baarda, Benjamin I.; Sikora, Aleksandra E. (2015). "Proteomics of Neisseria gonorrhoeae: the treasure hunt for countermeasures against an old disease". Frontiers in Microbiology. 6: 1190. doi:10.3389/fmicb.2015.01190. ISSN 1664-302X. PMC 4620152. PMID 26579097; Access provided by the University of Pittsburgh. 52. ^ Epling, John (20 February 2012). "Bacterial conjunctivitis". BMJ Clinical Evidence. 2012. ISSN 1752-8526. PMC 3635545. PMID 22348418. 53. ^ US Preventive Services Task Force; Curry, Susan J.; Krist, Alex H.; Owens, Douglas K.; Barry, Michael J.; Caughey, Aaron B.; Davidson, Karina W.; Doubeni, Chyke A.; Epling, John W. (29 January 2019). "Ocular Prophylaxis for Gonococcal Ophthalmia Neonatorum: US Preventive Services Task Force Reaffirmation Recommendation Statement". JAMA. 321 (4): 394–398. doi:10.1001/jama.2018.21367. ISSN 1538-3598. PMID 30694327. 54. ^ Datta, SD; Sternberg, M; Johnson, RE; Berman, S; Papp, JR; McQuillan, G; Weinstock, H (17 July 2007). "Gonorrhea and chlamydia in the United States among persons 14 to 39 years of age, 1999 to 2002". Annals of Internal Medicine. 147 (2): 89–96. doi:10.7326/0003-4819-147-2-200707170-00007. PMID 17638719. 55. ^ "Expedited partner therapy in the management of sexually transmitted diseases" Archived 2 November 2009 at the Wayback Machine. February 2006. Centers for Disease Control and Prevention (CDC). 56. ^ CDC (14 July 2014). "Gonorrhea – CDC Fact Sheet". Archived from the original on 16 December 2016. Retrieved 17 October 2014. 57. ^ Groopman, Jerome (1 October 2012). "Sex and the Superbug". The New Yorker. LXXXVIII (30): 26–31. Archived from the original on 9 October 2012. Retrieved 13 October 2012. "...public-health experts [see]...the emergence of a strain of gonorrhea that is resistant to the last drug available against it, and the harbinger of a sexually transmitted global epidemic." 58. ^ "Gonorrhoea treatment resistance risk falls but new diagnoses rise". Health Protection Agency. 12 September 2012. Archived from the original on 14 July 2014. 59. ^ "WHO guidelines for the treatment of Neisseria gonorrhoeae". World Health Organization. 2016. Retrieved 24 September 2020. 60. ^ a b Kumar, Vinay; Abbas, Abul K.; Fausto, Nelson; & Mitchell, Richard N. (2007). Robbins Basic Pathology (8th ed.). Saunders Elsevier. pp. 705–706 ISBN 978-1-4160-2973-1 61. ^ Kirkcaldy, R. D.; Weston, E.; Segurado, A. C.; Hughes, G. (September 2019). "Epidemiology of Gonorrhea: A Global Perspective". Sex Health. United States National Library of Medicine. 16 (5): 401–411. doi:10.1071/SH19061. PMC 7064409. PMID 31505159. 62. ^ GBD 2013 Mortality and Causes of Death, Collaborators (10 January 2015). "Global, regional, and national age-sex specific all-cause and cause-specific mortality for 240 causes of death, 1990–2013: a systematic analysis for the Global Burden of Disease Study 2013". Lancet. 385 (9963): 117–71. doi:10.1016/s0140-6736(14)61682-2. PMC 4340604. PMID 25530442. 63. ^ "Gonorrhea – CDC Fact Sheet". CDC. 29 May 2012. Archived from the original on 16 December 2016. Retrieved 20 December 2013. 64. ^ "CDC – STD Surveillance – Gonorrhea". Archived from the original on 6 March 2008. Retrieved 21 August 2008. 65. ^ "CDC Fact Sheet – Chlamydia". Archived from the original on 16 December 2016. Retrieved 21 August 2008. 66. ^ "STD Trends in the United States: 2010 National Data for Gonorrhea, Chlamydia, and Syphilis". Centers for Disease Control and Prevention (CDC). 22 November 2010. Archived from the original on 24 January 2012. 67. ^ "Untreatable gonorrhoea 'superbug' spreading around world, WHO warns". The Daily Telegraph. 7 July 2017. Archived from the original on 7 July 2017. 68. ^ "Daf Parashat Hashavua". Archived from the original on 3 October 2012. Retrieved 2 November 2012. 69. ^ Higgins, John (1587). The Mirror for Magistrates. as cited in the Oxford English Dictionary entry for "clap" 70. ^ Baarda, Benjamin I; Sikora, Aleksandra E (2015). "Proteomics of Neisseria gonorrhoeae: The treasure hunt for countermeasures against an old disease". Frontiers in Microbiology. 6: 1190. doi:10.3389/fmicb.2015.01190. PMC 4620152. PMID 26579097. 71. ^ Max Bender (1898). "Ueber neuere Antigonorrhoica (insbes. Argonin und Protargol)". Archives of Dermatological Research. 43 (1): 31–36. doi:10.1007/BF01986890. S2CID 45492365. 72. ^ MedlinePlus Encyclopedia: Neonatal Conjunctivitis 73. ^ W Sanger. History of Prostitution. NY, Harper, 1910. 74. ^ P. LaCroix. The History of Prostitution—Vol. 2. NY, MacMillan, 1931. 75. ^ Moen, Juliann (2017). Basic Healthcare Studies: Sexually Transmitted Disease. Lester Bivens. Alpha Editions. ISBN 9789386367570. 76. ^ WE Leiky. History of European Morals. NY, MacMillan, 1926. 77. ^ Moen, Juliann (2017). Basic Healthcare Studies: Sexually Transmitted Disease. Lester Bivens. Alpha Editions. ISBN 9789386367570. 78. ^ Jerse, AE; Bash, MC; Russell, MW (20 March 2014). "Vaccines against gonorrhea: current status and future challenges". Vaccine. 32 (14): 1579–87. doi:10.1016/j.vaccine.2013.08.067. PMC 4682887. PMID 24016806. 79. ^ Gottlieb, Sami L.; Johnston, Christine (2017). "Future prospects for new vaccines against sexually transmitted infections". Curr Opin Infect Dis. 30 (1): 77–86. doi:10.1097/QCO.0000000000000343. PMC 5325242. PMID 27922851. 80. ^ Petousis-Harris, Helen (2017). "Effectiveness of a group B outer membrane vesicle meningococcal vaccine against gonorrhoea in New Zealand: a retrospective case-control study". Lancet. 390 (10102): 1603–1610. doi:10.1016/S0140-6736(17)31449-6. PMID 28705462. S2CID 4230156. ## External links Wikimedia Commons has media related to Gonorrhea. * Gonorrhea at Curlie * "Gonorrhea – CDC Fact Sheet" Classification D * ICD-10: A54 * ICD-9-CM: 098 * MeSH: D006069 * DiseasesDB: 8834 External resources * MedlinePlus: 007267 * eMedicine: article/782913 * Patient UK: Gonorrhea * v * t * e Sexually transmitted infections (STI) Bacterial * Chancroid (Haemophilus ducreyi) * Chlamydia, lymphogranuloma venereum (Chlamydia trachomatis) * Donovanosis (Klebsiella granulomatis) * Gonorrhea (Neisseria gonorrhoeae) * Mycoplasma hominis infection (Mycoplasma hominis) * Syphilis (Treponema pallidum) * Ureaplasma infection (Ureaplasma urealyticum) Protozoal * Trichomoniasis (Trichomonas vaginalis) Parasitic * Crab louse * Scabies Viral * AIDS (HIV-1/HIV-2) * Cancer * cervical * vulvar * penile * anal * Human papillomavirus (HPV) * Genital warts (condyloma) * Hepatitis B (Hepatitis B virus) * Herpes simplex * HSV-1 & HSV-2 * Molluscum contagiosum (MCV) General inflammation female Cervicitis Pelvic inflammatory disease (PID) male Epididymitis Prostatitis either Proctitis Urethritis/Non-gonococcal urethritis (NGU) * 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 Authority control * GND: 4138035-6 * LCCN: sh85055863 * NDL: 00569533 [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	Gonorrhea	c0018081	775	wikipedia	https://en.wikipedia.org/wiki/Gonorrhea	2021-01-18T18:28:51	{"mesh": ["D006069"], "umls": ["C0018081"], "wikidata": ["Q101896"]}
## Description Focal dystonia, the most common form of dystonia, is often task-specific and referred to as FTSD. Specific learned motor tasks, such as writing or playing a musical instrument, can trigger muscle spasms and interfere with performance while other actions are unaffected. FTSD has a frequency of 1 in 3,400 in the general population but increases to 1 in 200 among musicians (Pullman and Hristova, 2005). Clinical Features Schmidt et al. (2006) reported 3 unrelated families in which the proband presented with musician's dystonia: 1 pianist and 2 guitarists. All probands had 2 or 3 family members with other forms of focal dystonia, mainly writer's cramp and 1 case of 'handicraft' dystonia while threading needles. Inheritance in all families was consistent with autosomal dominant. All but 1 affected individuals had onset of dystonia in the third or fourth decade. Two affected family members were professional musicians, but had only writer's cramp and no musician's dystonia. Conversely, 1 of the probands had both musician's dystonia and writer's cramp. The disorder was triggered by increased practice in about half of the affected individuals. All had an upper limb dystonia, and none carried common DYT1 mutations (TOR1A; 605204). Schmidt et al. (2006) concluded that musician's dystonia is not necessarily a sporadic condition and that there is a genetic contribution to focal task-specific dystonia with phenotypic variability, including musician's dystonia. Inheritance Schmidt et al. (2009) gathered information on families of 28 unrelated individuals with musician's dystonia, 14 of whom reported a positive family history of focal dystonia. The age of the probands ranged from 27 to 74 years, and most were German. Twenty-four patients (86%) had upper limb dystonias, and 4 (14%) had embouchure dystonias affecting the mouth. The age at onset of dystonia ranged from 16 to 66 years. Nineteen (20%) of 97 examined relatives were found to have dystonia, including 8 with musician's dystonia, 9 with FTSD, and 2 with other dystonias, and 5 of the 19 affected relatives came from families in which probands had reported negative family history of dystonia. Twenty-seven (62%) of the 47 affected individuals had additional forms of dystonia, and 23 had other more generalized movement disorders. In total, 18 (64%) families were multiplex, with 2 to 4 members having dystonia. Autosomal dominant inheritance was suggested in at least 12 families. The findings suggested that there is a genetic component to musician's dystonia, and that phenotypic variability includes focal task-specific dystonia. None of the affected individuals had a mutation in the DYT1 gene. INHERITANCE \- Autosomal dominant NEUROLOGIC Central Nervous System \- Focal dystonia, upper limb \- Writer's cramp \- Musician's cramp MISCELLANEOUS \- Onset in third or fourth decade \- May be progressive \- May be triggered by increased practice ▲ 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	DYSTONIA, FOCAL, TASK-SPECIFIC	c1969807	776	omim	https://www.omim.org/entry/611284	2019-09-22T16:03:24	{"mesh": ["C566973"], "omim": ["611284"]}
State in which the immune system's ability to fight infectious disease and cancer is compromised or absent 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: "Immunodeficiency" – news · newspapers · books · scholar · JSTOR (November 2007) (Learn how and when to remove this template message) Immunodeficiency Other namesImmunocompromisation, immune deficiency SpecialtyImmunology Immunodeficiency, also known as immunocompromisation, is a state in which the immune system's ability to fight infectious diseases and cancer is compromised or entirely absent. Most cases are acquired ("secondary") due to extrinsic factors that affect the patient's immune system. Examples of these extrinsic factors include HIV infection and environmental factors, such as nutrition.[1] Immunocompromisation may also be due to genetic diseases/flaws. An example here is SCID. In clinical settings, immunosuppression by some drugs, such as steroids, can either be an adverse effect or the intended purpose of the treatment. Examples of such use is in organ transplant surgery as an anti-rejection measure and in patients suffering from an overactive immune system, as in autoimmune diseases. Some people are born with intrinsic defects in their immune system, or primary immunodeficiency.[2] A person who has an immunodeficiency of any kind is said to be immunocompromised. An immunocompromised individual may particularly be vulnerable to opportunistic infections, in addition to normal infections that could affect anyone.[3] It also decreases cancer immunosurveillance, in which the immune system scans the body's cells and kills neoplastic ones. ## Contents * 1 Types * 1.1 By affected component * 1.2 Primary or secondary * 1.2.1 Primary immunodeficiency * 1.2.2 Secondary immunodeficiencies * 2 Immunodeficiency and autoimmunity * 3 Causes * 4 Treatment * 5 Prognosis * 6 See also * 7 References * 8 External links ## Types[edit] ### By affected component[edit] * Humoral immune deficiency (including B cell deficiency or dysfunction), with signs or symptoms depending on the cause, but generally include signs of hypogammaglobulinemia (decrease of one or more types of antibodies) with presentations including repeated mild respiratory infections, and/or agammaglobulinemia (lack of all or most antibody production) which results in frequent severe infections and is often fatal.[4] * T cell deficiency, often causes secondary disorders such as acquired immune deficiency syndrome (AIDS).[5] * Granulocyte deficiency, including decreased numbers of granulocytes (called as granulocytopenia or, if absent, agranulocytosis) such as of neutrophil granulocytes (termed neutropenia). Granulocyte deficiencies also include decreased function of individual granulocytes, such as in chronic granulomatous disease. * Asplenia, where there is no function of the spleen * Complement deficiency is where the function of the complement system is deficient In reality, immunodeficiency often affects multiple components, with notable examples including severe combined immunodeficiency (which is primary) and acquired immune deficiency syndrome (which is secondary). Comparison of immunodeficiencies by affected component Affected components Main causes[6] Main pathogens of resultant infections[6] Humoral immune deficiency B cell deficiency B cells, plasma cells or antibodies * Primary humoral * Multiple myeloma * Chronic lymphoid leukemia * AIDS * Streptococcus pneumoniae * Hemophilus influenzae * Pneumocystis jirovecii * Giardia intestinalis * Cryptosporidium parvum T cell deficiency T cells * Marrow and other transplantation * AIDS * Cancer chemotherapy * Lymphoma * Glucocorticoid therapy Intracellular pathogens, including Herpes simplex virus, Mycobacterium, Listeria,[7] and intracellular fungal infections.[6] Neutropenia Neutrophil granulocytes * Chemotherapy * Bone marrow transplantation * Dysfunction, such as chronic granulomatous disease * Enterobacteriaceae * Oral Streptococci * Pseudomonas aeruginosa * Enterococcus species * Candida species * Aspergillus species Asplenia Spleen * Splenectomy * Trauma * Sickle-cell anemia * Polysaccharide encapsulated bacteria,[8] particularly: * Streptococcus pneumoniae[8] * Haemophilus influenzae[8] * Neisseria meningitidis[8] * Plasmodium species * Babesia species Complement deficiency Complement system * Congenital deficiencies * Neisseria species * Streptococcus pneumoniae ### Primary or secondary[edit] The distinction between primary versus secondary immunodeficiencies is based on, respectively, whether the cause originates in the immune system itself or is, in turn, due to insufficiency of a supporting component of it or an external decreasing factor of it. #### Primary immunodeficiency[edit] Main article: Primary immunodeficiency A number of rare diseases feature a heightened susceptibility to infections from childhood onward. Primary Immunodeficiency is also known as congenital immunodeficiencies.[9] Many of these disorders are hereditary and are autosomal recessive or X-linked. There are over 95 recognised primary immunodeficiency syndromes; they are generally grouped by the part of the immune system that is malfunctioning, such as lymphocytes or granulocytes.[10] The treatment of primary immunodeficiencies depends on the nature of the defect, and may involve antibody infusions, long-term antibiotics and (in some cases) stem cell transplantation. The characteristics of lacking and/or impaired antibody functions can be related to illnesses such as X-Linked Agammaglobulinemia and Common Variable Immune Deficiency [11] #### Secondary immunodeficiencies[edit] Further information: Immunosuppression Secondary immunodeficiencies, also known as acquired immunodeficiencies, can result from various immunosuppressive agents, for example, malnutrition, aging, particular medications (e.g., chemotherapy, disease-modifying antirheumatic drugs, immunosuppressive drugs after organ transplants, glucocorticoids) and environmental toxins like mercury and other heavy metals, pesticides and petrochemicals like styrene, dichlorobenzene, xylene, and ethylphenol. For medications, the term immunosuppression generally refers to both beneficial and potential adverse effects of decreasing the function of the immune system, while the term immunodeficiency generally refers solely to the adverse effect of increased risk for infection. Many specific diseases directly or indirectly cause immunosuppression. This includes many types of cancer, particularly those of the bone marrow and blood cells (leukemia, lymphoma, multiple myeloma), and certain chronic infections. Immunodeficiency is also the hallmark of acquired immunodeficiency syndrome (AIDS),[9] caused by the human immunodeficiency virus (HIV). HIV directly infects a small number of T helper cells, and also impairs other immune system responses indirectly. Various hormonal and metabolic disorders can also result in immune deficiency including anemia, hypothyroidism and hyperglycemia. Smoking, alcoholism and drug abuse also depress immune response. ## Immunodeficiency and autoimmunity[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. (November 2016) (Learn how and when to remove this template message) There are a large number of immunodeficiency syndromes that present clinical and laboratory characteristics of autoimmunity. The decreased ability of the immune system to clear infections in these patients may be responsible for causing autoimmunity through perpetual immune system activation.[12] This section may be too technical for most readers to understand. Please help improve it to make it understandable to non-experts, without removing the technical details. (November 2016) (Learn how and when to remove this template message) One example is common variable immunodeficiency (CVID) where multiple autoimmune diseases are seen, e.g., inflammatory bowel disease, autoimmune thrombocytopenia, and autoimmune thyroid disease. Familial hemophagocytic lymphohistiocytosis, an autosomal recessive primary immunodeficiency, is another example. Low blood levels of red blood cells, white blood cells, and platelets, rashes, lymph node enlargement, and enlargement of the liver and spleen are commonly seen in these patients. Presence of multiple uncleared viral infections due to lack of perforin are thought to be responsible. In addition to chronic and/or recurrent infections many autoimmune diseases including arthritis, autoimmune hemolytic anemia, scleroderma and type 1 diabetes are also seen in X-linked agammaglobulinemia (XLA). Recurrent bacterial and fungal infections and chronic inflammation of the gut and lungs are seen in chronic granulomatous disease (CGD) as well. CGD is caused by a decreased production of [nicotinamide adenine dinucleotide phosphate]] (NADPH) oxidase by neutrophils. Hypomorphic RAG mutations are seen in patients with midline granulomatous disease; an autoimmune disorder that is commonly seen in patients with granulomatosis with polyangiitis and NK/T cell lymphomas. Wiskott–Aldrich syndrome (WAS) patients also present with eczema, autoimmune manifestations, recurrent bacterial infections and lymphoma. In autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) also autoimmunity and infections coexist: organ-specific autoimmune manifestations (e.g., hypoparathyroidism and adrenocortical failure) and chronic mucocutaneous candidiasis. Finally, IgA deficiency is also sometimes associated with the development of autoimmune and atopic phenomena. ## Causes[edit] The cause of immunodeficiency varies depending on the nature of the disorder. The cause can be either genetic or acquired by malnutrition and poor sanitary conditions.[13][14] Only for some genetic causes, the exact genes are known.[15] ## Treatment[edit] Available treatment falls into two modalities: treating infections and boosting the immune system. Prevention of Pneumocystis pneumonia using trimethoprim/sulfamethoxazole is useful in those who are immunocompromised.[16] In the early 1950s Immunoglobulin(Ig) was used by doctors to treat patients with primary immunodeficiency through intramuscular injection. Ig replacement therapy are infusions that can be either subcutaneous or intravenously administrated, resulting in higher Ig levels for about three to four weeks, although this varies with each patient.[11] ## Prognosis[edit] Prognosis depends greatly on the nature and severity of the condition. Some deficiencies cause early mortality (before age one), others with or even without treatment are lifelong conditions that cause little mortality or morbidity. Newer stem cell transplant technologies may lead to gene based treatments of debilitating and fatal genetic immune deficiencies. Prognosis of acquired immune deficiencies depends on avoiding or treating the causative agent or condition (like AIDS). ## See also[edit] * Acquired immune deficiency syndrome (AIDS) * Immune disorder * Autoimmune disease, immune response to self-proteins * Allergy, immune response to harmless non-self proteins * Histamine * Immunosenescence, age-associated immune deficiency * Steroids, commonly administered drugs like prednisone that suppress the immune system * Human genetic enhancement * Immune system * Immunology ## References[edit] 1. ^ Chinen J, Shearer WT (February 2010). "Secondary immunodeficiencies, including HIV infection". The Journal of Allergy and Clinical Immunology. 125 (2 Suppl 2): S195–203. doi:10.1016/j.jaci.2009.08.040. PMC 6151868. PMID 20042227. 2. ^ "Primary immunodeficiency". Mayo Clinic. 30 January 2020. Retrieved 13 May 2020. 3. ^ Meidani, Mohsen; Naeini, Alireza Emami; Rostami, Mojtaba; Sherkat, Roya; Tayeri, Katayoun (March 2014). "Immunocompromised patients: Review of the most common infections happened in 446 hospitalized patients". Journal of Research in Medical Sciences. 19 (Suppl 1): S71–S73. ISSN 1735-1995. PMC 4078380. PMID 25002900. 4. ^ Greenberg S. "Immunodeficiency". University of Toronto. Archived from the original on 10 July 2013. 5. ^ Schwartz RA (2019-10-22). Jyonouchi H (ed.). "T-cell Disorders". Medscape. 6. ^ a b c If not otherwise specified in boxes, then reference for entries is: Page 432, Chapter 22, Table 22.1 in: Jones J, Bannister BA, Gillespie SH (2006). Infection: Microbiology and Management. Wiley-Blackwell. ISBN 978-1-4051-2665-6. 7. ^ Page 435 in: Jones J, Bannister BA, Gillespie SH (2006). Infection: Microbiology and Management. Wiley-Blackwell. ISBN 978-1-4051-2665-6. 8. ^ a b c d Brigden ML (February 2001). "Detection, education and management of the asplenic or hyposplenic patient". American Family Physician. 63 (3): 499–506, 508. PMID 11272299. 9. ^ a b Basic Immunology: Functions and Disorders of the Immune System, 3rd Ed. 2011. 10. ^ Rosen FS, Cooper MD, Wedgwood RJ (August 1995). "The primary immunodeficiencies". The New England Journal of Medicine. 333 (7): 431–40. doi:10.1056/NEJM199508173330707. PMID 7616993. 11. ^ a b "Immune Deficiency Foundation". primaryimmune.org. Retrieved 2017-04-17. 12. ^ Grammatikos AP, Tsokos GC (February 2012). "Immunodeficiency and autoimmunity: lessons from systemic lupus erythematosus". Trends in Molecular Medicine. 18 (2): 101–8. doi:10.1016/j.molmed.2011.10.005. PMC 3278563. PMID 22177735. 13. ^ "Nutrition and Immunity". The Nutrition Source. Harvard T.H. Chan School of Public Health. Retrieved 8 November 2020. 14. ^ Bourke CD, Berkley JA, Prendergast AJ (2016). "Immune Dysfunction as a Cause and Consequence of Malnutrition". Trends in Immunology. 37 (6): 386–398. doi:10.1016/j.it.2016.04.003. PMC 4889773. PMID 27237815. Retrieved 10 May 2020. 15. ^ Immunobiology: The Immune System in Health and Disease. 5th edition., figure 11.8 16. ^ Stern A, Green H, Paul M, Vidal L, Leibovici L (October 2014). "Prophylaxis for Pneumocystis pneumonia (PCP) in non-HIV immunocompromised patients". The Cochrane Database of Systematic Reviews. 10 (10): CD005590. doi:10.1002/14651858.CD005590.pub3. PMC 6457644. PMID 25269391. ## External links[edit] Classification D * ICD-10: D84.9 * ICD-9-CM: 279.3 * MeSH: D007153 * DiseasesDB: 21506 * SNOMED CT: 234532001 External resources * Patient UK: Immunodeficiency * Immune Deficiency Foundation * The European Society of Immunodeficiencies * v * t * e Lymphocytic adaptive immune system and complement Lymphoid Antigens * Antigen * Superantigen * Allergen * Antigenic variation * Hapten * Epitope * Linear * Conformational * Mimotope * Antigen presentation/professional APCs: Dendritic cell * Macrophage * B cell * Immunogen Antibodies * Antibody * Monoclonal antibodies * Polyclonal antibodies * Autoantibody * Microantibody * Polyclonal B cell response * Allotype * Isotype * Idiotype * Immune complex * Paratope Immunity vs. tolerance * Action: Immunity * Autoimmunity * Alloimmunity * Allergy * Hypersensitivity * Inflammation * Cross-reactivity * Inaction: Tolerance * Central * Peripheral * Clonal anergy * Clonal deletion * Tolerance in pregnancy * Immunodeficiency * Immune privilege Immunogenetics * Affinity maturation * Somatic hypermutation * Clonal selection * V(D)J recombination * Junctional diversity * Immunoglobulin class switching * MHC/HLA Lymphocytes * Cellular * T cell * Humoral * B cell * NK cell Substances * Cytokines * Opsonin * Cytolysin * v * t * e Lymphoid and complement disorders causing immunodeficiency Primary Antibody/humoral (B) Hypogammaglobulinemia * X-linked agammaglobulinemia * Transient hypogammaglobulinemia of infancy Dysgammaglobulinemia * IgA deficiency * IgG deficiency * IgM deficiency * Hyper IgM syndrome (1 * 2 * 3 * 4 * 5) * Wiskott–Aldrich syndrome * Hyper-IgE syndrome Other * Common variable immunodeficiency * ICF syndrome T cell deficiency (T) * thymic hypoplasia: hypoparathyroid (Di George's syndrome) * euparathyroid (Nezelof syndrome * Ataxia–telangiectasia) peripheral: Purine nucleoside phosphorylase deficiency * Hyper IgM syndrome (1) Severe combined (B+T) * x-linked: X-SCID autosomal: Adenosine deaminase deficiency * Omenn syndrome * ZAP70 deficiency * Bare lymphocyte syndrome Acquired * HIV/AIDS Leukopenia: Lymphocytopenia * Idiopathic CD4+ lymphocytopenia Complement deficiency * C1-inhibitor (Angioedema/Hereditary angioedema) * Complement 2 deficiency/Complement 4 deficiency * MBL deficiency * Properdin deficiency * Complement 3 deficiency * Terminal complement pathway deficiency * Paroxysmal nocturnal hemoglobinuria * Complement receptor deficiency * v * t * e Diseases of monocytes and granulocytes Monocytes and macrophages ↑ -cytosis: * Monocytosis * Histiocytosis * Chronic granulomatous disease ↓ -penia: * Monocytopenia Granulocytes ↑ -cytosis: * granulocytosis * Neutrophilia * Eosinophilia/Hypereosinophilic syndrome * Basophilia * Bandemia ↓ -penia: * Granulocytopenia/agranulocytosis (Neutropenia/Severe congenital neutropenia/Cyclic neutropenia * Eosinopenia * Basopenia) Disorder of phagocytosis Chemotaxis and degranulation * Leukocyte adhesion deficiency * LAD1 * LAD2 * Chédiak–Higashi syndrome * Neutrophil-specific granule deficiency Respiratory burst * Chronic granulomatous disease * Neutrophil immunodeficiency syndrome * Myeloperoxidase deficiency * Biology portal * Medicine portal [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor *[BMI]: body mass index	Immunodeficiency	c0003257	777	wikipedia	https://en.wikipedia.org/wiki/Immunodeficiency	2021-01-18T18:42:18	{"mesh": ["D007153"], "icd-9": ["281.2"], "icd-10": ["D84.9"], "wikidata": ["Q641307"]}
Cohen syndrome is a congenital (present since birth) condition that was first described in 1973 by Dr. M.M. Cohen, Jr. When the syndrome was first described, it was believed that its main features were obesity, hypotonia (low muscle tone), intellectual disabilities, distinctive facial features with prominent upper central teeth and abnormalities of the hands and feet. Since Cohen syndrome was first described, over 100 cases have been reported worldwide. It is now known that the signs and symptoms present in people with Cohen syndrome may vary considerably. Although the exact cause of Cohen syndrome is unknown, some people with the condition have been found to have mutations in a gene called COH1 (also referred to as VPS13B). When Cohen syndrome is found to be inherited in families, it follows an autosomal recessive pattern. No cure is currently available; however, treatment for Cohen syndrome is focused on improving or alleviating signs and symptoms as they arise. [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	Cohen syndrome	c0265223	778	gard	https://rarediseases.info.nih.gov/diseases/6126/cohen-syndrome	2021-01-18T18:01:14	{"mesh": ["C536438"], "omim": ["216550"], "umls": ["C0265223"], "orphanet": ["193"], "synonyms": ["COH1", "Pepper syndrome", "Hypotonia, obesity, and prominent incisors"]}
Split hand foot malformation (SHFM) is a type of birth defect that consists of missing digits (fingers and/or toes), a deep cleft down the center of the hand or foot, and fusion of remaining digits. The severity of this condition varies widely among affected individuals. SHFM is sometimes called ectrodactyly; however, this is a nonspecific term used to describe missing digits. SHFM may occur by itself (isolated) or it may be part of a syndrome with abnormalities in other parts of the body. At least six different forms of isolated SHFM have been described. Each type is associated with a different underlying genetic cause. SHFM1 has been linked to chromosome 7, and SHFM2 is linked to the X chromosome. SHFM3 is caused by a duplication of chromosome 10 at position 10q24. Changes (mutations) in the TP63 gene cause SHFM4. SHFM5 is linked to chromosome 2, and SHFM6 is caused by mutations in the WNT10B gene. SHFM may be inherited in an autosomal dominant, autosomal recessive, or X-linked manner. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor *[BMI]: body mass index	Split hand/foot malformation X-linked	c1839258	779	gard	https://rarediseases.info.nih.gov/diseases/4968/split-handfoot-malformation-x-linked	2021-01-18T17:57:33	{"mesh": ["C564056"], "omim": ["313350"], "synonyms": ["SHFM2", "Split hand foot deformity 2", "SHFD2", "Split hand foot anomaly - X-linked", "SHSF2"]}
A rare disease characterised by myopathy with severe exercise intolerance and deficiencies of skeletal muscle succinate dehydrogenase and aconitase. ## Epidemiology It has been described in 19 individuals from nine families from northern Sweden. ## Clinical description Onset of the exercise intolerance occurs during childhood. Mild physical activity is associated with cardiac palpitations, lactic acidosis, muscle fatigue and weakness, and dyspnoea. Intense physical activity may trigger acute episodes associated with profound muscle weakness with pain and swelling, myoglobinuria, and in severe cases, extensive muscle paralysis and circulatory shock. Hypertrophy of the calves was also noted in some patients. ## Etiology Myopathy with succinate dehydrogenase and aconitase deficiency is transmitted in an autosomal recessive manner and has recently been found to be caused by mutations in the gene encoding the iron-sulphur cluster scaffold protein (ISCU; 12q24.1). ISCU plays an important role in iron-sulphur cluster assembly and is therefore essential for the activity mitochondrial iron-sulphur proteins such as succinate dehydrogenase and aconitase. ## Diagnostic methods Diagnosis requires physiological, biochemical and histochemical analysis. Exercise tests reveal low physical work tolerance with reduced oxidative capacity, low maximal muscle oxygen extraction and a hyperkinetic circulatory response (exaggerated cardiac output relative to the rate of oxygen consumption). Increased work loads result in high lactate and pyruvate concentrations in the blood. Analysis of skeletal muscle biopsies reveals the deficiencies in succinate dehydrogenase and aconitase. Histochemical studies also reveal the presence of iron-rich inclusions in the mitochondria, indicative of mitochondrial iron overload. Identification of ISCU as the causative gene may now allow confirmation of the diagnosis by molecular analysis. ## Management and treatment At present, there is no treatment for the disease. The recent discovery of the genetic defect may lead to the development of new therapeutic approaches revolving around correction of the defect in intracellular iron homeostasis. ## Prognosis The prognosis for patients is variable: acute attacks triggered by physical exertion have been associated with circulatory shock and a fatal outcome in some cases. [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	Hereditary myopathy with lactic acidosis due to ISCU deficiency	c1850718	780	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=43115	2021-01-23T18:52:59	{"mesh": ["C564972"], "omim": ["255125"], "umls": ["C1850718"], "icd-10": ["G71.3"], "synonyms": ["Aconitase deficiency", "ISCU myopathy", "Iron-sulfur cluster deficiency myopathy", "Myopathy with exercise intolerance, Swedish type"]}
A number sign (#) is used with this entry because oculocutaneous albinism type IA (OCA1A) is caused by homozygous or compound heterozygous mutation in the tyrosinase gene (TYR; 606933) on chromosome 11q14. Description Oculocutaneous albinism is a genetically heterogeneous congenital disorder characterized by decreased or absent pigmentation in the hair, skin, and eyes. The term 'albinism' includes specific ocular changes that are the results of reduced amounts of melanin in the developing eye; these abnormalities in the eye and optic system are specific and necessary for the diagnosis. Aside from decreased pigment in the iris and retina, optic changes include decreased visual acuity, misrouting of the optic nerves at the chiasm, and nystagmus (King et al., 2001). Although OCA caused by mutations in the TYR gene was classically known as 'tyrosinase-negative' OCA, Tripathi et al. (1992) noted that some patients with 'tyrosinase-positive' OCA may indeed have TYR mutations resulting in residual enzyme activity. These patients can be classified as having OCA1B. ### Genetic Heterogeneity of Oculocutaneous Albinism OCA1, caused by mutations in the TYR gene, is divided clinically into 2 types: type IA, OCA1A, characterized by complete lack of tyrosinase activity due to production of an inactive enzyme, and type IB (OCA1B; 606952), characterized by reduced activity of tyrosinase. OCA2 (203200), OCA3 (203290), and OCA4 (606574) are somewhat milder forms of the disorder, caused by mutations in the OCA2 (611409), TYRP1 (115501), and MATP (SLC45A2; 606202) genes, respectively. OCA5 (615312) has been mapped to chromosome 4q24. OCA6 (see 113750) is caused by mutation in the SLC24A5 gene (609802). OCA7 (615179) is caused by mutation in the C10ORF11 gene (614537). See also ocular albinism (OA1; 300500), which is restricted phenotypically to ocular involvement only. Clinical Features Taylor (1978) pointed out that in the albino the ganglion cell layer does not thin out in the foveolar pit but shows a layer 6 to 8 cells thick where there should be none. He commented that 'this must degrade the retinal image....There is therefore ample reason for the uncorrectable defective central fixation, and...the ocular nystagmus, in this case of the optical variety.' In 60% of his patients he noted an abnormal head posture, which minimized the nystagmus with slight improvement in visual acuity, at least for reading. All types of conditions with oculocutaneous or ocular hypopigmentation in man and animals with nystagmus tested to date have shown either electrophysiologic or anatomic evidence of a decussation defect in the optic tracts. Patients without nystagmus do not (Witkop et al., 1982). Evidence that anomalous decussation exists also in the auditory system was presented by Creel et al. (1980). The amount of pigment in the inner ear correlates directly with the amount in the iris; otic pigment is lacking in albinos. In homozygotes an abnormal proportion of fibers from the ganglion cells of the temporal retina decussate to the contralateral cerebral hemisphere; this can be demonstrated by monocular visual evoked potential (VEP) asymmetry (Apkarian et al., 1983). Van Dorp (1987) suggested that patients with autosomal recessive albinism may have normal pigmentation. In a family with several albinos, they found a cousin, the offspring of a consanguineous mating, who was normally pigmented but had absence of macromelanosomes on skin biopsy as well as ocular and electrophysiologic signs of albinism. Van Dorp (1987) also concluded that patients with X-linked ocular albinism (300500, 300600) may be generally underpigmented and that patients with the Hermansky-Pudlak syndrome (203300) may have a dark complexion. Summers et al. (1991) observed striking discordance in ocular expression of albinism in 2 brothers. Both had foveal hypoplasia and misrouting of the optic fibers at the chiasm, as judged by VEP: one had strabismus and nystagmus with maximum correction of vision to 20/100, whereas the other had vision with myopic correction to 20/20 in both eyes and no nystagmus or strabismus. Using MRI, Schmitz et al. (2003) found that the size and configuration of the optic chiasm in humans with albinism are distinctly different from the chiasms of normal control subjects. These chiasmal changes reflect the atypical crossing of the optic fibers, irrespective of the causative gene mutation. Eight patients had tyrosinase gene-related oculocutaneous albinism, 4 patients had pink-eyed dilution gene-related OCA2 (203200), 1 had ocular albinism (OA1; 300500); the albinism-causing mutation had not been identified in 4 other patients. Summers and King (1994) described minimal pigment oculocutaneous albinism, a tyrosinase-related form of the disorder. They reported the findings in 9 patients followed for up to 11 years. Patients were born with white scalp hair and skin, and nystagmus developed. Visual acuity was reduced, but in 1 patient vision improved with maturity. The irides were blue. In 7 of the 9 patients, including the 1 patient with improved visual acuity, iris pigment developed as demonstrated by transillumination with slit-lamp biomicroscopy. Meyer et al. (2002) found that optical coherence tomography (OCT) could be used to document foveal hypoplasia in patients with oculocutaneous albinism. In a patient with OCA, the OCT did not detect a foveal pit; instead, widespread thickening of the retina occurred throughout the entire fovea with no difference from the surrounding macula. Foveal thickness was 300 micrometers in the patient versus 150 micrometers in a normal subject. Recchia et al. (2002) also found that OCT allowed detailed examination of the macular anatomy in patients with foveal hypoplasia. Their patient's OCT data showed preservation of multiple inner retinal layers where there should have been none, indicating that the fovea was thicker than normal. The authors proposed that a more accurate term would be 'foveal dysgenesis,' and suggested that OCT might prove helpful in the evaluation of patients with unexplained visual loss. Albinism is associated with a variety of ophthalmologic signs, including iris transillumination, nystagmus, strabismus, high refractive errors, foveal dysgenesis, chorioretinal hypopigmentation, and the 'albinotic' optic disc. Brodsky and Fray (2004) reported that a positive angle kappa is also associated with albinism in patients with congenital nystagmus. The authors suggested that this association might be related to the anomalous decussation of the optic axons that characterizes the albinotic visual system. Biochemical Features Amelanic melanocytes are present in the skin of albinos. These contain granules similar to the premelanosomes of normal melanocytes. In the test developed by King and Witkop (1977), which determines free (unbound) tyrosine, heterozygotes have shown little or no tyrosinase (606933) activity. Witkop et al. (1989) postulated that what tyrosinase is synthesized in the heterozygote is immediately bound to the melanosome matrix. Inheritance Pipkin and Pipkin (1942) claimed dominant inheritance for total albinism without other features in one family, but a quasidominant pedigree pattern of the usual recessive forms seems likely. McLeod and Lowry (1976) observed seemingly dominant inheritance in 2 generations of 1 family but concluded that partial penetrance of the albinism II gene in heterozygotes was responsible. In an extensive review of modifier genes in mice and humans, Nadeau (2001) pointed out that albinism due to deficiency of the tyrosinase protein is one of the few examples of a phenotype in which the expression is constant regardless of genetic background. The reason for its lack of modification is thought to result from the structure of the melanin synthesis pathway, the position of tyrosinase in this pathway, and the nature of the molecular lesion. Tyrosinase catalyzes 3 steps in this linear pathway that is thought to consist of only 4 steps. In the absence of tyrosinase, there are no metabolites that can act as targets for modification. Although deficiency of tyrosinase results in a constant phenotype, mutations that affect the preceding biochemical step, which converts phenylalanine to tyrosine (see PAH; 612349), result in substantial phenotypic variability. Mapping Using RFLPs identified within the human tyrosinase gene, Spritz et al. (1989) did linkage analysis in albinism families and demonstrated absolute linkage. Giebel et al. (1990, 1991) demonstrated genetic linkage between classic tyrosinase-negative oculocutaneous albinism (type IA) and the tyrosinase gene RFLP (lod = 6.17 at theta = 0). Barton et al. (1988) mapped the TYR locus to 11q14-q21. Molecular Genetics In a child with tyrosinase-negative oculocutaneous albinism, Tomita et al. (1989) identified a homozygous 1-bp insertion in the TYR gene (606933.0001). In a patient with classic tyrosinase-negative OCA, Spritz et al. (1989) found a thr-to-lys substitution that abolished 1 of 6 putative N-linked glycosylation sites that are completely conserved between humans and mice; see 606933.0003. Spritz et al. (1989) found no cases of tyrosinase gene deletions or other rearrangements, even in DNAs from patients with both tyrosinase-deficient oculocutaneous albinism and mental retardation. The families studied exhibited several different pigmentation phenotypes suggesting that tyrosinase-deficient OCA results from heteroallelism for different small defects of the tyrosinase gene. Tripathi et al. (1992) stated that more than 60 independent albinism-producing alleles had been described at the TYR locus. They reviewed 29 of these and commented on 2 additional novel missense substitutions in a 'note added in proof.' They commented that type I OCA in Caucasians clearly results from a great variety of different uncommon alleles. About 90% of OCA in Caucasians was accounted for by the 29 mutations they described. More than 80% of the then-known missense substitutions clustered within 2 relatively small regions of the tyrosinase polypeptide, suggesting that these may represent functionally critical sites within the enzyme. Oetting and King (1993) tabulated 36 mutations identified in type I OCA: 24 missense, 4 nonsense, and 8 frameshift mutations. The affected individuals in these cases were compound heterozygotes. They also listed 6 polymorphic sites useful in haplotype analysis: 2 in the promoter region, 2 in the coding region associated with alternative amino acids in the tyrosinase protein, and 2 RFLPs in the first intron. Diagnosis King and Olds (1985) examined hairbulb tyrosinase activity in 72 individuals with albinism and 64 obligate heterozygotes. Several different types were distinguished based on biochemical features. Type IA was tyrosinase-negative and type IB had low or no measurable activity; heterozygotes in both groups could be detected with this assay. Type II was tyrosinase-positive with moderate-to-high activity; heterozygotes could not be detected with this assay. The authors cited a third type, previously referred to as 'minimal pigment' type, with low tyrosinase activity; this form is now considered to be a variant of OCA1B (King et al., 2001). ### Prenatal Diagnosis Commenting on the availability of prenatal diagnosis in albinism, Taylor (1987) argued that elective abortion of albino fetuses is difficult to defend because of the satisfactory adjustment and even success in some areas of activity of albino individuals. Persistent ocular albinism and nystagmus permit accurate diagnosis in the adult. Shimizu et al. (1994) made the prenatal diagnosis of tyrosinase-negative OCA by an electron-microscopic DOPA reaction test of fetal skin at 20 weeks' gestation. A previous child born with albinism was 9 years old at the time; the pregnancy in which the diagnosis had been made was terminated at 21 weeks. Population Genetics Froggatt (1960) estimated a phenotype frequency of albinism I to be 1 in 10,000 in Northern Ireland. First-cousin marriages occurred in 4.5% of the parents. An excess of males was almost exclusively in the probands and the sex ratio of secondary cases was about 1; therefore, bias of ascertainment probably accounted for the excess of males. The mutation rate was estimated to be between 3.3 and 7 x 10(-5) per gene per generation. Abnormal iris translucency, occurring in 70% of the parents and children of albinos, was interpreted as a heterozygous manifestation. In British Columbia, McLeod and Lowry (1976) found the incidence of type I albinism to be 1 in 67,800 live births and of type II albinism (203200) to be 1 in 35,700 live births. Jay et al. (1982) tabulated the frequency of different types of albinism in England: tyrosine-negative OCA, 54; tyrosinase-positive OCA, 50; yellow mutant OCA, 7; Hermansky-Pudlak syndrome, 2; X-linked ocular albinism hemizygotes, 21, and heterozygotes, 15; autosomal recessive ocular albinism, 16. In surveying congenital anomaly syndromes in a Spanish gypsy population, Martinez-Frias and Bermejo (1992) found an impressive frequency of albinism. In one of the pedigrees, there were 2 examples of pseudodominant inheritance, i.e., apparent parent-to-child transmission. King et al. (2003) evaluated proposed clinical criteria for OCA1 by performing mutation analysis on 120 probands who met these proposed criteria. They defined 2 types: OCA1A, in which there is life-long absence of melanin pigment after birth; and OCA1B, in which there is development of minimal to moderate amounts of cutaneous and ocular pigment. They concluded that (1) the presence of white hair at birth is a useful clinical tool suggesting OCA1 in a child or adult with OCA, although OCA2 (203200) may also have this presentation; (2) the molecular analysis of the tyrosinase and P genes are necessary for precise diagnosis; and (3) the presence of alleles without identifiable mutations of the tyrosinase gene, particularly in OCA1B, suggests that more complex mutation mechanisms of this gene are common in OCA. Gronskov et al. (2009) identified 218 individuals with albinism born in Denmark between 1961 and 2005, of whom 55% were categorized as having OCA and 45% as having ocular albinism only (autosomal recessive ocular albinism; AROA). However, the authors noted that in Nordic populations, the categorization of patients as having OCA or AROA is often arbitrary due to the abundance of fair skin and hair in the general population, and stated that the overdiagnosis of AROA in OCA cases could not be excluded. A minimum birth prevalence for albinism of 1 in 14,000 was calculated. Wei et al. (2013) stated that oculocutaneous albinism has a worldwide prevalence of approximately 1 in 17,000. Genotype/Phenotype Correlations Gronskov et al. (2009) analyzed 4 known OCA genes, TYR, OCA2, TYRP1, and MATP, in 62 patients with autosomal recessive albinism; they identified 2 mutations in 1 OCA gene in 44% of the patients. Mutations in TYR were found in 16 patients (26%), whereas mutations in OCA2 and MATP were present in 9 (15%) and 2 (3%) patients, respectively; no mutations were found in the TYRP1 gene. Of the remaining patients, 18 (29%) were heterozygous for a mutation in either TYR or OCA2, and no mutations were found in 17 patients (27%). Although there was a tendency toward a more severe phenotype in patients with TYR mutations, Gronskov et al. (2009) observed considerable overlap of skin color, hair color, and Fitzpatrick tanning pattern within the TYR and OCA2 subgroups. Ocular parameters were uninformative with respect to mutational background, except for a clear preponderance of severe photophobia among patients with TYR mutations. Simeonov et al. (2013) reviewed the clinical and molecular characteristics of OCA and reported 22 novel mutations in OCA patients, including 14 in TYR, 5 in OCA2, 1 in TYRP1, and 2 in SLC45A2. In addition, they provided a comprehensive list of almost 600 previously reported OCA mutations, along with ethnicity information, carrier frequencies, and in silico pathogenicity predictions. Simeonov et al. (2013) demonstrated the utility of multiple detection methods to identify mutations missed by Sanger sequencing. Animal Model Working with albino melanomas and tyrosinase inhibitor in animals, Chian and Wilgram (1967) found that the inhibitor is effective against soluble tyrosinase but not against tyrosinase aggregated into melanosomes. In one type of albino mutation, tyrosinase apparently could not aggregate because of genetic alteration in its protein carrier and therefore was vulnerable to the effects of the inhibitor. These workers suggested that a similar situation may obtain in some type of albinism of man. In a wide variety of animals, the albinism gene is known to have a pleiotropic effect on the visual pathways (Guillery, 1974). Some of the optic nerve fibers do not decussate as in the normal. This structural abnormality, the mechanism of which is unknown, can be associated with crossed eyes in albino animals. Carroll et al. (1980) presented evidence that the human albino has the same anatomic peculiarity of the visual pathways, resulting in misrouting of the retinogeniculate projections, that has been found in albinos of other species. Leventhal et al. (1985) studied cats who were obligatory heterozygotes for a c-locus tyrosinase-negative allele (Cc) and had no relationship to 'deaf white cats' (W). In these normally pigmented animals abnormalities of the retinogeniculocortical pathways were found to be similar to those in homozygous albinos. By unilateral injection of horseradish peroxidase (HRP) into the dorsal lateral geniculate nucleus, they could map the retrogradely labeled retinal ganglion cells. Compared to homozygous normal controls, heterozygotes showed labeling of an abnormally large number of cells, especially large alpha cells, in the contralateral temporal retina. The authors pointed out that 1 to 2% of the human population may be heterozygous for albinism and that the above described abnormality may have an adverse effect on binocular depth perception. The locus ceruleus and substantia nigra are normally pigmented in albinos. They owe their pigmentation to neuromelanin, which is synthesized by tyrosine hydroxylase rather than tyrosinase (Witkop et al., 1989). Snyder (1980) pointed out that in Mus musculus, Rattus norvegicus, and Peromyscus maniculatus, glucosephosphate isomerase (Gpi-1), albinism (c), and beta-type globin (Hbb) are linked. In the first 2 species, pink-eyed dilution (p) is also known to be in this same cluster. (Indeed, the pink-eye--albinism linkage in the mouse was the first to be demonstrated in any mammal, by Haldane et al., 1915.) See Lyon et al. (1992) and Gardner et al. (1992) for genetic and molecular analyses of the pink-eyed dilution gene in the mouse. Gardner et al. (1992) demonstrated that the human homolog of the mouse p mutation is a gene located on 15q11.2-q12, a region associated with Prader-Willi syndrome (176270) and Angelman syndrome (105830); see 203200. It is not linked to the human homolog of any of the 3 above-mentioned genes that are located on mouse chromosome 7 in linkage with 'pink-eye.' O'Brien et al. (1986) found that the albino locus in the domestic cat is linked to the beta-globin locus at a distance of approximately 8 cM. Evolutionary conservation of syntenic homology of feline chromosome D1 and human chromosome 11 is extensive. High resolution G-trypsin-banded preparations of the 2 chromosomes showed similarities. (A tyrosinase-related gene, which contains only exons 4 and 5, is located on 11p; see 191270.) 'Dark-eyed albino' is a recessive mutation at the mouse albino 'c' locus, which encodes tyrosinase. Similar to type IB OCA in humans, overall production of pigment is greatly reduced in dark-eyed albino mice and obvious only in the eyes. Using a human tyrosinase cDNA clone, Barton et al. (1988) and Kwon et al. (1989) isolated mouse tyrosinase genomic clones and used them to map the mouse tyrosinase locus to a site at or near the albino locus on mouse chromosome 7. Mouse tyrosinase mRNA was found to measure approximately 2.4 kb. A mutation in tyrosinase responsible for the albino mouse appears to be a change of cysteine-85 to serine (Kwon et al., 1988), resulting from a change of guanine 390 to cytosine. Jackson and Bennett (1990) studied revertant cells and found that loss of the mutant allele was responsible. History In describing albinism in the Caribe Cuna Indians, Keeler (1953) commented on the abundant straight white down consisting of hairs up to 2.5 cm long that develops on the body and extremities. It is not clear that this indicated genetic distinctness; it may somehow be related to the exposure of the subjects--partial hirsutism. Famous albinos include Noah of flood fame and the Rev. Dr. Spooner. Evidence that Noah was an albino was presented by Sorsby (1958). Spooner was a brilliant classicist at Oxford whose amusing tendency to errors of speech came to be known as spoonerisms. Although probably elaborated on by students, the aberration appears to have been marked. As a classicist, Spooner must have read extensively. The aberration of speech was probably related to his nystagmus which caused a jumbling of information from the printed page. His intelligence was such that his mind comprehended despite the jumbling, but a jumbling of sorts occurred with oral output (Edwards, 1980). (Spooner was warden of New College, Oxford University, where his brightly colored portrait hangs (Gibson, 1980).) It would be of interest to know whether spoonerism (as a process and phenomenon) is more frequent in albinos or others with nystagmus. An 'albino society' has been formed in England. Of interest in connection with the possible linkage of beta-globin and albinism (suggested by homology to the mouse) were the reports of a family with both albinism and sicklemia (Massie and Hartmann, 1957) and of a Sicilian boy with albinism and an unusual combination of hemoglobinopathies (Schiliro et al., 1983). INHERITANCE \- Autosomal recessive HEAD & NECK Eyes \- Absent iris pigment \- Translucent iris \- Pink irides (childhood) \- Blue-gray irides (adult) \- Absent retinal pigment \- Choroidal vessels visible \- Foveal hypoplasia \- Decreased visual acuity \- Strabismus \- Nystagmus \- Photophobia \- High refractive errors (hyperopia, myopia, with-the-rule astigmatism) \- Albinotic optic disc \- Misrouting of the optic nerves at the chiasm \- Absent stereopsis due to anomalous decussation at the optic chiasm \- Positive angle kappa (appearance of exotropia but no shift on cover test) \- Asymmetric visual evoked potentials SKIN, NAILS, & HAIR Skin \- Milky white skin \- Absent skin pigmentation \- No ability to tan Hair \- White hair LABORATORY ABNORMALITIES \- Absent tyrosinase activity MISCELLANEOUS \- Congenital onset \- Complete absence of melanin synthesis \- Pigment does not develop with age \- Prevalence of 1 in 28,000 Caucasians \- Prevalence of 1 in 28,000 African-Americans \- One of the 2 most common forms of albinism in the world, along with OCA2 \- See also OCA1B, or 'yellow albinism,' an allelic disorder with residual tyrosinase activity and some pigmentation MOLECULAR BASIS \- Caused by mutation in the tyrosinase gene (TYR, 606933.0001 ) ▲ 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	ALBINISM, OCULOCUTANEOUS, TYPE IA	c0268494	781	omim	https://www.omim.org/entry/203100	2019-09-22T16:31:21	{"doid": ["0070094"], "mesh": ["C537728"], "omim": ["203100"], "icd-10": ["E70.320"], "orphanet": ["79431", "352731"], "synonyms": ["OCULOCUTANEOUS ALBINISM, TYROSINASE-NEGATIVE", "OCA1A", "ALBINISM I", "OCULOCUTANEOUS ALBINISM, TYPE I", "Tyrosinase-negative oculocutaneous albinism", "Alternative titles"], "genereviews": ["NBK1166"]}
A number sign (#) is used with this entry because of evidence that the camptodactyly-arthropathy-coxa vara-pericarditis syndrome (CACP) can be caused by homozygous mutation in the proteoglycan-4 gene (PRG4; 604283) on chromosome 1q31. Description The camptodactyly-arthropathy-coxa vara-pericarditis syndrome is an autosomal recessive condition characterized by the association of congenital or early-onset camptodactyly and noninflammatory arthropathy with synovial hyperplasia. Progressive coxa vara deformity and/or noninflammatory pericardial or pleural effusions are found in some patients (summary by Faivre et al., 2000). Clinical Features Jacobs and Downey (1974) and Jacobs et al. (1976) described in brief a familial arthropathy associated with congenital flexion contractures of the fingers and characteristic changes on synovial biopsy. They called it 'E family arthritis,' or 'congenital familial hypertrophic synovitis.' They studied 4 cases from 2 families. Jacobs' first family was American black and the second Pakistani (Jacobs, 1981). Athreya and Schumacher (1978) reported the condition in the first, third, and fifth sibs of a 5-sib family born to parents who were not known to be related, but came from the same small village in Ireland. The first sib, a girl aged 16 at study, was born with flexion deformity of the right middle finger and developed polyarticular large joint arthritis in early infancy. The finger straightened spontaneously as she got older. The second affected sib, a boy aged 14, had flexion deformity of the thumb at birth which was corrected surgically. He also had symmetric swelling of multiple large joints with normal sedimentation rate. He had synovectomy of both hip joints at age 6. The youngest affected sib, a girl aged 4, was born with a flexed right middle finger. At age 2, she developed painless swelling of both knees and 2 years later of both ankles. She complained intermittently of hip pain and had generalized morning stiffness. Histologically, the synovium showed hyperplasia, necrotic villi, deposition of eosinophilic and PAS-positive material, and many multinucleate giant cells. Ochi et al. (1983) reported 2 sisters in whom several tenosynovectomies of the hands and synovectomy of the knee joints were performed to maintain mobility of affected joints. Abnormalities in tendons were restricted to the tenosynovium, with secondary involvement of tendons which in late stages were replaced by fibrous tissue. They suggested that the disorder is the result of an intrauterine tenosynovitis. In Newfoundland, Martin et al. (1985) observed an affected brother and sister and 2 other unrelated patients. Flexion contractures of the fingers were present at birth. There was synovial cell hyperplasia and giant cells but no inflammatory process. X-rays showed flattening of the metacarpal and metatarsal heads and the proximal femoral ossification centers. In the oldest patient the process had subsided, leaving slight contractures but severe impairment of hip mobility. It is likely that the familial syndrome of arthropathy, camptodactyly and pericarditis is the same disorder. Martinez-Lavin et al. (1983) described a family from a small village in southern Mexico in which 5 of 7 sibs had constrictive pericarditis in association with arthritis of large joints and flexion contracture of the fingers. Parental consanguinity was denied, but the parents shared the haplotype A1-Bw21. The proband was well until age 8 years when she developed enlargement of the right knee and exertional dyspnea. At age 9 she was found to have bilateral contracture of the fifth fingers due to fixation of the flexor tendons at the level of the proximal interphalangeal joints and swollen wrists, elbows and knees, as well as signs of pericardial constriction. Echocardiogram showed large pericardial effusion. After failure of response to empiric antituberculous therapy and prednisone, pericardiectomy was performed. The pericardium was markedly thickened, and fibrosis was demonstrated histologically. The circulatory problem was corrected, but the arthritis and camptodactyly were unchanged. A second sib had onset of flexion contractures of the fingers at age 12 years. Synovial biopsy of the right knee showed prominent fibrosis with mild inflammatory cell infiltration. He did not have pericardial involvement. A third sib had onset of joint and pericardial manifestations at age 4 years. Pericardiectomy was performed at age 6 with relief of symptoms. A fourth sib had onset of wrist and knee swelling at age 4 years. Although asymptomatic, examination showed signs of constrictive pericarditis for which pericardiectomy was performed with relief. A fifth sib, aged 4 years, had swollen knees and ankles without tenderness and flexion contractures of both thumbs but no signs of pericardial involvement. Histoplasmin skin tests were negative in the proband and fourth sib but positive in the second and third sibs mentioned above. Mulibrey nanism (253250), a clinically quite different disorder, has constrictive pericarditis as a consistent feature. From Istanbul, Turkey, Bulutlar et al. (1986) reported this disorder in 4 sisters. In addition to pericarditis and contractures of the elbows and wrists, all 4 had coxa vara. Three were teenagers; the fourth was aged 7 years. Camptodactyly and trigger finger were described. The oldest required pericardiectomy at age 13; histologic studies showed chronic nonspecific pericarditis. In 2, livedo reticularis of the legs was described. Laxer et al. (1986) reported a single case in a 5-year-old French-Canadian boy who was born with camptodactyly and developed painful swelling of the knees and ankles at age 18 months. Pericarditis developed at age 5. The parents were distant cousins. Verma et al. (1995) used the designation 'familial fibrosing serositis' for the disorder they described in 2 sisters with fibrosing pleuritis, pericarditis, and synovitis with infantile contractures of fingers and toes. The family came from northern India. The illness began at age 6 months in the younger sister, and by 2 years of age all her fingers and toes were deformed. Starting at age 9, she had recurrent left pleuritic chest pain and abdominal distention. At the age of 10 years, pericardiectomy was performed for pericardial constriction. The older sister had a strikingly similar disorder. At the age of 14 years, she had pleural pericardial effusion, which did not respond to antituberculous therapy given empirically. She showed severe contractures of the toes with a round foot deformity, flexion contractures of all fingers and both elbows, and bilateral swelling and tenderness of the wrist, knee, and ankle joints. Pericardiectomy was also necessary in the older sister. Verma et al. (1995) noted that it may be significant that the younger sister had mitral valve prolapse with mitral regurgitation. Verma et al. (1995) differentiated 4 types of familial arthropathies: (1) noninflammatory arthropathy, congenital flexion contractures of the fingers, and synovial hyperplasia with a large number of multinucleated giant cells, as reported by Jacobs et al. (1976), Athreya and Schumacher (1978), and Ochi et al. (1983); (2) familial arthritis and camptodactyly with inflammatory changes in synovial biopsy specimens, later onset of camptodactyly, iridocyclitis, elevated ESR, and erosive changes, as described by Malleson et al. (1981) and Gigante et al. (1990); see 108050; (3) Blau syndrome (186580), a syndrome of familial granulomatous arthritis, uveitis, rash and camptodactyly; and (4) the camptodactyly arthropathy pericarditis (CAP) syndrome, described by Martinez-Lavin et al. (1983) and Bulutlar et al. (1986), as well as by Laxer et al. (1986). Verma et al. (1995) concluded that the sisters they studied were in the fourth category. Suwairi et al. (1997) and Bahabri et al. (1998) evaluated 4 new patients and 4 previously reported patients who presented with congenital camptodactyly and developed large joint arthropathy during childhood. They compared the clinical features of these 8 patients, aged 2 to 15 years, with those of 21 previously reported patients. Coxa vara deformity occurred in all 8 of their patients and in 60% of published cases. Clinical pericarditis occurred in 2 of their 8 patients and in 40% of published cases. All 8 of their patients, from 4 different kindreds, were products of consanguineous marriages. Studying 12 CACP syndrome patients from 8 unrelated families, Faivre et al. (2000) emphasized hip and spine involvement, particularly in the course of the disease as shown in a 58-year-old patient. Despite clinical variability, linkage studies supported genetic homogeneity of the disorder. Yilmaz et al. (2018) described the clinical findings of CACP syndrome in 35 patients from 11 unrelated families, 10 of which were from the southeast region of Turkey. Consanguinity was noted in 9 of the 11 families. Median age was 16 years and mean follow-up duration was 7.8 years. Age at diagnosis ranged from 1 to 52 years. Seven families had more than 1 affected subject. Camptodactyly of the hands was the first sign seen in most patients (68%). Swelling of wrists, knees, and elbows began before 4 years of age, while the age of joint involvement was variable. Increased levels of pain were noted after the age of 10 years, with severe hip involvement after age 20. All patients had developmental coxa vara, and 7 (22%) had pleural effusion, ascites, and/or pericarditis. Mitral regurgitation or mitral valve prolapse was seen on echocardiography in 4 patients. There was a significant correlation between age of the patient and the number of clinical features, consistent with features being related to cumulative mechanical stress over time. Mapping By linkage studies in 4 kindreds with autosomal recessive camptodactyly-arthropathy-coxa vara-pericarditis syndrome, Suwairi et al. (1997) and Bahabri et al. (1998) demonstrated that all patients were homozygous for a contiguous series of markers on 1q, compatible with homozygosity by descent. Affected patients from 2 of the 4 kindreds (both from Saudi Arabia) had an identical haplotype within this region, compatible with a shared common ancestor. The regions of homozygosity overlapped at a 1.9-cM interval defined by D1S2701 and D1S222. Using fully informative markers within this interval, a lod score of 3.3 at theta = 0.0 was obtained. Therefore, Suwairi et al. (1997) and Bahabri et al. (1998) concluded that a locus for the disorder resides on chromosome 1q25-q31. Molecular Genetics In 6 unrelated patients with CACP, Marcelino et al. (1999) identified homozygous mutations in the PRG4 gene, including 4 frameshifts, 1 insertion, and 1 nonsense mutation (604283.0001-604283.0006). Yilmaz et al. (2018) performed whole-exome sequencing in 28 patients with CACP syndrome and identified 11 mutations in the PRG4 gene, including 9 novel mutations, which were confirmed by Sanger sequencing. The mutations were homozygous in 9 and compound heterozygous in 2 families. In this cohort, 6 frameshift mutations, 2 nonsense mutations, and the first case of a homozygous deletion of a complete exon (604283.0007) were identified. All of the mutations were predicted to abolish the functions of both copies of the PRG4 protein. Yilmaz et al. (2018) noted that of the 38 known CACP disease-causing mutations in PRG4, 70% are in exon 6, with the rest being distributed in other exons. Radiology \- Flattened metacarpal and metatarsal heads \- Flattened proximal femoral ossification centers Inheritance \- Autosomal recessive Joints \- Arthropathy \- Generalized morning stiffness \- Polyarticular large joint arthritis \- Congenital finger flexion contractures \- Elbow and wrist contractures \- Synovial hypertrophy Lab \- Normal sedimentation rate Skeletal \- Coxa vara Cardiovascular \- Constrictive pericarditis ▲ 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	CAMPTODACTYLY-ARTHROPATHY-COXA VARA-PERICARDITIS SYNDROME	c1859690	782	omim	https://www.omim.org/entry/208250	2019-09-22T16:30:47	{"doid": ["0090127"], "mesh": ["C537560"], "omim": ["208250"], "orphanet": ["2848"], "synonyms": ["Alternative titles", "ARTHROPATHY-CAMPTODACTYLY SYNDROME", "HYPERTROPHIC SYNOVITIS, CONGENITAL FAMILIAL", "JACOBS SYNDROME", "FIBROSING SEROSITIS, FAMILIAL", "PERICARDITIS-ARTHROPATHY-CAMPTODACTYLY SYNDROME", "PAC SYNDROME", "CAMPTODACTYLY-ARTHROPATHY-PERICARDITIS SYNDROME", "CAP SYNDROME"]}
A rare genetic lethal multiple congenital anomalies/dysmorphic syndrome characterized by severe hydranencephaly and renal dysplasia or agenesis. Pregnancy is complicated by oligo- or anhydramnios, leading to features of Potter sequence (including typical facies and microretrognathia, limb contractures, talipes equinovarus, and pulmonary hypoplasia) in the fetus. Affected fetuses either die in utero or shortly after birth. Histology of the brain shows widespread presence of multinucleated neurons and glial cells. [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	Multinucleated neurons-anhydramnios-renal dysplasia-cerebellar hypoplasia-hydranencephaly syndrome	c1856053	783	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=500135	2021-01-23T18:08:09	{"mesh": ["C565507"], "omim": ["236500"], "synonyms": ["MARCH syndrome"]}
A number sign (#) is used with this entry because of evidence that Weill-Marchesani syndrome-4 (WMS4) is caused by homozygous mutation in the ADAMTS17 gene (607511) on chromosome 15q26. Description Weill-Marchesani syndrome is a rare connective tissue disorder characterized by microspherophakia, severe myopia, acute and/or chronic glaucoma, and cataract. Other features include brachydactyly and short stature. Patients may also have stiff joints and thickened skin, especially on the hands. Occasionally, cardiac defects or an abnormal heart rhythm is present (summary by Shah et al., 2014). For a discussion of genetic heterogeneity of Weill-Marchesani syndrome, see WMS1 (277600). Clinical Features Morales et al. (2009) described 8 individuals, 6 from 2 Saudi Arabian families and 2 sporadic cases, who displayed many of the key features of Weill-Marchesani syndrome, including lenticular myopia, ectopia lentis, glaucoma, spherophakia, and short stature. Because none of the patients had brachydactyly or decreased joint flexibility, the authors considered this a 'Weill-Marchesani-like syndrome.' Khan et al. (2012) reported a Saudi sister and brother, born of first-cousin parents, who had high myopia and spherophakia, with narrow angles in the sister. Both also exhibited short stature. Ocular examination in the sister showed shallow anterior chambers and frequent peripheral anterior iris attachments across the angle, which were considered to represent acquired peripheral anterior synechiae; her brother had moderate anterior chamber depth and showed rare peripheral iris processes on gonioscopy. Neither sib had short hands or feet, joint stiffness, or other nonocular congenital abnormalities. Shah et al. (2014) studied a 21-year-old woman from a consanguineous Indian family who had bilateral microspherophakia with iridodonesis and phacodonesis, and who also exhibited short stature and brachydactyly. She had light perception only in her right eye, and visual acuity of 20/30 in her left eye. Anterior segment examination showed exotropia of the right eye with a fixed dilated pupil, whereas the left pupil reacted normally. Gonioscopy showed grade 2 angles bilaterally, with peripheral anterior synechiae on the right. Intraocular pressure (IOP) was elevated, and fundus evaluation showed glaucomatous optic atrophy on the right and glaucomatous cupping on the left. At age 23, she underwent trabeculectomy of the left eye, with subsequent control of IOP. She later developed a cataract of the left lens at age 31, for which she underwent surgery, and she underwent laser treatment of a left retinal hole at age 35. Her parents and sibs were unaffected, and she did not have joint stiffness or cardiac abnormalities. Mapping Morales et al. (2009) performed linkage analysis in a consanguineous Saudi Arabian family with a Weill-Marchesani-like syndrome and obtained a maximum lod score of 3.0 on chromosome 15q26.3, in a 2.05-Mb linkage region. In a consanguineous Saudi family in which a sister and brother had spherophakia and short stature, Khan et al. (2012) performed homozygosity mapping that revealed only 1 region of homozygosity shared by the affected sibs but not by unaffected family members: a 4.9-Mb region on chromosome 15 (chr15:97,531,229-102,397,317) containing 12 genes, of which the most likely candidate was ADAMTS17. Cytogenetics Radner et al. (2013) studied 4 patients from 3 consanguineous Tunisian families with features of Weill-Marchesani syndrome, including short stature, brachydactyly with joint stiffness, microspherophakia, ectopia lentis, and mitral valve defects, who also exhibited collodion membrane at birth that evolved to generalized ichthyosis. All 4 patients shared a 100-kb deletion on chromosome 15q26.3 between SNP markers rs1080492 and rs7179355 that encompassed the first 3 exons of the ADAMTS17 gene, the complete sequence of the noncoding RNA FLJ42289, and exon 13 of the CERS3 gene (615276), including the 3-prime UTR. Haplotype analysis in the 4 patients, who originated from the same geographic region in Tunisia, was consistent with a founder effect. Sequencing of the CERS3 gene in an unrelated Tunisian patient with isolated ichthyosis (ARCI9; 615023) revealed a splice site mutation (615276.0001), suggesting that the skin phenotype in the patients with the Weill-Marchesani syndrome features was due to partial deletion of the CERS3 gene. Inheritance Weill-Marchesani syndrome-4 is an autosomal recessive disorder (Morales et al., 2009). Molecular Genetics In 4 affected sibs from a consanguineous Saudi Arabian family with features of Weill-Marchesani syndrome, Morales et al. (2009) identified homozygosity for a 1-bp insertion in the ADAMTS17 gene (607511.0001) that fully segregated with the phenotype. Screening of the ADAMTS17 gene patients with a similar phenotype identified a homozygous truncating mutation (607511.0002) in 2 affected sisters from another Saudi Arabian family, and a homozygous splice site mutation in a sporadic case (607511.0003). None of the mutations were detected in 300 ethnically matched controls. A sporadic patient, a 36-year-old woman with similar features, had no mutations in ADAMTS10, ADAMTS17, or FBN1, suggesting genetic heterogeneity. In a consanguineous Saudi family in which a sister and brother had spherophakia and short stature mapping to chromosome 15, Khan et al. (2012) sequenced the candidate gene ADAMTS17 and identified a 1-bp deletion (607511.0004) that segregated with disease. In an Indian woman from a consanguineous family with microspherophakia, short stature, and brachydactyly, Shah et al. (2014) performed whole-exome sequencing and identified homozygosity for a splice site mutation in the ADAMTS17 gene (607511.0005) that segregated with disease and was not found in 50 ethnically matched controls or in public variant databases. The proband did not have mutations in other known WMS-associated genes, but did carry homozygous variants in 3 other genes (CAMK1D, 607957; PYROXD2, 617889; SIPA1L3, 616655) that were not found in ethnically matched controls; the authors stated that they could not exclude a contribution by these genes to some aspects of the phenotype. Shah et al. (2014) noted that all reported patients with ADAMTS17 mutations showed consistent features of microspherophakia and short stature, with brachydactyly, joint stiffness, glaucoma, cataract, and cardiac abnormalities being inconsistent findings; they suggested that patients with mutations in WMS-associated genes who exhibit microspherophakia and short stature should be classified as having WMS, rather than a 'WMS-like' syndrome. INHERITANCE \- Autosomal recessive GROWTH Height \- Short stature HEAD & NECK Eyes \- Lenticular myopia \- Ectopia lentis \- Iridodonesis \- Phacodonesis \- Shallow anterior chambers \- Narrow angles \- Peripheral anterior synechiae \- Elevated intraocular pressure \- Glaucoma \- Spherophakia SKELETAL Hands \- Brachydactyly (in some patients) MOLECULAR BASIS \- Caused by mutation in the a disintegrin-like and metalloproteinase with thrombospondin type 1 motif, 17 gene (ADAMTS17, 607511.0001 ) ▲ 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	WEILL-MARCHESANI SYNDROME 4	c2750787	784	omim	https://www.omim.org/entry/613195	2019-09-22T15:59:23	{"doid": ["0050475"], "mesh": ["C567710"], "omim": ["613195"], "orphanet": ["363992"], "synonyms": ["WEILL-MARCHESANI-LIKE SYNDROME", "Alternative titles", "15q26.3 microdeletion syndrome"]}
Nocardiosis SpecialtyInfectious disease Nocardiosis is an infectious disease affecting either the lungs (pulmonary nocardiosis) or the whole body (systemic nocardiosis). It is due to infection by a bacterium of the genus Nocardia, most commonly Nocardia asteroides or Nocardia brasiliensis. It is most common in adult males, especially those with a weakened immune system. In patients with brain nocardia infection, mortality exceeds 80%; in other forms, mortality is 50%, even with appropriate therapy.[1] It is one of several conditions that have been called "the great imitator".[2] Cutaneous nocardiosis commonly occurs in immunocompetent hosts.[3] ## Contents * 1 Signs and symptoms * 2 Causes * 3 Diagnosis * 4 Treatment * 5 Prognosis * 6 Epidemiology * 7 References * 8 External links ## Signs and symptoms[edit] Pulmonary infection * Produces a virulent form of pneumonia (progressive) * Night sweats, fever, cough, chest pain * Pulmonary nocardiosis is subacute in onset and refractory to treatment with standard antibiotics * Symptoms are more severe in immunocompromised individuals * Radiologic studies show multiple pulmonary infiltrates, with a tendency to central necrosis Neurological infection * Headache, lethargy, confusion, seizures, sudden onset of neurological deficit * CT scan shows cerebral abscess * Nocardial meningitis is difficult to diagnose Cardiac conditions * Nocardia has been highly linked to endocarditis as a main manifestation * In recorded cases, it has caused damage to heart valves whether natural or prosthetic[4][5] Lymphocutaneous disease * Nocardial cellulitis is akin to erysipelas but is less acute * Nodular lymphangeitis mimics sporotrichosis with multiple nodules alongside a lymphatic pathway * Chronic subcutaneous infection is a rare complication and osteitis may ensue * May be misidentified and treated as a staph infection, specifically superficial skin infections[6] * Cultures must incubate more than 48 hours to guarantee an accurate test Ocular disease * Very rarely, nocardiae cause keratitis * Generally there is a history of ocular trauma Disseminated nocardiosis * Dissemination occurs through the spreading enzymes possessed by the bacteria * Disseminated infection can occur in very immunocompromised patients * It generally involves both lungs and brain * Fever, moderate or very high can be seen * Multiple cavitating pulmonary infiltrates develop * Cerebral abscesses arise later * Cutaneous lesions are very rarely seen * If untreated, the prognosis is poor for this form of disease ## Causes[edit] Normally found in soil, these organisms cause occasional sporadic disease in humans and animals throughout the world. Another well publicized find is that of Nocardia as part of the oral microflora. Nocardia spp. have been reported in the normal gingivae and periodontal pockets along with other species such as Actinomyces, Arthromyces and Streptomyces spp.[7] The usual mode of transmission is inhalation of organisms suspended in dust. Another very common method is by traumatic introduction, especially in the jaw. This leads to the entrance of Nocardia into the blood stream and the propagation of its pathogenic effects. Transmission by direct inoculation through puncture wounds or abrasions is less common.[1] Generally, nocardial infection requires some degree of immune suppression.[citation needed] A weakened immune system is a general indicator of a person who is more susceptible to nocardiosis, such as someone who already has a disease that weakens their immune system. Additionally, those with low T-cell counts or other complications involving T-cells can expect to have a higher chance of becoming infected. Besides those with weak immune systems, a local traumatic inoculation can cause nocardiosis, specifically the cutaneous, lymphocutaneous, and subcutaneous forms of the disease.[8][9] There is no racial pattern in the risk of becoming infected with Nocardiosis.[citation needed] ## Diagnosis[edit] Diagnosis of nocardiosis can be made by a doctor using various techniques. These techniques include, but are not limited to: a chest x-ray to analyze the lungs, a bronchoscopy, a brain/lung/skin biopsy, or a sputum culture. However, diagnosis may be difficult. Nocardiae are gram positive, weakly acid-fast, branching rod-shaped bacteria and can be visualized by a modified Ziehl–Neelsen stain such as the Fite-Faraco method. In the clinical laboratory, routine cultures may be held for insufficient time to grow nocardiae, and referral to a reference laboratory may be needed for species identification.[10] Pulmonary infiltration and pleural effusion are usually detected via x-ray.[citation needed] ## Treatment[edit] Nocardiosis requires at least 6 months of treatment, preferably with trimethoprim/sulfamethoxazole or high doses of sulfonamides. In patients who do not respond to sulfonamide treatment, other drugs, such as ampicillin, erythromycin, or minocycline, may be added.[citation needed] Treatment also includes surgical drainage of abscesses and excision of necrotic tissue. The acute phase requires complete bed rest; as the patient improves, activity can increase.[1] A new combination drug therapy (sulfonamide, ceftriaxone, and amikacin) has also shown promise.[10] ## Prognosis[edit] The prognosis of nocardiosis is highly variable. The state of the host's health, site, duration, and severity of the infection all play parts in determining the prognosis. Currently, skin and soft tissue infections have a 100% cure rate, and pleuropulmonary infections have a 90% cure rate with appropriate therapy. The cure rate falls to 63% with those infected with disseminated nocardiosis, with only half of patients surviving infections that cause brain abscess. Additionally, 44% of people who are infected in the spinal cord/brain die, increasing to 85% if that person has an already weakened immune system. There are no preventative treatments for nocardiosis. The only recommendation is to protect open wounds to limit entrance of the bacterium.[citation needed] ## Epidemiology[edit] Although there are no international data available on worldwide infection rates per year, there are roughly 500–1000 documented cases of nocardiosis per year in the US. Most of these cases occur in men, as there is a 3:1 ratio of male of female cases annually; however, this difference may be due to exposure frequency rather than susceptibility differences. From an age perspective, it is not highly more prevalent in one age group than another.[8] Cutaneous nocardiosis is slightly more common in middle aged men, but as a whole, all age groups are susceptible.[11] There is no racial pattern in the risk of becoming infected with nocardiosis.[citation needed] ## References[edit] 1. ^ a b c "Nocardiosis (Professional Guide to Diseases (Eighth Edition))—WrongDiagnosis.com". Retrieved 2007-07-12. 2. ^ Lederman ER, Crum NF (September 2004). "A case series and focused review of nocardiosis: clinical and microbiologic aspects". Medicine (Baltimore). 83 (5): 300–13. doi:10.1097/01.md.0000141100.30871.39. PMID 15342974. S2CID 23940448. 3. ^ Rapini, Ronald P.; Bolognia, Jean L.; Jorizzo, Joseph L. (2007). Dermatology: 2-Volume Set. St. Louis: Mosby. ISBN 978-1-4160-2999-1. 4. ^ "Nocardia Endocarditis in a Native Mitral Valve Revista Espanola de Cardiologia Volume 57, Issue 8, August 2004, Pages 787–788". 5. ^ "Successful Antimicrobial Chemotherapy for Nocardia Asteroides Prosthetic Valve Endocarditis The American Journal of Medicine, Volume 115, Issue 4, Pages 330–332". 6. ^ "Dermatologic Manifestations of Nocardiosis: Background, Pathophysiology, Epidemiology". 2016-09-27. Cite journal requires `\|journal=` (help) 7. ^ Roth, GD; Thurn, AN (Nov–Dec 1962). "Continued study of oral nocardia". Journal of Dental Research. 41 (6): 1279–92. CiteSeerX 10.1.1.523.2905. doi:10.1177/00220345620410060401. PMID 13975308. S2CID 26640128. 8. ^ a b "Nocardiosis: Background, Pathophysiology, Epidemiology". 2016-07-25. Cite journal requires `\|journal=` (help) 9. ^ Wilson, John W. (2016-11-10). "Nocardiosis: Updates and Clinical Overview". Mayo Clinic Proceedings. 87 (4): 403–407. doi:10.1016/j.mayocp.2011.11.016. ISSN 0025-6196. PMC 3498414. PMID 22469352. 10. ^ a b "Nocardiosis: DBMD—WrongDiagnosis.com". Retrieved 2007-07-12. 11. ^ "Dermatologic Manifestations of Nocardiosis: Background, Pathophysiology, Epidemiology". 2016-09-27. Cite journal requires `\|journal=` (help) ## External links[edit] Webmd article on Nocardiosis Classification D * ICD-10: A43 * ICD-9-CM: 039.9 * MeSH: D009617 * DiseasesDB: 9058 * SNOMED CT: 29227009 External resources * eMedicine: med/1644 derm/297 ped/1610 * Orphanet: 31204 * v * t * e Gram-positive bacterial infection: Actinobacteria Actinomycineae Actinomycetaceae * Actinomyces israelii * Actinomycosis * Cutaneous actinomycosis * Tropheryma whipplei * Whipple's disease * Arcanobacterium haemolyticum * Arcanobacterium haemolyticum infection * Actinomyces gerencseriae Propionibacteriaceae * Propionibacterium acnes Corynebacterineae Mycobacteriaceae M. tuberculosis/ M. bovis * Tuberculosis: Ghon focus/Ghon's complex * Pott disease * brain * Meningitis * Rich focus * Tuberculous lymphadenitis * Tuberculous cervical lymphadenitis * cutaneous * Scrofuloderma * Erythema induratum * Lupus vulgaris * Prosector's wart * Tuberculosis cutis orificialis * Tuberculous cellulitis * Tuberculous gumma * Lichen scrofulosorum * Tuberculid * Papulonecrotic tuberculid * Primary inoculation tuberculosis * Miliary * Tuberculous pericarditis * Urogenital tuberculosis * Multi-drug-resistant tuberculosis * Extensively drug-resistant tuberculosis M. leprae * Leprosy: Tuberculoid leprosy * Borderline tuberculoid leprosy * Borderline leprosy * Borderline lepromatous leprosy * Lepromatous leprosy * Histoid leprosy Nontuberculous R1: * M. kansasii * M. marinum * Aquarium granuloma R2: * M. gordonae R3: * M. avium complex/Mycobacterium avium/Mycobacterium intracellulare/MAP * MAI infection * M. ulcerans * Buruli ulcer * M. haemophilum R4/RG: * M. fortuitum * M. chelonae * M. abscessus Nocardiaceae * Nocardia asteroides/Nocardia brasiliensis/Nocardia farcinica * Nocardiosis * Rhodococcus equi Corynebacteriaceae * Corynebacterium diphtheriae * Diphtheria * Corynebacterium minutissimum * Erythrasma * Corynebacterium jeikeium * Group JK corynebacterium sepsis Bifidobacteriaceae * Gardnerella vaginalis [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	Nocardiosis	c0028242	785	wikipedia	https://en.wikipedia.org/wiki/Nocardiosis	2021-01-18T19:02:25	{"gard": ["7210"], "mesh": ["D009617"], "umls": ["C0028242"], "icd-9": ["039.9"], "orphanet": ["31204"], "wikidata": ["Q1856914"]}
Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy, usually called CADASIL, is an inherited condition that causes stroke and other impairments. This condition affects blood flow in small blood vessels, particularly cerebral vessels within the brain. The muscle cells surrounding these blood vessels (vascular smooth muscle cells) are abnormal and gradually die. In the brain, the resulting blood vessel damage (arteriopathy) can cause migraines, often with visual sensations or auras, or recurrent seizures (epilepsy). Damaged blood vessels reduce blood flow and can cause areas of tissue death (infarcts) throughout the body. An infarct in the brain can lead to a stroke. In individuals with CADASIL, a stroke can occur at any time from childhood to late adulthood, but typically happens during mid-adulthood. People with CADASIL often have more than one stroke in their lifetime. Recurrent strokes can damage the brain over time. Strokes that occur in the subcortical region of the brain, which is involved in reasoning and memory, can cause progressive loss of intellectual function (dementia) and changes in mood and personality. Many people with CADASIL also develop leukoencephalopathy, which is a change in a type of brain tissue called white matter that can be seen with magnetic resonance imaging (MRI). The age at which the signs and symptoms of CADASIL first begin varies greatly among affected individuals, as does the severity of these features. CADASIL is not associated with the common risk factors for stroke and heart attack, such as high blood pressure and high cholesterol, although some affected individuals might also have these health problems. ## Frequency CADASIL is likely a rare condition; however, its prevalence is unknown. ## Causes Mutations in the NOTCH3 gene cause CADASIL. The NOTCH3 gene provides instructions for producing the Notch3 receptor protein, which is important for the normal function and survival of vascular smooth muscle cells. When certain molecules attach (bind) to Notch3 receptors, the receptors send signals to the nucleus of the cell. These signals then turn on (activate) particular genes within vascular smooth muscle cells. NOTCH3 gene mutations lead to the production of an abnormal Notch3 receptor protein that impairs the function and survival of vascular smooth muscle cells. Disruption of Notch3 functioning can lead to the self-destruction (apoptosis) of these cells. In the brain, the loss of vascular smooth muscle cells results in blood vessel damage that can cause the signs and symptoms of CADASIL. ### Learn more about the gene associated with Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy * NOTCH3 ## Inheritance Pattern This condition is inherited in an autosomal dominant pattern, which means one copy of the altered NOTCH3 gene in each cell is sufficient to cause the disorder. In most cases, an affected person inherits the mutation from one affected parent. A few rare cases may result from new mutations in the NOTCH3 gene. These cases occur in people with no history of the disorder in their family. [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	Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy	c0751587	786	medlineplus	https://medlineplus.gov/genetics/condition/cerebral-autosomal-dominant-arteriopathy-with-subcortical-infarcts-and-leukoencephalopathy/	2021-01-27T08:25:24	{"gard": ["1049"], "mesh": ["D046589"], "omim": ["125310"], "synonyms": []}
Bardet-Biedl syndrome is a disorder that affects many parts of the body. The signs and symptoms of this condition vary among affected individuals, even among members of the same family. Vision loss is one of the major features of Bardet-Biedl syndrome. Loss of vision occurs as the light-sensing tissue at the back of the eye (the retina) gradually deteriorates. Problems with night vision become apparent by mid-childhood, followed by blind spots that develop in the side (peripheral) vision. Over time, these blind spots enlarge and merge to produce tunnel vision. Most people with Bardet-Biedl syndrome also develop blurred central vision (poor visual acuity) and become legally blind by adolescence or early adulthood. Obesity is another characteristic feature of Bardet-Biedl syndrome. Abnormal weight gain typically begins in early childhood and continues to be an issue throughout life. Complications of obesity can include type 2 diabetes, high blood pressure (hypertension), and abnormally high cholesterol levels (hypercholesterolemia). Other major signs and symptoms of Bardet-Biedl syndrome include the presence of extra fingers or toes (polydactyly), intellectual disability or learning problems, and abnormalities of the genitalia. Most affected males produce reduced amounts of sex hormones (hypogonadism), and they are usually unable to father biological children (infertile). Many people with Bardet-Biedl syndrome also have kidney abnormalities, which can be serious or life-threatening. Additional features of Bardet-Biedl syndrome can include impaired speech, delayed development of motor skills such as standing and walking, behavioral problems such as emotional immaturity and inappropriate outbursts, and clumsiness or poor coordination. Distinctive facial features, dental abnormalities, unusually short or fused fingers or toes, and a partial or complete loss of the sense of smell (anosmia) have also been reported in some people with Bardet-Biedl syndrome. Additionally, this condition can affect the heart, liver, and digestive system. ## Frequency In most of North America and Europe, Bardet-Biedl syndrome has a prevalence of 1 in 140,000 to 1 in 160,000 newborns. The condition is more common on the island of Newfoundland (off the east coast of Canada), where it affects an estimated 1 in 17,000 newborns. It also occurs more frequently in the Bedouin population of Kuwait, affecting about 1 in 13,500 newborns. ## Causes Bardet-Biedl syndrome can result from mutations in at least 14 different genes (often called BBS genes). These genes are known or suspected to play critical roles in cell structures called cilia. Cilia are microscopic, finger-like projections that stick out from the surface of many types of cells. They are involved in cell movement and many different chemical signaling pathways. Cilia are also necessary for the perception of sensory input (such as sight, hearing, and smell). The proteins produced from BBS genes are involved in the maintenance and function of cilia. Mutations in BBS genes lead to problems with the structure and function of cilia. Defects in these cell structures probably disrupt important chemical signaling pathways during development and lead to abnormalities of sensory perception. Researchers believe that defective cilia are responsible for most of the features of Bardet-Biedl syndrome. About one-quarter of all cases of Bardet-Biedl syndrome result from mutations in the BBS1 gene. Another 20 percent of cases are caused by mutations in the BBS10 gene. The other BBS genes each account for only a small percentage of all cases of this condition. In about 25 percent of people with Bardet-Biedl syndrome, the cause of the disorder is unknown. In affected individuals who have mutations in one of the BBS genes, mutations in additional genes may be involved in causing or modifying the course of the disorder. Studies suggest that these modifying genes may be known BBS genes or other genes. The additional genetic changes could help explain the variability in the signs and symptoms of Bardet-Biedl syndrome. However, this phenomenon appears to be uncommon, and it has not been found consistently in scientific studies. ### Learn more about the genes associated with Bardet-Biedl syndrome * BBS1 * BBS10 * CEP290 * MKKS Additional Information from NCBI Gene: * ARL6 * BBS12 * BBS2 * BBS4 * BBS5 * BBS7 * BBS9 * MKS1 * TRIM32 * TTC8 ## Inheritance Pattern Bardet-Biedl syndrome is typically inherited in an autosomal recessive pattern, which means both copies of a BBS gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of 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	Bardet-Biedl syndrome	c2936862	787	medlineplus	https://medlineplus.gov/genetics/condition/bardet-biedl-syndrome/	2021-01-27T08:25:49	{"gard": ["6866"], "mesh": ["C537909"], "omim": ["209900"], "synonyms": []}
## Summary ### Clinical characteristics. GTP cyclohydrolase 1-deficient dopa-responsive dystonia (GTPCH1-deficient DRD) is characterized by childhood-onset dystonia and a dramatic and sustained response to low doses of oral administration of levodopa. This disorder typically presents with gait disturbance caused by foot dystonia, later development of parkinsonism, and diurnal fluctuation of symptoms (aggravation of symptoms toward the evening and alleviation of symptoms in the morning after sleep). Initial symptoms are often gait difficulties attributable to flexion-inversion (equinovarus posture) of the foot. Occasionally, initial symptoms are arm dystonia, postural tremor of the hand, or slowness of movements. Brisk deep-tendon reflexes in the legs, ankle clonus, and/or the striatal toe (dystonic extension of the big toe) are present in many affected individuals. In general, gradual progression to generalized dystonia is observed. Intellectual, cerebellar, sensory, and autonomic disturbances generally do not occur. ### Diagnosis/testing. The diagnosis of GTPCH1-deficient DRD is established in a proband by identification of a heterozygous pathogenic variant in GCH1 by molecular genetic testing. In individuals with a suspected diagnosis of GTPCH1-deficient DRD and no identifiable GCH1 pathogenic variants, biochemical testing may be necessary. ### Management. Treatment of manifestations: Initial suggested dose of levodopa/decarboxylase inhibitor (DCI): * Children age <6 years: 1-10 mg/kg levodopa/DCI daily, administered in multiple doses * Children age ≥6 years: 25-50 mg levodopa/DCI 1-3x daily * Adults: 50 mg levodopa/DCI 1-3x daily For all, dose should be changed slowly and by small increments as needed. Motor benefit occurs immediately or within a few days of starting levodopa; full benefit occurs within several days to a few months. Maximum benefit (complete or near-complete responsiveness of symptoms) is generally achieved by <300-400 mg/day of levodopa/DCI. Although dyskinesias may appear at the beginning of levodopa therapy, they subside following dose reduction and do not reappear when the dose is gradually increased. Typically, adverse motor effects of chronic levodopa therapy (motor response fluctuations and dopa-induced dyskinesias) do not occur. Prevention of secondary complications: Early diagnosis and therapy (with low doses of levodopa) may prevent transient dyskinesias at initiation of levodopa treatment. Surveillance: Examination by a movement disorder specialist at least several times yearly is recommended. Agents/circumstances to avoid: Discontinuation of levodopa treatment. Evaluation of relatives at risk: It is appropriate to clarify the genetic status of apparently asymptomatic older and younger at-risk relatives of an affected individual in order to identify as early as possible those who would benefit from prompt initiation of treatment. Molecular genetic testing cannot be used to predict the occurrence of symptoms, age of onset, severity and type of symptoms, or rate of disease progression in family members who are heterozygous for a GCH1 pathogenic variant. Pregnancy management: Levodopa therapy is continued during pregnancy without adverse effect in most. ### Genetic counseling. GTPCH1-deficient DRD is inherited in an autosomal dominant manner. Affected individuals often have an affected parent with typical GTPCH1-deficient DRD or adult-onset parkinsonism caused by a GCH1 pathogenic variant. A proband with GTPCH1-deficient DRD may have the disorder as the result of a de novo pathogenic variant. Every child of an individual with autosomal dominant GTPCH1-deficient DRD has a 50% chance of inheriting the pathogenic variant. However, because of gender-related incomplete penetrance (i.e., higher penetrance in women than in men), it is not possible to predict whether offspring with a GCH1 pathogenic variant will develop symptoms. ## Diagnosis ### Suggestive Findings GTP cyclohydrolase 1-deficient dopa-responsive dystonia (GTPCH1-deficient DRD) should be suspected in individuals with the following characteristics [Nygaard et al 1993a, Segawa & Nomura 1993, Furukawa 2004, Trender-Gerhard et al 2009, Furukawa et al 2013, Wijemanne & Jankovic 2015]: * Onset typically in childhood following normal early motor development * Onset of dystonia in a limb, typically foot dystonia (equinovarus posture) resulting in gait disturbance * Later development of parkinsonism (tremor is mainly postural) * Presence of brisk deep-tendon reflexes in the legs, ankle clonus, and/or striatal toe (dystonic extension of the big toe, which may be misinterpreted as a Babinski response) in many individuals * In general, normal intellectual and cognitive function and absence of cerebellar, sensory, and autonomic disturbances * Diurnal fluctuation (aggravation of symptoms toward the evening and alleviation of symptoms in the morning after sleep). The degree of diurnal fluctuation is variable. * Gradual progression to generalized dystonia, typically more pronounced dystonia in the legs throughout the disease course * Frequent attenuation in the magnitude of diurnal fluctuation with age and disease progression * A dramatic and sustained response (complete or near-complete responsiveness of symptoms) to relatively low doses of orally administered levodopa. Maximum benefit is generally achieved by less than 300-400 mg/day of levodopa with a decarboxylase inhibitor (DCI) or 20-30 mg/kg/day of levodopa without a DCI. * Typically, absence of adverse motor effects of long-term levodopa therapy (wearing-off and on-off phenomena and dopa-induced dyskinesias) under optimal doses of levodopa * Female predominance among clinically affected individuals ### Establishing the Diagnosis The diagnosis of GTPCH1-deficient DRD is established in a proband by identification of a heterozygous pathogenic variant in GCH1 by molecular genetic testing (see Table 1). In individuals with a suspected diagnosis of GTPCH1-deficient DRD and no identifiable GCH1 pathogenic variants, biochemical testing may be necessary. Molecular genetic testing approaches can include a combination of gene-targeted testing (single-gene testing, concurrent or serial single-gene testing, multigene panel) and comprehensive genomic testing (chromosomal microarray analysis, exome sequencing, exome array, genome sequencing) depending on the phenotype. Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Because the phenotype of GTPCH1-deficient DRD is broad, individuals with the distinctive findings described in Suggestive Findings are likely to be diagnosed using gene-targeted testing (see Option 1), whereas those with atypical features in whom the diagnosis of GTPCH1-deficient DRD has not been considered are more likely to be diagnosed using genomic testing (see Option 2). #### Option 1 When the phenotypic and laboratory findings suggest the diagnosis of GTPCH1-deficient DRD, molecular genetic testing approaches can include single-gene testing or use of a multigene panel. * Single-gene testing. Sequence analysis of GCH1 detects small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. Perform sequence analysis first. If no pathogenic variant is found, perform gene-targeted deletion/duplication analysis to detect intragenic deletions or duplications. * A multigene panel that includes GCH1 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 this disorder a multigene panel that also includes deletion/duplication analysis is recommended (see Table 1). For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here. #### Option 2 When the diagnosis of GTPCH1-deficient DRD is not considered because an individual has atypical phenotypic features, comprehensive genomic testing (which does not require the clinician to determine which gene[s] are likely involved) is the best option. Exome sequencing is the most commonly used genomic testing method; genome sequencing is also possible. If exome sequencing is not diagnostic – and particularly when evidence supports autosomal dominant inheritance – exome array (when clinically available) may be considered to detect (multi)exon deletions or duplications that cannot be detected by sequence analysis. 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 GTPCH1-Deficient DRD View in own window Gene 1Test MethodProportion of Probands with a Pathogenic Variant 2 Detectable by This Method GCH1Sequence analysis 3~87% 4 Gene-targeted deletion/duplication analysis 5~13% 4 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\. Hagenah et al [2005], Zirn et al [2008], Clot et al [2009], Liu et al [2010], Wu-Chou et al [2010], Dobričić et al [2017], Yoshino et al [2018]. Variant detection rate by deletion/duplication analysis ranged from 0% [Yoshino et al 2018] to 38% [Wu-Chou et al 2010]. 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. ### Biochemical Testing If molecular testing does not identify a pathogenic variant, biochemical testing should be performed. CSF pterins. The enzyme GTPCH1 catalyzes the first step in the biosynthesis of tetrahydrobiopterin (BH4), which is the cofactor for tyrosine hydroxylase, tryptophan hydroxylase, and phenylalanine hydroxylase. Concentrations of total biopterin (BP, most of which exists as BH4) and total neopterin (NP, the byproducts of the GTPCH1 reaction) in cerebrospinal fluid (CSF) are reduced in individuals with GTPCH1 deficiencies. A finding of reduced concentrations of both BP and NP in CSF is useful for the diagnosis of GTPCH1-deficient DRD [Furukawa & Kish 1999]. GTPCH1 activity. If CSF sampling is not available, evaluation of GTPCH1 activity in phytohemagglutinin-stimulated mononuclear blood cells or cytokine-stimulated fibroblasts may be useful [Ichinose et al 1994, Ichinose et al 1995, Bonafé et al 2001, Van Hove et al 2006]. ## Clinical Characteristics ### Clinical Description GTP cyclohydrolase 1-deficient dopa-responsive dystonia (GTPCH1-deficient DRD), the major form of DRD, is a clinical syndrome characterized by childhood-onset dystonia and a dramatic and sustained response (complete or near-complete responsiveness of symptoms) to relatively low doses of levodopa. The perinatal and postnatal periods are normal, as is early motor development. Symptoms and signs. Initial symptoms in most individuals with childhood-onset GTPCH1-deficient DRD are gait difficulties attributable to dystonia in the legs, typically flexion-inversion (equinovarus posture) of the foot. Affected individuals have a tendency to fall. A relatively small number of individuals have onset with arm dystonia, postural tremor of the hand, or slowness of movements. Standing position with equinovarus posture of the feet can induce increased lumbar lordosis. A variable degree of rigidity and slowness of movements are recognized in the affected limbs. Tremor is usually postural, especially in the early course of illness. Rapid fatiguing of effort with repetitive motor tasks (e.g., finger tapping or foot tapping) is often observed. Some clinical findings suggestive of pyramidal signs in the lower extremities (brisk deep-tendon reflexes, spasticity, ankle clonus, and/or intermittent extensor plantar responses) are detected in many affected individuals. However, normal efferent cortical spinal activity with magneto-electrical stimulation of the motor cortex suggests a non-pyramidal basis for these findings. In fact, after starting levodopa therapy, severe hyperreflexia and spasticity resolve and an extensor plantar response often disappears in individuals with GTPCH1-deficient DRD. Dystonic extension of the big toe (the striatal toe) may be misinterpreted as an extensor plantar response. In general, intellectual and cognitive function is normal and there is no evidence of cerebellar, sensory, and autonomic disturbances in individuals with GTPCH1-deficient DRD. Diurnal fluctuation (aggravation of symptoms toward the evening and alleviation of symptoms in the morning after sleep) is characteristic [Segawa et al 1976]. The degree of fluctuation is variable, with some individuals being normal in the morning and others being only less severely affected in the morning compared to later in the day. Some individuals demonstrate only exercise-induced exacerbation or manifestation of dystonia. Diurnal fluctuation often attenuates with age and disease progression. Progression of symptoms. In general, gradual progression to generalized dystonia occurs in individuals with childhood-onset GTPCH1-deficient DRD. Typically, dystonia remains more pronounced in the legs throughout the disease course. Symptoms in individuals with adolescent onset are usually milder than in those with childhood onset and disease progression is slower. Individuals with adolescent-onset GTPCH1-deficient DRD seldom develop severe generalized dystonia. Such individuals may become more symptomatic in mid-adulthood because of development of overt parkinsonism. Response to levodopa. All individuals with GTPCH1-deficient DRD demonstrate a dramatic and sustained complete or near-complete response of symptoms to relatively low doses of levodopa [Nygaard et al 1991, Segawa & Nomura 1993, Furukawa et al 2005] (see Treatment of Manifestations). Even individuals who have been untreated for more than 50 years (e.g., persons initially diagnosed with cerebral palsy) can show a remarkable response to levodopa. At the initiation of levodopa therapy, some individuals with GTPCH1-deficient DRD develop dyskinesias, which subside following dose reduction and do not reappear when the dose is slowly increased later; note that these transient dyskinesias are different from those with motor response fluctuations observed in persons with early-onset parkinsonism and Parkinson disease during chronic levodopa therapy. Under optimal doses, individuals with typical GTPCH1-deficient DRD on long-term levodopa treatment do not develop either motor response fluctuations or dopa-induced dyskinesias. Female predominance. A predominance of clinically affected females is observed, with reported female-to-male ratios ranging from 1.3:1 to 8.3:1 [Furukawa et al 1998b, Segawa et al 2003, Trender-Gerhard et al 2009, Furukawa et al 2013, Wijemanne & Jankovic 2015, Dobričić et al 2017]. See Penetrance. Phenotypic variability and spectrum. Wide intra- and interfamilial variations in expressivity have been reported in GTPCH1-deficient DRD [Bandmann et al 1998, Steinberger et al 1998, Furukawa et al 2000, Grimes et al 2002, Postuma et al 2003, Trender-Gerhard et al 2009]. The clinical phenotypic spectrum has been extended to include adult-onset "benign" parkinsonism, various types of focal dystonia, DRD-simulating cerebral palsy or spastic paraplegia, and spontaneous remission of dystonia and/or parkinsonism (sometimes with a relapse in the later course of illness) [Furukawa et al 2013]. Adult-onset parkinsonism. There are two types of adult-onset parkinsonism in families with GTPCH1-deficient DRD [Furukawa & Kish 2015]. * Individuals with adult-onset "benign" parkinsonism manifest no dystonia prior to the onset of parkinsonism in mid- or late adulthood. These individuals respond markedly to low doses of levodopa and, when treated with optimal doses of levodopa, remain functionally normal for a long period of time without developing motor response fluctuations or dopa-induced dyskinesias. PET and SPECT studies using presynaptic dopaminergic markers have demonstrated normal results in "benign" parkinsonism [Nygaard et al 1992, O'Sullivan et al 2001, De La Fuente-Fernández et al 2003, Kang et al 2004, Furukawa et al 2013, Lewthwaite et al 2015, Terbeek et al 2015, Lin et al 2018]. * "Neurodegenerative" parkinsonism, including Parkinson disease associated with GCH1 pathogenic variants, can be found in families with GTPCH1-deficient DRD; in contrast to findings in "benign" parkinsonism, individuals with "neurodegenerative" parkinsonism or dystonia-parkinsonism associated with GCH1 pathogenic variants were found to have abnormal 18F-fluorodopa PET or dopamine transporter (DAT) SPECT imaging [Kikuchi et al 2004, Hjermind et al 2006, Eggers et al 2012, Ceravolo et al 2013, Mencacci et al 2014, Lewthwaite et al 2015, Terbeek et al 2015, Lin et al 2018]. Myoclonus-dystonia. Leuzzi et al [2002] reported an individual who demonstrated delayed attainment of early motor milestones and involuntary jerky movements that were responsive to levodopa; myoclonus-dystonia as a phenotype of GTPCH1-deficient DRD was found only in this individual [Furukawa & Rajput 2002, Luciano et al 2009, Wijemanne & Jankovic 2015]. Non-motor symptoms. In individuals with GTPCH1-deficient DRD, there are conflicting reports on the frequency of non-motor symptoms. Antelmi et al [2015] analyzed published data on non-motor symptoms in GTPCH1-deficient DRD and stated that overt non-motor symptoms would suggest a diagnosis of DRD plus diseases (other neurotransmitter disorders that may sometimes mimic DRD) rather than of GTPCH1-deficient DRD. * In rare instances, anxiety, depression, obsessive-compulsive disorder, and/or sleep disturbances have been reported [Hahn et al 2001, Van Hove et al 2006, Trender-Gerhard et al 2009]. * Six of the 23 individuals with GTPCH1-deficient DRD described by Tadic et al [2012] reported one or more non-motor symptoms including depression, anxiety, and migraine. However, a more recent study by the same researchers did not confirm an increased frequency of non-motor symptoms in individuals with GCH1-associated DRD [Brüggemann et al 2014]. * Timmers et al [2017] found a higher lifetime prevalence of psychiatric disorders and daytime sleepiness in adults but not in children with GTPCH1-deficient DRD. Neuroimaging. Brain CT and MRI are normal. Positron emission tomography (PET) and single-photon emission computed tomography (SPECT) studies using presynaptic dopaminergic markers have demonstrated normal results in the striatum of DRD and "benign" parkinsonism due to GCH1 pathogenic variants [Jeon et al 1998, Kishore et al 1998, O'Sullivan et al 2001, De La Fuente-Fernández et al 2003, Kang et al 2004, Furukawa et al 2013, Lewthwaite et al 2015, Terbeek et al 2015, Lin et al 2018]. These PET and SPECT findings are supported by normal striatal levels of dopa decarboxylase, dopamine transporter, and vesicular monoamine transporter at autopsy of individuals with GTPCH1-deficient DRD, indicating that striatal dopamine nerve terminals are preserved in this disorder [Furukawa et al 1999, Furukawa et al 2002]. Using [11C]-raclopride PET, elevated D2-receptor binding in the striatum has been found in GTPCH1-deficient DRD [Kishore et al 1998]. Network analysis of [18F]-fluorodeoxyglucose PET images has shown that GTPCH1-deficient DRD is associated with a specific metabolic topography, which is characterized by increases in the dorsal midbrain, cerebellar vermis, and supplementary motor area and by decreases in the putamen as well as lateral premotor and motor cortical regions [Asanuma et al 2005]. Neuropathology. Neuropathologic studies demonstrated a normal population of cells with reduced melanin and no evidence of Lewy body formation in the substantia nigra of four individuals with GTPCH1-deficient DRD and one asymptomatic individual with a GCH1 pathogenic variant [Rajput et al 1994, Furukawa et al 1999, Furukawa et al 2002, Grötzsch et al 2002, Wider et al 2008, Segawa et al 2013]. Neurochemistry. Neurochemical data are available for GTPCH1-deficient DRD [Rajput et al 1994, Furukawa et al 1999, Furukawa et al 2002, Furukawa et al 2016]. At autopsy, biopterin (BP) and neopterin (NP) levels in the putamen were substantially lower in two affected individuals (mean: -84% and -62%) than in age-matched normal controls. The caudal portion of the putamen was the striatal subdivision most affected by dopamine loss (-88%). Striatal levels of dopa decarboxylase protein, dopamine transporter, and vesicular monoamine transporter were normal, but tyrosine hydroxylase (TH) protein levels were markedly decreased in the putamen (> -97%). These biochemical findings suggest that striatal dopamine reduction in GTPCH1-deficient DRD is caused by both decreased TH activity resulting from a low cofactor (BH4) level and actual loss of TH protein without nerve terminal loss. This TH protein reduction in the striatum may be caused by diminished regulatory effect of BH4 on the steady-state level of TH molecules [Furukawa et al 1999, Sumi-Ichinose et al 2001, Furukawa et al 2002, Sumi-Ichinose et al 2005]. In an asymptomatic individual with a GCH1 pathogenic variant, decreases in BP and NP levels in the putamen (-82% and -57%) paralleled those in the two symptomatic individuals who were autopsied [Furukawa et al 2002]. However, TH protein and dopamine levels in the caudal putamen (-52% and -44%) were not as severely affected as in the symptomatic individuals. Consistent with other postmortem brain data suggesting that greater than 60%-80% striatal dopamine loss is necessary for overt motor symptoms to occur [Furukawa 2003, Furukawa 2004], the maximal 44% dopamine reduction in the striatum of the asymptomatic individual with the GCH1 pathogenic variant was not sufficient to produce any symptoms of GTPCH1-deficient DRD. Striatal levels of serotonin markers (serotonin, TPH protein, serotonin transporter protein [Kish et al 2008]) were normal in GTPCH1-deficient DRD [Furukawa et al 2016]. ### Genotype-Phenotype Correlations No correlations between specific clinical features and types of pathogenic variants in GCH1 have been established in individuals with GTPCH1-deficient DRD. ### Penetrance Penetrance in individuals with GTPCH1-deficient DRD has been reported to be higher in females than in males: 87% vs 38% [Furukawa et al 1998b], 100% vs 55% [Steinberger et al 1998], and 87% vs 35% [Segawa et al 2003]. ### Nomenclature The term "DRD" is now used to delineate the following disease entities: * GTPCH1-deficient DRD (DYT-GCH1, DYT5a; the major form of DRD) * TH-deficient DRD (DYT-TH, DYT5b; the mild form of TH deficiency [Furukawa et al 2004b]) * SR-deficient DRD (DYT-SPR; the very mild form of SR deficiency [Arrabal et al 2011]) ### Prevalence Dopa-responsive dystonia (DRD) is observed worldwide, and prevalence of DRD (of any cause) in both England and Japan has been estimated at 0.5 per million [Nygaard et al 1993b]. Dobričić et al [2017] found that prevalence of GTPCH1-deficient DRD in Serbia was 2.96 per million (21 symptomatic individuals with GCH1 pathogenic variants per 7.1 million individuals). There was no evidence for a common founder; however, haplotype analysis indicated that some of the affected individuals had common ancestors. ## Differential Diagnosis A dramatic and sustained response to low doses of levodopa in dopa-responsive dystonia (DRD) distinguishes this disorder from cerebral palsy, spastic paraplegia, and all other forms of dystonia, including early-onset primary dystonia (DYT1). (For a differential diagnosis of dystonia, see Dystonia Overview.) The major differential diagnoses of GTPCH1-deficient DRD are summarized in Table 2 and include TH-deficient DRD, SR-deficient DRD (rare), and early-onset Parkinson disease. ### Table 2. Disorders to Consider in the Differential Diagnosis of GTPCH1-Deficient DRD View in own window DisorderGene(s)MOIClinical Features of Differential Diagnosis Disorder Overlapping w/GTPCH1-Deficient DRDDistinguishing from GTPCH1-Deficient DRD Tyrosine hydroxylase-deficient DRD (DYT5b; DYT-TH)TH 1AR * Individuals w/mild form of TH deficiency can develop DRD. * Complete responsiveness of symptoms to levodopa * Onset of symptoms generally age 12 mos - 6 yrs * Initial symptoms typically lower-limb dystonia &/or difficulty walking * No delay in psychomotor development Normal concentrations of BP & NP in CSF 2 Sepiapterin reductase-deficient DRD (DYT-SPR) 3SPRAR 4 * One family reported w/strikingly mild sepiapterin reductase deficiency phenotype (DRD w/out motor & cognitive delay) 5, 6 * Sepiapterin reductase deficiency w/mild findings may mimic GTPCH1-deficient DRD. * Remarkable response to levodopa * Diurnal fluctuation of symptoms * ↑ concentration of BP is associated w/normal concentration of NP in CSF. 2 * Manifestations of DYT-SPR typically begin earlier than those in GTPCH1-deficient DRD. Early-onset Parkinson disease (see Parkin Type of Early-Onset Parkinson Disease, PINK1 Type of Young-Onset Parkinson Disease, and Parkinson Disease Overview)PINK1 7 PRKN 8AR * In the early course, the clinical differentiation between early-onset Parkinson disease w/dystonia & GTPCH1-deficient DRD is difficult. * Individuals w/early-onset Parkinson disease (especially those w/onset age <20 yrs) often develop gait disturbance (attributable to foot dystonia) as the initial symptom. 9 * ↓ concentration of BP is associated w/normal concentration of NP in CSF of Parkinson disease (incl parkin type of early-onset Parkinson disease). 2 * PINK1 type of early-onset Parkinson disease often presents w/abnormal behavior &/or psychiatric manifestations. * The most reliable clinical distinction between early-onset Parkinson disease (especially parkin-type) & GTPCH1-deficient DRD is the subsequent occurrence of adverse motor effects of chronic levodopa therapy (wearing-off & on-off phenomena & dopa-induced dyskinesias) in early-onset Parkinson disease. AD = autosomal dominant; AR = autosomal recessive; BP = total biopterin; CSF = cerebrospinal fluid; DRD = dopa-responsive dystonia; MOI = mode of inheritance; NP = total neopterin; XL = X-linked 1\. Analyses of both GCH1 and TH demonstrated pathogenic variants in 86% of families with DRD or dystonia with motor delay [Furukawa 2004]. 2\. Both total biopterin (BP) and total neopterin (NP) are reduced in GTPCH1-deficient DRD [Furukawa et al 1996b]. 3\. Sepiapterin reductase deficiency is a rare cause of dopa-responsive dystonia. 4\. Shalash et al [2017] reported a rare heterozygous SPR variant as a cause of dominantly inherited SR-deficient DRD with incomplete penetrance and a common heterozygous dihydrofolate reductase (DHFR) variant as a potential modifier, affecting the penetrance of the pathogenic SPR variant; the presence of another individual with DRD caused by autosomal dominant SR deficiency was suggested previously [Steinberger et al 2004]. 5\. Arrabal et al [2011] 6\. Sepiapterin reductase deficiency is usually associated with more severe symptoms [Dill et al 2012, Friedman et al 2012, Friedman 2016]. 7\. Pathogenic variants in PINK1 account for 1%-7% of individuals with early-onset Parkinson disease. See Parkinson Disease Overview. 8\. Pathogenic variants in PRKN account for up to 50% of individuals with early-onset Parkinson disease. See Parkinson Disease Overview. 9\. Furukawa et al [1996a] ## Management ### Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with GTP cyclohydrolase 1-deficient dopa-responsive dystonia (GTPCH1-deficient DRD), the evaluations summarized in Table 3 (if not performed as part of the evaluation that led to the diagnosis) are recommended. ### Table 3. Recommended Evaluations Following Initial Diagnosis in Individuals with GTPCH1-Deficient DRD View in own window Organ SystemEvaluationComment NeurologicBaseline neurologic examinationImportant to assess severity of symptoms prior to starting levodopa administration OtherConsultation w/clinical geneticist &/or genetic counselor ### Treatment of Manifestations ### Table 4. Treatment of Manifestations in Individuals with GTPCH1-Deficient DRD View in own window ManifestationTreatmentConsiderations/Other Dystonia/ parkinsonismLevodopa/DCI * Initial suggested dose 1, 2, 3 (a levodopa trial): * Children ˂6 yrs: 1-10 mg/kg levodopa/DCI daily, administered in multiple doses 3 * Children ≥6 years: 25-50 mg levodopa/DCI 1-3x/day * Adults: 50 mg levodopa/DCI 1-3x/day * Changing the dose slowly & by small increments is recommended. * Motor benefit can be recognized immediately or w/in a few days of starting levodopa therapy; full benefit occurs w/in several days to a few months. * Maximum benefit (complete or near-complete responsiveness of symptoms) is generally achieved by <300-400 mg/day of levodopa/DCI. Transient dyskinesias associated w/initiation of treatment w/levodopa/DCIReduction of dose of levodopa/DCI * Transient dyskinesias do not reappear w/later gradual increment in dose. Note: Such transient dyskinesias are different from those observed in Parkinson disease during chronic levodopa therapy. * Typically, adverse motor effects of chronic levodopa therapy (motor response fluctuations and dopa-induced dyskinesias) do not occur. DCI = decarboxylase inhibitor 1\. Nygaard et al [1991] 2\. Furukawa et al [2013] 3\. Wijemanne & Jankovic [2015] ### Prevention of Secondary Complications Early diagnosis and therapy (with low doses of levodopa) may prevent transient dyskinesias at initiation of levodopa treatment. ### Surveillance Examination by a movement disorder specialist at least several times yearly is recommended. ### Agents/Circumstances to Avoid Discontinuation of levodopa treatment usually results in return of symptoms. ### Evaluation of Relatives at Risk It is appropriate to clarify the genetic status of apparently asymptomatic older and younger at-risk relatives of an affected individual in order to identify as early as possible those who would benefit from prompt initiation of treatment. Note: Molecular genetic testing cannot be used to predict the occurrence of symptoms (see Penetrance), age of onset, severity and type of symptoms, or rate of disease progression in family members found to be heterozygous for a GCH1 pathogenic variant. See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes. ### Pregnancy Management In 20 pregnancies reported in 12 affected individuals, levodopa was continued without adverse effect in most. Two women experienced remission resulting in a reduction or cessation of therapy. Two women reported mild deterioration of dystonia; an increase in dose was required in one. No fetal abnormalities were identified [Trender-Gerhard et al 2009]. See MotherToBaby for further information on medication use during pregnancy. ### Therapies Under Investigation Search ClinicalTrials.gov in the US and www.ClinicalTrialsRegister.eu in Europe for information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor *[BMI]: body mass index	GTP Cyclohydrolase 1-Deficient Dopa-Responsive Dystonia	c1851920	788	gene_reviews	https://www.ncbi.nlm.nih.gov/books/NBK1508/	2021-01-18T21:23:40	{"mesh": ["C538007"], "synonyms": ["Autosomal Dominant Dopa-Responsive Dystonia", "Autosomal Dominant Segawa Syndrome", "DYT5a", "Hereditary Progressive Dystonia with Marked Diurnal Fluctuation"]}
Early-onset primary dystonia is a condition characterized by progressive problems with movement, typically beginning in childhood. Dystonia is a movement disorder that involves involuntary tensing of the muscles (muscle contractions), twisting of specific body parts such as an arm or a leg, rhythmic shaking (tremors), and other uncontrolled movements. A primary dystonia is one that occurs without other neurological symptoms, such as seizures or a loss of intellectual function (dementia). Early-onset primary dystonia does not affect a person's intelligence. On average, the signs and symptoms of early-onset primary dystonia appear around age 12. Abnormal muscle spasms in an arm or a leg are usually the first sign. These unusual movements initially occur while a person is doing a specific action, such as writing or walking. In some affected people, dystonia later spreads to other parts of the body and may occur at rest. The abnormal movements persist throughout life, but they do not usually cause pain. The signs and symptoms of early-onset primary dystonia vary from person to person, even among affected members of the same family. The mildest cases affect only a single part of the body, causing isolated problems such as a writer's cramp in the hand. Severe cases involve abnormal movements affecting many regions of the body. ## Frequency Early-onset primary dystonia is among the most common forms of childhood dystonia. This disorder occurs most frequently in people of Ashkenazi (central and eastern European) Jewish heritage, affecting 1 in 3,000 to 9,000 people in this population. The condition is less common among people with other backgrounds; it is estimated to affect 1 in 10,000 to 30,000 non-Jewish people worldwide. ## Causes A particular mutation in the TOR1A gene (also known as DYT1) is responsible for most cases of early-onset primary dystonia. The TOR1A gene provides instructions for making a protein called torsinA. Although little is known about its function, this protein may help process and transport other proteins within cells. It appears to be critical for the normal development and function of nerve cells in the brain. A mutation in the TOR1A gene alters the structure of torsinA. The altered protein's effect on the function of nerve cells in the brain is unclear. People with early-onset primary dystonia do not have a loss of nerve cells or obvious changes in the structure of the brain that would explain the abnormal muscle contractions. Instead, the altered torsinA protein may have subtle effects on the connections between nerve cells and likely disrupts chemical signaling between nerve cells that control movement. Researchers are working to determine how a change in this protein leads to the characteristic features of this disorder. ### Learn more about the gene associated with Early-onset primary dystonia * TOR1A ## Inheritance Pattern Mutations in the TOR1A gene are inherited in an autosomal dominant pattern, which means one of the two copies of the gene is altered in each cell. Many people who have a mutation in this gene are not affected by the disorder and may never know they have the mutation. Only 30 to 40 percent of people who inherit a TOR1A mutation will ever develop signs and symptoms of early-onset primary dystonia. Everyone who has been diagnosed with early-onset primary dystonia has inherited a TOR1A mutation from one parent. The parent may or may not have signs and symptoms of the condition, and other family members may or may not be affected. [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	Early-onset primary dystonia	c1851945	789	medlineplus	https://medlineplus.gov/genetics/condition/early-onset-primary-dystonia/	2021-01-27T08:25:53	{"gard": ["2027"], "omim": ["128100"], "synonyms": []}
Central nervous system cyst Other namesBrain cyst A CT scan of an arachnoid cyst SpecialtyMedical genetics A central nervous system cyst is a type of cyst that presents and affects part of the central nervous system (CNS). They are usually benign and filled with either cerebrospinal fluid, blood, or tumor cells. CNS cysts are classified into two categories: cysts that originate from non-central nervous system tissue, migrate to, and form on a portion of the CNS, and cysts that originate within central nervous system tissue itself. Within these two categories, there are many types of CNS cysts that have been identified from previous studies. [1][2] ## Contents * 1 Classification * 1.1 Originating from non-central nervous system tissue * 1.2 Originating from the central nervous system tissue * 2 Signs and symptoms * 3 Causes * 4 Diagnosis * 5 Treatment * 5.1 Permanent drainage * 5.2 Fenestration * 5.3 Endoscopic cyst fenestration * 6 Epidemiology * 7 References * 8 External links ## Classification[edit] ### Originating from non-central nervous system tissue[edit] These classification of cysts are embedded in the endoderm (inner layer) and the ectoderm (outer layer) of the cranial or spinal cord germ layers. They normally take over the neuraxis, the axis of the central nervous system that determines how the nervous system is placed, which allows the cysts to infiltrate the CNS tissues.[3] They are most commonly found in the area near the pineal gland, the chiasmatic cistern, and the cerebellopontine angle space. These common places generally house extensive and continuously growing cysts.[2] Some examples of cysts originating from non-central nervous system tissue include: * Teratomas cysts (containing multiple body tissue types) * Dermoid (epidermoid/epidermoid tumor) * Rathke's cleft cysts * Pineal cysts * Tumor-associated cysts * Epithelial cysts that originate from upper respiratory and intestinal tracks. ### Originating from the central nervous system tissue[edit] Human brain showing a colloid cyst in the third ventricle This category of cysts takes over areas of necrotic tissue in the brain from injuries, diseases, or abnormalities, which occur due to the central nervous system's nonregenerative nature. These cysts can affect all germ layers of the CNS, but are most common in the arachnoid mater, and the ventricular space, which may block CSF pathways. These cysts can be static (stationary) or progressive. Some examples of cysts originating from the CNS tissue include: * Arachnoid cysts (Leptomeningeal cysts) * Ependymal cysts * Cystic cerebellar astrocytomas[4] * Colloid cysts ## Signs and symptoms[edit] Symptoms are assessed on a case by case basis.[5] Some cysts in the CNS can be asymptomatic (producing or showing no symptoms), depending on their location in the brain or spinal cord. If the cysts develop in critical areas of the central nervous system, they can present one or more of the following symptoms:[6] * Pressure in the spinal cord or brain * Rupture of nerves around the cyst * Weakness in specific parts of the body controlled by the cyst-infected brain region * Inflammation * Hydrocephalus[7] * Brainstem hemorrhage * Seizures[5] * Visual disturbances and hearing loss * Headache[6] * Difficulty with balance or walking[6] In general, symptoms vary depending on the type of cyst and its location within the CNS. ## Causes[edit] Many CNS cysts form in the womb during the first few weeks of development as a result of congenital defects.[7] In adults cysts may also form due to a head injury or trauma, resulting in necrotic tissues (dead tissue), and can sometimes be associated with cancerous tumors or infection in the brain. However, the underlying reasons for cyst formation are still unknown.[7] ## Diagnosis[edit] CT scan of a colloid cyst The diagnostic process typically begins with a medical history workup followed by a medical examination by a physician. Imaging tests, such as CT scans and MRIs, help provide a clearer picture. The physician typically looks for fluid (or other bodily substance) filled sacs to appear in the scans, as is shown in the CT scan of a colloid cyst. A primary health care provider will refer an individual to a neurologist or neurosurgeon for further examination. Other diagnostic methods include radiological examinations and macroscopic examinations. After a diagnosis has been made, immunohistochemistry may be used to differentiate between epithelial cysts and arachnoid cysts.[2] These examinations are useful to get a general idea of possible treatment options, but can be unsatisfactory to diagnose CNS cysts.[3][5] Professionals still do not fully understand how cysts form; however, analyzing the walls of different cyst types, using electron microscopes and light microscopes, has proven to be the best diagnostic tool. This has led to more accurate cyst classification and correct course of action for treatments that are cyst specific. In the past, before imaging scans or tests were available, medical professionals could only diagnose cysts via exploratory surgery.[2] ## Treatment[edit] Treatment is often largely dependent on the type of cyst. Asymptomatic cysts, termed pseudocysts, normally require active monitoring with periodic scans for future growth.[7] Symptomatic (producing or showing symptoms) cysts may require surgical removal if they are present in areas where brain damage is unavoidable, or if they produce chronic symptoms disruptive to the quality of life of the patient. Some examples of cyst removal procedures include: permanent drainage, fenestration, and endoscopic cyst fenestration.[3] ### Permanent drainage [edit] A neurosurgeon may open a portion of the body and insert a shunt into cerebral spinal fluid (CSF) filled cysts to allow drainage into CSF pathways. The fluid from the cyst is then drained into the abdomen, the body reabsorbs the fluid (reabsorption of fluid does not cause any harm). This type of surgical treatment is often performed to relieve pressure on the brain from a cyst within the cerebral cortex.[3] ### Fenestration[edit] A neurosurgeon performs a craniotomy as a means of entry to access the cyst. The cyst is then opened to release its contents, which are reabsorbed by the brain. [3] This is commonly used with inflammatory cysts located in the ventricles, and can result in increased ventricular fluid flow within the brain. ### Endoscopic cyst fenestration[edit] A neurosurgeon performs a same day surgery to insert an endoscope, which drains the cyst internally.[3] ## Epidemiology[edit] Cysts derived from CNS tissues are very common in America.[2] They are a subtype of cerebrovascular diseases, which are the third leading cause of death in America.[2] Generally, CNS cysts are present in all geographic regions, races, ages, and sexes.[8] However, certain types of CNS cysts are more prevalent in certain types of individuals than others. Some examples of incidence rates in specific types of cysts include:[1] * Arachnoid cysts are more prevalent in males than females * Colloid cysts are more prevalent in adults * Dermoid cysts are more prevalent in children under 10 years of age * Epidermoid cysts are more prevalent in middle-aged adults ## References[edit] 1. ^ a b Schiff, David (June 2010). "Cysts" (PDF). American Brain Tumor Association. Archived from the original (PDF) on 16 May 2017. Retrieved 3 March 2017. 2. ^ a b c d e f Hirano, Asao; Hirano, Michio (2004-03-01). "Benign cysts in the central nervous system: Neuropathological observations of the cyst walls". Neuropathology. 24 (1): 1–7. doi:10.1111/j.1440-1789.2003.00526.x. ISSN 1440-1789. 3. ^ a b c d e f Greenfield, Jerry (January 2015). "Surgery for an Arachnoid Cyst". Surgery for an Arachnoid cysts. Retrieved 2017-03-11. 4. ^ Chen, Yong; Fang, Hong-Juan; Li, Zhi-Feng; Yu, Sheng-Yuan; Li, Chu-Zhong; Wu, Zhe-Bao; Zhang, Ya-Zhuo (2016-08-01). "Treatment of Middle Cranial Fossa Arachnoid Cysts: A Systematic Review and Meta-Analysis". World Neurosurgery. 92: 480–490.e2. doi:10.1016/j.wneu.2016.06.046. 5. ^ a b c Sundaram C, Paul T R, Raju B V, Ramakrishna Murthy T, Sinha A K, Prasad V S, Purohit A K. Cysts of the central nervous system : a clinicopathologic study of 145 cases. Neurol India [serial online] 2001 [cited 2017 Apr 11];49:237. Available from: http://www.neurologyindia.com/text.asp?2001/49/3/237/1247 6. ^ a b c "Brain Cyst". www.saintlukeshealthsystem.org. June 2015. Retrieved 2017-03-26. 7. ^ a b c d "Brain and spinal cord cysts - Canadian Cancer Society". www.cancer.ca. Retrieved 2017-04-11. 8. ^ "Arachnoid Cysts - NORD (National Organization for Rare Disorders)". NORD (National Organization for Rare Disorders). Retrieved 2017-04-27. ## External links[edit] Classification D * ICD-10: G93.0, Q04.6 * ICD-9-CM: 348.0, 742.4 * MeSH: D020863 * v * t * e Diseases of the nervous system, primarily CNS Inflammation Brain * Encephalitis * Viral encephalitis * Herpesviral encephalitis * Limbic encephalitis * Encephalitis lethargica * Cavernous sinus thrombosis * Brain abscess * Amoebic Brain and spinal cord * Encephalomyelitis * Acute disseminated * Meningitis * Meningoencephalitis Brain/ encephalopathy Degenerative Extrapyramidal and movement disorders * Basal ganglia disease * Parkinsonism * PD * Postencephalitic * NMS * PKAN * Tauopathy * PSP * Striatonigral degeneration * Hemiballismus * HD * OA * Dyskinesia * Dystonia * Status dystonicus * Spasmodic torticollis * Meige's * Blepharospasm * Athetosis * Chorea * Choreoathetosis * Myoclonus * Myoclonic epilepsy * Akathisia * Tremor * Essential tremor * Intention tremor * Restless legs * Stiff-person Dementia * Tauopathy * Alzheimer's * Early-onset * Primary progressive aphasia * Frontotemporal dementia/Frontotemporal lobar degeneration * Pick's * Dementia with Lewy bodies * Posterior cortical atrophy * Vascular dementia Mitochondrial disease * Leigh syndrome Demyelinating * Autoimmune * Inflammatory * Multiple sclerosis * For more detailed coverage, see Template:Demyelinating diseases of CNS Episodic/ paroxysmal Seizures and epilepsy * Focal * Generalised * Status epilepticus * For more detailed coverage, see Template:Epilepsy Headache * Migraine * Cluster * Tension * For more detailed coverage, see Template:Headache Cerebrovascular * TIA * Stroke * For more detailed coverage, see Template:Cerebrovascular diseases Other * Sleep disorders * For more detailed coverage, see Template:Sleep CSF * Intracranial hypertension * Hydrocephalus * Normal pressure hydrocephalus * Choroid plexus papilloma * Idiopathic intracranial hypertension * Cerebral edema * Intracranial hypotension Other * Brain herniation * Reye syndrome * Hepatic encephalopathy * Toxic encephalopathy * Hashimoto's encephalopathy Both/either Degenerative SA * Friedreich's ataxia * Ataxia–telangiectasia MND * UMN only: * Primary lateral sclerosis * Pseudobulbar palsy * Hereditary spastic paraplegia * LMN only: * Distal hereditary motor neuronopathies * Spinal muscular atrophies * SMA * SMAX1 * SMAX2 * DSMA1 * Congenital DSMA * Spinal muscular atrophy with lower extremity predominance (SMALED) * SMALED1 * SMALED2A * SMALED2B * SMA-PCH * SMA-PME * Progressive muscular atrophy * Progressive bulbar palsy * Fazio–Londe * Infantile progressive bulbar palsy * both: * Amyotrophic lateral sclerosis * v * t * e Congenital malformations and deformations of nervous system Brain Neural tube defect * Anencephaly * Acephaly * Acrania * Acalvaria * Iniencephaly * Encephalocele * Chiari malformation Other * Microcephaly * Congenital hydrocephalus * Dandy–Walker syndrome * other reduction deformities * Holoprosencephaly * Lissencephaly * Microlissencephaly * Pachygyria * Hydranencephaly * Septo-optic dysplasia * Megalencephaly * Hemimegalencephaly * CNS cyst * Porencephaly * Schizencephaly * Polymicrogyria * Bilateral frontoparietal polymicrogyria Spinal cord Neural tube defect * Spina bifida * Rachischisis Other * Currarino syndrome * Diastomatomyelia * Syringomyelia [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	Central nervous system cyst	c0349606	790	wikipedia	https://en.wikipedia.org/wiki/Central_nervous_system_cyst	2021-01-18T18:40:46	{"mesh": ["D020863"], "umls": ["C0349606"], "icd-9": ["348.0", "742.4"], "icd-10": ["G93.0", "Q04.6"], "wikidata": ["Q5062119"]}
Asbestos-related disease Figure A shows the location of the lungs, airways, pleura, and diaphragm in the body. Figure B shows lungs with asbestos-related diseases, including pleural plaque, lung cancer, asbestosis, plaque on the diaphragm, and mesothelioma. SpecialtyRespirology Asbestos-related diseases are disorders of the lung and pleura caused by the inhalation of asbestos fibres. Asbestos-related diseases include non-malignant disorders such as asbestosis (pulmonary fibrosis due to asbestos), diffuse pleural thickening, pleural plaques, pleural effusion, rounded atelectasis and malignancies such as lung cancer and malignant mesothelioma. People who worked in jobs with high asbestos dust exposure are at the highest risk of developing asbestos-related disease. However, exposure to asbestos may also occur in the worker’s home due to dust that has accumulated on the worker's clothing (para-occupational exposure). Asbestos-related diseases can also occur as a result of non-occupational, environmental exposure. Asbestos was extensively used in many building materials, therefore large quantities of asbestos still remain in buildings that were built prior to the restriction of asbestos use that applies in many countries. The weathering and aging of such buildings may cause asbestos fragments to be released in the air and create a potential hazard. Anyone who disturbs the asbestos-containing material during home maintenance and renovation can be affected,[1] although the exact risks are difficult to quantify. ## Contents * 1 Pathophysiology * 2 Non-malignant asbestos-related pleural diseases * 2.1 Pleural plaques * 2.2 Diffuse pleural thickening * 2.3 Benign asbestos pleural effusion * 2.4 Rounded atelectasis * 3 Asbestosis * 4 Malignant asbestos-related diseases * 4.1 Malignant mesothelioma * 4.2 Asbestos-related lung cancer * 5 History * 6 References * 7 External links ## Pathophysiology[edit] Inhaled asbestos fibres enter the upper and lower respiratory tracts when asbestos is released into the air. Some of the inhaled fibers are cleared by the mucociliary clearance mechanism but long thin asbestos fibers may reach the lower airways and alveoli, and can be retained in the lungs for many years. Amphibole fibers are not cleared as effectively as serpentines and therefore accumulate more readily in the distal lung parenchyma.[2] Asbestos fibres are recognised by the lungs as foreign bodies and cause the activation of the lung’s local immune system leading to inflammation, cell and tissue damage. In the long term, this can lead to fibrosis, or rarely to malignancy. From the lungs, some asbestos fibres (mainly short fibres) can also migrate to pleural and peritoneal spaces.[3] ## Non-malignant asbestos-related pleural diseases[edit] Benign asbestos-related pleural abnormalities encompass four types of pleural changes: * Pleural plaques * Diffuse pleural thickening * Benign asbestos pleural effusions * Rounded atelectasis (folded lung) The pleura appears to be more sensitive than the lung parenchyma to the effects of asbestos fibres.[4] Thus asbestos-related pleural diseases can result from much lower doses than the fibrotic changes in the lung. ### Pleural plaques[edit] Pleural plaques are the most common manifestation of asbestos exposure, affecting up to 58% of asbestos-exposed workers. The prevalence among the general population exposed environmentally ranges from 0.53 to 8%.[4] Pleural plaques are discrete circumscribed areas of hyaline fibrosis (patches of thickening) of the parietal pleura and rarely the visceral pleura that develop 20 to 40 years after first exposure. Over time, usually more than 30 years, they often become partly calcified. They consist of mature collagen fibers arranged in an open basket-weave pattern and are covered by flattened or cuboidal mesothelial cells.[5] They have a white or pale yellow shaggy appearance and are typically distributed on the posterolateral chest wall, diaphragm, and mediastinal pleura.[6] The number and size varies. Pleural plaques are typically asymptomatic, however, there is still some controversy on this topic. An association between pleural plaques and chest pain has been reported,[7] but this has not been confirmed in more recent studies.[8] Similarly, an association between pleural plaques and a restrictive impairment with diminished diffusing capacity on pulmonary function testing has been described.[9] This has not been a consistent finding and it has been postulated that this might be related to undetected early fibrosis.[5] The pathogenesis of pleural plaques remains uncertain. The most likely explanation is that asbestos fibres reach the parietal pleura by passage through lymphatic channels where they excite an inflammatory reaction.[4] The chest X-ray is the usual tool for diagnosing pleural plaques but chest CT scan is more sensitive and specific in this regard. Pleural plaques are evidence of past asbestos exposure and indicate an increased risk for the future development of other asbestos-related diseases. Pleural plaques in themselves are not pre-malignant. Individuals with pleural plaques are usually not compensated in most compensation systems. ### Diffuse pleural thickening[edit] Diffuse pleural thickening (DPT) is non-circumscribed fibrous thickening of the visceral pleura with areas of adherence to the parietal pleura and obliteration of the pleural space.[10] It often extends over the area of an entire lobe or lung, with fibrotic areas involving costophrenic angles, apices, lung bases, and interlobar fissures. The thickness ranges from less than 1 mm up to 1 cm or more and may extend for a few millimeters into the lung parenchyma.[5] Fibrous strands (“crow's feet”) extending from the thickened pleura into the lung parenchyma can be often detected on CT scan. Diffuse pleural thickening develops 20 to 40 years after first exposure.[11] All types of asbestos can cause diffuse pleural thickening and a dose-related relationship has been described.[6] It is thought that asbestos fibres that reach the pleura induce subpleural fibroblasts and mesothelial cells to produce scar tissue and collagen deposition, resulting in subpleural thickening.[6] Pleural plaques often coexist with DPT although the latter is rare compared with pleural plaques. According to the Australian Surveillance of Australian Workplace Based Respiratory Events (SABRE) scheme, DPT accounted for 22% of all asbestos-related diseases.[12] It usually begins with an inflammation of the pleura that is accompanied by a pleural effusion. Most patients complain of exertional breathlessness, however, chest pain has been also associated with this disorder.[10][11] DPT has a significant impact on pulmonary function, causing a decrease in forced vital capacity, reducing total lung capacity and diffusing capacity.[10][13] The restrictive impairment is a result of adhesions of the parietal with the visceral pleura as well as possible diaphragmatic involvement. Medical imaging is needed for diagnosis of diffuse pleural thickening. The appearance on a postero-anterior chest radiograph is of a continuous, irregular pleural shadowing. In accordance with the International Labour Organization (2000) classification, diffuse pleural thickening is considered to be present if there is obliteration of the costophrenic angle in continuity with ≥3 mm pleural thickening.[14] CT scanning is more sensitive than chest radiography and can detect early pleural thickening (i.e. 1-2mm in thickness).[6] The most commonly used classification system defines diffuse pleural thickening as a continuous sheet of pleural thickening more than 5 cm wide, more than 8 cm in craniocaudal extent, and more than 3 mm thick.[15] Most patients are only mildly impaired by diffuse pleural thickening. Treatment options are limited but any new onset or severe pain should be investigated to exclude malignancy. In most compensation systems, patients are eligible for compensation which corresponds to the severity of disability. ### Benign asbestos pleural effusion[edit] Benign asbestos pleural effusion is an exudative pleural effusion (a buildup of fluid between the two pleural layers) following asbestos exposure. It is relatively uncommon and the earliest manifestation of disease following asbestos exposure, usually occurring within 10 years from exposure. Effusions may be asymptomatic but rarely, they can cause pain, fever, and breathlessness.[5] Effusions usually last for 3–4 months and then resolve completely. They can also progress to diffuse pleural thickening. Diagnosis relies on a compatible history of asbestos exposure and exclusion of other probable causes. ### Rounded atelectasis[edit] Rounded atelectasis (also known as Blesovsky’s or folded lung syndrome) develops from infolding of thickened visceral pleura with collapse of the intervening lung parenchyma.[5] It presents radiographically as a mass and may be mistaken for a tumour. On a CT scan of the chest it appears as a rounded mass like opacity in the peripheral lung adjacent to thickened pleura and with curvilinear opacities which are the bronchi and vessels (comet tail).[16] Rounded atelectasis is the least common asbestos-related benign pleural disease. Exposure to asbestos is the most likely cause today but it can occur following other medical conditions. It is a chronic condition and usually asymptomatic. ## Asbestosis[edit] Main article: Asbestosis Asbestosis is a chronic lung disease caused by scarring of lung tissue, which results from prolonged exposure to asbestos. It is defined as diffuse interstitial pulmonary fibrosis secondary to asbestos exposure. It initially affects the lung bases and usually manifests after 15 or more years from initial exposure. It occurs after high intensity and/or long-term exposure to asbestos. Asbestos-related fibrosis is progressive because it continues to progress in the lung even if no further asbestos is inhaled. The scar tissue causes the alveolar walls to thicken, reducing the lung capacity which leads to the patient experiencing shortness of breath (dyspnea). Sufferers are at an increased risk for heart failure and certain malignancies. ## Malignant asbestos-related diseases[edit] ### Malignant mesothelioma[edit] Main article: Mesothelioma Malignant mesothelioma is an aggressive and incurable tumour caused by asbestos arising from mesothelial cells of the pleura, peritoneum (the lining of the abdominal cavity) and rarely elsewhere. Pleural mesothelioma is the most common type of mesothelioma, representing about 75 percent of cases. Peritoneal mesothelioma is the second most common type, consisting of about 10 to 20 percent of cases. Mesothelioma appears from 20 to 50 years after the initial exposure to asbestos. The symptoms include shortness of breath, chronic chest pain, cough, and weight loss. Diagnosing mesothelioma is often difficult and can include physical examination, chest X-ray and lung function tests, followed by CT scan and MRI. A biopsy is needed to confirm a diagnosis of malignant mesothelioma. Mesothelioma has a poor prognosis, with most patients dying within 1 year of diagnosis. The treatment strategies include surgery, radiotherapy, chemotherapy or multimodality treatment. Several tumour biomarkers (soluble mesothelin-related protein (SMRP),[17] osteopontin[18] and fibulin3[19]) have been evaluated for diagnostic purposes to allow early detection of this disease. Novel biomarkers such as volatile organic compounds measured in exhaled breath are also promising.[20] ### Asbestos-related lung cancer[edit] Main article: Lung cancer Asbestos can cause lung cancer that is identical to lung cancer from other causes. Exposure to asbestos is associated with all major histological types of lung carcinoma (adenocarcinoma, squamous cell carcinoma, large-cell carcinoma and small-cell carcinoma). The latency period between exposure and development of lung cancer is 20 to 30 years. It is estimated that 3–8% of all lung cancers are related to asbestos.[21] The risk of developing lung cancer depends on the level, duration, and frequency of asbestos exposure (cumulative exposure). Smoking and individual susceptibility are other contributing factors towards lung cancer. Smokers who have been exposed to asbestos are at far greater risk of lung cancer. Smoking and asbestos exposure have a multiplicative (synergistic) effect on the risk of lung cancer. Symptoms include chronic cough, chest pain, breathlessness, haemoptysis (coughing up blood), wheezing or hoarseness of the voice, weight loss and fatigue. Treatment involves surgical removal of the cancer, chemotherapy, radiotherapy, or a combination of these (multimodality treatment). Prognosis is generally poor unless the cancer is detected in its early stages. Out of all patients diagnosed with lung cancer, only 15% survive for five years after diagnosis. ## History[edit] Thousands of scientific and medical articles have chronicled human understanding of the hazards of asbestos to human life.[22] This understanding paralleled the growth of the industrial revolution, particularly in the textile factories and mines of Great Britain. This body of knowledge is frequently referred to in litigation as the state of the art or the benchmark for determining if a company acted within the bounds of negligent behavior. The following is a chronological list of some of the major pre-1950 scientific and medical articles relating to the knowledge of the medical and scientific communities regarding asbestos and disease in humans: Year Publication 1898 "Annual Report of the Chief Inspector of Factories and Workshops, Part II". H.M. Stationery Office. 1898: 171–172. Cite journal requires `\|journal=` (help) 1912 "Effect of Asbestos Dust on Workers Health in Asbestos Mines and Factories". The Labour Gazette: 761–762. 1912. 1918 Hoffman, F.L. (1918). Mortality from Respiratory Diseases in Dusty Trades (Inorganic Dusts). U.S. Dept. of Labor, Bureau of Labor Statistics. pp. 35–47, 163–181. 1924 Cooke, W.E. (July 26, 1924). "Fibrosis of the Lungs due to the Inhalation of Asbestos Dust". British Medical Journal. 2 (3317): 147–140.2. doi:10.1136/bmj.2.3317.147. PMC 2304688. PMID 20771679. 1928 Editorial (1928). "Pulmonary Asbestosis". JAMA. 90 (2): 119–120. doi:10.1001/jama.1928.02690290049014. 1928 Simpson, F.W. (1929). "Pulmonary Asbestosis in South Africa". British Medical Journal. 1 (3516): 885–887. doi:10.1136/bmj.1.3516.885. PMC 2455583. 1929 Haddow, A.C. (August 3, 1929). "Asbestosis". The Lancet. 214: 231. doi:10.1016/s0140-6736(01)04102-2. 1929 Wood, W. Burton (May 1929). "Pulmonary asbestosis: Radiographic appearances in skiagrams of the chests of workers in asbestos". Tubercle. 10 (8): 353–363. doi:10.1016/S0041-3879(29)80024-4. 1930 Correspondence, Foreign Letters (June 28, 1930). "Compensation Act to be Extended to Asbestosis". JAMA. 94 (26): 2078. doi:10.1001/jama.1930.02710520044016. 1930 Mills, R.G. (June 28, 1930). "Report of a Case". Minnesota Medicine: 495–499. 1930 Editorial (1930). "Current Comment, Pulmonary Asbestosis". JAMA. 95 (19): 1431. doi:10.1001/jama.1930.02720190042014. 1930 Merewether, E.R.A. (May 1930). "The Occurrence of Pulmonary Fibrosis and Other Pulmonary Afflictions in Asbestos Workers". J.Indus.Hyg. 5. 12: 198–257. 1930 "Health and Industrial Hygiene - Pulmonary Asbestosis". Monthly Labor Review. 31: 74–76. 1930. 1930 Encyclopedia of Hygiene, Pathology and Social Welfare: Occupation and Health, Vol. I, A-H. Geneva: International Labor Office. 1930. pp. 189–181. 1930 Gardner, L.U. (1931). "Studies on Experimental Pneumonoconiosis: VI. Inhalation of Asbestos Dust, Its Effect Upon Primary Tuberculosis Infection". J.Indus.Hyg. 2. 13: 65–114. 1930 Gordon, B (June 1931). "Pulmonary Asbestosis". Penn.Med.J. 35: 637–639. 1934 Woods, W.B.; Gloyne, S.R. (1934). "Pulmonary Asbestosis". Lancet. 2 (5808): 1383–1385. doi:10.1016/s0140-6736(00)43332-5. 1938 Dreesen (August 1938). "A Study of Asbestos in the Asbestos Textile Industry". U.S. Treasury Dept., Public Health Bulletin: 1–126. 1941 Dublin (1941). "Occupational Hazards and Diagnostic Signs, Bulletin". U.S. Dept. Of Labor, Div. Of Labor Standards. 41: II, IV, V and 25. 1942 Holleb, H.B. (1942). "Bronchiogenic Carcinoma in Association with Pulmonary Asbestosis". American Journal of Pathology: 123–131. 1944 Wedler, H.W. (1944). "Asbestosis and Pulmonmary Carcinoma". Bulletin of Hygiene. 19: 362. 1944 Editorial (November 25, 1944). "Environmental Cancer". JAMA. 126 (13): 836. doi:10.1001/jama.1944.02850480036012. 1944 Hutchinson (1944). "Dust as an Industrial Health Hazard". Heating and Ventilating. 41 (6): 57–61. 1946 Fleischer, W.F. (1946). "Health Survey of Pipe Covering Operations in Constructing Naval Vessels". Journal of Industrial Hygiene and Toxicology. 1: 9–16. PMID 21016030. 1948 Lynch, K.M. (1948). "Asbestosis IV: Analysis of Forty Necropsied Cases, Diseases of the Chest": 79–81. Cite journal requires `\|journal=` (help) 1949 Merewether (1949). "Annual Report of the Chief Inspector of Factories for 1947". London: H.M. Stationary Ofc.: 79–81. Cite journal requires `\|journal=` (help) 1949 Wyers (1949). "Asbestosis". Postgraduate Medical Journal. 25 (290): 631–638. doi:10.1136/pgmj.25.290.631. PMC 2530167. PMID 15396262. ## References[edit] 1. ^ Olsen NJ, Franklin PJ, Reid A, et al. (2011). "Increasing incidence of malignant mesothelioma after exposure to asbestos during home maintenance and renovation". Medical Journal of Australia. 195 (5): 271–274. doi:10.5694/mja11.10125. PMID 21895596. 2. ^ Kamp D.W. (2009). "Asbestos-induced lung diseases: an update". Translational Research. 153 (4): 143–52. doi:10.1016/j.trsl.2009.01.004. PMC 3544481. PMID 19304273. 3. ^ Broaddus VC (May 2001). "Apoptosis and asbestos-induced disease: Is there a connection?". The Journal of Laboratory and Clinical Medicine. 137 (5): 314–5. doi:10.1067/mlc.2001.115172. PMID 11329527. 4. ^ a b c Peacock, C., S.J. Copley, and D.M. Hansell, Asbestos-related benign pleural disease. Clinical Radiology, 2000. 55(6): p. 422-32. [1] 5. ^ a b c d e American Thoracic Society. Diagnosis and Initial Management of Nonmalignant Diseases Related to Asbestos" American Journal of Respiratory and Critical Care Medicine 2004;170:691-715 [2] 6. ^ a b c d Miles SE, Sandrini A, Johnson AR, Yates DH Clinical consequences of asbestos-related diffuse pleural thickening: A review" Journal of Occupational Medicine and Toxicology 2008;3:20 [3] 7. ^ Mukherjee S, de Klerk N, Palmer LJ, et al. (2000). "Chest pain in asbestos-exposed individuals with benign pleural and parenchymal disease". American Journal of Respiratory and Critical Care Medicine. 162 (5): 1807–1811. doi:10.1164/ajrccm.162.5.9912012. PMID 11069817. 8. ^ Park EK, Thomas PS, Wilson D, et al. (2011). "Chest pain in asbestos and silica-exposed workers". Occupational Medicine. 61 (3): 178–183. doi:10.1093/occmed/kqr011. PMID 21406408. 9. ^ Oliver LC, Eisen EA, Greene R, Sprince NL. Asbestos-related pleural plaques and lung function" American Journal of Industrial Medicine 1988;14:649–656. 10. ^ a b c Yates D.H.; et al. (1996). ""Asbestos-related bilateral diffuse pleural thickening " natural history of radiographic and lung function abnormalities". American Journal of Respiratory and Critical Care Medicine. 153 (1): 301–6. doi:10.1164/ajrccm.153.1.8542134. PMID 8542134. 11. ^ a b Jeebun V, Stenton SC (2012). "The presentation and natural history of asbestos-induced diffuse pleural thickening". Occupational Medicine. 62 (4): 266–268. doi:10.1093/occmed/kqs028. PMID 22539640. 12. ^ Hannaford-Turner K, Elder D, Sim MR, Abramson MJ, Johnson AR, Yates DH (Aug 2010). "Surveillance of Australian workplace Based Respiratory Events (SABRE) in New South Wales". Occupational Medicine. 60 (5): 376–82. doi:10.1093/occmed/kqq011. PMID 20308261. 13. ^ Kee ST, Gamsu G, Blanc P. Causes of pulmonary impairment in asbestos- exposed individuals with diffuse pleural thickening" American Journal of Respiratory and Critical Care Medicine 1996;154:789–793 [4] 14. ^ International Labor Office International, Classification of Radiographs of Pneumoconioses. Geneva, Switzerland: International Labour Organization; 2011. [5] 15. ^ Lynch, DA; Gamsu, G; Aberle, DR (1989). "Conventional and high resolution computed tomography in the diagnosis of asbestos-related diseases". Radiographics. 9 (3): 523–51. doi:10.1148/radiographics.9.3.2727359. PMID 2727359. 16. ^ Batra, P., et al., Rounded atelectasis. Journal of Thoracic Imaging, 1996. 11(3): p. 187-97. [6] 17. ^ Park EK, Sandrini A, Yates DH, et al. (2008). "Soluble mesothelin-related protein in an asbestos-exposed population: the dust diseases board cohort study". American Journal of Respiratory and Critical Care Medicine. 178 (8): 832–837. doi:10.1164/rccm.200802-258oc. PMID 18583574. 18. ^ Park EK, Thomas PS, Johnson AR, Yates DH (2009). "Osteopontin levels in an asbestos-exposed population". Clinical Cancer Research. 15 (4): 1362–1366. doi:10.1158/1078-0432.ccr-08-0360. PMID 19174489. 19. ^ Pass HI, Levin SM, Harbut MR, et al. (2012). "Fibulin-3 as a blood and effusion biomarker for pleural mesothelioma". The New England Journal of Medicine. 367 (15): 1417–1427. doi:10.1056/nejmoa1115050. PMC 3761217. PMID 23050525. 20. ^ Chapman EA, Thomas PS, Stone E, et al. (2012). "A breath test for malignant mesothelioma using an electronic nose". The European Respiratory Journal. 40 (2): 448–54. doi:10.1183/09031936.00040911. PMID 22183490. 21. ^ McCormack V.; et al. (2012). "Estimating the asbestos-related lung cancer burden from mesothelioma mortality". British Journal of Cancer. 106 (3): 575–84. doi:10.1038/bjc.2011.563. PMC 3273352. PMID 22233924. 22. ^ Lemen, Richard; Dement (Feb 1980). "Epidemiology of asbestos-related diseases". Environ. Health Perspect. 34: 1–11. doi:10.1289/ehp.80341. PMC 1568524. PMID 6993197. ## External links[edit] Classification D [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor *[BMI]: body mass index	Asbestos-related diseases	None	791	wikipedia	https://en.wikipedia.org/wiki/Asbestos-related_diseases	2021-01-18T18:43:15	{"wikidata": ["Q4803677"]}
A number sign (#) is used with this entry because X-linked mental retardation-90 (MRX90) is caused by mutation in the DLG3 (300189) gene on chromosome Xq13. Clinical Features Tarpey et al. (2004) reported 4 families in each of which at least 2 males had moderate to severe nonsyndromic X-linked mental retardation. Philips et al. (2014) reported 2 unrelated Finnish families with MRX90. Three affected males in 1 family (D172) had delayed psychomotor development with speech delay, mild to moderate intellectual disability, narrow thorax, molar hypoplasia, short and upslanting palpebral fissures, high-arched palate, and hypotonia. Five males in the second family (D301) had delayed motor and language development with moderate to severe mental retardation. Three patients had ADHD, and 1 had seizures in childhood. Three had strabismus, but no other constant dysmorphic features were noted. One 60-year-old female was also affected. Mapping In a family segregating X-linked mental retardation, Tarpey et al. (2004) mapped the MRX locus to a 2-Mb region on Xq13, bound by markers DXS811 and DXS559. Molecular Genetics In affected members of 4 of 329 families with moderate to severe X-linked mental retardation, Tarpey et al. (2004) identified truncating mutations in the human DLG3 gene (300189.0001-300189.0004). In affected members of 2 unrelated Finnish families with MRX90, Philips et al. (2014) identified 2 different splice site mutations in the DLG3 gene (300189.0005 and 300189.0006). The mutations were found by X-chromosome exome sequencing in 14 Finnish families with X-linked mental retardation. INHERITANCE \- X-linked recessive HEAD & NECK Eyes \- Strabismus \- Upslanting palpebral fissures (1 family) Mouth \- High-arched palate (1 family) Teeth \- Molar hypoplasia (1 family) CHEST External Features \- Narrow thorax (1 family) GENITOURINARY Bladder \- Enuresis MUSCLE, SOFT TISSUES \- Hypotonia NEUROLOGIC Central Nervous System \- Delayed psychomotor development \- Mental retardation, mild to severe \- Delayed speech development \- Seizures (1 patient) Behavioral Psychiatric Manifestations \- Behavioral problems \- Attention-deficit hyperactivity disorder MISCELLANEOUS \- Affected females have been reported MOLECULAR BASIS \- Caused by mutation in the discs large MAGUK scaffold protein 3 gene (DLG3, 300189.0001 ) ▲ 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	MENTAL RETARDATION, X-LINKED 90	c2931498	792	omim	https://www.omim.org/entry/300850	2019-09-22T16:19:25	{"doid": ["0050776"], "mesh": ["C567906"], "omim": ["300850"], "orphanet": ["777"]}
## Clinical Features Khalifa et al. (2002) described 3 Canadian brothers of First Nation Canadian (Cree) origin with a previously undescribed pattern of malformations including distinctive craniofacial abnormalities with triangular facies, hypertelorism, low-set and posteriorly rotated ears, ocular colobomas, ptosis, brachycephaly with widely separated sutures, cleft soft palate, undescended testes, bifid scrotum and hypospadias, wide webbed neck, webbed fingers, pectus excavatum and hypersegmented sternum, and severe psychomotor retardation. The presence of normal brain imaging and physical growth distinguished this syndrome from other syndromes with overlapping abnormalities. Either X-linked or autosomal recessive inheritance was considered possible. Chodirker et al. (2002) considered the patients reported by Khalifa et al. (2002) to have the same disorder as that in the 8 aboriginal Canadians from Manitoba and Ontario reported as having Ritscher-Schinzel syndrome (RSS; 220210) by Marles et al. (1995). Thus they believed that the debate was not about whether or not the cases described by Khalifa et al. (2002) represented a 'new' syndrome, but whether or not the cases described in these 2 reports should be considered to have RSS or a separate 'new' syndrome first reported by Marles et al. (1995). In a rebuttal, Khalifa and Cappon (2002) argued that the patients of Marles et al. (1995) were phenotypically distinct from those they reported in the same ethnic group; furthermore, they questioned the diagnosis of RSS in their own patients because they did not fulfill the criteria for RSS, also known as the 3C syndrome because of cerebellar, cardiac, and characteristic craniofacial anomalies. Their patients had no cerebellar or other structural central nervous system abnormalities or significant cardiac anomalies, with the exception of a small ventricular septic defect in 1. The craniofacial changes were different from those of RSS. INHERITANCE \- Autosomal recessive HEAD & NECK Head \- Brachycephaly \- Wide fontanelles Face \- Triangular face \- Hypertelorism Ears \- Low-set ears \- Posteriorly rotated ears Eyes \- Ocular colobomas \- Ptosis \- Downslanting palpebral fissures Mouth \- Cleft soft palate \- Micrognathia Neck \- Wide, webbed neck CHEST Ribs Sternum Clavicles & Scapulae \- Pectus excavatum \- Hypersegmented sternum \- Hypoplastic or missing ribs GENITOURINARY External Genitalia (Male) \- Bifid scrotum \- Hypospadias Internal Genitalia (Male) \- Cryptorchidism SKELETAL Skull \- Widely spaced sutures Hands \- Webbed fingers Feet \- Rocker-bottom feet NEUROLOGIC Central Nervous System \- Psychomotor retardation, severe MISCELLANEOUS \- Possible X-linked recessive inheritance ▲ 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	CREE MENTAL RETARDATION SYNDROME	c1847361	793	omim	https://www.omim.org/entry/606851	2019-09-22T16:09:52	{"mesh": ["C564654"], "omim": ["606851"]}
## Summary ### Clinical characteristics. EZH2-related overgrowth includes EZH2-related Weaver syndrome at one end of the spectrum and tall stature at the other. Although most individuals diagnosed with a heterozygous EZH2 pathogenic variant have been identified because of a clinical suspicion of Weaver syndrome, a minority have been identified through molecular genetic testing of family members of probands or individuals with overgrowth who did not have a clinical diagnosis of Weaver syndrome. Thus, the extent of the phenotypic spectrum associated with a heterozygous EZH2 pathogenic variant is not yet known. Weaver syndrome is characterized by tall stature, variable intellect (ranging from normal intellect to severe intellectual disability), characteristic facial appearance, and a range of associated clinical features including advanced bone age, poor coordination, soft doughy skin, camptodactyly of the fingers and/or toes, umbilical hernia, abnormal tone, and hoarse low cry in infancy. Brain MRI has identified abnormalities in a few individuals with EZH2-related overgrowth. Neuroblastoma occurs at a slightly increased frequency in individuals with a heterozygous EZH2 pathogenic variant but data are insufficient to determine absolute risk. There is currently no evidence that additional malignancies (including hematologic malignancies) occur with increased frequency. ### Diagnosis/testing. The diagnosis of EZH2-related overgrowth is based on detection of a heterozygous germline EZH2 pathogenic variant on molecular genetic testing. ### Management. Treatment of manifestations: For individuals with developmental delay and/or learning disability, referral for learning/behavior/speech assessment and support may be indicated. Occasionally, toe camptodactyly may require surgical release. Physiotherapy may be of benefit to those experiencing joint pain secondary to ligamentous laxity or joint contractures. Treatment of scoliosis is routine. The appropriate specialist referral(s) should be made for other clinical issues. Surveillance: Regular medical follow up of young children with EZH2-related Weaver syndrome to monitor developmental progress, camptodactyly (for resolution/improvement), and/or hypotonia; medical follow up of older children/teenagers who do not have medical complications may be less frequent. If scoliosis is present, monitoring as per the recommendations of an orthopedist. Although current data do not support specific tumor surveillance programs, clinicians should have a low threshold for investigating any findings that may be tumor (particularly neuroblastoma) related. Pregnancy management: Families and their health care providers should be aware that an affected baby may be large so that appropriate delivery plans can be made. ### Genetic counseling. EZH2-related overgrowth is inherited in an autosomal dominant manner; however, many germline pathogenic EZH2 variants arise de novo. Each child of an individual with an EZH2 pathogenic variant has a 50% chance of inheriting the pathogenic variant; the severity of the phenotype in an individual inheriting the EZH2 pathogenic variant cannot be predicted. If the pathogenic variant has been identified in an affected family member, prenatal diagnosis for a pregnancy at increased risk and preimplantation genetic testing are possible. ## Diagnosis ### Suggestive Findings EZH2-related overgrowth should be suspected in an individual with combinations of the following clinical and imaging findings [Tatton-Brown et al 2013]: Clinical findings * Tall stature (height ≥+2 SD) * Macrocephaly (head circumference ≥+2 SD) * Intellectual disability * Characteristic facial appearance * In children younger than age three years: retrognathia, large and fleshy ears, and a "stuck on" appearance to the chin associated with a horizontal skin crease and sometimes a central dimple * In affected individuals of all ages, additional features including (Figure 1): * Broad forehead * Widely spaced eyes * Almond-shaped palpebral fissures Note: The characteristic facial appearance (which is most distinctive at a younger age) evolves over time; therefore, review of younger-childhood photographs may help the clinician reach a clinical diagnosis. * Poor coordination * Soft and doughy skin * Camptodactyly of the fingers and/or toes (see Note) * Umbilical hernia that is occasionally significant enough to require surgical reduction * Abnormal tone (central hypotonia and/or peripheral hypertonia) (see Note) * Hoarse, low-pitched cry (sometimes described as a quiet cry) #### Figure 1. Retrognathia present in younger children with EZH2-related Weaver syndrome usually resolves with age. In individuals of all ages the palpebral fissures are frequently almond-shaped and the eyes are widely spaced. Note: A detailed medical history may be necessary to determine if these findings were present in the newborn period / infancy given that they can resolve/improve throughout childhood. Imaging findings. Advanced bone age on plain radiographs Brain MRI. In many individuals a brain MRI has not been undertaken and thus imaging data are not available. One or more abnormalities identified in ten individuals included: isolated ventriculomegaly ( in 5); ventriculomegaly and periventricular leukomalacia (1); periventricular leukomalacia (1); cerebellar infarct (1); and cerebellar hypoplasia and neuronal migration defects (polymicrogyria) with and without pachygyria (2) [Al-Salem et al 2013, Tatton-Brown et al 2013]. ### Establishing the Diagnosis The diagnosis of EZH2-related overgrowth is established in a proband by identification of a heterozygous germline EZH2 pathogenic variant on molecular genetic testing (see Table 1). Molecular genetic testing approaches can include a combination of single-gene testing, multigene panel testing, and comprehensive genomic testing (exome sequencing, exome array, genome sequencing): * Single-gene testing. Single-gene testing requires that the clinician recognize the Weaver syndrome / EZH2-related overgrowth phenotype and request EZH2 molecular genetic testing. However, given that the phenotype is broad and the facial gestalt subtle, this can be challenging even for the experienced dysmorphologist. Sequence analysis of EZH2 detects small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. If sequence analysis does not identify a pathogenic variant, targeted deletion/duplication analysis to detect intragenic deletions or duplications can be considered. Note: Whole- or partial-gene deletions have been reported in several individuals with increased growth possibly due to Weaver syndrome [Imagawa et al 2017, Suri & Dixit 2017]. * Multigene panel testing. More frequently, an individual with EZH2-related overgrowth is diagnosed following testing with a multigene panel for conditions characterized by increased growth (height and/or head circumference) in association with intellectual disability (see Differential Diagnosis). EZH2 is frequently included in such multigene panels. Such a panel is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests. For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here. * Comprehensive genomic testing. Comprehensive genomic testing allows the sequencing of many genes, often with unrelated phenotypes, in a single experiment. This has particular clinical utility when the clinician does not recognize a particular phenotype and/or genes involved. Exome sequencing is most commonly used; genome sequencing is also possible. Exome array (when clinically available) may be considered if exome sequencing is not diagnostic. 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 EZH2-Related Overgrowth View in own window Gene 1MethodProportion of Probands with a Pathogenic Variant 2 Detectable by Method EZH2Sequence analysis 3Majority of variants reported to date 4 Gene-targeted deletion/duplication analysis 5See footnote 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. 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\. 54 individuals with an EZH2 germline pathogenic variant have been reported [Tatton-Brown et al 2011, Gibson et al 2012, Al-Salem et al 2013, Tatton-Brown et al 2013, Usemann et al 2016, Lui et al 2018]. 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\. Two individuals have had deletions wholly or partially encompassing EZH2 [Imagawa et al 2017, Suri & Dixit 2017]. ## Clinical Characteristics ### Clinical Description The phenotypic spectrum associated with germline EZH2 pathogenic variants is broad, with classic Weaver syndrome at one end of the spectrum and tall stature at the other. Although most individuals diagnosed with a heterozygous germline EZH2 pathogenic variant have been identified because of a clinical suspicion of Weaver syndrome, a minority have been identified through molecular genetic testing of family members of probands or individuals with overgrowth who did not have a clinical diagnosis of Weaver syndrome [Tatton-Brown et al 2011, Gibson et al 2012]. Thus, the extent of the phenotypic spectrum of heterozygous EZH2 pathogenic variants is not yet known. While data are still limited, clinical associations reported to date in 54 individuals with Weaver syndrome are summarized below [Tatton-Brown et al 2011, Gibson et al 2012, Al-Salem et al 2013, Tatton-Brown et al 2013, Usemann et al 2016, Suri & Dixit 2017, Lui et al 2018]. The denominators reflect the numbers of individuals for whom data are available. Growth. From data available on 23 newborns, the mean birth length was 2.2 standard deviations above the mean (+2.2 SD) with a range of -0.5 SD to +4.9 SD; the mean birth weight of 45 newborns was +1.7 SD with a range of -1.6 SD to +4.6 SD [Tatton-Brown et al 2013]. Tall stature is a near-consistent finding: height in 47/52 individuals was at least two standard deviations above the mean (ages 1-70 years). Of note, three of the four individuals with a height less than +2 SD had been tall as young children. The mean postnatal height was +3.5 SD. Of 45 individuals on whom information was available, 24 had a head circumference less than +2 SD and 21 had macrocephaly with a head circumference ranging up to +5.5 SD. Cognitive features. Information on cognitive function was available for 50 individuals. Eight had normal intellect; 42 individuals had variable intellectual disability (ID) including the following: * Mild ID (24/50). Children attend mainstream school and need some extra help – e.g., a statement of educational needs – but would be expected to live independently as adults and would be likely to have their own family. * Moderate ID (14/50). Children develop speech and need a high level of support in mainstream education but more likely will attend a school for individuals with special educational needs. While unlikely to live independently as adults, they may live in sheltered accommodation or with some additional support. * Severe ID (2/50). Individuals require special education during schooling and are likely to require considerable support in adulthood. * Unclassified ID (2/50). Information provided is insufficient to make a determination. Behavioral issues including autistic spectrum disorder, phobias, and anxiety have been anecdotally reported. Neurologic. Ventriculomegaly, reported in six individuals, was generally associated with normal CSF pressure and did not require shunting [Tatton-Brown et al 2013]. Other brain MRI findings included neuronal migration defects (pachy/polymicrogyria; in 2 individuals), periventricular leukomalacia (2 individuals), and cerebellar abnormalities (2 individuals). Intellectual disability in those with a brain MRI abnormality was: * Mild in six (ventriculomegaly [4], periventricular leukomalacia [1], and cerebellar hypoplasia [1]); * Moderate in three (periventricular leukomalacia with ventriculomegaly [1] and isolated ventriculomegaly [2]); * Severe in an individual with polymicrogyria and pachygyria; in contrast, the individual with polymicrogyria reported by Al-Salem et al [2013] had normal developmental milestones and body asymmetry (left side smaller than the right) with brisk reflexes and increased tone on the left. * Note: The degree of intellectual disability was not reported for one individual with ventriculomegaly. Four individuals had afebrile seizures. Skeletal features * Advanced bone age. Of 29 individuals evaluated, all had advanced bone age. * Scoliosis was reported in nine individuals and pectus abnormalities (excavatum or carinatum) in three. Scoliosis ranged from severe (early-childhood onset requiring surgical intervention) to mild (requiring monitoring but no therapeutic intervention). * Camptodactyly. Some affected individuals had camptodactyly of the fingers, some had camptodactyly of the toes, and some had camptodactyly of fingers and toes. On occasion the toe camptodactyly required surgical correction. * Adult boutonniere deformity. Several adults developed hyperextension of the distal interphalangeal joints and flexion of the proximal interphalangeal joints of the hands analogous to a mild boutonniere deformity (Figure 2). * Talipes equinovarus. Six individuals had talipes equinovarus ranging from fixed and bilateral (requiring surgery) in two individuals to mild (unilateral that resolved with physiotherapy) in three. #### Figure 2. Mild hyperextension of the distal interphalangeal joints and flexion of the proximal interphalangeal joints in a woman age 22 years with a heterozygous EZH2 pathogenic variant Connective tissue * Ligamentous laxity. While ligamentous laxity with associated joint hypermobility and pes planus is common, it is not usually reported unless complicated by joint pain. Individuals with EZH2-related overgrowth are frequently reported to have poor coordination that may be (at least partially) attributable to lax ligaments. * Skin that was soft and doughy to the touch was seen in 19/37 affected children. * Umbilical hernia, seen in 21/44 children, was sufficiently large to require surgery in the neonatal period in eight. Abnormal tone. In general, if present, abnormal tone (hypotonia, hypertonia, or mixed central hypotonia and peripheral hypertonia) resolved during childhood. * Hypotonia (predominantly central) was reported in 22/45 individuals. * Hypertonia (predominantly peripheral manifesting as stiffness in the limbs with brisk reflexes) was reported in 13/41. Note: Five of the individuals presenting with peripheral hypertonia were also reported to have central hypotonia. Poor feeding was reported in 10/28 neonates including one who required nasogastric tube feeding for two weeks. Although poor feeding may be attributable to neonatal hypotonia, this was only reported in three of the infants with poor feeding. Hoarse, low-pitched cry was reported in 10/27 affected infants. Tumors have been reported in four of 54 affected individuals [Tatton-Brown et al 2013, Usemann et al 2016]. * One boy with a c.2233G>A pathogenic variant developed a pre-T cell non-Hodgkins lymphoma at age 13 years. At age 25 years he remains well with no relapses or additional tumors. * One boy with a c.2044G>A pathogenic variant was diagnosed at age 13 months with acute lymphoblastic leukemia and neuroblastoma, both of which responded to therapy; he is well at age seven years. * One girl with a c.458A>G pathogenic variant was diagnosed with a neuroblastoma at age four years. * One girl with a c.395C>T pathogenic variant was diagnosed with acute myeloid leukemia and secondary hemophagocytic lymphohistiocytosis at age 16 years. Additional clinical features reported in a small number of individuals (and therefore, possibly not associated with the EZH2 pathogenic variant) are included for completeness: * Café au lait macules (in 2 individuals), hemangioma (in 4) * Hypermetropia (hyperopia) (3), myopia (1), strabismus (3) * Cryptorchidism (1), hydrocele (2), hypospadias (1) * Cleft palate (3) * Hearing loss (3) – conductive and sensorineural * Cardiac anomalies (4) including mitral valve prolapse (1), ventricular septal defect (2), and patent ductus arteriosus (1) * Gastroesophageal reflux (1), hiatal hernia (1) * Neonatal hypoglycemia (2) * Neonatal hypocalcemia (1) ### Genotype-Phenotype Correlations Because findings along the entire phenotypic spectrum have been observed in individuals with heterozygous truncating pathogenic variants or heterozygous missense pathogenic variants, within or outside the conserved SET domain (see Molecular Genetics, Normal gene product), no genotype-phenotype correlations are evident among the small number of individuals reported with EZH2-related overgrowth. ### Penetrance Data are currently insufficient to determine penetrance of EZH2 germline pathogenic variants. However, given the subtlety of the phenotype in some persons with a pathogenic EZH2 variant, the penetrance for some EZH2 pathogenic variants may be reduced [Tatton-Brown et al 2013]. ### Nomenclature Weaver syndrome is named after David Weaver, who reported two boys with accelerated osseous maturation, unusual facies, and camptodactyly [Weaver et al 1974]. Although pathogenic variants in NSD1 (the cause of Sotos syndrome) were once reported to cause Weaver syndrome [Douglas et al 2003], this association has been refuted [Tatton-Brown et al 2005]. ### Prevalence Because EZH2 pathogenic variants have only recently been shown to cause Weaver syndrome, and individuals with a mild phenotype may escape clinical diagnosis, it is currently difficult to estimate the prevalence of Weaver syndrome. ## Differential Diagnosis Conditions to be considered in the differential diagnosis of Weaver syndrome are summarized in Table 2. ### Table 2. Disorders to Consider in the Differential Diagnosis of Weaver Syndrome View in own window DisorderGene / Genetic MechanismMOIClinical Features OverlappingDistinguishing Sotos syndromeNSD1 1AD 2 * Pre- & postnatal overgrowth * Variable ID * Similar (but distinctive; see Distinguishing →) facial appearance * Advanced bone age * Scoliosis * Joint hypermobility Facial features in Sotos syndrome: * Downslanted palpebral fissures, prominent chin, malar flushing in children * Most easily distinguishable from Weaver syndrome at ages 1-3 yrs Malan syndrome (OMIM 614753)NFIXAD * Sotos syndrome-like condition * Tall stature * Variable ID 3 In Malan syndrome: * Ophthalmologic abnormalities common * Growth frequently normalizes in teenagers & young adults DNMT3A overgrowth (Tatton-Brown-Rahman) syndrome (OMIM 615879)DNMT3A4AD * Tall stature * Variable ID * ASD * Scoliosis * Joint hypermobility In DNMT3A overgrowth syndrome: * Facial appearance (round, heavy; w/horizontal eyebrows & narrow palpebral fissures) most recognizable in early teen/adult yrs * ↑ weight * Neuropsychiatric issues Beckwith-Wiedeman syndrome (BWS)Abnormal regulation of gene transcription in two imprinted domains at 11p15.5 5Footnote 6 * ↑ birth weight * Tall stature (not as frequent in BWS as the other conditions in the differential diagnosis) * Umbilical hernia In BWS: * Macroglossia * Earlobe creases/pits * Omphalocele * Visceromegaly * Usually normal intellect * Neonatal hypoglycemia * Polyhydramnios * Predisposition to embryonal tumors, esp Wilms tumor Simpson-Golabi-Behmel syndrome type 1 (SGBS1)GPC3 (possibly GPC4)XL * ↑ birth weight * Tall stature * Variable ID In SGBS1: * Characteristic facial appearance * Supernumerary nipples * Polydactyly * Diastasis recti 7 Marfan syndromeFBN1AD * Tall stature * Scoliosis * Joint hypermobility In Marfan syndrome: * Cognitive abilities usually normal * Ocular findings (myopia & lens dislocation) * Cardiovascular findings (dilatation of the aorta; mitral & tricuspid valve prolapse) * Pectus abnormalities common Congenital contractural arachnodactyly (CCA; Beals syndrome)FBN2AD * Tall stature * Scoliosis * Camptodactyly In CCA: * Cognitive abilities usually normal * Cardiovascular findings (dilatation of the aorta; mitral & tricuspid valve prolapse) * Crumpled appearance to the top of the ear * Pectus abnormalities common AD = autosomal dominant; ASD = autism spectrum disorder; ID = intellectual disability; MOI = mode of inheritance; XL = X-linked 1\. Pathogenic variants in NSD1 (the cause of Sotos syndrome) were once reported to cause Weaver syndrome [Douglas et al 2003]. However, this association has been refuted [Tatton-Brown et al 2005]. 2\. More than 95% of individuals have a de novo pathogenic variant. 3\. Malan et al [2010], Schanze et al [2014], Klaassens et al [2015], Priolo et al [2018] 4\. Tatton-Brown et al [2014], Tatton-Brown et al [2018] 5\. A clinical suspicion of BWS can be confirmed through testing that reveals dysregulation of the normal imprint at the 11p15 growth regulatory region [Choufani et al 2010]: loss of methylation at imprinting center 2 (IC2; see Beckwith-Wiedeman Syndrome, Figure 1 for detailed molecular mechanism) on the maternal allele (in ~50% of affected individuals); uniparental disomy for 11p15 (in ~20% of affected individuals); gain of methylation at imprinting center 1 (IC12; see Beckwith-Wiedeman Syndrome, Figure 1 for detailed molecular mechanism) of the maternal allele (in ~5% of affected individuals); or pathogenic variants within the maternal copy of CDKN1C (in 5%-10% of sporadic cases of BWS; ≤40% of familial cases). In approximately 20% of individuals with a clinical diagnosis of BWS the underlying molecular abnormality is not elucidated. 6\. Approximately 85% of individuals with BWS have no family history of BWS; approximately 15% have a family history consistent with parent-of-origin autosomal dominant transmission. 7\. Golabi & Rosen [1984], Cottereau et al [2013] ## Management The following information represents typical evaluation and management recommendations for individuals in the United States; standard recommendations may vary from country to country [Author, personal observation]. ### Evaluations Following Initial Diagnosis To establish the extent of disease and needs of an individual diagnosed with a heterozygous EZH2 pathogenic variant, the evaluations summarized in Table 3 (if not performed as part of the evaluation that led to the diagnosis) are recommended. ### Table 3. Recommended Evaluations Following Initial Diagnosis in Individuals with EZH2-Related Overgrowth View in own window System/ConcernEvaluationComment NeurologicDevelopmental assessmentTo incl motor, speech/language evaluation, general cognitive, & vocational skills Muscle toneHypotonia & mixed hypo/hypertonia common SeizuresIf seizure activity is suspected: * Brain MRI * EEG Psychiatric/ BehavioralAssessment for ASD & other behavioral issues ConstitutionalMeasurement of height, weight, head circumference MusculoskeletalAssessment for scoliosis, camptodactyly, ligamentous laxity GenitourinaryAssessment for cryptorchidism, hydrocele, hypospadias CardiovascularCardiac auscultationBaseline echocardiogram for evidence of structural cardiac anomalies MalignancyAssessment for potential malignancy, esp neuroblastoma & hematologic malignanciesWhile no specific surveillance is recommended, a low threshold for investigation of any possible tumor-related symptoms is advised. ASD = autism spectrum disorder ### Treatment of Manifestations ### Table 4. Treatment of Manifestations in Individuals with EZH2-Related Overgrowth View in own window Manifestation/ConcernTreatmentConsiderations/Other Developmental delay &/or learning disabilityEducational supportReferral for learning/behavior/speech assessment & support may be indicated. CamptodactylySurgical interventionOccasionally toe camptodactyly may require surgical intervention. PhysiotherapyMay be beneficial Abnormal muscle tonePhysiotherapyMay be beneficial Ligamentous laxityPhysiotherapyMay reduce joint pain secondary to ligamentous laxity ScoliosisFurther eval & monitoringReferral to orthopedist If additional clinical issues are detected through the history and/or examination, the appropriate specialist referral(s) should be made. #### Developmental Delay / 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 US, developmental preschool through the local public school district is recommended. Before placement, an evaluation is made to determine needed services and therapies and an individualized education plan (IEP) is developed. 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 system until age 21. * Discussion about transition plans including financial, vocation/employment if feasible, 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 and to support parents in maximizing quality of life. Consideration of private supportive therapies based on the affected individual's needs is recommended. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. In the US: * Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. * Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. #### Motor Dysfunction Gross motor dysfunction * Physical therapy is recommended to maximize mobility. * Consider use of durable medical equipment as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers). Fine motor dysfunction. Occupational therapy is recommended for difficulty with fine motor skills that affect adaptive function such as feeding, grooming, dressing, and writing. Oral motor dysfunction. Assuming that the individual is safe to eat by mouth, feeding therapy – typically from an occupational or speech therapist – is recommended for affected individuals who have difficulty feeding due to poor oral motor control. Communication issues. Consider evaluation for alternative means of communication (e.g., Augmentative and Alternative Communication [AAC]) for individuals who have expressive language difficulties. ### Surveillance ### Table 5. Recommended Surveillance for Individuals with EZH2-Related Overgrowth View in own window System/ConcernEvaluationFrequency 1 MusculoskeletalMonitoring by pediatrician for resolution/improvement of camptodactyly &/or hypotoniaRegular follow up w/frequency dependent on severity If scoliosis is present, monitor per orthopedist. MalignancyNeuroblastoma surveillance: current recommendations include clinical vigilance & thorough investigation of any symptoms that may be tumor related. 2 Note: Neuroblastoma surveillance has been inconsistent, w/no data supporting modality of surveillance, screening interval, or duration. Miscellaneous/ OtherMonitoring of developmental progress & educational needsRegular follow up w/frequency dependent on severity Clinical genetics evaluationAt diagnosis, soon after to answer further questions, & when appropriate to support reproductive decisions (i.e., for parents to discuss recurrence risk or for affected individuals to discuss offspring risk) 1\. In older children/teenagers who do not have medical complications, the clinician may wish to review less frequently than in yonger children. 2\. Current data suggest a slightly increased relative risk for the development of neuroblastoma in individuals with heterozygous germline EZH2 pathogenic variants. Although the numbers are too small to quantify the absolute tumor risk, it appears to be low (see Clinical Description, Tumors). ### Evaluation of Relatives at Risk See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes. ### Pregnancy Management In general, pregnancies in which the mother and/or fetus has a heterozygous EZH2 pathogenic variant are uncomplicated. Families and their health care providers should be aware that an affected baby may be large so that appropriate delivery plans can be made; in addition, information about the EZH2-related overgrowth phenotype should be provided. ### Therapies Under Investigation Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor *[BMI]: body mass index	EZH2-Related Overgrowth	None	794	gene_reviews	https://www.ncbi.nlm.nih.gov/books/NBK148820/	2021-01-18T21:28:45	{"synonyms": []}
Deficiency in anterior pituitary function-variable immunodeficiency syndrome is a rare, genetic endocrine disease characterized by the association of common variable immunodeficiency, manifesting with hypogammaglobulinemia and recurrent or severe childhood-onset sinopulmonary infections, followed, possibly many years later, by symptomatic adrenocorticotropic hormone (ACTH) deficiency resulting from anterior pituitary hormone deficiency. [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	Deficiency in anterior pituitary function-variable immunodeficiency syndrome	c3809991	795	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=293978	2021-01-23T19:03:46	{"omim": ["615577"], "synonyms": ["DAVID syndrome"]}
This article is about abnormal patterns of eating. For clinical eating disorders, see Eating disorders. Disordered eating describes a variety of abnormal eating behaviors that, by themselves, do not warrant diagnosis of an eating disorder. Disordered eating includes behaviors that are common features of eating disorders, such as: * Chronic restrained eating.[1] * Compulsive eating.[1] * Binge eating, with associated loss of control.[2] * Self-induced vomiting.[3] Disordered eating also includes behaviors that are not characteristic of a specific eating disorder, such as: * Irregular, chaotic eating patterns. * Ignoring physical feelings of hunger and satiety (fullness).[1] * Use of diet pills.[4] * Emotional eating.[5] * Night eating.[5] * Secretive food concocting: the consumption of embarrassing food combinations, such as mashed potatoes mixed with sandwich cookies.[6] See also Food craving § Pregnancy and Nocturnal sleep-related eating disorder § Symptoms and behaviors. ## Contents * 1 Potential causes of disordered eating * 1.1 Nuclear family environment * 1.2 Social stresses * 1.3 Athletic influences * 1.4 Social media * 2 See also * 3 References ## Potential causes of disordered eating[edit] Disordered eating can represent a change in eating patterns caused by other mental disorders (e.g. clinical depression), or by factors that are generally considered to be unrelated to mental disorders (e.g. extreme homesickness).[7] Certain factors among adolescents tend to be associated with disordered eating, including perceived pressure from parents and peers, nuclear family dynamic, body mass index, negative affect (mood), self-esteem, perfectionism, drug use, and participation in sports that focus on leanness. These factors are similar among boys and girls alike.[3] However, the reported incidence rates of disordered eating are consistently and significantly higher in female than male participants. 61% of females and 28% of males reported disordered eating behaviors in a study of over 1600 adolescents.[8] ### Nuclear family environment[edit] The nuclear family dynamic of an adolescent plays a large part in the formation of their psychological, and thus behavioral, development. A research article published in the Journal of Adolescence concluded that, “…while families do not appear to play a primary casual role in eating pathology, dysfunctional family environments and unhealthy parenting can affect the genesis and maintenance of disordered eating.”[8] One study explored the connection between the disordered eating patterns of adolescents and the poor socioemotional coping mechanisms of guardians with mental disorders. It was found that in homes of parents with mental health issues (such as depression or anxiety), the children living in these environments self-reported experiencing stressful home environments, parental withdrawal, rejection, unfulfilled emotional needs, or over-involvement from their guardians.[8] It was hypothesized that this was directly related to adolescent study participants also reporting poor emotional awareness, expression, and regulation in relation to internalized/externalized eating disordered habits. Parental anxiety/depression could not be directly linked to disordered eating, but could be linked to the development of poor coping skills that can lead to disordered eating behaviors.[8] Another study specifically investigated whether a parental's eating disorder could predict disordered eating in their children. It was found that rates of eating disorder appearances in children with either parent or the mother having a history of an eating disorder were much higher than those with parents without an eating disorder.[9] Reported disordered eating peaked between ages 15 and 17 with the risk of eating disorder occurrences in females 12.7 times greater than of that in males. This is, "of particular interest as it has been shown that maternal ED [eating disorders] predict disordered eating behaviour in their daughters."[9] This suggests that poor eating habits result as a coping mechanism for other direct issues presented by an unstable home environment. ### Social stresses[edit] Additional stress from outside the home environment influence disordered eating characteristics. Social stresses from peer environments, such as feeling out of place or discriminated against, has been shown to increase feelings of body shame and social anxiety in studies of minority groups that lead to a prevalence of disordered eating.[10] A study published in the International Journal of Eating Disorders used data from the Massachusetts Youth Risk Behavior Surveys from 1999 to 2013 to examine how disordered eating has trended in heterosexual versus LGB (lesbian, gay, bisexual) youth.[11] The data from over 26,000 surveys investigated the practices of purging, fasting, and using diet pills. It was found that, "sexual minority youth report disproportionately higher prevalence of disordered eating compared to heterosexual peers: up to 1 in 4 sexual minority youth report…patterns of disordered eating…"[11] In addition, the gap between the number of LGBT females and heterosexual females controlling weight in unhealthy ways has continued to widen.[11] The concept this study proposed to explain this disparity comes from the minority stress theory. This states that unhealthy behaviors are directly related to the distal stress, or social stress, that minorities experience.[11] These stressors could include rejection or pressure by peers, and physical, mental, and emotional harassment. A study published in Psychology of Women Quarterly explored the connection between social anxiety stresses and eating disordered habits more in depth in women in the LGBTQ community who were also racial minorities.[10] Over 450 women ranked their interactions with everyday discrimination, their LGBTQ identity, social anxiety, their objectified body consciousness, and an eating disorder inventory diagnostic scale. The findings of the compilation of survey responses indicated that increased discrimination led to proximal minority stress, leading to feelings of social anxiety and body shame, which could be directly associated with binge eating, bulimia, and other signs of disordered eating.[10] It has also been suggested that being a “double” or “triple” minority who experiences discrimination towards multiple characteristics contributes to more intense psychological distress and maladaptive coping mechanisms.[10] ### Athletic influences[edit] Disordered eating among athletes, particularly female athletes, has been the subject of much research. In one study, women with disordered eating were 3.6 times as likely to have an eating disorder if they were athletes. In addition, female collegiate athletes who compete in heavily body conscious sports like gymnastics, swimming, or diving are shown to be more at risk for developing an eating disorder. This is a result of the engagement in sports where weekly repeated weigh-ins are standard, and usually required by coaches.[6] A study published in Eating Behaviors examined the pressure of mandated weigh-ins on female collegiate athletes and how that pressure was dealt with in terms of weight management.[12] After analyzing over 400 survey responses, it was found that athletes reported increased uses of diet pills/laxatives, consuming less calories than needed for their sport, and following nutrition information from unqualified sources. 75% of the weighed athletes reported using a weight-management method such as restricting food intake, increasing exercise, eating low fat foods, taking laxatives, vomiting, and other.[12] These habits were found to be worse in athletes that were weighed in front of their peers than those weighed in private.[12] In addition, especially in gymnasts, preoccupation and anxiety about gaining weight and being weighed, and viewing food as the enemy were prevalent mindsets. This harmful mindset continued even after the gymnasts were retired from their sport: "Although retired, these gymnasts were still afraid to step onto a scale, were anxious about gaining weight…suggesting that the negative effects of being weighed can linger…[and] suggest[ing] that the weight/ fitness requirements acted as a socio-cultural pressure that would substantially increase the women’s risk of developing an eating disorder in the future."[12] Disordered eating, along with amenorrhea and bone demineralization, form what clinicians refer to as the female athletic triad, or FAT.[13] In contribution to these eating disorders that these female athletes develop, Results in the lack of nutrition. This can lead to the loss of several or more consecutive periods which then leads to calcium and bone loss, putting the athlete at great risk of fracturing bones and damaging tissues. Each of these conditions is a medical concern as they create serious health risks that may be life-threatening to the individual. While any female athlete can develop the triad, adolescent girls are considered most at risk because of the active biological changes and growth spurts that they experience, rapidly changing life circumstances that are observed within the teenage years, and peer and social pressures.[14] ### Social media[edit] Researchers have said the most pervasive and influential factor controlling body image perception is the mass media.[15] One study examined the impact of celebrity and peer Instagram images on women's body image as, “comparisons will be most readily made with individuals who are perceived as being similar” to the target as there is more of a relationship between the two parties.[15] The participants in this study, 138 female undergraduate students ages 18–30, were shown 15 images each of attractive celebrities, attractive unknown peers, and travel destinations. The participant's reactions were observed and visual scales were used to measure mood and dissatisfaction before and after viewing the images. The findings of this experiment determined that negative mood and body dissatisfaction rankings were greater after being exposed to the celebrity and peer images, with no difference between celebrity versus peer images.[15] The media is especially dangerous for females at risk for developing body image issues, and disordered eating, because the sheer number of possible comparisons become larger. ## See also[edit] * Night eating syndrome * Overeaters Anonymous ## References[edit] 1. ^ a b c "Definitions". nedic.ca. Retrieved 31 August 2014. 2. ^ "Binge eating disorder". www.nedc.com.au. Retrieved 2019-02-03. 3. ^ a b Ricciardelli, Lina A.; McCabe, Marita P. (March 2004). "A Biopsychosocial Model of Disordered Eating and the Pursuit of Muscularity in Adolescent Boys". Psychological Bulletin. 130 (2): 179–205. doi:10.1037/0033-2909.130.2.179. PMID 14979769. 4. ^ Jones, Jennifer M.; Susan, Bennett; Olmsted, Marion P.; Lawson, Margaret L.; Rodin, Gary (September 4, 2001). "Disordered eating attitudes and behaviours in teenaged girls: a school-based study". CMAJ. 165 (5): 547–552. PMC 81412. PMID 11563206. Retrieved 31 August 2014. 5. ^ a b Quick, Virginia M.; Byrd-Bredbenner, Carol; Neumark-Sztainer, Dianne (May 2013). "Chronic Illness and Disordered Eating: A Discussion of the Literature". Advances in Nutrition. 4 (3): 277–286. doi:10.3945/an.112.003608. PMC 3650496. PMID 23674793. Retrieved 31 August 2014. 6. ^ a b Voelker, Dana K.; Petrie, Trent A.; Neumann, Craig S.; Anderson, Carlin M. (2016). "Psychosocial Factors as Longitudinal Predictors of Bulimic Symptomatology Among Female Collegiate Athletes". Psychology of Sport and Exercise. 26: 123–129. doi:10.1016/j.psychsport.2016.06.009. 7. ^ "Understanding the causes of eating disorders \| The Butterfly Foundation". thebutterflyfoundation.org.au. Retrieved 2019-02-03. 8. ^ a b c d Martinson, Laura E.; Esposito-Smythers, Christianne; Blalock, Dan V. (2016). "The Effects of Parental Mental Health and Social-emotional Coping on Adolescent Eating Disorder Attitudes and Behaviors". Journal of Adolescence. 52: 154–161. doi:10.1016/j.adolescence.2016.08.007. PMC 5028292. PMID 27567519. 9. ^ a b Bould, H.; Sovio, U.; Koupil, I.; Dalman, C.; Micali, N.; Lewis, G.; Magnusson, C. (2015). "Do Eating Disorders in Parents Predict Eating Disorders in Children? Evidence from a Swedish Cohort". Acta Psychiatrica Scandinavica. 132: 51–59. doi:10.1111/acps.12389. 10. ^ a b c d Mason, Tyler B.; Lewis, Robin J. (2016). "Minority Stress, Body Shame, and Binge Eating Among Lesbian Women: Social Anxiety as a Linking Mechanism". Psychology of Women Quarterly. 40 (3): 428–440. doi:10.1177/0361684316635529. 11. ^ a b c d Watson, Ryan J.; Adjei, Jones; Saewyc, Elizabeth; Homma, Yuko; Goodenow, Carol (2017). "Trends and Disparities in Disordered Eating Among Heterosexual and Sexual Minority Adolescents". International Journal of Eating Disorders. 50 (1): 22–31. doi:10.1002/eat.22576. PMC 5768430. PMID 27425253. 12. ^ a b c d Tackett, Bailey P.; Petrie, Trent A.; Anderson, Carlin M. (2016). "The Frequency of Weigh-ins, Weight Intentionality and Management, and Eating Among Female Collegiate Athletes". Eating Behaviors. 23: 82–85. doi:10.1016/j.eatbeh.2016.08.007. 13. ^ Morgado de Oliveira Coelho, Gabriela; Innocencio da Silva Gomes, Ainá; Gonçalves Ribeiro, Beatriz; de Abreu Soares, Eliane (May 12, 2014). "Prevention of eating disorders in female athletes". Open Access Journal of Sports Medicine. 5: 105–113. doi:10.2147/OAJSM.S36528. PMC 4026548. PMID 24891817. 14. ^ "Athletes and Eating Disorders". National Eating Disorders Association. Retrieved 2016-11-24. 15. ^ a b c Brown, Zoe; Tiggemann, Marika (2016). "Attractive Celebrity and Peer Images on Instagram: Effect on Women's Mood and Body Image". Body Image. 19: 37–43. doi:10.1016/j.bodyim.2016.08.007. PMID 27598763. [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	Disordered eating	c0855228	796	wikipedia	https://en.wikipedia.org/wiki/Disordered_eating	2021-01-18T18:50:15	{"umls": ["CL494123"], "wikidata": ["Q5282515"]}
Urea cycle disorder Ornithine transcarbamylase deficiency Other namesOTC deficiency The urea cycle. The enzyme OTC, labeled prominently in the center of the mitochondria, is deficient in patients with this disorder. SpecialtyMedical genetics, metabolic syndrome, pediatrics Differential diagnosisOrotic aciduria; other urea cycle disorders TreatmentLow protein diet; dialysis; liver transplant MedicationSodium benzoate PrognosisIn severe cases, death may occur within one week of birth. In mild cases, diagnosis may not be made until middle age.[1] Frequency1:60,000 to 1:72,000 Ornithine transcarbamylase deficiency is the most common urea cycle disorder in humans. It is an inherited disorder which causes toxic levels of ammonia to build up in the blood.[2] Ornithine transcarbamylase, the defective enzyme in this disorder, is the final enzyme in the proximal portion of the urea cycle. It is responsible for converting carbamoyl phosphate and ornithine into citrulline. OTC deficiency is inherited in an X-linked recessive manner, meaning males are more commonly affected than females. In severely affected individuals, ammonia concentrations increase rapidly, causing ataxia, lethargy, and death without rapid intervention. OTC deficiency is diagnosed using a combination of clinical findings and biochemical testing, while confirmation is often done using molecular genetics techniques. Once an individual has been diagnosed, the treatment goal is to avoid precipitating episodes that can cause an increased ammonia concentration. The most common treatment combines a low protein diet with nitrogen scavenging agents. Liver transplant is considered curative for this disease. Experimental trials of gene therapy using adenoviral vectors resulted in the death of one participant, Jesse Gelsinger, and were initially discontinued. ## Contents * 1 Signs and symptoms * 2 Genetics * 3 Diagnosis * 4 Treatment * 5 Prognosis * 6 In popular culture * 7 References * 8 External links ## Signs and symptoms[edit] OTC deficiency can become apparent at any age. Early-onset OTC deficiency is most commonly found in males. Later in life, the disease may present in both males and females.[citation needed] In the classic presentation, a male infant appears well initially, but by the second day of life becomes irritable, lethargic, and stops feeding. Infants may have poorly-controlled body temperature and respiratory rates, and may experience seizures.[2] Without urgent intervention, a metabolic encephalopathy develops; this can progress to coma and death within the first week of life.[1] High levels of ammonia cause preferential damage to the brain, leading to devastating consequences.[3] Later onset forms of OTC deficiency can have variable presentations. Although late onset forms of the disease are often considered milder than the classic infantile presentation, any affected individual is at risk for an episode of hyperammonemia that could still be life-threatening if presented with the appropriate stressors.[4] These patients will often present with headaches, nausea, vomiting, delirium, erratic behavior, or seizures.[2] A detailed dietary history of an affected individual with undiagnosed OTC deficiency will often reveal a history of protein avoidance.[4] The prognosis of a patient with severe OTC deficiency is well correlated with the length of the hyperammonemic period rather than the degree of hyperammonemia or the presence of other symptoms, such as seizures.[4] Even for patients with late onset forms of the disease, their overall clinical picture is dependent on the extent of hyperammonemia they have experienced, even if it has remained unrecognized.[3] ## Genetics[edit] OTC deficiency is inherited in a X-linked recessive manner OTC deficiency is caused by mutations in the OTC gene, which is located on the X chromosome.[5] OTC codes for the mitochondrial enzyme ornithine transcarbamylase, which is expressed only in liver. The functional enzyme consists of three identical subunits.[6] OTC is the last enzyme in the proximal portion of the urea cycle, which consists of the reactions that take place in the mitochondria. The substrates of the reaction catalyzed by ornithine transcarbamylase are ornithine and carbamoyl phosphate, while the product is citrulline.[3] There are no common mutations that cause disease, however 10 - 15% of disease causing mutations are deletions.[5] It is inherited in an X-linked recessive manner, meaning males are more commonly affected than females. Females who carry a defective copy of the gene can be severely affected or asymptomatic, largely depending on the random nature of X-inactivation.[5] There is some degree of genotype - phenotype correlation with OTC deficiency, but this depends on a number of situations. Individuals with milder mutations, often associated with late onset disease can still present with severe illness when exposed to sufficient metabolic stress. Correlations are more difficult to ascertain in females, since the residual activity of OTC in the liver is impacted not only by the nature of the mutation, but also by the random pattern of X-inactivation.[4] OTC deficiency is estimated to be the most common urea cycle disorder.[4] An exact incidence is difficult to calculate, due to the varying clinical presentations of later onset forms of the disease. Early estimates of the incidence were as high as 1:14,000 live births, however later studies have decreased these estimates to approximately 1:60,000 - 1:72,000.[4] ## Diagnosis[edit] In individuals with marked hyperammonemia, a urea cycle disorder is usually high on the list of possible causes. While the immediate focus is lowering the patient's ammonia concentrations, identifying the specific cause of increased ammonia levels is key as well.[citation needed] Diagnostic testing for OTC deficiency, or any individual with hyperammonemia involves plasma and urine amino acid analysis, urine organic acid analysis (to identify the presence or absence of orotic acid, as well as rule out an organic acidemia) and plasma acylcarnitines (will be normal in OTC deficiency, but can identify some other causes of hyperammonemia). An individual with untreated OTC deficiency will show decreased citrulline and arginine concentrations (because the enzyme block is proximal to these intermediates) and increased orotic acid. The increased orotic acid concentrations result from the buildup of carbamoyl phosphate. This biochemical phenotype (increased ammonia, low citrulline and increased orotic acid) is classic for OTC deficiency, but can also be seen in neonatal presentations of ornithine aminotransferase deficiency.[1] Only severely affected males consistently demonstrate this classic biochemical phenotype. Heterozygous females can be difficult to diagnose. With the rise of sequencing techniques, molecular testing has become preferred, particularly when the disease causing mutations in the family are known.[5] Historically, heterozygous females were often diagnosed using an allopurinol challenge. In a female with reduced enzyme activity, an oral dose of allopurinol would be metabolized to oxypurinol ribonucleotide, which blocks the pyrimidine biosynthetic pathway. When this induced enzymatic block is combined with reduced physiologic enzyme activity as seen in heterozygotes, the elevation of orotic acid could be used to differentiate heterozygotes from unaffected individuals. This test was not universally effective, as it had both false negative and false positive results.[3] Ornithine transcarbamylase is only expressed in the liver, thus performing an enzyme assay to confirm the diagnosis requires a liver biopsy. Before molecular genetic testing was commonly available, this was one of the only methods for confirmation of a suspected diagnosis. In cases where prenatal diagnosis was requested, a fetal liver biopsy used to be required to confirm if a fetus was affected.[1] Modern molecular techniques have eliminated this need, and gene sequencing is now the preferred method of diagnosis in asymptomatic family members after the diagnosis has been confirmed in a proband.[4][5] ## Treatment[edit] The treatment goal for individuals affected with OTC deficiency is the avoidance of hyperammonemia. This can be accomplished through a strictly controlled low-protein diet, as well as preventive treatment with nitrogen scavenging agents such as sodium benzoate. The goal is to minimize the nitrogen intake while allowing waste nitrogen to be excreted by alternate pathways.[5] Arginine is typically supplemented as well, in an effort to improve the overall function of the urea cycle.[5] If a hyperammonemic episode occurs, the aim of treatment is to reduce the individual's ammonia levels as soon as possible. In extreme cases, this can involve hemodialysis.[1] Gene therapy had been considered a possibility for curative treatment for OTC deficiency, and clinical trials were taking place at the University of Pennsylvania in the late 1990s. These were halted after the death of Jesse Gelsinger, a young man taking part in a phase I trial using an adenovirus vector.[7] Experiment trials resumed in 2016 using a different vector, and are ongoing.[8] Currently, the only option for curing OTC deficiency is a liver transplant, which restores normal enzyme activity.[9] A 2005 review of 51 patients with OTC deficiency who underwent liver transplant estimated 5-year survival rates of greater than 90%.[9] Severe cases of OTC deficiency are typically evaluated for liver transplant by 6 months of age.[4] ## Prognosis[edit] A 1999 retrospective study of 74 cases of neonatal onset found that 32 (43%) patients died during their first hyperammonemic episode. Of those who survived, less than 20% survived to age 14. Few of these patients received liver transplants.[10] Even with proper identification and treatment, the majority of patients who present in the neonatal period have severe neurological and intellectual impairments. Liver transplantation cannot cure brain damage which has already occurred, but it will prevent future hyperammonemic episodes and prevent further damage.[1] ## In popular culture[edit] * Mob Rules (House) ## References[edit] 1. ^ a b c d e f Wraith, J. E. (2001). "Ornithine carbamoyltransferase deficiency". Archives of Disease in Childhood. 84 (1): 84–88. doi:10.1136/adc.84.1.84. PMC 1718609. PMID 11124797. 2. ^ a b c "Ornithing transcarbamylase deficiency". United States National Library of Medicine. 22 May 2018. Retrieved 25 May 2018. 3. ^ a b c d Walker, V. (2009). "Ammonia toxicity and its prevention in inherited defects of the urea cycle". Diabetes, Obesity and Metabolism. 11 (9): 823–835. doi:10.1111/j.1463-1326.2009.01054.x. PMID 19531057. 4. ^ a b c d e f g h Lichter-Konecki, U.; Caldovic, L.; Morizono, H.; Simpson, K.; Pagon, R. A.; Adam, M. P.; Bird, T. D.; Dolan, C. R.; Fong, C. T.; Stephens, K. (1993). "Ornithine Transcarbamylase Deficiency". PMID 24006547. Cite journal requires `\|journal=` (help) 5. ^ a b c d e f g "#311250 - Ornithine Transcarbamylase Deficiency, Hyperammonemia Due To". Johns Hopkins University. Retrieved 2014-01-01. 6. ^ "Human ornithine transcarbamylase (OTC) mRNA, complete coding sequence". US National Library of Medicine. 7. ^ Deakin, C. T.; Alexander, I. E.; Kerridge, I. (2009). "Accepting Risk in Clinical Research: Is the Gene Therapy Field Becoming Too Risk-averse?". Molecular Therapy. 17 (11): 1842–1848. doi:10.1038/mt.2009.223. PMC 2835028. PMID 19773741. 8. ^ "Safety and Dose-Finding Study of DTX301 (scAAV8OTC) in Adults With Late-Onset OTC Deficiency - Full Text View - ClinicalTrials.gov". clinicaltrials.gov. Retrieved 2020-08-07. 9. ^ a b Morioka, D.; Kasahara, M.; Takada, Y.; Shirouzu, Y.; Taira, K.; Sakamoto, S.; Uryuhara, K.; Egawa, H.; Shimada, H.; Tanaka, K. (2005). "Current role of liver transplantation for the treatment of urea cycle disorders: A review of the worldwide English literature and 13 cases at Kyoto University". Liver Transplantation. 11 (11): 1332–1342. doi:10.1002/lt.20587. PMID 16237708. 10. ^ Maestri, N. E.; Clissold, D.; Brusilow, S. W. (1999-03-01). "Neonatal onset ornithine transcarbamylase deficiency: A retrospective analysis". The Journal of Pediatrics. 134 (3): 268–272. doi:10.1016/s0022-3476(99)70448-8. ISSN 0022-3476. PMID 10064660. ## External links[edit] Classification D * ICD-10: E72.4 * ICD-9-CM: 270.6 * OMIM: 311250 * MeSH: D020163 * DiseasesDB: 9286 External resources * MedlinePlus: 000372 * eMedicine: ped/2744 * Orphanet: 664 * v * t * e Inborn error of amino acid metabolism K→acetyl-CoA Lysine/straight chain * Glutaric acidemia type 1 * type 2 * Hyperlysinemia * Pipecolic acidemia * Saccharopinuria Leucine * 3-hydroxy-3-methylglutaryl-CoA lyase deficiency * 3-Methylcrotonyl-CoA carboxylase deficiency * 3-Methylglutaconic aciduria 1 * Isovaleric acidemia * Maple syrup urine disease Tryptophan * Hypertryptophanemia G G→pyruvate→citrate Glycine * D-Glyceric acidemia * Glutathione synthetase deficiency * Sarcosinemia * Glycine→Creatine: GAMT deficiency * Glycine encephalopathy G→glutamate→ α-ketoglutarate Histidine * Carnosinemia * Histidinemia * Urocanic aciduria Proline * Hyperprolinemia * Prolidase deficiency Glutamate/glutamine * SSADHD G→propionyl-CoA→ succinyl-CoA Valine * Hypervalinemia * Isobutyryl-CoA dehydrogenase deficiency * Maple syrup urine disease Isoleucine * 2-Methylbutyryl-CoA dehydrogenase deficiency * Beta-ketothiolase deficiency * Maple syrup urine disease Methionine * Cystathioninuria * Homocystinuria * Hypermethioninemia General BC/OA * Methylmalonic acidemia * Methylmalonyl-CoA mutase deficiency * Propionic acidemia G→fumarate Phenylalanine/tyrosine Phenylketonuria * 6-Pyruvoyltetrahydropterin synthase deficiency * Tetrahydrobiopterin deficiency Tyrosinemia * Alkaptonuria/Ochronosis * Tyrosinemia type I * Tyrosinemia type II * Tyrosinemia type III/Hawkinsinuria Tyrosine→Melanin * Albinism: Ocular albinism (1) * Oculocutaneous albinism (Hermansky–Pudlak syndrome) * Waardenburg syndrome Tyrosine→Norepinephrine * Dopamine beta hydroxylase deficiency * reverse: Brunner syndrome G→oxaloacetate Urea cycle/Hyperammonemia (arginine * aspartate) * Argininemia * Argininosuccinic aciduria * Carbamoyl phosphate synthetase I deficiency * Citrullinemia * N-Acetylglutamate synthase deficiency * Ornithine transcarbamylase deficiency/translocase deficiency Transport/ IE of RTT * Solute carrier family: Cystinuria * Hartnup disease * Iminoglycinuria * Lysinuric protein intolerance * Fanconi syndrome: Oculocerebrorenal syndrome * Cystinosis Other * 2-Hydroxyglutaric aciduria * Aminoacylase 1 deficiency * Ethylmalonic encephalopathy * Fumarase deficiency * Trimethylaminuria * 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 http://www.otcdeficiency.com [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	Ornithine transcarbamylase deficiency	c1839530	797	wikipedia	https://en.wikipedia.org/wiki/Ornithine_transcarbamylase_deficiency	2021-01-18T19:08:40	{"gard": ["8391"], "mesh": ["D020163"], "umls": ["C1839530"], "icd-9": ["270.6"], "orphanet": ["664"], "wikidata": ["Q3043161"]}
Illustration of a dog's pancreas: Alveolus in the illustration refers to the acinar cells of the exocrine pancreas. The cells form circular clusters.[1] They are the cells which produce pancreatic enzymes needed for digestion of food. Canine pancreatitis is inflammation of the pancreas that can occur in two very different forms. Acute pancreatitis[2] is sudden, while chronic pancreatitis is characterized by recurring or persistent form of pancreatic inflammation. Cases of both can be considered mild or severe.[3] ## Contents * 1 Background * 2 Pathophysiology * 3 Clinical signs * 4 Risk factors * 5 Treatment * 6 Postpancreatitis management * 7 See also * 8 References ## Background[edit] The pancreas is composed of two sections: the smaller endocrine portion, which is responsible for producing hormones such as insulin, somatostatin, and glucagon, and the larger, exocrine portion,[4] which produces enzymes needed for the digestion of food. Acinar cells make up 82% of the total pancreas; these cells are responsible for the production of the digestive enzymes.[1][5] ## Pathophysiology[edit] Pancreatitis is caused by autodigestion of the pancreas thought to begin with an increase in secretion of pancreatic enzymes in response to a stimulus,[6][7] which can be any source from table scraps to getting into the garbage to drugs, toxins, and trauma.[3][8] The digestive enzymes are released too quickly and begin acting on the pancreas instead of the food they normally digest.[2][8][9][10] Once the process cascades, inflammatory mediators and free radicals are released and pancreatitis develops, causing amplification of the process.[9] ## Clinical signs[edit] The clinical signs can vary from mild gastrointestinal upset to death, with most dogs presenting with common gastrointestinal signs of upset, such as vomiting, anorexia, painful abdomen, hunched posture, diarrhea, fever, dehydration, and lack of energy, with vomiting being the most common symptom.[8][11][12] These signs are not specific just for pancreatitis and may be associated with other gastrointestinal diseases and conditions.[3][8][13] Acute pancreatitis can trigger a build-up of fluid, particularly in abdominal and thoracic (chest) areas, acute kidney injury, and cause inflammation in arteries and veins. The inflammation triggers the body's clotting factors, possibly depleting them to the point of spontaneous bleeding.[8][14] This form can be fatal in animals and in humans.[12] Chronic pancreatitis can be present though no clinical signs of the disease are seen.[13] Pancreatitis can result in exocrine pancreatic insufficiency, if the organ's acinar cells are permanently damaged; the pancreatic enzymes then need replacement with pancrelipase or similar products. The damage can also extend into the endocrine portion of the pancreas, resulting in diabetes mellitus.[15] Whether the diabetes is transient (temporary) or permanent depends on the severity of the damage to the endocrine pancreas beta cells.[14] ## Risk factors[edit] Although various causes of dog pancreatitis are known, such as drugs, fatty diet, trauma, etc., the pathophysiology is very complex.[2][13] Pancreatitis can be idiopathic; no real causation factor can be found.[9][12] Obese animals as well as animals fed a diet high in fat may be more prone to developing acute and chronic pancreatitis.[2][11][16] Certain breeds of dogs are considered predisposed to developing pancreatitis including Miniature Schnauzers, Cocker Spaniels, and some terrier breeds.[8][9][11][17] Miniature Schnauzers as a breed tend toward developing hyperlipidemia, an excess of circulating fats in the blood.[18] The breed that appears to be at risk for the acute form of pancreatitis is the Yorkshire Terrier, while Labrador Retrievers and Miniature Poodles seem to have a decreased risk for the acute form of the disease. Genetics may play a part in the risk factor.[2] Dogs suffering from diabetes mellitus, Cushing's disease (hyperadrenocorticism), hypothyroidism, and epilepsy are at increased risk for pancreatitis.[2][14] Diabetes and hypothyroidism are also associated with hyperlipidemia.[19][20] Those with other types of gastrointestinal conditions and dogs that have had previous pancreatitis attacks are also at increased risk for the disorder.[2] ## Treatment[edit] No treatments for canine pancreatitis have been approved. Treatment for this disease is supportive, and may require hospitalization to attend to the dog's nutritional and fluid needs, pain management, and addressing any other disease processes (infection, diabetes, etc.)[15] while letting the pancreas heal on its own.[3][11] Treatment often involves "resting" the pancreas for a short period of time by which the patient receives no food or fluids by mouth, but is fed and hydrated by intravenous fluids and a feeding tube.[8][12] Dehydration is also managed by the use of fluid therapy.[21][14][15] However, a specialist from Texas A&M University has stated, "There is no evidence whatsoever that withholding food has any beneficial effect." Other specialists have agreed with his opinion.[13] Canine pancreatitis is complex, often limiting the ability to approach the disease. ## Postpancreatitis management[edit] A low-fat diet is indicated.[3] The use of drugs that are known to have an association with pancreatitis should be avoided.[13][14] Some patients benefit from the use of pancreatic enzymes on a supplemental basis. One study indicated that 57% dogs followed for six months after an acute pancreatitis attack, either continued to exhibit inflammation of the organ or had decreased acinar cell function, though they had no pancreatitis symptoms.[13][22] ## See also[edit] * Pancreatitis ## References[edit] 1. ^ a b "Gross and Microscopic Anatomy of the Pancreas". Colorado State University School of Veterinary Medicine. Archived from the original on 14 May 2011. Retrieved 8 April 2011. 2. ^ a b c d e f g Washabau, Robert J. (2009). "Canine Pancreatic Disease: What's New in Diagnosis and Therapy?". 34th Congress-World Small Animal Veterinary Association (WSAVA). Retrieved 8 April 2011. 3. ^ a b c d e Steiner, Jörg M. (August 2003). "Pancreatitis" (PDF). Clinician's Brief-North American Veterinary Conference. Retrieved 9 April 2011. 4. ^ "Exocrine Sections of the Pancreas". Colorado State University School of Veterinary Medicine. Archived from the original on 14 May 2011. Retrieved 8 April 2011. 5. ^ "Acinar Cell". Auckland Bioengineering Institute-University of Auckland. Archived from the original on 26 February 2008. Retrieved 8 April 2011. 6. ^ "Enteric Endocrine System". Colorado State University School of Veterinary Medicine. Archived from the original on 14 May 2011. Retrieved 8 April 2011. 7. ^ "Control of Pancreatic Exocrine Secretion". Colorado State University School of Veterinary Medicine. Archived from the original on 14 May 2011. Retrieved 8 April 2011. 8. ^ a b c d e f g "Big Steak Dinner" (PDF). Tufts School of Veterinary Medicine. 2007. Retrieved 8 April 2011. 9. ^ a b c d West, Laura D.; Almy, Frederic S. "Diagnosing Pancreatitis in Dogs and Cats by Laboratory Methods". University of Georgia School of Veterinary Medicine. Retrieved 8 April 2011. 10. ^ J. M. Steiner (2003). "Diagnosis of acute pancreatitis". Vet Clin North Am Small Anim Pract. 33: 1181–1195. 11. ^ a b c d Armstrong, P. Jane (2011). "Canine Pancreatitis: Diagnosis and Management" (PDF). Western Veterinary Conference. Archived from the original (PDF) on 29 March 2016. Retrieved 8 April 2011. 12. ^ a b c d "Pancreatitis". Merck Veterinary Manual. Retrieved 8 April 2011. 13. ^ a b c d e f "Diagnosing and Treating Pancreatitis" (PDF). IDEXX Laboratories. 2006. p. 3. Archived (PDF) from the original on 4 March 2016. Retrieved 21 April 2011. 14. ^ a b c d e Brooks, Wendy C. "Canine Pancreatitis". Veterinary Partner. Retrieved 8 April 2011. 15. ^ a b c Hoskins, Johnny D. (2002). "Can You Rule Out Pancreatitis?". DVM 360. Retrieved 8 April 2011. 16. ^ Williams DA, Steiner JM. Canine Exocrine Pancreatic Disease. In Ettinger SJ, Feldman EC (eds): Textbook of Veterinary Internal Medicine, Diseases of the Dog and Cat, 6th ed. St. Louis, Elsevier Saunders, 2005, pp. 1482-1487 17. ^ Simpson, KW. Diseases of the Pancreas. In Tams T. (ed): Handbook of Small Animal Gastroenterology, 2nd ed. St. Louis, W. B. Saunders Co, 2003, pp. 353-365. 18. ^ Xenoulis, Panagiotis G.; Suchodolski, Jan S.; Levinski, Melinda D.; Steiner, Jörg M. (2007). "Investigation of Hypertriglyceridemia in Healthy Miniature Schnauzers". Journal of Veterinary Internal Medicine. doi:10.1111/j.1939-1676.2007.tb01942.x. 19. ^ Herrtage, Michael (2009). "New Strategies in the Management of Canine Diabetes Mellitus". WSAVA. Retrieved 8 April 2011. 20. ^ "Abstract #216-Association Between Hyperlipidemia & Hypothyroid in Dogs" (PDF). American College of Veterinary Internal Medicine. 2004. p. 81. Retrieved 8 April 2011. 21. ^ Carsten, Elizabeth. "Treatment Options for Canine Pancreatitis" (PDF). IDEXX Laboratories. Archived from the original (PDF) on 5 September 2012. Retrieved 8 April 2011. 22. ^ "Mild Chronic Pancreatitis". Merck Veterinary Manual. Retrieved 8 April 2011. [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	Canine pancreatitis	None	798	wikipedia	https://en.wikipedia.org/wiki/Canine_pancreatitis	2021-01-18T18:31:48	{"wikidata": ["Q5032415"]}
A rare disorder characterised by the association of aplasia cutis congenita with high myopia, congenital nystagmus and cone-rod dysfunction. It has been described in two siblings (brother and sister). Transmission is 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	Aplasia cutis-myopia syndrome	c1832826	799	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=1117	2021-01-23T18:41:46	{"gard": ["756"], "mesh": ["C563394"], "omim": ["601075"], "umls": ["C1832826"], "icd-10": ["Q84.8"], "synonyms": ["Gershoni-Baruch-Leibo syndrome"]}

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