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Spastic paraplegia type 49 is part of a group of genetic disorders known as hereditary spastic paraplegias. These disorders are characterized by progressive muscle stiffness (spasticity) and the development of paralysis of the lower limbs (paraplegia). Hereditary spastic paraplegias are divided into two types: pure and complex. The pure types involve only the lower limbs, whereas the complex types also involve the upper limbs (to a lesser degree) and other problems with the nervous system. Spastic paraplegia type 49 is a complex hereditary spastic paraplegia. Spastic paraplegia type 49 often begins with weak muscle tone (hypotonia) that starts in infancy. During childhood, spasticity and paraplegia develop and gradually worsen, causing difficulty walking and frequent falls. In addition, affected individuals have moderate to severe intellectual disability and distinctive physical features, including short stature; chubbiness; an unusually small head size (microcephaly); a wide, short skull (brachycephaly); a short, broad neck; and facial features described as coarse. Some people with spastic paraplegia type 49 develop seizures. Problems with autonomic nerve cells (autonomic neurons), which control involuntary body functions such as heart rate, digestion, and breathing, result in several features of spastic paraplegia type 49. Affected individuals have difficulty feeding beginning in infancy. They experience a backflow of stomach acids into the esophagus (called gastroesophageal reflux or GERD), causing vomiting. GERD can also lead to recurrent bacterial lung infections called aspiration pneumonia, which can be life-threatening. In addition, people with spastic paraplegia type 49 have problems regulating their breathing, resulting in pauses in breathing (apnea), initially while sleeping but eventually also while awake. Their blood pressure, pulse rate, and body temperature are also irregular. People with spastic paraplegia type 49 can develop recurrent episodes of severe weakness, hypotonia, and abnormal breathing, which can be life threatening. By early adulthood, some affected individuals need a machine to help them breathe (mechanical ventilation). Other signs and symptoms of spastic paraplegia type 49 reflect problems with sensory neurons, which transmit information about sensations such as pain, temperature, and touch to the brain. Many affected individuals are less able to feel pain or temperature sensations than individuals in the general population. Affected individuals also have abnormal or absent reflexes (areflexia). Because of the nervous system abnormalities that occur in spastic paraplegia type 49, it has been suggested that the condition also be classified as a hereditary sensory and autonomic neuropathy, which is a group of conditions that affect sensory and autonomic neurons. ## Frequency Spastic paraplegia type 49 is a rare disorder. Its prevalence is unknown. ## Causes Spastic paraplegia type 49 is caused by mutations in the TECPR2 gene. The protein produced from this gene plays a role in a cellular process called autophagy, by which worn-out or unnecessary cell parts are broken down and recycled. During autophagy, materials that are no longer needed are isolated in compartments called autophagosomes and transported to cell structures that break them down. The TECPR2 protein is thought to be important for the formation of autophagosomes. The TECPR2 gene mutations that cause spastic paraplegia type 49 likely result in an abnormal or absent TECPR2 protein. Alteration or loss of this protein is thought to impair autophagy, making cells less efficient at removing unneeded materials. Researchers suggest that neurons may be particularly vulnerable to impaired autophagy because it is especially difficult to transport waste materials through their long extensions (axons and dendrites) for breakdown. The waste materials can build up in neurons and damage them. Damage to autonomic and sensory neurons and neurons that control movement (motor neurons) results in the signs and symptoms of spastic paraplegia type 49. ### Learn more about the gene associated with Spastic paraplegia type 49 * TECPR2 ## 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 [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Spastic paraplegia type 49	c3542549	3,200	medlineplus	https://medlineplus.gov/genetics/condition/spastic-paraplegia-type-49/	2021-01-27T08:24:34	{"gard": ["13568"], "omim": ["615031"], "synonyms": []}
Supravalvular aortic stenosis SpecialtyMedical genetics CausesWilliams syndrome Diagnostic methodechocardiography or MRI Supravalvular aortic stenosis is a congenital obstructive narrowing of the aorta just above the aortic valve and is least common type of aortic stenosis. It is often associated with other cardiovascular anomalies and is one of the characteristic findings of Williams syndrome. The diagnosis can be made by echocardiography or MRI. ## Pathophysiology[edit] Supravalvular aortic stenosis is due to diffuse or discrete narrowing of ascending aorta. The murmur associated with it is systolic murmur and is similar in character to valvular aortic stenosis murmur but commonly present at 1st Intercostal space (ICS) on the right. Individuals with this anomaly may have unequal carotid pulses, differential blood pressure in upper extremities and a palpable thrill in Suprasternal notch. Individuals with significant supravalvular AS chronically may develop left ventricular hypertrophy and also are at risk of developing coronary artery stenosis. With increased metabolic demands (e.g. exercise) such individuals may develop subendocardial or myocardial ischemia due to increased myocardial oxygen demand and seek medical help with symptoms of exercise induced angina. ## Genetics[edit] Supravalvular aortic stenosis is associated with genetic damage at the Elastin gene locus on chromosome 7q11.23.[1] Fluorescent in situ hybridisation techniques have revealed that 96% of patients with Williams syndrome, where supravalvular aortic stenosis is characteristic, have a hemizygous deletion of the Elastin gene.[2] Further studies have shown that patients with less extensive deletions featuring the Elastin gene also tend to develop supravalvular aortic stenosis [1] ## References[edit] 1. ^ a b Tassabehji, May, and Zsolt Urban. "Congenital Heart Disease." Congenital Heart Disease. Humana Press, 2006. 129-156. 2. ^ Lowery, Mary C., et al. "Strong correlation of elastin deletions, detected by FISH, with Williams syndrome: evaluation of 235 patients." American journal of human genetics 57.1 (1995): 49. This cardiovascular system article is a stub. You can help Wikipedia by expanding it. * v * t * e [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Supravalvular aortic stenosis	c1305147	3,201	wikipedia	https://en.wikipedia.org/wiki/Supravalvular_aortic_stenosis	2021-01-18T18:36:17	{"gard": ["743"], "mesh": ["D021921"], "umls": ["C1305147"], "orphanet": ["3193"], "wikidata": ["Q16874615"]}
Nonsmall-cell lung carcinoma Micrograph of a squamous carcinoma, a type of nonsmall-cell lung carcinoma, FNA specimen, Pap stain. SpecialtyOncology Nonsmall-cell lung carcinoma (NSCLC) is any type of epithelial lung cancer other than small-cell lung carcinoma (SCLC). NSCLC accounts for about 85% of all lung cancers.[1][2] As a class, NSCLCs are relatively insensitive to chemotherapy, compared to small-cell carcinoma. When possible, they are primarily treated by surgical resection with curative intent, although chemotherapy has been used increasingly both preoperatively (neoadjuvant chemotherapy) and postoperatively (adjuvant chemotherapy). ## Contents * 1 Types * 1.1 Lung adenocarcinoma * 1.2 Squamous-cell lung carcinoma * 1.3 Large-cell lung carcinoma * 2 Symptoms * 3 Cause * 3.1 DNA repair deficiency in NSCLC * 4 Staging * 4.1 Five-year survival rates * 5 Treatment * 5.1 Early/nonmetastatic NSCLC * 5.2 Advanced/metastatic NSCLC * 5.3 EGFR mutations * 5.4 ALK gene rearrangements * 5.5 Other treatment options * 6 References * 7 External links ## Types[edit] Pie chart showing incidences of nonsmall-cell lung cancers as compared to small-cell carcinoma shown at right, with fractions of smokers versus nonsmokers shown for each type[3] The most common types of NSCLC are squamous-cell carcinoma, large-cell carcinoma, and adenocarcinoma, but several other types occur less frequently. A few of the less common types are pleomorphic, carcinoid tumor, salivary gland carcinoma, and unclassified carcinoma.[4] All types can occur in unusual histologic variants and as mixed cell-type combinations.[5] Nonsquamous-cell carcinoma almost occupies the half of NSCLC.[dubious – discuss][citation needed] In the tissue classification, the central type contains about one-ninth.[citation needed] Sometimes, the phrase "not otherwise specified" (NOS) is used generically, usually when a more specific diagnosis cannot be made. This is most often the case when a pathologist examines a small number of malignant cells or tissue in a cytology or biopsy specimen.[5] Lung cancer in people who have never smoked is almost universally NSCLC, with a sizeable majority being adenocarcinoma.[6] On relatively rare occasions, malignant lung tumors are found to contain components of both SCLC and NSCLC. In these cases, the tumors are classified as combined small-cell lung carcinoma (c-SCLC),[7] and are (usually) treated as "pure" SCLC.[8] ### Lung adenocarcinoma[edit] Main article: Adenocarcinoma of the lung Adenocarcinoma of the lung is currently the most common type of lung cancer in "never smokers" (lifelong nonsmokers).[9] Adenocarcinomas account for about 40% of lung cancers. Historically, adenocarcinoma was more often seen peripherally in the lungs than SCLC and squamous-cell lung cancer, both of which tended to be more often centrally located.[10][11] Recent studies, though, suggest that the "ratio of centrally to peripherally occurring" lesions may be converging toward unity for both adenocarcinoma and squamous-cell carcinoma.[citation needed] ### Squamous-cell lung carcinoma[edit] Main article: Squamous cell carcinoma of the lung Photograph of a squamous-cell carcinoma: The tumour is on the left, obstructing the bronchus (lung). Beyond the tumour, the bronchus is inflamed and contains mucus. Squamous-cell carcinoma (SCC) of the lung is more common in men than in women. It is closely correlated with a history of tobacco smoking, more so than most other types of lung cancer. According to the Nurses' Health Study, the relative risk of SCC is around 5.5, both among those with a previous duration of smoking of 1 to 20 years, and those with 20 to 30 years, compared to "never smokers" (lifelong nonsmokers).[12] The relative risk increases to about 16 with a previous smoking duration of 30 to 40 years, and roughly 22 with more than 40 years.[12] ### Large-cell lung carcinoma[edit] Main article: Large-cell lung carcinoma Large-cell lung carcinoma (LCLC) is a heterogeneous group of undifferentiated malignant neoplasms originating from transformed epithelial cells in the lung. LCLCs have typically comprised around 10% of all NSCLC in the past, although newer diagnostic techniques seem to be reducing the incidence of diagnosis of "classic" LCLC in favor of more poorly differentiated SCCs and adenocarcinomas.[13] LCLC is, in effect, a "diagnosis of exclusion", in that the tumor cells lack light microscopic characteristics that would classify the neoplasm as a small-cell carcinoma, squamous-cell carcinoma, adenocarcinoma, or other more specific histologic type of lung cancer. LCLC is differentiated from SCLC primarily by the larger size of the anaplastic cells, a higher cytoplasmic-to-nuclear size ratio, and a lack of "salt-and-pepper" chromatin.[citation needed] ## Symptoms[edit] Many of the symptoms of NSCLC can be signs of other diseases, but having chronic or overlapping symptoms may be a signal of the presence of the disease. Some symptoms are indicators of less advanced cases, while some may signal that the cancer has spread. Some of the symptoms of less advanced cancer include chronic cough, coughing up blood, chest pain, hoarseness, shortness of breath, wheezing, chest pain, weight loss, and loss of appetite.[14] A few more symptoms associated with the early progression of the disease are feeling weak, being very tired, having trouble swallowing, swelling in the face or neck, and continuous or recurring infections such as bronchitis or pneumonia.[4][14][15] Signs of more advanced cases include bone pain, nervous-system changes (headache, weakness, dizziness, balance problems, seizures), jaundice, lumps near the surface of the body, numbness of extremities due to Pancoast syndrome, and nausea, vomiting, and constipation brought on by hypercalcemia.[14][15] Some more of the symptoms that indicate further progression of the cancer include shortness of breath, superior vena cava syndrome, trouble swallowing, large amounts of mucus, weakness, fatigue, and hoarseness.[15] ## Cause[edit] Smoking is by far the leading risk factor for lung cancer.[16] Cigarette smoke contains more than 6,000 components, many of which lead to DNA damage[17] (see table of tobacco-related DNA damages in Tobacco smoking). Other causes include radon, exposure to secondhand smoke, exposure to substances such as asbestos, chromium, nickel, beryllium, soot, or tar, family history of lung cancer, and air pollution.[4][16] In general, DNA damage appears to be the primary underlying cause of cancer.[18] Though most DNA damages are repairable,[17] leftover unrepaired DNA damages from cigarette smoke are the likely cause of NSCLC. DNA replication past an unrepaired damage can give rise to a mutation because of inaccurate translesion synthesis. In addition, during repair of DNA double-strand breaks, or repair of other DNA damages, incompletely cleared sites of repair can lead to epigenetic gene silencing.[19][20] ### DNA repair deficiency in NSCLC[edit] Deficiencies in DNA repair underlie many forms of cancer.[21] If DNA repair is deficient, the frequency of unrepaired DNA damages increases, and these tend to cause inaccurate translesion synthesis leading to mutation. Furthermore, increased damages can elevate incomplete repair, leading to epigenetic alterations.[citation needed] As indicated as in the article Carcinogenesis, mutations in DNA repair genes occasionally occur in cancer, but deficiencies of DNA repair due to epigenetic alterations that reduce or silence DNA repair-gene expression occur much more frequently in cancer.[citation needed] Epigenetic gene silencing of DNA repair genes occurs frequently in NSCLC. At least nine DNA repair genes that normally function in relatively accurate DNA repair pathways are often repressed by promoter hypermethylation in NSCLC. One DNA repair gene, FEN1, that functions in an inaccurate DNA repair pathway, is expressed at an increased level due to hypo-, rather than hyper-, methylation of its promoter region (deficiency of promoter methylation) in NSCLC.[citation needed] Epigenetic promoter methylation in DNA repair genes in NSCLC Gene Frequency of hyper- (or hypo-) methylation DNA repair pathway Ref. NEIL1 42% base excision repair [22] WRN 38% homologous recombinational repair, nonhomologous end joining, base excision repair [23] MGMT 13% - 64% direct reversal [22][24][25] ATM 47% homologous recombinational repair [26] MLH1 48% - 73% mismatch repair [26][27] MSH2 42% - 63% mismatch repair [26][27] BRCA2 42% homologous recombinational repair [28] BRCA1 30% homologous recombinational repair [28] XRCC5 (Ku80) 20% nonhomologous end joining [28] FEN1 100% hypomethylated (increased expression) microhomology-mediated end joining [29] The frequent deficiencies in accurate DNA repair, and the increase in inaccurate repair, likely cause the high level of mutation in lung cancer cells of more than 100,000 mutations per genome (see Whole genome sequencing). ## Staging[edit] Staging is a formal procedure to determine how developed the cancer is, which determines treatment options. The American Joint Committee on Cancer and the International Union Against Cancer recommend TNM staging, using a uniform scheme for NSCLC, SCLC, and bronchopulmonary carcinoid tumors.[30] With TNM staging, the cancer is classified based on the size of the tumor and spread to lymph nodes and other organs. As the tumor grows in size and the areas affected become larger, the staging of the cancer becomes more advanced as well. Several components of NSCLC staging then influence physicians' treatment strategies.[31] The lung tumor itself is typically assessed both radiographically for overall size and by a pathologist under the microscope to identify specific genetic markers or to see if invasion into important structures within the chest (e.g., bronchus or pleural cavity) has occurred. Next, the patient's nearby lymph nodes within the chest cavity, known as the mediastinum, are checked for disease involvement. Finally, the patient is evaluated for more distant sites of metastatic disease, most typically with brain imaging and or scans of the bones.[32] ### Five-year survival rates[edit] The survival rates for stages I through IV decrease significantly due to the advancement of the disease. For stage I, the five-year survival rate is 47%, stage II is 30%, stage III is 10%, and stage IV is 1%.[33] Further information: Lung cancer staging ## Treatment[edit] Main article: Treatment of lung cancer See also: Lung cancer surgery More than one kind of treatment is often used, depending on the stage of the cancer, the individual's overall health, age, response to chemotherapy, and other factors such as the likely side effects of the treatment. After full staging, the NSCLC patient can typically be classified in one of three different categories: patients with early, nonmetastatic disease (stages I and II, and select type III tumors), patients with locally advanced disease confined to the thoracic cavity (e.g., large tumors, tumors involving critical chest structures, or patients with positive mediastinal lymph nodes), or patients with distant metastasis outside of the thoracic cavity. ### Early/nonmetastatic NSCLC[edit] NSCLCs are usually not very sensitive to chemotherapy[34] and/or radiation, so surgery (lung resection to remove the tumor) remains the treatment of choice if patients are diagnosed at an early stage.[35] If the persons have a small, but inoperable tumor, they may undergo highly targeted, high-intensity radiation therapy. New methods of giving radiation treatment allow doctors to be more accurate in treating lung cancers. This means less radiation affects nearby healthy tissues. New methods include cyberknife and stereotactic body radiation therapy. Certain people who are deemed to be higher risk may also receive adjuvant (ancillary) chemotherapy after initial surgery or radiation therapy. A number of possible chemotherapy agents can be selected, but most involve the platinum-based chemotherapy drug called cisplatin. Other treatments include percutaneous ablation and chemoembolization.[36] The most widely used ablation techniques for lung cancer are radiofrequency ablation (RFA), cryoablation, and microwave ablation.[37] Ablation may be an option for patients whose tumors are near the outer edge of the lungs. Nodules less than 1 cm from the trachea, main bronchi, oesophagus, and central vessels should be excluded from RFA given high risk of complications and frequent incomplete ablation. Additionally, lesions greater than 5 cm should be excluded and lesions 3 to 5 cm should be considered with caution given high risk of recurrence.[38] As a minimally invasive procedure, it can be a safer alternative for patients who are poor candidates for surgery due to comorbidities or limited lung function. A study comparing thermal ablation to sublobar resection as treatment for early stage NSCLC in older people found no difference in overall survival of the patients.[39] It is possible that RFA followed by radiation therapy has a survival benefit due to synergism of the two mechanisms of cell destruction.[40] ### Advanced/metastatic NSCLC[edit] The treatment approach for people who have advanced NSCLC is first aimed at relieving pain and distress (palliative), but a wide variety of chemotherapy options exists.[41][42][needs update] These agents include both traditional chemotherapies, such as cisplatin, which indiscriminately target all rapidly dividing cells, and newer targeted agents, which are more tailored to specific genetic aberrations found within a person's tumor. When choosing an appropriate chemotherapy approach, the toxicity profile (side effects of the drug) should be taken into account and balanced with the person's comorbidities (other conditions or side effects that the person is experiencing).[42] Carboplatin is a chemotherapy agent that has a similar effect on a person's survival when compared to cisplatin, and has a different toxicity profile from cisplatin.[42] At present, two genetic markers are routinely profiled in NSCLC tumors to guide further treatment decision-making - mutations within epidermal growth factor (EGFR) and anaplastic lymphoma kinase.[43] Also, a number of additional genetic markers are known to be mutated within NSCLC and may impact treatment in the future, including BRAF, HER2/neu, and KRAS. For advanced NSCLC, a combined chemotherapy treatment approach that includes cetuximab, an antibody that targets the EGFR signalling pathway, is more effective at improving a person's overall survival when compared to standard chemotherapy alone.[44] Thermal ablations, i.e. RFA, cryoablation, and microwave ablation, are appropriate for palliative treatment of tumor-related symptoms or recurrences within treatment fields. People with severe pulmonary fibrosis and severe emphysema with a life expectancy less than a year should be considered poor candidates for this treatment.[45] ### EGFR mutations[edit] Roughly 10–35% of people who have NSCLC will have drug-sensitizing mutations of the EGFR.[43] The distribution of these mutations has been found to be race-dependent, with one study estimating that 10% of Caucasians, but 50% of Asians, will be found to have such tumor markers.[46] A number of different EGFR mutations have been discovered, but certain aberrations result in hyperactive forms of the protein. People with these mutations are more likely to have adenocarcinoma histology and be nonsmokers or light smokers. These people have been shown to be sensitized to certain medications that block the EGFR protein known as tyrosine kinase inhibitors specifically, erlotinib, gefitinib, afatinib, or osimertinib.[47] Reliable identification of mutations in lung cancer needs careful consideration due to the variable sensitivity of diagnostic techniques.[48] ### ALK gene rearrangements[edit] Up to 7% of NSCLC patients have EML4-ALK translocations or mutations in the ROS1 gene; these patients may benefit from ALK inhibitors, which are now approved for this subset of patients.[49] Crizotinib, which gained FDA approval in August 2011, is an inhibitor of several kinases, specifically ALK, ROS1, and MET. Crizotinib has been shown in clinical studies to have response rates around 60% if patients are shown to have ALK-positive disease.[35] Several studies have also shown that ALK mutations and EGFR activating mutations are typically mutually exclusive. Thus, patients who fail crizotinib are not recommended to be switched to an EGFR-targeted drug such as erlotinib.[35] ### Other treatment options[edit] Micrograph showing a PD-L1-positive NSCLC, PD-L1 immunostain NSCLC patients with advanced disease who are not found to have either EGFR or ALK mutations may receive bevacizumab, which is a monoclonal antibody medication targeted against the vascular endothelial growth factor (VEGF). This is based on an Eastern Cooperative Oncology Group study that found that adding bevacizumab to carboplatin and paclitaxel chemotherapy for certain patients with recurrent or advanced NSCLC (stage IIIB or IV) may increase both overall survival and progression-free survival.[50] The main treatment arms of phase 3 clinical trials providing immunotherapy in the first line for patients with non-small cell lung cancer.[51] Non-small cell lung cancer (NSCLC) cells expressing programmed death-ligand 1 (PD-L1) could interact with programmed death receptor 1 (PD-1) expressed on the surface of T cells, and result in decreased tumor cell kill by the immune system. Atezolizumab is an anti PD-L1 monoclonal antibody. Nivolumab and Pembrolizumab are anti PD-1 monoclonal antibodies. Ipilimumab is a monoclonal antibody that targets Cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) on the surface of T cells. Bevacizumab is a monoclonal antibody that targets Vascular Endothelial Growth Factor (VEGF) in the circulation and functions as an angiogenesis inhibitor.[51] NSCLC cells expressing programmed death-ligand 1 (PD-L1) could interact with programmed death receptor 1 (PD-1) expressed on the surface of T cells, and result in decreased tumor cell kill by the immune system. Atezolizumab is an anti PD-L1 monoclonal antibody. Nivolumab and Pembrolizumab are anti PD-1 monoclonal antibodies. Ipilimumab is a monoclonal antibody that targets Cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) on the surface of T cells. Bevacizumab is a monoclonal antibody that targets Vascular Endothelial Growth Factor (VEGF) in the circulation and functions as an angiogenesis inhibitor. Multiple phase 3 clinical trials utilizing immunotherapy in the first line for treatment of NSCLC were published, including Pembrolizumab in KEYNOTE-024, KEYNOTE-042, KEYNOTE-189 and KEYNOTE-407; Nivolumab and Ipilimumab in CHECKMATE-227 and CHECKMATE 9LA; and Atezolizumab in IMpower110, IMpower130 and IMpower150.[51] In 2015, the US Food and Drug Administration (FDA) approved the anti-PD-1 agent nivolumab for advanced or metastatic SCC. 2 October 2015, the FDA approved pembrolizumab for the treatment of metastatic NSCLC in patients whose tumors express PD-L1 and who have failed treatment with other chemotherapeutic agents. October 2016, pembrolizumab became the first immunotherapy to be used first line in the treatment of NSCLC if the cancer overexpresses PDL1 and the cancer has no mutations in EGFR or in ALK; if chemotherapy has already been administered, then pembrolizumab can be used as a second-line treatment, but if the cancer has EGFR or ALK mutations, agents targeting those mutations should be used first. Assessment of PDL1 must be conducted with a validated and approved companion diagnostic. Overall survival in non-small cell lung cancer patients treated with protocols incorporating immunotherapy in the first line for advanced or metastatic disease. Nasser NJ, Gorenberg M, Agbarya A. Pharmaceuticals2020, 13(11), 373; https://doi.org/10.3390/ph13110373 The prognosis of patients with non small cell lung cancer improved significantly in the last years with the introduction of immunotherapy.[51] Patients with tumor PDL-1 expressed over half or more of the tumor cells achieved a median overall survival of 30 months with pembrolizumab.[52][53] Multiple phase 3 trials providing immunotherapy in the first line for patients with non-small cell lung cancer have been published.[51] ## References[edit] 1. ^ Non-Small Cell Lung Cancer at eMedicine 2. ^ "What Is Non-Small Cell Lung Cancer?". www.cancer.org. 3. ^ Smokers defined as current or former smoker of more than 1 year of duration. See image page in Commons for percentages in numbers. Reference: Table 2 in: Kenfield SA, Wei EK, Stampfer MJ, Rosner BA, Colditz GA (June 2008). "Comparison of aspects of smoking among the four histological types of lung cancer". Tobacco Control. 17 (3): 198–204. doi:10.1136/tc.2007.022582. PMC 3044470. PMID 18390646. 4. ^ a b c "Non-Small Cell Lung Cancer Treatment". National Cancer Institute. 1 January 1980. Retrieved 4 December 2017. 5. ^ a b "Non-small cell lung cancer treatment – National Cancer Institute". 1 January 1980. Retrieved 19 October 2008. 6. ^ Hanna N (2007). "Lung Cancer in the Never Smoker Population". Hematology-Oncology. Medscape. 7. ^ Travis WD, Brambilla E, Muller-Hermelink HK, et al., eds. (2004). Pathology and Genetics of Tumours of the Lung, Pleura, Thymus and Heart (PDF). World Health Organization Classification of Tumours. Lyon: IARC Press. ISBN 978-92-832-2418-1. Archived from the original (PDF) on 23 August 2009. Retrieved 27 March 2010. 8. ^ Simon GR, Turrisi A (September 2007). "Management of small cell lung cancer: ACCP evidence-based clinical practice guidelines (2nd edition)". Chest. 132 (3 Suppl): 324S–339S. doi:10.1378/chest.07-1385. PMID 17873178. Archived from the original on 12 January 2013. 9. ^ Subramanian J, Govindan R (February 2007). "Lung cancer in never smokers: a review". Journal of Clinical Oncology. 25 (5): 561–70. doi:10.1200/JCO.2006.06.8015. PMID 17290066. 10. ^ Mitchell RS, Kumar V, Abbas AK, Fausto N (2007). "morphology of adenocarcinoma". Robbins Basic Pathology (8th ed.). Philadelphia: Saunders. ISBN 978-1-4160-2973-1.[page needed] 11. ^ Travis WD, Travis LB, Devesa SS (January 1995). "Lung cancer". Cancer. 75 (1 Suppl): 191–202. doi:10.1002/1097-0142(19950101)75:1+<191::AID-CNCR2820751307>3.0.CO;2-Y. PMID 8000996. 12. ^ a b Kenfield SA, Wei EK, Stampfer MJ, Rosner BA, Colditz GA (June 2008). "Comparison of aspects of smoking among the four histological types of lung cancer". Tobacco Control. 17 (3): 198–204. doi:10.1136/tc.2007.022582. PMC 3044470. PMID 18390646. 13. ^ Popper HH (2011). "Large cell carcinoma of the lung – a vanishing entity?". Memo - Magazine of European Medical Oncology. 4: 4–9. doi:10.1007/s12254-011-0245-8. S2CID 71238993. 14. ^ a b c "Non-Small Cell Lung Cancer Signs and Symptoms". www.cancer.org. Retrieved 4 December 2017. 15. ^ a b c "Non-small cell lung cancer". University of Maryland Medical Center. Retrieved 4 December 2017. 16. ^ a b "Non-Small Cell Lung Cancer Risk Factors". www.cancer.org. 17. ^ a b Liu X, Conner H, Kobayashi T, Kim H, Wen F, Abe S, et al. (August 2005). "Cigarette smoke extract induces DNA damage but not apoptosis in human bronchial epithelial cells". American Journal of Respiratory Cell and Molecular Biology. 33 (2): 121–9. doi:10.1165/rcmb.2003-0341OC. PMID 15845867. 18. ^ Kastan MB (April 2008). "DNA damage responses: mechanisms and roles in human disease: 2007 G.H.A. Clowes Memorial Award Lecture". Molecular Cancer Research. 6 (4): 517–24. doi:10.1158/1541-7786.MCR-08-0020. PMID 18403632. 19. ^ O'Hagan HM, Mohammad HP, Baylin SB (August 2008). Lee JT (ed.). "Double strand breaks can initiate gene silencing and SIRT1-dependent onset of DNA methylation in an exogenous promoter CpG island". PLOS Genetics. 4 (8): e1000155. doi:10.1371/journal.pgen.1000155. PMC 2491723. PMID 18704159. 20. ^ Cuozzo C, Porcellini A, Angrisano T, Morano A, Lee B, Di Pardo A, et al. (July 2007). "DNA damage, homology-directed repair, and DNA methylation". PLOS Genetics. 3 (7): e110. doi:10.1371/journal.pgen.0030110. PMC 1913100. PMID 17616978. 21. ^ Harper JW, Elledge SJ (December 2007). "The DNA damage response: ten years after". Molecular Cell. 28 (5): 739–45. doi:10.1016/j.molcel.2007.11.015. PMID 18082599. 22. ^ a b Do H, Wong NC, Murone C, John T, Solomon B, Mitchell PL, Dobrovic A (February 2014). "A critical re-assessment of DNA repair gene promoter methylation in non-small cell lung carcinoma". Scientific Reports. 4: 4186. Bibcode:2014NatSR...4E4186D. doi:10.1038/srep04186. PMC 3935198. 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PMID 21288129. 26. ^ a b c Safar AM, Spencer H, Su X, Coffey M, Cooney CA, Ratnasinghe LD, et al. (June 2005). "Methylation profiling of archived non-small cell lung cancer: a promising prognostic system". Clinical Cancer Research. 11 (12): 4400–5. doi:10.1158/1078-0432.CCR-04-2378. PMID 15958624. 27. ^ a b Gomes A, Reis-Silva M, Alarcão A, Couceiro P, Sousa V, Carvalho L (2014). "Promoter hypermethylation of DNA repair genes MLH1 and MSH2 in adenocarcinomas and squamous cell carcinomas of the lung". Revista Portuguesa de Pneumologia. 20 (1): 20–30. doi:10.1016/j.rppneu.2013.07.003. PMID 24360395. 28. ^ a b c Lee MN, Tseng RC, Hsu HS, Chen JY, Tzao C, Ho WL, Wang YC (February 2007). "Epigenetic inactivation of the chromosomal stability control genes BRCA1, BRCA2, and XRCC5 in non-small cell lung cancer". Clinical Cancer Research. 13 (3): 832–8. doi:10.1158/1078-0432.CCR-05-2694. PMID 17289874. 29. ^ Nikolova T, Christmann M, Kaina B (July 2009). 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Serrated polyposis syndrome Other namesHyperplastic polyposis syndrome (former) SpecialtyGastroenterology SymptomsAsymptomatic ComplicationsColorectal cancer (15-30%)[1] Usual onset55 years of age (average)[2] TypesDistal and proximal CausesEnvironmental and genetic factors Risk factorsSmoking, Lymphoma[3] Diagnostic methodColonoscopy TreatmentSurveillance colonoscopy Polypectomy Surgery Frequency0.03 - 0.5%.[1] Serrated polyposis syndrome (SPS), previously known as hyperplastic polyposis syndrome, is a disorder characterized by the appearance of serrated polyps in the colon. While serrated polyposis syndrome does not cause symptoms, the condition is associated with a higher risk of colorectal cancer (CRC). The lifelong risk of CRC is between 25 and 40%. SPS is the most common polyposis syndrome affecting the colon, but is under recognized due to a lack of systemic long term monitoring.[4] Diagnosis requires colonoscopy, and is defined by the presence of either of two criteria: ≥5 serrated lesions/polyps proximal to the rectum (all ≥ 5 mm in size, with two lesions ≥10 mm), or >20 serrated lesions/polyps of any size distributed throughout the colon with 5 proximal to the rectum.[5] A family history of SPS and smoking tobacco are associated with a higher risk of serrated polyposis syndrome, whereas the use of aspirin and Nonsteroidal anti-inflammatory drug (NSAIDs) are associated with a lower risk. While there are several genetic abnormalities associated with SPS, including RNF43, BRAF, abnormal CpG island methylator phenotype, and microsatellite instability. However, most individuals with the syndrome do not have an associated germline mutation. The types of polyps found in SPS include sessile serrated adenomas/polyps, traditional serrated adenomas, and hyperplastic polyps. SPS occurs in 2 phenotypes: proximal and distal. Proximal SPS has a greater risk of CRC than distal SPS. The vast majority of cases may be managed with colonoscopy with removal polyps (polypectomy). Polyp removal is recommended to decrease the risk of colorectal cancer. Repeat colonoscopy should be performed every 1-2 years. If polyps are very large, numerous, or increase in number rapidly, then surgery may be necessary. Surgery may also be warranted if CRC is suspected or confirmed. First-degree relatives of people with SPS have an increased risk of CRC, and should undergo early screening with colonoscopy. ## Contents * 1 Signs and symptoms * 2 Pathophysiology * 3 Types * 4 Diagnosis * 5 Treatment * 6 Prognosis * 7 History * 8 Epidemiology * 9 References ## Signs and symptoms[edit] Sessile serrated adenoma seen under microscopy with H&E stain. Serrated polyposis syndrome often does not cause symptoms. The risk of colon cancer is between 25 and 40%.[6] Sessile serrated polyps, as seen during endoscopy or colonoscopy, are flat (rather than raised) and are easily overlooked. Serrated lesions range in size from small (<5 mm) to large, and often have a "mucous cap" overlying the polyp. Serrated lesions are frequently located on the folds of the colon (haustral folds). ## Pathophysiology[edit] SPS is not caused by a single gene mutation. Several genetic abnormalities are associated with the condition, and a familial or inherited pattern may occur. Key genetic abnormalities include mutations in BRAF, abnormal CpG island methylator phenotype, and microsatellite instability. Additional implicated genes include: SMAD4, BMPR1A, PTEN, GREM1, and MUTYH. The only validated genetic cause of SPS is RNF43.[7] However, most individuals with SPS do not have a germline mutation in any of the associated genes, including RNF43.[1] As the underlying genetic risks for SPS are not fully understood, genetic testing is not recommended. Both autosomal dominant and autosomal recessive patterns of inheritance have been reported,[6] as well as sporadic. Individuals with SPS have serrated polyps, which include hyperplastic polyps, traditional serrated adenomas, and sessile serrated polyps.[4] In addition to serrated polyps, adenomas are often identified. ## Types[edit] Traditional serrated adenoma seen under microscopy with H&E stain, showing serrated crypts. SPS may occur with one of two phenotypes: distal or proximal.[5] The distal phenotype may demonstrate numerous small polyps in the distal colon (sigmoid) and rectum, whereas the proximal phenotype may be characterized by relatively fewer, but larger polyps in the proximal colon (cecum, ascending colon, etc.).[5] Individuals meeting only criterion 3 from 2010 criteria, or only criterion 2 from the 2019 classification, have a distal phenotype have a lower risk of CRC compared with the proximal phenotype.[5] ## Diagnosis[edit] The diagnosis of serrated polyposis syndrome is achieved when either one of two criteria are met: ≥5 serrated lesions/polyps proximal to the rectum (all ≥ 5 mm in size, with two lesions ≥10 mm), or >20 serrated lesions/polyps of any size distributed throughout the large bowel with 5 proximal to the rectum.[5] Any serrated polyp is counted towards the diagnosis, including sessile serrated lesions, hyperplastic polyps, and traditional serrated adenomas.[1] In addition, the cumulative number of serrated lesions is cumulative over time and includes multiple colonoscopies.[1] The diagnosis of SPS is often overlooked,[8] and requires lifelong tracking of cumulative serrated polyps.[4] ## Treatment[edit] Colonoscopy is the mainstay of treatment for SPS, which allows for the identification of polyps and removal.[4] Polyp removal is recommended to prevent the development of colorectal cancer. If polyps are relatively few, then removal may be achieved with colonoscopy. After polyps are removed, repeat colonoscopy is recommended in 1 to 3 year intervals.[9][4] On average, about 2.8 colonscopies are necessary to achieve control of disease.[10] The majority of cases may be managed with colonoscopy alone.[10] Narrow-band imaging, an imaging technique used to enhance features of mucosa seen during colonoscopy, may improve detection of serrated lesions;[11] however, one multicenter trial did not show improved detection.[12] If polyps are very numerous, very large, or their growth cannot be controlled with colonoscopy, then surgery may be necessary.[13] When surgery is necessary, a total abdominal colectomy with ileorectal anastomosis should be considered to minimize the risk of colon cancer.[14] If surgery is necessary and involvement of polyps is focal or largely confined to a particular section of bowel, then segmental resection may be considered.[14] Segmental resection is also recommended for cancer.[15] In most cases, the rectum is left in place. Any remaining segments of colon or rectum require annual surveillance with colonoscopy.[15] First degree relatives of people with SPS are at a higher risk of colorectal cancer[4][16][17] and SPS.[18] As such, these individuals should undergo screening with colonoscopy[19] beginning at the earliest of the following: 40 years of age, the age of the youngest diagnosis of SPS in the family, or 10 years younger than the earliest CRC related to SPS.[4] Repeat colonoscopy should be performed at 5 year intervals.[5] ## Prognosis[edit] The average long term risk of colon cancer is between 15 and 30%.[1] However, the risk of cancer varies widely and depends on age, polyp burden, phenotype and the presence of dysplasia on histology.[1] Endoscopic surveillance can decrease the risk of progression to cancer.[1] ## History[edit] Hyperplastic polyp seen under microscopy with H&E stain. The condition was originally known as hyperplastic polyposis syndrome.[13] When the syndrome was first recognized, only hyperplastic polyps were included in its definition,[13] and the syndrome was believed to not be associated with a higher risk of colorectal cancer.[20] In 1996, a case series revealed an association of the syndrome with cancer and serrated adenomas.[21] Subsequently, other types of serrated polyps were found to occur in this condition, so the name was adjusted to the present "serrated polyposis syndrome."[13] The World Health Organization released diagnostic criteria in 2010, which were updated in 2010 and again in 2019.[5] The 2010 classification defined SPS as meeting any of the following criteria: 1) five or more serrated polyps proximal to the sigmoid colon with 2 larger than 10 mm in size, 2) any serrated polyps found proximal to the sigmoid colon in a person with a first-degree relative with serrated polyposis, or 3) more than 20 serrated colon polyps. The updated 2019 classification revised the first criterion to include lesions in the sigmoid colon, and excluded very small polyps (<5 mm).[5] The updated 2019 classification also removed the criterion that included any serrated lesions proximal to the sigmoid colon in a person with a first degree relative with SPS.[5] ## Epidemiology[edit] Data regarding overall prevalence of SPS is lacking, but it is estimated to occur in roughly 1 in 100,000.[13] SPS is equally common among men and women.[2] Most individuals with SPS are diagnosed between 40 and 60 years of age,[1] with an average age of 55 years.[2] Nearly half of individuals with SPS have a family member with colorectal cancer.[15] Most individuals (37-70%) with SPS fulfill criterion 3 of the 2010 criteria (now criteria 2 from the 2019 classification). Of the remaining individuals with SPS, roughly half meet only criterion 1 and half meet both criteria 1 and 3 (2010 classification). Among individuals undergoing colonoscopy for the evaluation of an abnormal fecal occult blood test, the prevalence of SPS ranges from 0.34 to 0.66%. The overall prevalence of SPS is 0.03 - 0.5%.[1] The prevalence of SPS is between 1 in 127 and 1 in 242 among individuals undergoing colonoscopy.[4] SPS is associated with tobacco use.[13] Aside from colorectal cancer, the risk of others cancers is not increased in people with SPS.[13] Aspirin and nonsteroidal anti-inflammatory drug (NSAIDs) may be associated with a lower risk of SPS.[6] SPS is the most common polyposis syndrome affecting the colon.[4] There is no clear association of SPS with any cancers other than colorectal cancer. However, there is mixed evidence regarding a possible association with SPS and pancreatic cancer.[16][22] Individuals with a history of lymphoma have a higher risk of developing sessile serrated polyposis syndrome.[3] ## References[edit] 1. ^ a b c d e f g h i j Crockett, SD; Nagtegaal, ID (October 2019). "Terminology, Molecular Features, Epidemiology, and Management of Serrated Colorectal Neoplasia". Gastroenterology. 157 (4): 949–966.e4. doi:10.1053/j.gastro.2019.06.041. PMID 31323292. 2. ^ a b c Guarinos, C; Sánchez-Fortún, C; Rodríguez-Soler, M; Alenda, C; Payá, A; Jover, R (28 May 2012). "Serrated polyposis syndrome: molecular, pathological and clinical aspects". World Journal of Gastroenterology. 18 (20): 2452–61. doi:10.3748/wjg.v18.i20.2452. PMC 3360443. PMID 22654442. 3. ^ a b Rigter, LS; Spaander, MCW; Aleman, BMP; Bisseling, TM; Moons, LM; Cats, A; Lugtenburg, PJ; Janus, CPM; Petersen, EJ; Roesink, JM; van der Maazen, RWM; Snaebjornsson, P; Kuipers, EJ; Bruno, MJ; Dekker, E; Meijer, GA; de Boer, JP; van Leeuwen, FE; van Leerdam, ME (15 March 2019). "High prevalence of advanced colorectal neoplasia and serrated polyposis syndrome in Hodgkin lymphoma survivors". Cancer. 125 (6): 990–999. doi:10.1002/cncr.31903. PMC 6590398. PMID 30561773. S2CID 56172996. 4. ^ a b c d e f g h i Mankaney, G; Rouphael, C; Burke, CA (April 2020). "Serrated Polyposis Syndrome". Clinical Gastroenterology and Hepatology. 18 (4): 777–779. doi:10.1016/j.cgh.2019.09.006. PMID 31520728. 5. ^ a b c d e f g h i Dekker, E; Bleijenberg, A; Balaguer, F; Dutch-Spanish-British Serrated Polyposis Syndrome, collaboration. (May 2020). "Update on the World Health Organization Criteria for Diagnosis of Serrated Polyposis Syndrome". Gastroenterology. 158 (6): 1520–1523. doi:10.1053/j.gastro.2019.11.310. PMID 31982410. 6. ^ a b c Fan, C; Younis, A; Bookhout, CE; Crockett, SD (March 2018). "Management of Serrated Polyps of the Colon". Current Treatment Options in Gastroenterology. 16 (1): 182–202. doi:10.1007/s11938-018-0176-0. PMC 6284520. PMID 29445907. 7. ^ Stanich, PP; Pearlman, R (December 2019). "Hereditary or Not? Understanding Serrated Polyposis Syndrome". Current Treatment Options in Gastroenterology. 17 (4): 692–701. doi:10.1007/s11938-019-00256-z. PMID 31673925. S2CID 207810042. 8. ^ van Herwaarden, YJ; Pape, S; Vink-Börger, E; Dura, P; Nagengast, FM; Epping, LSM; Bisseling, TM; Nagtegaal, ID (March 2019). "Reasons why the diagnosis of serrated polyposis syndrome is missed". European Journal of Gastroenterology & Hepatology. 31 (3): 340–344. doi:10.1097/MEG.0000000000001328. PMID 30520764. S2CID 54521984. 9. ^ Rex, DK; Ahnen, DJ; Baron, JA; Batts, KP; Burke, CA; Burt, RW; Goldblum, JR; Guillem, JG; Kahi, CJ; Kalady, MF; O'Brien, MJ; Odze, RD; Ogino, S; Parry, S; Snover, DC; Torlakovic, EE; Wise, PE; Young, J; Church, J (September 2012). "Serrated lesions of the colorectum: review and recommendations from an expert panel". The American Journal of Gastroenterology. 107 (9): 1315–29, quiz 1314, 1330. doi:10.1038/ajg.2012.161. PMC 3629844. PMID 22710576. 10. ^ a b Pellisé, Maria; Balaguer, Francesc (July 2019). "Serrated polyposis syndrome: time to rethink endoscopic treatment and surveillance". Gastrointestinal Endoscopy. 90 (1): 101–104. doi:10.1016/j.gie.2019.04.224. PMID 31228973. 11. ^ Murakami, T; Sakamoto, N; Nagahara, A (7 August 2018). "Endoscopic diagnosis of sessile serrated adenoma/polyp with and without dysplasia/carcinoma". World Journal of Gastroenterology. 24 (29): 3250–3259. doi:10.3748/wjg.v24.i29.3250. PMC 6079289. PMID 30090005. 12. ^ Hazewinkel, Y; Tytgat, KM; van Leerdam, ME; Koornstra, JJ; Bastiaansen, BA; van Eeden, S; Fockens, P; Dekker, E (March 2015). "Narrow-band imaging for the detection of polyps in patients with serrated polyposis syndrome: a multicenter, randomized, back-to-back trial". Gastrointestinal Endoscopy. 81 (3): 531–8. doi:10.1016/j.gie.2014.06.043. PMID 25088921. 13. ^ a b c d e f g Syngal, S; Brand, RE; Church, JM; Giardiello, FM; Hampel, HL; Burt, RW; American College of, Gastroenterology. (February 2015). "ACG clinical guideline: Genetic testing and management of hereditary gastrointestinal cancer syndromes". The American Journal of Gastroenterology. 110 (2): 223–62, quiz 263. doi:10.1038/ajg.2014.435. PMC 4695986. PMID 25645574. 14. ^ a b Ashburn, JH; Plesec, TP; Kalady, MF (December 2016). "Serrated Polyps and Serrated Polyposis Syndrome". Clinics in Colon and Rectal Surgery. 29 (4): 336–344. doi:10.1055/s-0036-1584088. PMC 6878941. PMID 31777465. 15. ^ a b c Sleisenger and Fordtran's gastrointestinal and liver disease : pathophysiology/diagnosis/management (Tenth ed.). Saunders. 2016. pp. 2246–2247. ISBN 978-1455746927. 16. ^ a b Win, AK; Walters, RJ; Buchanan, DD; Jenkins, MA; Sweet, K; Frankel, WL; de la Chapelle, A; McKeone, DM; Walsh, MD; Clendenning, M; Pearson, SA; Pavluk, E; Nagler, B; Hopper, JL; Gattas, MR; Goldblatt, J; George, J; Suthers, GK; Phillips, KD; Woodall, S; Arnold, J; Tucker, K; Field, M; Greening, S; Gallinger, S; Aronson, M; Perrier, R; Woods, MO; Green, JS; Walker, N; Rosty, C; Parry, S; Young, JP (May 2012). "Cancer risks for relatives of patients with serrated polyposis". The American Journal of Gastroenterology. 107 (5): 770–8. doi:10.1038/ajg.2012.52. PMC 3488375. PMID 22525305. 17. ^ Boparai, KS; Reitsma, JB; Lemmens, V; van Os, TA; Mathus-Vliegen, EM; Koornstra, JJ; Nagengast, FM; van Hest, LP; Keller, JJ; Dekker, E (September 2010). "Increased colorectal cancer risk in first-degree relatives of patients with hyperplastic polyposis syndrome". Gut. 59 (9): 1222–5. doi:10.1136/gut.2009.200741. PMID 20584785. S2CID 206950814. 18. ^ Oquiñena, S; Guerra, A; Pueyo, A; Eguaras, J; Montes, M; Razquin, S; Ciaurriz, A; Aznárez, R (January 2013). "Serrated polyposis: prospective study of first-degree relatives". European Journal of Gastroenterology & Hepatology. 25 (1): 28–32. doi:10.1097/MEG.0b013e3283598506. PMID 23011040. S2CID 24555717. 19. ^ Hazewinkel, Y; Koornstra, JJ; Boparai, KS; van Os, TA; Tytgat, KM; Van Eeden, S; Fockens, P; Dekker, E (2015). "Yield of screening colonoscopy in first-degree relatives of patients with serrated polyposis syndrome". Journal of Clinical Gastroenterology. 49 (5): 407–12. doi:10.1097/MCG.0000000000000103. PMID 24583756. S2CID 38054015. 20. ^ East, James E; Atkin, Wendy S; Bateman, Adrian C; Clark, Susan K; Dolwani, Sunil; Ket, Shara N; Leedham, Simon J; Phull, Perminder S; Rutter, Matt D; Shepherd, Neil A; Tomlinson, Ian; Rees, Colin J (July 2017). "British Society of Gastroenterology position statement on serrated polyps in the colon and rectum". Gut. 66 (7): 1181–1196. doi:10.1136/gutjnl-2017-314005. PMC 5530473. PMID 28450390. 21. ^ Torlakovic, E; Snover, DC (March 1996). "Serrated adenomatous polyposis in humans". Gastroenterology. 110 (3): 748–55. doi:10.1053/gast.1996.v110.pm8608884. PMID 8608884. 22. ^ Hazewinkel, Y; Reitsma, JB; Nagengast, FM; Vasen, HF; van Os, TA; van Leerdam, ME; Koornstra, JJ; Dekker, E (December 2013). "Extracolonic cancer risk in patients with serrated polyposis syndrome and their first-degree relatives". Familial Cancer. 12 (4): 669–73. doi:10.1007/s10689-013-9643-x. PMID 23591707. S2CID 17110463. * v * t * e Digestive system neoplasia GI tract Upper Esophagus * Squamous cell carcinoma * Adenocarcinoma Stomach * Gastric carcinoma * Signet ring cell carcinoma * Gastric lymphoma * MALT lymphoma * Linitis plastica Lower Small intestine * Duodenal cancer * Adenocarcinoma Appendix * Carcinoid * Pseudomyxoma peritonei Colon/rectum * Colorectal polyp: adenoma, hyperplastic, juvenile, sessile serrated adenoma, traditional serrated adenoma, Peutz–Jeghers Cronkhite–Canada * Polyposis syndromes: Juvenile * MUTYH-associated * Familial adenomatous/Gardner's * Polymerase proofreading-associated * Serrated polyposis * Neoplasm: Adenocarcinoma * Familial adenomatous polyposis * Hereditary nonpolyposis colorectal cancer Anus * Squamous cell carcinoma Upper and/or lower * Gastrointestinal stromal tumor * Krukenberg tumor (metastatic) Accessory Liver * malignant: Hepatocellular carcinoma * Fibrolamellar * Hepatoblastoma * benign: Hepatocellular adenoma * Cavernous hemangioma * hyperplasia: Focal nodular hyperplasia * Nodular regenerative hyperplasia Biliary tract * bile duct: Cholangiocarcinoma * Klatskin tumor * gallbladder: Gallbladder cancer Pancreas * exocrine pancreas: Adenocarcinoma * Pancreatic ductal carcinoma * cystic neoplasms: Serous microcystic adenoma * Intraductal papillary mucinous neoplasm * Mucinous cystic neoplasm * Solid pseudopapillary neoplasm * Pancreatoblastoma Peritoneum * Primary peritoneal carcinoma * Peritoneal mesothelioma * Desmoplastic small round cell tumor [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Serrated polyposis syndrome	c4296896	3,203	wikipedia	https://en.wikipedia.org/wiki/Serrated_polyposis_syndrome	2021-01-18T18:29:04	{"orphanet": ["157798"], "synonyms": ["Serrated polyposis"], "wikidata": ["Q55785530"]}
Skin fragility syndrome Other namesPlakophilin 1 deficiency SpecialtyDermatology Skin fragility syndrome (also known as "plakophilin 1 deficiency") is a cutaneous condition characterized by trauma-induced blisters and erosions.[1] It is associated with PKP1.[2] ## See also[edit] * List of conditions caused by problems with junctional proteins ## 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. ^ McMillan JR, Haftek M, Akiyama M, et al. (July 2003). "Alterations in desmosome size and number coincide with the loss of keratinocyte cohesion in skin with homozygous and heterozygous defects in the desmosomal protein plakophilin 1". J. Invest. Dermatol. 121 (1): 96–103. doi:10.1046/j.1523-1747.2003.12324.x. PMID 12839569. ## External links[edit] Classification D * OMIM: 604536 * MeSH: C536183 * v * t * e Cytoskeletal defects Microfilaments Myofilament Actin * Hypertrophic cardiomyopathy 11 * Dilated cardiomyopathy 1AA * DFNA20 * Nemaline myopathy 3 Myosin * Elejalde syndrome * Hypertrophic cardiomyopathy 1, 8, 10 * Usher syndrome 1B * Freeman–Sheldon syndrome * DFN A3, 4, 11, 17, 22; B2, 30, 37, 48 * May–Hegglin anomaly Troponin * Hypertrophic cardiomyopathy 7, 2 * Nemaline myopathy 4, 5 Tropomyosin * Hypertrophic cardiomyopathy 3 * Nemaline myopathy 1 Titin * Hypertrophic cardiomyopathy 9 Other * Fibrillin * Marfan syndrome * Weill–Marchesani syndrome * Filamin * FG syndrome 2 * Boomerang dysplasia * Larsen syndrome * Terminal osseous dysplasia with pigmentary defects IF 1/2 * Keratinopathy (keratosis, keratoderma, hyperkeratosis): KRT1 * Striate palmoplantar keratoderma 3 * Epidermolytic hyperkeratosis * IHCM * KRT2E (Ichthyosis bullosa of Siemens) * KRT3 (Meesmann juvenile epithelial corneal dystrophy) * KRT4 (White sponge nevus) * KRT5 (Epidermolysis bullosa simplex) * KRT8 (Familial cirrhosis) * KRT10 (Epidermolytic hyperkeratosis) * KRT12 (Meesmann juvenile epithelial corneal dystrophy) * KRT13 (White sponge nevus) * KRT14 (Epidermolysis bullosa simplex) * KRT17 (Steatocystoma multiplex) * KRT18 (Familial cirrhosis) * KRT81/KRT83/KRT86 (Monilethrix) * Naegeli–Franceschetti–Jadassohn syndrome * Reticular pigmented anomaly of the flexures 3 * Desmin: Desmin-related myofibrillar myopathy * Dilated cardiomyopathy 1I * GFAP: Alexander disease * Peripherin: Amyotrophic lateral sclerosis 4 * Neurofilament: Parkinson's disease * Charcot–Marie–Tooth disease 1F, 2E * Amyotrophic lateral sclerosis 5 * Laminopathy: LMNA * Mandibuloacral dysplasia * Dunnigan Familial partial lipodystrophy * Emery–Dreifuss muscular dystrophy 2 * Limb-girdle muscular dystrophy 1B * Charcot–Marie–Tooth disease 2B1 * LMNB * Barraquer–Simons syndrome * LEMD3 * Buschke–Ollendorff syndrome * Osteopoikilosis * LBR * Pelger–Huet anomaly * Hydrops-ectopic calcification-moth-eaten skeletal dysplasia Microtubules Kinesin * Charcot–Marie–Tooth disease 2A * Hereditary spastic paraplegia 10 Dynein * Primary ciliary dyskinesia * Short rib-polydactyly syndrome 3 * Asphyxiating thoracic dysplasia 3 Other * Tauopathy * Cavernous venous malformation Membrane * Spectrin: Spinocerebellar ataxia 5 * Hereditary spherocytosis 2, 3 * Hereditary elliptocytosis 2, 3 Ankyrin: Long QT syndrome 4 * Hereditary spherocytosis 1 Catenin * APC * Gardner's syndrome * Familial adenomatous polyposis * plakoglobin (Naxos syndrome) * GAN (Giant axonal neuropathy) Other * desmoplakin: Striate palmoplantar keratoderma 2 * Carvajal syndrome * Arrhythmogenic right ventricular dysplasia 8 * plectin: Epidermolysis bullosa simplex with muscular dystrophy * Epidermolysis bullosa simplex of Ogna * plakophilin: Skin fragility syndrome * Arrhythmogenic right ventricular dysplasia 9 * centrosome: PCNT (Microcephalic osteodysplastic primordial dwarfism type II) Related topics: Cytoskeletal proteins This dermatology article is a stub. You can help Wikipedia by expanding it. * v * t * e [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Skin fragility syndrome	c1858302	3,204	wikipedia	https://en.wikipedia.org/wiki/Skin_fragility_syndrome	2021-01-18T19:08:20	{"gard": ["9705"], "mesh": ["C536183"], "umls": ["C1858302"], "orphanet": ["158668"], "wikidata": ["Q7535394"]}
AL amyloidosis Other namesPrimary systemic amyloidosis (PSA), primary amyloidosis SpecialtyHematology Amyloid light-chain (AL) amyloidosis, also known as primary amyloidosis, is the most common form of systemic amyloidosis in the US.[1] The disease is caused when a person's antibody-producing cells do not function properly and produce abnormal protein fibers made of components of antibodies called light chains. These light chains come together to form amyloid deposits which can cause serious damage to different organs.[2][3] Abnormal light chains in urine are sometimes referred to as "Bence Jones protein". ## Contents * 1 Signs and symptoms * 2 Causes * 3 Diagnosis * 4 Treatment * 5 Prognosis * 6 Epidemiology * 7 See also * 8 References * 9 External links ## Signs and symptoms[edit] AL amyloidosis can affect a wide range of organs, and consequently present with a range of symptoms. The kidneys are the most commonly affected organ in AL amyloidosis. Symptoms of kidney disease and kidney failure can include fluid retention, swelling, and shortness of breath.[4] In addition to kidneys, AL amyloidosis may affect the heart, peripheral nervous system, gastrointestinal tract, blood, lungs and skin. Heart complications, which affect more than a third of AL patients, include heart failure and irregular heart beat. Other symptoms can include stroke, gastrointestinal disorders, enlarged liver, diminished spleen function, diminished function of the adrenal and other endocrine glands, skin color change or growths, lung problems, bleeding and bruising problems, fatigue, and weight loss.[4][5] ## Causes[edit] AL amyloidosis can occur spontaneously. It is, however, often associated with other blood disorders, such as multiple myeloma and Waldenström's macroglobulinemia.[4] About 10% to 15% of patients with multiple myeloma may develop overt AL amyloidosis.[6] ## Diagnosis[edit] Both blood and the urine can be tested for the light chains, which may form amyloid deposits, causing disease. However, the diagnosis requires a sample of an affected organ.[4][7] ## Treatment[edit] The most effective treatment is autologous bone marrow transplants with stem cell rescues. However many patients are too weak to tolerate this approach.[8][9] Other treatments can involve application of chemotherapy similar to that used in multiple myeloma.[9] A combination of melphalan and dexamethasone has been found effective in those who are ineligible for stem cell transplantation,[8] and a combination of bortezomib and dexamethasone is now in widespread clinical use.[10][11] ## Prognosis[edit] Median survival for patients diagnosed with AL amyloidosis was 13 months in the early 1990s, but had improved to c. 40 months a decade later.[12] ## Epidemiology[edit] AL amyloidosis is a rare disease; only 1200 to 3200 new cases are reported each year in the United States. Two thirds of patients with AL amyloidosis are male and less than 5% of patients are under 40 years of age.[4][13] ## See also[edit] * Light chain deposition disease ## References[edit] 1. ^ Gertz MA (June 2004). "The classification and typing of amyloid deposits". Am. J. Clin. Pathol. 121 (6): 787–9. doi:10.1309/TR4L-GLVR-JKAM-V5QT. PMID 15198347. Archived from the original on 2016-05-30. 2. ^ "Amyloidosis Causes, Diagnosis, Symptoms, and Treatment on MedicineNet.com". 3. ^ "Amyloidosis and Kidney Disease". National Institute of Diabetes and Digestive and Kidney Diseases. Retrieved 23 November 2011. 4. ^ a b c d e UNC. "AL Amyloidosis". UNC. Archived from the original on 22 December 2011. Retrieved 22 November 2011. 5. ^ "Amyloidosis". University of Maryland Medical Center. Retrieved 23 November 2011. 6. ^ Madin, Sumit; Dispenzieri, Angela (2010). "Clinical Features and Treatment Response of Light Chain (AL) Amyloidosis Diagnosed in Patients With Previous Diagnosis of Multiple Myeloma" (PDF). Mayo Clinic Proceedings. 83 (3): 232–238. doi:10.4065/mcp.2009.0547. PMC 2843113. PMID 20194151. Retrieved 22 November 2011.[permanent dead link] 7. ^ Sanchorawala, Vaishali (2006). "Light-Chain (AL) Amyloidosis: Diagnosis and Treatment". Clinical Journal of the American Society of Nephrology. 1 (6): 1334–1341. doi:10.2215/cjn.02740806. PMID 17699366. Retrieved 1 December 2011. 8. ^ a b Palladini G, Perfetti V, Obici L, et al. (April 2004). "Association of melphalan and high-dose dexamethasone is effective and well tolerated in patients with AL (primary) amyloidosis who are ineligible for stem cell transplantation". Blood. 103 (8): 2936–8. doi:10.1182/blood-2003-08-2788. PMID 15070667. 9. ^ a b "BU: Amyloid Treatment & Research Program". Archived from the original on 2008-07-20. 10. ^ Chakra P. Chaulagain, MD; Raymond L. Comenzo, MD (May 2015). "How We Treat Systemic Light-Chain Amyloidosis". Clinical Advances in Hematology & Oncology. 13 (5): 315–24. PMID 26352777. 11. ^ Kastritis E, Anagnostopoulos A, Roussou M, et al. (October 2007). "Treatment of light chain (AL) amyloidosis with the combination of bortezomib and dexamethasone". Haematologica. 92 (10): 1351–8. doi:10.3324/haematol.11325. PMID 18024372. 12. ^ Ashutosh D. Wechalekar (2007). "Perspectives in treatment of AL amyloidosis". British Journal of Haematology. 140 (4): 365–377. doi:10.1111/j.1365-2141.2007.06936.x. PMID 18162121. 13. ^ "Primary AL". Amyloidosis Foundation. Archived from the original on 3 October 2011. Retrieved 23 November 2011. ## External links[edit] Classification D * ICD-10: E85 * ICD-9-CM: 277.3 * OMIM: 254500 * MeSH: C531616 * DiseasesDB: 315 External resources * MedlinePlus: 000533 * eMedicine: med/3363 * v * t * e Amyloidosis Common amyloid forming proteins * AA * ATTR * Aβ2M * AL * Aβ/APP * AIAPP * ACal * APro * AANF * ACys * ABri Systemic amyloidosis * AL amyloidosis * AA amyloidosis * Aβ2M/Haemodialysis-associated * AGel/Finnish type * AA/Familial Mediterranean fever * ATTR/Transthyretin-related hereditary Organ-limited amyloidosis Heart AANF/Isolated atrial Brain * Familial amyloid neuropathy * ACys+ABri/Cerebral amyloid angiopathy * Aβ/Alzheimer's disease Kidney * AApoA1+AFib+ALys/Familial renal Skin * Primary cutaneous amyloidosis * Amyloid purpura Endocrine Thyroid ACal/Medullary thyroid cancer Pituitary APro/Prolactinoma Pancreas AIAPP/Insulinoma AIAPP/Diabetes mellitus type 2 * v * t * e Immunoproliferative immunoglobulin disorders PCDs/PP * Plasmacytoma * Multiple myeloma (Plasma cell leukemia) * MGUS * IgM (Macroglobulinemia/Waldenström's macroglobulinemia) * heavy chain (Heavy chain disease) * light chain (Primary amyloidosis) Other hypergammaglobulinemia * Cryoglobulinemia [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	AL amyloidosis	c0268381	3,205	wikipedia	https://en.wikipedia.org/wiki/AL_amyloidosis	2021-01-18T18:45:52	{"gard": ["5797"], "mesh": ["D000075363", "C531616"], "umls": ["C0268381"], "icd-9": ["277.3"], "icd-10": ["E85"], "orphanet": ["85443"], "wikidata": ["Q4652470"]}
For the gene HSN2, see HSN2. Not to be confused with Hereditary motor and sensory neuropathy. This article has multiple issues. Please help improve it or discuss these issues on the talk page. (Learn how and when to remove these template messages) This article 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. (June 2009) (Learn how and when to remove this template message) This article needs editing for compliance with Wikipedia's Manual of Style. In particular, it has problems with not using MEDMOS. Please help improve it if you can. (July 2017) (Learn how and when to remove this template message) (Learn how and when to remove this template message) Hereditary sensory and autonomic neuropathy SpecialtyNeurology Hereditary sensory and autonomic neuropathy (HSAN) or hereditary sensory neuropathy (HSN) is a condition used to describe any of the types of this disease[1] which inhibit sensation. They are less common than Charcot-Marie-Tooth disease.[2] ## Contents * 1 Classification * 1.1 Type 1 * 1.2 Type 2, Congenital sensory neuropathy * 1.3 Type 3, Familial dysautonomia * 1.4 Type 4, Congenital insensitivity to pain with anhidrosis * 1.5 Type 5, Congenital insensitivity to pain with partial anhidrosis * 2 Genetics * 2.1 Associated genes * 3 Diagnosis * 4 Treatment * 5 References * 6 Further reading * 7 External links ## Classification[edit] Five different clinical entities have been described under hereditary sensory and autonomic neuropathies – all characterized by progressive loss of function that predominantly affects the peripheral sensory nerves. Their incidence has been estimated to be about 1 in 25,000. ### Type 1[edit] Main article: Hereditary sensory and autonomic neuropathy type I Hereditary sensory neuropathy type 1 is a condition characterized by nerve abnormalities in the legs and feet (peripheral neuropathy). Many people with this condition have tingling, weakness, and a reduced ability to feel pain and sense hot and cold. Some affected individuals do not lose sensation, but instead feel shooting pains in their legs and feet. As the disorder progresses, the sensory abnormalities can affect the hands, arms, shoulders, and abdomen. Affected individuals may also experience muscle wasting and weakness as they get older, but this varies widely within families. Affected individuals typically get open sores (ulcers) on their feet or hands or infections of the soft tissue of the fingertips (whitlows) that are slow to heal. Because affected individuals cannot feel the pain of these sores, they may not seek treatment right away. Without treatment, the ulcers can become infected and may require amputation of the surrounding area. Albeit rarely, people with hereditary sensory neuropathy type 1 may develop hearing loss caused by abnormalities of the inner ear (sensorineural hearing loss). The signs and symptoms of hereditary sensory neuropathy type 1 typically appear during a person's teens or twenties. While the features of this disorder tend to worsen over time, affected individuals have a normal life expectancy if signs and symptoms are properly treated. Type 1 is the most common form among the 5 types of HSAN. Its historical names include mal perforant du pied, ulcero-mutilating neuropathy, hereditary perforating ulcers, familial trophoneurosis, familial syringomyelia, hereditary sensory radicular neuropathy, among others.[3] This type includes a popular disease Charcot-Marie-Tooth type 2B syndrome (HMSN 2B).[3] that is also named as HSAN sub-type 1C. Type 1 is inherited as an autosomal dominant trait. The disease usually starts during early adolescence or adulthood. The disease is characterized by the loss of pain sensation mainly in the distal parts of the lower limbs; that is, in the parts of the legs farther away from the center of the body. Since the affected individuals cannot feel pain, minor injuries in this area may not be immediately recognized and may develop into extensive ulcerations. Once infection occurs, further complications such as progressive destruction of underlying bones may follow and may necessitate amputation. In rare cases, the disease is accompanied with nerve deafness and muscle wasting. Autonomic disturbance, if present, appears as anhidrosis, a sweating abnormality. Examinations of the nerve structure and function showed signs of neuronal degeneration such as a marked reduction in the number of myelinated fibers and axonal loss. Sensory neurons lose the ability to transmit signals, while motor neurons has reduced ability to transmit signals.[3] Genes related to Hereditary sensory and autonomic neuropathy Type 1: Mutations in the SPTLC1 gene cause hereditary sensory neuropathy type 1. The SPTLC1 gene provides instructions for making one part (subunit) of an enzyme called serine palmitoyltransferase (SPT). The SPT enzyme is involved in making certain fats called sphingolipids. Sphingolipids are important components of cell membranes and play a role in many cell functions. SPTLC1 gene mutations reduce the amount of SPTLC1 subunit that is produced and result in an SPT enzyme with decreased function. A lack of functional SPT enzyme leads to a decrease in sphingolipid production and a harmful buildup of certain byproducts. Sphingolipids are found in myelin, which is the covering that protects nerves and promotes the efficient transmission of nerve impulses. A decrease in sphingolipids disrupts the formation of myelin, causing nerve cells to become less efficient and eventually die. When sphingolipids are not made, an accumulation of toxic byproducts can also lead to nerve cell death. This gradual destruction of nerve cells results in loss of sensation and muscle weakness in people with hereditary sensory neuropathy type 1. ### Type 2, Congenital sensory neuropathy[edit] Hereditary sensory and autonomic neuropathy type II (HSAN2) is a condition that primarily affects the sensory nerve cells (sensory neurons) which transmit information about sensations such as pain, temperature, and touch. These sensations are impaired in people with HSAN2. In some affected people, the condition may also cause mild abnormalities of the autonomic nervous system, which controls involuntary body functions such as heart rate, digestion, and breathing. The signs and symptoms of HSAN2 typically begin in infancy or early childhood. The first sign of HSAN2 is usually numbness in the hands and feet. Soon after, affected individuals lose the ability to feel pain or sense hot and cold. People with HSAN2 often develop open sores (ulcers) on their hands and feet. Because affected individuals cannot feel the pain of these sores, they may not seek treatment right away. Without treatment, the ulcers can become infected and may lead to amputation of the affected area. Unintentional self-injury is common in people with HSAN2, typically by biting the tongue, lips, or fingers. These injuries may lead to spontaneous amputation of the affected areas. Affected individuals often have injuries and fractures in their hands, feet, limbs, and joints that go untreated because of the inability to feel pain. Repeated injury can lead to a condition called Charcot joints, in which the bones and tissue surrounding joints are destroyed. The effects of HSAN2 on the autonomic nervous system are more variable. Some infants with HSAN2 have trouble sucking, which makes it difficult for them to eat. People with HSAN2 may experience episodes in which breathing slows or stops for short periods (apnea); digestive problems such as the backflow of stomach acids into the esophagus (gastroesophageal reflux); or slow eye blink or gag reflexes. Affected individuals may also have weak deep tendon reflexes, such as the reflex being tested when a doctor taps the knee with a hammer. Some people with HSAN2 experience a diminished sense of taste due to the loss of a type of taste bud on the tip of the tongue called lingual fungiform papillae. Type 2, congenital sensory neuropathy (also historically known as Morvan's disease[4]), is characterized by onset of symptoms in early infancy or childhood. Upper & lower extremities are affected with chronic ulcerations and multiple injuries to fingers and feet. Pain sensation is affected predominantly and deep tendon reflexes are reduced. Autoamputation of the distal phalanges is common and so is neuropathic joint degeneration. The NCV shows reduced or absent sensory nerve action potentials and nerve biopsy shows total loss of myelinated fibers and reduced numbers of unmyelinated fibers. It is inherited as an autosomal recessive condition. Genes related to Hereditary sensory and autonomic neuropathy Type 2: There are two types of HSAN2, called HSAN2A and HSAN2B, each caused by mutations in a different gene. HSAN2A is caused by mutations in the WNK1 gene, and HSAN2B is caused by mutations in the FAM134B gene. Although two different genes are involved, the signs and symptoms of HSAN2A and HSAN2B are the same. The WNK1 gene provides instructions for making multiple versions (isoforms) of the WNK1 protein. HSAN2A is caused by mutations that affect a particular isoform called the WNK1/HSN2 protein. This protein is found in the cells of the nervous system, including nerve cells that transmit the sensations of pain, temperature, and touch (sensory neurons). The mutations involved in HSAN2A result in an abnormally short WNK1/HSN2 protein. Although the function of this protein is unknown, it is likely that the abnormally short version cannot function properly. People with HSAN2A have a reduction in the number of sensory neurons; however, the role that WNK1/HSN2 mutations play in that loss is unclear. HSAN2B is caused by mutations in the FAM134B gene. These mutations may lead to an abnormally short and nonfunctional protein. The FAM134B protein is found in sensory and autonomic neurons. It is involved in the survival of neurons, particularly those that transmit pain signals, which are called nociceptive neurons. When the FAM134B protein is nonfunctional, neurons die by a process of self-destruction called apoptosis. The loss of neurons leads to the inability to feel pain, temperature, and touch sensations and to the impairment of the autonomic nervous system seen in people with HSAN2. ### Type 3, Familial dysautonomia[edit] Main article: Familial dysautonomia Familial dysautonomia is a genetic disorder that affects the development and survival of certain nerve cells. The disorder disturbs cells in the autonomic nervous system, which controls involuntary actions such as digestion, breathing, production of tears, and the regulation of blood pressure and body temperature. It also affects the sensory nervous system, which controls activities related to the senses, such as taste and the perception of pain, heat, and cold. Familial dysautonomia is also called hereditary sensory and autonomic neuropathy, type III. Problems related to this disorder first appear during infancy. Early signs and symptoms include poor muscle tone (hypotonia), feeding difficulties, poor growth, lack of tears, frequent lung infections, and difficulty maintaining body temperature. Older infants and young children with familial dysautonomia may hold their breath for prolonged periods of time, which may cause a bluish appearance of the skin or lips (cyanosis) or fainting. This breath-holding behavior usually stops by age 6. Developmental milestones, such as walking and speech, are usually delayed, although some affected individuals show no signs of developmental delay. Additional signs and symptoms in school-age children include bed wetting, episodes of vomiting, reduced sensitivity to temperature changes and pain, poor balance, abnormal curvature of the spine (scoliosis), poor bone quality and increased risk of bone fractures, and kidney and heart problems. Affected individuals also have poor regulation of blood pressure. They may experience a sharp drop in blood pressure upon standing (orthostatic hypotension), which can cause dizziness, blurred vision, or fainting. They can also have episodes of high blood pressure when nervous or excited, or during vomiting incidents. About one-third of children with familial dysautonomia have learning disabilities, such as a short attention span, that require special education classes. By adulthood, affected individuals often have increasing difficulties with balance and walking unaided. Other problems that may appear in adolescence or early adulthood include lung damage due to repeated infections, impaired kidney function, and worsening vision due to the shrinking size (atrophy) of optic nerves, which carry information from the eyes to the brain. Type 3, familial dysautonomia (FD) or Riley-Day syndrome, is an autosomal recessive disorder seen predominantly in Jews of eastern European descent. Patients present with sensory and autonomic disturbances. Newborns have absent or weak suck reflex, hypotonia and hypothermia. Delayed physical development, poor temperature and motor incoordination are seen in early childhood. Other features include reduced or absent tears, depressed deep tendon reflexes, absent corneal reflex, postural hypotension and relative indifference to pain. Scoliosis is frequent. Intelligence remains normal. Many patients die in infancy and childhood. Lack of flare with intradermal histamine is seen. Histopathology of peripheral nerve shows reduced number of myelinated and non-myelinated axons. The catecholamine endings are absent. Genes related to Hereditary sensory and autonomic neuropathy Type 3: Mutations in the IKBKAP gene cause familial dysautonomia. The IKBKAP gene provides instructions for making a protein called IKK complex-associated protein (IKAP). This protein is found in a variety of cells throughout the body, including brain cells. Nearly all individuals with familial dysautonomia have two copies of the same IKBKAP gene mutation in each cell. This mutation can disrupt how information in the IKBKAP gene is pieced together to make a blueprint for the production of IKAP protein. As a result of this error, a reduced amount of normal IKAP protein is produced. This mutation behaves inconsistently, however. Some cells produce near normal amounts of the protein, and other cells—particularly brain cells—have very little of the protein. Critical activities in brain cells are probably disrupted by reduced amounts or the absence of IKAP protein, leading to the signs and symptoms of familial dysautonomia. ### Type 4, Congenital insensitivity to pain with anhidrosis[edit] Main article: Congenital insensitivity to pain with anhidrosis Congenital insensitivity to pain with anhidrosis (CIPA), also known as hereditary sensory and autonomic neuropathy type IV (HSAN IV), is characterized by insensitivity to pain, anhidrosis (the inability to sweat), and intellectual disability. The ability to sense all pain (including visceral pain) is absent, resulting in repeated injuries including: oral self-mutilation (biting of tongue, lips, and buccal mucosa); biting of fingertips; bruising, scarring, and infection of the skin; multiple bone fractures (many of which fail to heal properly); and recurrent joint dislocations resulting in joint deformity. Sense of touch, vibration, and position are normal. Anhidrosis predisposes to recurrent febrile episodes that are often the initial manifestation of CIPA. Hypothermia in cold environments also occurs. Intellectual disability of varying degree is observed in most affected individuals; hyperactivity and emotional lability are common. Hereditary sensory neuropathy type IV (HSN4) is a rare genetic disorder characterized by the loss of sensation (sensory loss), especially in the feet and legs and, less severely, in the hands and forearms. The sensory loss is due to abnormal functioning of small, unmyelinated nerve fibers and portions of the spinal cord that control responses to pain and temperature as well as other involuntary or automatic body processes. Sweating is almost completely absent with this disorder. Intellectual disability is usually present. Type 4, congenital insensitivity to pain with anhidrosis (CIPA), is an autosomal recessive condition and affected infants present with episodes of hyperthermia unrelated to environmental temperature, anhidrosis and insensitivity to pain. Palmar skin is thickened and charcot joints are commonly present. NCV shows motor and sensory nerve action potentials to be normal. The histopathology of peripheral nerve biopsy reveals absent small unmyelinated fibers and mitochondria are abnormally enlarged. Management of Hereditary sensory and autonomic neuropathy Type 4: Treatment of manifestations: Treatment is supportive and is best provided by specialists in pediatrics, orthopedics, dentistry, ophthalmology, and dermatology. For anhidrosis: Monitoring body temperature helps to institute timely measures to prevent/manage hyperthermia or hypothermia. For insensitivity to pain: Modify as much as reasonable a child's activities to prevent injuries. Inability to provide proper immobilization as a treatment for orthopedic injuries often delays healing; additionally, bracing and invasive orthopedic procedures increase the risk for infection. Methods used to prevent injuries to the lips, buccal mucosa, tongue, and teeth include tooth extraction, and/or filing (smoothing) of the sharp incisal edges of teeth, and/or use of a mouth guard. Skin care with moisturizers can help prevent palmar and plantar hyperkeratosis and cracking and secondary risk of infection; neurotrophic keratitis is best treated with routine care for dry eyes, prevention of corneal infection, and daily observation of the ocular surface. Interventions for behavioral, developmental and motor delays, as well as educational and social support for school-age children and adolescents, are recommended. Prevention of secondary complications: Regular dental examinations and restriction of sweets to prevent dental caries; early treatment of dental caries and periodontal disease to prevent osteomyelitis of the mandible. During and following surgical procedures, potential complications to identify and manage promptly include hyper- or hypothermia and inadequate sedation, which may trigger unexpected movement and result in secondary injuries. ### Type 5, Congenital insensitivity to pain with partial anhidrosis[edit] Hereditary sensory and autonomic neuropathy type V (HSAN5) is a condition that primarily affects the sensory nerve cells (sensory neurons), which transmit information about sensations such as pain, temperature, and touch. These sensations are impaired in people with HSAN5. The signs and symptoms of HSAN5 appear early, usually at birth or during infancy. People with HSAN5 lose the ability to feel pain, heat, and cold. Deep pain perception, the feeling of pain from injuries to bones, ligaments, or muscles, is especially affected in people with HSAN5. Because of the inability to feel deep pain, affected individuals suffer repeated severe injuries such as bone fractures and joint injuries that go unnoticed. Repeated trauma can lead to a condition called Charcot joints, in which the bones and tissue surrounding joints are destroyed. Type 5, congenital insensitivity to pain with partial anhidrosis,[4] also manifests with congenital insensitivity to pain & anhidrosis. There is a selective absence of small myelinated fibers differentiating it from Type IV (CIPA). Genes related to Hereditary sensory and autonomic neuropathy Type 5: Mutations in the NGF gene cause HSAN5. The NGF gene provides instructions for making a protein called nerve growth factor beta (NGFβ) that is important in the development and survival of nerve cells (neurons), including sensory neurons. The NGFβ protein functions by attaching (binding) to its receptors, which are found on the surface of neurons. Binding of the NGFβ protein to its receptor transmits signals to the cell to grow and to mature and take on specialized functions (differentiate). This binding also blocks signals in the cell that initiate the process of self-destruction (apoptosis). Additionally, NGFβ signaling plays a role in pain sensation. Mutation of the NGF gene leads to the production of a protein that cannot bind to the receptor and does not transmit signals properly. Without the proper signaling, sensory neurons die and pain sensation is altered, resulting in the inability of people with HSAN5 to feel pain. ## Genetics[edit] ### Associated genes[edit] Type Sub-type Gene Locus HSAN 1 1A SPTLC1[5] 9q22.1-q22.3 1B unknown (OMIM 608088)[3] 3p24–p22 1C (= CMT2B, HMSN IIB) RAB7A[3] 3q21 1D unknown[3] unknown 1E DNMT1 (OMIM 614116)[6] 19p13.2 HSAN 2 HSN2[7] 12p13.33 HSAN 3 (Familial dysautonomia) IKBKAP 9q31 HSAN 4 (CIPA) NTRK1 1q21-q22 HSAN5 NGFβ[8][9] 1p13.1 NTRK1[10] ## Diagnosis[edit] This section is empty. You can help by adding to it. (December 2017) ## Treatment[edit] This section is empty. You can help by adding to it. (December 2017) ## References[edit] 1. ^ "eMedicine - Autonomic Neuropathy : Article by Cory Toth". 2019-07-03. Cite journal requires `\|journal=` (help) 2. ^ Houlden H, Blake J, Reilly MM (October 2004). "Hereditary sensory neuropathies". Curr. Opin. Neurol. 17 (5): 569–77. doi:10.1097/00019052-200410000-00007. PMID 15367861. S2CID 28906295. 3. ^ a b c d e f Michaela Auer-Grumbach (March 2008). "Hereditary sensory neuropathy type I". Orphanet Journal of Rare Diseases. 3 (7): 7. doi:10.1186/1750-1172-3-7. PMC 2311280. PMID 18348718. 4. ^ a b Felicia B Axelrod; Gabrielle Gold-von Simson (October 3, 2007). "Hereditary sensory and autonomic neuropathies: types II, III, and IV". Orphanet Journal of Rare Diseases. 2 (39): 39. doi:10.1186/1750-1172-2-39. PMC 2098750. PMID 17915006. 5. ^ Houlden H, King R, Blake J, et al. (February 2006). "Clinical, pathological and genetic characterization of hereditary sensory and autonomic neuropathy type 1 (HSAN I)". Brain. 129 (Pt 2): 411–25. doi:10.1093/brain/awh712. PMID 16364956. 6. ^ Klein, C. J., Botuyan, M. V., Wu, Y.; et al. (Jun 2011). "Mutations in DNMT1 cause hereditary sensory neuropathy with dementia and hearing loss". Nature Genetics. 43 (6): 595–600. doi:10.1038/ng.830. PMC 3102765. PMID 21532572.CS1 maint: multiple names: authors list (link) 7. ^ Lafreniere RG, MacDonald ML, Dube MP, et al. (May 2004). "Identification of a novel gene (HSN2) causing hereditary sensory and autonomic neuropathy type II through the Study of Canadian Genetic Isolates". Am. J. Hum. Genet. 74 (5): 1064–73. doi:10.1086/420795. PMC 1181970. PMID 15060842. 8. ^ Einarsdottir E, Carlsson A, Minde J, et al. (February 19, 2004). "A mutation in the nerve growth factor beta gene (NGFB) causes loss of pain perception". Hum. Mol. Genet. 13 (8): 799–805. doi:10.1093/hmg/ddh096. PMID 14976160. 9. ^ Minde J, Toolanen G, Andersson T, et al. (December 2004). "Familial insensitivity to pain (HSAN V) and a mutation in the NGFB gene. A neurophysiological and pathological study". Muscle Nerve. 30 (6): 752–760. doi:10.1002/mus.20172. PMID 15468048. S2CID 23764234. 10. ^ Henry Houlden; R. H. M. King; A. Hashemi-Nejad; et al. (April 2001). "A novel TRK A (NTRK1) mutation associated with hereditary sensory and autonomic neuropathy type V". Annals of Neurology. 49 (4): 521–525. doi:10.1002/ana.103. PMID 11310631. S2CID 7888893. ## Further reading[edit] * GeneReviews/NIH/NCBI/UW entry on Hereditary Sensory and Autonomic Neuropathy IV * GeneReviews/NIH/NCBI/UW entry on Hereditary Sensory Neuropathy Type I * GeneReviews/NIH/NCBI/UW entry on Hereditary Sensory and Autonomic Neuropathy Type II ## External links[edit] Classification D * ICD-9-CM: 356.2 * OMIM: 162400 201300 223900 256800 608654 * MeSH: D009477 * DiseasesDB: 32501 * v * t * e Diseases of the autonomic nervous system General * Dysautonomia * Autonomic dysreflexia * Autonomic neuropathy * Pure autonomic failure Hereditary * Hereditary sensory and autonomic neuropathy * Familial dysautonomia * Congenital insensitivity to pain with anhidrosis Orthostatic intolerance * Orthostatic hypotension * Postural orthostatic tachycardia syndrome Other * Horner's syndrome * Multiple system atrophy [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Hereditary sensory and autonomic neuropathy	c0027889	3,206	wikipedia	https://en.wikipedia.org/wiki/Hereditary_sensory_and_autonomic_neuropathy	2021-01-18T19:09:49	{"gard": ["12267", "12688"], "mesh": ["D009477"], "icd-9": ["356.2"], "orphanet": ["140471"], "wikidata": ["Q3702898"]}
A number sign (#) is used with this entry because of evidence that auriculocondylar syndrome-3 (ARCND3) is caused by homozygous mutation in the EDN1 gene (131240) on chromosome 6p24. Heterozygous mutation in EDN1 causes isolated question mark ears (612798). Description Auriculocondylar syndrome (ARCND) is a rare craniofacial disorder involving first and second pharyngeal arch derivatives and includes the key features of micrognathia, temporomandibular joint and condyle anomalies, microstomia, prominent cheeks, and question mark ears (QMEs). QMEs consist of a defect between the lobe and the upper two-thirds of the pinna, ranging from a mild indentation in the helix to a complete cleft between the lobe and helix (summary by Gordon et al., 2013). For a general phenotypic description and discussion of genetic heterogeneity of auriculocondylar syndrome, see ARCND1 (602483). Clinical Features Guion-Almeida et al. (2002) described a 9-year-old boy with auriculocondylar syndrome whose parents were consanguineous. He had characteristic ears, unique bilateral appendages emerging from the anterior tonsillar pillars almost into the tip of the normal uvula, and a hypoplastic mandibular condyle on x-ray films. He also had mild ptosis and mild developmental delay, which the authors noted was also present in the patient described by Priolo et al. (2000). Gordon et al. (2013) studied a brother and sister ('case 10'), born to healthy first-cousin parents, who had auriculocondylar syndrome. The brother presented with bifid uvula, laryngeal cleft, short velum, retrognathia, a typical QME on the right, a severely dysmorphic left ear, and an aneurysm of the vein of Galen, while his sister displayed a left QME, over-folded helix on the right, glossoptosis, and mandibular hypoplasia requiring distraction. Gordon et al. (2013) restudied the consanguineous family originally reported by Gordon et al. (2013) and stated that the pedigree included 4 sibs, 3 affected and 1 unaffected. CT scan of the previously reported sister revealed hypoplasia of the mandibular ramus and a thickened zygomatic process of the right temporal bone. The previously unreported sister presented with micrognathia, QMEs, microstomia, full cheeks, several hamartomatous pedicles on the ventral surface of the tongue, bilateral paramedian submucosal cleft of the velum, and bifid uvula with adjacent ectopic tissue. Molecular Genetics In 2 affected sibs from a consanguineous family with auriculocondylar syndrome that was previously studied by Gordon et al. (2013) and found to be negative for mutation in the coding regions of the GNAI3 (139370), PLCB4 (600810), GNAQ (600998), and GNA11 (139313) genes and the catalytic domain exons of the PLCB3 gene (600230), Gordon et al. (2013) performed whole-exome sequencing and identified homozygosity for a missense mutation in the EDN1 gene (K91E; 131240.0002). The mutation was present in heterozygosity in the unaffected parents and an unaffected sib. Sanger sequencing of EDN1 in a 23-year-old man with auriculocondylar syndrome who was originally described by Guion-Almeida et al. (2002) (patient 2) revealed homozygosity for a missense mutation (P77H; 131240.0003); his unaffected mother was heterozygous for the mutation. INHERITANCE \- Autosomal recessive HEAD & NECK Face \- Full cheeks \- Micrognathia \- Retrognathia Ears \- Question mark ears \- Bilateral conductive hearing loss (rare) \- Narrow auditory canals (rare) Mouth \- Bifid uvula \- Ectopic uvula \- Lingual hamartomas \- Lingual appendages \- Glossoptosis \- Submucosal velar cleft CARDIOVASCULAR Vascular \- Dilation of vein of Galen (rare) RESPIRATORY Larynx \- Laryngeal cleft SKELETAL Skull \- Mandibular hypoplasia \- Thickened zygomatic process of right temporal bone (rare) MOLECULAR BASIS \- Caused by mutation in the endothelin-1 gene (EDN1, 131240.0002 ) ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	AURICULOCONDYLAR SYNDROME 3	c1865295	3,207	omim	https://www.omim.org/entry/615706	2019-09-22T15:51:13	{"mesh": ["C538270"], "omim": ["615706"], "orphanet": ["137888"]}
A number sign (#) is used with this entry because of evidence that susceptibility to age-related macular degeneration-15 (ARMD15) is conferred by variation in the C9 gene (120940) on chromosome 5p13. For a phenotypic description and discussion of genetic heterogeneity of ARMD, see 603075. Molecular Genetics Seddon et al. (2013) sequenced the exons of 681 genes within all reported age-related macular degeneration loci and related pathways in 2,493 cases and controls. They identified a pro167-to-ser mutation in C9 (120940.0006), rs34882957, which, when genotyped in 5,115 independent samples and joined with the initial evaluation, showed a p value of 6.5 x 10(-7) and an odds ratio of 2.2. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	MACULAR DEGENERATION, AGE-RELATED, 15	c3810042	3,208	omim	https://www.omim.org/entry/615591	2019-09-22T15:51:33	{"omim": ["615591"]}
Human disease Tuber cinereum hamartoma Other namesHypothalamic hamartoma A hypothalamic hamartoma (black arrows) on MRI Tuber cinereum hamartoma is a benign tumor in which a disorganized collection of neurons and glia accumulate at the tuber cinereum of the hypothalamus on the floor of the third ventricle. It is a congenital malformation, included on the spectrum of gray matter heterotopias. Formation occurs during embryogenesis, typically between days 33 and 41 of gestation. Size of the tumor varies from one to three centimeters in diameter, with the mean being closer to the low end of this range. It is estimated to occur at a frequency of one in one million individuals.[1] ## Contents * 1 Signs and symptoms * 1.1 Associated conditions * 2 Diagnosis * 2.1 Anatomic and imaging findings * 3 Treatment * 4 In popular culture * 5 References * 6 External links ## Signs and symptoms[edit] Electroencephalography is used to find the source of electrical activity causing the gelastic seizure. The classic presentation is gelastic or laughing epilepsy, a disorder characterized by spells of involuntary laughter with interval irritability and depressed mood. The tumor can be associated with other seizure types as well as precocious puberty and behavioral disorders. Gelastic epilepsy has been more classically associated with sessile lesions and precocious puberty reported with pedunculated morphology. More recent epidemiologic studies have found these associations to be less consistent, with gelastic epilepsy predominant in the majority of patients regardless of morphology.[citation needed] Hypothalamic hamartomas are found in 33% of patients with true precocious puberty.[2] The etiology of this relationship is unclear, but it is suspected in some cases to be due to a nonphysiological secretion of GnRH.[3][4] A case of hamartoma has also been reported to secrete CRH, causing excessive ACTH production.[5] Seizures often begin when patients are young, although studies have shown adult onset as well. Many causes of the epilepsy have been theorized, with EEG often finding the hamartoma itself as the source of electrical activity, or epileptogenic focus. With chronic seizures, cognitive decline can develop, which can manifest as poor school performance, decreased nervous stimulus IQ, or limited socialization. Other symptoms of this tumor type include visual disturbances, such as the appearance of motion from a stationary object, or inappropriate color perception of the entire visual field.[6] ### Associated conditions[edit] Tuber cinereum hamartoma may be associated with Pallister-Hall syndrome, a diagnosis characterized by multiple malformations, including polydactyly and imperforate anus. Neurologic symptoms are less severe in Pallister-Hall than in isolated cases of hamartoma.[1] ## Diagnosis[edit] ### Anatomic and imaging findings[edit] The mass is usually located at the tuber cinereum of the hypothalamus. The tumor is difficult to detect by CT due to decreased sensitivity of the scan at the level of the sella turcica. MRI is the primary imaging modality for detection, with the lesion being of similar signal intensity to gray matter and non-enhancing with contrast. Lack of enhancement is an important imaging characteristic to help distinguish the tumor from similar masses that can occur in this region. These include germ cell tumors, granulomas of Langerhans cell histiocytosis and hypothalamic astrocytomas, as these lesions usually demonstrate at least partial uptake of contrast.[1] ## Treatment[edit] Surgical approach for removal is transsphenoidal at the base of the skull. Hormonal suppressive therapy with luteinizing hormone receptor agonists like leuprorelin can be used to treat the seizure component, and are effective in most patients.[7] Surgery is offered if there is failure of medical therapy or rapid growth of lesion, with specific options including stereotactic thermocoagulation, gamma knife radiosurgery, and physical resection by transsphenoidal microsurgery. Surgical response is typically better when the seizure focus has been found by EEG to originate in or near the mass. The specific location of the lesion relative to the pituitary and infundibulum and the amount of hormonal disturbance at presentation can help predict risk of hypopituitarism following surgery.[8] ## In popular culture[edit] In the T.V. series Prison Break, Sara Tancredi tells Michael Scofield that he suffers from Tuber cinereum hamartoma at the end of the tenth episode of Season 4. Mentioned in Royal Pains Season five; an adult patient is diagnosed with it after describing what he calls "church giggles" and early puberty. In the medical drama Grey's Anatomy ("Put Me In, Coach"), a patient with an "HH tumor" comes to Dr. Derek Shepherd. ## References[edit] 1. ^ a b c Arita K, Ikawa F, Kurisu K, et al. (August 1999). "The relationship between magnetic resonance imaging findings and clinical manifestations of hypothalamic hamartoma". J. Neurosurg. 91 (2): 212–20. doi:10.3171/jns.1999.91.2.0212. PMID 10433309. 2. ^ Cacciari, E.; et al. (Mar 1983). "How many cases of true precocious puberty in girls are idiopathic?". J Pediatr. 102 (3): 357–60. doi:10.1016/s0022-3476(83)80648-9. PMID 6827406. 3. ^ Vinicius N de Brito; et al. (Mar 1999). "Treatment of gonadotropin dependent precocious puberty due to hypothalamic hamartoma with gonadotropin releasing hormone agonist depot". Arch Dis Child. 80 (3): 231–4. doi:10.1136/adc.80.3.231. PMC 1717869. PMID 10325702. 4. ^ Ricardo V. Lloyd (14 January 2010). Endocrine Pathology: Differential Diagnosis and Molecular Advances. Springer. p. 51. ISBN 978-1-4419-1068-4. 5. ^ Voyadzis JM, Guttman-Bauman I, Santi M, Cogen P (2004). "Hypothalamic hamartoma secreting corticotropin-releasing hormone. Case report". J Neurosurg. 100 (2 Suppl Pediatrics): 212–6. doi:10.3171/ped.2004.100.2.0212. PMID 14758953. 6. ^ Sturm JW, Andermann F, Berkovic SF (February 2000). ""Pressure to laugh": an unusual epileptic symptom associated with small hypothalamic hamartomas". Neurology. 54 (4): 971–3. doi:10.1212/wnl.54.4.971. PMID 10690995. S2CID 33066385. 7. ^ Mahachoklertwattana P, Kaplan SL, Grumbach MM (July 1993). "The luteinizing hormone-releasing hormone-secreting hypothalamic hamartoma is a congenital malformation: natural history". J. Clin. Endocrinol. Metab. 77 (1): 118–24. doi:10.1210/jc.77.1.118. PMID 8325933. 8. ^ Pascual-Castroviejo I, Moneo JH, Viaño J, García-Segura JM, Herguido MJ, Pascual Pascual SI (2000). "[Hypothalamic hamartomas: control of seizures after partial removal in one case]". Rev Neurol (in Spanish). 31 (2): 119–22. PMID 10951665. ## External links[edit] * Images of Hypothalamic Hamartoma * v * t * e Phakomatosis Angiomatosis * Sturge–Weber syndrome * Von Hippel–Lindau disease Hamartoma * Tuberous sclerosis * Hypothalamic hamartoma (Pallister–Hall syndrome) * Multiple hamartoma syndrome * Proteus syndrome * Cowden syndrome * Bannayan–Riley–Ruvalcaba syndrome * Lhermitte–Duclos disease Neurofibromatosis * Type I * Type II Other * Abdallat–Davis–Farrage syndrome * Ataxia telangiectasia * Incontinentia pigmenti * Peutz–Jeghers syndrome * Encephalocraniocutaneous lipomatosis * v * t * e Physiology of the endocrine system Regulatory systems * Hypothalamic–pituitary–thyroid axis * Hypothalamic–pituitary–adrenal axis * Hypothalamic–pituitary–gonadal axis * Hypothalamic–pituitary–somatotropic axis * Hypothalamic–pituitary–prolactin axis * Hypothalamic–neurohypophyseal system * Renin–angiotensin system Metabolism * Blood sugar regulation * Calcium metabolism Fields * Neuroendocrinology * Pediatric endocrinology * Psychoneuroendocrinology * Reproductive endocrinology and infertility Other * Wolff–Chaikoff effect/Jod-Basedow effect * v * t * e Tumours of endocrine glands Pancreas * Pancreatic cancer * Pancreatic neuroendocrine tumor * α: Glucagonoma * β: Insulinoma * δ: Somatostatinoma * G: Gastrinoma * VIPoma Pituitary * Pituitary adenoma: Prolactinoma * ACTH-secreting pituitary adenoma * GH-secreting pituitary adenoma * Craniopharyngioma * Pituicytoma Thyroid * Thyroid cancer (malignant): epithelial-cell carcinoma * Papillary * Follicular/Hurthle cell * Parafollicular cell * Medullary * Anaplastic * Lymphoma * Squamous-cell carcinoma * Benign * Thyroid adenoma * Struma ovarii Adrenal tumor * Cortex * Adrenocortical adenoma * Adrenocortical carcinoma * Medulla * Pheochromocytoma * Neuroblastoma * Paraganglioma Parathyroid * Parathyroid neoplasm * Adenoma * Carcinoma Pineal gland * Pinealoma * Pinealoblastoma * Pineocytoma MEN * 1 * 2A * 2B [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Tuber cinereum hamartoma	c0342418	3,209	wikipedia	https://en.wikipedia.org/wiki/Tuber_cinereum_hamartoma	2021-01-18T19:09:35	{"gard": ["2934"], "mesh": ["C537158"], "umls": ["C0342418"], "orphanet": ["2113"], "wikidata": ["Q7850809"]}
Leukemia cutis SpecialtyDermatology Leukemia cutis is the infiltration of neoplastic leukocytes or their precursors into the skin resulting in clinically identifiable cutaneous lesions.[1] This condition may be contrasted with leukemids, which are skin lesions that occur with leukemia, but which are not related to leukemic cell infiltration.[1][2] Leukemia cutis can occur in most forms of leukemia, including chronic myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, acute myeloid leukemia, and prolymphocytic leukemia.[3] ## See also[edit] * Granulocytic sarcoma * List of cutaneous conditions ## References[edit] 1. ^ a b James, William Daniel; Berger, Timothy G.; Elston, Dirk M. (2006). Andrews' Diseases of the Skin: clinical Dermatology. Saunders Elsevier. pp. 744–5. ISBN 978-0-7216-2921-6. 2. ^ Rapini, Ronald P.; Bolognia, Jean L.; Jorizzo, Joseph L. (2007). Dermatology: 2-Volume Set. St. Louis: Mosby. p. 1892. ISBN 978-1-4160-2999-1. 3. ^ Leukemia Cutis at eMedicine ## External links[edit] Classification D External resources * eMedicine: article/1097702 This cutaneous condition article is a stub. You can help Wikipedia by expanding it. * v * t * e [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Leukemia cutis	c0948976	3,210	wikipedia	https://en.wikipedia.org/wiki/Leukemia_cutis	2021-01-18T18:46:26	{"umls": ["C0948976"], "wikidata": ["Q6534501"]}
A rare familial congenital mitral malformation characterized by systolic displacement of one or both mitral leaflets >2 mm beyond the annular plane into the left atrium. Typical histological findings include myxomatous degeneration and degradation of collagen and elastin. Patients may remain asymptomatic or develop complications such as severe mitral regurgitation, endocarditis, and heart failure. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Familial mitral valve prolapse	c0340364	3,211	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=741	2021-01-23T18:48:31	{"gard": ["3687"], "omim": ["157700", "607829", "610840"], "umls": ["C0340364"], "icd-10": ["I34.1"]}
Urogenital tuberculosis SpecialtyInfectious disease Urogenital tuberculosis is a form of tuberculosis that affects the urogenital system. ## Contents * 1 Symptoms * 1.1 Other signs * 1.2 Complications * 2 Pathogenesis * 3 Epidemiology * 4 References ## Symptoms[edit] * Persistent cystitis, unresponsive to antibiotics.[1] * Urinary frequency[1] * Dysuria[1] * Loin discomfort[1] * Malaise and general symptoms of tuberculosis [1] * Ulcer However, the infection arises insidiously, being potentially asymptomatic for a long period of time.[1] ### Other signs[edit] * Pus cells and red cells in the urine, but no bacterial growth on routine bacterial culture[1] * Painless intermittent microscopic haematuria[1] * A painless, non-tender, irregular, and sometimes fluctuating mass on one side of the scrotum.[1] ### Complications[edit] Urogenital tuberculosis may cause strictures of the ureter, which, however, may heal when infection is treated. ## Pathogenesis[edit] The infection may affect the kidneys, ureter and bladder and may cause significant damage to each. ## Epidemiology[edit] It usually strikes young adults with tuberculosis in other places of the body as well. It is common in Asia, but less common in sub-Saharan Africa.[1] ## References[edit] 1. ^ a b c d e f g h i j Primary Surgery: Volume One: Non-trauma. Chapter 16. The surgery of tuberculosis Rheinische Friedrich-Wilhelms-Universität Bonn * 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 [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Urogenital tuberculosis	c0041333	3,212	wikipedia	https://en.wikipedia.org/wiki/Urogenital_tuberculosis	2021-01-18T18:51:54	{"mesh": ["D014401"], "umls": ["C0041333"], "wikidata": ["Q2500965"]}
Secondary short bowel syndrome is an intestinal failure caused by any condition that results in a functional small intestine of less than 200 cm in length and is characterized by diarrhea, nutrient malabsoption, bowel dilation and dysmobility. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Secondary short bowel syndrome	None	3,213	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=95427	2021-01-23T17:17:38	{"icd-10": ["K91.2"]}
A rare disorder characterized by epiphyseal stippling and osteoclastic overactivity. It has been described in less than 10 patients but may be underdiagnosed. It is characterized radiographically by severe stippling of the lower spine and long bones, and periosteal cloaking. Patients also have short metacarpals. The syndrome may be inherited as an autosomal recessive trait. This disorder should be included in the differential diagnosis of mucolipidosis type II. In order to make a definitive diagnosis, lysosomal storage should be investigated by electron microscopy, or enzyme assays should be performed. Familial recurrence can be easily detected by prenatal ultrasonography. This skeletal dysplasia is lethal. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Pacman dysplasia	c1833676	3,214	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=1952	2021-01-23T18:41:10	{"gard": ["4189"], "mesh": ["C538095"], "omim": ["167220"], "umls": ["C1833676"], "icd-10": ["Q77.8"], "synonyms": ["Epiphyseal stippling syndrome-osteoclastic hyperplasia syndrome"]}
Schmid metaphyseal chondrodysplasia is a rare disorder characterized by moderately short stature with short limbs, coxa vara, bowlegs and an abnormal gait. ## Epidemiology Prevalence is unknown. ## Etiology The disorder is caused by mutations in the COL10A1 (6q21-q22) gene encoding the collagen alpha-1(X) chain. ## Diagnostic methods The condition is usually diagnosed during the second or third year of life. Diagnosis relies on detection of the metaphyseal lesions at radiography. ## Differential diagnosis Hypochondroplasia (see this term) and sequelae from rickets are the principle differential diagnoses. Other metaphyseal dysplasias (such as cartilage-hair hypoplasia or Jansen type metaphyseal chondrodysplasia; see these terms) can be excluded as they are associated with very short stature and other features. ## Antenatal diagnosis Prenatal diagnosis should not be proposed for this disease. ## Genetic counseling Schmid metaphyseal chondrodysplasia is transmitted in an autosomal dominant manner. Genetic counseling may be recommended with a 50% risk of recurrence. ## Management and treatment Orthopedic correction is the only possible treatment. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Metaphyseal chondrodysplasia, Schmid type	c0265289	3,215	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=174	2021-01-23T17:36:27	{"gard": ["7029"], "mesh": ["C537352"], "omim": ["156500"], "umls": ["C0265289"], "icd-10": ["Q78.5"]}
## Summary ### Clinical characteristics. X-linked hyper IgM syndrome (HIGM1), a disorder of abnormal T- and B-cell function, is characterized by low serum concentrations of IgG, IgA, and IgE with normal or elevated serum concentrations of IgM. Mitogen proliferation may be normal, but NK- and T-cell cytotoxicity can be impaired. Antigen-specific responses are usually decreased or absent. Total numbers of B cells are normal but there is a marked reduction of class-switched memory B cells. Defective oxidative burst of both neutrophils and macrophages has been reported. The range of clinical findings varies, even within the same family. More than 50% of males with HIGM1 develop symptoms by age one year, and more than 90% are symptomatic by age four years. HIGM1 usually presents in infancy with recurrent upper- and lower-respiratory tract bacterial infections, opportunistic infections including Pneumocystis jirovecii pneumonia, and recurrent or protracted diarrhea that can be infectious or noninfectious and is associated with failure to thrive. Neutropenia is common; thrombocytopenia and anemia are less commonly seen. Autoimmune and/or inflammatory disorders (such as sclerosing cholangitis) as well as increased risk for neoplasms have been reported as medical complications of this disorder. Significant neurologic complications, often the result of a CNS infection, are seen in 5%-15% of affected males. Liver disease, a serious complication of HIGM1 once observed in more than 80% of affected males by age 20 years, may be decreasing with adequate screening and treatment of Cryptosporidium infection. ### Diagnosis/testing. The diagnosis of X-linked hyper IgM syndrome is established in a male proband with typical clinical and laboratory findings and a hemizygous pathogenic variant in CD40LG identified by molecular genetic testing. ### Management. Treatment of manifestations: Hematopoietic stem cell transplantation (HSCT) (the only curative treatment currently available), ideally performed before age ten years, prior to evidence of organ damage; immunoglobulin replacement therapy (either intravenous or subcutaneous); appropriate antimicrobial therapy for acute infections; antimicrobial prophylaxis for opportunistic infection against Pneumocysitis jirovecii pneumonia; recombinant granulocyte colony-stimulating factor for chronic neutropenia; immunosuppressants for autoimmune disorders. Agents/circumstances to avoid: Areas that place individual at risk of contracting Cryptosporidium including pools, lakes, ponds, or certain water sources; drinking unpurified or unfiltered water; live vaccines such as rotavirus, MMR, varicella, live attenuated polio, and BCG. Surveillance: At least annually: CBC with differential to monitor for cytopenias, testing of IgG levels and lymphocyte subpopulations, pulmonary function tests after age seven years. Regular assessment of liver function, consider abdominal imaging; as well as polymerase chain reaction-based testing for the presence of enteric pathogens including Cryptosporidium. Monitor growth and general health with a low threshold for lymph node biopsy, given elevated oncologic risk. Evaluation of relatives at risk: It is appropriate to clarify the genetic status of newborn at-risk relatives of an affected individual in order to identify as early as possible those who would benefit from early diagnosis and prompt initiation of treatment and prevention of infections. ### Genetic counseling. By definition, X-linked hyper IgM syndrome (HIGM1) is inherited in an X-linked manner. Affected males transmit the pathogenic variant to all their daughters and none of their sons. Women with a CD40LG pathogenic variant have a 50% chance of transmitting the pathogenic variant in each pregnancy. Males who inherit the pathogenic variant will be affected. Female who inherit the pathogenic variant will typically be asymptomatic but may have a range of clinical manifestation depending on X-chromosome inactivation. Once the CD40LG pathogenic variant has been identified in an affected family member, heterozygote testing for at-risk female relatives, prenatal testing for a pregnancy at increased risk, and preimplantation genetic testing for HIGM1 are possible. ## Diagnosis ### Suggestive Findings X-linked hyper IgM syndrome (HIGM1) should be suspected in any male presenting with Pneumocystis jirovecii pneumonia, persistent Cryptosporidium diarrhea, recurrent upper- and lower-respiratory tract bacterial infections, neutropenia, sclerosing cholangitis, and associated bile duct tumors with the following laboratory abnormalities: * Absent or low serum concentrations of IgG and IgA * Normal or elevated serum concentrations of IgM * Normal: * Number and distribution of T, B, and NK lymphocyte subsets * T-cell proliferation in response to mitogens * Decreased expression of CD40L on the surface of activated CD4 cells (not universal) ### Establishing the Diagnosis The diagnosis of HIGM1 is established in a male proband with typical clinical and laboratory findings by identification of a hemizygous pathogenic variant in CD40LG on molecular genetic testing (see Table 1). The diagnosis of HIGM1 is extremely rare in a female, as heterozygous females are typically asymptomatic unless there is skewed X-chromosome inactivation (see Clinical Description). Molecular genetic testing approaches can include a combination of gene-targeted testing (single-gene testing, multigene panel) and comprehensive genomic testing (exome sequencing, exome array, genome sequencing) depending on the phenotype and the family history. Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Because the phenotype of X-linked hyper IgM syndrome 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 a phenotype indistinguishable from many other inherited disorders with immunodeficiency are more likely to be diagnosed using genomic testing (see Option 2). #### Option 1 When the phenotypic and laboratory findings suggest the diagnosis of HIGM1 syndrome, molecular genetic testing approaches can include single-gene testing or use of a multigene panel: * Single-gene testing. Sequence analysis of CD40LG is performed first to detect small intragenic deletions/insertions and missense, nonsense, and splice site variants. Note: Depending on the sequencing method used, single-exon, multiexon, or whole-gene deletions/duplications may not be detected. If no variant is detected by the sequencing method used, the next step is to perform gene-targeted deletion/duplication analysis to detect exon and whole-gene deletions or duplications. * An immunodeficiency multigene panel that includes CD40LG 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 phenotype is indistinguishable from many other inherited disorders characterized by immunodeficiency, comprehensive genomic testing (which does not require the clinician to determine which gene[s] are likely involved) is the best option. Exome sequencing is most commonly used; genome sequencing is also possible. If exome sequencing is not diagnostic, 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 X-Linked Hyper IgM Syndrome (HIGM1) View in own window Gene 1MethodProportion of Probands with a Pathogenic Variant 2 Detectable by Method CD40LGSequence analysis 3, 485%-95% 5 Gene-targeted deletion/duplication analysis 65%-15% 5 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\. Lack of amplification by PCR prior to sequence analysis can suggest a putative (multi)exon or whole-gene deletion on the X chromosome in affected males; confirmation requires additional testing by gene-targeted deletion/duplication analysis. 5\. Lee et al [2005], Prasad et al [2005], Cabral-Marques et al [2014], Leven et al [2016] 6\. Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. #### Additional Confirmatory Testing Measurement by flow cytometry of CD40 ligand (CD40L) protein expression after in vitro stimulation of T cells. In the resting state, only a low level of CD40L protein expression is seen on normal CD4+ T cells. After in vitro stimulation: * Controls show increased expression (up-regulation) of CD40L protein in the majority of CD4+ T cells which is determined by monoclonal anti-human IgG to CD40L. Note: Infants younger than age six months may not express normal amounts of CD40L protein [Gilmour et al 2003]. * Persons with HIGM1 do not show increased expression of CD40L protein in CD4+ T cells. NOTE: This testing should not be used as the only diagnostic test when HIGM1 is suspected. Up to 32% of individuals with HIGM1 may have normal extracellular domains of CD40L detected by this laboratory measure, which uses CD40L binding; but the intracellular signaling pathway from CD40L is nonfunctional, and thus genetic testing is required for diagnosis [Lee et al 2005]. ## Clinical Characteristics ### Clinical Description X-linked hyper IgM syndrome (HIGM1), a disorder of abnormal T- and B-cell function, is characterized by low serum concentrations of IgG, IgA, and IgE and normal or elevated serum concentrations of IgM. HIGM1 is due to defects or deficiencies in the CD40L protein that affect T cell communication with B lymphocytes. Mitogen proliferation may be normal but NK- and T-cell cytotoxicity can be impaired. Antigen-specific responses are usually decreased or absent. #### Males The range of clinical findings varies, even within the same family. More than 50% of males with HIGM1 develop symptoms by age one year, and more than 90% are symptomatic by age four years [Winkelstein et al 2003]. Presentation. HIGM1 usually presents in infancy with recurrent upper- and lower-respiratory tract bacterial infections, opportunistic infections including Pneumocystis jirovecii pneumonia, and recurrent or protracted diarrhea that can be infectious or noninfectious and is associated with failure to thrive. Neutropenia is common; thrombocytopenia and anemia are also (though less commonly) seen. Autoimmune and/or inflammatory disorders (such as sclerosing cholangitis) as well as increased risk for neoplasms have been reported as medical complications of this disorder [Lee et al 2005, Leven et al 2016, de la Morena et al 2017]. Infection. Increased susceptibility to recurrent bacterial infections consisting of upper- and lower-respiratory tract infections is seen in 75%-80% of affected individuals (typically streptococcus pneumonia and pseudomonas), otitis in 42%, and sinusitis in 36% [Leven et al 2016]. Susceptibility to invasive fungal infections (primarily Candida, Cryptococcus, and Histoplasma) is also increased. Boys with HIGM1 are also at a significant risk for opportunistic infections from Pneumocystis jirovecii (PJP; formerly known as Pneumocystis carinii) and gastrointestinal infection with Cryptosporidium parvum. Pneumocystis jirovecii pneumonia is the first clinical symptom of HIGM1 in more than 40% of infants with the disorder and is shown as the pathogenic organism in roughly 30% of individuals with HIGM1 [Levy et al 1997, Lee et al 2005, de la Morena 2016, Leven et al 2016] and accounts for 10%-15% of the mortality associated with HIGM1 [Levy et al 1997, Winkelstein et al 2003]. The presentation of HIGM1 across different ethnic backgrounds and in different countries has been shown to be consistent in the infectious organisms at present across all individuals with HIGM1 but they are also at risk for the pathogens that are endemic to their specific region [Cabral-Marques et al 2014, Wang et al 2014, Rawat et al 2018, Tafakori Delbari et al 2019]. Gastrointestinal manifestations. Chronic diarrhea is the most frequent GI complication of HIGM1, occurring in approximately 20%-30% of affected males [Winkelstein et al 2003, Leven et al 2016]. Recurrent or protracted diarrhea may result from infection with Cryptosporidium parvum or other microorganisms; however, in at least 50% of males with recurrent or protracted diarrhea, no infectious agent can be detected [Winkelstein et al 2003, Leven et al 2016]. Poor growth is a serious complication of chronic diarrhea. Additionally, aphthous ulcers can be present in 21% of affected males [Leven et al 2016]. Hematologic and immunologic abnormalities. Neutropenia occurs in roughly 45%-50% of males with HIGM1, with anemia seen in 10%-15% and thrombocytopenia in 5% [Levy et al 1997, Lee et al 2005, Cabral-Marques et al 2014, Leven et al 2016]. Severe aplastic anemia secondary to parvovirus B19 has been found, but was reported as the initial finding in individuals with a milder phenotype and later age of presentation [Seyama et al 1998, Leven et al 2016, de la Morena 2016]. The total number of B cells in circulation is normal, however, there is a marked reduction of class-switched memory B cells [Agematsu et al 1998]. Furthermore, some individuals with HIGM1 may show progressive loss of B and NK cell populations over time, which can contribute to the increased morbidity [Lougaris et al 2018]. Defective oxidative burst of both neutrophils and macrophages have been reported – the result of impaired interaction between neutrophils, macrophages and, activated T lymphocytes through CD40 and CD40LG [Cabral-Marques et al 2018]. Histologic examination of lymph nodes shows absence of germinal center formation. Neurologic involvement. Significant neurologic complications, often the result of a CNS infection, are seen in 5%-15% of males with HIGM1 [Levy et al 1997, Cabral-Marques et al 2014, Leven et al 2016]. However, in at least half of affected individuals a specific infectious agent cannot be isolated [Winkelstein et al 2003]. Hepatobiliary disease. Liver disease, a serious complication of HIGM1, historically was observed in more than 80% of affected males by age 20 years [Hayward et al 1997] but with adequate screening and treatment of Cryptosporidium infections, that number may now be lower [Leven et al 2016]. Hepatitis and sclerosing cholangitis occur in 6%-10% of affected individuals. CD40, the receptor to which CD40Ligand (CD40L) binds, has been shown to be expressed on bile duct epithelium; chronic infection with Cryptosporidium or other inflammatory changes are thought to contribute to sclerosing cholangitis and malignant transformation [Hayward et al 1997, de la Morena 2016, Leven et al 2016]. Oncologic disease. Malignancies occur in approximately 5% of individuals with HIGM1 and are associated with high mortality [Winkelstein et al 2003, de la Morena 2016, Leven et al 2016]. Malignancies reported in individuals with HIGM1 include neuroendocrine tumors of the GI tract, colon cancer, bile duct carcinomas, hepatocellular carcinomas, hepatoma, adrenal adenomas, and adenocarcinomas of the liver and gall bladder [Hayward et al 1997, Winkelstein et al 2003, Filipovich & Gross 2004, Erdos et al 2008, Leven et al 2016, Nicolaides & de la Morena 2017]. Males with HIGM1 are also at increased risk for acute myelogenous leukemia and lymphoma, particularly Hodgkin disease associated with Epstein-Barr virus infection [Filipovich & Gross 2004]. Other (rarely) reported complications of HIGM1 include autoimmune retinopathy, cutaneous granulomas, and disseminated cutaneous warts [Gallerani et al 2004, Schuster et al 2005, Ho et al 2018]. Life span. The current reported median survival time from diagnosis is 25 years [de la Morena et al 2017]. Pneumocystis jirovecii pneumonia in infancy, liver disease, and malignancies in adolescence or young adulthood are important contributors to mortality [Levy et al 1997, Winkelstein et al 2003, de la Morena 2016, Leven et al 2016]. Hematopoietic stem cell transplant (HSCT) is the only curative therapy available for HIGM1. In a retrospective series of 130 affected individuals who had undergone HSCT, overall survival, event-free survival, and disease-free survival rates were respectively 78.2%, 58.1%, and 72.3% five years post HSCT [Ferrua et al 2019]. #### Heterozygous Females Typically, heterozygous females are asymptomatic but on immunologic testing have been shown to have reduced expression of CD40L on activation of CD4+ T lymphocytes. Those females with more dramatic reduction in circulating lymphocytes with CD40L due to skewed X-chromosome inactivation can have a presentation similar to HIGM1 or common variable immunodeficiency [Hollenbaugh et al 1994, de Saint Basile et al 1999, Lobo et al 2002]. ### Genotype-Phenotype Correlations Males with HIGM1 show remarkable variability in clinical symptoms. No specific genotype-phenotype correlations for CD40LG have been identified [Notarangelo & Hayward 2000, Prasad et al 2005]. However, the p.Thr254Met and p.Arg11Ter pathogenic variants have been reported in unrelated families with milder and later-onset disease [Seyama et al 1998, Lee et al 2005]. Whether or not this is a true association needs to be evaluated with study of additional families with the pathogenic variant. ### Prevalence The estimated prevalence of HIGM is 1:1,000,000 males [Winkelstein et al 2003] with nearly 75% of these individuals having HIGM1 [Leven et al 2016]. HIGM1 has been reported in families of European, African, and Asian descent; thus, no evidence exists for a racial or ethnic predilection. ## Differential Diagnosis ### Table 2. Disorders to Consider in the Differential Diagnosis of X-Linked Hyper IgM Syndrome (HIGM1) View in own window Gene(s)Differential DisorderMOIClinical Features of Differential Disorder Overlapping w/HIGM1Distinguishing from HIGM1 AICDA (AID)HIGM2 (OMIM 605258)ARAbnormalities in B-cell differentiation → recurrent URTI, LRTI, GI infections * Opportunistic infections rare * Lymphoid hyperplasia common; incl: hepatomegaly, splenomegaly, giant germinal centers, follicular hyperplasia. * Autoimmunity w/hemolytic anemia more common 1 Note: Clinical course milder in HIGM4 than in HIGM2 2 HIGM4 (OMIM 608184)AD 3 * Recurrent URTI, LRTI * ↓ production of IgG, abnormalities in B cell differentiation 2 CD40HIGM3 (OMIM 606843)ARClinically indistinguishable w/recurrent bacterial infections & opportunistic infections w/P jirovecii, Cryptosporidium, & sclerosing cholangitis 4Clinically indistinguishable 4 UNGHIGM5 (OMIM 608106)ARRecurrent bacterial infectionsHIGM5 resembles HIGM2 in the ↑ in lymphoid hyperplasia compared to HIGM1. 2 MSH6Constitutional mismatch repair deficiency (see Lynch Syndrome)AR↑ or normal IgM, ↓ or normal IgG, normal B cell counts, & normal memory B cells w/↓ class-switched B cells * No recurrent infections * ↑ risk for cancers incl colorectal cancer, hereditary nonpolyposis colon cancer, & endometrial cancer PMS2Constitutional mismatch repair deficiency (see Lynch Syndrome)AR * Recurrent infections * ↑ or normal IgM w/↓ IgG & IgA * Normal B cell counts but ↓ memory B cells * Café au lait spots * Colorectal adenocarcinoma CD19 CD81 CR2 ICOS IKZF1 IL21 IRF2BP2 LRBA MS4A1 NFKB1 NFKB2 TNFRSF13B TNFRSF13CCommon variable immunodeficiency (CVID) (OMIM PS607594)AR AD * Recurrent sinopulmonary infections * ↓ immunoglobulins incl IgG & IgA * CD40LG protein may be ↓. * No CD40LG pathogenic variant * May be assoc w/↓ number of total T cells or ↓ T-cell function 5 ADA AK2 CD3D CD3E CD247 CORO1A DCLRE1C IL2RG IL7R JAK3 PRKDC PTPRC RAG1 RAG2 6Severe combined immunodeficiency (SCID) (see X-Linked SCID & Adenosine Deaminase Deficiency)AR XLAll SCIDs must be considered in infants presenting w/P jirovecii pneumonia. * Most forms of SCID present w/absent T-cell function, quantitative abnormalities of T lymphocyte populations, & markedly ↓ mitogen function. * Hypomorphic RAG2 variants reported in a male w/clinical & immunologic studies suggestive of HIGM 7 AGMX2 BLNK BTK CD79A CD79B IGHM IGLL1 LRRC8A PIK3R1 TCF3 SLC39A7 8Agammaglobulinemia (see X-Linked Agammaglobulinemia [XLA])AR AD XL * Males w/agammaglobulinemia should be considered in differential of HIGM1. * XLA typically presents in 1st yr of life w/recurrent bacterial infections Most individuals w/agammaglobulinemia lack circulating B cells. IKBKG (NEMO)Ectodermal dysplasia & immunodeficiency 1 (OMIM 300291)XL * Serious infections, incl opportunistic infections, are a common complication at any age. * Variable immunoglobulins from agammaglobulinemia to normal or ↑ IgM, ↓ IgG, & low/↑ IgA w/↓ memory B cells * IKBKG-related hyper IgM syndrome is generally assoc w/hypohydrotic ectodermal dysplasia. 9 * Invasive disease by MRSA & MSSA; osteopetrosis, lymphedema; conical shaped teeth PIK3CDActivated PI3 kinase-δ syndrome (OMIM 615513]AD * Recurrent infections w/S pneumoniae or H influenzae * Chronic lung disease * ↑ IgM, ↓/normal IgG/IgA * ↓ class-switched memory B cells * Lymphoid hyperplasia * Lymphopenia, ↓ T/B cell counts * Severe response to herpes family virus (EBV, CMV, HSV, VZV) ATMAtaxia-telangiectasiaAR * Recurrent URTI/LRTI, malignancy * Normal/↑ IgM, normal to ↓ IgG/IgA, normal to ↓ T/B cells * Ataxia, telangiectasias, hypotonia, dysarthria, radiosensitivity * Lymphopenia, ↑ α-fetoprotein, variable mitogen & antigen response NBNNijmegen breakage syndromeAR * Recurrent URTI/LRTI, malignancy, autoimmune conditions (primarily hemolytic anemia) * Variable immunoglobulins w/agammaglobulinemia to ↓ IgG/IgA & normal/↑ IgM Microcephaly, facial features, short stature, café au lait spots, vitiligo, radiosensitivity INO80INO80 deficiency 10 (OMIM 610169) * Recurrent bacterial infections * COPD * ↓ IgG & IgA * ↓ class-switched memory B cells Normal CD40LG protein expression & no CD40LG pathogenic variant AD = autosomal dominant; AR = autosomal recessive; COPD = chronic obstructive pulmonary disease; GI = gastrointestinal; H = Haemophilus; HIGM = hyper IgM syndrome; LRTI = lower respiratory tract infection; MOI = mode of inheritance; P = Pneumocystis; S = Streptococcus; URTI = upper respiratory tract infection; XL = X-linked 1\. Minegishi et al [2000], Revy et al [2000], Lee et al [2005] 2\. Imai et al [2003] 3\. An autosomal dominant form of hyper IgM syndrome has been reported in four unrelated families with an identical pathogenic nonsense variant (p.Arg190Ter) in AICDA (reference sequence NM_020661.2) [Durandy et al 2005]. 4\. Ferrari et al [2001] 5\. See Park et al [2011], Yong et al [2011], and Abbott & Gelfand [2015] for current reviews of CVID. 6\. Note: A growing list of rare causes of SCID-like phenotypes include pathogenic variants in the following additional genes: CD3G, CD8A, CHD7, CIITA, DOCK8, FOXN1, LCK, LIG4, MTHFD1, NHEJ1, ORAI1, PGM3, PNP, PRKDC, RFXANK (RFX-B), RFX5, RFXAP, RMRP, SLC46A1, STIM1, TBX1, TTC7A, ZAP70. 7\. Chou et al [2012] 8\. Anzilotti et al [2019] 9\. Jain et al [2001] 10\. Kracker et al [2015] The differential diagnosis of HIGM1 also includes the following disorders: * HIV infection. Infection with HIV should be considered in any infant presenting with Pneumocystis jirovecii pneumonia. * Transient hypogammaglobulinemia of infancy. Transient hypogammaglobulinemia of infancy is characterized by normal antibody production, normal growth patterns, and lack of opportunistic infections. Neonates and young infants may have diminished CD40L expression that improves with time [Nonoyama et al 1995]. ## Management ### Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with X-linked hyper IgM syndrome, 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 X-Linked Hyper IgM Syndrome View in own window System/ConcernEvaluationComment Hematology/ Immunology * CBC w/differential * IgG levels * T, B, & NK cell numbers For evidence of cytopenias PulmonaryBaseline chest radiograph & pulmonary function testingFor chronic lung changes due to infection; if present, consider pulmonology evaluation. GastrointestinalPCR-based testing of stoolsFor presence of Cryptosporodium or other enteric pathogens; if present, partner w/gastroenterologist. Nutritional assessment HepatobiliaryBaseline liver function testing & liver / biliary tree ultrasoundFor evidence of hepatocyte dysfunction & developing biliary dilation TransplantationAll individuals should be offered HLA typing at diagnosis.For consideration of HSCT OtherConsultation w/clinical geneticist &/or genetic counselor CBC = complete blood count; HLA = human leukocyte antigen; HSCT = hematopoietic stem cell transplant; PCR = polymerase chain reaction ### Treatment of Manifestations For a concise summary of current clinical management practices in this disorder, see Davies & Thrasher [2010] and de la Morena et al [2017]. Hematopoietic stem cell transplant (HSCT). Currently HSCT is the only curative therapy available for HIGM1. Best outcomes are reported for those individuals transplanted before age ten years and without evidence of end organ damage, especially liver disease [de la Morena et al 2017, Ferrua et al 2019]. Myeloablative conditioning regimens result in better survival; mismatched-related-donor and matched-unrelated-donor transplants were associated with increased morbidity compared to matched sib donors. Approximately 15% of individuals may reject the graft (mainly after matched unrelated transplant and reduced intensity conditioning) and require a second or third transplant. In one series, among 130 transplanted individuals with HIGM1, a third required ongoing immunoglobulin replacement five years after transplantation [Ferrua et al 2019]. Note: Liver transplantation has been performed successfully for end-stage liver disease but for best outcome requires that HSCT be performed following the liver allograft [Bucciol et al 2019]. ### Table 4. Treatment of Manifestations in Individuals with X-Linked Hyper IgM Syndrome View in own window Manifestation/ ConcernTreatmentConsiderations/Other Recurrent infections * Immunoglobulin replacement w/intravenous or subcutaneous immunoglobulin starting at diagnosis Initial dosing for IgG replacement: 0.4-0.6 g/kg every 3-4 wks for IV, or ≥100 mg/kg dose weekly for subcutaneous Ig. Titrate IgG levels as for primary antibody deficiency syndromes. * Prophylactic antibiotics against opportunistic infections incl P jirovecii * Institute appropriate antimicrobial therapy for acute infections. * Aggressively evaluate pulmonary infections (incl use of diagnostic bronchoalveolar lavage) to define specific etiology. * Prevention of infections 1 Discussion re prophylactic use of azithromycin or nitazoxanide for all affected individuals for prevention of Crypstosporidium is ongoing. While not standard of care, it should be considered for those living in / traveling to an area w/↑ Cryptosporidium rates. ImmunodeficiencyOnly current curative treatment is HSCT, preferably at age <10 yrs.Modified conditioning regimens may be needed in those w/preexisting liver disease, & hepatic transplant along w/HSCT may be required. Chronic neutropeniaRecombinant GCSF Malnutrition & poor growthTotal parenteral nutrition & consultation w/clinical dietary nutritionist may be required to optimize caloric intake. Sclerosing cholangitisSome males w/end-stage sclerosing cholangitis have been treated successfully w/orthotopic liver transplantation closely assoc w/allogeneic bone marrow transplantation. Infectious etiologies need to be pursued & treated prior to transplantation. Autoimmune disordersTreatment of autoimmune disorders usually involves judicious use of immunosuppressants tailored to individual's diagnosis. CancerTreatment should follow standard protocols/therapies for individual cancers in conjunction w/immunologist. GCSF = granulocyte colony-stimulating factor; HSCT = hematopoietic stem-cell transplantation; P = Pneumocystis 1\. The following methods are used to prevent infection: Antibiotic prophylaxis. Prophylaxis for pneumonia secondary to Pneumocystis jirovecii (PJP) is indicated for all children with HIGM1 due to the high risk of developing PJP during the first two years of life. There is no standard-of-care approach established for length of PJP prophylaxis. However, individuals with HIGM1 who develop PJP after age two years should continue prophylaxis for life or until after HSCT transplant when normal immune function is established. Typical prophylaxis is trimethoprim-sulfamethoxazole orally, pentamidine by intravenous or inhalation therapy, dapsone, and atovaquone. Immunoglobulin (either subcutaneous or intravenous). Immunoglobulin replacement should be considered at the time of diagnosis, as individuals with HIGM1 cannot generate antibodies to encapsulated bacteria naturally and are at risk for overwhelming infection from these organisms. IgG replacement is a highly purified blood derivative (a combination of many specific antimicrobial antibodies) that is typically given every three to four weeks or can be given subcutaneously, usually on a weekly basis. Additional antibiotic prophylaxis should be evaluated on a case-by-case basis with ongoing questions regarding Cryptosporidum prophylaxis not yet being standardized. Routine childhood immunizations (killed vaccines) may be safely administered but do not preclude the need for immunoglobulin replacement. Live vaccines (e.g., rotavirus, MMR, varicella, live attenuated polio, and BCG) should not be given to individuals with HIGM1. Only boiled and/or filtered water should be ingested. Avoid swimming in non-chlorinated pools. Avoid swimming in lakes and ponds. Children should avoid water parks and farm animals. ### Surveillance No guidelines have been published for ongoing surveillance in individuals with HIGM1. Table 5 presents the current recommendations of the authors. ### Table 5. Recommended Surveillance for Individuals with X-Linked Hyper IgM Syndrome View in own window System/ConcernEvaluationFrequency HematologyCBC w/differential to monitor for cytopeniasAt least every 6 mos to yrly if stable or w/any change in clinical status ImmunologyIgG levels * IgG frequency depends on time needed to achieve adequate IgG levels; similar to those w/primary antibody deficiency syndromes. * Adults: at least yrly Lymphocyte subpopulations: T, B, & NK cell numbersGiven progressive T, B, & NK loss over time, consider obtaining yrly in nontransplanted adolescents & adults. CD40L expression in transplanted individualsMonitor CD40L expression in activated T-cells at least yrly in those who have had HSCT, or if any change in clinical status. PulmonaryPulmonary function testsYrly for those age >7 yrs or if change in clinical status Chest radiograph w/follow up of pulmonary infiltrates w/high-resolution CT scanAs clinically indicated GastrointestinalPCR-based testing of stools for infectious etiologiesAt least every 6 mos or if diarrhea present or exposure occurs Liver function tests * Children: at least every 4-6 mos or if change in clinical status * Adults: at least 1-2x/yr or if change in clinical status Liver ultrasound≥1x/yr or if change in clinical status * Monitor growth in children. * Measure weight in adolescents & adults at least 2x/yr * Children: at every visit; at least every 4-6 mos * Adolescents/adults: at least 2x/yr * If any change in clinical status OncologyPhysical exam * Children: at least every 4-6 mos * Adolescents/adults: at least 1-2x/yr * Low threshold for lymph node biopsy CBC = complete blood count; PCR = polymerase chain reaction ### Agents/Circumstances to Avoid Avoid areas that place the individual at risk of contracting Cryptosporidium including pools, lakes, ponds, or certain water sources. Avoid drinking unpurified or unfiltered water. Live vaccines (e.g., rotavirus, MMR, varicella, live attenuated polio, and BCG) should not be given to individuals with HIGM1. ### Evaluation of Relatives at Risk It is appropriate to clarify the genetic status of newborn at-risk relatives of an affected individual in order to identify as early as possible those who would benefit from early diagnosis and prompt initiation of treatment and prevention of infections. See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes. ### Therapies Under Investigation Research into autologous gene corrective therapy is ongoing [Hubbard et al 2016, Kuo et al 2018]. 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. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	X-Linked Hyper IgM Syndrome	c0398689	3,216	gene_reviews	https://www.ncbi.nlm.nih.gov/books/NBK1402/	2021-01-18T20:48:28	{"mesh": ["D053307"], "synonyms": ["HIGM1", "X-Linked Hyper-IgM Immunodeficiency (XHIGM)"]}
"Goodpasture" redirects here. For other uses, see Goodpasture (disambiguation). Rare autoimmune disease Goodpasture syndrome Other namesGoodpasture’s disease, antiglomerular basement antibody disease, anti-GBM disease Micrograph of a crescentic glomerulonephritis that was shown to be antiglomerular basement membrane disease, PAS stain SpecialtyNephrology, pulmonology, immunology Diagram of a monomeric (one-unit) antibody Goodpasture syndrome (GPS), also known as anti-glomerular basement membrane disease, is a rare autoimmune disease in which antibodies attack the basement membrane in lungs and kidneys, leading to bleeding from the lungs, glomerulonephritis,[1] and kidney failure.[2] It is thought to attack the alpha-3 subunit of type IV collagen, which has therefore been referred to as Goodpasture's antigen.[3] Goodpasture syndrome may quickly result in permanent lung and kidney damage, often leading to death. It is treated with medications that suppress the immune system such as corticosteroids and cyclophosphamide, and with plasmapheresis, in which the antibodies are removed from the blood. The disease was first described by an American pathologist Ernest Goodpasture of Vanderbilt University in 1919 and was later named in his honor.[4][5] ## Contents * 1 Signs and symptoms * 2 Cause * 3 Pathophysiology * 4 Diagnosis * 5 Treatment * 6 Prognosis * 7 Epidemiology * 8 See also * 9 References * 10 External links ## Signs and symptoms[edit] The antiglomerular basement membrane (GBM) antibodies primarily attack the kidneys and lungs, although, generalized symptoms like malaise, weight loss, fatigue, fever, and chills are also common, as are joint aches and pains.[6] 60 to 80% of those with the condition experience both lung and kidney involvement; 20-40% have kidney involvement alone, and less than 10% have lung involvement alone.[6] Lung symptoms usually antedate kidney symptoms and usually include: coughing up blood, chest pain (in less than 50% of cases overall), cough, and shortness of breath.[7] Kidney symptoms usually include blood in the urine, protein in the urine, unexplained swelling of limbs or face, high amounts of urea in the blood, and high blood pressure.[6] ## Cause[edit] While the exact cause is unknown, the genetic predisposition to GPS involves the human leukocyte antigen (HLA) system, specifically HLA-DR15.[8] In addition to genetic susceptibility, an initial environmental insult to the pulmonary vasculature is needed to allow the anti-glomerular basement membrane (anti-GBM) antibodies to reach the alveolar capillaries. Examples of such an insult include: exposure to organic solvents (e.g. chloroform) or hydrocarbons, exposure to tobacco smoke, infection (such as influenza A), cocaine inhalation, metal dust inhalation, bacteremia, sepsis, high-oxygen environments, and antilymphocyte therapies (especially with monoclonal antibodies).[9] Exposure to dry cleaning chemicals and Paraquat brand weed killer have also been implicated as potential insults. [10] In GPS, anti-GBM antibodies are produced and circulated throughout the bloodstream, damaging the membranes lining the lungs and kidneys as well as targeting their capillaries.[11] ## Pathophysiology[edit] GPS is caused by abnormal plasma cell production of anti-GBM antibodies.[9] The major target of these abnormal antibodies is the non-collagen domain of the alpha-3 chain of type 4 collagen, which is mostly found in the basal membranes of glomerular and alveolar capillaries, explaining the obscurely specific symptoms of this condition.[12] These antibodies bind their reactive epitopes to the basement membranes and activate the complement cascade, leading to the death of tagged cells.[9] A specific antibody and epitope binding that shows the highest affinity and is pathogenic occurs between GPA antibodies and the anti-GBM epitope region, designated EA, which is residues 17-31 of the alpha 3 subunit of non-collagenous domain of type IV collagen.[13] T cells are also implicated, though it is generally considered a type II hypersensitivity reaction.[9] ## Diagnosis[edit] The diagnosis of GPS is often difficult, as numerous other diseases can cause the various manifestations of the condition and the condition itself is rare.[14] The most accurate means of achieving the diagnosis is testing the affected tissues by means of a biopsy, especially the kidney, as it is the best-studied organ for obtaining a sample for the presence of anti-GBM antibodies.[14] On top of the anti-GBM antibodies implicated in the disease, about one in three of those affected also has cytoplasmic antineutrophilic antibodies in their bloodstream, which often predates the anti-GBM antibodies by about a few months or even years.[14] The later the disease is diagnosed, the worse the outcome is for the affected person.[9] In addition, if there is substantial suspicion of the disease, seralogic testing for ELISA assay is usually done by looking for alpha3 NC1 domain area of collagen IV in order to avoid false positives.[15] ## Treatment[edit] The major mainstay of treatment for GPS is plasmapheresis, a procedure in which the affected person's blood is sent through a centrifuge and the various components separated based on weight.[16] The plasma contains the anti-GBM antibodies that attack the affected person's lungs and kidneys, and is filtered out.[16] The other parts of the blood (the red blood cells, white blood cells, and platelets) are recycled and intravenously reinfused.[16] Most individuals affected by the disease also need to be treated with immunosuppressant drugs, especially cyclophosphamide, prednisone, and rituximab, to prevent the formation of new anti-GBM antibodies so as to prevent further damage to the kidneys and lungs.[16] Other, less toxic immunosuppressants such as azathioprine may be used to maintain remission.[16] ## Prognosis[edit] With treatment, the five-year survival rate is >80% and fewer than 30% of affected individuals require long-term dialysis.[9] A study performed in Australia and New Zealand demonstrated that in patients requiring renal replacement therapy (including dialysis) the median survival time is 5.93 years.[9] Without treatment, virtually every affected person will die from either advanced kidney failure or lung hemorrhages.[9] ## Epidemiology[edit] GPS is rare, affecting about 0.5–1.8 per million people per year in Europe and Asia.[9] It is also unusual among autoimmune diseases in that it is more common in males than in females and is also less common in blacks than whites, but more common in the Māori people of New Zealand.[9] The peak age ranges for the onset of the disease are 20–30 and 60–70 years.[9] ## See also[edit] * HLA-DR § DR2 * Pulmonary-renal syndrome ## References[edit] 1. ^ "Goodpasture Syndrome". www.hopkinsmedicine.org. Retrieved 2020-12-05. 2. ^ Thibaud, V.; Rioux-Leclercq, N.; Vigneau, C.; Morice, S. (December 2019). "Recurrence of Goodpasture syndrome without circulating anti-glomerular basement membrane antibodies after kidney transplant, a case report". BMC Nephrology. 20 (1): 6. doi:10.1186/s12882-018-1197-6. ISSN 1471-2369. PMC 6323659. PMID 30621605. 3. ^ "COL4A3 gene". 4. ^ Goodpasture EW (1919). "The significance of certain pulmonary lesions in relation to the etiology of influenza". Am J Med Sci. 158 (6): 863–870. doi:10.1097/00000441-191911000-00012. S2CID 71773779. 5. ^ Salama AD, Levy JB, Lightstone L, Pusey CD (September 2001). "Goodpasture's disease". Lancet. 358 (9285): 917–920. doi:10.1016/S0140-6736(01)06077-9. PMID 11567730. S2CID 40175400. 6. ^ a b c Kathuria, P; Sanghera, P; Stevenson, FT; Sharma, S; Lederer, E; Lohr, JW; Talavera, F; Verrelli, M (21 May 2013). Batuman, C (ed.). "Goodpasture Syndrome Clinical Presentation". Medscape Reference. WebMD. Retrieved 14 March 2014. 7. ^ Schwarz, MI (November 2013). "Goodpasture Syndrome: Diffuse Alveolar Hemorrhage and Pulmonary-Renal Syndrome". Merck Manual Professional. Retrieved 14 March 2014. 8. ^ "Goodpasture syndrome \| Genetic and Rare Diseases Information Center (GARD) – an NCATS Program". rarediseases.info.nih.gov. Retrieved 2020-12-01. 9. ^ a b c d e f g h i j k Kathuria, P; Sanghera, P; Stevenson, FT; Sharma, S; Lederer, E; Lohr, JW; Talavera, F; Verrelli, M (21 May 2013). Batuman, C (ed.). "Goodpasture Syndrome". Medscape Reference. WebMD. Retrieved 14 March 2014. 10. ^ https://www.hopkinsmedicine.org/health/conditions-and-diseases/goodpasture-syndrome#:~:text=Goodpasture%20syndrome%20is%20a%20group,attack%20the%20lungs%20and%20kidneys. 11. ^ "Goodpasture Syndrome". NORD (National Organization for Rare Disorders). Retrieved 2020-11-29. 12. ^ Marques, C., et al. (2020). Review on anti-glomerular basement membrane disease or Goodpasture's syndrome. The Journal of Internal Medicine, 41(1), 14-20. 13. ^ Borza, D., et al. (2003). Pathogenesis of Goodpasture syndrome: a molecular perspective. Seminars in Nephrology, 23(6), 522-531. 14. ^ a b c Kathuria, P; Sanghera, P; Stevenson, FT; Sharma, S; Lederer, E; Lohr, JW; Talavera, F; Verrelli, M (21 May 2013). Batuman, C (ed.). "Goodpasture Syndrome Workup". Medscape Reference. WebMD. Retrieved 14 March 2014. 15. ^ "Goodpasture Syndrome". NCBI. 25 March 2020. Retrieved 20 December 2020. 16. ^ a b c d e Kathuria, P; Sanghera, P; Stevenson, FT; Sharma, S; Lederer, E; Lohr, JW; Talavera, F; Verrelli, M (21 May 2013). Batuman, C (ed.). "Goodpasture Syndrome Treatment & Management". Medscape Reference. WebMD. Retrieved 14 March 2014. ## External links[edit] * GBM antibodies: immunofluorescence image Classification D * ICD-10: M31.0 (ILDS M31.010) * ICD-9-CM: 446.21 * OMIM: 233450 * MeSH: D019867 * DiseasesDB: 5363 External resources * MedlinePlus: 000142 * eMedicine: med/923 ped/888 * v * t * e Systemic vasculitis Large vessel * Takayasu's arteritis * Giant cell arteritis Medium vessel * Polyarteritis nodosa * Kawasaki disease * Thromboangiitis obliterans Small vessel Pauci-immune * c-ANCA * Granulomatosis with polyangiitis * p-ANCA * Eosinophilic granulomatosis with polyangiitis * Microscopic polyangiitis Type III hypersensitivity * Cutaneous small-vessel vasculitis * IgA vasculitis Ungrouped * Acute hemorrhagic edema of infancy * Cryoglobulinemic vasculitis * Bullous small vessel vasculitis * Cutaneous small-vessel vasculitis Other * Goodpasture syndrome * Sneddon's syndrome * v * t * e Hypersensitivity and autoimmune diseases Type I/allergy/atopy (IgE) Foreign * Atopic eczema * Allergic urticaria * Allergic rhinitis (Hay fever) * Allergic asthma * Anaphylaxis * Food allergy * common allergies include: Milk * Egg * Peanut * Tree nut * Seafood * Soy * Wheat * Penicillin allergy Autoimmune * Eosinophilic esophagitis Type II/ADCC * * IgM * IgG Foreign * Hemolytic disease of the newborn Autoimmune Cytotoxic * Autoimmune hemolytic anemia * Immune thrombocytopenic purpura * Bullous pemphigoid * Pemphigus vulgaris * Rheumatic fever * Goodpasture syndrome * Guillain–Barré syndrome "Type V"/receptor * Graves' disease * Myasthenia gravis * Pernicious anemia Type III (Immune complex) Foreign * Henoch–Schönlein purpura * Hypersensitivity vasculitis * Reactive arthritis * Farmer's lung * Post-streptococcal glomerulonephritis * Serum sickness * Arthus reaction Autoimmune * Systemic lupus erythematosus * Subacute bacterial endocarditis * Rheumatoid arthritis Type IV/cell-mediated (T cells) Foreign * Allergic contact dermatitis * Mantoux test Autoimmune * Diabetes mellitus type 1 * Hashimoto's thyroiditis * Multiple sclerosis * Coeliac disease * Giant-cell arteritis * Postorgasmic illness syndrome * Reactive arthritis GVHD * Transfusion-associated graft versus host disease Unknown/ multiple Foreign * Hypersensitivity pneumonitis * Allergic bronchopulmonary aspergillosis * Transplant rejection * Latex allergy (I+IV) Autoimmune * Sjögren syndrome * Autoimmune hepatitis * Autoimmune polyendocrine syndrome * APS1 * APS2 * Autoimmune adrenalitis * Systemic autoimmune disease * v * t * e Diseases of collagen, laminin and other scleroproteins Collagen disease COL1: * Osteogenesis imperfecta * Ehlers–Danlos syndrome, types 1, 2, 7 COL2: * Hypochondrogenesis * Achondrogenesis type 2 * Stickler syndrome * Marshall syndrome * Spondyloepiphyseal dysplasia congenita * Spondyloepimetaphyseal dysplasia, Strudwick type * Kniest dysplasia (see also C2/11) COL3: * Ehlers–Danlos syndrome, types 3 & 4 * Sack–Barabas syndrome COL4: * Alport syndrome COL5: * Ehlers–Danlos syndrome, types 1 & 2 COL6: * Bethlem myopathy * Ullrich congenital muscular dystrophy COL7: * Epidermolysis bullosa dystrophica * Recessive dystrophic epidermolysis bullosa * Bart syndrome * Transient bullous dermolysis of the newborn COL8: * Fuchs' dystrophy 1 COL9: * Multiple epiphyseal dysplasia 2, 3, 6 COL10: * Schmid metaphyseal chondrodysplasia COL11: * Weissenbacher–Zweymüller syndrome * Otospondylomegaepiphyseal dysplasia (see also C2/11) COL17: * Bullous pemphigoid COL18: * Knobloch syndrome Laminin * Junctional epidermolysis bullosa * Laryngoonychocutaneous syndrome Other * Congenital stromal corneal dystrophy * Raine syndrome * Urbach–Wiethe disease * TECTA * DFNA8/12, DFNB21 see also fibrous proteins * v * t * e Disease of the kidney glomerules Primarily nephrotic Non-proliferative * Minimal change * Focal segmental * Membranous Proliferative * Mesangial proliferative * Endocapillary proliferative * Membranoproliferative/mesangiocapillary By condition * Diabetic * Amyloidosis Primarily nephritic, RPG Type I RPG/Type II hypersensitivity * Goodpasture syndrome Type II RPG/Type III hypersensitivity * Post-streptococcal * Lupus * diffuse proliferative * IgA Type III RPG/Pauci-immune * Granulomatosis with polyangiitis * Microscopic polyangiitis * Eosinophilic granulomatosis with polyangiitis General * glomerulonephritis * glomerulonephrosis [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Goodpasture syndrome	c0403529	3,217	wikipedia	https://en.wikipedia.org/wiki/Goodpasture_syndrome	2021-01-18T18:50:21	{"gard": ["2551"], "mesh": ["D019867"], "umls": ["C0403529"], "orphanet": ["375"], "wikidata": ["Q1345792"]}
A number sign (#) is used with this entry because of evidence that achondrogenesis type IB (ACG1B) is caused by homozygous or compound heterozygous mutation in the DTDST gene (606718) on chromosome 5q32. Description The term achondrogenesis has been used to characterize the most severe forms of chondrodysplasia in humans, invariably lethal before or shortly after birth. Achondrogenesis type I is a severe chondrodystrophy characterized radiographically by deficient ossification in the lumbar vertebrae and absent ossification in the sacral, pubic and ischial bones and clinically by stillbirth or early death (Maroteaux and Lamy, 1968; Langer et al., 1969). In addition to severe micromelia, there is a disproportionately large cranium due to marked edema of soft tissues. ### Classification of Achondrogenesis Achondrogenesis was traditionally divided into 2 types: type I (Parenti-Fraccaro) and type II (Langer-Saldino). Borochowitz et al. (1988) suggested that achondrogenesis type I of Parenti-Fraccaro should be classified into 2 distinct disorders: type IA (ACG1A; 200600), corresponding to the cases originally published by Houston et al. (1972) and Harris et al. (1972), and type IB, corresponding to the case originally published by Fraccaro (1952). Analysis of the case reported by Parenti (1936) by Borochowitz et al. (1988) suggested the diagnosis of achondrogenesis type II, i.e., the Langer-Saldino type (200610). Type IA would be classified as lethal achondrogenesis, Houston-Harris type; type IB, lethal achondrogenesis, Fraccaro type; and type II, lethal achondrogenesis-hypochondrogenesis, Langer-Saldino type. Superti-Furga (1996) suggested that hypochondrogenesis should be considered separately from achondrogenesis type II because the phenotype can be much milder. Clinical Features In a patient considered to have achondrogenesis type IB, Superti-Furga (1994) found that cartilage extracts showed a reduced content of proteoglycans and that unlike control cartilage they did not stain with toluidine blue and did not bind to DEAE. Impaired synthesis of sulfated proteoglycans was observed in fibroblast cultures from the patient. Radioactive labeling and immunoprecipitation studies indicated that core protein and side chains of proteoglycans were synthesized normally but were not sulfated. Analysis of sulfate metabolism in cultured fibroblasts in the patient's cells showed normal intracellular levels of free sulfate but markedly reduced levels of the 2 intermediate compounds in the sulfate activation pathway, adenosine-phosphosulfate and phosphoadenosine-phosphosulfate. Superti-Furga (1994) suggested that the results can be explained by deficient activity of one of the enzymes responsible for the biologic activation of sulfate, possibly similar to that observed in cartilage (but not in skin) of the recessive, nonlethal mouse mutant 'brachymorphic' and leading to defective sulfation of macromolecules (Orkin et al., 1976; Sugahara and Schwartz, 1979; Sugahara and Schwartz, 1982). Superti-Furga et al. (1995) identified a sulfation defect in tissues and/or cells of 5 other type IB patients. Diagnosis Superti-Furga et al. (1996) observed that elucidation of the basic defect in ACG1B allows diagnosis by biochemical and molecular studies. They emphasized that accurate genetic counseling, particularly the distinction between ACG1B (which has a 25% recurrence risk) and the more frequent, autosomal dominant condition ACG2 (which usually involves the occurrence of new mutations and has a much lower recurrence risk), will be improved, and heterozygous carriers can be more readily detected. Couples at risk for having a child with ACG1B may decide to take advantage of molecular prenatal diagnosis by chorionic villus sampling, which can be done earlier than ultrasonographic diagnosis. Molecular Genetics In 6 patients with ACG1B, Superti-Furga et al. (1996) identified 7 different, putatively pathogenic, homozygous or compound heterozygous mutations in the DTDST gene (see, e.g., 606718.0005 and 606718.0006). The mutations were identified by genomic PCR, SSCP, and direct sequencing. One of the mutations (606718.0001) had previously been identified in patients with diastrophic dysplasia (222600). Thus, achondrogenesis type IB is a recessive disorder allelic to diastrophic dysplasia. INHERITANCE \- Autosomal recessive GROWTH Height \- Short-limbed dwarfism identifiable at birth Other \- Fetal hydrops HEAD & NECK Head \- Flat face RESPIRATORY Lung \- Respiratory insufficiency CHEST External Features \- Narrow chest Ribs Sternum Clavicles & Scapulae \- Thin short ribs \- Occasional rib fractures ABDOMEN External Features \- Umbilical hernia \- Inguinal herniae \- Distended abdomen SKELETAL Skull \- Slightly less ossified than expected for gestational age Spine \- Absent or minimally ossified vertebral bodies Pelvis \- Small iliac bones \- Unossified ischium and pubis Limbs \- Severe micromelia \- Marked shortness, broad tubular bone \- Metaphyseal spurring PRENATAL MANIFESTATIONS Amniotic Fluid \- Polyhydramnios Delivery \- Breech presentation at birth \- Often stillborn LABORATORY ABNORMALITIES \- No cartilage staining with toluidine blue \- Impaired synthesis of fibroblast sulfated proteoglycans MOLECULAR BASIS \- Caused by mutation in the solute carrier family 26 (sulfate transporter), member 2 gene (SLC26A2, 222600.0005 ) ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	ACHONDROGENESIS, TYPE IB	c0265274	3,218	omim	https://www.omim.org/entry/600972	2019-09-22T16:15:39	{"doid": ["0080055"], "mesh": ["C536016"], "omim": ["600972"], "orphanet": ["93298", "932"], "synonyms": ["Alternative titles", "ACHONDROGENESIS, FRACCARO TYPE"], "genereviews": ["NBK1516"]}
A cat with the genetic deformity radial hypoplaisia or radial aplaysia while resting, showing twisted forelimbs A squitten is a cat with a genetic deformity which causes a partial formation or complete absence of the radius bone making it resemble a squirrel. These cats should be kept indoors and seen to by specialist veterinarians, as long term management of the condition is essential for quality of life in these cats.[1] It is an example of a cat body type genetic mutation. The word is a portmanteau of squirrel and kitten. The term kangaroo cat is also, rarely, used; this derives from a 1953 specimen known as the Stalingrad Kangaroo Cat.[2] ## Characteristics[edit] A squitten with foreleg micromelia sitting in upright posture, showing short forelimbs The term squitten is generally used to refer to cats with the condition radial hypoplasia (underdeveloped radius bones) or foreleg micromelia (small forelegs) and related conditions known as radial aplasia (absent radius bones), radial agenesis (failure of radius bones to form) that produces stunted forelegs. The mutation sometimes occurs in the random-breeding population, particularly in inbred populations where recessive genes may be exhibited. Such cats have also been called twisty cats; In the late 1990s, several were deliberately bred at Karma Farms, a horse farm and cattery in Marshall, Texas,[3][4] resulting in a public outcry against the operators of the farm. Radial hypoplasia is related to one form of polydactyly, sometimes called patty feet or hamburger feet by cat lovers to distinguish them from thumb cat polydactyls. Ordinary mitten cat polydactyls are not affected.[5][6] Cats with radial hypoplasia or similar mutations often sit on their rump with their forelegs unable to touch the floor; this gives them a resemblance to a squirrel or kangaroo. This raises special care considerations for owners of affected cats. Kittens may be unable to knead effectively with their short forelegs; kneading is required to stimulate milk flow in the mother. The short or twisted forelegs cause mobility problems and such cats may adapt by using their hindlegs in a hopping gait. A corresponding condition affecting the hind legs is called femoral hypoplasia and has only been reported three times in cats.[7] Typical characteristics of a squitten are short forelegs, with a short radius and ulna which may be twisted or absent, extra front toes, and normal-length hind legs. ## See also[edit] * Chimera * Dwarf cats * Munchkin—a cat breed with short legs * Polydactyl cat ## References[edit] 1. ^ Kangaroo Cats and Squittens Revealed (October 2006) 2. ^ Robinson Roy (1999), "Genetics for Cat Breeders and Veterinarians", Butterworth Heinemann, ISBN 0-7506-4069-3 3. ^ Flipper-One Cute Twisty Kat and the Truth! 4. ^ [VETPET] National News Coverage of Twisty Cat Story 5. ^ Polydactyl Cats (October 2006) 6. ^ What Happened to the Maine Coon Polydactyl? (October 2006) 7. ^ Feline Radial and Femoral Hypoplasia (October 2006) * v * t * e Domestic cats Felinology * Anatomy * Genetics * Dwarf cat * Kitten * Odd-eyed cat * Squitten Coat genetics Bicolor cat Black cat Calico cat Tabby cat Tortoiseshell cat Health * Aging * Declawing * Diet * dental health * senior * Neutering * Spaying * Vaccination Behavior * Body language * Catfight * Catnip * valerian * Communication * Meow * Purr * Kneading * Intelligence * Play and toys * Righting reflex * Senses Human–cat interaction * Ailurophobia * Animal-assisted therapy * Bodega cat * Cat cafés * Cat massage * Cat meat * Cat-scratch disease * Cat show * Cats in ancient Egypt * Cultural depictions * Internet * Farm cat * Feral cat * Cats and Islam * Lolcat * National Cat Day * Puppy cat * Ship's cat * Zoonosis Registries * American Cat Fanciers Association * Associazione Nazionale Felina Italiana * Canadian Cat Association * Cat Aficionado Association * Cat Fanciers' Association * Fédération Internationale Féline * Governing Council of the Cat Fancy * Southern Africa Cat Council * The International Cat Association * World Cat Congress * World Cat Federation Breeds (full list) (experimental) Fully domestic Abyssinian American Curl American Shorthair Balinese Brazilian Shorthair British Shorthair Birman Bombay Burmese Burmilla California Spangled Chartreux Chinese Li Hua Colorpoint Shorthair Cornish Rex Cymric Devon Rex Donskoy Egyptian Mau European Shorthair Exotic Shorthair German Rex Himalayan Japanese Bobtail Javanese Khao Manee Korat Kurilian Bobtail Lykoi Maine Coon Manx Munchkin Norwegian Forest Ocicat Ojos Azules Oriental Shorthair Persian Peterbald Pixie-bob Raas Ragdoll Ragamuffin Russian Blue Scottish Fold Selkirk Rex Siamese Siberian Singapura Snowshoe Somali Sphynx Thai Traditional Persian Tonkinese Toyger Turkish Angora Turkish Van Hybrid Bengal Chausie Highlander Savannah Serengeti Landraces * Aegean * Cyprus * Domestic long-haired * Domestic short-haired * Kellas * Sokoke * Van Diseases and disorders * Acne * Asthma * Calicivirus * Congenital sensorineural deafness * Feline corneal sequestrum * Flea * Heartworm * Hepatic lipidosis * Hypertrophic cardiomyopathy * Immunodeficiency virus * Infectious peritonitis * Leukemia virus * Lower urinary tract disease * Panleukopenia * Polydactyly * Rabies * Ringworm * Roundworm * Skin disorders * Tick * Toxoplasmosis * Viral rhinotracheitis * Book * Category [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Squitten	None	3,219	wikipedia	https://en.wikipedia.org/wiki/Squitten	2021-01-18T19:01:03	{"wikidata": ["Q7582359"]}
A number sign (#) is used with this entry because Rubinstein-Taybi syndrome-2 (RSTS2) is caused by heterozygous mutation in the EP300 gene (602700) on chromosome 22q13. Most, if not all, mutations occur de novo. Description Rubinstein-Taybi syndrome (RSTS) is a multiple congenital anomaly syndrome characterized by mental retardation, postnatal growth deficiency, microcephaly, broad thumbs and halluces, and dysmorphic facial features. The classic facial appearance is striking, with highly arched eyebrows, long eyelashes, downslanting palpebral fissures, broad nasal bridge, beaked nose with the nasal septum, highly arched palate, mild micrognathia, and characteristic grimacing or abnormal smile (Rubinstein and Taybi, 1963; review by Hennekam, 2006). About 50 to 70% of patients have RSTS1 due to mutation in the CREBBP gene (600140). RSTS2 is much less common, and about 3% of patients have mutations in the EP300 gene. RSTS2 appears to be associated with a milder phenotype than RSTS1. Patients with RSTS2 have less severe facial dysmorphism and better cognitive function, but may have more severe microcephaly and malformation of facial bone structures compared to those with RSTS1 (Bartsch et al., 2010). For a discussion of genetic heterogeneity of Rubinstein-Taybi syndrome, see RSTS1 (180849). Clinical Features Roelfsema et al. (2005) reported 3 unrelated patients with RSTS2. The phenotypes were compatible with RSTS in most respects: all patients had heavy and arched eyebrows, long eyelashes, a prominent nose with long columella, and a pouting lower lip. However, only 1 patient had micrognathia, 1 had mildly downslanted palpebral fissures, and none had the grimacing smile. All had short broad thumbs and big toes, and square distal fingertips. The patients were identified from a larger cohort of 92 patients with a clinical diagnosis of RSTS. Bartholdi et al. (2007) reported detailed clinical features of 4 RSTS patients with mutations in the EP300 gene; 3 of the patients had been reported by Roelfsema et al. (2005). The patients had the typical facial gestalt, malformation patterns, and mental and behavioral signs consistent with the syndrome, but 3 patients did not show the classic malformations on both hands and feet, which originally had been considered mandatory for the diagnosis. The authors concluded that clinical variability in RSTS may be due to genetic heterogeneity and emphasized that the diagnosis must be expanded to include individuals without broad thumbs or halluces. Zimmermann et al. (2007) reported a female with a mild form of RSTS due to a de novo heterozygous mutation in the EP300 gene (602700.0006). She had microcephaly, beaked nose, narrow high-arched palate, and borderline intelligence (IQ of about 75). Bartsch et al. (2010) provided more detailed information on the patient reported by Zimmermann et al. (2007). At age 19, she had global developmental delay, but was able to work in a sheltered workshop after being schooled in special needs. She had marked mandibular retrognathism, requiring surgical correction. Other features included mild myopia, bilateral pes valgus, genu valgum, and scoliosis. Radiographs showed sphenoid bone asymmetry and deformity of the left side of the atlas. Foley et al. (2009) described a 7-year-old boy with global developmental delay, slightly broad halluces and terminal phalanges but normal thumbs, and facial dysmorphism reminiscent of RSTS, especially while smiling, in whom they identified a de novo deletion in the EP300 gene (602700.0007). Dysmorphic features included microcephaly, slightly prominent columella, long eyelashes with rather full arched eyebrows, overlapping toes, and evidence of hirsutism on his back with a hair tuft on the left paravertebral region. Bartsch et al. (2010) reported a 3-year-old boy with RSTS2. He had severe microcephaly, retrognathia, broad thumbs and great toes, and delayed psychomotor development with marked speech delay. He also had posterior helical pits, but normal palpebral fissures, nose, and mouth. Genetic analysis identified an apparently de novo heterozygous mutation in the EP300 gene (638delG; 602700.0008). Bartsch et al. (2010) proposed that RSTS individuals with EP300 mutations have a slightly different phenotype than those with CREBBP mutations, including less severe mental impairment, more severe microcephaly, and a greater degree of changes in facial bone structure. Woods et al. (2014) reported a 5-year-old Caucasian male with a phenotype suggesting Cornelia de Lange syndrome (CDLS; 122470) in whom no mutations were found in CDLS-related genes. The boy presented with intrauterine growth restriction, failure to thrive, microcephaly, cryptorchidism, hirsutism, short stature, and intellectual disability. He also had severe progressive scoliosis and chest deformity. He did not have the cardinal features of RSTS such as the typical facial gestalt or broad thumbs or toes. Exome sequencing after the child's death from bronchopneumonia identified a novel mutation in the EP300 gene (602700.0009). Autopsy showed intestinal malrotation, lung lobulation, and genitourinary anomalies. Woods et al. (2014) noted that this was the fourth RSTS case with a mutation in EP300 associated with preeclampsia and premature birth. Hamilton et al. (2016) described 9 unrelated patients, aged 3 to 19 years, with RSTS2. Two of the pregnancies were complicated by preeclampsia. All 9 patients had mild or moderate intellectual impairment, and 8 had delays in gross motor development. Eight patients had behavioral or social difficulties, and 3 had a diagnosis of autism spectrum disorder. Typical dysmorphic features were variably present. Additional features included scoliosis in 2, syndactyly in 3, feeding/swallowing issues beyond the neonatal period in 3, and hypermobility or dislocation of the elbow in 2. Three patients had overlapping features with Floating-Harbor syndrome (136140), including thin upper vermilion, long nose, and low-hanging columella in 2 and delayed bone age in 2. Molecular Genetics In 3 of 92 patients with a clinical diagnosis of RSTS, Roelfsema et al. (2005) identified 3 different mutations in the EP300 gene (602700.0003-602700.0005), and stated that these were the first mutations found in EP300 as the basis of a congenital disorder. EP300 and CREBBP (600140) both function as transcriptional coactivators in the regulation of gene expression through various signal transduction pathways, and both are potent histone acetyltransferases. These findings suggested that the disorder is caused by aberrant chromatin regulation. In 1 (2.6%) of 38 patients with RSTS who did not have mutations in the CREBBP gene, Zimmermann et al. (2007) identified a mutation in the EP300 gene (602700.0006) predicted to result in mild protein truncation. The patient had a very mild form of the disorder. Zimmermann et al. (2007) concluded that mutations in the EP300 gene play only a minor role in the etiology of RSTS. In a 7-year-old boy with global developmental delay and a mild skeletal phenotype but facial dysmorphism reminiscent of RSTS, especially while smiling, Foley et al. (2009) identified a de novo deletion in the EP300 gene (602700.0007). Using high resolution array comparative genomic hybridization (array CGH) targeting exons, Tsai et al. (2011) identified a de novo 5-kb deletion on chromosome 22q13.32 encompassing exons 24 to 27 of the EP300 gene in a girl referred for mild developmental delay and mild dysmorphic features. The diagnosis was consistent with RSTS2. She had microcephaly, short stature, and behavioral problems, but notably did not have abnormalities of the thumb or great toe. Her mother had preeclampsia during the pregnancy, and the patient was born prematurely at age 28 weeks' gestation. Hamilton et al. (2016) reported heterozygous de novo mutations at highly conserved residues in the EP300 gene in 9 unrelated patients from the UK or Ireland with RSTS2. Six mutations were truncating mutations and 3 were missense (see, e.g., 602700.0010 and 602700.0011) mutations. Hamilton et al. (2016) confirmed all 9 mutations by Sanger sequencing. INHERITANCE \- Autosomal dominant HEAD & NECK Head \- Microcephaly Face \- Micrognathia \- Retrognathia Ears \- Posterior helical pits Eyes \- Heavy, arched eyebrows \- Long eyelashes \- Downslanting palpebral fissures, mild \- Normal palpebral fissures Nose \- Prominent nose \- Beaked nose \- Long columella extending below the alae nasi Mouth \- Narrow palate \- High-arched palate Teeth \- Dental malocclusion \- Overbite \- Dental caries ABDOMEN Gastrointestinal \- Malrotation (in some patients) \- Feeding/swallowing issues beyond the neonatal period (in some patients) SKELETAL Hands \- Broad thumbs \- Square distal fingertips \- Syndactyly (in some patients) Feet \- Broad great toes SKIN, NAILS, & HAIR Hair \- Hirsutism (in some patients) NEUROLOGIC Central Nervous System \- Mental retardation, mild to moderate \- Low-normal intelligence \- Autism spectrum disorder (in some patients) \- Delayed psychomotor development \- Delayed gross motor development \- Speech delay \- Hypotonia Behavioral Psychiatric Manifestations \- Hyperactivity \- Behavioral difficulties PRENATAL MANIFESTATIONS Maternal \- Preeclampsia (in some patients) MISCELLANEOUS \- De novo mutation \- Onset at birth \- May have less severe phenotype than RSTS patients with CREBBP mutations MOLECULAR BASIS \- Caused by mutation in the 300-KD E1A-binding protein gene (EP300, 602700.0003 ) ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	RUBINSTEIN-TAYBI SYNDROME 2	c0035934	3,220	omim	https://www.omim.org/entry/613684	2019-09-22T15:57:51	{"doid": ["1933"], "mesh": ["D012415"], "omim": ["613684"], "orphanet": ["353284", "783"], "synonyms": [], "genereviews": ["NBK1526"]}
Granulomatosis with polyangiitis (GPA) is a condition that causes inflammation that primarily affects the respiratory tract (including the lungs and airways) and the kidneys. This disorder is formerly known as Wegener granulomatosis. A characteristic feature of GPA is inflammation of blood vessels (vasculitis), particularly the small- and medium-sized blood vessels in the lungs, nose, sinuses, windpipe, and kidneys, although vessels in any organ can be involved. Polyangiitis refers to the inflammation of multiple types of vessels, such as small arteries and veins. Vasculitis causes scarring and tissue death in the vessels and impedes blood flow to tissues and organs. Another characteristic feature of GPA is the formation of granulomas, which are small areas of inflammation composed of immune cells that aid in the inflammatory reaction. The granulomas usually occur in the lungs or airways of people with this condition, although they can occur in the eyes or other organs. As granulomas grow, they can invade surrounding areas, causing tissue damage. The signs and symptoms of GPA vary based on the tissues and organs affected by vasculitis. Many people with this condition experience a vague feeling of discomfort (malaise), fever, weight loss, or other general symptoms of the body's immune reaction. In most people with GPA, inflammation begins in the vessels of the respiratory tract, leading to nasal congestion, frequent nosebleeds, shortness of breath, or coughing. Severe inflammation in the nose can lead to a hole in the tissue that separates the two nostrils (nasal septum perforation) or a collapse of the septum, causing a sunken bridge of the nose (saddle nose). The kidneys are commonly affected in people with GPA. Tissue damage caused by vasculitis in the kidneys can lead to decreased kidney function, which may cause increased blood pressure or blood in the urine, and life-threatening kidney failure. Inflammation can also occur in other regions of the body, including the eyes, middle and inner ear structures, skin, joints, nerves, heart, and brain. Depending on which systems are involved, additional symptoms can include skin rashes, inner ear pain, swollen and painful joints, and numbness or tingling in the limbs. GPA is most common in middle-aged adults, although it can occur at any age. If untreated, the condition is usually fatal within 2 years of diagnosis. Even after treatment, vasculitis can return. ## Frequency GPA is a rare disorder that affects an estimated 3 in 100,000 people in the United States. ## Causes The genetic basis of GPA is not well understood. Having a particular version of the HLA-DPB1 gene is the strongest genetic risk factor for developing this condition, although several other genes, some of which have not been identified, may be involved. It is likely that a combination of genetic and environmental factors lead to GPA. GPA is an autoimmune disorder. Such disorders occur when the immune system malfunctions and attacks the body's own tissues and organs. Approximately 90 percent of people with GPA have an abnormal immune protein called an anti-neutrophil cytoplasmic antibody (ANCA) in their blood. Antibodies normally bind to specific foreign particles and germs, marking them for destruction, but ANCAs attack normal human proteins. Most people with GPA have an ANCA that attacks the human protein proteinase 3 (PR3). A few affected individuals have an ANCA that attacks a protein called myeloperoxidase (MPO). When these antibodies attach to the protein they recognize, they trigger inflammation, which contributes to the signs and symptoms of GPA. The HLA-DPB1 gene belongs to a family of genes called the human leukocyte antigen (HLA) complex. The HLA complex helps the immune system distinguish the body's own proteins from proteins made by foreign invaders (such as viruses and bacteria). Each HLA gene has many different normal variations, allowing each person's immune system to react to a wide range of foreign proteins. A particular variant of the HLA-DPB1 gene called HLA-DPB10401 has been found more frequently in people with GPA, especially those with ANCAs, than in people without the condition. Because the HLA-DPB1 gene is involved in the immune system, changes in it might be related to the autoimmune response and inflammation in the respiratory tract and kidneys characteristic of GPA. However, it is unclear what specific role the HLA-DPB10401 gene variant plays in development of this condition. ### Learn more about the gene associated with Granulomatosis with polyangiitis * HLA-DPB1 ## Inheritance Pattern The inheritance pattern of GPA is unknown. Most instances are sporadic and occur in individuals with no history of the disorder in their family. Only rarely is more than one member of the same family affected by the disorder. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Granulomatosis with polyangiitis	c3495801	3,221	medlineplus	https://medlineplus.gov/genetics/condition/granulomatosis-with-polyangiitis/	2021-01-27T08:25:07	{"gard": ["7880"], "mesh": ["D014890"], "omim": ["608710"], "synonyms": []}
A rare ophthalmic disorder characterized by visual abnormalities (such as myopia, strabismus, or amblyopia) due to the presence of myelinated retinal nerve fibers, which appear as whitish patches with feathery edges at the level of the retinal nerve fiber layer and may be continuous or discontinuous with the optic nerve head. The defect can be unilateral or bilateral. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Extensive peripapillary myelinated nerve fibers	None	3,222	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=440724	2021-01-23T18:33:34	{}
Branchiootorenal (BOR) syndrome is characterized by branchial arch anomalies (branchial clefts, fistulae, cysts), hearing impairment (malformations of the auricle with pre-auricular pits, conductive or sensorineural hearing impairment), and renal malformations (urinary tree malformation, renal hypoplasia or agenesis, renal dysplasia, renal cysts). ## Epidemiology Prevalence is 1/40,000. Renal involvement can lead to chronic renal insufficiency. ## Clinical description The expression of the disease varies widely from one family to another and among individuals of the same family. Some families do not present with renal abnormalities or a urinary tree malformation. ## Etiology The causative gene, EYA1, is located on the long arm of chromosome 8. Point mutations and deletions in EYA1 have been identified in approximately 40% of affected individuals. Mutations have also been identified in the SIX1 and SIX5 genes, the products of which interact with EYA1 to form transcription factor complexes. ## Antenatal diagnosis Prenatal testing can be proposed to families in which the disease-causing mutation has been identified, but genetic counseling is difficult because of the clinical heterogeneity between individuals. ## Genetic counseling BOR syndrome is transmitted in an autosomal dominant manner. ## Management and treatment Management of affected patients includes excision of branchial fistulae or cysts, hearing aids and education programs appropriate for the hearing impaired, and follow-up by a nephrologist. Dialysis or renal transplantation may be required. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	BOR syndrome	c0265234	3,223	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=107	2021-01-23T18:40:30	{"gard": ["10147"], "mesh": ["D019280"], "omim": ["113650", "610896"], "umls": ["C0265234"], "icd-10": ["Q87.8"], "synonyms": ["Branchiootorenal syndrome"]}
Chromosomal anomaly 49,XXXXYsyndrome SpecialtyMedical genetics 49,XXXXY syndrome is an extremely rare aneuploidic sex chromosomal abnormality. It occurs in approximately 1 out of 85,000 to 100,000 males.[1][2][3] This syndrome is the result of maternal non-disjunction during both meiosis I and II.[4] It was first diagnosed in 1960 and was coined Fraccaro syndrome after the researcher.[2] ## Contents * 1 Signs and symptoms * 1.1 Reproductive * 1.2 Physical * 1.3 Cognitive and developmental * 2 Pathophysiology * 3 Diagnosis * 4 Treatment * 5 See also * 6 References * 7 Further reading * 8 External links ## Signs and symptoms[edit] The symptoms of 49,XXXXY are slightly similar to that of Klinefelter syndrome and 48,XXXY however, they are usually much more severe in 49, XXXXY syndrome. Aneuploidy is often fatal, but in this case there is "X-inactivation" where the effect of the additional gene dosage due to the presence of extra X chromosomes is greatly reduced.[5] ### Reproductive[edit] Those with 49,XXXXY syndrome tend to exhibit infantile secondary sex characteristics with sterility in adulthood.[5] * Hypoplastic genitalia[5] ### Physical[edit] Males with 49,XXXXY tend to have numerous skeletal anomalies. These skeletal anomalies include: * Genu valgum * Pes cavus * Fifth finger clinodactyly The effects also include: * Cleft palate * Club feet * Respiratory conditions * Short or/and broad neck * Low birth weight * Hyperextensible joints * Short stature * Narrow shoulders * Coarse features in older age * Hypertelorism * Epicanthal folds * Prognathism * Gynecomastia (rare) * Muscular hypotonia * Cryptorchidism * Congenital heart defects * A very round face in infancy[5] ### Cognitive and developmental[edit] Much like Down syndrome, the mental effects of 49,XXXXY syndrome vary. Impaired speech and maladaptive behavioral problems are typical.[6] One study looked at males that were diagnosed with 48,XXYY, 48,XXXY and 49,XXXXY. They found that males with 48,XXXY and 49,XXXXY function at a much lower cognitive level than males their age. These males also tend to exhibit more immature behavior for their chronological age; increased aggressive tendencies were also cited in this study.[6] ## Pathophysiology[edit] As its name indicates, a person with the syndrome has one Y chromosome and four X chromosomes on the 23rd pair, thus having forty-nine chromosomes rather than the normal forty-six. As with most categories of aneuploidy disorders, 49,XXXXY syndrome is often accompanied by intellectual disability. It can be considered a form or variant of Klinefelter syndrome (47,XXY).[7] Individuals with this syndrome are typically mosaic, being 49,XXXXY/48, XXXX.[4] It is genetic but not hereditary, meaning that while the genes of the parents cause the syndrome, there is a small chance of more than one child having the syndrome. The probability of inheriting the disease is about one percent.[5] ## Diagnosis[edit] 49,XXXXY can be clinically diagnosed through karyotyping.[8] Facial dysmorphia and other somatic abnormalities may be reason to have the genetic testing done.[4] ## Treatment[edit] While there is no treatment to correct the genetic abnormality of this syndrome, there is the potential to treat the symptoms. As a result of infertility, one man from Iran used artificial reproductive methods.[4] An infant in Iran diagnosed with 49,XXXXY syndrome was born with patent ductus arteriosus, which was corrected with surgery, and other complications that were managed with replacement therapy.[4] ## See also[edit] * Aneuploidy * Turner syndrome * Klinefelter syndrome * 49, XXXXX, a similar syndrome that affects females ## References[edit] 1. ^ Visootsak J, Graham JM (2006). "Klinefelter syndrome and other sex chromosomal aneuploidies". Orphanet J Rare Dis. 1: 42. doi:10.1186/1750-1172-1-42. PMC 1634840. PMID 17062147. 2. ^ a b Fraccaro, M.; Kaijser, K.; Lindsten, J. (1960-10-22). "A child with 49 chromosomes". Lancet. 2 (7156): 899–902. doi:10.1016/s0140-6736(60)91963-2. ISSN 0140-6736. PMID 13701146. 3. ^ Etemadi, Katayoon; Basir, Behnaz; Ghahremani, Safieh (March 2015). "Neonatal diagnosis of 49, XXXXY syndrome". Iranian Journal of Reproductive Medicine. 13 (3): 181–184. ISSN 1680-6433. PMC 4426158. PMID 26000009. 4. ^ a b c d e Hadipour, Fatemeh; Shafeghati, Yousef; Bagherizadeh, Eiman; Behjati, Farkhondeh; Hadipour, Zahra (2013). "Fraccaro syndrome: report of two Iranian cases: an infant and an adult in a family". Acta Medica Iranica. 51 (12): 907–909. ISSN 1735-9694. PMID 24442548. 5. ^ a b c d e Webspawner.com article on 49,XXXXY syndrome Archived 2008-09-14 at the Wayback Machine. Retrieved 26 March 2008. 6. ^ a b Visootsak J, Rosner B, Dykens E, Tartaglia N, Graham JM (June 2007). "Behavioral phenotype of sex chromosome aneuploidies: 48,XXYY, 48,XXXY, and 49,XXXXY". Am. J. Med. Genet. A. 143A (11): 1198–203. doi:10.1002/ajmg.a.31746. PMID 17497714. S2CID 25732790. 7. ^ Cotran, Ramzi S.; Kumar, Vinay; Fausto, Nelson; Nelso Fausto; Robbins, Stanley L.; Abbas, Abul K. (2005). Robbins and Cotran pathologic basis of disease. St. Louis, Mo: Elsevier Saunders. p. 179. ISBN 0-7216-0187-1. 8. ^ Blumenthal, Jonathan D.; Baker, Eva H.; Lee, Nancy Raitano; Wade, Benjamin; Clasen, Liv S.; Lenroot, Rhoshel K.; Giedd, Jay N. (2013). "Brain morphological abnormalities in 49,XXXXY syndrome: A pediatric magnetic resonance imaging study". NeuroImage: Clinical. 2: 197–203. doi:10.1016/j.nicl.2013.01.003. PMC 3649771. PMID 23667827. ## Further reading[edit] * Jonathan D. Blumenthal; Eva H. Baker; Nancy Raitano Lee; Benjamin Wade; Liv S. Clasen; Rhoshel K. Lenroot; Jay N. Giedd (2013). "Brain morphological abnormalities in 49,XXXXY syndrome: A pediatric magnetic resonance imaging study". NeuroImage: Clinical. 2: 197–203. doi:10.1016/j.nicl.2013.01.003. PMC 3649771. PMID 23667827. ## External links[edit] Classification D * ICD-9-CM: 758.81 * DiseasesDB: 32552 * 49 XXXXY at the National Organization of Rare Diseases * v * t * e Chromosome abnormalities Autosomal Trisomies/Tetrasomies * Down syndrome * 21 * Edwards syndrome * 18 * Patau syndrome * 13 * Trisomy 9 * Tetrasomy 9p * Warkany syndrome 2 * 8 * Cat eye syndrome/Trisomy 22 * 22 * Trisomy 16 Monosomies/deletions * (1q21.1 copy number variations/1q21.1 deletion syndrome/1q21.1 duplication syndrome/TAR syndrome/1p36 deletion syndrome) * 1 * Wolf–Hirschhorn syndrome * 4 * Cri du chat syndrome/Chromosome 5q deletion syndrome * 5 * Williams syndrome * 7 * Jacobsen syndrome * 11 * Miller–Dieker syndrome/Smith–Magenis syndrome * 17 * DiGeorge syndrome * 22 * 22q11.2 distal deletion syndrome * 22 * 22q13 deletion syndrome * 22 * genomic imprinting * Angelman syndrome/Prader–Willi syndrome (15) * Distal 18q-/Proximal 18q- X/Y linked Monosomy * Turner syndrome (45,X) Trisomy/tetrasomy, other karyotypes/mosaics * Klinefelter syndrome (47,XXY) * XXYY syndrome (48,XXYY) * XXXY syndrome (48,XXXY) * 49,XXXYY * 49,XXXXY * Triple X syndrome (47,XXX) * Tetrasomy X (48,XXXX) * 49,XXXXX * Jacobs syndrome (47,XYY) * 48,XYYY * 49,XYYYY * 45,X/46,XY * 46,XX/46,XY Translocations Leukemia/lymphoma Lymphoid * Burkitt's lymphoma t(8 MYC;14 IGH) * Follicular lymphoma t(14 IGH;18 BCL2) * Mantle cell lymphoma/Multiple myeloma t(11 CCND1:14 IGH) * Anaplastic large-cell lymphoma t(2 ALK;5 NPM1) * Acute lymphoblastic leukemia Myeloid * Philadelphia chromosome t(9 ABL; 22 BCR) * Acute myeloblastic leukemia with maturation t(8 RUNX1T1;21 RUNX1) * Acute promyelocytic leukemia t(15 PML,17 RARA) * Acute megakaryoblastic leukemia t(1 RBM15;22 MKL1) Other * Ewing's sarcoma t(11 FLI1; 22 EWS) * Synovial sarcoma t(x SYT;18 SSX) * Dermatofibrosarcoma protuberans t(17 COL1A1;22 PDGFB) * Myxoid liposarcoma t(12 DDIT3; 16 FUS) * Desmoplastic small-round-cell tumor t(11 WT1; 22 EWS) * Alveolar rhabdomyosarcoma t(2 PAX3; 13 FOXO1) t (1 PAX7; 13 FOXO1) Other * Fragile X syndrome * Uniparental disomy * XX male syndrome/46,XX testicular disorders of sex development * Marker chromosome * Ring chromosome * 6; 9; 14; 15; 18; 20; 21, 22 [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	49,XXXXY	c0265499	3,224	wikipedia	https://en.wikipedia.org/wiki/49,XXXXY	2021-01-18T18:38:24	{"gard": ["5679"], "mesh": ["D007713"], "umls": ["C0265499"], "icd-9": ["758.81"], "orphanet": ["96264"], "wikidata": ["Q4638720"]}
Succinyl-CoA:3-oxoacid CoA transferase deficiency Other namesSCOT deficiency Succinyl-CoA:3-oxoacid CoA transferase deficiency is inherited via autosomal recessive manner Succinyl-CoA:3-oxoacid CoA transferase deficiency is an inborn error of ketone body utilization. Succinyl-CoA:3-oxoacid CoA transferase catalyzes the transfer of coenzyme A from succinyl-coenzyme A to acetoacetate. It can be caused by mutation in the OXCT1 gene. First described in 1972, more than 30 people have been reported in the medical literature with this inborn error of metabolism. They experience attacks of ketoacidosis during illness, and even when well may have elevated levels of ketone bodies in blood and urine (ketonemia and ketonuria, respectively). Not all people with SCOT deficiency have persistent ketonemia and ketonuria, particularly those with milder defects of enzyme activity.[1] ## References[edit] 1. ^ Fukao, Toshiyuki; Mitchell, Grant; Sass, Jörn Oliver; Hori, Tomohiro; Orii, Kenji; Aoyama, Yuka (8 April 2014). "Ketone body metabolism and its defects". Journal of Inherited Metabolic Disease. 37 (4): 541–551. doi:10.1007/s10545-014-9704-9. PMID 24706027. ## External links[edit] Classification D * ICD-10: E71.3 * OMIM: 245050 * MeSH: C537527 External resources * Orphanet: 832 This article about an endocrine, nutritional, or metabolic disease is a stub. You can help Wikipedia by expanding it. * v * t * e [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Succinyl-CoA:3-oxoacid CoA transferase deficiency	c0342792	3,225	wikipedia	https://en.wikipedia.org/wiki/Succinyl-CoA:3-oxoacid_CoA_transferase_deficiency	2021-01-18T18:52:15	{"gard": ["4774"], "mesh": ["C537527"], "umls": ["C0342792"], "orphanet": ["832"], "wikidata": ["Q7632698"]}
A number sign (#) is used with this entry because primary ciliary dyskinesia-29 (CILD29) is caused by homozygous or compound heterozygous mutation in the CCNO gene (607752) on chromosome 5q11. Description Primary ciliary dyskinesia-29 is an autosomal recessive disorder characterized by early childhood onset of recurrent respiratory infections due to defective mucociliary clearance. Patients do not have situs inversus (summary by Wallmeier et al., 2014). For a phenotypic description and a discussion of genetic heterogeneity of primary ciliary dyskinesia, see 244400. Clinical Features Wallmeier et al. (2014) reported 16 patients from 10 families who had recurrent upper and lower respiratory infections from early childhood. The disorder was progressive, resulting in bronchiectasis, chronic airway disease with atelectasis, mucus plugging, and deterioration of lung function. Two patients required lung transplantation as adults. Nasal nitric oxide was markedly reduced. One female presented with infertility and used assisted reproduction to become pregnant. None of the patients had situs inversus. Patient respiratory epithelial cells showed either a complete absence or markedly decreased numbers of cilia, and cultured patient respiratory epithelial cells showed a severe defect in generation of multiple motile cilia associated with insufficient centriole numbers and decreased basal bodies. Some basal bodies were mislocalized in the cytoplasm, suggesting a basal body migration defect. However, the few residual cilia that correctly expressed axonemal motor proteins were motile and did not exhibit obvious beating defects. Casey et al. (2015) reported 2 brothers from a consanguineous Irish Traveller family (family B) with primary ciliary dyskinesia. Both presented with recurrent lower respiratory tract infections, and 1 also had recurrent otitis media. Nasal nitric oxide was decreased. Neither patient had situs inversus. Nasal respiratory epithelial cells were completely nude, suggesting ciliary aplasia, but this may have been secondary to active infection. Inheritance The transmission pattern of CILD29 in the families reported by Wallmeier et al. (2014) was consistent with autosomal recessive inheritance. Molecular Genetics In 16 patients from 10 families with primary ciliary dyskinesia-29, Wallmeier et al. (2014) identified homozygous or compound heterozygous mutations in the CCNO gene (see, e.g., 607752.0001-607752.0006). All but 1 of the mutations resulted in a truncated protein, consistent with a loss of function. Several of the families were consanguineous and 1 was of Kuwaiti origin. The first mutation was found by whole-exome sequencing of 1 family, and the remaining families were identified from a cohort of 53 families with a similar phenotype. Studies of patient cells and in vitro studies suggested that CCNO functions in a pathway to promote mother centriole amplification and maturation in preparation for apical docking and ciliogenesis. In 2 brothers of Irish Traveller descent with CILD29, Casey et al. (2015) identified a homozygous truncating mutation in the CCNO gene (607752.0002). The mutation, which was found by a combination of homozygosity mapping and exome variant analysis, was confirmed by Sanger sequencing. The mutation segregated with the disorder in the family. INHERITANCE \- Autosomal recessive RESPIRATORY \- Respiratory infections, recurrent \- Decreased numbers of motile cilia in respiratory epithelial cells Lung \- Bronchiectasis \- Atelectasis \- Deterioration of lung function ABDOMEN \- No situs inversus GENITOURINARY Internal Genitalia (Female) \- Infertility (in some patients) LABORATORY ABNORMALITIES \- Decreased nasal nitric oxide MISCELLANEOUS \- Onset in early childhood \- Progressive disorder MOLECULAR BASIS \- Caused by mutation in the cyclin O gene (CCNO, 607752.0001 ) ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	CILIARY DYSKINESIA, PRIMARY, 29	c4014534	3,226	omim	https://www.omim.org/entry/615872	2019-09-22T15:50:46	{"doid": ["0110600"], "omim": ["615872", "244400"], "orphanet": ["244"], "synonyms": ["Alternative titles", "CILIARY DYSKINESIA, PRIMARY, 29, WITHOUT SITUS INVERSUS", "PCD"], "genereviews": ["NBK1122"]}
A number sign (#) is used with this entry because Brown-Vialetto-Van Laere syndrome-1 (BVVLS1), a form of progressive bulbar palsy with sensorineural deafness, is caused by homozygous or compound heterozygous mutation in the C20ORF54 gene (SLC52A3; 613350) on chromosome 20p13. Mutations in the SLC52A3 gene also result in Fazio-Londe disease (211500), a disorder similar to BVVLS but without sensorineural deafness. Description Brown-Vialetto-Van Laere syndrome is a rare autosomal recessive neurologic disorder characterized by sensorineural hearing loss and a variety of cranial nerve palsies, usually involving the motor components of the seventh and ninth to twelfth (more rarely the third, fifth, and sixth) cranial nerves. Spinal motor nerves and, less commonly, upper motor neurons are sometimes affected, giving a picture resembling amyotrophic lateral sclerosis (ALS; 105400). The onset of the disease is usually in the second decade, but earlier and later onset have been reported. Hearing loss tends to precede the onset of neurologic signs, mostly progressive muscle weakness causing respiratory compromise. However, patients with very early onset may present with bulbar palsy and may not develop hearing loss until later. The symptoms, severity, and disease duration are variable (summary by Green et al., 2010). ### Genetic Heterogeneity of Brown-Vialetto-Van Laere Syndrome See also BVVLS2 (614707), caused by mutation in the SLC52A2 gene (607882) on chromosome 8q. Clinical Features The first case of BVVLS was reported by Brown (1894) as a form of familial infantile amyotrophic lateral sclerosis. Familial cases in a pattern consistent with autosomal recessive inheritance were reported by Vialetto (1936), Van Laere (1966), and Boudin et al. (1971). Most familial cases involved affected females. Gallai et al. (1981) described the clinical features of 2 patients and the clinical and postmortem findings in the sib of one of these. One of these patients was a girl who became deaf at age 2 and developed multiple cranial and spinal nerve palsies at age 14. Her brother died of the condition at age 2. The parents were unrelated. The third case, sporadic, had onset of deafness at age 6 and of other neurologic disturbances at age 12. Hawkins et al. (1990) reported an affected family. The proband was a healthy, athletic young girl until the age of 12 years when, over the course of a few weeks, she had rapid onset of neurosensory deafness. The following year she developed rapidly progressive weakness with clumsiness of her arms and difficulty in washing, dressing, writing, and combing her hair. At that time she also tended to shake and twitch, particularly at night. She complained of sleepiness during the day and of shortness of breath and was unable to rise from a supine position. Her speech was soft and she had difficulty swallowing. Treatment with steroids for 12 months when she was 13 years old resulted in improvement, but at the age of 15 she began to deteriorate again. She had nocturnal hypoventilation and daytime sleepiness resulting from diaphragmatic weakness, as well as right vocal cord paralysis and increasing difficulty swallowing. She died at the age of 17 years 4 months. A paternal aunt who had had breathing difficulties for 20 years and facial weakness for 2 years showed pallor of the left optic disc and weakness of the facial and neck muscles as well as neurosensory deafness. The tongue was wasted and fasciculating, and the diaphragm was weak. She refused examination of her 10 children. According to the school doctor, 1 of her sons had developed neurosensory deafness in his teens. The paternal grandfather died at the age of 40 years with chronic respiratory problems. Dipti et al. (2005) reported 4 sibs, born of consanguineous Pakistani parents, with BVVLS. Two presented in the first 16 months of life with stridor and died of respiratory failure by the age of 2 years. Both had normal early psychomotor development before onset of the disorder. Hearing loss was not apparent in these infants, and they were given a diagnosis of Fazio-Londe disease (211500). In contrast, the 2 other sibs showed onset of a bulbar palsy at age 5 and 7 years, followed by onset of deafness and an anterior horn neuropathy with corticospinal tract involvement. Features included dysphagia, facial weakness with ptosis, tongue weakness and fasciculations, muscle weakness, particularly of the upper limbs, hyperreflexia, ankle clonus, and extensor plantar responses. They exhibited a relatively slow but relentless decline over a period of several years, resulting in death at age 10 years in one and severe muscle weakness in the other. Dipti et al. (2005) noted the overlap between BVVLS and Fazio-Londe syndrome, and suggested that both younger children may have developed deafness later. The authors suggested that these disorders may be a single disease entity, which could be considered a form of juvenile amyotrophic lateral sclerosis. Green et al. (2010) reported 9 patients with BVVLS from 7 families, including 1 reported by Dipti et al. (2005). Members of 4 families showed onset of the disorder before 2 years of age, with bulbar palsy, hypotonia, anterior horn involvement, respiratory insufficiency, and early death in most. Two sisters in another family showed onset of sensorineural deafness at age 12 years and were still alive in their twenties and thirties with muscle weakness and respiratory compromise. The proband from another family showed onset in his early twenties of a peripheral neuropathy, and later developed deafness and ataxia without respiratory compromise. He was alive at age 57 years. Green et al. (2010) noted the variable age at onset and variable severity of this disorder. Johnson et al. (2010) reported a consanguineous Turkish family in which 3 children had BVVLS. The phenotype was homogeneous, even though there was over 20 years' difference in the age at onset. The proband developed normally until she presented in mid-childhood with acute respiratory distress, stridor, and paralysis of vocal cord abduction, requiring ventilation. She later developed cranial nerve palsies with ophthalmoplegia, dysarthria, dysphagia, tongue fasciculation, facial weakness, and weakness and wasting of the limbs. She died at age 8 years of respiratory failure. Postmortem examination showed replacement gliosis of the cranial nuclei, particularly at the bulbo-pontine level, but only mild anterior horn cell involvement. The proband's affected sister developed rapid onset of hearing loss at the age of 10 years. In the following years she developed similar features as her sister, with progressive bulbar palsy, dysarthria, dysphagia, tongue fasciculation, facial weakness, weakness and wasting of the limbs, and breathing problems. She had a motor neuronopathy and axonal degeneration. She died at age 29 from respiratory failure. A younger niece was also affected, but was in the early stages of the disease with hearing problems and cranial nerve palsies. Clinical Management The patient of Bosch et al. (2011) with BVVLS had an acylcarnitine profile suggestive of multiple acyl-CoA dehydrogenase deficiency (MADD; 231680) and was placed on a fat-restricted diet with carnitine, riboflavin (10 mg/kg per day), glycine, and 3-hydroxybutyrate. Her muscle strength improved and from the age of 2 years, artificial ventilation was necessary only during sleep. Acylcarnitine profiles normalized and fat restriction was gradually discontinued. Glycine, 3-hydroxybutyrate, and carnitine supplementation were stopped without problems. However, withdrawal of riboflavin at the age of 4 years resulted in a rapid clinical deterioration with vomiting, progressive fatigue, and elevations of lactate, liver enzymes, and creatine kinase. The acylcarnitine profile became abnormal again. Reintroduction of riboflavin (50 mg twice daily) resulted in clinical improvement and normalization of biochemical abnormalities. However, by age 7 the patient demonstrated the neurologic deterioration frequently observed in untreated BVVLS. Inheritance Familial cases of BVVLS in a pattern consistent with autosomal recessive inheritance were reported by Vialetto (1936), Van Laere (1966), and Boudin et al. (1971). The family reported by Hawkins et al. (1990) raised questions about the genetics of this disorder. The proband, a teenaged girl, had the full syndrome; her father, a paternal uncle, and possibly a paternal first cousin had neurosensory deafness, and a paternal aunt had clinical symptoms indicative of the syndrome. Hawkins et al. (1990) suggested that the disorder may be genetically heterogeneous with autosomal recessive and autosomal dominant forms, or alternatively that it may be caused by a mutant gene on the X chromosome. Molecular Genetics By autozygosity mapping followed by candidate gene analysis of a consanguineous Pakistani family with Brown-Vialetto-Van Laere syndrome, Green et al. (2010) identified a homozygous mutation in the C20ORF54 gene (613350.0001) on chromosome 20p13. Analysis of other families with the disorder identified 7 additional homozygous or compound heterozygous C20ORF54 mutations (see, e.g., 613350.0002-613350.0006). One of the families had been reported by Dipti et al. (2005). Green et al. (2010) noted that the C20ORF54 gene is thought to play a role in riboflavin transport. Riboflavin is essential for synthesis of the cofactors flavin adenine dinucleotide (FAD) and flavin mononucleotide (FMN), which are involved in energy metabolism. It is plausible that the C20ORF54 protein has a maintenance function in the nervous system, and that the disease is precipitated by defect in a pathway tightly regulated by this protein. In 3 affected members of a consanguineous Turkish family with Brown-Vialetto-Van Laere syndrome, Johnson et al. (2010) identified a homozygous mutation in the C20ORF54 gene (P28T; 613350.0007). The authors used an exome sequencing technique to identify the candidate gene. Bosch et al. (2011) identified an additional patient with BVVLS who carried a missense (613350.0009) and a nonsense mutation (613350.0010) in the C20ORF54 gene. ### Associations Pending Confirmation For discussion of a possible association between BVVLS and variation in the UBQLN1 gene, see 605046.0002. INHERITANCE \- Autosomal recessive HEAD & NECK Face \- Facial muscle weakness \- Myopathic facies Ears \- Sensorineural hearing loss Eyes \- External ophthalmoplegia \- Ptosis Mouth \- Tongue atrophy \- Tongue fasciculations Neck \- Neck muscle weakness RESPIRATORY \- Shortness of breath \- Stridor \- Nocturnal hypoventilation \- Increased susceptibility to respiratory infections Larynx \- Vocal cord paralysis CHEST Diaphragm \- Diaphragmatic weakness ABDOMEN Gastrointestinal \- Dysphagia SKELETAL Spine \- Scoliosis \- Kyphosis Hands \- Hand muscle atrophy MUSCLE, SOFT TISSUES \- Muscle weakness, proximal and distal \- Muscle atrophy, proximal and distal \- Shoulder muscle weakness \- Hypotonia, truncal and appendicular NEUROLOGIC Central Nervous System \- Cranial nerve palsies \- Bulbar palsy \- Spinal neuropathy \- Clumsiness \- Lower motor signs \- Upper motor signs \- Hyperreflexia \- Ankle clonus \- Fasciculations \- Fibrillations \- Twitching of the fingers and toes \- Ataxia (less common) \- Cerebellar signs (less common) Peripheral Nervous System \- Peripheral neuropathy (reported in 1 patient) VOICE \- Soft voice due to vocal cord paralysis MISCELLANEOUS \- Variable age at onset, most often in second decade \- Onset in infancy and third decade had been reported \- Earlier onset is associated with more rapid progression \- Deafness tends to occur before other neurologic signs, except in patients with very early onset \- Progressive disorder \- Death usually due to respiratory failure MOLECULAR BASIS \- Caused by mutation in the solute carrier family 52 (riboflavin transporter), member 3 gene (SLC52A3, 613350.0001 ) ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	BROWN-VIALETTO-VAN LAERE SYNDROME 1	c0796274	3,227	omim	https://www.omim.org/entry/211530	2019-09-22T16:30:19	{"doid": ["0050694"], "mesh": ["C537111"], "omim": ["211530"], "orphanet": ["97229"], "synonyms": ["Alternative titles", "BULBAR PALSY, PROGRESSIVE, WITH SENSORINEURAL DEAFNESS", "PONTOBULBAR PALSY WITH DEAFNESS"], "genereviews": ["NBK299312"]}
Not to be confused with Erythema annulare centrifugum. Palpable purpura is a condition where purpura, which constitutes visible non-blanching hemorrhages, are raised and able to be touched or felt upon palpation.[1] It indicates some sort of vasculitis secondary to a serious disease.[1][2] ## Contents * 1 Causes * 2 Diagnosis * 3 Treatment * 4 References * 5 Further reading ## Causes[edit] * Rocky mountain spotted fever * Acute meningococcemia * Disseminated gonococcal infection * Ecthyma gangrenosum * Henoch–Schönlein purpura * Eosinophilic granulomatosis with polyangiitis * Polyarteritis nodosa * Leucocytoclastic vasculitis * Microscopic polyangiitis * Mixed essential cryoglobulinemia * Subacute bacterial endocarditis ## Diagnosis[edit] Identification of underlying cause. ## Treatment[edit] Treat the underlying disease. ## References[edit] 1. ^ a b Mushlin, Stuart B.; Greene, Harry Lemoine (2009). Decision Making in Medicine: An Algorithmic Approach. Elsevier Health Sciences. p. 122. ISBN 978-0323041072. Retrieved 19 December 2017. 2. ^ Crain, Ellen F.; Gershel, Jeffrey C. (2010). Clinical Manual of Emergency Pediatrics. Cambridge University Press. p. 126. ISBN 9781139492867. Retrieved 19 December 2017. ## Further reading[edit] * Bagai, A; Albert, S; Shenoi, SD (Nov–Dec 2001). "Evaluation and therapeutic outcome of palpable purpura". Indian Journal of Dermatology, Venereology and Leprology. 67 (6): 320–3. PMID 17664788. * ARIAS-SANTIAGO, S.; ANEIROS-FERNANDEZ, J.; GIRON-PRIETO, M. S.; FERNANDEZ-PUGNAIRE, M. A.; NARANJO-SINTES, R. (3 March 2010). "Palpable purpura". Cleveland Clinic Journal of Medicine. 77 (3): 205–206. doi:10.3949/ccjm.77a.09065. PMID 20200171. S2CID 35801901. * v * t * e Hypersensitivity and autoimmune diseases Type I/allergy/atopy (IgE) Foreign * Atopic eczema * Allergic urticaria * Allergic rhinitis (Hay fever) * Allergic asthma * Anaphylaxis * Food allergy * common allergies include: Milk * Egg * Peanut * Tree nut * Seafood * Soy * Wheat * Penicillin allergy Autoimmune * Eosinophilic esophagitis Type II/ADCC * * IgM * IgG Foreign * Hemolytic disease of the newborn Autoimmune Cytotoxic * Autoimmune hemolytic anemia * Immune thrombocytopenic purpura * Bullous pemphigoid * Pemphigus vulgaris * Rheumatic fever * Goodpasture syndrome * Guillain–Barré syndrome "Type V"/receptor * Graves' disease * Myasthenia gravis * Pernicious anemia Type III (Immune complex) Foreign * Henoch–Schönlein purpura * Hypersensitivity vasculitis * Reactive arthritis * Farmer's lung * Post-streptococcal glomerulonephritis * Serum sickness * Arthus reaction Autoimmune * Systemic lupus erythematosus * Subacute bacterial endocarditis * Rheumatoid arthritis Type IV/cell-mediated (T cells) Foreign * Allergic contact dermatitis * Mantoux test Autoimmune * Diabetes mellitus type 1 * Hashimoto's thyroiditis * Multiple sclerosis * Coeliac disease * Giant-cell arteritis * Postorgasmic illness syndrome * Reactive arthritis GVHD * Transfusion-associated graft versus host disease Unknown/ multiple Foreign * Hypersensitivity pneumonitis * Allergic bronchopulmonary aspergillosis * Transplant rejection * Latex allergy (I+IV) Autoimmune * Sjögren syndrome * Autoimmune hepatitis * Autoimmune polyendocrine syndrome * APS1 * APS2 * Autoimmune adrenalitis * Systemic autoimmune disease * v * t * e Systemic vasculitis Large vessel * Takayasu's arteritis * Giant cell arteritis Medium vessel * Polyarteritis nodosa * Kawasaki disease * Thromboangiitis obliterans Small vessel Pauci-immune * c-ANCA * Granulomatosis with polyangiitis * p-ANCA * Eosinophilic granulomatosis with polyangiitis * Microscopic polyangiitis Type III hypersensitivity * Cutaneous small-vessel vasculitis * IgA vasculitis Ungrouped * Acute hemorrhagic edema of infancy * Cryoglobulinemic vasculitis * Bullous small vessel vasculitis * Cutaneous small-vessel vasculitis Other * Goodpasture syndrome * Sneddon's syndrome [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Palpable purpura	c1368065	3,228	wikipedia	https://en.wikipedia.org/wiki/Palpable_purpura	2021-01-18T18:52:15	{"mesh": ["C537256"], "umls": ["C1368065"], "wikidata": ["Q12738740"]}
Types of FGM Female genital mutilation (FGM), also known as female circumcision or female genital cutting, includes any procedure involving the removal or injury of part or all of external female genitalia for non-medical reasons.[1] While the practice is most common in Africa, Asia, and the Middle East, FGM is also widespread in immigrant communities and metropolitan areas in the United States, and was performed by doctors regularly until the 1980s.[2][3][4] There are four main types of FGM, distinguished by the World Health Organization by their severity.[5] Type 1, clitoridectomy, describes the partial or total removal of the clitoris, and includes circumcision (removal of just the clitoral hood) and clitoridectomy (removal of the entire clitoral glans and hood).[5][1] Type 2, excision, involves the partial or total removal of the clitoris and labia minora, with or without the additional removal of the labia majora.[1][5] Type 3, infibulation, is the most severe type of FGM. It describes the narrowing of the vaginal opening through creation of a seal, by cutting and repositioning the labia minora or labia majora.[1][5] Type 4 describes any other type of harmful non-medical procedures performed on female genitalia, including cutting, burning, and scraping.[5] In the United States, FGM is most common in immigrant communities and in major metropolitan areas. Data on the prevalence of FGM in the United States was first collected in 1990, using census information.[2] CDC reports using information from the early 2010-2013 have shown a decrease in FGM in the United States, although growing levels of immigration cause numbers to appear higher.[2] In addition to its prevalence in immigrant communities in the US, FGM was considered a standard medical procedure in America for most of the 19th and 20th centuries.[6] Physicians performed surgeries of varying invasiveness to treat a number of diagnoses, including hysteria, depression, nymphomania, and frigidity. The medicalization of FGM in the United States allowed these practices to continue until the end of the 20th century, with some procedures covered by Blue Cross Blue Shield Insurance until 1977.[7][6] With the passage of the federal law ban, the Female Genital Mutilation Act, in 1996, performing FGM on anyone under age 18 became a felony in the United States.[8] However, in 2018, the act was stuck down as unconstitutional by US federal district judge Bernard A. Friedman in Michigan, who argued that the federal government did not have authority to enact legislation outside the "Interstate commerce" clause.[9] As part of the ruling, Friedman also ordered that charges be dropped against 8 people who had mutilated the genitals of 9 girls.[10][11] The Department of Justice decided not to appeal the ruling;[12] however, the US House of Representatives appealed it.[13] In 2021, the STOP FGM Act of 2020 was signed into law, and it gives federal authorities the power to prosecute those who carry out or conspire to carry out FGM, as well as increasing the maximum prison sentence from five to ten years. It also requires government agencies to report to Congress about the estimated number of females who are at risk of or have had FGM, and on efforts to prevent FGM.[14] As of September 2020, 39 U.S. states have made specific laws that prohibit FGM, while the remaining 11 states have no specific laws against FGM.[15] The US has also participated in several UN resolutions that advocate for the eradication of FGM, including the UN's 1948 Universal Declaration of Human Rights, 1989 Convention on the Rights of the Child, and the Convention on the Elimination of All Forms of Discrimination Against Women (CEDAW).[16][3][17] ## Contents * 1 Prevalence * 2 History * 2.1 Medicalization * 3 Legislative framework * 3.1 Federal and state policy * 3.2 International policy * 3.3 Prosecutions * 3.4 Asylum * 4 Controversy * 4.1 American Academy of Pediatrics * 5 See also * 6 References * 7 Further reading ## Prevalence[edit] World prevalence rates of FGM according to the 2020 Global Response report. Grey countries' data are not covered. The current prevalence of FGM in the US is uncertain. In early 2014, Equality Now campaigned with survivor and activist Jaha Dukureh, Representatives Joseph Crowley (D-NY) and Sheila Jackson Lee (D-TX), and The Guardian to petition the Obama Administration to conduct a new prevalence study into the current state of FGM in the U.S. as the first step towards its elimination.[18] In 1996, the first report on FGM in the United States was developed using data from the 1990 census.[2] It reported that 168,000 girls and women were at risk, with 48,000 under 18.[2] In 2004, the African Women's Health Center at Brigham and Women's Hospital and the PRC revamped these numbers with information from recent surveys and the 2000 U.S. census.[2] They reported 227,887 girls and women at risk in United States, with 62,519 under 18. This increase can be attributed to increases in total immigration.[2] In 2016, the Centers for Disease Control and Prevention (CDC) released a report compiled with data from 2010-2013. The CDC report estimated 513,000 girls and women in the United States were either victims of FGM or at risk of FGM, with ⅓ under age 18.[19] The marked increase in the number of girls and women at risk of FGM in the United States was attributed to an increase in the total number of immigrants from countries where FGM is most common, not an increase in the frequency of the practice.[20] Of the women at risk, 60% are from 8 states: California, Maryland, Minnesota, New Jersey, New York, Texas, Virginia, and Washington. Additionally, 40% of those reported are concentrated in 5 major metropolitan areas: New York, Washington, Minneapolis-St. Paul, Los Angeles, and Seattle. 55% of the women are from Egypt, Somalia, or Ethiopia.[2] These three "sending countries" have a high prevalence of FGM, as well as high numbers of U.S. immigrants.[2] The report used information from US census reports and the American Community Survey (2012) to identify the number of immigrants from countries where FGM is most prevalent.[2] FGM in the United States is commonly associated with African and Asian migrants with an Islamic cultural background,[21] including the small Dawoodi Bohra Muslim community that has its roots in India.[22] It has also anecdotally been found to occur in some local white conservative Christian communities in the American Midwest (as of June 2019, two white women from conservative Christian homes in North Dakota and Kentucky had come forward[22]), where female sexual pleasure is believed to be a "sin against God", and FGM is employed as a way to make women "obedient to God" and their husbands.[21][23][24] ## History[edit] ### Medicalization[edit] Tools used in education and community outreach During the 19th century, FGM was frequently performed by doctors as a treatment for many sexual and psychological conditions. During the 19th and 20th centuries, the clitoris was considered the center of female sexuality.[4] In addition, Victorian concepts of female sexuality resulted in a widely-held belief that women were less sexual than men.[25] Female sexuality was typically thought of only within the constructs of heterosexual marriage, and behaviors that strayed from this schema, such as masturbation, were deemed symptomatic, and often resulted in operation on the clitoris.[26][4] Depending on the symptoms and diagnosis, physicians performed four different procedures of varying invasiveness on women.[4] Doctors would either remove the smegma surrounding the clitoris, lacerate adhesions restricting the clitoris, or remove the clitoral hood altogether (female circumcision).[4] In the most extreme cases, doctors would perform a clitoridectomy, removing the clitoris entirely.[4] Reflex neurosis was a common diagnosis in the 19th century.[4] Characterized by excessive nervous stimulation, this condition could often manifest in an overstimulation of the clitoris that women would attempt to quell with masturbation.[4] Women diagnosed with reflex neurosis were often circumcised in an effort to remove the irritant.[4] From the 1880s to 1950s, excision was often performed to prevent and treat lesbianism, masturbation, depression, hysteria, and nymphomania.[27][28] These procedures continued well into the 1970s, and were covered by Blue Cross Blue Shield Insurance until 1977.[7] Dr. James Burt, a physician from Ohio, performed a so-called "surgery of love" on over 170 women throughout the 1960s and 1970s.[29] During the non-consensual procedure, Burt would cut around, move, and reshape the clitoris of women who had been admitted for other operations.[29] This continued well into the 1970s, when a former co-worker served witness to several of Burt's victims, and he was fired and cast out of the medical community.[29] ## Legislative framework[edit] ### Federal and state policy[edit] As of August 2020, 39 states, most recently, Massachusetts, had passed legislation making FGM illegal.[15] Several of these states passed legislation that made it illegal to perform FGM on anyone (not just girls under 18).[3] The U.S. Congress required the Department of Health and Human services to provide information for medical students about treatment recommendations.[30] Education policy was also included in the Illegal Immigration Reform and Immigrant Responsibility Act of 1996.[31] The IIRARA mandated that visa recipients from 28 high-risk countries receive culturally appropriate information on the personal and legal repercussions of FGM in the United States at or before the time of entry.[31][32] Prior to the Act being declared unconstitutional, FGM on anyone under the age of 18 had become a felony in the United States with the passage of the Female Genital Mutilation Act of 1996.[8] The law was introduced by former congresswoman Pat Schroeder in October 1993.[33][34] The Female Genital Mutilation Act included education and community outreach programs that provide information about the physical and emotional harm caused by FGM.[8][33][35] In November 20, 2018, Federal Judge Barnard A. Friedman ruled the Female Genital Mutilation Act of 1996 unconstitutional because it exceeds the enumerated powers of Congress and cannot be justified by the commerce clause.[36][37] The Department of Justice decided not to appeal the ruling,[12] but the US House of Representatives appealed it.[13] However, in 2021 the STOP FGM Act of 2020 was signed into law, and it gives federal authorities the power to prosecute those who carry out or conspire to carry out FGM, as well as increasing the maximum prison sentence from five to ten years. It also requires government agencies to report to Congress about the estimated number of females who are at risk of or have had FGM, and on efforts to prevent FGM.[14] In 2013, the Transport for Female Genital Mutilation Act specifically prohibited the practice of "vacation cutting", the transport of a girl outside of the United States with the intention of performing FGM.[2] ### International policy[edit] See also: Female genital mutilation laws by country § Geographic perspective In addition to policies within the U.S., FGM has been condemned by international organizations and bodies that the U.S. is a part of. The UN's 1948 Universal Declaration of Human Rights and 1989 Convention on the Rights of the Child both include statements against the practice of FGM.[16][3][17] In 1979, the Convention on the Elimination of All Forms of Discrimination Against Women (CEDAW) required participating State parties to work to "abolish customs and practices which constitute discrimination against women".[16][2] In 1990, CEDAW's General Recommendation 14 included many suggested actions for participating State parties to eradicate FGM, including the collection of data on the prevalence of FGM, education and outreach programs to prevent and discourage FGM, incorporating information on the eradication of FGM into public health programs, and encouraging politicians and public figures to speak out against FGM.[2] In 1999, CEDAW's General Recommendation recommended that participating State parties enact laws to prohibit FGM.[2] In 2007, the United Nations Children's Emergency Fund (UNICEF) and the United Nations Population Fund (UNPF) created a joint UN initiative with the goal of ending FGM within a generation.[3] In 2015, the UN's Sustainable Development Goals included the end of practices that prevent gender equality, including FGM.[3] ### Prosecutions[edit] The first conviction of FGM in the US occurred in 2006. Khalid Adem, an Ethiopian American, was both the first person prosecuted and first person convicted for FGM in the United States. Adem, an Ethiopian immigrant, circumcised his two-year-old daughter with a pair of scissors. He was found guilty of aggravated battery and cruelty to children by the State of Georgia, which had no specific law on FGM at the time.[38][39] In 2010, Georgia successfully passed a law criminalizing FGM.[40] In April 2017, Jumana Nagarwala, a doctor working at the Henry Ford Hospital in Detroit, was charged with allegedly performing FGM at the Burhani Medical Clinic in Livonia, Michigan.[41][42] This was the first federal prosecution for female genital mutilation in US history.[43] Nagarwala, who denied the charges, was accused of performing FGM on two girls who had traveled from Minnesota with their mothers.[41] The owners of the clinic where it was performed, Dr. Fakhruddin Attar and his wife, Farida Attar, were also arrested and charged with FGM for conspiring with Nagarwala and letting her use their clinic.[44][41] But when the 1996 federal law that criminalized female genital mutilation was declared unconstitutional in 2018, all charges against the Attars and Nagarwala other than conspiracy and obstruction were dismissed.[45] In 2021 it was announced that Zahra Badri had become the first person to have charges brought against them by the Justice Department for transporting a child outside the borders of America to have FGM performed on them (the charge referred to actions taken from approximately July 10, 2016 through October 14, 2016).[46] ### Asylum[edit] In 1996, Fauziya Kasinga was granted political asylum by the United States Board of Immigration Appeals.[34] Kasinga, a 19-year-old member of the Tchamba-Kunsuntu tribe of Togo, was granted asylum on the grounds that she would be at risk of FGM if she returned to her arranged marriage in Togo.[34] This set a precedent in U.S. immigration law because it was the first time FGM was accepted as a form of persecution.[47] In addition, this was the first situation in which asylum was granted based on gender.[48] ## Controversy[edit] ### American Academy of Pediatrics[edit] In 2010, the American Academy of Pediatrics came under fire for advising doctors to consider offering patients the option of "a ritual nick as a possible compromise to avoid greater harm".[49] The Academy stated that although harmful genital mutilation is illegal in the United States, physicians could consider this option in countries where FGM is more widely practiced. This advice appeared in a journal section entitled, "Education of patients and parents".[49] After facing backlash from medical institutions worldwide, the AAP retracted their statement. The organization also subsequently clarified in a statement released in May 2010 that it "opposes all types of female genital cutting", and "counsels its members not to perform such procedures".[50] ## See also[edit] * Female genital mutilation laws by country * Prevalence of female genital mutilation by country ## References[edit] 1. ^ a b c d "Female genital mutilation". World Health Organization. Retrieved 2017-11-16. 2. ^ a b c d e f g h i j k l m n Goldberg, Howard; Stupp, Paul; Okoroh, Ekwutosi; Besera, Ghenet; Goodman, David; Danel, Isabella (2016). "Female Genital Mutilation/Cutting in the United States: Updated Estimates of Women and Girls at Risk, 2012". Public Health Reports. 131 (2): 340–347. doi:10.1177/003335491613100218. ISSN 0033-3549. PMC 4765983. PMID 26957669. 3. ^ a b c d e f Mpinga, Emmanuel Kabengele; Macias, Aurélie; Hasselgard-Rowe, Jennifer; Kandala, Ngianga-Bakwin; Félicien, Tshimungu Kandolo; Verloo, Henk; Bukonda, Ngoyi K. Zacharie; Chastonay, Philippe (2016-12-01). "Female genital mutilation: a systematic review of research on its economic and social impacts across four decades". Global Health Action. 9 (1): 31489. doi:10.3402/gha.v9.31489. ISSN 1654-9716. PMC 5052514. PMID 27707452. 4. ^ a b c d e f g h i Rodriguez, Sarah W. (2008-07-01). "Rethinking the History of Female Circumcision and Clitoridectomy: American Medicine and Female Sexuality in the Late Nineteenth Century". Journal of the History of Medicine and Allied Sciences. 63 (3): 323–347. doi:10.1093/jhmas/jrm044. ISSN 0022-5045. PMID 18065832. S2CID 9234753. 5. ^ a b c d e Wagner, Natascha (2015-03-04). "Female Genital Cutting and Long-Term Health Consequences – Nationally Representative Estimates across 13 Countries". The Journal of Development Studies. 51 (3): 226–246. doi:10.1080/00220388.2014.976620. ISSN 0022-0388. S2CID 154455515. 6. ^ a b Webber, Sara; Schonfeld, Toby L. (2003-06-27). "Cutting History, Cutting Culture: Female Circumcision in the United States". The American Journal of Bioethics. 3 (2): 65–66. doi:10.1162/152651603766436324. ISSN 1536-0075. PMID 12859826. S2CID 13202773. 7. ^ a b Kinnear, Karen L. (2011). Women in Developing Countries: A Reference Handbook. ABC-CLIO. ISBN 9781598844252. 8. ^ a b c "18 U.S. Code § 116 - Female genital mutilation". LII / Legal Information Institute. Retrieved 2017-11-16. 9. ^ McVeigh, Karen (2018-11-22). "'US is moving backwards': Female genital mutilation ruling a blow to girls at risk". The Guardian. 10. ^ "Genital mutilation ban ruled unconstitutional; judge drops charges against sect". Detroit News. Nov 21, 2018. 11. ^ "Michigan Judge Strikes Down Federal Female-Genital-Mutilation Ban". National Review. Nov 20, 2018. 12. ^ a b "Justice Department Decides Not to Appeal Court Ruling Striking Down Federal Law Banning Female Genital Mutilation". Reason.com. 2019-04-15. Retrieved 2019-04-16. 13. ^ a b https://www.speaker.gov/wp-content/uploads/2019/05/Nagarwala-Motion-to-Intervene-As-Filed.pdf 14. ^ a b "Sight Magazine - US toughens ban on "abhorrent" female genital mutilation". www.sightmagazine.com.au. 15. ^ a b "FGM Legislation by State". 16. ^ a b c "General recommendations made by the Committee on the Elimination of Discrimination against Women". www.un.org. Retrieved 2017-11-23. 17. ^ a b Cohen, Cynthia (April 1997). "The United Nations Convention of the Rights of the Child: A Feminist Landmark". William & Mary Journal of Women and the Law. 3 (1): 51. 18. ^ "Archived copy" (PDF). Archived from the original (PDF) on 2015-02-10. Retrieved 2015-02-10.CS1 maint: archived copy as title (link) 19. ^ "Women and Girls at Risk of Female Genital Mutilation/Cutting in the United States". www.prb.org. Retrieved 2017-10-20. 20. ^ Goldberg, Howard; Stupp, Paul; Okoroh, Ekwutosi; Besera, Ghenet; Goodman, David; Danel, Isabella (2016). "Female Genital Mutilation/Cutting in the United States: Updated Estimates of Women and Girls at Risk, 2012". Public Health Reports. 131 (2): 340–347. doi:10.1177/003335491613100218. ISSN 0033-3549. PMC 4765983. PMID 26957669. 21. ^ a b A Renee Bergstrom (2 December 2016). "FGM happened to me in white, midwest America". The Guardian. Retrieved 11 May 2020. 22. ^ a b Milena Mikael-Debass (4 June 2019). "Female Genital Mutilation Is Happening in the U.S. These Survivors Are Fighting to Stop It". Vice News. Retrieved 11 May 2020. 23. ^ Emma Batha (1 April 2019). "U.S. woman says strict Christian parents subjected her to FGM". Reuters. Retrieved 11 May 2020. 24. ^ Jenny (2019). "Stories of Survivors: Jenny - USA". Equality Now. Retrieved 11 May 2020. 25. ^ "Nymphomania: The Historical Construction of Female Sexuality". www.brown.uk.com. Retrieved 2017-11-25. 26. ^ Degler, Carl N. (1974). "What Ought To Be and What Was: Women's Sexuality in the Nineteenth Century". The American Historical Review. 79 (5): 1467–1490. doi:10.2307/1851777. JSTOR 1851777. PMID 11609340. 27. ^ Watson, Mary Ann (2005-01-01). "Female circumcision from Africa to the Americas: Slavery to the present". The Social Science Journal. 42 (3): 421–437. doi:10.1016/j.soscij.2005.06.006. S2CID 145537024. 28. ^ Studd, John; Schwenkhagen, Anneliese (2009-06-20). "The historical response to female sexuality". Maturitas. Female sexual dysfunctions in the office. 63 (2): 107–111. doi:10.1016/j.maturitas.2009.02.015. PMID 19487089. 29. ^ a b c Johnsdotter, Sara (2012). "Projected Cultural Histories of the Cutting of Female Genitalia: A Poor Reflection as in a Mirror". History and Anthropology. 23 (1): 91–114. doi:10.1080/02757206.2012.649270. hdl:2043/13464. S2CID 53500332. 30. ^ Horowitz, Carol R; Jackson, J Carey (August 1997). "Female "Circumcision"". Journal of General Internal Medicine. 12 (8): 491–499. doi:10.1046/j.1525-1497.1997.00088.x. ISSN 0884-8734. PMC 1497147. PMID 9276655. 31. ^ a b "Notice of Implementation of the Illegal Immigration Reform and Immigrant Responsibility Act of 1996 Pertaining to Female Genital Mutilation (FGM) [63 FR 13433] [FR 20-98] \| USCIS". www.uscis.gov. Retrieved 2017-11-23. 32. ^ Female genital mutilation: a guide to laws and policies worldwide. Rahman, Anika., Toubia, Nahid., Center for Reproductive Law & Policy., RAINBO (Organization). London: Zed Books. 2000. ISBN 9781856497732. OCLC 44548936.CS1 maint: others (link) 33. ^ a b Ann, James, Mary (2013). "Federal Prohibition of Female Genital Mutilation: The Female Genital Mutilation Act of 1993, H.R. 3247". Berkeley Journal of Gender, Law & Justice. 9 (1). doi:10.15779/z38dk2f. ISSN 1933-1045. 34. ^ a b c Leonard, Lori (2000-03-01). "Interpreting Female Genital Cutting: Moving beyond the Impasse". Annual Review of Sex Research. 11 (1): 158–190. doi:10.1080/10532528.2000.10559787 (inactive 2021-01-10). ISSN 1053-2528. PMID 11351831.CS1 maint: DOI inactive as of January 2021 (link) 35. ^ MacReady, N. (1996). "Female Genital Mutilation Outlawed In United States". BMJ: British Medical Journal. 313 (7065): 1103. doi:10.1136/bmj.313.7065.1103a. JSTOR 29733347. PMID 8916692. S2CID 36392473. 36. ^ "Federal Ban on Female Genital Mutilation Ruled Unconstitutional by Judge". Retrieved 2018-12-02. 37. ^ content-static.detroitnews.com (PDF) https://content-static.detroitnews.com/pdf/2018/US-v-Nagarwala-dismissal-order-11-20-18.pdf. Retrieved 2018-12-20. Missing or empty `\|title=` (help) 38. ^ "Father jailed for US mutilation". 2006-11-02. 39. ^ "Man gets 10-year sentence for circumcision of 2-year-old daughter - USATODAY.com". usatoday30.usatoday.com. 40. ^ "2010 Georgia Code :: TITLE 16 - CRIMES AND OFFENSES :: CHAPTER 5 - CRIMES AGAINST THE PERSON :: ARTICLE 2 - ASSAULT AND BATTERY :: § 16-5-27 - Female genital mutilation". Justia Law. Retrieved 2017-11-24. 41. ^ a b c Archive, United States Courts. "United States of America v. Nagarwala et al Docket Item 16 \| United States Courts Archive". www.unitedstatescourts.org. Archived from the original on 2017-12-01. Retrieved 2017-11-24. 42. ^ "Criminal Complaint", The U.S. District Court for the Eastern District of Michigan, 12 April 2017. 43. ^ Rubin, Rita. "Doctor Charged With Female Genital Mutilation Has Published Research, Overseen Residents". Forbes. Retrieved 2017-11-24. 44. ^ Allen, Tresa Baldas and Robert. "Another doctor, wife charged with female genital mutilation in Michigan". chicagotribune.com. Retrieved 2017-11-24. 45. ^ Baldas, Tresa (November 20, 2018). "Judge Dismisses Female Genital Mutilation Charges in Historic Case". Detroit Free Press. Retrieved November 21, 2018. 46. ^ "Texas Woman Indicted for Transporting Minor for Female Genital Mutilation". www.justice.gov. January 13, 2021. 47. ^ Dugger, Celia W. "June 9-15; Asylum From Mutilation",The New York Times, 16 June 1996. * "In re Fauziya KASINGA, file A73 476 695, U.S. Department of Justice, Executive Office for Immigration Review, decided 13 June 1996. * Dugger, Celia W. "Woman's Plea for Asylum Puts Tribal Ritual on Trial", The New York Times, 15 April 1996. 48. ^ "Global feminism at the local level: Criminal and asylum laws regarding female genital surgeries". Journal of Gender, Race and Justice. 3: 45–62. 49. ^ a b Kmietowkz, Zosia (22 May 2010). "UK colleges criticise US advice on female genital mutilation". BMJ: British Medical Journal. 340 (7756): 1103. JSTOR 40702226. 50. ^ Davis, D. S. (2010). "Ritual Genital Cutting of Female Minors". Pediatrics. 125 (5): 1088–1093. doi:10.1542/peds.2010-0187. PMID 20421257. S2CID 30337719. Retrieved 13 October 2017. ## Further reading[edit] * Abdelkader E, Abugideiri SE, Diallo M (2014). "Female Genital Mutilation In The United States". Islamic Horizons. 43 (5): 36–38. * Jones WK, Smith J, Kieke B Jr, Wilcox L (1997). "Female genital mutilation. Female circumcision. Who is at risk in the U.S.?". Public Health Reports. 112 (5): 368–377. PMC 1381943. PMID 9323387. * McConnell, Kathryn (7 February 2013). "U.S. Taking Steps to Stop Female Genital Mutilation". IIP Digital. U.S. Department of State. Retrieved 8 December 2014. * v * t * e Female genital mutilation Health issues * Clitoridectomy * Dysmenorrhea * Dyspareunia * Gishiri cutting * Husband stitch * Infibulation * Keloid scars * Pelvic inflammatory disease * Rectovaginal fistula * Vesicovaginal fistula By country * Prevalence by country * Laws by country * FGM in India * colonial Kenya * Kurdistan * New Zealand * Nigeria * Sierra Leone * Sudan * United Kingdom * United States * Religious views on FGM Writers/groups Early writers and activists * Raqiya Haji Dualeh Abdalla * Janice Boddy * Mary Daly * Efua Dorkenoo * Asma El Dareer * Benoîte Groult * Rose Oldfield Hayes * Fran Hosken * Edna Adan Ismail * Nawal El Saadawi * Lilian Passmore Sanderson * Marion Scott Stevenson * Hulda Stumpf * Nahid Toubia * Amina Warsame Others * Fuambai Ahmadu * Ayaan Hirsi Ali * Ellen Gruenbaum * Waris Dirie * Gerry Mackie * Molly Melching * Layli Miller-Muro * Comfort Momoh * Alice Walker Groups * Babiker Bedri Scientific Association for Women's Studies * Equality Now * FORWARD * Inter-African Committee on Traditional Practices Affecting the Health of Women and Children * RAINBO * Tostan * Tahirih Justice Center * Zero Tolerance Day Media Books * Woman at Point Zero (1975) * Woman, Why Do You Weep? (1982) * Possessing the Secret of Joy (1992) * Desert Flower (1998) Films * Moolaadé (2004) * Desert Flower (2009) * My Body My Rules (2015) Legislation * Matter of Kasinga * Prohibition of Female Circumcision Act 1985 * Female Genital Mutilation Act 2003 * 2005 (Scotland) Act * Children Act 1989 (Amendment) (Female Genital Mutilation) Act 2019 Categories * Female genital mutilation * Activists against female genital mutilation [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Female genital mutilation in the United States	None	3,229	wikipedia	https://en.wikipedia.org/wiki/Female_genital_mutilation_in_the_United_States	2021-01-18T19:08:14	{"wikidata": ["Q18354996"]}
A number sign (#) is used with this entry because spinal muscular atrophy type III (SMA3) is caused by homozygous or compound heterozygous mutation in the SMN1 gene (600354) on chromosome 5q13. Description SMA is an autosomal recessive neuromuscular disorder characterized by progressive proximal muscle weakness and atrophy affecting the upper and lower limbs. By convention, SMA is classified into 4 types: I (SMA1; 253300), II (SMA2; 253550), III (SMA3), and IV (271150), by increasing age at onset and decreasing clinical severity. SMA1 is the most severe form of the disorder and often results in death in early childhood. SMA3, known as the juvenile form, tends to show onset in childhood or adolescence (summary by Fraidakis et al., 2012). Clinical Features Kugelberg and Welander (1956) reported 5 children, among the 12 offspring of normal parents, with a juvenile form of spinal muscular atrophy; 2 of the 5 were monozygotic twins. Levy and Wittig (1962) described proximal muscular atrophy in 2 half brothers, with onset at 13 and 16 years. Onset of the juvenile form is usually between 2 and 17 years of age. Atrophy and weakness of proximal limb muscles, primarily in the legs, is followed by distal involvement. Usually the cases are diagnosed as limb-girdle muscular dystrophy until they are studied fully. Twitchings (fasciculations) are an important differentiating sign. Muscular biopsy and electromyography show the true nature of the process as a lower motor neuron disease. Pulmonary dysfunction is often a cause of morbidity in these patients. Samaha et al. (1994) studied forced vital capacity longitudinally in 40 SMA patients ranging in age from 5 to 18 years. Although the majority of the patients grew in height, only 35% showed an increase in height-adjusted forced vital capacity. In the most seriously affected patients, all lost height-adjusted forced vital capacity over time. Furukawa et al. (1968) reported 2 families, each with affected brother and sister. The parents in one family were first cousins. The authors pointed out that in their cases, as well as in those in the literature, the symptoms of female patients were mild and the clinical course slow whereas male sibs were severely affected. They interpreted this as sex-influence. Bundey and Filomeno (1974) described a black sibship in which 5 sibs out of 10 had this disorder. Pearn et al. (1978) reported a spinal muscular atrophy syndrome characterized by adolescent onset, gross hypertrophy of the calves, and a slowly progressive clinical course. One of their families with 2 affected brothers and 2 affected maternal uncles probably had Kennedy disease (313200), an X-linked form of SMA with which calf hypertrophy has been observed. Fraidakis et al. (2012) reported 2 unrelated French men, aged 44 and 50 years, with SMA type III. Both had onset of slowly progressive proximal lower limb weakness beginning in adolescence, followed by proximal upper limb weakness. At age 44, the first patient patient had proximal lower limb amyotrophy, proximal upper and lower limb weakness, and absence of lower limb reflexes; he used a cane to walk. Muscle biopsy and EMG showed a chronic neuropathic process. The second patient developed muscle cramps and was wheelchair-bound at age 48. Physical examination showed severe motor deficit and amyotrophy in the pelvic and shoulder girdles, as well as severe motor deficit and amyotrophy in the distal limb muscles. EMG was consistent with severe chronic denervation at all extremities. Fraidakis et al. (2012) commented on the relatively mild disease course in these patients and suggested that there were likely compensatory factors affecting expression of the SMN genes. Inheritance Spira (1963) described 7 affected members in 2 sibships of a family with proximal spinal muscular atrophy. In each case the affected persons were offspring of a first-cousin marriage, consistent with autosomal recessive inheritance. Pearn et al. (1978) reviewed 141 cases of SMA with onset before age 14 years (excluding SMA type I, or Werdnig-Hoffmann disease). Autosomal recessive inheritance could account for over 90% of cases. In these, onset was before age 5 and usually before age 2 years. The disorder was compatible with life into the third decade. A small group of cases appeared to be either new dominant mutations or phenocopies. Hausmanowa-Petrusewicz et al. (1985) called this the mild childhood and adolescent type of spinal muscular atrophy and emphasized the significance of sex influence (Hausmanowa-Petrusewicz et al., 1984). Zerres et al. (1987) advanced Becker's allelic model as a possible explanation for unusual pedigrees with spinal muscular atrophy. Because of the finding of linkage of SMA I, II (SMA2; 253550), and III to the same region, 5q11.2-q13.3 (Brzustowicz et al., 1990), it is likely that these are allelic disorders. Clinical Management In fibroblast cultures from patients with SMA1, SMA2, or SMA3, Andreassi et al. (2004) found a significant increase in SMN2 gene (601627) expression (increase in SMN2 transcripts of 50 to 160% in SMA1, and of 80 to 400% in SMA2 and SMA3) and a more moderate increase in SMN protein expression in response to treatment with 4-phenylbutyrate (PBA). PBA treatment also resulted in an increase in the number of SMN-containing nuclear structures (GEMS). The authors suggested a potential use for PBA in treatment of various types of SMA. Grzeschik et al. (2005) reported that cultured lymphocytes from patients with SMA showed increased production of the full-length SMN mRNA and protein in response to treatment with hydroxyurea. The findings suggested that hydroxyurea promoted inclusion of exon 7 during SMN2 transcription. Weihl et al. (2006) reported increased quantitative muscle strength and subjective function in 7 adult patients with SMA3/SMA4 who were treated with oral valproate for a mean duration of 8 months. Most patients reported improvement within a few months of beginning treatment. The authors noted that previous studies (see Brichta et al., 2003) had suggested that inhibitors of histone deacetylase, such as valproate, may increase SMN2 gene transcription and result in increased production of full-length SMN protein. In a study of valproic acid (VPA) treatment in 10 SMA carriers and 20 patients with SMA1, SMA2, or SMA3, Brichta et al. (2006) found that VPA increased peripheral blood full-length SMN mRNA and protein levels in 7 carriers, increased full-length SMN2 mRNA in 7 patients, and left full-length SMN2 mRNA levels unchanged or decreased in 13 patients. The effect on protein levels in carriers was more pronounced than on mRNA levels, and the variability in augmentation among carriers and patients suggested to the authors that VPA interferes with transcription of genes encoding translation factors or regulates translation or SMN protein stability. Cytogenetics Brzustowicz et al. (1994) detected paternal isodisomy for chromosome 5 in a 2-year-old boy with type III SMA. Examination of 17 short-sequence repeat polymorphisms spanning a large part of the chromosome produced no evidence of maternally inherited alleles. Cytogenetic analysis showed a normal male karyotype, and fluorescence in situ hybridization with probes closely flanking the SMA locus confirmed the presence of 2 copies of chromosome 5. No developmental abnormalities other than those attributable to classic childhood-onset SMA were present. In an analysis of uniparental disomy cases, Kotzot (1999) found only one example of uniparental disomy involving chromosome 5, that of Brzustowicz et al. (1994). No reports were found of uniparental disomy of chromosomes 12, 17, 18, and 19. On the other hand, 33 examples of chromosome 16 UPD were found, all of them maternal except 1. The bases of UPD are always 2 events: 2 meiotic; 1 meiotic and 1 mitotic; or 2 mitotic. Abnormal phenotypes result from an aberrant imprint, homozygosity of autosomal recessive gene mutations, homozygosity of X-chromosomal mutations in females, and father-to-son transmission of X-linked traits. The most frequent mechanism of UPD appears to be fertilization of a disomic gamete by a gamete monosomic for the same chromosome and subsequent loss of the normally inherited chromosome (trisomy rescue). This mechanism might result in mosaicism in the placenta or even in a subset of fetal tissues. This low level mosaicism can remain undetected and renders the delineation of a phenotype difficult. In general, the phenotype of cases with UPD is determined by mosaicism, genomic imprinting, nonmendelian inheritance of monogenic disorders, or a combination of these factors. Kotzot (1999) reviewed the entire bibliography of UPD other than that involving chromosome 15 and found a predominance of maternal versus paternal UPD (approximately 3 in 1) and a nonuniform chromosomal distribution. Molecular Genetics Matthijs et al. (1996) used an SSCP assay for the molecular diagnosis of 58 patients with SMA, including 8 patients (6 Belgian and 2 Turkish) with SMA III. The SSCP assay discriminates between the SMN gene (600354) and the almost identical centromeric BCD541 repeating unit. In 7 of the 8 SMA III patients, homozygous deletion of exon 7 of the SMN gene was detected. In 6 of the 7, the deletion was associated with homozygous deletion of exon 8, and in 1 it was associated with heterozygous deletion of exon 8. Deletion of the SMN gene was not found in 1 Belgian patient with typical manifestations of SMA III. In families with proximal spinal muscular atrophy affecting individuals in 2 generations, Rudnik-Schoneborn et al. (1996) examined whether there was pseudodominant inheritance of the regular autosomal recessive form or a dominant form of SMA which is not linked to 5q (see 158590). Four families had affected members in 2 generations who showed SMN gene deletions. The range of variability in severity was striking. In family 4, the father had onset at age 16, whereas the son had onset in the first year; both had deletion of exons 7 and 8 of the SMN gene. Even more striking was family 3, in which the father had onset 'in youth' and the first son was asymptomatic thus far, whereas the second son had onset at 6 months of age (SMA I); all 3 had deletion of exons 7 and 8 of the SMN gene. Two sons had inherited different haplotypes from their affected father and shared identical maternal haplotypes. Rudnik-Schoneborn et al. (1996) noted that, although homozygous deletions in the telomeric copy of the SMN gene can be detected in 95% to 98% of patients with early-onset SMA types I and II (Hahnen et al., 1995), as many as 10% to 20% of patients with type III SMA do not show deletions. Since no molecular genetic test was available to support a locus other than that on 5q, the question of heterogeneity remained an important issue in proximal SMA. Given an incidence of more than 1/10,000 for autosomal recessive SMA (what Rudnik-Schoneborn et al. (1996) referred to as 'SMA 5q'), patients with autosomal recessive SMA have a recurrence risk of approximately 1% to their offspring. In 2 unrelated French men with onset of SMA type III in adolescence, Fraidakis et al. (2012) identified compound heterozygosity for a deletion of the SMN1 gene (600354.0021) and a missense mutation affecting the same codon in exon 3 (Y130C, 600354.0019 and Y130H, 600354.0020, respectively). Both missense mutations affected highly conserved residues in the Tudor domain, but the patients had a relatively mild form of the disorder. One patient had 1 copy of SMN2 and the other had 2 copies of SMN2. Fraidakis et al. (2012) commented on the relatively mild disease course in these patients and suggested that there were likely compensatory factors affecting expression of the SMN genes. ### Modifying Factors Feldkotter et al. (2002) developed a quantitative test for either SMN1 or SMN2 to analyze SMA patients for their SMN2 copy number and to correlate the SMN2 copy number with type of SMA and duration of survival. The quantitative analysis of SMN2 copies in 375 patients with type I, type II, or type III SMA showed a significant correlation between SMN2 copy number and type of SMA as well as duration of survival. Thus, 80% of patients with type I SMA carried 1 or 2 SMN2 copies and 82% of patients with type II SMA carried 3 SMN2 copies, whereas 96% of patients with type III SMA carried 3 or 4 SMN2 copies. Among 113 patients with type I SMA, 9 with 1 SMN2 copy lived less than 11 months, 88 of 94 with 2 SMN2 copies lived less than 21 months, and 8 of 10 with 3 SMN2 copies lived 33 to 66 months. On the basis of SMN2 copy number, Feldkotter et al. (2002) calculated the posterior probability that a child with homozygous absence of SMN1 will develop type I, type II, or type III SMA. Wirth et al. (2006) analyzed SMN2 copy number in 115 patients with SMA3 or SMA4 (271150) who had confirmed homozygous absence of SMN1 and found that 62% of SMA3 patients with age of onset less than 3 years had 2 or 3 SMN2 copies, whereas 65% of SMA3 patients with age of onset greater than 3 years had 4 to 5 SMN2 copies. Of the 4 adult-onset (SMA4) patients, 3 had 4 SMN2 copies and 1 had 6 copies. Wirth et al. (2006) concluded that SMN2 may have a disease-modifying role in SMA, with a greater SMN2 copy number associated with later onset and better prognosis. Jedrzejowska et al. (2008) reported 3 unrelated families with asymptomatic carriers of a biallelic deletion of the SMN1 gene. In the first family, the biallelic deletion was found in 3 sibs: 2 affected brothers with SMA3 and a 25-year-old asymptomatic sister. All of them had 4 copies of the SMN2 gene. In the second family, 4 sibs were affected, 3 with SMA2 and 1 with SMA3, and each had 3 copies of SMN2. The clinically asymptomatic 47-year-old father had the biallelic deletion and 4 copies of SMN2. In the third family, the biallelic SMN1 deletion was found in a girl affected with SMA1 and in her healthy 53-year-old father who had 5 copies of SMN2. The findings again confirmed that an increased number of SMN2 copies in healthy carriers of the biallelic SMN1 deletion is an important SMA phenotype modifier, but also suggested that other factors play a role in disease modification. In a 42-year-old woman with a mild form of SMA type III, despite a homozygous absence of SMN1 exon 7, Prior et al. (2009) identified a homozygous variant (G287R; 601627.0001) in the SMN2 gene. In vitro functional expression studies showed that the variant resulted in the creation of an exonic splicing enhancer element and increased the amount of full-length SMN2 transcripts compared to wildtype. The SMN1 genotype (0 SMN1, 0 SMN2) predicted a more severe disorder (SMA1; 253300), but the SMN2 variant increased SMN2 transcripts, resulting in a less severe phenotype. The same G287R variant was identified in heterozygosity in 2 additional unrelated patients with mild forms of SMA, who were predicted to have a more severe form of the disorder from their genotypes (0 SMN1/1 SMN2 and 0 SMN1, 2 SMN2). Stratigopoulos et al. (2010) evaluated blood levels of PLS3 (300131) mRNA transcripts in 88 patients with SMA, including 29 males under age 11 years, 12 males over age 11, 29 prepubertal girls, and 18 postpubertal girls in an attempt to examine whether PLS3 was a modifier of the phenotype. PLS3 expression was decreased in the older patients of both sexes. However, expression correlated with phenotype only in postpubertal girls: expression was greatest in those with SMA type III, intermediate in those with SMA type II, and lowest in those with SMA type I, and correlated with residual motor function as well as SMN2 copy number. Stratigopoulos et al. (2010) concluded that the PLS3 gene may be an age- and/or puberty-specific and sex-specific modifier of SMA. Riessland et al. (2017) identified NCALD (606722), a negative regulator of endocytosis, as a modifying factor in SMA. They identified 5 asymptomatic members of a 4-generation Mormon family from Utah who were homozygous for SMN1 deletions and had 4 SMN2 copies, resembling a genotype associated with type 3 SMA. Linkage analysis combined with transcriptome-wide expression analysis identified significant downregulation of NCALD in these individuals compared to controls. The decreased expression of NCALD was associated with 2 polymorphisms on chromosome 8q: a 2-bp insertion (rs147264092) in intron 1 of the NCALD gene and a 17-bp deletion (rs150254064) located 600-kb upstream of NCALD. These 2 variants were also found in an unrelated patient with a homozygous SMN1 deletion and only 1 copy of SMN2: this genotype would have been predicted to result in perinatal lethality, but the patient survived for 9 months. Cellular studies in SMN-deficient cells showed that knockdown of Ncald triggered motor neuron differentiation and restored neurite and axonal growth. Knockdown of Ncald in several SMA animal models ameliorated SMA-associated pathologic defects and improved endocytosis and synaptic function. The findings suggested that decreased levels of NCALD may act as a protective modifier in SMA, and that perturbed synaptic vesicle endocytosis plays a role in the pathogenesis of the disease. Population Genetics In a carrier screening of autosomal recessive mutations involving 1,644 Schmiedeleut (S-leut) Hutterites in the United States, Chong et al. (2012) identified deletion of SMN1 exon 7 in heterozygous state in 179 individuals among 1,415 screened and in homozygous state in 2, giving a carrier frequency of 0.127 (1 in 8). The carrier frequency in other populations is 1 in 35 (Hendrickson et al., 2009). One adult was homozygous for the SMA-causing deletion. She was previously reported by Chong et al. (2011). At the time of the initial evaluation she was 41 years old and asymptomatic. She subsequently died of cancer at the age of 50 without any symptoms related to SMA, according to her close relatives. History A dominant form represented by the mother and 2 children described by Ford (1961) may also exist and this may be the same as what has been termed scapuloperoneal amyotrophy (181400). Animal Model Simon et al. (2010) analyzed Smn +/- mice, a model of type III/IV SMA, electrophysiologically and histologically to characterize single motor units. Smn +/- mice exhibit progressive loss of motor neurons and denervation of motor endplates starting at 4 weeks of age. Confocal analysis revealed pronounced sprouting of innervating motor axons. As ciliary neurotrophic factor (CNTF; 118945) is highly expressed in Schwann cells, Simon et al. (2010) investigated its role in a compensatory sprouting response and maintenance of muscle strength in this mouse model. Genetic ablation of CNTF resulted in reduced sprouting and decline of muscle strength in Smn +/- mice. The authors concluded that CNTF is necessary for a sprouting response and thus may enhance the size of motor units in skeletal muscles of Smn +/- mice. Although human SMN1 and SMN2 both encode the SMN protein, the SMN2 gene is unable to compensate for the loss of SMN1 protein in SMA patients. A translationally silent T at nucleotide +6 of SMN2 exon 7 instead of SMN1's C causes the final RNA product to be improperly regulated, with the majority of SMN2 pre-mRNA transcripts lacking exon 7. While humans have both SMN1 and SMN2 genes, mice and other mammals have only a single Smn gene. Using mouse and human SMN minigenes and homologous recombination, Gladman et al. (2010) created a mouse model of SMA by inserting the SMN2 C-to-T nucleotide alteration into the endogenous mouse Smn gene. The C-to-T mutation was sufficient to induce exon 7 skipping in the mouse minigene as in the human SMN2. When the mouse Smn gene was humanized to carry the C-to-T mutation, keeping it under the control of the endogenous promoter, and in the natural genomic context, the resulting mice exhibited exon 7 skipping and mild adult-onset SMA characterized by muscle weakness, decreased activity, and an alteration of muscle fiber size. Gladman et al. (2010) proposed that the Smn C-to-T mouse is a model for the adult-onset form of SMA (type III/IV) known as Kugelberg-Welander disease. INHERITANCE \- Autosomal recessive MUSCLE, SOFT TISSUES \- Proximal muscle weakness and atrophy \- Muscle cramps \- Chronic denervation seen on EMG \- Neuropathic process seen on muscle biopsy NEUROLOGIC Central Nervous System \- Muscle weakness, symmetric, proximal (lower limbs more affected than upper limbs) due to motor neuronopathy \- Tongue fasciculation/fibrillation \- Limb fasciculation \- Degeneration of anterior horn cells \- Hand tremor Peripheral Nervous System \- Hyporeflexia \- Areflexia of the lower limbs MISCELLANEOUS \- Presentation after 18 months \- Onset usually in childhood or adolescence \- Progressive disorder \- Individuals develop ability to stand and walk \- Deletions in NAIP gene ( 600355 ) found in 18% of SMA2 patients MOLECULAR BASIS \- Caused by mutation in the survival of motor neuron 1 gene (SMN1, 600354.0003 ) ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	SPINAL MUSCULAR ATROPHY, TYPE III	c0152109	3,230	omim	https://www.omim.org/entry/253400	2019-09-22T16:24:49	{"doid": ["12376"], "mesh": ["D014897"], "omim": ["253400"], "icd-9": ["335.11"], "orphanet": ["70", "83419"], "synonyms": ["SPINAL MUSCULAR ATROPHY, MILD CHILDHOOD AND ADOLESCENT FORM", "Alternative titles", "SMA III", "SMA", "MUSCULAR ATROPHY, JUVENILE", "KUGELBERG-WELANDER SYNDROME"], "genereviews": ["NBK1352"]}
Blepharitis An infant with mild blepharitis on his right side Pronunciation * /blɛfəˈraɪtɪs/ BLEF-ər-EYE-tis SpecialtyOphthalmology Symptomscrusty eyelids Blepharitis is one of the most common ocular conditions characterized by inflammation, scaling, reddening, and crusting of the eyelid. This condition may also cause burning, itching, or a grainy sensation when introducing foreign objects or substances to the eye. Although blepharitis is not sight-threatening, it can lead to permanent alterations of the eyelid margin. The overall etiology is a result of bacteria and inflammation from congested meibomian oil glands at the base of each eyelash. Other conditions may give rise to blepharitis, whether they be infectious or noninfectious, including, but not limited to, bacterial infections or allergies. Different variations of blepharitis can be classified as seborrheic, staphylococcal, mixed, posterior or meibomitis, or parasitic.[1] In a survey of US ophthalmologists and optometrists, 37% to 47% of patients seen by those surveyed had signs of blepharitis, which can affect all ages and ethnic groups.[2] One single-center study of 90 patients with chronic blepharitis found that the average age of patients was 50 years old.[2] ## Contents * 1 Signs and symptoms * 2 Mechanism * 3 Diagnosis * 3.1 Examination * 3.2 Procedures * 4 Prevention * 5 Treatment * 6 Prognosis * 7 Recent research * 8 References * 9 External links ## Signs and symptoms[edit] Blepharitis is characterized by chronic inflammation of the eyelid, usually at the base of the eyelashes.[3][4][5] Symptoms include inflammation, irritation, itchiness, a burning sensation, excessive tearing, and crusting and sticking of eyelids.[3][4] Additional symptoms may include visual impairment such as photophobia and blurred vision. Symptoms are generally worse in the mornings and patients may experience exacerbation and several remissions if left untreated.[2] It is typically caused by bacterial infection or blockage of the meibomian oil glands.[4] Diseases and conditions that may lead to blepharitis include: rosacea, herpes simplex dermatitis, varicella-zoster dermatitis, molluscum contagiosum, allergic dermatitis, contact dermatitis, seborrheic dermatitis, staphylococcal dermatitis, demodicosis (Demodex), and parasitic infections (e.g., Demodex and Phthiriasis palpebrarum).[2][3][5] The parasite Demodex folliculorum (D. folliculorum) causes blepharitis when the parasite is present in excessive numbers within the dermis of the eyelids. These parasites can live for approximately 15 days. The parasites (both adult and eggs) live on the hair follicle, inhabiting the sebaceous and apocrine gland of the human lid. Direct contact allows this pathogen to spread. Factors that allow this pathogen to multiply include hypervascular tissue, poor hygienic conditions, and immune deficiency. In treating Blepharitis caused by D. folliculorum, mechanical cleaning and proper hygiene are important towards decreasing the parasites numbers. [6] Scaling and bacterial debris at the base of the eyelashes Associated Symptoms: * Watery eyes - due to excessive tearing.[7] * Red eyes - due to dilated blood vessels on the sclera.[7] * Swollen eyelids - due to inflammation.[7] * Crusting at the eyelid margins/base of the eyelashes/medial canthus, generally worse on waking - due to excessive bacterial buildup along the lid margins.[4][5][7] * Eyelid sticking - due to crusting along the eyelid margin.[7] * Eyelid itching - due to the irritation from inflammation and epidermis scaling of the eyelid.[7] * Flaking of skin on eyelids - due to tear film suppressed by clogged meibomian glands.[7] * Gritty/burning sensation in the eye, or foreign-body sensation - due to crusting from bacteria and clogged oil glands[7] * Frequent blinking - due to impaired tear film from clogged oil glands unable to keep tears from evaporating.[7] * Light sensitivity/photophobia[5][7] * Misdirected eyelashes that grow abnormally - due to permanent damage to the eyelid margin[7] * Eyelash loss - due to excessive buildup of bacteria along the base of the eyelashes.[7] * Infection of the eyelash follicle/sebaceous gland (hordeolum) * Debris in the tear film, seen under magnification (improved contrast with use of fluorescein drops) External hordeolum Chronic blepharitis may result in damage of varying severity and, in the worst cases, may have a negative effect on vision. This can be resolved with a proper eyeglass prescription.[8] Long-term untreated blepharitis can lead to eyelid scarring, excess tearing, difficulty wearing contact lenses, development of a stye (an infection near the base of the eyelashes, resulting in a painful lump on the edge of the eyelid) or a chalazion (a blockage/bacteria infection in a small oil glands at the margin of the eyelid, just behind the eyelashes, leading to a red, swollen eyelid), chronic pink eye (conjunctivitis), keratitis, and corneal ulcer or irritation.[4][9][10] The lids may become red and may have ulcerate, non-healing areas that may lead to bleeding.[8] Blepharitis can also cause blurred vision due to a poor tear film.[4] Tears may be frothy or bubbly, which can contribute to mild scarring along the eyelids. Symptoms and signs of blepharitis are often erroneously ascribed by the patient as "recurrent conjunctivitis".[11] Staphylococcal blepharitis and Posterior blepharitis or rosacea-associated blepharitis Symptoms Symptoms include a foreign body sensation, matting of the lashes, and burning. Collarette around eyelashes, a ring-like formation around the lash shaft, can be observed.[12] Other symptoms include loss of eyelashes or broken eyelashes.[13] The condition can sometimes lead to a chalazion or a stye.[14] Chronic bacterial blepharitis may also lead to ectropion.[15] Posterior blepharitis or rosacea-associated blepharitis is manifested by a broad spectrum of symptoms involving the lids including inflammation and plugging of the meibomian orifices and production of abnormal secretion upon pressure over the glands.[1] ## Mechanism[edit] The mechanism by which the bacteria causes symptoms of blepharitis is not fully understood and may include direct irritation of bacterial toxins and/or enhanced cell-mediated immunity to S. aureus. Staphylococcal blepharitis is caused by an infection of the anterior portion of the eyelid by Staphylococcal bacteria. In a study of ocular flora, 46% to 51% of those diagnosed with staphylococcal blepharitis had cultures positive for Staphylococcus aureus in comparison to 8% of normal patients.[2] Staphylococcal blepharitis may start in childhood and continue into adulthood.[16] It is commonly recurrent and it requires special medical care. The prevalence of Staphylococcus aureus in the conjunctival sac and on the lid margin varies among countries, likely due to differences in climate and environment.[17] Seborrheic blepharitis is characterized by less inflammation than Staphylococcal blepharitis; however, it causes more excess oil or greasy scaling. Meibomian Gland Dysfunction is a result of abnormalities of the meibomian glands and altered secretion meibum, which plays an imperative role in lagging the evaporation of tear films and smoothing of the tear film to produce an even optical surface. Posterior blepharitis is an inflammation of the eyelids, secondary to dysfunction of the meibomian glands. Like anterior blepharitis, it is a bilateral chronic condition and may be associated with skin rosacea.[1] There is growing evidence that, in some cases, it is caused by Demodex mites.[18] ## Diagnosis[edit] Blepharitis: swollen and reddened eyelid Diagnosis of the condition is done via a physical examination under a slit lamp. Cultures of debris are occasionally collected for bacterial or fungal testing.[19][20] ### Examination[edit] In all forms of blepharitis, optometrists or ophthalmologists examine the tear film, which is the most efficient method in determining instability. The most frequently used method is to measure tear production via tear break-up time (TBUT), which calculates the duration interval between complete blinks. This serves as a primary indication of regional dryness in the pre-corneal tear film after fluorescein injections. If TBUT is shorter than 10 seconds, then this suggests instability.[2] Staphylococcal blepharitis is diagnosed by examining erythema and edema of the eyelid margin. Patients may exhibit alopecia areata of eyelashes and/or growth misdirection, trichiasis. Other signs may include telangiectasia on the anterior eyelid, collarettes encircling the lash base, and corneal changes.[2] Seborrheic blepharitis is distinguished by less erythema, edema, and telangiectasia of the eyelid margins. Posterior blepharitis and Meibomian gland dysfunction are frequently associated with rosacea and can be seen during an ocular examination of the posterior eyelid margin. The Meibomian glands may appear caked with oil or visibly obstructed.[2] ### Procedures[edit] Cultures of the eyelid margins can be a clear indicator for patients suffering from recurrent anterior blepharitis with severe inflammation, in addition to patients who are not responding to therapy.[2] Measurements of tear osmolarity may be beneficial in diagnosing concurrent dry eye syndrome (DES), which may be responsible for overlapping symptoms and would allow the physician to decipher between conditions and move forward with the most beneficial protocol for the patient. Consequently, the measurement of tear osmolarity has various limitations in differentiating between aqueous deficiencies and evaporative dry eye.[21] Microscopic evaluation of epilated eyelashes may reveal mites, which have been evident in cases of chronic blepharoconjunctivitis. A biopsy of the eyelid can also determine the exclusion of carcinoma, therapy resistance, or unifocal recurrent chalazia.[22] Condition Entity Bacterial infections Erysipelas (due to Streptococcus pyogenes) Impetigo (due to Staphylococcus aureus) Viral infections Herpes simplex virus Molluscum contagiosum Varicella zoster virus Papillomavirus Vaccinia Parasitic infection Pediculosis palperbrarum Immunologic conditions Atopic dermatitis Contact dermatitis Erythema multiforme Crohn's disease Dermatoses Psoriasis Erythroderma Benign eyelid tumors Actinic keratosis Pyogenic granuloma Malignant eyelid tumors Melanoma Mycosis fungoides Basal cell carcinoma Trauma Chemical Radiation Surgical Thermal Toxic conditions Medicamentosa ## Prevention[edit] Blepharitis is a result of bacteria and inflammation from congested meibomian oil glands at the base of each eyelash. Routine washing of the eyelids helps subdue symptoms and prevent blepharitis. Washing each eyelid for 30 seconds, twice a day, with a single drop of hypoallergenic soap (e.g. baby shampoo) and ample water can help. The most effective treatment is over the counter lid scrubs used twice a day. Some doctors may recommend using a hypochlorous acid treatment depending on the severity.[2] ## Treatment[edit] Blepharitis is a chronic condition causing frequent exacerbation, thus requiring routine eyelid hygiene. Hygienic practices include warm compresses, eyelid massages, and eyelid scrubs.[2] A Cochrane Systematic Review found topical antibiotics to be effective in providing symptomatic relief and clearing bacteria for individuals with anterior blepharitis.[23] Topical steroids provided some symptomatic relief, but they were ineffective in clearing bacteria from the eyelids.[23] Lid hygiene measures such as warm compresses and lid scrubs were found to be effective in providing symptomatic relief for participants with anterior and posterior blepharitis.[23] Ophthalmologists or optometrists may prescribe a low-dose, oral antibiotic such as Doxycycline.[1][24] Steroid eyedrops/ointments: Eye drops or ointments containing corticosteroids are frequently used in conjunction with antibiotics and can reduce eyelid inflammation.[4][10][25] ## Prognosis[edit] Blepharitis is a chronic condition that has periods of exacerbation and remission. Patients should be informed that symptoms can frequently improve but are rarely eliminated. Infrequently, severe blepharitis can result in permanent alterations in the eyelid margin or vision loss from superficial keratopathy, corneal neovascularization, and ulceration. Patients with an inflammatory eyelid lesion that appears suspicious of malignancy should be referred to an appropriate specialist.[2][26] ## Recent research[edit] A study conducted in November 2017, conveyed a correlation between blepharitis and early onset metabolic syndrome (MetS). To investigate the relationship between blepharitis and MetS, researchers used the Longitudinal Health Insurance Database in Taiwan. Results indicated that hyperlipidaemia and coronary artery disease were significantly correlated with the prior development of blepharitis. Therefore, blepharitis was shown to be significantly related to MetS and can serve as an early indication of the condition.[27] In another recent study, the presence of Demodex has been unveiled as a common cause of blepharitis. However, the pathogenesis of demodicosis is still unclear. In this study, researchers provide a diagnosis of the disease and propose diagnostic criteria of Demodex blepharitis.[28] ## References[edit] 1. ^ a b c d Emmett T. Cunningham; Paul Riordan-Eva (2011-05-17). Vaughan & Asbury's general ophthalmology (18th ed.). McGraw-Hill Medical. ISBN 978-0071634205. 2. ^ a b c d e f g h i j k l Singh Tonk R, Hossain K (November 27, 2014). "Blepharitis". 3. ^ a b c Blepharitis Definition - Diseases and Conditions - Mayo Clinic 4. ^ a b c d e f g Blepharitis: Symptoms, Treatment, and Prevention 5. ^ a b c d Medscape: Medscape Access 6. ^ Inceboz T, Yaman A, Over L, Ozturk AT, Akisu C (2009). "Diagnosis and treatment of demodectic blepharitis". Turkiye Parazitolojii Dergisi. 33 (1): 32–6. PMID 19367544. 7. ^ a b c d e f g h i j k l Blepharitis Symptoms - Diseases and Conditions - Mayo Clinic 8. ^ a b Frank J. Weinstock. "Eyelid Inflammation Symptoms". emedicinehealth.com. Retrieved 21 December 2012. 9. ^ Blepharitis Complications - Diseases and Conditions - Mayo Clinic 10. ^ a b Medscape: Medscape Access 11. ^ Dahl, Andrew. "What are the symptoms and signs of blepharitis?". medicinenet.com. Retrieved 21 December 2012. 12. ^ R Scott Lowery (Jun 17, 2011). "Adult Blepharitis". Medscape. Retrieved 21 December 2012. 13. ^ James Garrity (August 2012). "Blepharitis". The Merck Manual. Retrieved 21 December 2012. 14. ^ "Blepharitis, Stye and Chalazion". University of Illinois College of Medicine. Archived from the original on 19 April 2014. Retrieved 21 December 2012. 15. ^ "How to Get Rid of Sore, Red Eyelids (Blepharitis)". 16. ^ "Blepharitis". Angeles Vision Clinic. Archived from the original on 4 May 2012. Retrieved 21 December 2012. 17. ^ Smolin G, Okumoto M (1977). "Staphylococcal blepharitis". Archives of Ophthalmology. 95 (5): 812–816. doi:10.1001/archopht.1977.04450050090009. PMID 324453. 18. ^ Liu J, Sheha H, Tseng SCG (October 2010). "Pathogenic Role of Demodex Mites in Blepharitis". Curr Opin Allergy Clin Immunol. 10 (5): 505–510. doi:10.1097/aci.0b013e32833df9f4. PMC 2946818. PMID 20689407. 19. ^ Blepharitis Tests and diagnosis - Diseases and Conditions - Mayo Clinic 20. ^ Medscape: Medscape Access 21. ^ Savini G, Prabhawasat P, Kojima T, Grueterich M, Espana E, Goto E (March 2008). "The challenge of dry eye diagnosis". Clinical Ophthalmology (Auckland, N.Z.). 2 (1): 31–55. doi:10.2147/opth.s1496. PMC 2698717. PMID 19668387. 22. ^ Yuji Nemoto, Atsushi Mizota, Reiko Arita, Yuko Sasajima (September 2014). "Differentiation between chalazion and sebaceous carcinoma by noninvasive meibography". Clinical Ophthalmology. 8: 1869–1875. doi:10.2147/OPTH.S69804. PMC 4172083. PMID 25258508. 23. ^ a b c Lindsey K, Matsumara S, Hatel E, Akpek EK (2012). "Interventions for chronic blepharitis". Cochrane Database Syst Rev. 5 (5): CD00556. doi:10.1002/14651858.CD005556.pub2. PMC 4270370. PMID 22592706. 24. ^ Liu J, Sheha H, Tsenga CG (2010). "Pathogenic role of Demodex mites in blepharitis". Curr Opin Allergy Clin Immunol. 10 (5): 505–510. doi:10.1097/ACI.0b013e32833df9f4. PMC 2946818. PMID 20689407. 25. ^ Blepharitis Treatments and drugs - Diseases and Conditions - Mayo Clinic 26. ^ Dahl, Andrew A. "Blepharitis". MedicineNet. 27. ^ Lee CY, Chen HC, Lin HW, Huang JY, Chao SC, Yeh CB, Lin HY, Yang SF (November 2017). "Blepharitis as an early sign of metabolic syndrome: a nationwide population-based study". The British Journal of Ophthalmology. 102 (9): 1283–1287. doi:10.1136/bjophthalmol-2017-310975. PMID 29146760. S2CID 26261977. 28. ^ Liang LY, Liu Y, Li J (September 11, 2017). "Diagnostic criteria of demodex blepharitis". [Zhonghua Yan Ke Za Zhi] Chinese Journal of Ophthalmology. 53 (9): 648–652. doi:10.3760/cma.j.issn.0412-4081.2017.09.003. PMID 28926882. ## External links[edit] Classification D * ICD-10: H01.0 * ICD-9-CM: 373.0 * MeSH: D001762 * DiseasesDB: 1455 External resources * MedlinePlus: 001619 * eMedicine: oph/81 * Patient UK: Blepharitis Wikimedia Commons has media related to Blepharitis. * blepharitis Resource Guide from the National Eye Institute (NEI). * eMedicine Health: Eyelid Inflammation (blepharitis) * 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]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Blepharitis	c0005741	3,231	wikipedia	https://en.wikipedia.org/wiki/Blepharitis	2021-01-18T18:49:42	{"mesh": ["D001762"], "umls": ["C0339063", "C0005741", "C0155181"], "wikidata": ["Q845698"]}
This article includes a list of general references, but it remains largely unverified because it lacks sufficient corresponding inline citations. Please help to improve this article by introducing more precise citations. (June 2014) (Learn how and when to remove this template message) Acute eosinophilic leukemia SpecialtyHematology, oncology Acute eosinophilic leukemia (AEL) is a rare subtype of acute myeloid leukemia with 50 to 80 percent of eosinophilic cells in the blood and marrow. It can arise de novo or may develop in patients having the chronic form of a hypereosinophilic syndrome. Patients with acute eosinophilic leukemia have a propensity for developing bronchospasm as well as symptoms of the acute coronary syndrome and/or heart failure due to eosinophilic myocarditis and eosinophil-based endomyocardial fibrosis.[1][2] Hepatomegaly and splenomegaly are more common than in other variants of AML. ## Contents * 1 Diagnosis * 2 Treatment and prognosis * 3 References * 4 External links ## Diagnosis[edit] A specific histochemical reaction, cyanide-resistant peroxidase, permits identification of leukemic blast cells with eosinophilic differentiation and diagnosis of acute eosinoblastic leukemia in some cases of AML with few identifiable eosinophils in blood or marrow. ## Treatment and prognosis[edit] Acute eosinophilic leukemia is treated as other subtypes of AML. Response to treatment is approximately the same as in other types of AML. ## References[edit] 1. ^ Séguéla PE, Iriart X, Acar P, Montaudon M, Roudaut R, Thambo JB (2015). "Eosinophilic cardiac disease: Molecular, clinical and imaging aspects". Archives of Cardiovascular Diseases. 108 (4): 258–68. doi:10.1016/j.acvd.2015.01.006. PMID 25858537. 2. ^ Rose NR (2016). "Viral myocarditis". Current Opinion in Rheumatology. 28 (4): 383–9. doi:10.1097/BOR.0000000000000303. PMC 4948180. PMID 27166925. ## External links[edit] Classification D * ICD-O: M9880/3 * MeSH: D015472 * v * t * e Myeloid-related hematological malignancy CFU-GM/ and other granulocytes CFU-GM Myelocyte AML: * Acute myeloblastic leukemia * M0 * M1 * M2 * APL/M3 MP * Chronic neutrophilic leukemia Monocyte AML * AMoL/M5 * Myeloid dendritic cell leukemia CML * Philadelphia chromosome * Accelerated phase chronic myelogenous leukemia Myelomonocyte AML * M4 MD-MP * Juvenile myelomonocytic leukemia * Chronic myelomonocytic leukemia Other * Histiocytosis CFU-Baso AML * Acute basophilic CFU-Eos AML * Acute eosinophilic MP * Chronic eosinophilic leukemia/Hypereosinophilic syndrome MEP CFU-Meg MP * Essential thrombocytosis * Acute megakaryoblastic leukemia CFU-E AML * Erythroleukemia/M6 MP * Polycythemia vera MD * Refractory anemia * Refractory anemia with excess of blasts * Chromosome 5q deletion syndrome * Sideroblastic anemia * Paroxysmal nocturnal hemoglobinuria * Refractory cytopenia with multilineage dysplasia CFU-Mast Mastocytoma * Mast cell leukemia * Mast cell sarcoma * Systemic mastocytosis Mastocytosis: * Diffuse cutaneous mastocytosis * Erythrodermic mastocytosis * Adult type of generalized eruption of cutaneous mastocytosis * Urticaria pigmentosa * Mast cell sarcoma * Solitary mastocytoma Systemic mastocytosis * Xanthelasmoidal mastocytosis Multiple/unknown AML * Acute panmyelosis with myelofibrosis * Myeloid sarcoma MP * Myelofibrosis * Acute biphenotypic leukaemia [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Acute eosinophilic leukemia	c0023439	3,232	wikipedia	https://en.wikipedia.org/wiki/Acute_eosinophilic_leukemia	2021-01-18T19:10:38	{"mesh": ["D015472"], "wikidata": ["Q4677921"]}
## Clinical Features Bangstad et al. (1989) described 2 sibs, a 26-year-old male and his 16-year-old sister, born of nonconsanguineous Norwegian parents, who had primordial bird-headed dwarfism, progressive ataxia, goiter, primary gonadal insufficiency, and insulin-resistant diabetes mellitus. Plasma concentrations of TSH, PTH, LH, FSH, ACTH, glucagon, and insulin, all hormones working through cell membrane receptors, were elevated. Bangstad et al. (1989) suggested that a generalized cell membrane defect was responsible for the pathophysiologic abnormality in these patients. Neuro \- Progressive ataxia \- Mental retardation \- Brain very small Neck \- Goiter Inheritance \- Autosomal recessive Eyes \- Large Face \- Narrow Nose \- Beaklike protrusion Head \- Small Metabolic \- Insulin-resistant diabetes mellitus Endocrine \- Primary gonadal insufficiency Misc \- Chromosome instability Lab \- Elevated plasma TSH, PTH, LH, FSH, ACTH, glucagon, and insulin Heme \- Pancytopenia Mandible \- Receding Growth \- Dwarfism, 'low birth weight' type ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	BANGSTAD SYNDROME	c0342284	3,233	omim	https://www.omim.org/entry/210740	2019-09-22T16:30:23	{"mesh": ["C537902"], "omim": ["210740"], "orphanet": ["1227"], "synonyms": ["Alternative titles", "BIRD-HEADED DWARFISM WITH PROGRESSIVE ATAXIA, INSULIN-RESISTANT DIABETES, GOITER, AND PRIMARY GONADAL INSUFFICIENCY"]}
Iatrogenic botulism is the most recent man-made form of botulism (see this term), a rare acquired neuromuscular junction disease with descending flaccid paralysis caused by botulinum neurotoxins (BoNTs), and it may occur as an adverse event after therapeutic or cosmetic use. ## Epidemiology Prevalence is unknown. As of 2008, 180 cases occurring between 1997 and 2006 have been reported to the FDA, including 87 hospitalized cases and 16 deaths. ## Clinical description Clinical manifestations are similar to other forms of botulism, with symmetrical cranial nerve palsies followed by descending, symmetric flaccid paralysis of voluntary muscles, which may progress to respiratory compromise and death. ## Etiology After injection, the toxin is absorbed into the blood stream and distributed throughout the body, causing the typical manifestations of botulism. Therapeutic BoNT injections are a first-line treatment for hemifacial spasm and focal dystonia, such as cervical dystonia and blepharospasm (see these terms). They can also be proposed to treat strabismus and other oculomotor disorders, focal spasticity (spastic foot, upper and lower limb spasticity), overactive bladder and autonomic disorders such as hyperhidrosis, Frey's syndrome and sialorrhea. BoNT injections may have a potential antinociceptive effect. Injected doses, that may be relatively high mostly in the treatment of lower limb spasticity, have caused events reported as adverse reactions including limited botulism-related symptoms (ptosis, diplopia, dysphagia), rare systemic events (flu-like syndrome, generalized weakness and respiratory distress) and occasional deaths following the use of BoNT types A and B. Doses recommended for cosmetic treatment are too low to cause systemic disease, but injection of unlicensed, highly concentrated botulinum toxin may cause severe botulism. All cases of botulism should be reported to the appropriate government agency. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Iatrogenic botulism	c4288922	3,234	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=254509	2021-01-23T18:26:12	{"icd-10": ["A05.1"], "synonyms": ["Inadvertent botulism"]}
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: "Sertoli cell nodule" – news · newspapers · books · scholar · JSTOR (November 2018) (Learn how and when to remove this template message) Sertoli cell nodule Other namesPick's adenoma, testicular tubular adenoma, tubular adenoma of the testis Micrograph of a Sertoli cell nodule. H&E stain. SpecialtyUrology A Sertoli cell nodule is a benign proliferation of Sertoli cells that arises in association with cryptorchidism (undescended testis). They are not composed of a clonal cell population, i.e. neoplastic; thus, technically, they should not be called an adenoma.[1] ## Pathology[edit] Sertoli cell nodules are unencapsulated nodules that consist of:[1][2][3] 1. cells arranged in well-formed tubules (that vaguely resemble immature Sertoli cells), with 2. bland hyperchromatic oval/round nuclei that are stratified, and 3. may contain eosinophilic (hyaline) blob in lumen (centre). * Micrograph of a Sertoli cell nodule. H&E stain. * Micrograph of a Sertoli cell nodule. H&E stain. ## References[edit] 1. ^ a b Tadrous, Paul J. (2007). Diagnostic criteria handbook in histopathology: a surgical pathology vade mecum. John Wiley & Sons Canada. p. 227 =. ISBN 978-0-470-51903-5. 2. ^ "Ashwagandha". 2018-09-24. Retrieved 19 November 2018. 3. ^ Ricco R, Bufo P (October 1980). "[Histologic study of 3 cases of so-called tubular adenoma of the testis]". Boll. Soc. Ital. Biol. Sper. (in Italian). 56 (20): 2110–5. PMID 6109541. ## External links[edit] Classification D Wikimedia Commons has media related to Sertoli cell nodule. * Testis, Sex Cord Stromal Tumor \- eMedicine. * Govender, D.; Sing, Y.; Chetty, R. (2004). "Sertoli cell nodules in the undescended testis: A histochemical, immunohistochemical, and ultrastructural study of hyaline deposits". Journal of Clinical Pathology. 57 (8): 802–806. doi:10.1136/jcp.2004.015982. PMC 1770379. PMID 15280399. * Barghorn, A.; Alioth, H-R; Hailemariam, S.; Bannwart, F.; Ulbright, T. M. (2006). "Giant Sertoli cell nodule of the testis: Distinction from other Sertoli cell lesions". Journal of Clinical Pathology. 59 (11): 1223–1225. doi:10.1136/jcp.2005.035253. PMC 1860496. PMID 17071812. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Sertoli cell nodule	None	3,235	wikipedia	https://en.wikipedia.org/wiki/Sertoli_cell_nodule	2021-01-18T18:59:39	{"wikidata": ["Q7455473"]}
Mucinous cystadenoma Micrograph showing a mucinous cystadenoma of the ovary. H&E stain. SpecialtyOncology Mucinous cystadenoma is a benign cystic tumor lined by a mucinous epithelium. It is a type of cystic adenoma (cystadenoma). Mucinous cystadenomata may arise in a number of locations; however, mucinous cystadenoma at different locations are not generally considered to be related to one another. ## Contents * 1 Overview * 2 Ovarian mucinous cystadenoma * 2.1 Macroscopy * 2.2 Microscopy * 3 Pancreatic Mucinous Cystadenoma * 3.1 Epidemology * 4 Primary Retroperitoneal Mucinous Cystadenoma * 5 Mucinous Cystadenoma Of The Liver * 6 See also * 7 References * 8 External links ## Overview[edit] Mucinous cystadenomas may be found in the: * Ovary—ovarian mucinous cystadenoma * Pancreas—pancreatic mucinous cystadenoma * Peritoneum—peritoneal mucinous cystadenoma * Liver—mucinous cystadenoma of the liver[1] * Vermiform appendix—appendiceal mucinous cystadenoma (see cystadenoma) ## Ovarian mucinous cystadenoma[edit] Mucinous cystadenomas make up 15–20% of all ovarian tumors. They often become very large and can extend up into the abdomen. These tumors are usually evaluated using ultrasound, CT scan, or MRI. Findings on imaging studies are nonspecific. These ovarian tumors are usually multi-septated, cystic masses with thin walls. They also contain varying amounts of solid tissue which consists of proliferating stromal tissue, papillae, or malignant tumor cells. Benign mucinous cystadenomas compose 80% of mucinous ovarian tumors[2] and 20–25% of benign ovarian tumors overall. The peak incidence occurs between 30 and 50 years of age. Benign tumors are bilateral in 5–10% of cases. ### Macroscopy[edit] * * * ### Microscopy[edit] * * * * * * * * ## Pancreatic Mucinous Cystadenoma[edit] Pancreatic Mucinous Cystadenoma or Mucinous Cystadenoma of the pancreas (MCN) are a type of mucinous cystic neoplasm of the pancreas.[3] The cure rate is very high in cases on benign cystic lesions, but the case changes if malignant changes ensue.[4] Benign cystadenomas are the most common cystic tumors of the pancreas accounting for 75% of the cases. On an average, mucinous accounts for 40%-50% of cystic tumors, and serous cytadenoma accounts for 30% of it. Mucinous cystadenomas are in the dital pancreas in about 80% of the cases and distal pancreatectomy is needed for resection.[4] In 20% of the cases it is in the head of the pancreas.[3] ### Epidemology[edit] Earlier it was believed that MCN occurs exclusively in females who are middle aged. However, occasional occurrence in men have been reported,[3] especially those who are 45 years of age or above.[5] ## Primary Retroperitoneal Mucinous Cystadenoma[edit] Cases of primary retroperitoneal mucinous cystadenoma (PRMC) are extremely rare. However, they are observed more frequently in women, with only 4 cases having been found in men.[6] Even though mucinous cystadenoma are common ovarian tumor, what makes PRMC so rare is their retroperitoneal location. PRMC and benign mucinous cystadenoma of the ovary are microscopically similar. Both are multiloculated cystic neoplasms and are lined by a single layer of tall columnar cells with a clear basal nucleus and cytoplasm. Both of them have identical histochemical and ultrastructural features.[7] Flat to low cuboidal cells, resembling mesothelial cells, in the lining interspersed between columnar cells in the same area is the only histological difference between the two tumors.[7] ## Mucinous Cystadenoma Of The Liver[edit] A rare neoplasm, 95% cases occur in women, especially at the mean age of 45.[8] Biliary cystadenoma and cystadenocarcinoma constitute less than 5% of intrahepatic cysts originating from the bile duct.[8] Cystadenomas in liver are often confused with hydatid cyst as their appearance on various imaging techniques is nearly same.[9] Treating cystadenomas as hydatid cyst has resulted in recurrence of the cyst.[9] ## See also[edit] * Mucinous adenocarcinoma ## References[edit] 1. ^ Grubor, NM.; Colovic, RB.; Atkinson, HD.; Micev, MT. (2013). "Giant biliary mucinous cystadenoma of the liver". Ann Hepatol. 12 (6): 979–83. doi:10.1016/S1665-2681(19)31306-7. PMID 24114831. 2. ^ Hart WR (January 2005). "Mucinous tumors of the ovary: a review". Int. J. Gynecol. Pathol. 24 (1): 4–25. PMID 15626914. 3. ^ a b c Weerakkody, Yuranga. "Mucinous cystadenoma of the pancreas \| Radiology Reference Article \| Radiopaedia.org". Radiopaedia. Retrieved 2019-09-21. 4. ^ a b Weledji, Elroy P.; Eyongetah, Divine; Nana, Theophile C.; Ngowe, Marcelin N. (February 2018). "Excision of mucinous cystadenoma of pancreas is safe and effective: a case report". IJS Oncology. 3 (2): e47. doi:10.1097/IJ9.0000000000000047. ISSN 2471-3864. S2CID 80040000. 5. ^ "Mucinous cystic neoplasm (MCN)". www.pathologyoutlines.com. Retrieved 2019-09-21. 6. ^ Lee, Seok Youn; Han, Weon Cheol (February 2016). "Primary Retroperitoneal Mucinous Cystadenoma". Annals of Coloproctology. 32 (1): 33–37. doi:10.3393/ac.2016.32.1.33. ISSN 2287-9714. PMC 4783510. PMID 26962534. 7. ^ a b Subramon, Charu; Habibpour, Saied; Hashimoto, Louis A (2001). "Retroperitoneal Mucinous Cystadenoma: Report of a Case With Reference to Histogenesis". Archives of Pathology & Laboratory Medicine. 125 (5): 691–694. doi:10.1043/0003-9985(2001)125<0691:RMC>2.0.CO;2 (inactive 2021-01-15). ISSN 0003-9985.CS1 maint: DOI inactive as of January 2021 (link) 8. ^ a b "Biliary cystadenoma". www.pathologyoutlines.com. Retrieved 2019-09-21. 9. ^ a b Ahmad, Zubair; Uddin, Nasir; Memon, Wasim; Abdul-Ghafar, Jamshid; Ahmed, Arsalan (2017-11-10). "Intrahepatic biliary cystadenoma mimicking hydatid cyst of liver: a clinicopathologic study of six cases". Journal of Medical Case Reports. 11 (1): 317. doi:10.1186/s13256-017-1481-2. ISSN 1752-1947. PMC 5680786. PMID 29121977. ## External links[edit] Classification D * ICD-10: D27.X * ICD-O: 8470/0 * MeSH: D018291 * v * t * e Glandular and epithelial cancer Epithelium Papilloma/carcinoma * Small-cell carcinoma * Combined small-cell carcinoma * Verrucous carcinoma * Squamous cell carcinoma * Basal-cell carcinoma * Transitional cell carcinoma * Inverted papilloma Complex epithelial * Warthin's tumor * Thymoma * Bartholin gland carcinoma Glands Adenomas/ adenocarcinomas Gastrointestinal * tract: Linitis plastica * Familial adenomatous polyposis * pancreas * Insulinoma * Glucagonoma * Gastrinoma * VIPoma * Somatostatinoma * Cholangiocarcinoma * Klatskin tumor * Hepatocellular adenoma/Hepatocellular carcinoma Urogenital * Renal cell carcinoma * Endometrioid tumor * Renal oncocytoma Endocrine * Prolactinoma * Multiple endocrine neoplasia * Adrenocortical adenoma/Adrenocortical carcinoma * Hürthle cell Other/multiple * Neuroendocrine tumor * Carcinoid * Adenoid cystic carcinoma * Oncocytoma * Clear-cell adenocarcinoma * Apudoma * Cylindroma * Papillary hidradenoma Adnexal and skin appendage * sweat gland * Hidrocystoma * Syringoma * Syringocystadenoma papilliferum Cystic, mucinous, and serous Cystic general * Cystadenoma/Cystadenocarcinoma Mucinous * Signet ring cell carcinoma * Krukenberg tumor * Mucinous cystadenoma / Mucinous cystadenocarcinoma * Pseudomyxoma peritonei * Mucoepidermoid carcinoma Serous * Ovarian serous cystadenoma / Pancreatic serous cystadenoma / Serous cystadenocarcinoma / Papillary serous cystadenocarcinoma Ductal, lobular, and medullary Ductal carcinoma * Mammary ductal carcinoma * Pancreatic ductal carcinoma * Comedocarcinoma * Paget's disease of the breast / Extramammary Paget's disease Lobular carcinoma * Lobular carcinoma in situ * Invasive lobular carcinoma Medullary carcinoma * Medullary carcinoma of the breast * Medullary thyroid cancer Acinar cell * Acinic cell carcinoma * 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 [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Mucinous cystadenoma	c0010635	3,236	wikipedia	https://en.wikipedia.org/wiki/Mucinous_cystadenoma	2021-01-18T19:00:52	{"mesh": ["D018291"], "umls": ["C0010635"], "icd-10": ["C56.9"], "wikidata": ["Q6931143"]}
Thyroid nodule Ultrasound artifacts showing a "comet tail" from a colloid nodule indicate a benign nodule SpecialtyENT surgery, oncology Thyroid nodules are nodules (raised areas of tissue or fluid) which commonly arise within an otherwise normal thyroid gland.[1] They may be hyperplastic or tumorous, but only a small percentage of thyroid tumors are malignant. Small, asymptomatic nodules are common, and often go unnoticed.[2] Nodules that grow larger or produce symptoms may eventually need medical care. A goitre may have one nodule – uninodular, multiple nodules – multinodular, or be diffuse. ## Contents * 1 Signs and symptoms * 2 Diagnosis * 2.1 Workup of incidental nodules * 2.2 Ultrasound * 2.3 Fine needle biopsy * 2.4 Blood tests * 2.5 Other imaging * 3 Malignancy * 4 Solitary thyroid nodule * 4.1 Risks for cancer * 4.2 Signs and symptoms * 4.3 Investigations * 4.4 Thyroid scan * 4.5 Surgery * 4.6 Minimally-invasive procedures * 4.7 Treatment * 5 Autonomous thyroid nodule * 6 See also * 7 References * 8 External links ## Signs and symptoms[edit] Often these abnormal growths of thyroid tissue are located at the edge of the thyroid gland and can be felt as a lump in the throat. When they are large, they can sometimes be seen as a lump in the front of the neck.[citation needed] Sometimes a thyroid nodule presents as a fluid-filled cavity called a thyroid cyst. Often, solid components are mixed with the fluid. Thyroid cysts most commonly result from degenerating thyroid adenomas, which are benign, but they occasionally contain malignant solid components.[3] ## Diagnosis[edit] After a nodule is found during a physical examination, a referral to an endocrinologist, a thyroidologist or otolaryngologist may occur. Most commonly an ultrasound is performed to confirm the presence of a nodule, and assess the status of the whole gland. Measurement of thyroid stimulating hormone and anti-thyroid antibodies will help decide if there is a functional thyroid disease such as Hashimoto's thyroiditis present, a known cause of a benign nodular goitre.[4] Fine needle biopsy for cytopathology is also used.[5][6][7] Thyroid nodules are extremely common in young adults and children. Almost 50% of people have had one, but they are usually only detected by a physician during the course of a health examination or fortuitously discovered during the investigation of an unrelated condition.[8] ### Workup of incidental nodules[edit] The American College of Radiology recommends the following workup for thyroid nodules as incidental imaging findings on CT, MRI or PET-CT:[9] Features Workup * High PET signal or * Local invasiveness or * Suspicious lymph nodes Very likely ultrasonography Multiple nodules Likely ultrasonography Solitary nodule in person younger than 35 years old * Likely ultrasonography if at least 1 cm large in adults, or for any size in children. * None needed if less than 1 cm in adults Solitary nodule in person at least 35 years old * Likely ultrasonography if at least 1.5 cm large * None needed if less than 1.5 cm ### Ultrasound[edit] Ultrasound imaging is useful as the first-line, non-invasive investigation in determining the size, texture, position, and vascularity of a nodule, accessing lymph nodes metastasis in the neck, and for guiding fine needle aspiration cytology (FNAC) or biopsy. Ultrasonographic findings will also guide the indication to biopsy and the long term follow-up.[10] High frequency transducer (7–12 MHz) is used to scan the thyroid nodule, while taking cross-sectional and longitudinal sections during scan. Suspicious findings in a nodule are hypoechoic, ill-defined margins, absence of peripheral halo or irregular margin, fine, punctate microcalcifications, presence of solid nodule, high levels of irregular blood flow within the nodule[11] or "taller-than-wide sign" (anterior-posterior diameter is greater than transverse diameter of a nodule). Features of benign lesion are: hyperechoic, having coarse, dysmorphic or curvilinear calcifications, comet tail artifact (reflection of a highly calcified object), absence of blood flow in the nodule, and presence of cystic (fluid-filled) nodule. However, the presence of solitary or multiple nodules is not a good predictor of malignancy. Malignancy is only diagnosed when ultrasound findings and FNAC report are suggestive of malignancy.[11] The TI-RADS (Thyroid Imaging Reporting and Data Systems) are sonographic classification systems which describe the suspicious findings of thyroid nodules.[12] It was first proposed by Horvath et al,[13] based on the BI-RADS (Breast Imaging Reporting and Data System) concept. Several systems were subsequently proposed and adopted by international scientific societies. Their main aims are to characterize the risk of malignancy of nodules to better select nodules to submit to fine-needle aspiration cytology.[14] Another imaging modality, which is ultrasound elastography, is also useful in diagnosing thyroid malignancy especially for follicular thyroid cancer. However, it is limited by the presence of adequate amount of normal tissue around the lesion, calcified shell around a nodule, cystic nodules, coalescent nodules.[15] ### Fine needle biopsy[edit] Fine Needle Aspiration Cytology (FNAC) is a cheap, simple, and safe method in obtaining cytological specimens for diagnosis by using a needle and a syringe.[16] The Bethesda System for Reporting Thyroid Cytopathology is the system used to report whether the thyroid cytological specimen is benign or malignant. It can be divided into six categories: Bethesda system Category Description Risk of malignancy[17] Recommendation[17] I Non diagnostic/unsatisfactory - Repeating FNAC with ultrasound-guidance in more than 3 months II Benign (colloid and follicular cells) 0 - 3% Clinical follow-up III Atypia of undetermined significance/follicular lesion of undetermined significance (follicular or lymphoid cells with atypical features) 5 - 15% Repeating FNAC IV Follicular nodule/suspicious follicular nodule (cell crowding, micro follicles, dispersed isolated cells, scant colloid) 15 - 30% Surgical lobectomy V Suspicious for malignancy 60 - 75% Surgical lobectomy or near-total thyroidectomy VI Malignant 97 - 99% Near-total thyroidectomy ### Blood tests[edit] Blood tests may be done prior to or in lieu of a biopsy. The possibility of a nodule which secretes thyroid hormone (which is less likely to be cancer) or hypothyroidism is investigated by measuring thyroid stimulating hormone (TSH), and the thyroid hormones thyroxine (T4) and triiodothyronine (T3).Tests for serum thyroid autoantibodies are sometimes done as these may indicate autoimmune thyroid disease (which can mimic nodular disease).[citation needed] ### Other imaging[edit] Thyroid scan A thyroid scan using a radioactive iodine uptake test can be used in viewing the thyroid.[18] A scan using iodine-123 showing a hot nodule, accompanied by a lower than normal TSH, is strong evidence that the nodule is not cancerous, as most hot nodules are benign. Computed tomography of the thyroid plays an important role in the evaluation of thyroid cancer.[19] CT scans often incidentally find thyroid abnormalities, and thereby practically becomes the first investigation modality.[19] ## Malignancy[edit] Main article: Thyroid neoplasm Only a small percentage of lumps in the neck are malignant (around 4 – 6.5%[20]), and most thyroid nodules are benign colloid nodules. There are many factors to consider when diagnosing a malignant lump. Trouble swallowing or speaking, swollen cervical lymph nodes or a firm, immobile nodule are more indicative of malignancy, whereas a family history of autoimmune disease or goiter, thyroid hormonal dysfunction or a soft, painful nodule are more indicative of benignancy.[citation needed] The prevalence of cancer is higher in males, patients under 20 years old or over 70 years old, and patients with a history of head and neck irradiation or a family history of thyroid cancer.[21] ## Solitary thyroid nodule[edit] ### Risks for cancer[edit] Solitary thyroid nodules are more common in females yet more worrisome in males. Other associations with neoplastic nodules are family history of thyroid cancer and prior radiation to the head and neck. Most common cause of solitary thyroid nodule is benign colloid nodules and second most common cause is follicular adenoma.[22] Radiation exposure to the head and neck may be for historic indications such as tonsillar and adenoid hypertrophy, "enlarged thymus", acne vulgaris, or current indications such as Hodgkin's lymphoma. Children living near the Chernobyl nuclear power plant during the catastrophe of 1986 have experienced a 60-fold increase in the incidence of thyroid cancer. Thyroid cancer arising in the background of radiation is often multifocal with a high incidence of lymph node metastasis and has a poor prognosis.[citation needed] ### Signs and symptoms[edit] Worrisome sign and symptoms include voice hoarseness, rapid increase in size, compressive symptoms (such as dyspnoea or dysphagia) and appearance of lymphadenopathy.[citation needed] ### Investigations[edit] * TSH – A thyroid-stimulating hormone level should be obtained first. If it is suppressed, then the nodule is likely a hyperfunctioning (or "hot") nodule. These are rarely malignant. * FNAC – fine needle aspiration cytology is the investigation of choice given a non-suppressed TSH.[23][24] * Imaging – Ultrasound and radioiodine scanning. ### Thyroid scan[edit] 85% of nodules are cold nodules, and 5–8% of cold and warm nodules are malignant.[25] 5% of nodules are hot. Malignancy is virtually non-existent in hot nodules.[26] ### Surgery[edit] Surgery (thyroidectomy) may be indicated in the following instances: * Reaccumulation of the nodule despite 3–4 repeated FNACs * Size in excess of 4 cm in some cases * Compressive symptoms * Signs of malignancy (vocal cord dysfunction, lymphadenopathy) * Cytopathology that does not exclude thyroid cancer ### Minimally-invasive procedures[edit] Non-surgical, minimally invasive ultrasound-guided techniques are now being used for the treatment of large, symptomatic nodules. They include percutaneous ethanol injection, laser thermal ablation, radiofrequency ablation, high intensity focused ultrasound (HIFU), and percutaneous microwave ablation.[27] HIFU has recently proved its effectiveness in treating benign thyroid nodules. This method is noninvasive, without general anesthesia and is performed in an ambulatory setting. Ultrasound waves are focused and produce heat enabling to destroy thyroid nodules.[28] Focused ultrasounds have been used to treat other benign tumors, such as breast fibroadenomas and fibroid disease in the uterus.[citation needed] ### Treatment[edit] Levothyroxine (T4) is a prohormone that peripheral tissues convert to the primary active thyroid hormone, triiodothyronine (T3). Hypothyroid patients normally take it once per day. ## Autonomous thyroid nodule[edit] An autonomous thyroid nodule or "hot nodule" is one that has thyroid function independent of the homeostatic control of the HPT axis (hypothalamic–pituitary–thyroid axis). According to a 1993 article, such nodules need to be treated only if they become toxic; surgical excision (thyroidectomy), radioiodine therapy, or both may be used.[29] ## See also[edit] Wikimedia Commons has media related to Thyroid nodules. * Thyroid adenoma ## References[edit] 1. ^ "New York Thyroid Center: Thyroid Nodules". Archived from the original on 2010-09-17. 2. ^ Vanderpump, MP (2011), "The epidemiology of thyroid disease", Br Med Bull, 99 (1): 39–51, doi:10.1093/bmb/ldr030, PMID 21893493. 3. ^ "Symptoms and causes - Mayo Clinic". Mayo Clinic. 4. ^ Bennedbaek FN, Perrild H, Hegedüs L (1999). "Diagnosis and treatment of the solitary thyroid nodule. Results of a European survey". Clin. Endocrinol. 50 (3): 357–63. doi:10.1046/j.1365-2265.1999.00663.x. PMID 10435062. S2CID 21514672. 5. ^ Ravetto C, Colombo L, Dottorini ME (2000). "Usefulness of fine-needle aspiration in the diagnosis of thyroid carcinoma: a retrospective study in 37,895 patients". Cancer. 90 (6): 357–63. doi:10.1002/1097-0142(20001225)90:6<357::AID-CNCR6>3.0.CO;2-4. PMID 11156519. 6. ^ "Thyroid Nodule". 7. ^ Grani, Giorgio; Sponziello, Marialuisa; Pecce, Valeria; Ramundo, Valeria; Durante, Cosimo (2020-09-01). "Contemporary Thyroid Nodule Evaluation and Management". The Journal of Clinical Endocrinology & Metabolism. 105 (9): dgaa322. doi:10.1210/clinem/dgaa322. ISSN 0021-972X. PMC 7365695. PMID 32491169. 8. ^ Russ G (Sep 2014). "Thyroid incidentalomas: epidemiology, risk stratification with ultrasound and workup". European Thyroid Journal. 3 (3): 154–63. doi:10.1159/000365289. PMC 4224250. PMID 25538897. 9. ^ Jenny Hoang (2013-11-05). "Reporting of incidental thyroid nodules on CT and MRI". Radiopaedia., citing: * Hoang, Jenny K.; Langer, Jill E.; Middleton, William D.; Wu, Carol C.; Hammers, Lynwood W.; Cronan, John J.; Tessler, Franklin N.; Grant, Edward G.; Berland, Lincoln L. (2015). "Managing Incidental Thyroid Nodules Detected on Imaging: White Paper of the ACR Incidental Thyroid Findings Committee". Journal of the American College of Radiology. 12 (2): 143–150. doi:10.1016/j.jacr.2014.09.038. ISSN 1546-1440. PMID 25456025. 10. ^ Durante, Cosimo; Grani, Giorgio; Lamartina, Livia; Filetti, Sebastiano; Mandel, Susan J.; Cooper, David S. (2018-03-06). "The Diagnosis and Management of Thyroid Nodules: A Review". JAMA. 319 (9): 914–924. doi:10.1001/jama.2018.0898. ISSN 0098-7484. PMID 29509871. S2CID 5042725. 11. ^ a b Wong KT, Ahuja AT (2005). "Ultrasound of thyroid cancer". Cancer Imaging. 5: 157–66. doi:10.1102/1470-7330.2005.0110. PMC 1665239. PMID 16361145. 12. ^ Fernández Sánchez, J. (July 2014). "Clasificación TI-RADS de los nódulos tiroideos en base a una escala de puntuación modificada con respecto a los criterios ecográficos de malignidad". Revista Argentina de Radiología. 78 (3): 138–148. doi:10.1016/j.rard.2014.07.015. 13. ^ Horvath, Eleonora; Majlis, Sergio; Rossi, Ricardo; Franco, Carmen; Niedmann, Juan P.; Castro, Alex; Dominguez, Miguel (May 2009). "An Ultrasonogram Reporting System for Thyroid Nodules Stratifying Cancer Risk for Clinical Management". The Journal of Clinical Endocrinology & Metabolism. 94 (5): 1748–1751. doi:10.1210/jc.2008-1724. PMID 19276237. 14. ^ Grani, Giorgio; Lamartina, Livia; Ascoli, Valeria; Bosco, Daniela; Biffoni, Marco; Giacomelli, Laura; Maranghi, Marianna; Falcone, Rosa; Ramundo, Valeria; Cantisani, Vito; Filetti, Sebastiano; Durante, Cosimo (8 October 2018). "Reducing the number of unnecessary thyroid biopsies while improving diagnostic accuracy: towards the "right" TIRADS". The Journal of Clinical Endocrinology & Metabolism. 104 (1): 95–102. doi:10.1210/jc.2018-01674. PMID 30299457. 15. ^ Diaz Soto, Gonzalo; Halperin, Irene; Squarcia, Mattia; Lomena, Francisco; Puig Domingo, Manuel (10 September 2010). "Update in thyroid imaging. The expanding world of thyroid imaging and its translation to clinical practice" (PDF). Hormones. 9 (4): 287–298. doi:10.14310/horm.2002.1279. PMID 21112859. S2CID 15979225. 16. ^ Diana, S Dean; Hossein, Gharib. "Fine-Needle Aspiration Biopsy of the Thyroid Gland". Thyroid Disease Manager. Archived from the original on 12 July 2017. Retrieved 16 October 2017. 17. ^ a b Renuka, I. V.; Saila Bala, G.; Aparna, C.; Kumari, Ramana; Sumalatha, K. (December 2012). "The Bethesda System for Reporting Thyroid Cytopathology: Interpretation and Guidelines in Surgical Treatment". Indian Journal of Otolaryngology and Head & Neck Surgery. 64 (4): 305–311. doi:10.1007/s12070-011-0289-4. PMC 3477437. PMID 24294568. 18. ^ MedlinePlus Encyclopedia: Thyroid scan 19. ^ a b Bin Saeedan, Mnahi; Aljohani, Ibtisam Musallam; Khushaim, Ayman Omar; Bukhari, Salwa Qasim; Elnaas, Salahudin Tayeb (2016). "Thyroid computed tomography imaging: pictorial review of variable pathologies". Insights into Imaging. 7 (4): 601–617. doi:10.1007/s13244-016-0506-5. ISSN 1869-4101. PMC 4956631. PMID 27271508. Creative Commons Attribution 4.0 International License 20. ^ "UpToDate". 21. ^ Thyroid Nodule at eMedicine 22. ^ Schwartz 7th/e page 1679,1678 23. ^ Ali, SZ; Cibas, ES (2016). "The Bethesda System for Reporting Thyroid Cytopathology II". Acta Cytologica. 60 (5): 397–398. doi:10.1159/000451071. PMID 27788511. S2CID 32693137. 24. ^ Grani, G; Calvanese, A; Carbotta, G; D'Alessandri, M; Nesca, A; Bianchini, M; Del Sordo, M; Fumarola, A (January 2013). "Intrinsic factors affecting adequacy of thyroid nodule fine-needle aspiration cytology". Clinical Endocrinology. 78 (1): 141–4. doi:10.1111/j.1365-2265.2012.04507.x. PMID 22812685. S2CID 205287747. 25. ^ Gates, Jeremy D.; Benavides, Linda C.; Shriver, Craig D.; Peoples, George E.; Stojadinovic, Alexander (2009). "Preoperative Thyroid Ultrasound In All Patients Undergoing Parathyroidectomy?". Journal of Surgical Research. 155 (2): 254–60. doi:10.1016/j.jss.2008.09.012. PMID 19482296. 26. ^ Robbins pathology 8ed page 767 27. ^ Tumino, D; Grani, G; Di Stefano, M; Di Mauro, M; Scutari, M; Rago, T; Fugazzola, L; Castagna, MG; Maino, F (2019). "Nodular Thyroid Disease in the Era of Precision Medicine". Frontiers in Endocrinology. 10: 907. doi:10.3389/fendo.2019.00907. PMC 6989479. PMID 32038482. 28. ^ "Echotherapy: Thyroid nodules". 29. ^ Vigneri, R; et al. (1993), "[Physiopathology of the autonomous thyroid nodule]", Minerva Endocrinol, 18 (4): 143–145, PMID 8190053. ## External links[edit] Classification D * ICD-10: E04.1 * ICD-9-CM: 241.0 * MeSH: D016606 * DiseasesDB: 5332 * SNOMED CT: 237495005 External resources * MedlinePlus: 007265 * eMedicine: med/3224 * v * t * e Thyroid disease Hypothyroidism * Iodine deficiency * Cretinism * Congenital hypothyroidism * Myxedema * Myxedema coma * Euthyroid sick syndrome * Signs and symptoms * Queen Anne's sign * Woltman sign * Thyroid dyshormonogenesis * Pickardt syndrome Hyperthyroidism * Hyperthyroxinemia * Thyroid hormone resistance * Familial dysalbuminemic hyperthyroxinemia * Hashitoxicosis * Thyrotoxicosis factitia * Thyroid storm Graves' disease * Signs and symptoms * Abadie's sign of exophthalmic goiter * Boston's sign * Dalrymple's sign * Stellwag's sign * lid lag * Griffith's sign * Möbius sign * Pretibial myxedema * Graves' ophthalmopathy Thyroiditis * Acute infectious * Subacute * De Quervain's * Subacute lymphocytic * Palpation * Autoimmune/chronic * Hashimoto's * Postpartum * Riedel's Enlargement * Goitre * Endemic goitre * Toxic nodular goitre * Toxic multinodular goiter * Thyroid nodule * Colloid nodule [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Thyroid nodule	c0040137	3,237	wikipedia	https://en.wikipedia.org/wiki/Thyroid_nodule	2021-01-18T18:52:27	{"mesh": ["D016606"], "icd-9": ["241.0"], "icd-10": ["E05.1", "E05.2", "E04.1"], "wikidata": ["Q53829"]}
Polyrrhinia is an extremely rare, major congenital malformation characterized by complete duplication of the nose resulting in twofully developed noses often associated with choanal atresia, causing respiratory distress and necessitating surgical repair. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Polyrrhinia	c4274730	3,238	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=141091	2021-01-23T17:53:56	{"icd-10": ["Q30.8"], "synonyms": ["Double nose", "Polyrhinia"]}
Mental disorder "Self-amputation" redirects here. See also Autotomy and Amputation § Self-amputation. "BIID" redirects here. For the organisation, see British Institute of Interior Design. Body integrity dysphoria Other namesBody integrity identity disorder SpecialtyPsychiatry, Clinical Psychology SymptomsDesire to become disabled, discomfort with being able-bodied ComplicationsSelf-amputation Usual onset8–12 years old Risk factorsKnowing an amputee as a child TreatmentCognitive behavioral therapy MedicationAntidepressants Body integrity dysphoria (BID, also referred to as body integrity identity disorder, amputee identity disorder and xenomelia, formerly called apotemnophilia) is a disorder characterized by a desire to be disabled or having discomfort with being able-bodied beginning in early adolescence and resulting in harmful consequences.[1] BID appears to be related to somatoparaphrenia.[2] People with this condition may refer to themselves as "transabled".[3][4][5] ## Contents * 1 Signs and symptoms * 2 Causes * 3 Diagnosis * 3.1 Classification * 4 Treatment * 5 Prognosis * 6 History * 7 See also * 8 References * 9 Further reading * 10 External links ## Signs and symptoms[edit] BID is a rare, infrequently studied condition in which there is a mismatch between the mental body image and the physical body, characterized by an intense desire for amputation of a limb, usually a leg, or to become blind or deaf.[2] The person sometimes has a sense of sexual arousal connected with the desire for loss of a limb or sense.[2] Some act out their desires, pretending they are amputees using prostheses and other tools to ease their desire to be one. Some people with BID have reported to the media or by interview over the telephone with researchers that they have resorted to self-amputation of a "superfluous" limb by, for example, allowing a train to run over it or otherwise damaging it so severely that surgeons will have to amputate it. However, the medical literature records few, if any, cases of actual self-amputation.[6][7] To the extent that generalizations can be made, people with BID appear to start to wish for amputation when they are young, between eight and twelve years of age, and often knew a person with an amputated limb when they were children; however, people with BID tend to seek treatment only when they are much older.[7] People with BID seem to be predominantly male, and while there is no evidence that sexual preference is relevant, there does seem to be a correlation with BID and a person having a paraphilia; there appears to be a weak correlation with personality disorders.[7] Family psychiatric history does not appear to be relevant, and there does not appear to be any strong correlation with the site of the limb or limbs that the person wishes they did not have, nor with any past trauma to the undesired limb.[7] ## Causes[edit] As of 2014 the cause was not clear and was a subject of ongoing research.[8] However a small sample of people with body integrity dysphoria connected to their left leg have had MRI scans that showed less gray matter in the right side of their superior parietal lobule. The amount of gray matter missing was correlated to the strength of the patients' desire to remove their leg. [9] ## Diagnosis[edit] As of 2014 there were no formal diagnostic criteria.[2] ### Classification[edit] As of 2014 it remained unclear whether BID is a form of human diversity or a mental disorder. There was debate about including it in the DSM-5 and it was not included; it was also not included in the ICD-10.[2][8] It has been included in the ICD-11, which reached a stable version in June 2018, as 'Body integrity dysphoria' with code 6C21.[1] The ethics of surgically amputating the undesired limb of a person with BID are difficult and controversial.[6][10][11] ## Treatment[edit] There is no evidence-based treatment for BID; there are reports of the use of cognitive behavioral therapy and antidepressants.[7] ## Prognosis[edit] Outcomes of treated and untreated BID are not known; there are numerous case reports that amputation permanently resolves the desire in affected individuals.[7][12] ## History[edit] Apotemnophilia was first described in a 1977 article by psychologists Gregg Furth and John Money as primarily sexually oriented. In 1986 Money described a similar condition he called acromotophilia; namely, sexual arousal in response to a partner's amputation. Publications before 2004 were generally case studies.[13] The condition received public attention in the late 1990s after Scottish surgeon Robert Smith amputated limbs of two otherwise healthy people who were desperate to have this done.[13] In 2004 Michael First published the first clinical research in which he surveyed fifty-two people with the condition, a quarter of whom had undergone an amputation. Based on that work, First coined the term "body integrity identity disorder" to express what he saw as more of an identity disorder than a paraphilia.[8] After First's work, efforts to study BID as a neurological condition looked for possible causes in the brains of people with BID using neuroimaging and other techniques.[2][13] Research provisionally found that people with BID were more likely to want removal of a left limb than right, consistent with damage to the right parietal lobe; in addition, skin conductance response is significantly different above and below the line of desired amputation, and the line of desired amputation remains stable over time, with the desire often beginning in early childhood.[13] This work did not completely explain the condition, and psychosexual research has been ongoing as well.[13][14][15] ## See also[edit] * Abasiophilia * Armless * Attraction to disability * Body dysmorphic disorder * Body image * Body modification * Disability pretenders * Penectomy * Quid Pro Quo * Whole ## References[edit] 1. ^ a b "ICD-11 – Mortality and Morbidity Statistics". icd.who.int. Archived from the original on 1 August 2018. Retrieved 6 July 2018. 2. ^ a b c d e f Brugger, P; Lenggenhager, B (December 2014). "The bodily self and its disorders: neurological, psychological and social aspects". Current Opinion in Neurology. 27 (6): 644–52. doi:10.1097/WCO.0000000000000151. PMID 25333602. Archived from the original on 14 January 2018. Retrieved 13 January 2018. 3. ^ Baril, Alexandre; Trevenen, Kathryn (14 April 2016). "Transabled women lost in translation? An introduction to: '"Extreme" transformations: (Re)Thinking solidarities among social movements through the case of voluntary disability acquisition'". Medicine Anthropology Theory. 3 (1): 136. doi:10.17157/mat.3.1.388. 4. ^ Shad (11 June 2015). "Desiring disability: What does it mean to be transabled?". CBC Radio. Archived from the original on 11 June 2015. Retrieved 11 June 2015. 5. ^ Davis, Jenny L. (1 June 2014). "Morality Work among the Transabled". Deviant Behavior. 35 (6): 433–455. doi:10.1080/01639625.2014.855103. ISSN 0163-9625. S2CID 144412724. 6. ^ a b Levy, Neil (2007). Neuroethics — Challenges for the 21st Century. Cambridge University Press. pp. 3–5. ISBN 978-0-521-68726-3. 7. ^ a b c d e f Bou Khalil, R; Richa, S (December 2012). "Apotemnophilia or body integrity identity disorder: a case report review". The International Journal of Lower Extremity Wounds. 11 (4): 313–9. doi:10.1177/1534734612464714. PMID 23089967. S2CID 30991969. 8. ^ a b c Sedda, A; Bottini, G (2014). "Apotemnophilia, body integrity identity disorder or xenomelia? Psychiatric and neurologic etiologies face each other". Neuropsychiatric Disease and Treatment. 10: 1255–65. doi:10.2147/NDT.S53385. PMC 4094630. PMID 25045269. 9. ^ Longo, Matthew (June 2020). "Body Image: Neural Basis of 'Negative' Phantom Limbs". Current Biology. 30 (11): 2191–2195. Retrieved 23 December 2020. 10. ^ Costandi, Mo (30 May 2012). "The science and ethics of voluntary amputation \| Mo Costandi". The Guardian. Archived from the original on 2 January 2018. Retrieved 13 January 2018. 11. ^ Dua, A (February 2010). "Apotemnophilia: ethical considerations of amputating a healthy limb". Journal of Medical Ethics. 36 (2): 75–8. doi:10.1136/jme.2009.031070. PMID 20133399. S2CID 23988376. 12. ^ Blom, RM; Hennekam, RC; Denys, D (2012). "Body integrity identity disorder". PLOS ONE. 7 (4): e34702. Bibcode:2012PLoSO...734702B. doi:10.1371/journal.pone.0034702. PMC 3326051. PMID 22514657. 13. ^ a b c d e De Preester, H (May 2013). "Merleau-Ponty's sexual schema and the sexual component of body integrity identity disorder". Medicine, Health Care and Philosophy. 16 (2): 171–84. doi:10.1007/s11019-011-9367-3. PMID 22139385. 14. ^ Lawrence, A. A. (2006). "Clinical and theoretical parallels between desire for limb amputation and gender identity disorder" (PDF). Archives of Sexual Behavior. 35 (3): 263–278. doi:10.1007/s10508-006-9026-6. PMID 16799838. S2CID 17528273. 15. ^ Lawrence, A. A. (2009). "Erotic target location errors: An underappreciated paraphilic dimension". Journal of Sex Research. 46 (2–3): 194–215. doi:10.1080/00224490902747727. PMID 19308843. S2CID 10105602. ## Further reading[edit] * Davis, Jenny L. (2012). "Narrative Construction of a Ruptured Self: Stories of Transability on Transabled.org". Sociological Perspectives. 55 (2): 319–340. doi:10.1525/sop.2012.55.2.319. JSTOR 10.1525/sop.2012.55.2.319. S2CID 145521213. * First, MB; Fisher, CE (2012). "Body integrity identity disorder: the persistent desire to acquire a physical disability". Psychopathology. 45 (1): 3–14. doi:10.1159/000330503. PMID 22123511. S2CID 19615762. * Furth, Gregg M.; Smith, Robert (2000). Apotemnophilia : information, questions, answers, and recommendations about self-demand amputation (Rev. (05/15/2002). ed.). Bloomington, IN: 1stBooks. ISBN 978-1588203908. * Sacks, Oliver W. (1998). A Leg To Stand On. Touchstone Books. ISBN 978-0-684-85395-6. * Stirn, A.; Thiel, A.; Oddo, S. (2009). Body Integrity Identity Disorder: Psychological, Neurobiological, Ethical and Legal Aspects. Pabst Science Publishers. ISBN 978-3-89967-592-4. ## External links[edit] * Complete Obsession, a Horizon episode on BIID (transcript) * https://www.okwhatever.org/topics/selfie/biid [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Body integrity dysphoria	c4546282	3,239	wikipedia	https://en.wikipedia.org/wiki/Body_integrity_dysphoria	2021-01-18T18:49:06	{"wikidata": ["Q890069"]}
Pgp-1 glycoprotein, as it is termed in the mouse, was first demonstrated in that species. It is a polymorphic cell-surface antigen present in many tissues and is coded by a gene on mouse chromosome 2. Isacke et al. (1986) identified and characterized the homologous protein in man. In both species, it is an abundant plasma membrane component of fibroblasts and is uniformly distributed over the cell surface. It has a large extracellular domain. It can be metabolically labeled with (32)P exclusively on serine residues indicating that it is a transmembrane glycoprotein (Isacke et al., 1986). Both this glycoprotein and the Thy-1 glycoprotein (188230) are abundant on mouse thymocytes but are not expressed on human thymocytes. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	PHOSPHOGLYCOPROTEIN 1	c1868352	3,240	omim	https://www.omim.org/entry/172290	2019-09-22T16:36:17	{"omim": ["172290"]}
For a phenotypic description and a discussion of genetic heterogeneity of essential tremor, see ETM1 (190300). Mapping Higgins et al. (1997) reported linkage of an essential tremor locus on chromosome 2 in a large American family of Czech descent with dominantly inherited 'pure' essential tremor. They symbolized the locus ETM; it is also referred to as ETM2. A maximum lod score of 5.92 was obtained for the locus D2S272 located at 2p25-p22. Obligate recombinant events placed the ETM2 gene in a 15-cM candidate interval between the genetic loci D2S168 and D2S224. In the assessment of tremor in the family studies, Higgins et al. (1997) had the subjects hold their arms in a wing-beating position (with the elbows partially flexed and the shoulders abducted in the horizontal plane). Tremor amplitude was assessed by visual inspection and classified as fine, moderate, or coarse. Without presenting the data in detail, Higgins et al. (1997) suggested that the family showed anticipation. Higgins et al. (1998) found evidence for linkage to 2p in 3 other unrelated American families. Multipoint linkage analysis in all 4 American families suggested a minimal critical region of 2.18 cM between loci D2S2150 and D2S220. They also excluded linkage to the ETM1 locus on chromosome 3. The age at disease onset was 32 years +/- 18 (SD). Anticipation was not well borne out by the new families. Higgins et al. (2003) stated that the ETM2 gene maps to 2p24.1. They identified 3 unreported dinucleotide polymorphic sites on a physical map of the ETM2 interval in a region of no recombination. A haplotype formed by 2 of these sites occurred with a frequency of 29% in 45 white cases and 9% in a sample of 35 white newborns (P less than 0.0001). The haplotype was not found in 35 normal individuals older than 60 years without tremor (P = 0.0063). This study provided evidence that an ancestral haplotype on chromosome 2p24.1 segregates with the essential tremor disease phenotype in individuals with a family history of the disorder. Using BAC clone analysis, Higgins et al. (2004) constructed an integrated physical map of the ETM2 region on chromosome 2p24.3-p24.2. Molecular Genetics Although Higgins et al. (2005) reported an association between essential tremor and a substitution in the HS1BP3 gene (609359), Deng et al. (2005) found no association between the same substitution and essential tremor or Parkinson disease (168600) among 222 and 285 affected patients, respectively. Furthermore, the substitution allele was present in 12 (9.1%) of 132 control individuals, indicating it is a polymorphism. Misc \- Aggravated by emotions, hunger, fatigue, and temperature extremes \- Beta-adrenergic blocking agents and primidone partially effective \- Significant side-effects of therapy \- Anticipation suggested in one family Neuro \- Essential tremor \- Postural tremor of arms \- Variable tremor of head, legs, trunk, voice, jaw, and facial muscles 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 [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	TREMOR, HEREDITARY ESSENTIAL, 2	c1865810	3,241	omim	https://www.omim.org/entry/602134	2019-09-22T16:13:55	{"mesh": ["C536546"], "omim": ["602134"]}
Marburg hemorrhagic fever (MHF), caused by Marburg virus, is a severe viral hemorrhagic disease characterized by initial fever and malaise followed by gastrointestinal symptoms, bleeding, shock, and multi-organ system failure. ## Epidemiology MHF is endemic to Central Africa and is generally recognized in sporadic small outbreaks (<50 cases), although one large (>250 cases) nosocomial outbreak occurred in Angola in 2004-2005. Less than 500 cases have been reported to date. ## Clinical description After an incubation period of about 8 days (range 3-21 days), patients typically present with the abrupt onset of non-specific signs and symptoms including fever, malaise, headache, chest pain and myalgia/arthralgia, followed rapidly by gastrointestinal manifestations (vomiting, diarrhea, abdominal pain) and, in some cases, a maculopapular skin rash. Severe cases develop bleeding (sub-conjunctival hemorrhage, epistaxis, bleeding from the mouth and rectum, oozing from venipuncture sites), neurologic involvement (disorientation, convulsions, coma), shock and multi-organ system failure. Mild-to-moderate leukopenia and thrombocytopenia are often present and disseminated intravascular coagulation (DIC) commonly develops, best indicated by the presence of D-dimers. ## Etiology Over 25 different viruses cause viral hemorrhagic fever. Marburg virus is a member of the virus family Filoviridae, along with Ebola virus. Numerous strains have been identified, putatively with different degrees of lethality. Accumulating evidence implicates fruit bats as the Marburg virus reservoir, with primary human infection presumably from unwitting contact with bat excreta or saliva. Entry into caves and mines where fruit bats roost is a risk factor. Infection has also rarely occurred through contact with tissues of wild monkeys, presumably also infected through bat exposure. Human-to-human transmission occurs through direct contact with blood or bodily fluids of infected persons. ## Diagnostic methods Common diagnostic modalities include cell culture (restricted to biosafety level-4 laboratories), serologic testing by enzyme linked immunosorbent assay (ELISA) or indirect fluorescent antibody (IFA), and reverse transcription polymerase chain reaction (RT-PCR). Because no commercial assays are presently available, these tests are typically performed only in a few specialized laboratories. ## Differential diagnosis MHF is difficult to distinguish from a host of other febrile illnesses, at least early in the course of disease. Other viral hemorrhagic fevers need to be excluded, especially Ebola hemorrhagic fever, as well as malaria, typhoid fever, leptospirosis, rickettsial infection, plague (see these terms), bacterial dysenteryand meningococcemia. ## Management and treatment Patients should be isolated and viral hemorrhagic fever precautions (face shields, surgical masks, double gloves, surgical gowns and aprons) should be used to prevent nosocomial transmission. As there is presently no antiviral drug available for MHF, treatment is supportive, following the guidelines for treatment of severe septicemia. Persons who have unprotected contact with someone with MHF should be monitored. ## Prognosis Case-fatality rates are typically over 80%, although it was only 22% in one outbreak in Europe stemming from imported monkeys. Shock, bleeding, neurological manifestations, high viremia, aspartate aminotransferase (AST) > 150 IU/L, and pregnancy confer a poor prognosis. Convalescence may last up to a year but survivors usually have no lasting sequelae. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Marburg hemorrhagic fever	c0024788	3,242	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=99826	2021-01-23T18:08:08	{"gard": ["9444"], "mesh": ["D008379"], "umls": ["C0024788"], "icd-10": ["A98.3"], "synonyms": ["Green monkey disease", "MHF", "Marburg virus disease"]}
Perlman syndrome Other namesNephroblastomatosis-fetal ascites-macrosomia-Wilms tumor syndrome Perlman syndrome has an autosomal recessive pattern of inheritance. SpecialtyOncology Perlman syndrome (PS) (also called renal hamartomas, nephroblastomatosis and fetal gigantism) is a rare overgrowth disorder present at birth. It is characterized by polyhydramnios and fetal overgrowth, including macrocephaly, neonatal macrosomia, visceromegaly, dysmorphic facial features, and an increased risk for Wilms' tumor at an early age. The prognosis for Perlman syndrome is poor and it is associated with a high neonatal mortality. Perlman syndrome is an uncommon genetic disorder grouped with overgrowth syndrome in which an abnormal increase is often noted at birth in the size of the body or a body part of the infant. The disorder, also called renal hamartomas, nephroblastomatosis and fetal gigantism, has also been grouped with Renal cell carcinoma.[1] The characteristic features include polyhydramnios, fetal overgrowth, including macrocephaly, neonatal macrosomia, visceromegaly, dysmorphic facial features, and an increased risk for Wilms' tumor at an early age.[2] ## Contents * 1 Genetics * 2 Diagnosis * 2.1 Differential diagnosis * 3 Treatment * 4 Epidemiology * 5 See also * 6 References * 7 External links ## Genetics[edit] The gene thought to cause some of the cases of Perlman syndrome is DIS3L2 found on chromosome 2 at 2q37.2 and is thought to have an important role in the mitotic cell cycle. Although both sexes are affected, the sex ratio of male to female is 2:1. The syndrome has been described in both consanguineous and non-consanguineous couplings.[3] No chromosomal abnormalities have been observed, except for in the case of Chernos et al., which showed a de novo mutation — an extra G positive band, a genetic mutation that neither parent possessed nor transmitted — on the tip of the short arm of chromosome 11.[4] ## Diagnosis[edit] The diagnosis of Perlman syndrome is based on observed phenotypic features and confirmed by histological examination of the kidneys. Prenatal diagnosis is possible for families that have a genetic disposition for Perlman syndrome although there is no conclusive laboratory test to confirm the diagnosis. Fetal overgrowth, particularly with an occipitofrontal circumference (OFC) greater than the 90th centile for gestational age, as well as an excess of amniotic fluid in the amniotic sac (polyhydramnios), may be the first signs of Perlman.[3] Using ultrasound diagnosis, Perlman syndrome has been detected at 18 weeks. During the first trimester, the common abnormalities of the syndrome observed by ultrasound include cystic hygroma and a thickened nuchal lucency. Common findings for the second and third trimesters include macrosomia, enlarged kidneys, renal tumors (both hamartoma and Wilms), cardiac abnormalities and visceromegaly.[5] Prompt recognition and identification of the disorder along with accurate follow-up and clinical assistance is recommended as the prognosis for Perlman is severe and associated with a high neonatal death rate.[3][6] ### Differential diagnosis[edit] Perlman syndrome shares clinical overlaps with other overgrowth disorders, with similarities to Beckwith–Wiedemann syndrome and Simpson-Golabi-Behmel syndrome having been particularly emphasized in scientific study. Similarities with Beckwith-Wiedemann syndrome include polyhydramnios, macrosomia, nephromegaly and hypoglycaemia. It is the distinctive facial dysmorphology of Perlman, including deep-set eyes, depressed nasal bridge, everted upper lip, and macrocephaly which allows the two conditions to be distinguished from one another. Diagnosis of Perlman syndrome also overlaps with other disorders associated with Wilms tumor, namely, Sotos syndrome and Weaver syndrome.[3][6] ## Treatment[edit] This section is empty. You can help by adding to it. (August 2017) ## Epidemiology[edit] Perlman syndrome is a rare disease with an estimated incidence of less than 1 in 1,000,000. As of 2008, fewer than 30 patients had ever been reported in the world literature.[1] ## See also[edit] * Beckwith–Wiedemann syndrome * Multiple abnormalities * Renal cell carcinoma ## References[edit] 1. ^ a b "Perlman syndrome". Orphanet. May 2008. Retrieved 2010-10-21. 2. ^ Perlman M (December 1986). "Perlman syndrome: familial renal dysplasia with Wilms tumor, fetal gigantism, and multiple congenital anomalies". Am J Med Genet. 25 (Pt 4): 793–5. doi:10.1002/ajmg.1320250418. PMID 3024486. 3. ^ a b c d Piccione, Maria; Giovanni Corsello (December 2006). "Perlman syndrome (renal hamartomas, nephroblastomatosis and fetal gigantism)". Atlas Genet Cytogenet Oncol Haematol. Retrieved 2010-10-18. 4. ^ Chernos JE, Fowler SB, Cox DM (September 1990). "A case of Perlman syndrome associated with a cytogenetic abnormality of chromosome 11 (abstract)". Am J Hum Genet. 47(suppl) (Suppl): A28. PMC 1683946. 5. ^ Benacerraf, Beryl R. (2007), Ultrasound of fetal syndromes (2 ed.), Elsevier Health Sciences, p. 147, ISBN 978-0-443-06641-2 6. ^ a b Emery and Rimoisn's principles and practice of medical genetics, Volume 2, Elsevier Health Sciences, p. 1522, ISBN 978-0-443-06870-6 ## External links[edit] Classification D * ICD-10: C64 * OMIM: 267000 * MeSH: C536399 External resources * Orphanet: 2849 * v * t * e Tumors of the urinary and genital systems Kidney Glandular and epithelial neoplasm * Renal cell carcinoma * Renal oncocytoma Mixed tumor * Wilms' tumor * Mesoblastic nephroma * Clear-cell sarcoma of the kidney * Angiomyolipoma * Cystic nephroma * Metanephric adenoma by location * Renal medullary carcinoma * Juxtaglomerular cell tumor * Renal medullary fibroma Ureter * Ureteral neoplasm Bladder * Transitional cell carcinoma * Squamous-cell carcinoma * Inverted papilloma Urethra * Transitional cell carcinoma * Squamous-cell carcinoma * Adenocarcinoma * Melanoma Other * Malignant fibrous histiocytoma * v * t * e Congenital abnormality syndromes Craniofacial * Acrocephalosyndactylia * Apert syndrome * Carpenter syndrome * Pfeiffer syndrome * Saethre–Chotzen syndrome * Sakati–Nyhan–Tisdale syndrome * Bonnet–Dechaume–Blanc syndrome * Other * Baller–Gerold syndrome * Cyclopia * Goldenhar syndrome * Möbius syndrome Short stature * 1q21.1 deletion syndrome * Aarskog–Scott syndrome * Cockayne syndrome * Cornelia de Lange syndrome * Dubowitz syndrome * Noonan syndrome * Robinow syndrome * Silver–Russell syndrome * Seckel syndrome * Smith–Lemli–Opitz syndrome * Snyder–Robinson syndrome * Turner syndrome Limbs * Adducted thumb syndrome * Holt–Oram syndrome * Klippel–Trénaunay–Weber syndrome * Nail–patella syndrome * Rubinstein–Taybi syndrome * Gastrulation/mesoderm: * Caudal regression syndrome * Ectromelia * Sirenomelia * VACTERL association Overgrowth syndromes * Beckwith–Wiedemann syndrome * Proteus syndrome * Perlman syndrome * Sotos syndrome * Weaver syndrome * Klippel–Trénaunay–Weber syndrome * Benign symmetric lipomatosis * Bannayan–Riley–Ruvalcaba syndrome * Neurofibromatosis type I Laurence–Moon–Bardet–Biedl * Bardet–Biedl syndrome * Laurence–Moon syndrome Combined/other, known locus * 2 (Feingold syndrome) * 3 (Zimmermann–Laband syndrome) * 4/13 (Fraser syndrome) * 8 (Branchio-oto-renal syndrome, CHARGE syndrome) * 12 (Keutel syndrome, Timothy syndrome) * 15 (Marfan syndrome) * 19 (Donohue syndrome) * Multiple * Fryns syndrome [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Perlman syndrome	c0796113	3,243	wikipedia	https://en.wikipedia.org/wiki/Perlman_syndrome	2021-01-18T18:40:27	{"gard": ["3936"], "mesh": ["C536399"], "umls": ["C0796113"], "orphanet": ["2849"], "wikidata": ["Q7169165"]}
Endodermal sinus tumor Other namesYolk sac tumor (YST) Micrograph showing the yolk sac component of a mixed germ cell tumour. H&E stain. SpecialtyOncology Endodermal sinus tumor (EST) is a member of the germ cell tumor group of cancers.[1] It is the most common testicular tumor in children under 3,[2] and is also known as infantile embryonal carcinoma. This age group has a very good prognosis. In contrast to the pure form typical of infants, adult endodermal sinus tumors are often found in combination with other kinds of germ cell tumor, particularly teratoma and embryonal carcinoma. While pure teratoma is usually benign, endodermal sinus tumor is malignant. ## Contents * 1 Cause * 2 Diagnosis * 2.1 Pathology * 3 Treatment * 4 See also * 5 References * 6 External links ## Cause[edit] Causes are poorly understood. ## Diagnosis[edit] The histology of EST is variable, but usually includes malignant endodermal cells. These cells secrete alpha-fetoprotein (AFP), which can be detected in tumor tissue, serum, cerebrospinal fluid, urine and, in the rare case of fetal EST, in amniotic fluid. When there is incongruence between biopsy and AFP test results for EST, the result indicating presence of EST dictates treatment.[3] This is because EST often occurs as small "malignant foci" within a larger tumor, usually teratoma, and biopsy is a sampling method; biopsy of the tumor may reveal only teratoma, whereas elevated AFP reveals that EST is also present. GATA-4, a transcription factor, also may be useful in the diagnosis of EST.[4] Diagnosis of EST in pregnant women and in infants is complicated by the extremely high levels of AFP in those two groups. Tumor surveillance by monitoring AFP requires accurate correction for gestational age in pregnant women, and age in infants. In pregnant women, this can be achieved simply by testing maternal serum AFP rather than tumor marker AFP. In infants, the tumor marker test is used, but must be interpreted using a reference table or graph of normal AFP in infants.[medical citation needed] ### Pathology[edit] EST can have a multitude of morphologic patterns including: reticular, endodermal sinus-like, microcystic, papillary, solid, glandular, alveolar, polyvesicular vitelline, enteric and hepatoid.[medical citation needed] Schiller-Duval bodies on histology are pathognomonic and seen in the context of the endodermal sinus-like pattern. Rarely, it can be found in the vagina.[5][6] ## Treatment[edit] Most treatments involve some combination of surgery and chemotherapy. Treatment with cisplatin, etoposide, and bleomycin has been described.[7] Before modern chemotherapy, this type of neoplasm was highly lethal, but the prognosis has significantly improved since then.[citation needed] When endodermal sinus tumors are treated promptly with surgery and chemotherapy, fatal outcomes are exceedingly rare.[8] ## See also[edit] * Germ cell tumor * Testicular cancer ## References[edit] 1. ^ "Endodermal Sinus Tumor". Retrieved 2018-10-10. 2. ^ Hari, Anil; Grossfeld, Gary; Hricak, Hedvig (2002-01-01), Bragg, David G.; Rubin, Philip; Hricak, Hedvig (eds.), "Chapter 29 - Tumors of the Scrotum", Oncologic Imaging, Oxford: Elsevier, pp. 603–628, doi:10.1016/b0-72-167494-1/50032-3, ISBN 978-0-7216-7494-0, retrieved 2020-10-21 3. ^ Luther N, Edgar MA, Dunkel IJ, Souweidane MM (Aug 2006). "Correlation of endoscopic biopsy with tumor marker status in primary intracranial germ cell tumors". Journal of Neurooncolpgy. 79 (1): 45–50. doi:10.1007/s11060-005-9110-0. PMID 16598424. S2CID 19124218. 4. ^ Siltanen S, Anttonen M, Heikkilä P, Narita N, Laitinen M, Ritvos O, Wilson DB, Heikinheimo M (Dec 1999). "Transcription Factor GATA-4 Is Expressed in Pediatric Yolk Sac Tumors". American Journal of Pathology. 155 (6): 1823–9. doi:10.1016/S0002-9440(10)65500-9. PMC 1866939. PMID 10595911. Archived from the original on 2009-03-16. 5. ^ Bhatt MD, Braga LH, Stein N, Terry J, Portwine C (July 2015). "Vaginal Yolk Sac Tumor in an Infant: A Case Report and Literature Review of the Last 30 Years". Journal of Pediatric Hematology/Oncology. 37 (5): e336–40. doi:10.1097/MPH.0000000000000325. PMID 25851552. S2CID 7605939. 6. ^ Coran, Arnold G.; Caldamone, Anthony; Adzick, N. Scott; Krummel, Thomas M.; Laberge, Jean-Martin; Shamberger, Robert (2012-01-25). Pediatric Surgery E-Book. Elsevier Health Sciences. ISBN 978-0323091619. 7. ^ Motegi M, Takakura S, Takano H, Tanaka T, Ochiai K (February 2007). "Adjuvant chemotherapy in a pregnant woman with endodermal sinus tumor of the ovary". Obstetrics and Gynecology. 109 (2 Pt2): 537–40. doi:10.1097/01.AOG.0000245450.62758.47. PMID 17267887. S2CID 24159507. 8. ^ Prepubertal Testicular and Paratesticular Tumors at eMedicine ## External links[edit] Classification D * ICD-10: C56 C62.9 * ICD-O: M9071/3 * OMIM: 273300 * MeSH: D018240 * DiseasesDB: 4248 * SNOMED CT: 74409009 External resources * Orphanet: 876 * v * t * e Germ cell tumors Germinomatous * Germinoma * Seminoma * Dysgerminoma Nongerminomatous * Embryonal carcinoma * Endodermal sinus tumor/Yolk sac tumor * Teratoma: Fetus in fetu * Dermoid cyst * Struma ovarii * Strumal carcinoid * Trophoblastic neoplasm: Gestational trophoblastic disease * Hydatidiform mole * Choriocarcinoma * Placental site trophoblastic tumor * Polyembryoma * Gonadoblastoma * 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 * t * e * Tumors of the male urogenital system Testicles Sex cord– gonadal stromal * Sertoli–Leydig cell tumour * Sertoli cell tumour * Leydig cell tumour Germ cell G * Seminoma * Spermatocytic tumor * Germ cell neoplasia in situ NG * Embryonal carcinoma * Endodermal sinus tumor * Gonadoblastoma * Teratoma * Choriocarcinoma * Embryoma Prostate * Adenocarcinoma * High-grade prostatic intraepithelial neoplasia * HGPIN * Small-cell carcinoma * Transitional cell carcinoma Penis * Carcinoma * Extramammary Paget's disease * Bowen's disease * Bowenoid papulosis * Erythroplasia of Queyrat * Hirsuties coronae glandis [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Endodermal sinus tumor	c0014145	3,244	wikipedia	https://en.wikipedia.org/wiki/Endodermal_sinus_tumor	2021-01-18T18:57:55	{"mesh": ["D018240"], "umls": ["C0014145"], "orphanet": ["876"], "wikidata": ["Q3542021"]}
X-linked intellectual deficit-cerebellar hypoplasia, also known as OPHN1 syndrome, is a rare syndromic form of cerebellar dysgenesis characterized by moderate to severe intellectual deficit and cerebellar abnormalities. ## Epidemiology OPHN1 syndrome is very rare. To date, up to 12 families have been reported. ## Clinical description Affected male patients present moderate to severe intellectual disability, hypotonia, severe developmental delay, early-onset complex partial or tonic-clonic seizures, strabismus, dysmetria and occasionally ataxia. Cryptorchidism and genital hypoplasia have been reported. Some patients have abnormal behavior and a characteristic facial phenotype (long face, prominent forehead, infraorbital creases, deep-set eyes, upturned philtrum and large ears). Carrier females have been reported to have mild learning disabilities, mild cognitive impairment, strabismus, and subtle facial changes. ## Etiology Various mutations including deletions and splice site mutations in the OPHN1 gene (Xq12) have been reported in patients with this syndrome. ## Diagnostic methods Neuroradiological findings include posterior vermis dysgenesis, vermian parasagittal cleft, cerebellar hypoplasia, cortical atrophy, and enlargement of the cerebral ventricles. Molecular genetic testing is needed to confirm diagnosis. ## Genetic counseling Transmission appears to follow an X-linked semi-dominant pattern. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	X-linked intellectual disability-cerebellar hypoplasia syndrome	c1845366	3,245	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=137831	2021-01-23T18:13:05	{"gard": ["9947"], "mesh": ["C537456"], "omim": ["300486"], "umls": ["C1845366"], "icd-10": ["Q04.3"], "synonyms": ["OPHN1 syndrome", "Oligophrenin-1 syndrome"]}
Carotidynia Drawing from Gray's anatomy with blue arrow showing the bifurcation area which is painful in Carotidynia. Carotidynia is a syndrome characterized by unilateral (one-sided) tenderness of the carotid artery, near the bifurcation. It was first described in 1927 by Temple Fay.[1] The most common cause of carotidynia may be migraine, and then it is usually self-correcting. Common migraine treatments may help alleviate the carotidynia symptoms. Recent histological evidence has implicated an inflammatory component of carotidynia, but studies are limited.[2] Carotid arteritis is a much less common cause of carotidynia, but has much more serious consequences. It is a form of giant cell arteritis, which is a condition that usually affects arteries in the head. Due to this serious condition possibly causing carotidynia, and the possibility that neck pain is related to some other non-carotidynia and serious condition, the case should be investigated by a medical doctor.[3] Because carotidynia can be caused by numerous causes, Biousse and Bousser in 1994 recommended the term not be used in the medical literature.[4] However, recent MRI and ultrasound studies have supported the existence of a differential diagnosis of carotidynia consistent with Fay's characterization.[5][6] ## References[edit] 1. ^ Hill and Hastings list this reference as: Fay, Temple (1927) "Atypical neuralgia." Arch Neurol Psychiatry. 2. ^ Upton, P.; Smith, J. G.; Charnock, D. R. (2003). "Histologic confirmation of carotidynia". Otolaryngology–Head and Neck Surgery. 129 (4): 443–444. doi:10.1016/S0194-5998(03)00611-9. PMID 14574303. 3. ^ Hill LM, Hastings G (1994). "Carotidynia: a pain syndrome". J Fam Pract. 39 (1): 71–5. PMID 8027735. 4. ^ Biousse V, Bousser MG (1994). "The myth of carotidynia". Neurology. 44 (6): 993–5. doi:10.1212/wnl.44.6.993. PMID 8208434. S2CID 34614803.Available here 5. ^ Lee TC, Swartz R, McEvilly R, Aviv RI, Fox AJ, Perry J, Symons SP. CTA, MR and MRA imaging of carotidynia: case report. Canadian Journal of Neurological Sciences. 2009 May; 36(3):373-375. 6. ^ Kuhn, J.; Harzheim, A.; Horz, R.; Bewermeyer, H. (2006). "MRI and ultrasonographic imaging of a patient with carotidynia". Cephalalgia. 26 (4): 483–485. doi:10.1111/j.1468-2982.2006.01053.x. PMID 16556251. S2CID 19120721. ## External links[edit] * Family Practice notebook.com This cardiovascular system article is a stub. You can help Wikipedia by expanding it. * v * t * e [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Carotidynia	c0238902	3,246	wikipedia	https://en.wikipedia.org/wiki/Carotidynia	2021-01-18T18:34:57	{"gard": ["10369"], "umls": ["C0238902"], "wikidata": ["Q5045550"]}
A number sign (#) is used with this entry because autosomal dominant thrombophilia due to protein C deficiency (THPH3) is caused by heterozygous mutation in the PROC gene (612283) on chromosome 2q14. See also autosomal recessive thrombophilia due to protein C deficiency (THPH4; 612304), a more severe disorder caused by homozygous mutation in the PROC gene. Description Heterozygous protein C deficiency is characterized by recurrent venous thrombosis. However, many adults with heterozygous disease may be asymptomatic (Millar et al., 2000). Individuals with decreased amounts of protein C are classically referred to as having type I deficiency and those with normal amounts of a functionally defective protein as having type II deficiency (Bertina et al., 1984). Acquired protein C deficiency is a clinically similar disorder caused by development of an antibody against protein C. Clouse and Comp (1986) reviewed the structural and functional properties of protein C and discussed both hereditary and acquired deficiency of protein C. Clinical Features Griffin et al. (1981) reported a 22-year-old Caucasian man with recurrent thrombophlebitis complicated by pulmonary embolism. His 56-year-old father had thrombophlebitis with pulmonary embolism following a minor leg injury at age 24, a cerebrovascular accident at age 43, and a myocardial infarction at age 45. A paternal uncle had thrombophlebitis and recurrent pulmonary emboli dating from age 20. The paternal grandfather died abruptly at age 45 after developing pulmonary infiltrates while confined to bed due to a leg injury in a fall from a horse. The paternal great-grandfather died unexpectedly of a cerebrovascular accident at age 61. The propositus, his father, and his paternal uncle showed decreased levels of plasma protein C antigen, determined immunologically by the Laurell rocket technique, that were 38 to 49% of normal values. Clinically unaffected members of the kindred had normal levels. Bertina et al. (1984) and Barbui et al. (1984) reported families with a discrepancy between normal protein C antigen levels and low functional activity of protein C. The proband in the latter report was a man with myocardial infarction at age 28 and severe thrombotic episodes thereafter, including cerebral thrombophlebitis, and both superficial and deep venous thrombosis of the leg. Although no other member of the family had a history of thromboses, the father also was found to have decreased functional activity of protein C. Immunoelectrophoretic studies showed an abnormal migration pattern of the protein, which the authors termed 'protein C Bergamo.' Using an immunologic and a functional assay, Horellou et al. (1984) identified 22 patients from 9 French families with protein C deficiency. Six were asymptomatic, 15 had a history of venous thromboembolism, and 1 had a history of arterial thromboembolism. The first thrombotic episode occurred at a mean age of 24.1 years. Five patients (56%) had absence of a precipitating condition. One patient with severe protein C deficiency developed skin necrosis soon after starting oral anticoagulant treatment. Family history suggested autosomal dominant transmission of the defect. Israels and Seshia (1987) described stroke in a 17-month-old girl with heterozygous protein C deficiency. In a large New England kindred, Bovill et al. (1989) found a strong statistical correlation between thromboembolic disease and heterozygous protein C deficiency. On the other hand, they found no thromboembolic manifestations in many protein C-deficient family members, indicating that some factors other than heterozygous protein C deficiency must play an important role in the clinical expression. Berdeaux et al. (1993) described 11 subjects from 3 families with dysfunctional protein C, or type II deficiency, characterized by a disproportionate decrease in protein C activity compared to the amount of antigen. In their own series, 4 of the 11 patients were symptomatic. They compared the findings in these subjects with those in 67 reported patients, including 39 symptomatic and 28 asymptomatic, with dysfunctional protein C deficiency. In a study in the Netherlands, Allaart et al. (1993) found a significant difference in the thrombosis-free survival of 77 heterozygotes and 84 controls in the same families: by age 45, 50% of the heterozygotes and 10% of normal relatives had a manifestation of venous thromboembolism. Thrombotic events occurred more often in years in which the patient had been immobile for more than a week or had had surgery. There was no predisposing event such as surgery or pregnancy in 50% of all first episodes and 65% of recurrences of venous thromboembolism in the heterozygotes. ### Acquired Protein C Deficiency Using an electroimmunoassay, Mannucci and Vigano (1982) evaluated acquired protein C deficiency in conditions associated with an increased tendency to thrombosis. Mitchell et al. (1987) described a fatal thrombophilia associated with the development of an antibody to protein C. Acquired nonmendelian autoimmune phenocopies are known for several other disorders, including dystrophic epidermolysis bullosa (226600), hemophilia A (306700), hereditary angioedema (106100), and von Willebrand disease (see 193400). Gruppo et al. (2000) reported a 20-month-old child with acquired protein C deficiency who had a stroke while receiving valproic acid for a seizure disorder. They studied 20 children on valproic acid therapy and 20 children receiving other anticonvulsants and found that protein C levels were reduced to less than 5% of normal in up to 45% of the children receiving valproic acid. Other Features Pabinger et al. (1986) described coumarin-associated hemorrhagic skin necrosis of the toes in a patient with heterozygous protein C deficiency. The complication occurred on the 4th day of coumarin treatment overlapping with effective intravenous anticoagulation with heparin. Family studies revealed protein C deficiency in 2 sisters of the proposita without a history of thromboembolic disease. Pabinger et al. (1986) noted 3 earlier reports of this complication. Conlan et al. (1988) described a family with type II protein C deficiency in which the proband had the simultaneous development of warfarin-induced skin necrosis and bilateral adrenal hemorrhage. The adrenal hemorrhage was manifested by abdominal pain, hypotension, and hyponatremia, and was confirmed by abdominal ultrasonography. Among 8 patients with Legg-Perthes disease (150600), Glueck et al. (1994) found 3 instances of protein C deficiency; the patients came from kindreds with previously undiagnosed protein C deficiency. In 1 of these 3 kindreds, there were 6 protein C-deficient family members, 4 of whom had thrombotic events as adults. Protein S deficiency (612336) was found in 1 of the 8 patients; his brother had sustained mesenteric vein thrombosis at age 43. The other 4 patients had normal protein C, protein S, and antithrombin III, but 1 of them had hypofibrinolysis, failing to elevate tissue plasminogen activator activity (PLAT; 173370) after 10 minutes of venous occlusion at 100 mm Hg. Beyond their Legg-Perthes disease, none of the 8 patients had evidence of venous thrombosis. Glueck et al. (1994) suggested that thrombophilia contributed to thrombotic venous occlusion in the femoral head with subsequent venous hypertension and bone death that characterize Legg-Perthes disease. Debus et al. (1998) found that 6 of 24 children with porencephaly (see 175780) had protein C deficiency, 1 of whom had a positive family history of thrombosis. Ten children had other prothrombotic conditions, including factor V Leiden (188055), protein S deficiency, and familial elevated serum Lp(a) concentration (152200). The authors concluded that protein C deficiency plays an important role in the etiology of congenital brain cysts but that other putative interacting factors, such as perinatal infection, placental insufficiency, and fetal cardiac arrhythmias, should also be considered. Biochemical Features Iijima et al. (1991) identified an abnormal protein C in a 60-year-old man with recurrent thrombosis. The anticoagulant protein C activity was reduced to nearly half of normal, but the total antigen protein levels were in the normal range. Immunoelectrophoretic studies showed an abnormal pattern. Further studies indicated that a half population of protein C in the patient's plasma was dysfunctional in the gamma-carboxyglutamic acid (Gla)-domain or its related structures. Four other family members were found to have the same abnormality of protein C but all were asymptomatic. The protein was designated 'protein C Yonago.' Mapping By studies of 11 heterozygotes with partial protein C deficiency Rocchi et al. (1985, 1986) found linkage to chromosome 2. Molecular Genetics In affected members of 2 unrelated families with protein C deficiency, Romeo et al. (1987) identified 2 different heterozygous mutations in the PROC gene (612283.0001 and 612283.0002), respectively. Affected individuals showed 50% reduction of both enzymatic and antigen levels of protein C. Reitsma et al. (1993) provided a listing of mutations causing protein C deficiency, including a total of 67 different single basepair substitutions. Of these, 29 (43%) occurred in CpG dinucleotides and were C-to-T or G-to-A transitions compatible with a model of methylation-mediated deamination. A 1995 update on PROC mutations was provided by Reitsma et al. (1995). Reitsma (1996) stated that the 1995 update of the database comprised 331 entries describing 160 unique mutation events. Genotype/Phenotype Correlations Koeleman et al. (1994) found that heterozygous carriers of both the factor V Leiden mutation (R506Q; 612309.0001) and a mutation in the protein C gene were at higher risk of thrombosis compared to patients with either defect alone. Among 120 unrelated Swedish/Danish patients with protein C deficiency, Hallam et al. (1995) found a significantly increased frequency of the factor V Leiden allele compared to healthy controls; however, this was not found in a British population with protein C deficiency. Hallam et al. (1995) concluded that coinheritance of factor V Leiden was unlikely to be the sole determinant of whether a person with protein C deficiency will come to clinical attention. Gandrille et al. (1995) detected the factor V R506Q mutation in 15 (14%) of 113 patients with protein C deficiency and in 1 (1%) of 113 healthy controls. There was a significant difference in the allele frequency of the R506Q mutation between heterozygous protein C-deficient patients and protein C-deficient patients with no identified mutation in the PROC gene. The results demonstrated that a significant subset of thrombophilic patients have multiple genetic risk factors, although additional secondary genetic risk factors remained to be identified in a majority of symptomatic protein C-deficient patients. The authors concluded that the factor V gene abnormality could help account for clinical expression of protein C deficiency in approximately 14% of the patients. Population Genetics Rocchi et al. (1986) quoted a frequency of 1/5000 for thrombophilia due to protein C deficiency in the Netherlands. Animal Model Lay et al. (2005) generated mouse models expressing 1 to 18% of normal protein C levels. The mice developed thrombosis and inflammation, the onset and severity of which varied significantly and were strongly dependent on plasma protein C levels. Maternal protein C was vital for sustaining pregnancy beyond 7.5 days postcoitum; Lay et al. (2005) suggested that protein C may regulate the balance of coagulation and inflammation during trophoblast invasion. INHERITANCE \- Autosomal dominant CARDIOVASCULAR Vascular \- Superficial thrombophlebitis \- Deep venous thrombosis RESPIRATORY Lung \- Pulmonary embolism SKIN, NAILS, & HAIR Skin \- Warfarin-induced skin necrosis NEUROLOGIC Central Nervous System \- Cerebral thrombosis (e.g. 612283.0014 protein C deficiency) LABORATORY ABNORMALITIES \- Plasma protein C deficiency MISCELLANEOUS \- Vast majority of heterozygotes are asymptomatic \- Protein C deficiency is found in 3-4% of patients with venous thromboembolism \- Acquired protein C deficiency seen in liver disease, DIC, and following surgery \- See also autosomal recessive form ( 612304 ) MOLECULAR BASIS \- Caused by mutation in the protein C gene (PROC, 612283.0001 ) ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	THROMBOPHILIA DUE TO PROTEIN C DEFICIENCY, AUTOSOMAL DOMINANT	c2930896	3,247	omim	https://www.omim.org/entry/176860	2019-09-22T16:35:41	{"doid": ["3756"], "mesh": ["C535424"], "omim": ["176860"], "orphanet": ["745"], "synonyms": ["Alternative titles", "PROTEIN C DEFICIENCY, AUTOSOMAL DOMINANT", "PROC DEFICIENCY, AUTOSOMAL DOMINANT"]}
Bone dysplasia lethal Holmgren type (BDLH) is a lethal bone dysplasia characterized at birth by low birth weight, a rhizomelic dwarfism, bent femora and short chest producing asphyxia. It was described in three siblings from healthy, non-consanguineous parents of Finnish and in four siblings from non-consanguineous parents of French origin with no family history of dwarfism. The initial cases could have been diagnosed as Desbuquois syndrome, or a recessive Larsen syndrome. There has been no further description of BDLH in the literature since 1988. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Bone dysplasia, lethal Holmgren type	c1859407	3,248	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=1842	2021-01-23T18:43:55	{"gard": ["922"], "mesh": ["C565896"], "omim": ["211120"], "umls": ["C1859407"], "icd-10": ["Q77.8"], "synonyms": ["Autosomal recessive lethal chondrodysplasia, round femoral inferior epiphysis type"]}
Kajii et al. (1991) described a 'new' genetic polymorphism of the human platelet detected by 2-D polyacrylamide gel electrophoresis followed by silver-staining. The polymorphic polypeptide had a molecular weight of 34 kD and an isoelectric point of 4.7-4.8. Three different electrophoretic types were identified: 1-1, 1-2, and 2-2. Family and population studies indicated that the 3 phenotypes were determined by 2 common alleles at a single autosomal locus. In a Japanese population, the gene frequencies of THB1 and THB2 were 0.74 and 0.26, respectively. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	THROMBOCYTE B	None	3,249	omim	https://www.omim.org/entry/187940	2019-09-22T16:32:41	{"omim": ["187940"]}
Gerstmann-Straussler-Scheinker syndrome (GSSS) is a particular and rare form of human transmissible spongiform encephalopathy (TSE) due to a defective gene encoding the prion protein (PRNP gene) and marked by particular multicentric amyloid plaques in the brain. ## Clinical description The codon 102 mutation is the most frequent, as it can be found in several European countries and in Japan. It causes the ataxic form of GSSS: cerebellar syndrome at onset, followed by oculomotor, pyramidal and intellectual signs. Death occurs anywhere between 1 and 11 years after onset. Amyloid plaques can be found mainly in the cerebellum. The codon 117 mutation has been described in 2 families (German and Alsacian); it causes dementia with pyramidal or pseudobulbar signs. Amyloid plaques are mono- or multicentric. Other mutations are uncommon: 198 (one American family), 217 (one Swedish family), 145 (one Japanese patient) and 105 (one case in Japan). The codon 198 and 217 mutations are particular in that multicentric plaques and neurofibrillar degeneration identical to those found in Alzheimer's disease are observed. The codon 145 mutation causes clinical symptoms similar to Alzheimer's disease; amyloid plaques are made of truncated PrP. The transmissible nature of the previously mentioned mutations has not yet been demonstrated. Finally the codon 105 mutation causes spastic paraparesia with late dementia. Amyloid plaques are predominant in the frontal lobe. GSSS may not actually be a TSE. ## Management and treatment To date, there is no treatment of the underlying pathological mechanisms 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 [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Gerstmann-Straussler-Scheinker syndrome	c0017495	3,250	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=356	2021-01-23T18:41:48	{"gard": ["7690"], "mesh": ["D016098"], "omim": ["137440"], "umls": ["C0017495"], "icd-10": ["A81.8"], "synonyms": ["Subacute spongiform encephalopathy, Gerstmann-Straussler type"]}
A number sign (#) is used with this entry because of evidence that isolated microphthalmia-8 (MCOP8) is caused by homozygous mutation in the ALDH1A3 gene (600463) on chromosome 15q26. For a general phenotypic description and a discussion of genetic heterogeneity of isolated microphthalmia, see MCOP1 (251600). Clinical Features Fares-Taie et al. (2013) studied a consanguineous Pakistani family in which the proband was a girl born with severe bilateral clinical anophthalmia. Cerebral MRI at 1 week of age showed small optic nerves and a small optic chiasm. Autism was diagnosed at 3 years of age. There were 2 healthy sisters in the family, and a fourth pregnancy was terminated due to detection of apparent bilateral anophthalmia with normal brain structures on prenatal ultrasound. A maternal cousin was also born with severe bilateral microphthalmia; he had a rudimentary globe on the left and a grossly abnormal globe associated with a cyst on the right. In addition, he had moderate pulmonary and supravalvular pulmonary stenosis and a moderately sized atrial septal defect. At 4 years of age, he was given a possible diagnosis of autism. Fares-Taie et al. (2013) also studied a consanguineous Turkish family in which the proband was a girl with bilateral microphthalmia, more severe on the right. She had no other health problems and displayed normal intelligence. A maternal uncle had died at age 1 month with bilateral clinical anophthalmia. In a third consanguineous family of Moroccan ancestry, the proband had severe bilateral microphthalmia, associated with a cyst on the left. MRI showed dysplastic globes and a hypoplastic chiasm and optic nerves, with the remainder of the brain appearing normal. She had no other health problems and was of normal intelligence. Mapping In a consanguineous Pakistani pedigree with bilateral severe microphthalmia in which mutation in 7 microphthalmia-associated genes had been excluded, Fares-Taie et al. (2013) performed homozygosity mapping and obtained a lod score greater than 3 at a 3.8-Mb region on chromosome 15q26.3 that was confirmed by analysis of informative microsatellite markers. Molecular Genetics In the proband from a consanguineous Pakistani pedigree with bilateral severe microphthalmia mapping to 15q26.3, Fares-Taie et al. (2013) performed whole exome sequencing and identified homozygosity for a missense mutation in the ALDH1A3 gene (R89C; 600463.0001) that was confirmed by Sanger sequencing and also found in an affected fetus from a terminated pregnancy and an affected cousin. The proband's unaffected parents were heterozygous for the mutation as was 1 unaffected sib; her other unaffected sib did not carry the mutation. Analysis of ALDH1A3 in 23 additional patients with microphthalmia identified 1 Turkish and 1 Moroccan proband who were homozygous for a missense mutation (A493P; 600463.0002) and a splice site mutation (600463.0003), respectively. The 3 mutations were not found in SNP databases, in the Exome Variant Server, or in 200 control chromosomes. Fares-Taie et al. (2013) noted that additional features present in affected individuals from the Pakistani pedigree such as autism, seen in 2 patients, and cardiac anomalies, present in 1, might be unrelated to alteration in ALDH1A3. In 2 Egyptian brothers, 1 with bilateral anophthalmia and the other with right anophthalmia and left microphthalmia, posterior coloboma, and detached retina, Yahyavi et al. (2013) performed exome sequencing and identified homozygosity for a nonsense mutation in the ALDH1A3 gene (K190X; 600463.0004). The mutation was not found in the unaffected parents, in 92 Egyptian control chromosomes, or in 384 European chromosomes. In a 4.5-year-old Hispanic girl with bilateral anophthalmia and hypoplasia of the optic nerves and chiasm, Yahyavi et al. (2013) identified homozygosity for a nonsense mutation in ALDH1A3 (K389X; 600463.0005) by whole-genome sequencing in regions where loss of heterozygosity had been detected. The mutation, which was present in heterozygosity in her unaffected parents, was not found in 120 control chromosomes. Yahyavi et al. (2013) generated Aldh1a3-knockdown zebrafish, which displayed a significant reduction in eye size. The phenotype that could be rescued by wildtype ALDH1A3 mRNA, but not by mRNA containing the K190X or K389X mutations, indicative of likely loss of function caused by the mutations. Animal Model In zebrafish larvae injected with antisense morpholinos (MOs) against Aldh1a3, Yahyavi et al. (2013) observed a significant reduction in eye size at 48 to 72 hours postfertilization compared to wildtype larvae. Additional phenotypes seen with variable penetrance in morphants included delayed closure of the optic fissure, coloboma-like lesions, cardiac edema, and kinking of the tail. Confocal imaging at 5 days postfertilization showed that the tectum from wildtype larvae was filled with retinal axons and the optic tract had branched into stereotyped fascicles, whereas the tectum from MO-treated larvae appeared less innervated. The morphant phenotype was rescued by wildtype human ALDH1A3 mRNA. INHERITANCE \- Autosomal recessive HEAD & NECK Eyes \- Microphthalmia, severe, bilateral \- Cyst associated with dysplastic globe (in some patients) \- Hypoplastic optic chiasm \- Hypoplastic optic nerves \- Coloboma (in some patients) \- Detached retina (in some patients) \- Entropion, bilateral (in some patients) MOLECULAR BASIS \- Caused by mutation in the aldehyde dehydrogenase 1 family, member A3 gene (ALDH1A3, 600463.0001 ) ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	MICROPHTHALMIA, ISOLATED 8	c1855052	3,251	omim	https://www.omim.org/entry/615113	2019-09-22T15:53:08	{"doid": ["0060841"], "mesh": ["C565377"], "omim": ["251600", "615113"], "orphanet": ["2542"], "synonyms": ["Isolated anophthalmia-microphthalmia syndrome", "MAC spectrum", "Microphthalmia-anophthalmia-coloboma spectrum"]}
Amino acid transport disorder SpecialtyNephrology Amino acid transport disorders are medical conditions associated with a failure of amino acids to be absorbed from the kidney or intestine. An example is Hartnup disease. ## Reference[edit] ## External links[edit] Classification D * ICD-10: E72.0 * ICD-9-CM: 270 * MeSH: D020157 * Milne MD (1971). "Disorders of intestinal amino-acid transport". J Clin Pathol. 5 (Suppl): 41–4. doi:10.1136/jcp.s3-5.1.41. PMC 1176258. * 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 This article about an endocrine, nutritional, or metabolic disease is a stub. You can help Wikipedia by expanding it. * v * t * e [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Amino acid transport disorder	c0268641	3,252	wikipedia	https://en.wikipedia.org/wiki/Amino_acid_transport_disorder	2021-01-18T19:10:35	{"mesh": ["D020157"], "umls": ["C0268641"], "icd-9": ["270.0", "270"], "icd-10": ["E72.0"], "orphanet": ["79166"], "wikidata": ["Q471778"]}
A number sign (#) is used with this entry because susceptibility to type 2 diabetes (T2D) can be conferred by homozygosity for a nonsense variant in the TBC1D4 gene (612465) on chromosome 13q22. For a phenotypic description and a discussion of genetic heterogeneity of noninsulin-dependent diabetes mellitus (NIDDM), see 125853. Clinical Features Homozygous carriers of the TBC1D4 R684X variant (rs61736969) are at increased risk for a phenotype characterized by insulin resistance in skeletal muscle and deterioration of postprandial glucose homeostasis (Moltke et al., 2014). Molecular Genetics Moltke et al. (2014) performed association mapping of T2D-related quantitative traits in up to 2,575 Greenlandic individuals without known diabetes from the Inuit Health in Transition (IHIT) cohort. Using array-based genotyping and exome sequencing, Moltke et al. (2014) discovered a nonsense mutation (R684X; 612465.0002) in the TBC1D4 gene, with an allele frequency of 17%. The authors showed that homozygous carriers of this variant had markedly higher concentrations of plasma glucose (beta = 3.8 mmol/l, p = 2.5 x 10(-35)) and serum insulin (beta = 165 pmol/l, p = 1.5 x 10(-20)) 2 hours after an oral glucose load compared with individuals with other genotypes (both noncarriers and heterozygous carriers). Furthermore, homozygous carriers had marginally lower concentrations of fasting plasma glucose (beta = -0.18 mmol/l, p = 1.1 x 10(-6)) and fasting serum insulin (beta = 8.3 pmol/l, p = 0.0014), and their T2D risk was markedly increased (OR = 10.3, p = 1.6 x 10(-24)). Heterozygous carriers had a moderately higher plasma glucose concentration 2 hours after an oral glucose load than noncarriers (beta = 0.43 mmol/l, p = 5.3 x 10(-5)). Analyses of skeletal muscle biopsies showed lower mRNA and protein levels of the long isoform of TBC1D4 and lower muscle protein levels of GLUT4 (SLC2A4; 138190) with an increasing number of R684X alleles. These findings were concomitant with a severely decreased insulin-stimulated glucose uptake in muscle, leading to postprandial hyperglycemia, impaired glucose tolerance, and T2D. The phenotype of global Tbc1d4-knockout mice, which show lower fasting glucose levels and markedly lower insulin-stimulated glucose uptake than Tbc1d4-sufficient mice (Wang et al., 2013), is comparable to the phenotype observed in homozygous carriers of the R684X variant. Between 40 and 60 years of age, more than 60% of homozygous carriers developed T2D; this increased to more than 80% above the age of 60. Population Genetics Moltke et al. (2014) found that the R684X variant has a minor allele frequency (MAF) of 17% in the IHIT cohort, and estimated it to have a MAF of 23% and 0% in the unobserved Inuit and European populations, respectively, that are ancestral populations to the Greenlanders. In comparison, this variant was found in 1 Japanese individual out of the 1,092 individuals sequenced in the 1000 Genomes Project, and it was not present in exome sequencing data from 2,000 Danish individuals, 448 Han Chinese, or approximately 6,500 European and African American individuals. Moltke et al. (2014) stated that 3.8% of Greenlanders were homozygous carriers of the risk allele, and that the R684X variant accounts for more than 10% of all cases of T2D in Greenland. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	DIABETES MELLITUS, NONINSULIN-DEPENDENT, 5	c4015183	3,253	omim	https://www.omim.org/entry/616087	2019-09-22T15:49:58	{"omim": ["616087"]}
Human disease Iron overload Other namesHaemochromatosis or Hemochromatosis Micrograph of liver biopsy showing iron deposits due to haemosiderosis. Iron stain. SpecialtyHematology Iron overload or hemochromatosis indicates accumulation of iron in the body from any cause. The most important causes are hereditary haemochromatosis (HHC), a genetic disorder, and transfusional iron overload, which can result from repeated blood transfusions.[1] ## Contents * 1 Signs and symptoms * 2 Causes * 2.1 Primary haemochromatosis * 2.2 Secondary haemochromatosis * 3 Diagnosis * 4 Treatment * 4.1 Chelating polymers * 5 Prognosis * 6 Epidemiology * 7 History * 7.1 Stone Age * 7.2 Viking hypothesis * 7.3 Modern times * 8 Terminology * 9 See also * 10 References * 11 External links ## Signs and symptoms[edit] Organs most commonly affected by haemochromatosis are the liver, heart, and endocrine glands.[2] Haemochromatosis may present with the following clinical syndromes:[3] * Chronic liver disease and cirrhosis of the liver * Heart involvement: heart failure, irregular heart rhythm * Hormonal issues: diabetes (see below) and hypogonadism (insufficiency of the sex hormone producing glands) which leads to low sex drive and/or loss of fertility in men and loss of menstrual cycle in women Diabetes in people with iron overload occurs as a result of selective iron deposition in islet beta cells in the pancreas leading to functional failure and cell death.[4] Arthritis, from calcium pyrophosphate deposition in joints leading to joint pains. The most commonly affected joints are those of the hands, particularly the knuckles of the second and third fingers.[5] Bronzing of the skin. This deep tan color, in concert with insulin insufficiency due to pancreatic damage, is the source of a nickname for this condition: "bronze diabetes". ## Causes[edit] The causes can be distinguished between primary cases (hereditary or genetically determined) and less frequent secondary cases (acquired during life).[6] People of Celtic (Irish, Scottish, Welsh, Cornish, Breton etc.), English, and Scandinavian origin[7] have a particularly high incidence, with about 10% being carriers of the principal genetic variant, the C282Y mutation on the HFE gene, and 1% having the condition.[8] This has been recognised in several alternative names such as Celtic curse, Irish illness, British gene, and Scottish sickness. ### Primary haemochromatosis[edit] Although it was known most of the 20th century that most cases of haemochromatosis were inherited, they were incorrectly assumed to depend on a single gene.[9] The overwhelming majority depend on mutations of the HFE gene discovered in 1996, but since then others have been discovered and sometimes are grouped together as "non-classical hereditary haemochromatosis",[10] "non-HFE related hereditary haemochromatosis",[11] or "non-HFE haemochromatosis".[12] Description OMIM Mutation Haemochromatosis type 1: "classical" haemochromatosis 235200 HFE Haemochromatosis type 2A: juvenile haemochromatosis 602390 Haemojuvelin (HJV, also known as RGMc and HFE2) Haemochromatosis type 2B: juvenile haemochromatosis 606464 hepcidin antimicrobial peptide (HAMP) or HFE2B Haemochromatosis type 3 604250 transferrin receptor-2 (TFR2 or HFE3) Haemochromatosis type 4 / African iron overload 604653 ferroportin (SLC11A3/SLC40A1) Neonatal haemochromatosis 231100 (unknown) Acaeruloplasminaemia (very rare) 604290 caeruloplasmin Congenital atransferrinaemia (very rare) 209300 transferrin GRACILE syndrome (very rare) 603358 BCS1L Most types of hereditary haemochromatosis have autosomal recessive inheritance, while type 4 has autosomal dominant inheritance.[13] ### Secondary haemochromatosis[edit] * Severe chronic haemolysis of any cause, including intravascular haemolysis and ineffective erythropoiesis (haemolysis within the bone marrow) * Multiple frequent blood transfusions (either whole blood or just red blood cells), which are usually needed either by individuals with hereditary anaemias (such as beta-thalassaemia major, sickle cell anaemia, and Diamond–Blackfan anaemia) or by older patients with severe acquired anaemias such as in myelodysplastic syndromes.[14] * Excess parenteral iron supplements, such as what can acutely happen in iron poisoning * Excess dietary iron * Some disorders do not normally cause haemochromatosis on their own, but may do so in the presence of other predisposing factors. These include cirrhosis (especially related to alcohol abuse), steatohepatitis of any cause, porphyria cutanea tarda, prolonged haemodialysis, and post-portacaval shunting ## Diagnosis[edit] Selective iron deposition (blue) in pancreatic islet beta cells(red). There are several methods available for diagnosing and monitoring iron loading. Blood tests are usually the first test if there is a clinical suspicion of iron overload. Serum ferritin testing is a low-cost, readily available, and minimally invasive method for assessing body iron stores. However, the major problem with using it as an indicator of iron overload is that it can be elevated in a variety of other medical conditions including infection, inflammation, fever, liver disease, kidney disease, and cancer. Also, total iron binding capacity may be low, but can also be normal.[15] In males and postmenopausal females, normal range of serum ferritin is between 12 and 300 ng/mL (670 pmol/L) .[16][17][18] In premenopausal females, normal range of serum ferritin is between 12 and 150[16] or 200[17] ng/mL (330 or 440 pmol/L).[18] If the person is showing the symptoms, they may need to be tested more than once throughout their lives as a precaution, most commonly in women after menopause.[citation needed] Transferrin saturation is a more specific test.[citation needed] DNA/screening: the standard of practice in diagnosis of haemochromatosis, places emphasis on genetic testing.[19] Positive HFE analysis confirms the clinical diagnosis of haemochromatosis in asymptomatic individuals with blood tests showing increased iron stores, or for predictive testing of individuals with a family history of haemochromatosis. The alleles evaluated by HFE gene analysis are evident in ~80% of patients with haemochromatosis; a negative report for HFE gene does not rule out haemochromatosis. First degree relatives of those with primary haemochromatosis should be screened to determine if they are a carrier or if they could develop the disease. This can allow preventive measures to be taken. Screening the general population is not recommended.[20] Liver biopsy is the removal of small sample in order to be studied and can determine the cause of inflammation or cirrhosis. In someone with negative HFE gene testing, elevated iron status for no other obvious reason, and family history of liver disease, additional evaluation of liver iron concentration is indicated. In this case, diagnosis of haemochromatosis is based on biochemical analysis and histologic examination of a liver biopsy. Assessment of the hepatic iron index (HII) is considered the "gold standard" for diagnosis of haemochromatosis. Magnetic resonance imaging (MRI) is used as a noninvasive way to accurately estimate iron deposition levels in the liver as well as heart, joints, and pituitary gland. ## Treatment[edit] Phlebotomy/venesection: routine treatment consists of regularly scheduled phlebotomies (bloodletting or erythrocytapheresis). When first diagnosed, the phlebotomies may be performed every week or fortnight, until iron levels can be brought to within normal range. Once the serum ferritin and transferrin saturation are within the normal range, treatments may be scheduled every two to three months depending upon the rate of reabsorption of iron. A phlebotomy session typically draws between 450 and 500 mL of blood.[21] The blood drawn is sometimes donated.[22] A diet low in iron is generally recommended, but has little effect compared to venesection. The human diet contains iron in two forms: heme iron and non-heme iron. Heme iron is the most easily absorbed form of iron. People with iron overload may be advised to avoid food that are high in heme iron. Highest in heme iron is red meat such as beef, venison, lamb, buffalo, and fish such as bluefin tuna. A strict low-iron diet is usually not necessary. Non-heme iron is not as easily absorbed in the human system and is found in plant-based foods like grains, beans, vegetables, fruits, nuts, and seeds.[23] Medication: For those unable to tolerate routine blood draws, there are chelating agents available for use.[24] The drug deferoxamine binds with iron in the bloodstream and enhances its elimination in urine and faeces. Typical treatment for chronic iron overload requires subcutaneous injection over a period of 8–12 hours daily.[citation needed] Two newer iron-chelating drugs that are licensed for use in patients receiving regular blood transfusions to treat thalassaemia (and, thus, who develop iron overload as a result) are deferasirox and deferiprone.[25][26] ### Chelating polymers[edit] A nover experimental approach to the hereditary haemochromatosis treatment is the maintenance therapy with polymeric chelators.[27][28][29] These polymers or particles have a negligible or null systemic biological availability and they are designed to form stable complexes with Fe2+ and Fe3+ in the GIT and thus limiting their uptake and long-term accumulation. Although this method has only a limited efficacy, unlike small-molecular chelators, the approach has virtually no side effects in sub-chronic studies.[29] Interestingly, the simultaneous chelation of Fe2+ and Fe3+ increases the treatment efficacy.[29] ## Prognosis[edit] In general, provided there has been no liver damage, patients should expect a normal life expectancy if adequately treated by venesection. If the serum ferritin is greater than 1000 ug/L at diagnosis there is a risk of liver damage and cirrhosis which may eventually shorten their life.[30] The presence of cirrhosis increases the risk of hepatocellular carcinoma.[31] ## Epidemiology[edit] It is most common in certain European populations (such as the Irish and Norwegians) and occurs in 0.6% of some unspecified population.[20] Men have a 24-fold increased rate of iron-overload disease compared with women.[20] ## History[edit] ### Stone Age[edit] Diet and the environment are thought to have had large influence on the mutation of genes related to iron overload. Starting during the Mesolithic era, communities of people lived in an environment that was fairly sunny, warm and had the dry climates of the Middle East. Most humans who lived at that time were foragers and their diets consisted largely of game, fish and wild plants. Archaeologists studying dental plaque have found evidence of tubers, nuts, plantains, grasses and other foods rich in iron. Over many generations, the human body became well-adapted to a high level of iron content in the diet.[32] In the Neolithic era, significant changes are thought to have occurred in both the environment and diet. Some communities of foragers migrated north, leading to changes in lifestyle and environment, with a decrease in temperatures and a change in the landscape which the foragers then needed to adapt to. As people began to develop and advance their tools, they learned new ways of producing food, and farming also slowly developed. These changes would have led to serious stress on the body and a decrease in the consumption of iron-rich foods. This transition is a key factor in the mutation of genes, especially those that regulated dietary iron absorption. Iron, which makes up 70% of red blood cell composition, is a critical micronutrient for effective thermoregulation in the body.[33] Iron deficiency will lead to a drop in the core temperature. In the chilly and damp environments of Northern Europe, supplementary iron from food was necessary to keep temperatures regulated, however, without sufficient iron intake the human body would have started to store iron at higher rates than normal. In theory, the pressures caused by migrating north would have selected for a gene mutation that promoted greater absorption and storage of iron.[34] ### Viking hypothesis[edit] Studies and surveys conducted to determine the frequencies of hemochromatosis help explain how the mutation migrated around the globe. In theory, the disease initially evolved from travelers migrating from the north. Surveys show a particular distribution pattern with large clusters and frequencies of gene mutations along the western European coastline.[35] This led the development of the "Viking Hypothesis".[36] Cluster locations and mapped patterns of this mutation correlate closely to the locations of Viking settlements in Europe established c.700 AD to c.1100 AD. The Vikings originally came from Norway, Sweden and Denmark. Viking ships made their way along the coastline of Europe in search of trade, riches, and land. Genetic studies suggest that the extremely high frequency patterns in some European countries are the result of migrations of Vikings and later Normans, indicating a genetic link between hereditary hemochromatosis and Viking ancestry.[37] ### Modern times[edit] In 1865, Armand Trousseau (a French internist) was one of the first to describe many of the symptoms of a diabetic patient with cirrhosis of the liver and bronzed skin color. The term hemochromatosis was first used by German pathologist Friedrich Daniel von Recklinghausen in 1890 when he described an accumulation of iron in body tissues. In 1935 J.H. Sheldon, a British physician, described the link to iron metabolism for the first time as well as demonstrating its hereditary nature.[38] In 1996 Felder and colleagues identified the hemochromatosis gene, HFE gene. Felder found that the HFE gene has two main mutations, C282Y and H63D, which were the main cause of hereditary hemochromatosis.[38][39] The next year the CDC and the National Human Genome Research Institute sponsored an examination of hemochromatosis following the discovery of the HFE gene, which helped lead to the population screenings and estimates that are still being used today.[40] ## Terminology[edit] Historically, the term haemochromatosis (spelled hemochromatosis in American English) was initially used to refer to what is now more specifically called haemochromatosis type 1 (or HFE-related hereditary haemochromatosis). Currently, haemochromatosis (without further specification) is mostly defined as iron overload with a hereditary or primary cause,[41][42] or originating from a metabolic disorder.[43] However, the term is currently also used more broadly to refer to any form of iron overload, thus requiring specification of the cause, for example, hereditary haemochromatosis. Hereditary haemochromatosis is an autosomal recessive disorder with estimated prevalence in the population of 1 in 200 among patients with European ancestry, with lower incidence in other ethnic groups.[44] The gene responsible for hereditary haemochromatosis (known as HFE gene) is located on chromosome 6; the majority of hereditary haemochromatosis patients have mutations in this HFE gene. Hereditary haemochromatosis is characterized by an accelerated rate of intestinal iron absorption and progressive iron deposition in various tissues. This typically begins to be expressed in the third to fifth decades of life, but may occur in children. The most common presentation is hepatic (liver) cirrhosis in combination with hypopituitarism, cardiomyopathy, diabetes, arthritis, or hyperpigmentation. Because of the severe sequelae of this disorder if left untreated, and recognizing that treatment is relatively simple, early diagnosis before symptoms or signs appear is important.[19][45] In general, the term haemosiderosis is used to indicate the pathological effect of iron accumulation in any given organ, which mainly occurs in the form of the iron-storage complex haemosiderin.[46][47] Sometimes, the simpler term siderosis is used instead. Other definitions distinguishing haemochromatosis or haemosiderosis that are occasionally used include: * Haemosiderosis is haemochromatosis caused by excessive blood transfusions, that is, haemosiderosis is a form of secondary haemochromatosis.[48][49] * Haemosiderosis is haemosiderin deposition within cells, while haemochromatosis is haemosiderin within cells and interstitium.[50] * Haemosiderosis is iron overload that does not cause tissue damage,[51] while haemochromatosis does.[52] * Haemosiderosis is arbitrarily differentiated from haemochromatosis by the reversible nature of the iron accumulation in the reticuloendothelial system.[53] ## See also[edit] * Human iron metabolism * Iron deficiency ## References[edit] 1. ^ Hider, Robert C.; Kong, Xiaole (2013). "Chapter 8. Iron: Effect of Overload and Deficiency". In Astrid Sigel, Helmut Sigel and Roland K. O. Sigel (ed.). Interrelations between Essential Metal Ions and Human Diseases. Metal Ions in Life Sciences. 13. Springer. pp. 229–294. doi:10.1007/978-94-007-7500-8_8. ISBN 978-94-007-7499-5. PMID 24470094. 2. ^ Andrews, Nancy C. (1999). "Disorders of Iron Metabolism". New England Journal of Medicine. 341 (26): 1986–95. doi:10.1056/NEJM199912233412607. PMID 10607817. 3. ^ John Murtagh (2007). General Practice. McGraw Hill Australia. ISBN 978-0-07-470436-3.[page needed] 4. ^ Lu, JP (1994). "Selective iron deposition in pancreatic islet B cells of transfusional iron‐overloaded autopsy cases". Pathol Int. 44: 194–199. doi:10.1111/j.1440-1827.1994.tb02592.x. PMID 8025661. 5. ^ Bruce R Bacon, Stanley L Schrier. "Patient information: Hemochromatosis (hereditary iron overload) (Beyond the Basics)". UpToDate. Retrieved 2016-07-14. Literature review current through: Jun 2016. \| This topic last updated: Apr 14, 2015. 6. ^ Pietrangelo, A (2003). "Haemochromatosis". Gut. 52 (90002): ii23–30. doi:10.1136/gut.52.suppl_2.ii23. PMC 1867747. PMID 12651879. 7. ^ The Atlantic: "The Iron in Our Blood That Keeps and Kills Us" by Bradley Wertheim January 10, 2013 8. ^ "Hemachromatosis". Encyclopædia Britannica.com. Retrieved 17 April 2017. 9. ^ Cam Patterson; Marschall S. Runge (2006). Principles of molecular medicine. Totowa, NJ: Humana Press. p. 567. ISBN 978-1-58829-202-5. 10. ^ Mendes, Ana Isabel; Ferro, Ana; Martins, Rute; Picanço, Isabel; Gomes, Susana; Cerqueira, Rute; Correia, Manuel; Nunes, António Robalo; Esteves, Jorge; Fleming, Rita; Faustino, Paula (2008). "Non-classical hereditary hemochromatosis in Portugal: novel mutations identified in iron metabolism-related genes" (PDF). Annals of Hematology. 88 (3): 229–34. doi:10.1007/s00277-008-0572-y. PMID 18762941. 11. ^ Maddrey, Willis C.; Schiff, Eugene R.; Sorrell, Michael F. (2007). Schiff's diseases of the liver. Hagerstwon, MD: Lippincott Williams & Wilkins. p. 1048. ISBN 978-0-7817-6040-9. 12. ^ Pietrangelo, Antonello (2005). "Non-HFE Hemochromatosis". Seminars in Liver Disease. 25 (4): 450–60. doi:10.1055/s-2005-923316. PMID 16315138. 13. ^ Franchini, Massimo (2006). "Hereditary iron overload: Update on pathophysiology, diagnosis, and treatment". American Journal of Hematology. 81 (3): 202–9. doi:10.1002/ajh.20493. PMID 16493621. 14. ^ Lu, JP (1994). "Selective iron deposition in pancreatic islet B cells of transfusional iron‐overloaded autopsy cases". Pathol Int. 44: 194–199. doi:10.1111/j.1440-1827.1994.tb02592.x. PMID 8025661. 15. ^ labtestsonline.org TIBC & UIBC, Transferrin Last reviewed on October 28, 2009. 16. ^ a b Ferritin by: Mark Levin, MD, Hematologist and Oncologist, Newark, NJ. Review provided by VeriMed Healthcare Network 17. ^ a b Andrea Duchini. "Hemochromatosis Workup". Medscape. Retrieved 2016-07-14. Updated: Jan 02, 2016 18. ^ a b Molar concentration is derived from mass value using molar mass of 450,000 g•mol−1 for ferritin 19. ^ a b Pietrangelo, Antonello (2010). "Hereditary Hemochromatosis: Pathogenesis, Diagnosis, and Treatment". Gastroenterology. 139 (2): 393–408. doi:10.1053/j.gastro.2010.06.013. PMID 20542038. 20. ^ a b c Crownover, BK; Covey, CJ (Feb 1, 2013). "Hereditary hemochromatosis". American Family Physician. 87 (3): 183–90. PMID 23418762. 21. ^ Barton, James C. (1 December 1998). "Management of Hemochromatosis". Annals of Internal Medicine. 129 (11_Part_2): 932–9. doi:10.7326/0003-4819-129-11_Part_2-199812011-00003. PMID 9867745. 22. ^ NIH blood bank. "Hemochromatosis Donor Program". 23. ^ "Welcome". Hemochromatosis.org - An Education Website for Hemochromatosis and Too Much Iron. Retrieved 2018-04-11. 24. ^ Miller, Marvin J. (1989-11-01). "Syntheses and therapeutic potential of hydroxamic acid based siderophores and analogs". Chemical Reviews. 89 (7): 1563–1579. doi:10.1021/cr00097a011. 25. ^ Choudhry VP, Naithani R (2007). "Current status of iron overload and chelation with deferasirox". Indian J Pediatr. 74 (8): 759–64. doi:10.1007/s12098-007-0134-7. PMID 17785900. 26. ^ Hoffbrand, A. V. (20 March 2003). "Role of deferiprone in chelation therapy for transfusional iron overload". Blood. 102 (1): 17–24. doi:10.1182/blood-2002-06-1867. PMID 12637334. 27. ^ Polomoscanik, Steven C.; Cannon, C. Pat; Neenan, Thomas X.; Holmes-Farley, S. Randall; Mandeville, W. Harry; Dhal, Pradeep K. (2005). "Hydroxamic Acid-Containing Hydrogels for Nonabsorbed Iron Chelation Therapy: Synthesis, Characterization, and Biological Evaluation". Biomacromolecules. 6 (6): 2946–2953. doi:10.1021/bm050036p. ISSN 1525-7797. 28. ^ Qian, Jian; Sullivan, Bradley P.; Peterson, Samuel J.; Berkland, Cory (2017). "Nonabsorbable Iron Binding Polymers Prevent Dietary Iron Absorption for the Treatment of Iron Overload". ACS Macro Letters. 6 (4): 350–353. doi:10.1021/acsmacrolett.6b00945. ISSN 2161-1653. 29. ^ a b c Groborz, Ondřej; Poláková, Lenka; Kolouchová, Kristýna; Švec, Pavel; Loukotová, Lenka; Miriyala, Vijay Madhav; Francová, Pavla; Kučka, Jan; Krijt, Jan; Páral, Petr; Báječný, Martin; Heizer, Tomáš; Pohl, Radek; Dunlop, David; Czernek, Jiří; Šefc, Luděk; Beneš, Jiří; Štěpánek, Petr; Hobza, Pavel; Hrubý, Martin (2020). "Chelating Polymers for Hereditary Hemochromatosis Treatment". Macromolecular Bioscience: 2000254. doi:10.1002/mabi.202000254. ISSN 1616-5187. 30. ^ Allen, KJ; Gurrin, LC; Constantine, CC; Osborne, NJ; Delatycki, MB; Nicoll, AJ; McLaren, CE; Bahlo, M; Nisselle, AE; Vulpe, CD; Anderson, GJ; Southey, MC; Giles, GG; English, DR; Hopper, JL; Olynyk, JK; Powell, LW; Gertig, DM (17 January 2008). "Iron-overload-related disease in HFE hereditary hemochromatosis" (PDF). The New England Journal of Medicine. 358 (3): 221–30. doi:10.1056/NEJMoa073286. PMID 18199861. 31. ^ Kowdley, KV (November 2004). "Iron, hemochromatosis, and hepatocellular carcinoma". Gastroenterology. 127 (5 Suppl 1): S79–86. doi:10.1016/j.gastro.2004.09.019. PMID 15508107. 32. ^ "The Evolution of Diet". National Geographic. Retrieved 2018-04-11. 33. ^ Rosenzweig, P. H.; Volpe, S. L. (March 1999). "Iron, thermoregulation, and metabolic rate". Critical Reviews in Food Science and Nutrition. 39 (2): 131–148. doi:10.1080/10408399908500491. ISSN 1040-8398. PMID 10198751. 34. ^ Heath, Kathleen M.; Axton, Jacob H.; McCullough, John M.; Harris, Nathan (May 2016). "The evolutionary adaptation of the C282Y mutation to culture and climate during the European Neolithic". American Journal of Physical Anthropology. 160 (1): 86–101. doi:10.1002/ajpa.22937. ISSN 0002-9483. PMC 5066702. PMID 26799452. 35. ^ "Clinical Penetrance of HFE Hereditary Hemochromatosis, Serum Ferritin Levels, and Screening Implications: Can We Iron This Out?". www.hematology.org. 2008-05-01. Retrieved 2018-04-11. 36. ^ Symonette, Caitlin J; Adams, Paul C (June 2011). "Do all hemochromatosis patients have the same origin? A pilot study of mitochondrial DNA and Y-DNA". Canadian Journal of Gastroenterology. 25 (6): 324–326. doi:10.1155/2011/463810. ISSN 0835-7900. PMC 3142605. PMID 21766093. 37. ^ "Videos: Hereditary Hemochromatosis \| Canadian Hemochromatosis Society". www.toomuchiron.ca. Retrieved 2018-04-11. 38. ^ a b Fitzsimons, Edward J.; Cullis, Jonathan O.; Thomas, Derrick W.; Tsochatzis, Emmanouil; Griffiths, William J. H.; the British Society for Haematology (May 2018). "Diagnosis and therapy of genetic haemochromatosis (review and 2017 update)". British Journal of Haematology. 181 (3): 293–303. doi:10.1111/bjh.15164. PMID 29663319. 39. ^ Feder, J.N.; Gnirke, A.; Thomas, W.; Tsuchihashi, Z.; Ruddy, D.A.; Basava, A.; Dormishian, F.; Domingo, R.; Ellis, M.C. (August 1996). "A novel MHC class I–like gene is mutated in patients with hereditary haemochromatosis". Nature Genetics. 13 (4): 399–408. doi:10.1038/ng0896-399. PMID 8696333. 40. ^ Burke, Wylie; Thomson, Elizabeth; Khoury, Muin J.; McDonnell, Sharon M.; Press, Nancy; Adams, Paul C.; Barton, James C.; Beutler, Ernest; Brittenham, Gary (1998-07-08). "Hereditary Hemochromatosis: Gene Discovery and Its Implications for Population-Based Screening". JAMA. 280 (2): 172–8. doi:10.1001/jama.280.2.172. ISSN 0098-7484. PMID 9669792. 41. ^ thefreedictionary.com > hemochromatosis, citing: * The American Heritage Medical Dictionary, 2004 by Houghton Mifflin Company * McGraw-Hill Concise Dictionary of Modern Medicine. 2002 42. ^ Merriam-Webster's Medical Dictionary > hemochromatosis Retrieved on December 11, 2009 43. ^ thefreedictionary.com, citing: * Dorland's Medical Dictionary for Health Consumers, 2007 * Mosby's Medical Dictionary, 8th edition. 2009 * Jonas: Mosby's Dictionary of Complementary and Alternative Medicine. 2005. 44. ^ "Hemochromatosis". Archived from the original on 2007-03-18. Retrieved 2012-10-05. 45. ^ Brandhagen, D J; Fairbanks, V F; Batts, K P; Thibodeau, S N (1999). "Update on hereditary hemochromatosis and the HFE gene". Mayo Clinic Proceedings. 74 (9): 917–21. doi:10.4065/74.9.917. PMID 10488796. 46. ^ Merriam-Webster's Medical Dictionary > hemosideroses Retrieved on December 11, 2009 47. ^ thefreedictionary.com > hemosiderosis, citing: * The American Heritage Medical Dictionary, 2004 by Houghton Mifflin Company * Mosby's Medical Dictionary, 8th edition. 48. ^ eMedicine Specialties > Radiology > Gastrointestinal > Hemochromatosis Author: Sandor Joffe, MD. Updated: May 8, 2009 49. ^ thefreedictionary.com > hemosiderosis, citing: * Gale Encyclopedia of Medicine. Copyright 2008 50. ^ Notecards on radiology gamuts, diseases, anatomy Archived 2010-07-21 at the Wayback Machine 2002, Charles E. Kahn, Jr., MD. Medical College of Wisconsin 51. ^ thefreedictionary.com > hemosiderosis, citing: * Dorland's Medical Dictionary for Health Consumers, 2007 * Mosby's Dental Dictionary, 2nd edition. * Saunders Comprehensive Veterinary Dictionary, 3rd ed. 2007 52. ^ The HealthScout Network > Health Encyclopedia > Diseases and Conditions > Hemochromatosis Archived 2010-02-09 at the Wayback Machine Retrieved on December 11, 2009 53. ^ thefreedictionary.com > hemosiderosis, citing: * McGraw-Hill Concise Dictionary of Modern Medicine. 2002 ## External links[edit] Classification D * ICD-10: E83.1 * ICD-9-CM: 275.03 * MeSH: D019190 * DiseasesDB: 5581 External resources * MedlinePlus: 000327 Wikimedia Commons has media related to Hemochromatosis. * Iron overload at Curlie * GeneReview/NCBI/NIH/UW entry on HFE-Associated Hereditary Hemochromatosis * GeneReview/NCBI/NIH/UW entry on TFR2-Related Hereditary Hemochromatosis * GeneReview/NCBI/NIH/UW entry on Juvenile Hereditary Hemochromatosis * GeneReview/NCBI/NIH/UW entry on Aceruloplasminemia * v * t * e Metal deficiency and toxicity disorders Iron excess: * Iron overload * Hemochromatosis * Hemochromatosis/HFE1 * Juvenile/HFE2 * HFE3 * African iron overload/HFE4 * Aceruloplasminemia * Atransferrinemia * Hemosiderosis deficiency: * Iron deficiency Copper excess: * Copper toxicity * Wilson's disease deficiency: * Copper deficiency * Menkes disease/Occipital horn syndrome Zinc excess: * Zinc toxicity deficiency: * Acrodermatitis enteropathica Other * Inborn errors of metabolism [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Iron overload	c0282193	3,254	wikipedia	https://en.wikipedia.org/wiki/Iron_overload	2021-01-18T18:39:00	{"mesh": ["D019190"], "icd-9": ["275.03"], "icd-10": ["R79.0"], "wikidata": ["Q2025687"]}
For a phenotypic description and a discussion of genetic heterogeneity of essential hypertension, see 145500. Mapping Gong et al. (2003) genotyped 94 members of a 387-member Chinese kindred with essential hypertension. An additional 32 Chinese nuclear families with essential hypertension were also recruited. Genomewide parametric linkage analysis identified a locus for primary hypertension on chromosome 12p12.2-p12.1 (parametric lod score 3.44). Gong et al. (2003) noted that this locus overlaps the assigned locus for autosomal dominant hypertension and brachydactyly (HTNB; 112410), the only form of monogenic hypertension known to that time that resembles primary hypertension. The authors identified 2 candidate genes in the region: PDE3A (123805), a cyclic nucleotide phosphodiesterase, and the sulfonylurea receptor SUR2 (601439), a subunit of an ATP-sensitive potassium channel. (The hypertension and brachydactyly syndrome is caused by heterozygous mutation in the PDE3A gene.) [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	HYPERTENSION, ESSENTIAL, SUSCEPTIBILITY TO, 4	c1837479	3,255	omim	https://www.omim.org/entry/608742	2019-09-22T16:07:18	{"omim": ["608742"], "synonyms": ["Alternative titles", "HYT4"]}
Dog with flea allergy dermatitis and secondary folliculitis Flea allergy dermatitis (FAD) is an eczematous itchy skin disease of dogs and cats. For both of these domestic species, flea allergy dermatitis is the most common cause of skin disease. Affected animals develop allergic reactions to chemicals in flea saliva. Symptoms of this reaction include erythema (redness), papules (bumps), pustules (pus-filled bumps), and crusts (scabs). If severe, hair loss will occur in the affected area. Dogs with flea allergy dermatitis often show hair loss and eczematous skin rash on the lower back, upper tail, neck, and down the back of the legs. Cats with flea allergy dermatitis may develop a variety of skin problems, including feline eosinophilic granuloma, miliary dermatitis, or self-inflicted alopecia from excessive grooming.[1] ## Contents * 1 Cause * 2 Diagnosis * 3 Treatment * 4 See also * 5 References ## Cause[edit] The flea found most commonly on both dogs and cats with a flea infestation is the cat flea, Ctenocephalides felis.[2] Pets that develop FAD have an allergic response to flea saliva injected during flea feeding. The itch associated with just one flea bite persists long after that flea is gone and leads to significant self-trauma.[1] ## Diagnosis[edit] The diagnosis of flea allergy dermatitis is complicated by the grooming habits of pets. Cats in particular are very efficient at grooming out fleas, often removing any evidence of infestation. Fleas begin biting within 5 minutes of finding a host, and there are no flea treatments that kill fleas before biting occurs.[3] ## Treatment[edit] Further information: Flea treatments The aim of treatment is to relieve the allergy-induced itch and to remove the fleas from the pet and its home environment.[2] In some cases, secondary bacterial or yeast infections will also need treatment before the itching subsides. The administration of oral or topical flea prevention is also required to kill fleas currently on the animal.[4] Environmental flea control includes using flea foggers or bombs, vacuuming, and treating pet bedding by washing on a hot cycle (over 60 degrees Celsius) in the washing machine. Many pets with FAD may also have other allergies, such as allergies to food, contact allergies, and atopic dermatitis. ## See also[edit] * Dog skin disorders * Cat skin disorders ## References[edit] 1. ^ a b April 22; 2014. "Flea Allergy Dermatitis in Cats and Dogs". Vetstreet. Retrieved 2019-08-11.CS1 maint: numeric names: authors list (link) 2. ^ a b Sousa, CA (2010). "Chapter 21: Fleas, flea allergy, and flea control". In Ettinger, SJ; Feldman, EC (eds.). Textbook of veterinary internal medicine (7th ed.). St Louis, MO: Saunders. pp. 99-101. ISBN 978-999606-2773. 3. ^ Dryden, MW; Rust, MK (March 1994). "The cat flea: biology, ecology and control". Veterinary parasitology. 52 (1–2): 1–19. doi:10.1016/0304-4017(94)90031-0. PMID 8030176. 4. ^ "Flea Allergy Dermatitis in Dogs". vca_corporate. Retrieved 2019-08-11. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Flea allergy dermatitis	c3670841	3,256	wikipedia	https://en.wikipedia.org/wiki/Flea_allergy_dermatitis	2021-01-18T19:06:01	{"wikidata": ["Q656339"]}
Hereditary hypotrichosis with recurrent skin vesicles is a very rare inherited hair loss disorder described in a family and characterized by sparse, fragile or absent hair on the scalp, eyebrows, eyelashes, axillae and rest of the body, associated with vesicle formation on various parts of the scalp and body which regularly burst and release watery fluid. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Hereditary hypotrichosis with recurrent skin vesicles	c2751292	3,257	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=217407	2021-01-23T17:57:41	{"mesh": ["C567751"], "omim": ["613102"]}
## Description Hypertrophic cardiomyopathy (CMH) is characterized by unexplained cardiac hypertrophy: thickening of the myocardial wall in the absence of any other identifiable cause for left ventricular hypertrophy such as systemic hypertension or valvular heart disease. Myocyte hypertrophy, disarray, and fibrosis are the histopathologic hallmarks of this disorder. Clinical features are diverse and include arrhythmias, sudden cardiac death, and heart failure. With an estimated prevalence of 1 in 500, CMH is the most common cardiovascular genetic disease and the most common cause of sudden death in competitive athletes in the United States (summary by Song et al., 2006). For a discussion of genetic heterogeneity of familial hypertrophic cardiomyopathy, see CMH1 (192600). Clinical Features Song et al. (2006) studied 32 individuals from a large 4-generation family segregating autosomal dominant hypertrophic cardiomyopathy. The 9 affected family members had left ventricular hypertrophy (LVH) by electrocardiography (ECG) and/or echocardiography; the youngest patient was diagnosed at 13 years of age, at which time he was asymptomatic but had LVH and right axis deviation on ECG and mild LVH with mitral valve prolapse on echocardiography. Eight of the 9 patients had left ventricular end-diastolic diameters (LVEDD) of 5.1 cm or less and ejection fractions that were at least 60 to 65%. The remaining patient was a 61-year-old woman who underwent cardiac transplantation for heart failure at 49 years of age. She presented with what was initially thought to be dilated cardiomyopathy (CMD); the explanted heart showed marked cardiomegaly (1035 g) caused by chamber dilation, but histologic findings were nonspecific and nondiagnostic, without intramyocardial arteriolar medial hypertrophy or myocyte disarray. Another family member, who was reported to have had congenital subaortic membrane that was resected at 16 years of age, died suddenly at 40 years of age; serial echocardiograms in the years prior to his death were reported to show 'mild septal hypertrophy' and mild cavity enlargement to an LVEDD of 5.7 cm. Histopathologic examination showed mild interstitial fibrosis and myocyte hypertrophy but no disarray. Although this family member was designated as having an 'unknown' phenotype, persistent LVH and sudden death 24 years after treatment for subvalvular stenosis suggested the presence of a primary cardiomyopathy. No family members showed evidence of abnormal LV trabeculation or noncompaction. Mapping In a large 4-generation family segregating autosomal dominant hypertrophic cardiomyopathy, in which mutation in the 8 sarcomere genes most commonly associated with CMH as well as the PRKAG2 gene (602743) had been ruled out, Song et al. (2006) performed genomewide linkage analysis and obtained a maximum lod score of 4.11 (theta = 0) at D7S669. Analysis of recombination events defined a 27.2-Mb critical disease interval on chromosome 7p12.1-q21. Molecular Genetics ### Exclusion Studies In a large 4-generation family segregating autosomal dominant hypertrophic cardiomyopathy mapping to chromosome 7p12.1-q21, Song et al. (2006) analyzed 9 candidate genes and did not identify any disease-causing mutations. INHERITANCE \- Autosomal dominant CARDIOVASCULAR Heart \- Left ventricular hypertrophy \- Interventricular septum thickness increased \- Posterior wall thickness increased \- Mitral valve prolapse (in some patients) \- Arrhythmias (in some patients) \- Sudden death (rare) ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	CARDIOMYOPATHY, FAMILIAL HYPERTROPHIC, 21	c3553442	3,258	omim	https://www.omim.org/entry/614676	2019-09-22T15:54:34	{"omim": ["614676"]}
Congenital portosystemic shunt is a rare, congenital anomaly of the great veins characterized by an abnormal communication between one or more veins of the portal and the caval systems, resulting in complete or partial diversion of the portal blood away from the liver to the systemic circulation. Clinical manifestations include liver atrophy, hypergalactosemia without uridine diphosphate enzyme deficiency, hyperammonemia, encephalopathy (resulting in learning disabilities, extreme fatigability and seizures), pulmonary hypertension, hypoxemia from hepatopulmonary syndrome and benign or malignant tumours. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Congenital portosystemic shunt	c1290495	3,259	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=480531	2021-01-23T17:01:33	{"synonyms": ["Congenital portosystemic venous fistula"]}
Fetal and neonatal alloimmune blood condition Not to be confused with Hemorrhagic disease of the newborn. Hemolytic disease of the newborn Other namesHDN SpecialtyPediatrics, Immunohaematology Complicationsheart failure, splenomegaly Hemolytic disease of the newborn, also known as hemolytic disease of the fetus and newborn, HDN, HDFN, or erythroblastosis foetalis,[1] is an alloimmune condition that develops in a fetus at or around birth, when the IgG molecules (one of the five main types of antibodies) produced by the mother pass through the placenta. Among these antibodies are some which attack antigens on the red blood cells in the fetal circulation, breaking down and destroying the cells. The fetus can develop reticulocytosis and anemia. The intensity of this fetal disease ranges from mild to very severe, and fetal death from heart failure (hydrops fetalis) can occur. When the disease is moderate or severe, many erythroblasts (immature red blood cells) are present in the fetal blood, earning these forms of the disease the name erythroblastosis fetalis (British English: erythroblastosis foetalis). HDFN represents a breach of immune privilege for the fetus or some other form of impairment of the immune tolerance in pregnancy. Various types of HDFN are classified by which alloantigen provokes the response. The types include ABO, anti-RhD, anti-RhE, anti-Rhc, anti-Rhe, anti-RhC, multiantigen combinations, and anti-Kell. Although global prevalence studies of the differential contribution of those types are lacking, regional population studies have shown the anti-RhD type to be the most common cause of HDFN, followed by anti-RhE, anti-RhC, and anti-Rhc.[2] ## Contents * 1 Signs and symptoms * 1.1 Complications * 2 Pathophysiology * 2.1 Serological types * 3 Diagnosis * 4 Prevention * 5 After birth testing * 6 Treatment * 7 Transfusion reactions * 8 Epidemiology * 9 Other animals * 10 See also * 11 References * 12 Further reading * 13 External links ## Signs and symptoms[edit] Signs of hemolytic disease of the newborn include a positive direct Coombs test (also called direct agglutination test), elevated cord bilirubin levels, and hemolytic anemia. It is possible for a newborn with this disease to have neutropenia and neonatal alloimmune thrombocytopenia as well. Hemolysis leads to elevated bilirubin levels. After delivery bilirubin is no longer cleared (via the placenta) from the neonate's blood and the symptoms of jaundice (yellowish skin and yellow discoloration of the whites of the eyes, or icterus) increase within 24 hours after birth. Like other forms of severe neonatal jaundice, there is the possibility of the neonate developing acute or chronic kernicterus, however the risk of kernicterus in HDN is higher because of the rapid and massive destruction of blood cells. It is important to note that isoimmunization is a risk factor for neurotoxicity and lowers the level at which kernicterus can occur. Untreated profound anemia can cause high-output heart failure, with pallor, enlarged liver and/or spleen, generalized swelling, and respiratory distress.[citation needed] HDN can be the cause of hydrops fetalis, an often-severe form of prenatal heart failure that causes fetal edema.[3] ### Complications[edit] Complications of HDN could include kernicterus, hepatosplenomegaly, inspissated (thickened or dried) bile syndrome and/or greenish staining of the teeth, hemolytic anemia and damage to the liver due to excess bilirubin. Conditions that may cause similar symptoms in the newborn period include: acquired hemolytic anemia, congenital toxoplasma, congenital syphilis infection, congenital obstruction of the bile duct, and cytomegalovirus (CMV) infection.[citation needed] * High at birth or rapidly rising bilirubin[4] * Prolonged hyperbilirubinemia[4] * Bilirubin Induced Neurological Dysfunction[5] * Cerebral Palsy[6] * Kernicterus[7] * Neutropenia[8][9] * Thrombocytopenia[8] * Hemolytic anemia – Must NOT be treated with iron[10] * Late onset anemia – Must NOT be treated with iron. Can persist up to 12 weeks after birth.[11][12][13] ## Pathophysiology[edit] Antibodies are produced when the body is exposed to an antigen foreign to the make-up of the body. If a mother is exposed to a foreign antigen and produces IgG (as opposed to IgM which does not cross the placenta), the IgG will target the antigen, if present in the fetus, and may affect it in utero and persist after delivery. The three most common models in which a woman becomes sensitized toward (i.e., produces IgG antibodies against) a particular antigen are hemorrhage, blood transfusion, and ABO incompatibility.[citation needed] Fetal-maternal hemorrhage, which is the movement of fetal blood cells across the placenta, can occur during abortion, ectopic pregnancy, childbirth, ruptures in the placenta during pregnancy (often caused by trauma), or medical procedures carried out during pregnancy that breach the uterine wall. In subsequent pregnancies, if there is a similar incompatibility in the fetus, these antibodies are then able to cross the placenta into the fetal bloodstream to attach to the red blood cells and cause their destruction (hemolysis). This is a major cause of HDN, because 75% of pregnancies result in some contact between fetal and maternal blood, and 15–50% of pregnancies have hemorrhages with the potential for immune sensitization. The amount of fetal blood needed to cause maternal sensitization depends on the individual's immune system and ranges from 0.1 mL to 30 mL.[3] The woman may have received a therapeutic blood transfusion. ABO blood group system and the D antigen of the Rhesus (Rh) blood group system typing are routine prior to transfusion. Suggestions have been made that women of child-bearing age or young girls should not be given a transfusion with Rhc-positive blood or Kell1-positive blood to avoid possible sensitization, but this would strain the resources of blood transfusion services, and it is currently considered uneconomical to screen for these blood groups. HDFN can also be caused by antibodies to a variety of other blood group system antigens, but Kell and Rh are the most frequently encountered.[citation needed] The third sensitization model can occur in women of blood type O. The immune response to A and B antigens, that are widespread in the environment, usually leads to the production of IgM or IgG anti-A and anti-B antibodies early in life. Women of blood type O are more prone than women of types A and B to making IgG anti-A and anti-B antibodies, and these IgG antibodies are able to cross the placenta. For unknown reasons, the incidence of maternal antibodies against type A and B antigens of the IgG type that could potentially cause hemolytic disease of the newborn is greater than the observed incidence of "ABO disease." About 15% of pregnancies involve a type O mother and a type A or type B child; only 3% of these pregnancies result in hemolytic disease due to A/B/O incompatibility. In contrast to antibodies to A and B antigens, production of Rhesus antibodies upon exposure to environmental antigens seems to vary significantly across individuals.[14] In cases where there is ABO incompatibility and Rh incompatibility, the risk of alloimmunization is decreased because fetal red blood cells are removed from maternal circulation due to anti-ABO antibodies before they can trigger an anti-Rh response.[3] ### Serological types[edit] HDN is classified by the type of antigens involved. The main types are ABO HDN, Rhesus HDN, Kell HDN, and other antibodies. Combinations of antibodies (for example, anti-Rhc and anti-RhE occurring together) can be especially severe.[citation needed] ABO hemolytic disease of the newborn can range from mild to severe, but generally it is a mild disease. It can be caused by anti-A and anti-B antibodies.[citation needed] Rhesus D hemolytic disease of the newborn (often called Rh disease) is the most common and only preventable form of severe HDN. Since the introduction of Rho-D immunoglobulin, (Rhogam, at 1968, which prevents the production of maternal Rho-D antibodies, the incidence of anti-D HDN has decreased dramatically.[3][15] Rhesus c HDFN can range from a mild to severe disease and is the third most common form of severe HDN.[16] Rhesus e and rhesus C hemolytic disease of the newborn are rare. Anti-C and anti-c can both show a negative DAT but still have a severely affected infant.[17][18] An indirect Coombs must also be run. Anti-Kell hemolytic disease of the newborn is most commonly caused by anti-K1 antibodies, the second most common form of severe HDN. Over half of the cases of anti-K1 related HDN are caused by multiple blood transfusions. Antibodies to the other Kell antigens are rare.[16] Anti-Kell can cause severe anemia regardless of titer.[19] It suppresses the bone marrow by inhibiting the erythroid progenitor cells.[20][21][22] Anti-M also recommends antigen testing to rule out the presence of HDN as the direct coombs can come back negative in a severely affected infant.[23] Kidd antigens are also present on the endothelial cells of the kidneys.[24][25] One study states that it would be unwise to routinely dismiss anti-E as being of little clinical consequence. It also found that the most severe case of anti-E HDFN occurred with titers 1:2, concluding that titers are not reliable for the diagnosis of the anti-E type.[26] ## Diagnosis[edit] The diagnosis of HDN is based on history and laboratory findings:[citation needed] Blood tests done on the newborn baby * Biochemistry tests for jaundice including total and direct bilirubin levels. * Complete blood count (CBC) which may show a decreased hemoglobin and hematocrit due to red blood cell destruction * Reticulocyte count which will usually be increased as the bone marrow makes new red blood cells to replace the ones that are being destroyed, and a peripheral blood smear to look at cell morphology. In the presence of significant hemolysis the smear will show schistocytes (fragmented red blood cells), reticulocytosis, and in severe cases Erythroblasts (also known as nucleated red blood cells). * Positive direct Coombs test (might be negative after fetal interuterine blood transfusion) Blood tests done on the mother * Positive indirect Coombs test Blood tests done on the father (rarely needed) * Erythrocyte antigen status ## Prevention[edit] In cases of Rho(D) incompatibility, Rho(D) immunoglobulin is given to prevent sensitization. However, there is no comparable immunotherapy available for other blood group incompatibilities.[3] Early pregnancy * IVIG – IVIG stands for Intravenous Immunoglobulin. It is used in cases of previous loss, high maternal titers, known aggressive antibodies, and in cases where religion prevents blood transfusion. IVIG can be more effective than IUT alone.[27] Fetal mortality was reduced by 36% in the IVIG and IUT group than in the IUT alone group. IVIG and plasmapheresis together can reduce or eliminate the need for an IUT.[28] * Plasmapheresis – Plasmapheresis aims to decrease the maternal titer by direct plasma replacement and physical removal of antibody.[23] Plasmapheresis and IVIG together can even be used on women with previously hydropic fetuses and fetal losses.[29][30] Mid- to late- pregnancy * IUT – Intrauterine Transfusion (IUT) is done either by intraperitoneal transfusion (IPT) or intravenous transfusion (IVT).[31] IVT is preferred over IPT.[32] IUTs are only done until 35 weeks. After that, the risk of an IUT is greater than the risk from post birth transfusion.[33] * Steroids – Steroids are sometimes given to the mother before IUTs and early delivery to mature the fetal lungs.[33][34] * Phenobarbital – Phenobarbital is sometimes given to the mother to help mature the fetal liver and reduce hyperbilirubinemia.[34][35] * Early Delivery – Delivery can occur anytime after the age of viability.[32] Emergency delivery due to failed IUT is possible, along with induction of labor at 35–38 weeks.[33][36] Rhesus-negative mothers who are pregnant with a rhesus-positive infant are offered Rho(D) immune globulin (RhIG, or RhoGam) at 28 weeks during pregnancy, at 34 weeks, and within 48 hours after delivery to prevent sensitization to the D antigen. It works by binding any fetal red blood cells with the D antigen before the mother is able to produce an immune response and form anti-D IgG.[3] A drawback to pre-partum administration of RhIG is that it causes a positive antibody screen when the mother is tested, which can be difficult to distinguish from natural immunological responses that result in antibody production.[citation needed] Without Rho(D) immunoglobulin, the risk of isoimmunization is approximately 17%; with proper administration the risk is reduced to less than 0.1–0.2%.[3] ## After birth testing[edit] * Coombs – in certain instances (when there is concern for blood group incompatibility between mom and baby for example), after birth a baby will have a direct Coombs test run to confirm the antibodies attached to the infant's red blood cells. This test is run on the infant's cord blood.[4] In some cases, the direct Coombs will be negative but severe, even fatal HDN can occur.[17] An indirect Coombs needs to be run in cases of anti-C,[18] anti-c,[18] and anti-M. Infants with Anti-M are also recommended to receive antigen testing to rule out the presence of HDN.[23] The below tests are often useful in cases of hemolytic disease of the newborn, but are not required for treatment of all newborns. * Hgb – the infant's hemoglobin should be tested from cord blood.[4] * Reticulocyte count – Reticulocytes are elevated when the infant is producing more red blood cells in response to anemia.[4] A rise in the retic count can mean that an infant may not need additional transfusions.[37] Low retic is observed in infants treated with IUT and in those with HDN from anti-Kell.[18] * Neutrophils – as neutropenia is one of the complications of HDN, the neutrophil count should be checked.[8][9] * Thrombocytes - as thrombocytopenia is one of the complications of HDN, the thrombocyte count should be checked.[8] * Bilirubin should be tested from cord blood.[4] * Ferritin – because most infants affected by HDN have iron overload, a ferritin must be run before giving the infant any additional iron.[10] * Newborn Screening Tests – Transfusion with donor blood during pregnancy or shortly after birth can affect the results of the Newborn Screening Tests. It is recommended to wait and retest 10–12 months after last transfusion. In some cases, DNA testing from saliva can be used to rule out certain conditions.[citation needed] ## Treatment[edit] After birth, treatment depends on the severity of the condition, but could include temperature stabilization and monitoring, phototherapy, transfusion with compatible packed red blood, exchange transfusion, sodium bicarbonate for correction of acidosis and/or assisted ventilation.[citation needed] * Phototherapy – Exposure to ultraviolet light (phototherapy) is recommended when the cord bilirubin is 3 or higher. Some doctors use it at lower levels while awaiting lab results.[38] This converts unconjugated bilirubin to an conjugated form that is easier for the infant to clear. * IVIG - IVIG has been used to successfully treat many cases of HDN. It has been used not only on anti-D, but on anti-E as well.<[39] IVIG can be used to reduce the need for exchange transfusion and to shorten the length of phototherapy.[40] The AAP recommends "In isoimmune hemolytic disease, administration of intravenousγ-globulin (0.5-1 g/kg over 2 hours) is recommended if the TSB is rising despite intensive phototherapy or the TSB level is within 2 to 3 mg/dL (34–51 μmol/L) of the exchange level. If necessary, this dose can be repeated in 12 hours (evidence quality B: benefits exceed harms). Intravenous γ-globulin has been shown to reduce the need for exchange transfusions in Rh and ABO hemolytic disease."[38] * Exchange transfusion – Exchange transfusion is used when bilirubin reaches either the high or medium risk lines on the nonogram provided by the American Academy of Pediatrics (Figure 4).[38] Cord bilirubin >4 is also indicative of the need for exchange transfusion.[41] ## Transfusion reactions[edit] Once a woman has antibodies, she is at high risk for a future transfusion reaction if she is in need of a blood transfusion.[42] For this reason, she must carry a medical alert card at all times and inform all doctors and emergency personnel of her antibody status.[citation needed] The absence of antibodies however does not preclude a woman from having a transfusion reaction: "Acute hemolytic transfusion reactions may be either immune-mediated or nonimmune-mediated. Immune-mediated hemolytic transfusion reactions caused by immunoglobulin M (IgM) anti-A, anti-B, or anti-A,B typically result in severe, potentially fatal complement-mediated intravascular hemolysis. Immune-mediated hemolytic reactions caused by IgG, Rh, Kell, Duffy, or other non-ABO antibodies typically result in extravascular sequestration, shortened survival of transfused red cells, and relatively mild clinical reactions. Acute hemolytic transfusion reactions due to immune hemolysis may occur in patients who have no antibodies detectable by routine laboratory procedures."[43] For a summary of transfusion reactions in the US, see reference.[44] ## Epidemiology[edit] In 2003, the incidence of Rh(D) sensitization in the United States was 6.8 per 1000 live births; 0.27% of women with an Rh incompatible fetus experience alloimmunization.[3] ## Other animals[edit] Main article: Neonatal isoerythrolysis Hemolytic disease of the newborn is most commonly seen in kittens (where it is known as "fading kitten syndrome") and foals. It has also been reported in puppies.[citation needed] ## See also[edit] * Exchange transfusion * Rh disease * Alloimmunization * Hemolytic disease of the newborn (anti-Kell) * Hemolytic disease of the newborn (anti-Rhc) * Hemolytic disease of the newborn (anti-RhE) * Hemolytic disease of the newborn (ABO) * Neonatal red cell transfusion ## References[edit] 1. ^ "erythroblastosis fetalis" at Dorland's Medical Dictionary 2. ^ Fan J, Lee BK, Wikman AT, Johansson S, Reilly M (August 2014). "Associations of Rhesus and non-Rhesus maternal red blood cell alloimmunization with stillbirth and preterm birth". International Journal of Epidemiology. 43 (4): 1123–31. doi:10.1093/ije/dyu079. PMC 4258779. PMID 24801308. 3. ^ a b c d e f g h Arraut A (2017-03-09). "Erythrocyte Alloimmunization and Pregnancy: Overview, Background, Pathophysiology". Medscape. 4. ^ a b c d e f Murray NA, Roberts IA (March 2007). "Haemolytic disease of the newborn". Archives of Disease in Childhood. Fetal and Neonatal Edition. 92 (2): F83-8. doi:10.1136/adc.2005.076794. PMC 2675453. PMID 17337672. 5. ^ Shapiro SM (January 2005). "Definition of the clinical spectrum of kernicterus and bilirubin-induced neurologic dysfunction (BIND)". Journal of Perinatology. 25 (1): 54–9. doi:10.1038/sj.jp.7211157. PMID 15578034. S2CID 19663259. 6. ^ Blair E, Watson L (April 2006). "Epidemiology of cerebral palsy". Seminars in Fetal & Neonatal Medicine. 11 (2): 117–25. doi:10.1016/j.siny.2005.10.010. PMID 16338186. 7. ^ Lande L (June 1948). "Clinical signs and development of survivors of kernicterus due to Rh sensitization". The Journal of Pediatrics. 32 (6): 693–705. doi:10.1016/S0022-3476(48)80225-8. PMID 18866937. 8. ^ a b c d Koenig JM, Christensen RD (April 1989). "Neutropenia and thrombocytopenia in infants with Rh hemolytic disease". The Journal of Pediatrics. 114 (4 Pt 1): 625–31. doi:10.1016/s0022-3476(89)80709-7. 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"Three examples of Rh haemolytic disease of the newborn with a negative direct antiglobulin test". Transfusion Medicine. 5 (2): 113–6. doi:10.1111/j.1365-3148.1995.tb00197.x. PMID 7655573. S2CID 21936425. 18. ^ a b c d Hemolytic Disease of Newborn~workup at eMedicine 19. ^ van Wamelen DJ, Klumper FJ, de Haas M, Meerman RH, van Kamp IL, Oepkes D (May 2007). "Obstetric history and antibody titer in estimating severity of Kell alloimmunization in pregnancy". Obstetrics and Gynecology. 109 (5): 1093–8. doi:10.1097/01.AOG.0000260957.77090.4e. PMID 17470588. S2CID 24848319. 20. ^ Al-Dughaishi T, Al-Rubkhi IS, Al-Duhli M, Al-Harrasi Y, Gowri V (2015). "Alloimmunization due to red cell antibodies in Rhesus positive Omani Pregnant Women: Maternal and Perinatal outcome". Asian Journal of Transfusion Science. 9 (2): 150–4. doi:10.4103/0973-6247.162710. PMC 4562135. PMID 26420934. 21. ^ Vaughan JI, Manning M, Warwick RM, Letsky EA, Murray NA, Roberts IA (March 1998). "Inhibition of erythroid progenitor cells by anti-Kell antibodies in fetal alloimmune anemia". The New England Journal of Medicine. 338 (12): 798–803. doi:10.1056/NEJM199803193381204. PMID 9504940. 22. ^ "Kell sensitization can cause fetal anemia, too". Contemporary OB/GYN. UBM Medica. 1 September 2008. Retrieved 23 May 2018. 23. ^ a b c Arora S, Doda V, Maria A, Kotwal U, Goyal S (2015). "Maternal anti-M induced hemolytic disease of newborn followed by prolonged anemia in newborn twins". Asian Journal of Transfusion Science. 9 (1): 98–101. doi:10.4103/0973-6247.150968. PMC 4339947. PMID 25722586. 24. ^ Lu Q (5 February 2009), Kidd Blood Group System (PDF), Los Angeles, California: Department of Pathology and Laboratory Medicine, University of California, Los Angeles, School of Medicine, retrieved 23 May 2018 25. ^ Dean L (2005). "Chapter 10: The Kidd blood group". Blood Groups and Red Cell Antigens. Bethesda, Maryland: National Center for Biotechnology Information. Retrieved 23 May 2018. 26. ^ Moran P, Robson SC, Reid MM (November 2000). "Anti-E in pregnancy". BJOG. 107 (11): 1436–8. doi:10.1111/j.1471-0528.2000.tb11662.x. PMID 11117776. S2CID 1240358. 27. ^ Voto LS, Mathet ER, Zapaterio JL, Orti J, Lede RL, Margulies M (1997). "High-dose gammaglobulin (IVIG) followed by intrauterine transfusions (IUTs): a new alternative for the treatment of severe fetal hemolytic disease". Journal of Perinatal Medicine. 25 (1): 85–8. doi:10.1515/jpme.1997.25.1.85. PMID 9085208. S2CID 22822621. 28. ^ Novak DJ, Tyler LN, Reddy RL, Barsoom MJ (2008). "Plasmapheresis and intravenous immune globulin for the treatment of D alloimmunization in pregnancy". Journal of Clinical Apheresis. 23 (6): 183–5. doi:10.1002/jca.20180. PMID 19003884. S2CID 206013087. 29. ^ Palfi M, Hildén JO, Matthiesen L, Selbing A, Berlin G (October 2006). "A case of severe Rh (D) alloimmunization treated by intensive plasma exchange and high-dose intravenous immunoglobulin". Transfusion and Apheresis Science. 35 (2): 131–6. doi:10.1016/j.transci.2006.07.002. PMID 17045529. 30. ^ Ruma MS, Moise KJ, Kim E, Murtha AP, Prutsman WJ, Hassan SS, Lubarsky SL (February 2007). "Combined plasmapheresis and intravenous immune globulin for the treatment of severe maternal red cell alloimmunization". American Journal of Obstetrics and Gynecology. 196 (2): 138.e1–6. doi:10.1016/j.ajog.2006.10.890. PMID 17306655. 31. ^ Deka D (2016). "Intrauterine Transfusion". Journal of Fetal Medicine. 3 (1): 13–17. doi:10.1007/s40556-016-0072-4. ISSN 2348-1153. S2CID 42005756. 32. ^ a b Erythrocyte Alloimmunization and Pregnancy at eMedicine 33. ^ a b c Moise Jr KJ (15 March 2018). "Intrauterine fetal transfusion of red cells". UpToDate. UpToDate, Inc. Retrieved 31 March 2018. 34. ^ a b Hemolytic Disease of Newborn~treatment at eMedicine 35. ^ UNC Detection & Prevention: Isoimmunization Protocol (PDF), University of North Carolina, School of Medicine at Chapel Hill, October 2001, retrieved 23 May 2018 36. ^ Rimon E, Peltz R, Gamzu R, Yagel S, Feldman B, Chayen B, et al. (November 2006). "Management of Kell isoimmunization--evaluation of a Doppler-guided approach". Ultrasound in Obstetrics & Gynecology. 28 (6): 814–20. doi:10.1002/uog.2837. PMID 16941575. S2CID 19672347. 37. ^ "Hemolytic Disease of the Newborn" (PDF), Intensive Care Nursery House Staff Manual, Children's Hospital at University of California, San Francisco, Medical Center, pp. 121–124, retrieved 23 May 2018 38. ^ a b c American Academy of Pediatrics Subcommittee on Hyperbilirubinemia (July 2004). "Management of hyperbilirubinemia in the newborn infant 35 or more weeks of gestation". Pediatrics. 114 (1): 297–316. doi:10.1542/peds.114.1.297. PMID 15231951. 39. ^ Onesimo R, Rizzo D, Ruggiero A, Valentini P (September 2010). "Intravenous Immunoglobulin therapy for anti-E hemolytic disease in the newborn". The Journal of Maternal-Fetal & Neonatal Medicine. 23 (9): 1059–61. doi:10.3109/14767050903544751. PMID 20092394. S2CID 25144401. 40. ^ Gottstein R, Cooke RW (January 2003). "Systematic review of intravenous immunoglobulin in haemolytic disease of the newborn". Archives of Disease in Childhood. Fetal and Neonatal Edition. 88 (1): F6-10. doi:10.1136/fn.88.1.F6. PMC 1755998. PMID 12496219. 41. ^ Hemolytic Disease of Newborn~followup at eMedicine 42. ^ Strobel E (2008). "Hemolytic Transfusion Reactions". Transfusion Medicine and Hemotherapy. 35 (5): 346–353. doi:10.1159/000154811. PMC 3076326. PMID 21512623. 43. ^ Transfusion Reactions at eMedicine 44. ^ "Fatalities Reported to FDA Following Blood Collection and Transfusion: Annual Summary for Fiscal Year 2011", Vaccines, Blood & Biologics, U.S. Food and Drug Administration, 8 May 2012, archived from the original on 11 November 2012 ## Further reading[edit] * Geifman-Holtzman O, Wojtowycz M, Kosmas E, Artal R (February 1997). "Female alloimmunization with antibodies known to cause hemolytic disease". Obstetrics and Gynecology. 89 (2): 272–5. doi:10.1016/S0029-7844(96)00434-6. PMID 9015034. S2CID 36953155. * Mollison PL, Engelfriet CP, Contreras M (1997). Blood Transfusion in Clinical Medicine (10th ed.). Oxford, UK: Blackwell Science. ISBN 978-0-86542-881-2. * Dean L (2005). "Hemolytic disease of the newborn". Blood Groups and Red Blood Cell Antigens. National Center for Biotechnology Information. ## External links[edit] Classification D * ICD-10: P55 * ICD-9-CM: 773 * MeSH: D004899 * DiseasesDB: 5545 External resources * MedlinePlus: 001298 * eMedicine: ped/959 * Patient UK: Hemolytic disease of the newborn * v * t * e Conditions originating in the perinatal period / fetal disease Maternal factors complicating pregnancy, labour or delivery placenta * Placenta praevia * Placental insufficiency * Twin-to-twin transfusion syndrome chorion/amnion * Chorioamnionitis umbilical cord * Umbilical cord prolapse * Nuchal cord * Single umbilical artery presentation * Breech birth * Asynclitism * Shoulder presentation Growth * Small for gestational age / Large for gestational age * Preterm birth / Postterm pregnancy * Intrauterine growth restriction Birth trauma * scalp * Cephalohematoma * Chignon * Caput succedaneum * Subgaleal hemorrhage * Brachial plexus injury * Erb's palsy * Klumpke paralysis Affected systems Respiratory * Intrauterine hypoxia * Infant respiratory distress syndrome * Transient tachypnea of the newborn * Meconium aspiration syndrome * Pleural disease * Pneumothorax * Pneumomediastinum * Wilson–Mikity syndrome * Bronchopulmonary dysplasia Cardiovascular * Pneumopericardium * Persistent fetal circulation Bleeding and hematologic disease * Vitamin K deficiency bleeding * HDN * ABO * Anti-Kell * Rh c * Rh D * Rh E * Hydrops fetalis * Hyperbilirubinemia * Kernicterus * Neonatal jaundice * Velamentous cord insertion * Intraventricular hemorrhage * Germinal matrix hemorrhage * Anemia of prematurity Gastrointestinal * Ileus * Necrotizing enterocolitis * Meconium peritonitis Integument and thermoregulation * Erythema toxicum * Sclerema neonatorum Nervous system * Perinatal asphyxia * Periventricular leukomalacia Musculoskeletal * Gray baby syndrome * muscle tone * Congenital hypertonia * Congenital hypotonia Infections * Vertically transmitted infection * Neonatal infection * rubella * herpes simplex * mycoplasma hominis * ureaplasma urealyticum * Omphalitis * Neonatal sepsis * Group B streptococcal infection * Neonatal conjunctivitis Other * Miscarriage * Perinatal mortality * Stillbirth * Infant mortality * Neonatal withdrawal * v * t * e Hypersensitivity and autoimmune diseases Type I/allergy/atopy (IgE) Foreign * Atopic eczema * Allergic urticaria * Allergic rhinitis (Hay fever) * Allergic asthma * Anaphylaxis * Food allergy * common allergies include: Milk * Egg * Peanut * Tree nut * Seafood * Soy * Wheat * Penicillin allergy Autoimmune * Eosinophilic esophagitis Type II/ADCC * * IgM * IgG Foreign * Hemolytic disease of the newborn Autoimmune Cytotoxic * Autoimmune hemolytic anemia * Immune thrombocytopenic purpura * Bullous pemphigoid * Pemphigus vulgaris * Rheumatic fever * Goodpasture syndrome * Guillain–Barré syndrome "Type V"/receptor * Graves' disease * Myasthenia gravis * Pernicious anemia Type III (Immune complex) Foreign * Henoch–Schönlein purpura * Hypersensitivity vasculitis * Reactive arthritis * Farmer's lung * Post-streptococcal glomerulonephritis * Serum sickness * Arthus reaction Autoimmune * Systemic lupus erythematosus * Subacute bacterial endocarditis * Rheumatoid arthritis Type IV/cell-mediated (T cells) Foreign * Allergic contact dermatitis * Mantoux test Autoimmune * Diabetes mellitus type 1 * Hashimoto's thyroiditis * Multiple sclerosis * Coeliac disease * Giant-cell arteritis * Postorgasmic illness syndrome * Reactive arthritis GVHD * Transfusion-associated graft versus host disease Unknown/ multiple Foreign * Hypersensitivity pneumonitis * Allergic bronchopulmonary aspergillosis * Transplant rejection * Latex allergy (I+IV) Autoimmune * Sjögren syndrome * Autoimmune hepatitis * Autoimmune polyendocrine syndrome * APS1 * APS2 * Autoimmune adrenalitis * Systemic autoimmune disease [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Hemolytic disease of the newborn	c0014761	3,260	wikipedia	https://en.wikipedia.org/wiki/Hemolytic_disease_of_the_newborn	2021-01-18T18:35:50	{"mesh": ["D004899"], "umls": ["C0014761"], "orphanet": ["275938"], "wikidata": ["Q743545"]}
Pallister-Hall syndrome (PHS) is a genetic disease that affects the development of many parts of the body. Common features include extra fingers and/or toes (polydactyly), extra skin between the fingers or toes (syndactyly), an abnormal growth in the brain called a hypothalamic hamartoma, and a malformation of the airway known as bifid epiglottis. The bifid epiglottis in rare cases may lead to respiratory failure. While the hypothalamic hamartoma in most cases does not cause problems, in some cases it may cause neurological problems such as seizures, growth hormone deficiency, precocious puberty, or a deficiency of many hormones (panhypopituitarism) that can result in cortisol deficiency. Other symptoms of PHS may include imperforate anus, abnormalities in the kidneys, heart defects, small genitalia, lack of fingers, nail problems, cleft palate, bifid uvula, and development delay and behavioral problems. Pallister-Hall syndrome is caused by mutations in the GLI3 gene. Inheritance is autosomal dominant, however, in about a quarter of cases Pallister-Hall syndrome results from a new (de novo) mutation. The diagnosis of Pallister-Hall syndrome can be made when there is a hypothalamic hamartoma and polydactyly. The genetic test that identifies a mutation in the GLI3 gene confirms the diagnosis. Treatment is based on the symptoms, and may include medication for the early treatment of cortisol deficiency and seizures, surgery for imperforate anus and/or polydactyly, and special education when developmental delays are present. The prognosis depends on which symptoms are present and their severity. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Pallister-Hall syndrome	c0265220	3,261	gard	https://rarediseases.info.nih.gov/diseases/7305/pallister-hall-syndrome	2021-01-18T17:58:28	{"mesh": ["D054975"], "omim": ["146510"], "umls": ["C0265220"], "orphanet": ["672"], "synonyms": ["PHS", "Hypothalamic hamartoblastoma, hypopituitarism, imperforate anus, and postaxial polydactyly", "Pallister Hall syndrome"]}
## Clinical Features Morris and Augsburger (1977) reported a 4-generation kindred with teeth resembling those in dentin dysplasia type I (125400), also known as radicular dentin dysplasia. The long bones, as well as the maxillary and mandibular alveoli, were more dense than normal, with narrow or occluded marrow spaces and thick cortices. Male-to-male transmission was observed. Inheritance The transmission pattern of dentin dysplasia with sclerotic bones in the family reported by Morris and Augsburger (1977) was consistent with autosomal dominant inheritance. Skel \- Cortical sclerosis Radiology \- Dense long bones \- Dense maxillary and mandibular alveoli \- Narrow or occluded marrow spaces and thick cortices Inheritance \- Autosomal dominant Teeth \- Radicular dentin dysplasia ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	DENTIN DYSPLASIA WITH SCLEROTIC BONES	c1852201	3,262	omim	https://www.omim.org/entry/125440	2019-09-22T16:42:32	{"mesh": ["C538213"], "omim": ["125440"], "orphanet": ["99792"]}
Fructose-1,6-biphosphatase (FBP) deficiency is a disorder of fructose metabolism (see this term) characterized by recurrent episodes of fasting hypoglycemia with lactic acidosis, that may be life-threatening in neonates and infants. ## Epidemiology FBP deficiency birth prevalence has been estimated at 1/147,575 in Italy. This disorder has been reported in Japanese, Asian, European, North American, Arab and Moroccan patients. ## Clinical description FBP deficiency may occur neonatally with hepatomegaly, but it usually presents in infants of 3-4 months of age or early childhood, with manifestations including fast-induced hypoglycemia and metabolic acidosis, episodes of tachypnea/apnea, hypoglycemia, ketosis and lactic acidosis. Episodes are often triggered by catabolic conditions such as prolonged fasting (more than 8 to 10 hours), fructose, sorbitol or glycerol ingestion, vomiting, diarrhea or febrile infectious diseases. Patients are asymptomatic between episodes. ## Etiology FBP deficiency is due to homozygous or compound heterozygous mutations in the FBP1(9q22) gene encoding fructose-1,6-bisphosphatase1, resulting in impaired gluconeogenesis. To date, 11deleterious mutations have been reported. ## Diagnostic methods FBP deficiency diagnosis is based on clinical presentation, along with glycemia and lactacidemia levels. Enzyme activity may be measured in leukocytes, and genetic testing of the FBP1 gene confirms diagnosis. ## Differential diagnosis Differential diagnosis includes glycogen storage disease due to glucose-6-phosphatase deficiency (see this term). ## Antenatal diagnosis Prenatal diagnosis is feasible through molecular analysis of amniocytes or chorionic villous cells. ## Genetic counseling Transmission is autosomal recessive. Genetic counseling should be offered to at-risk couples (both individuals are carriers of a disease-causing mutation) informing them that there is a 25% risk of having an affected child at each pregnancy. ## Management and treatment FBP deficiency management aims at avoiding hypoglycemia and lactic acidosis through frequent feeding, enriched with glucose or maltodextrin, especially in illness associated with fever. Prevention and treatment of metabolic decompensation (with glucose orally or intravenously) is essential. Fasting periods longer than 8 hours should be avoided and infectious episodes should be carefully monitored. Fructose or sucrose should be avoided during acute episodes. ## Prognosis With timely adapted management and proper treatment, FPB deficiency prognosis is excellent, even if this condition may be potentially fatal in the newborn period and early infancy. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Fructose-1,6-bisphosphatase deficiency	c0016756	3,263	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=348	2021-01-23T18:36:07	{"gard": ["2400"], "mesh": ["D015319"], "omim": ["229700"], "umls": ["C0016756"], "icd-10": ["E74.1"], "synonyms": ["FBPase deficiency", "Fructose-1,6-diphosphatase deficiency"]}
A rare otorhinolaryngological malformation characterized by narrowing of the pyriform aperture (i. e. < 8 to 10 mm in a full-term infant) due to an overgrowth of the nasal process of the maxilla, resulting in potentially lethal nasal airway obstruction in the newborn. Depending on the degree of obstruction, clinical signs and symptoms include inspiratory stridor, respiratory distress, cyanosis, sternal retraction, ribcage asymmetry, and feeding difficulties. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Isolated congenital nasal pyriform aperture stenosis	None	3,264	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=162516	2021-01-23T17:27:45	{"icd-10": ["Q30.8"], "synonyms": ["Isolated apertura pyriformis stenosis", "Isolated nasal pyriform aperture hypoplasia"]}
Pigmentation disorder SpecialtyDermatology Pigmentation disorders are disturbances of human skin color, either loss or reduction, which may be related to loss of melanocytes or the inability of melanocytes to produce melanin or transport melanosomes correctly.[1] ## References[edit] 1. ^ James, William; Berger, Timothy; Elston, Dirk (2005). Andrews' Diseases of the Skin: Clinical Dermatology. (10th ed.). Saunders. ISBN 0-7216-2921-0. ## External links[edit] Classification D * ICD-10: L80-L81 * ICD-9-CM: 709.01 * MeSH: D010859 * v * t * e Pigmentation disorders/Dyschromia Hypo-/ leucism Loss of melanocytes Vitiligo * Quadrichrome vitiligo * Vitiligo ponctué Syndromic * Alezzandrini syndrome * Vogt–Koyanagi–Harada syndrome Melanocyte development * Piebaldism * Waardenburg syndrome * Tietz syndrome Loss of melanin/ amelanism Albinism * Oculocutaneous albinism * Ocular albinism Melanosome transfer * Hermansky–Pudlak syndrome * Chédiak–Higashi syndrome * Griscelli syndrome * Elejalde syndrome * Griscelli syndrome type 2 * Griscelli syndrome type 3 Other * Cross syndrome * ABCD syndrome * Albinism–deafness syndrome * Idiopathic guttate hypomelanosis * Phylloid hypomelanosis * Progressive macular hypomelanosis Leukoderma w/o hypomelanosis * Vasospastic macule * Woronoff's ring * Nevus anemicus Ungrouped * Nevus depigmentosus * Postinflammatory hypopigmentation * Pityriasis alba * Vagabond's leukomelanoderma * Yemenite deaf-blind hypopigmentation syndrome * Wende–Bauckus syndrome Hyper- Melanin/ Melanosis/ Melanism Reticulated * Dermatopathia pigmentosa reticularis * Pigmentatio reticularis faciei et colli * Reticulate acropigmentation of Kitamura * Reticular pigmented anomaly of the flexures * Naegeli–Franceschetti–Jadassohn syndrome * Dyskeratosis congenita * X-linked reticulate pigmentary disorder * Galli–Galli disease * Revesz syndrome Diffuse/ circumscribed * Lentigo/Lentiginosis: Lentigo simplex * Liver spot * Centrofacial lentiginosis * Generalized lentiginosis * Inherited patterned lentiginosis in black persons * Ink spot lentigo * Lentigo maligna * Mucosal lentigines * Partial unilateral lentiginosis * PUVA lentigines * Melasma * Erythema dyschromicum perstans * Lichen planus pigmentosus * Café au lait spot * Poikiloderma (Poikiloderma of Civatte * Poikiloderma vasculare atrophicans) * Riehl melanosis Linear * Incontinentia pigmenti * Scratch dermatitis * Shiitake mushroom dermatitis Other/ ungrouped * Acanthosis nigricans * Freckle * Familial progressive hyperpigmentation * Pallister–Killian syndrome * Periorbital hyperpigmentation * Photoleukomelanodermatitis of Kobori * Postinflammatory hyperpigmentation * Transient neonatal pustular melanosis Other pigments Iron * Hemochromatosis * Iron metallic discoloration * Pigmented purpuric dermatosis * Schamberg disease * Majocchi's disease * Gougerot–Blum syndrome * Doucas and Kapetanakis pigmented purpura/Eczematid-like purpura of Doucas and Kapetanakis * Lichen aureus * Angioma serpiginosum * Hemosiderin hyperpigmentation Other metals * Argyria * Chrysiasis * Arsenic poisoning * Lead poisoning * Titanium metallic discoloration Other * Carotenosis * Tar melanosis Dyschromia * Dyschromatosis symmetrica hereditaria * Dyschromatosis universalis hereditaria See also * Skin color * Skin whitening * Tanning * Sunless * Tattoo * removal * Depigmentation * v * t * e Congenital malformations and deformations of integument / skin disease Genodermatosis Congenital ichthyosis/ erythrokeratodermia AD * Ichthyosis vulgaris AR * Congenital ichthyosiform erythroderma: Epidermolytic hyperkeratosis * Lamellar ichthyosis * Harlequin-type ichthyosis * Netherton syndrome * Zunich–Kaye syndrome * Sjögren–Larsson syndrome XR * X-linked ichthyosis Ungrouped * Ichthyosis bullosa of Siemens * Ichthyosis follicularis * Ichthyosis prematurity syndrome * Ichthyosis–sclerosing cholangitis syndrome * Nonbullous congenital ichthyosiform erythroderma * Ichthyosis linearis circumflexa * Ichthyosis hystrix EB and related * EBS * EBS-K * EBS-WC * EBS-DM * EBS-OG * EBS-MD * EBS-MP * JEB * JEB-H * Mitis * Generalized atrophic * JEB-PA * DEB * DDEB * RDEB * related: Costello syndrome * Kindler syndrome * Laryngoonychocutaneous syndrome * Skin fragility syndrome Ectodermal dysplasia * Naegeli syndrome/Dermatopathia pigmentosa reticularis * Hay–Wells syndrome * Hypohidrotic ectodermal dysplasia * Focal dermal hypoplasia * Ellis–van Creveld syndrome * Rapp–Hodgkin syndrome/Hay–Wells syndrome Elastic/Connective * Ehlers–Danlos syndromes * Cutis laxa (Gerodermia osteodysplastica) * Popliteal pterygium syndrome * Pseudoxanthoma elasticum * Van der Woude syndrome Hyperkeratosis/ keratinopathy PPK * diffuse: Diffuse epidermolytic palmoplantar keratoderma * Diffuse nonepidermolytic palmoplantar keratoderma * Palmoplantar keratoderma of Sybert * Meleda disease * syndromic * connexin * Bart–Pumphrey syndrome * Clouston's hidrotic ectodermal dysplasia * Vohwinkel syndrome * Corneodermatoosseous syndrome * plakoglobin * Naxos syndrome * Scleroatrophic syndrome of Huriez * Olmsted syndrome * Cathepsin C * Papillon–Lefèvre syndrome * Haim–Munk syndrome * Camisa disease * focal: Focal palmoplantar keratoderma with oral mucosal hyperkeratosis * Focal palmoplantar and gingival keratosis * Howel–Evans syndrome * Pachyonychia congenita * Pachyonychia congenita type I * Pachyonychia congenita type II * Striate palmoplantar keratoderma * Tyrosinemia type II * punctate: Acrokeratoelastoidosis of Costa * Focal acral hyperkeratosis * Keratosis punctata palmaris et plantaris * Keratosis punctata of the palmar creases * Schöpf–Schulz–Passarge syndrome * Porokeratosis plantaris discreta * Spiny keratoderma * ungrouped: Palmoplantar keratoderma and spastic paraplegia * desmoplakin * Carvajal syndrome * connexin * Erythrokeratodermia variabilis * HID/KID Other * Meleda disease * Keratosis pilaris * ATP2A2 * Darier's disease * Dyskeratosis congenita * Lelis syndrome * Dyskeratosis congenita * Keratolytic winter erythema * Keratosis follicularis spinulosa decalvans * Keratosis linearis with ichthyosis congenita and sclerosing keratoderma syndrome * Keratosis pilaris atrophicans faciei * Keratosis pilaris Other * cadherin * EEM syndrome * immune system * Hereditary lymphedema * Mastocytosis/Urticaria pigmentosa * Hailey–Hailey see also Template:Congenital malformations and deformations of skin appendages, Template:Phakomatoses, Template:Pigmentation disorders, Template:DNA replication and repair-deficiency disorder Developmental anomalies Midline * Dermoid cyst * Encephalocele * Nasal glioma * PHACE association * Sinus pericranii Nevus * Capillary hemangioma * Port-wine stain * Nevus flammeus nuchae Other/ungrouped * Aplasia cutis congenita * Amniotic band syndrome * Branchial cyst * Cavernous venous malformation * Accessory nail of the fifth toe * Bronchogenic cyst * Congenital cartilaginous rest of the neck * Congenital hypertrophy of the lateral fold of the hallux * Congenital lip pit * Congenital malformations of the dermatoglyphs * Congenital preauricular fistula * Congenital smooth muscle hamartoma * Cystic lymphatic malformation * Median raphe cyst * Melanotic neuroectodermal tumor of infancy * Mongolian spot * Nasolacrimal duct cyst * Omphalomesenteric duct cyst * Poland anomaly * Rapidly involuting congenital hemangioma * Rosenthal–Kloepfer syndrome * Skin dimple * Superficial lymphatic malformation * Thyroglossal duct cyst * Verrucous vascular malformation * Birthmark This cutaneous condition article is a stub. You can help Wikipedia by expanding it. * v * t * e [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Pigmentation disorder	c0375489	3,265	wikipedia	https://en.wikipedia.org/wiki/Pigmentation_disorder	2021-01-18T18:39:46	{"mesh": ["D010859"], "umls": ["C0375489"], "icd-10": ["L81"], "orphanet": ["79374"], "wikidata": ["Q7193408"]}
Carney complex-trismus-pseudocamptodactyly syndrome is a rare genetic heart-hand syndrome characterized by typical manifestations of the Carney complex (spotty pigmentation of the skin, familial cardiac and cutaneous myxomas and endocrinopathy) associated with trismus and distal arthrogryposis (presenting as involuntary contraction of distal and proximal interphalangeal joints of hands evident only on dorsiflexion of wrist and similar lower-limb contractures producing foot deformities). [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Carney complex-trismus-pseudocamptodactyly syndrome	c1837245	3,266	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=319340	2021-01-23T18:46:29	{"mesh": ["C563845"], "omim": ["608837"], "umls": ["C1837245"], "icd-10": ["Q68.8"], "synonyms": ["Carney complex variant"]}
## Summary ### Clinical characteristics. AP-4-associated hereditary spastic paraplegia (HSP), also known as AP-4 deficiency syndrome, is a group of neurodegenerative disorders characterized by a progressive, complex spastic paraplegia with onset typically in infancy or early childhood. Early-onset hypotonia evolves into progressive lower-extremity spasticity. The majority of children become non-ambulatory and usually wheelchair bound. Over time spasticity progresses to involve the upper extremities, resulting in a spastic tetraplegia. Associated complications include dysphagia, contractures, foot deformities, dysregulation of bladder and bowel function, and a pseudobulbar affect. About 50% of affected individuals have seizures. Postnatal microcephaly (usually in the -2SD to -3SD range) is common. All have developmental delay. Speech development is significantly impaired and many affected individuals remain nonverbal. Intellectual disability in older children is usually moderate to severe. ### Diagnosis/testing. The diagnosis of AP-4-associated HSP is established in a proband by identification of biallelic pathogenic variants in one of four genes: AP4B1, AP4E1, AP4M1, or AP4S1. ### Management. Treatment of manifestations: Management by an interdisciplinary team (including a neurologist, clinical geneticist, developmental specialist, orthopedic surgeon/physiatrist, physical therapist, occupational therapist, and a speech and language pathologist) to address spasticity/weakness, secondary musculoskeletal findings, developmental delay and intellectual disability, seizures, and swallowing and feeding difficulties. Surveillance: Evaluation every six to 12 months by an interdisciplinary team to assess disease progression and to maximize ambulation and communication skills while reducing the effect of other manifestations (e.g., musculoskeletal complications, dysphagia / feeding difficulties, and seizures). ### Genetic counseling. AP-4-associated HSP is inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Once the AP-4-associated HSP-causing pathogenic variants have been identified in an affected family member, carrier testing for at-risk relatives, prenatal testing for a pregnancy at increased risk, and preimplantation genetic testing are possible. ## Diagnosis Formal diagnostic criteria for AP-4-associated hereditary spastic paraplegia (HSP) have not been established. ### Suggestive Findings AP-4-associated HSP should be suspected in individuals with the following clinical findings and characteristic brain imaging findings [Verkerk et al 2009, Abou Jamra et al 2011, Moreno-De-Luca et al 2011, Ebrahimi-Fakhari et al 2018]. #### Clinical Findings Characteristic findings: * Progressive spastic paraplegia with progression to tetraplegia in the later stages (94%, 58/62) * * Early-onset developmental delay (100%, 68/68) * * Delayed motor milestones (100%, 54/54) * * Failure to achieve or loss of independent ambulation (93%, 41/44) * * Impaired or absent speech development (98%, 51/52) * * Neonatal/infantile hypotonia (usually mild) (100%, 41/41) * * Postnatal microcephaly (77%, 47/61) (usually in -2SD to -3SD range) * * Early-onset seizures including frequent febrile seizures (42%, 25/59) * Less frequent findings: * Short statue (65%, 17/26) * * Nonspecific dysmorphic facial features (82%, 41/50) * * Episodes of stereotypic laughter [Ebrahimi-Fakhari et al 2018] * Foot deformities (i.e., clubfoot) #### Brain Imaging Findings Characteristic findings: * Thinning of the corpus callosum (with prominent thinning of the posterior parts) (88%, 37/42) * * Delayed myelination and nonspecific loss of the periventricular white matter (69%, 29/42) * * Ex-vacuo ventriculomegaly, often with prominent enlargement of the posterior horns of the lateral ventricles (60%, 24/40) * Less frequent findings: * Cortical atrophy and cerebellar atrophy * Brain iron accumulation [Vill et al 2017, Roubertie et al 2018] * Data from the International Registry and Natural History Study of Adaptor-Protein 4-Related Hereditary Spastic Paraplegia (updated 5-20-18) ### Establishing the Diagnosis The diagnosis of AP-4-associated HSP is established in a proband by identification of biallelic pathogenic variants in one of four genes: AP4B1, AP4E1, AP4M1, or AP4S1 (see Table 1). Molecular genetic testing approaches can include a combination of gene-targeted testing (multigene panel) and comprehensive genomic testing (typically exome sequencing). Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Developmental delay / intellectual disability, spasticity, epilepsy, or microcephaly multigene panels that include AP4B1, AP4E1, AP4M1, AP4S1, and other genes of interest (see Differential Diagnosis) are 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. Of note, given the rarity of AP-4-associated HSP, some panels for developmental delay / intellectual disability and/or spasticity and/or epilepsy and/or microcephaly may not include this gene. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests. For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here. Comprehensive genomic testing (which does not require the clinician to determine which gene[s] are likely involved) is the best option when the clinician cannot determine which multigene panel best fits the affected individual's clinical findings. Exome sequencing is most commonly used; genome sequencing is also possible. If exome sequencing is not diagnostic, 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 AP-4 Associated Hereditary Spastic Paraplegia View in own window Gene 1, 2Proportion of AP-4 Deficiency Attributed to Pathogenic Variants in Gene 3Proportion of Pathogenic Variants 4 Detectable by Method 3 Sequence analysis 5Gene-targeted deletion/duplication analysis 6 AP4B1~40% (32/80 probands)100% (25/25 probands)None reported AP4E1~14% (11/80 probands)70% (7/10 probands)30% (3/10 probands) AP4M1~31% (25/80 probands)100% (22/22 probands)None reported AP4S1~15% (12/80 probands)100% (11/11 probands)None reported 1\. Genes are listed in alphabetic order. 2\. See Table A. Genes and Databases for chromosome locus and protein. 3\. International Registry and Natural History Study of Adaptor-Protein 4-Related HSP (updated 5-20-18) 4\. See Molecular Genetics for information on allelic variants detected in this gene. 5\. 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. 6\. Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. ## Clinical Characteristics ### Clinical Description AP-4-associated hereditary spastic paraplegia (HSP) is characterized by complex spastic paraplegia in all affected individuals reported to date. Onset is usually before age one year. Infants manifest hypotonia, microcephaly, and delayed developmental milestones; some also have seizures. The early-childhood hypotonia evolves into progressive lower-extremity weakness and spasticity with pyramidal signs (plantar extension and hyperreflexia). Over time children often become non-ambulatory and ultimately require mobility aids / wheelchairs. Spasticity progresses to involve the upper extremities, resulting in spastic tetraplegia. Associated complications include dysphagia, contractures secondary to progressive spasticity, foot deformities, and dysregulation of bladder and bowel function. Microcephaly becomes evident in infancy in the majority and is often in the -2 SD to -3 SD range. Developmental delay is universal. Delayed motor milestones are often the presenting manifestation: * Rolling (mean age: 6.5 months) * Sitting (mean age: 10.2 months) * Crawling (mean age: 22.8 months) Only a subset of children achieve independent walking (mean age: 33.5 months), a skill that is often lost as the disease progresses [Data from the International Registry and Natural History Study of AP-4-Related HSP; updated 5-20-18]. Speech and language development is significantly impaired and many affected individuals remain nonverbal. Intellectual disability in older children is usually moderate to severe. Seizures often occur in the first two years of life; about 50% of individuals with AP-4-associated HSP have a diagnosis of epilepsy. Seizure types include focal-onset seizures (often with secondary generalization) as well as primary generalized seizures. Status epilepticus has been reported in a significant subset of patients. About 50% of affected individuals, including individuals with and without epilepsy, have seizures in the setting of fever. In general, seizures become less frequent with age and are often well controlled with standard antiepileptic drugs. Episodes of stereotypic laughter, perhaps indicating a pseudobulbar affect, are a characteristic finding in a subset of individuals [Ebrahimi-Fakhari et al 2018]. Less frequent clinical manifestations include short stature, nonspecific dysmorphic facial features, optic nerve atrophy, dystonia, and ataxia. To date, uncomplicated hereditary spastic paraplegia, a pure spastic paraplegia without other neurological manifestations, has not been reported in individuals with AP-4 deficiency. Prognosis. Natural history data are not currently available. The oldest reported individuals are young adults. ### Phenotype Correlations by Gene AP-4-associated HSP is caused by biallelic loss-of-function variants in one of the four genes that encode subunits of the AP-4 complex (β4, ε, μ4, σ4). Because loss of any one subunit renders the entire complex nonfunctional, biallelic loss-of-function variants in any one of the four genes cause the same molecular defect – loss of AP-4 complex function – and the same phenotype. Brain iron accumulation has been reported in one family with AP4M1-related AP-4 deficiency syndrome [Roubertie et al 2018] and one individual with AP4S1-related AP-4 deficiency syndrome [Vill et al 2017]. Given the rarity of this finding and a potential age bias, it is unknown if brain iron accumulation is a feature of AP-4-associated HSP regardless of cause. ### Genotype-Phenotype Correlations No genotype-phenotype correlations have been reported for any of the four genes known to cause AP-4-associated HSP (AP4B1, AP4E1, AP4M1, AP4S1). ### Nomenclature ### Table 2. Other Terms Used to Refer to AP-4-Associated Hereditary Spastic Paraplegia Subtypes View in own window SubtypeTerms AP4B1-related AP-4 deficiency syndrome * Hereditary spastic paraplegia type 47 * Spastic paraplegia type 47 (SPG47 1) * AP4B1-related hereditary spastic paraplegia (HSP-AP4B1) AP4E1-related AP-4 deficiency syndrome * Hereditary spastic paraplegia type 51 * Spastic paraplegia type 51 (SPG51) * AP4E1-related hereditary spastic paraplegia (HSP-AP4E1) AP4M1-related AP-4 deficiency syndrome * Hereditary spastic paraplegia type 50 * Spastic paraplegia type 50 (SPG50) * AP4M1-related hereditary spastic paraplegia (HSP-AP4M1) AP4S1-related AP-4 deficiency syndrome * Hereditary spastic paraplegia type 52 * Spastic paraplegia type 52 (SPG52) * AP4S1-related hereditary spastic paraplegia (HSP-AP4S1) 1\. Genetic loci for HSP are designated "SPG" (for "spastic paraplegia") followed by a number indicating the order of their discovery [Fink 2013]. Recommendations for the nomenclature of genetic movement disorders, including AP-4-associated HSP, have been published [Marras et al 2016]. ### Prevalence AP-4-associated HSP is rare. To date about 80 individuals are known; all have been included in the International Registry and Natural History Study of AP-4-Related Hereditary Spastic Paraplegia (updated 5-20-18). Families with AP-4-associated HSP have been reported from North America, Europe, the Middle East, and the Indian subcontinent. * About two thirds of individuals with AP-4-associated HSP have consanguineous parents; * however, this could be the result of ascertainment bias, as initial reports have mainly focused on families from countries with high rates of consanguinity [Verkerk et al 2009, Abou Jamra et al 2011, Moreno-De-Luca et al 2011]. More recently, AP-4-associated HSP has been reported in populations with low rates of consanguinity [Ebrahimi-Fakhari et al 2018]. * International Registry and Natural History Study of AP-4-Related HSP ## Differential Diagnosis Many of the initial manifestations of AP-4-associated HSP are nonspecific and may resemble other disorders characterized by spasticity, developmental delay / intellectual disability, and a thin corpus callosum. Many children with AP-4-associated HSP are diagnosed with cerebral palsy before genetic testing is obtained. Table 3 summarizes the features that distinguish the disorders most likely considered in the differential diagnosis from AP-4-associated HSP. ### Table 3. Distinguishing Clinical Features of Hereditary Disorders to Consider in the Differential Diagnosis of AP-4-Associated HSP View in own window Gene(s) 1 (Locus/Disorder)MOIDistinguishing Clinical Features of the Differential Diagnosis Disorder AMPD2 (SPG63)AR * Central visual impairment * Cerebellar hypoplasia/atrophy ARSI (SPG66)ARPeripheral neuropathy MTRFR (formerly C12orf65) (SPG55)AR * Optic atrophy * Motor sensory neuropathy CYP2U1 (SPG56)ARBasal ganglia calcification DDHD2 (SPG54)AROptic-nerve hypoplasia is more common. FA2H (SPG35; fatty acid hydroxylase-associated neurodegeneration)AR * Later onset * Brain iron accumulation is more common. GBA2 (SPG46)AR * Congenital cataracts * Hearing loss * Neuropathy GJC2 (SPG44)ARLater onset L1CAM (SPG1; L1 syndrome)XLAdducted thumbs NT5C2 (SPG45 [SPG65])AROptic atrophy is more common. PGAP1 (SPG67)ARTremor RUSC2 (RUSC2-associated ID; OMIM 617773)ARDescribed in 1 family only SPG11 (spastic paraplegia 11)AR * Later onset * Distal amyotrophy * Pigmentary retinopathy * Ataxia * Parkinsonism * Ears of the lynx sign on MRI SPG21 (SPG21)AR * Onset in young adulthood * Cerebellar signs TECPR2 (SPG49)AR * Autonomic-sensory neuropathy * Apneas/chronic respiratory disease * Dysmorphism ZFR (SPG71)ARDescribed in 1 individual only ZFYVE26 (SPG15)AR * Later onset * Pigmentary retinopathy * Neuropathy * Parkinsonism Note: See Hereditary Spastic Paraplegia Overview for a general discussion of this phenotype. AR = autosomal recessive; ID = intellectual disability; MOI = mode of inheritance; SPG = spastic paraplegia; XL = X-linked 1\. Genes are in alphabetic order. Other hereditary disorders to consider in the differential diagnosis of AP-4-associated HSP include the leukodystrophies and certain inborn errors of metabolism (particularly important are treatable conditions such as dopa-responsive dystonia (see GTP Cyclohydrolase 1-Deficient Dopa-Responsive Dystonia). ## Management ### Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with AP-4-associated hereditary spastic paraplegia (HSP), the evaluations summarized in Table 4 (if not performed as part of the evaluation that led to the diagnosis) are recommended. ### Table 4. Recommended Evaluations Following Initial Diagnosis in Individuals with AP-4-Associated HSP View in own window System/ConcernEvaluationComment EyesOphthalmologic evaluation * To assess visual acuity * To perform fundoscopic exam for evidence of optic atrophy NeurologicNeurologic evaluationTo incl brain MRI. Consider EEG if seizures are a concern. Gastrointestinal/ FeedingGastroenterology / nutrition / feeding team evaluation * To incl evaluation of aspiration risk & nutritional status * Consider evaluation for gastric tube placement in patients w/dysphagia &/or aspiration risk. PulmonaryPulmonary evaluationTo incl evaluation of aspiration risk & secretion management GenitourinaryNeuro-urologic evaluationTo incl urodynamic testing MusculoskeletalOrthopedics / physiatry / PT / OT evaluationTo incl PT/OT evaluation & assessment for mobility, activities of daily living, contractures, scoliosis, & foot deformities Referral to pediatric pain specialistFor those who have pain due to deforming joint contractures Miscellaneous/ OtherDevelopmental assessment * To incl motor, adaptive, cognitive, & speech/language evaluation * Evaluation for early intervention / special education Consultation w/clinical geneticist &/or genetic counselorTo incl genetic counseling Family supports/resources * Community or online resources e.g., Parent to Parent * Social work involvement for parental support * Home nursing referral if needed Referral to palliative careWhen deemed appropriate by family & health care providers OT = occupational therapy; PT = physical therapy ### Treatment of Manifestations At present, no treatment prevents, halts, or reverses neuronal degeneration in AP-4-associated HSP. Treatment is directed at reducing symptoms and preventing secondary complications. ### Table 5. Treatment of Manifestations in Individuals with AP-4-Associated HSP View in own window Manifestation/ ConcernTreatmentConsiderations/Other Feeding difficulties & growth failure * Nutritional supplementation * G-tube feeds * Referral to nutritionist * Gastrostomy feeding ↓ aspiration risk / provides a reliable route for medication / can improve nutritional status. DysphagiaG-tube feedsDysphagia-associated aspiration may → recurrent aspiration pneumonia. Sialorrhea * Anticholinergic drugs * Botulinum toxin injections * Surgery Management by an interdisciplinary aerodigestive team Aspiration * Management of secretions * G-tube feeds Pulmonary complications * Minimize aspiration risk (see above) * Pulmonary toilet * Aspiration, pulmonary infections, restrictive lung disease secondary to scoliosis & spasticity * Referral to pulmonologist Bowel dysfunction, chronic constipation, gastroesophageal reflux * Stool softeners, prokinetics, osmotic agents, or laxatives as needed * Proton pump inhibitors, histamine receptor antagonists, or antacids as needed * Consideration of fundoplication in refractory cases Referral to gastroenterologist Delayed speech developmentSpeech & language therapySee Developmental Delay / Intellectual Disability Management Issues. Delayed motor development * Physiotherapy * Occupational therapy Spasticity/ Weakness/ Hypotonia * Physiotherapy * Antispasticity medications such as oral or intrathecal baclofen * Botulinum toxin injections * Surgical treatment * Progression of contractures, scoliosis, & foot deformities may be delayed w/regular physiotherapy & antispastic medications. * Consider need for positioning and mobility devices. * Monitor skin integrity. MusculoskeletalContracturesPhysical therapy, referral to orthopedic surgery Scoliosis Foot deformitiesPhysical therapy, ankle-foot orthoses, referral to orthopedic surgery Urinary urgencyAnticholinergic drugsReferral to urologist EpilepsyStandard antiepileptic drugsMost patients respond to standard antiepileptic therapy. 1 OsteopeniaVitamin D & calcium supplementation Routine health careStandard immunizations per local guidelines Family/ Community * Ensure appropriate social work involvement to connect families w/local resources & support. * Ensure care coordination to manage multiple subspecialty appointments, equipment, medications, & supplies. Ongoing assessment for need of palliative care involvement &/or home nursing. 1\. Education of parents regarding common seizure presentations is appropriate. For information on non-medical interventions and coping strategies for parents or caregivers of children diagnosed with epilepsy, see Epilepsy & My Child Toolkit. #### Developmental Delay / Intellectual Disability Management Issues The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country. Ages 0-3 years. Referral to an early intervention program is recommended for access to occupational, physical, speech, and feeding therapy as well as infant mental health services, special educators, and sensory-impairment specialists. In the US, early intervention is a federally funded program available in all states; it provides in-home services to target individual therapy needs. Ages 3-5 years. In the US, developmental preschool through the local public school district is recommended. Before placement, an evaluation is made to determine needed services and therapies and an individualized education plan (IEP) is developed for those who qualify based on established motor, language, social, and/or cognitive delay. The early intervention program typically assists with this transition. Developmental preschool is center based; however, for children too medically unstable to attend, home-based services are provided. Ages 5-21 years. IEP services: * In the US, an IEP based on the individual's level of function should be developed by the local public school district and will dictate specially designed instruction/related services. * IEP services will be reviewed annually to determine if any changes are needed. * As required by special education law, children should be in the least restrictive environment at school and included in general education as much as possible and when appropriate. * Vision consultants should be a part of the child's IEP team to support access to academic material if the child has visual impairment. * PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. * As a child enters adolescence, an educational transition plan should be discussed and incorporated into the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. Discussion about transition plans including financial 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 and positioning devices 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 should be reassessed in regular intervals and clinical feeding evaluations and/or radiographic swallowing studies should be obtained for choking/gagging during feeds, poor weight gain, frequent respiratory illnesses, or feeding refusal that is not otherwise explained. Feeds can be thickened or chilled to minimize feeding problems; when severe feeding dysfunction is present, a gastrostomy tube may be necessary. Assuming that the individual is safe to eat by mouth, feeding therapy, typically from an occupational or speech therapist, can be helpful to improve coordination or sensory-related feeding issues. Communication issues. Consider evaluation for alternative means of communication (e.g., Augmentative and Alternative Communication [AAC]) for individuals who have expressive language difficulties. An AAC evaluation can be completed by a speech-language pathologist who has expertise in this area. The evaluation will consider cognitive abilities and sensory impairments to determine the most appropriate form of communication. AAC devices can range from low-tech, such as picture exchange communication, to high-tech, such as voice-generating devices. Contrary to popular belief, AAC devices do not hinder verbal development of speech, and in many cases can improve it. ### Surveillance Patients should be evaluated periodically (i.e., every 6-12 months) by an interdisciplinary team that includes a neurologist, clinical geneticist, developmental specialist, orthopedic surgeon/physiatrist, physical therapist, occupational therapist, and speech and language pathologist to assess disease progression, maximize ambulation and communication skills, and reduce other manifestations (Table 6). ### Table 6. Recommended Surveillance for Individuals with AP-4 Associated Hereditary Spastic Paraplegia View in own window System/ConcernEvaluationFrequency EyesOphthalmologic eval for visual acuity & need for support services for the visually impairedAs needed Gastrointestinal/ Feeding * Aspiration risk & nutritional status * Monitor for constipation & bowel dysfunction. PulmonaryMonitor for aspiration & pulmonary complications. GenitourinaryUrodynamic testing Musculoskeletal * PT/OT eval; assess for contractures, scoliosis, & foot deformities. * Hip/spine x-rays Annually; more frequently if needed Neurologic * Monitor & treat spasticity. * Monitor those w/seizures as clinically indicated. Miscellaneous/ OtherMonitor developmental progress & educational/family needs. OT = occupational therapy; PT = physicial therapy ### Evaluation of Relatives at Risk See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes. ### Therapies Under Investigation Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	AP-4-Associated Hereditary Spastic Paraplegia	None	3,267	gene_reviews	https://www.ncbi.nlm.nih.gov/books/NBK535153/	2021-01-18T21:45:14	{"synonyms": ["Adaptor Protein Complex 4 Deficiency (AP-4 Deficiency)", "AP-4-Associated HSP", "AP-4 Deficiency Syndrome"]}
A number sign (#) is used with this entry because of evidence that orofaciodigital syndrome XVI (OFD16) is caused by homozygous or compound heterozygous mutation in the TMEM107 gene (616183) on chromosome 17p13. Mutation in the TMEM107 gene can also cause Meckel syndrome-13 (MKS13) and Joubert syndrome-29 (JBTS29); see 617562. Clinical Features Shylo et al. (2016) reported a patient with OFD16. The patient had postaxial polydactyly of the hands and feet, multiple tongue cysts, and dysmorphic features, including frontal narrowing, short palpebral fissures, flat nasal bridge, retrognathia, and low-set ears. The patient also had developmental delay, inguinal hernia, and muscle hypotonia associated with motor delay. Other typical ciliopathy-associated features were not present, such as situs abnormalities. Extra digits on both hands had only 2 phalanges, suggesting thumb identity, despite the postaxial location. Brain imaging did not show molar tooth sign (MTS), ruling out Joubert syndrome. Lambacher et al. (2016) studied 9-year-old twin girls, born of consanguineous Turkish parents, with OFD16. The patients had previously been reported by Darmency-Stamboul et al. (2013) as patients 3 and 4. These girls had delayed psychomotor development with severe cognitive impairment and inability to walk. Other neurologic signs included ataxia, orofacial dyspraxia, fine motor disorder, oculomotor dyspraxia, retinopathy, and apnea/hyperpnea. Additional features included lingual hamartoma, multiple frenula, and postaxial polydactyly of the hands and feet. One had a sacrococcygeal teratoma and the other had a ventricular septal defect. Brain imaging showed multiple infra- and supratentorial abnormalities, including cerebellar and brainstem malformations consistent with MTS, enlarged ventricles, hippocampal malrotation, heterotopia, and temporal lobe hypoplasia. Inheritance The transmission pattern of OFD16 in the family reported by Darmency-Stamboul et al. (2013) and Lambacher et al. (2016) was consistent with autosomal recessive inheritance. Molecular Genetics In a patient with OFD16, Shylo et al. (2016) identified a homozygous in-frame deletion in the TMEM107 gene (phe106del; 616183.0002). Patient cells showed fewer cilia, and cilia that were formed had a very broad range of lengths compared to controls. The findings indicated that the mutation disrupted cilia formation or maintenance. Patient cilia also showed loss of certain transition zone (TZ) proteins. In female twins, born of consanguineous parents, with OFD16, Lambacher et al. (2016) identified a homozygous missense mutation in the TMEM107 gene (E45G; 616183.0003). The mutation segregated with the disorder in the family and was not found in the Exome Variant Server or ExAC databases. The E45G mutant protein retained the ability to localize to the transition zone, indicating that the mutation disrupted TMEM107 functions at the transition zone, rather than having a gross effect on TMEM107 localization or stability. INHERITANCE \- Autosomal recessive HEAD & NECK Face \- Orofacial dyspraxia \- Frontal narrowing \- Retrognathia Ears \- Low-set ears Eyes \- Oculomotor apraxia \- Retinopathy \- Ptosis \- Short palpebral fissures Nose \- Flat nasal bridge Mouth \- Lingual hamartoma \- Multiple frenula \- Tongue cysts RESPIRATORY \- Apnea \- Hyperpnea ABDOMEN External Features \- Inguinal hernia SKELETAL Hands \- Polydactyly, postaxial Feet \- Polydactyly, postaxial MUSCLE, SOFT TISSUES \- Hypotonia NEUROLOGIC Central Nervous System \- Delayed psychomotor development \- Intellectual disability, severe \- Inability to walk \- Ataxia \- Fine motor disorder \- Molar tooth sign \- Cerebellar malformations \- Brainstem malformations \- Supratentorial abnormalities \- Enlarged ventricles \- Hippocampal malrotation \- Heterotopia \- Temporal lobe hypoplasia Behavioral Psychiatric Manifestations \- Abnormal behavior MISCELLANEOUS \- Three patients from 2 unrelated families have been reported (last curated July 2017) MOLECULAR BASIS \- Caused by mutation in the transmembrane protein 107 gene (TMEM107, 616183.0002 ) ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	OROFACIODIGITAL SYNDROME XVI	c4539729	3,268	omim	https://www.omim.org/entry/617563	2019-09-22T15:45:34	{"omim": ["617563"], "synonyms": ["Alternative titles", "OFDS XVI", "ORAL-FACIAL-DIGITAL SYNDROME, TYPE XVI"]}
Maydl's hernia (Hernia-in-W) is a rare type of hernia and may be lethal if undiagnosed. The hernial sac contains two loops of bowel with another loop of bowel being intra-abdominal. A loop of bowel in the form of 'W lies in the hernial sac and the centre portion of the 'W loop may become strangulated, either alone or in combination with the bowel in the hernial sac.[1] It is more often seen in men, and predominantly on the right side. Maydl's hernia should be suspected in patients with large incarcerated herniae and in patients with evidence of intra-abdominal strangulation or peritonitis. Postural or manual reduction of the hernia is contra-indicated as it may result in non-viable bowel being missed.[2] It is named after Czech surgeon Karel Maydl.[3] ## References[edit] 1. ^ Publishers, Jaypee Brothers, Medical; Sriram Bhat M (2007). Srb's Manual of Surgery by Bhat. Jaypee Brothers Publishers. ISBN 978-81-8061-847-5. 2. ^ Ganesaratnam, M (September 1985). "Maydl's hernia: report of a series of seven cases and review of the literature". The British Journal of Surgery. 72 (9): 737–8. doi:10.1002/bjs.1800720922. PMID 4041736. 3. ^ "Maydl's hernia". Whonamedit?. Retrieved 2017-08-23. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Maydl's hernia	None	3,269	wikipedia	https://en.wikipedia.org/wiki/Maydl%27s_hernia	2021-01-18T19:03:33	{"wikidata": ["Q6797036"]}
Female foeticide in India (Hindi: भ्रूण हत्या, romanized: bhrūṇ-hatyā, lit. 'foeticide') is the abortion of a female foetus outside of legal methods. The natural sex ratio is assumed to be between 103 and 107, and any number above it is considered as suggestive of female foeticide. According to the decennial Indian census, the sex ratio in 0 to 6 age group in India has risen from 102.4 males per 100 females in 1961,[1] to 104.2 in 1980, to 107.5 in 2001, to 108.9 in 2011.[2] The child sex ratio is within the normal natural range in all eastern and southern states of India,[3] but significantly higher in certain western and particularly northwestern states such as Maharashtra, Haryana, Jammu & Kashmir (118, 120 and 116, as of 2011, respectively).[4] The western states of Maharashtra and Rajasthan 2011 census found a child sex ratio of 113, Gujarat at 112 and Uttar Pradesh at 111.[5] The Indian census data indicates that the sex ratio is poor when women have one or two children, but gets better as they have more children, which is result of sex-selective "stopping practices" (stopping having children based on sex of those born).[6] The Indian census data also suggests there is a positive correlation between abnormal sex ratio and better socio-economic status and literacy. This may be connected to the dowry system in India where dowry deaths occur when a girl is seen as a financial burden. Urban India has higher child sex ratio than rural India according to 1991, 2001 and 2011 Census data, implying higher prevalence of female foeticide in urban India. Similarly, child sex ratio greater than 115 boys per 100 girls is found in regions where the predominant majority is Hindu, Muslim, Sikh or Christian; furthermore "normal" child sex ratio of 104 to 106 boys per 100 girls are also found in regions where the predominant majority is Hindu, Muslim, Sikh or Christian. These data contradict any hypotheses that may suggest that sex selection is an archaic practice which takes place among uneducated, poor sections or particular religion of the Indian society.[4][7] There is an ongoing debate as to whether these high sex ratios are only caused by female foeticide or some of the higher ratio is explained by natural causes.[8] The Indian government has passed Pre-Conception and Pre-Natal Diagnostic Techniques Act (PCPNDT) in 1994 to ban and punish prenatal sex screening and female foeticide. It is currently illegal in India to determine or disclose sex of the foetus to anyone. However, there are concerns that PCPNDT Act has been poorly enforced by authorities.[9] ## Contents * 1 High sex ratio implication * 1.1 India's Son Preference Leads to High Sex Ratio * 2 Origin * 2.1 Magnitude estimates for female foeticide * 3 Reasons for female foeticide * 3.1 Cultural preference * 3.2 Disparate gendered access to resource * 3.2.1 Public goods provisions by female leaders (majority vs. minority spillover goods) * 3.3 Dowry system * 3.4 India's weak social security system * 4 Consequences of a declining sex ratio in Indian states * 4.1 Marriage Market and Importation of Brides * 4.2 Negative spillovers of pre-natal sex selection and female foeticide * 4.3 Empirical study on male/female child mortality * 5 Laws and regulations * 5.1 Laws passed in India to alleviate female foeticide * 5.2 Central and state government schemes to alleviate female foeticide and child mortality * 5.2.1 Select Schemes by the Central and State Governments * 6 Responds by others * 7 See also * 8 References * 9 External links ## High sex ratio implication[edit] One school of scholars suggest that any birth sex ratio of boys to girls that is outside of the normal 105-107 range, necessarily implies sex-selective abortion. These scholars[10] claim that both the sex ratio at birth and the population sex ratio are remarkably constant in human populations. Significant deviations in birth sex ratios from the normal range can only be explained by manipulation, that is sex-selective abortion.[11] In a widely cited article,[12] Amartya Sen compared the birth sex ratio in Europe (106) and United States (105+) with those in Asia (107+) and argued that the high sex ratios in East Asia, West Asia and South Asia may be due to excessive female mortality. Sen pointed to research that had shown that if men and women receive similar nutritional and medical attention and good health care then females have better survival rates, and it is the male which is the genetically fragile sex.[13] Sen estimated 'missing women' from extra women who would have survived in Asia if it had the same ratio of women to men as Europe and United States. According to Sen, the high birth sex ratio over decades, implies a female shortfall of 11% in Asia, or over 100 million women as missing from the 3 billion combined population of India, other South Asian countries, West Asia, North Africa and China. ### India's Son Preference Leads to High Sex Ratio[edit] There is a strong son preference in India and this leads to a high sex ratio prioritizing male lives over female lives.[14] This graph depicts a typical Indian family's indifference curves between wanting to have a daughter or a son. Most families find greater utility in having a son so the curves are higher up on the y axis. When having a female becomes more expensive (due to dowry prices, lack of financial return in the future, educational and health expenses) then the budget curve has to swing inward on the x axis. Even though the budget stays the same, it is relatively more expensive to have a girl than to have a boy. The substitution effect shows that people move from point A on the first indifference curve to point B on the second indifference curve. They move from an already low number of females due to social reasons to even fewer daughters than before due to the added financial liability of daughters being more expensive. The number of males grows and the contrasting increase and decrease in quantities results in a high sex ratio. This is based on the unitary model of the household where the household is seen as a single decision making entity under the same budget constraint.[15] However, the non-unitary model of households argues that people have different preferences in a family and are able to carry those out according to their level of bargaining power.[15] In India, the unitary model is more likely to occur because of the patriarchal society that prioritizes male opinion and bargaining power in the household. This is not to say that all households follow this model, but enough of them do that it results in a high sex ratio.[12] ## Origin[edit] Male to female sex ratio for India, based on its official census data, from 1941 through 2011. The data suggests the existence of high sex ratios before and after the arrival of ultrasound-based prenatal care and sex screening technologies in India. Female foeticide has been linked to the arrival, in the early 1990s, of affordable ultrasound technology and its widespread adoption in India. Obstetric ultrasonography, either transvaginally or transabdominally, checks for various markers of fetal sex. It can be performed at or after week 12 of pregnancy. At this point, 3⁄4 of fetal sexes can be correctly determined, according to a 2001 study.[16] Accuracy for males is approximately 50% and for females almost 100%. When performed after week 13 of pregnancy, ultrasonography gives an accurate result in almost 100% of cases.[16] Availability Ultrasound technology arrived in China and India in 1979, but its expansion was slower in India. Ultrasound sex discernment technologies were first introduced in major cities of India in 1980s, its use expanded in India's urban regions in 1990s, and became widespread in 2000s.[17] ### Magnitude estimates for female foeticide[edit] Estimates for female foeticide vary by scholar. One group estimates more than 10 million female foetuses may have been illegally aborted in India since 1990s, and 500,000 girls were being lost annually due to female foeticide.[18] MacPherson estimates that 100,000 abortions every year continue to be performed in India solely because the fetus is female.[19] ## Reasons for female foeticide[edit] Various theories have been proposed as possible reasons for sex-selective abortion. Culture is favored by some researchers,[20] while some favor disparate gender-biased access to resources.[19] Some demographers question whether sex-selective abortion or infanticide claims are accurate, because underreporting of female births may also explain high sex ratios.[21][22] Natural reasons may also explain some of the abnormal sex ratios.[8][23] Klasen and Wink suggest India and China's high sex ratios are primarily the result of sex-selective abortion.[11] ### Cultural preference[edit] One school of scholars suggest that female foeticide can be seen through history and cultural background. Generally, male babies were preferred because they provided manual labor and success the family lineage. The selective abortion of female fetuses is most common in areas where cultural norms value male children over female children for a variety of social and economic reasons.[24] A son is often preferred as an "asset" since he can earn and support the family; a daughter is a "liability" since she will be married off to another family, and so will not contribute financially to her parents. Female foeticide then, is a continuation in a different form, of a practice of female infanticide or withholding of postnatal health care for girls in certain households.[25] Furthermore, in some cultures sons are expected to take care of their parents in their old age.[26] These factors are complicated by the effect of diseases on child sex ratio, where communicable and noncommunicable diseases affect males and females differently.[25] ### Disparate gendered access to resource[edit] Some of the variation in birth sex ratios and implied female foeticide may be due to disparate access to resources. As MacPherson (2007) notes, there can be significant differences in gender violence and access to food, healthcare, immunizations between male and female children. This leads to high infant and childhood mortality among girls, which causes changes in sex ratio.[19] Disparate, gendered access to resources appears to be strongly linked to socioeconomic status. Specifically, poorer families are sometimes forced to ration food, with daughters typically receiving less priority than sons (Klasen and Wink 2003).[11] However, Klasen's 2001 study revealed that this practice is less common in the poorest families, but rises dramatically in the slightly less poor families.[11] Klasen and Wink's 2003 study suggests that this is “related to greater female economic independence and fewer cultural strictures among the poorest sections of the population.” In other words, the poorest families are typically less bound by cultural expectations and norms, and women tend to have more freedom to become family breadwinners out of necessity.[11] Lopez and Ruzikah (1983) found that, when given the same resources, women tend to outlive men at all stages of life after infancy. However, globally, resources are not always allocated equitably. Thus, some scholars argue that disparities in access to resources such as healthcare, education, and nutrition play at least a small role in the high sex ratios seen in some parts of the world.[11] #### Public goods provisions by female leaders (majority vs. minority spillover goods)[edit] Minority goods provided by female leaders in India help to alleviate some of the problems of disparate gendered access to resources for women.[27] Public goods are defined as non-excludable and non-rival, but India lacks a system of public goods and has many problems with access to clean water or roads.[28] Additionally, many of the "public goods" exclude females because families choose to prioritize their male children's access to those resources. In India, previous research has found that women leaders' invest in public goods that are more in line with female preferences, in particular water infrastructure, which leads to a reduction in time spent on domestic chores by adolescent girls.[27] This in turn results in more time for young girls to gain an education and increases their value to their families and to society so that they are more likely to give them access to resources in the future.[27] Minority groups, like women, are likely to provide minority or low spillover goods such as transfers, rations, and water connections, which only benefit other women. The majority of men do not find any benefit from these goods and are less likely to invest in them.[29] For example, in a study conducted by political scientists Chattopadhyay and Duflo, results show that in West Bengal women complain more about water and roads and the women politicians invest more in those issues. In Rajasthan, where women complain more often about drinking water, women politicians invest more in water and less in roads.[28] ### Dowry system[edit] Even though the Dowry System legally ended with the Dowry Prohibition Act of 1961, the impossibility of monitoring families and the prevalence of corruption have led to its continuance all over India.[30] A dowry is a payment from the bride's family to the groom's family at the time of marriage. It is often found in "socially stratified, monogamous societies that are economically complex and where women have a relatively small productive role".[31] Theoretically, marriage results in partners choosing the mate who best maximizes their utility and there is equal distribution of returns to both participants. The outcome is pareto optimal and reaches equilibrium when no one can be better off with any other partner or choosing not to marry. However, if both partners do not share an equal distribution of the returns then there must be a transfer of funds between them in order to reach efficiency.[31] In Indian society, the rise of economic growth has allowed men to work in "productive" jobs and gain an income, but many women are not afforded these opportunities. Therefore, women and their families have to compete for men and pay a dowry as a transaction payment to make up for the lack of productive inputs they bring into a marriage.[31] Dowries have been rising in India for the last six decades and increased 15 percent annually between 1921 and 1981.[32] Women are valued less in this partnership and therefore are asked to pay in order to gain the benefits a man brings. The power hierarchy and financial obligation created through this system help perpetuate acts like female foeticide and a high son preference. Additionally, the technological progress leading to sex selective abortions lowers the cost of discrimination and many people think that it is better to pay a "500 rupees now (abortion) instead of 50,000 rupees in the future (dowry).[31]" Furthermore, dowry-related expenses also extend well beyond marriage.[33] The bride's family is expected to bear the burden of high expenses for the groom. ### India's weak social security system[edit] Another reason for this male preference is based on the economic benefits of having a son and the costs of having a daughter. In India, there is a very limited social security system so parents look to their sons to ensure their futures and care for them in old age.[34] Daughters are liabilities because they have to leave to another family once they are married and cannot take care of their parents. Additionally, they do not contribute economically to the family wealth and are costly because of the dowry system.[12] People in India usually see men's work as "productive" and contributing the family, while the social perception of female labor does not have that connotation. This also ties to the fact that it is easier for men in India to get high paying jobs and provide financially for their families.[31] Women need increased access to education and economic resources in order to reach that level of gainful employment and change people's perceptions of daughters being financial liabilities. With this cost and benefit analysis, many families come to the conclusion that they must prioritize male children's lives over female lives in order to ensure their financial future. The traditional social security system in India is family centered, with the joint family of three generations living together and taking care of each other. ## Consequences of a declining sex ratio in Indian states[edit] 2011 Census sex ratio map for the states and Union Territories of India, boys per 100 girls in 0 to 1 age group.[35] This table gives information on the child sex ratio in major states in India throughout the years 1981, 1991, and 2001[36] The following table presents the child sex ratio data for India's states and union territories, according to 2011 Census of India for population count in the 0-1 age group.[37] The data suggests 18 states/UT had birth sex ratio higher than 107 implying excess males at birth and/or excess female mortalities after birth but before she reaches the age of 1, 13 states/UT had normal child sex ratios in the 0-1 age group, and 4 states/UT had birth sex ratio less than 103 implying excess females at birth and/or excess male mortalities after birth but before he reaches the age of 1. State / UT Boys (0-1 age) 2011 Census[37] Girls (0-1 age) 2011 Census[37] Sex ratio (Boys per 100 girls) India 10,633,298 9,677,936 109.9 Jammu and Kashmir 154,761 120,551 128.4 Haryana 254,326 212,408 119.7 Punjab 226,929 193,021 117.6 Uttarakhand 92,117 80,649 114.2 DELHI 135,801 118,896 114.2 Maharashtra 946,095 829,465 114.1 Lakashadweep 593 522 114.0 Rajasthan 722,108 635,198 113.7 Gujarat 510,124 450,743 113.2 Uttar Pradesh 1,844,947 1,655,612 111.4 Chandigarh 8,283 7,449 111.2 Daman and Diu 1,675 1,508 111.1 Bihar 1,057,050 957,907 110.3 Himchal Pradesh 53,261 48,574 109.6 Madhya Pradesh 733,148 677,139 108.3 Goa 9,868 9,171 107.6 Jharkhand 323,923 301,266 107.5 Manipur 22,852 21,326 107.2 Andhra Pradesh 626,538 588,309 106.5 Tamil Nadu 518,251 486,720 106.5 Odisha 345,960 324,949 106.5 Dadra and Nagar Haveli 3,181 3,013 105.6 Karnataka 478,346 455,299 105.1 West Bengal 658,033 624,760 105.0 Assam 280,888 267,962 104.8 Nagaland 17,103 16,361 104.5 Sikkim 3,905 3,744 104.3 Chhattisgarh 253,745 244,497 103.8 Tripura 28,650 27,625 103.7 Meghalaya 41,353 39,940 103.5 Arunachal Pradesh 11,799 11,430 103.2 Andaman and Nicobar Islands 2,727 2,651 102.9 Kerala 243,852 238,489 102.2 Puducherry 9,089 8,900 102.1 Mizoram 12,017 11,882 ### Marriage Market and Importation of Brides[edit] Classic economic theory views the market for marriage as one in which people bargain for a spouse who maximizes their utility gains from marriage.[38] In India, many of these bargains actually take place within the family and therefore individual utility is replaced by family utility. In this marriage market, men and their families are trying to maximize their utility, which creates a supply and demand for wives.[30] However, female foeticide and a high sex ratio have high implications for this market. Dharma Kumar, argues that, "Sex selection at conception will reduce the supply of women, they will become more valuable, and female children will be better cared for and will live longer".[39] In the graph, this is depicted by the leftward shift of the supply curve and the subsequent decrease in quantity of females from Q1 to Q2 and increase in their value from P1 to P2. However, this model does not work for the situation in India because it does not account for the common act of males importing brides from other regions.[40] A low supply of women results in men and their families trafficking women from other areas and leads to increased sexual violence and abuse against women and children, increased child marriages, and increased maternal deaths due to forced abortions and early marriages.[40] This ends up devaluing women instead of the presumed effect of increasing their value. In the graph, the supply of brides outside each village, locality, or region is depicted as 'supply foreign'. This foreign supply values the price of getting a wife at much cheaper than the first domestic price P1 and the second domestic price P2. Therefore, due to the decrease of women domestically due to sex selection and the low price of foreign women (because they are often bought as slaves or kidnapped), the resulting gap of imported women is from Q3 to Q4. Women act like imports in an international trade market if the import price is lower than the high price of domestic dowries with a low supply of women. The foreign price is lower than the market price and this results in even fewer domestic brides than without importation (Q3 instead of Q2). In turn, this creates a self-fulfilling cycle of limiting females domestically and continually importing them and there is no end to the cycle of female feticide if these acts can continue and importation is an option. The imported brides are known as "paros" and are treated like slaves because they have no cultural, regional, or familial ties to their husbands before being brought into their homes.[41] One of the field studies in Haryana revealed that more than 9000 married women are bought from other Indian states as imported brides.[42] This act also results in wife sharing and polyandry by family members in some areas of Haryana, Rajasthan, and Punjab, which maintains the gender imbalance if one family can make do with only one female.[39] For example, the polyandrous Toda of Nilgiri Hills in southern India practiced female infanticide in order to maintain a certain demographic imbalance.[39] ### Negative spillovers of pre-natal sex selection and female foeticide[edit] When families choose to partake in pre-natal sex selection through illegal ultrasounds or abortions, they impart a negative spillover on society. These include increased gender disparity, a high sex ratio, lives lost, lack of development, and abuse and violence against women and children.[14] Families do not often keep this spillover in mind and this results in sex selection and female foeticide, which hurts society as a whole.[43] ### Empirical study on male/female child mortality[edit] A study by Satish B. Agnihotri[44] infers the gender bias in India by studying the relationship between male and female infant and child mortality rates in the face of mortality as a whole looking like it is decreasing. Hypothetically, if males and females are identical, then there should be no difference in mortality rates and no gender gap. However, male and female children are perceived as psychologically and socially different so the equation relating mortality looks like this: MRf = a + bMRm. MRf is female child mortality, a is residual female mortality when male mortality is 0, the slope b shows the rate of decline in female mortality for a decline in male mortality, and MRm is male mortality. In India, the infant mortality equation for 1982-1997 was IMRf = 6.5 + 0.93 IMRm, which shows that there is a high level of residual female mortality and male mortality declines slightly faster than female mortality. The author then breaks down the information by states and rural or urban population. Many states, like Haryana, that are known for high levels of female mortality have slopes greater than 1, which seems counterintuitive. However, this actually goes to show that pre-natal selection may reduce the extent of infanticide or poor treatment of girls who are born. It has a substitution effect on the post-natal discrimination and replaces its effects instead of adding to it. Additionally, urban households usually have a high constant term and a low slope. This shows that simply reducing mortality may not result in a subsequent reduction of female mortality. This research goes to show the extent of gender discrimination in India and how this affects the high sex ratio. It is important to not only target mortality, but specifically female mortality if there is to be any change in gender disparities.[44] ## Laws and regulations[edit] A sign in an Indian hospital stating that prenatal sex determination is a crime. India passed its first abortion-related law, the so-called Medical Termination of Pregnancy Act of 1971, making abortion legal in most states, but specified legally acceptable reasons for abortion such as medical risk to mother and rape. The law also established physicians who can legally provide the procedure and the facilities where abortions can be performed, but did not anticipate female foeticide based on technology advances.[45] With increasing availability of sex screening technologies in India through the 1980s in urban India, and claims of its misuse, the Government of India passed the Pre-natal Diagnostic Techniques Act (PNDT) in 1994. This law was further amended into the Pre-Conception and Pre-natal Diagnostic Techniques (Regulation and Prevention of Misuse) (PCPNDT) Act in 2004 to deter and punish prenatal sex screening and female foeticide. However, there are concerns that PCPNDT Act has been poorly enforced by authorities.[9] The impact of Indian laws on female foeticide and its enforcement is unclear. United Nations Population Fund and India's National Human Rights Commission, in 2009, asked the Government of India to assess the impact of the law. The Public Health Foundation of India, an premier research organization in its 2010 report, claimed a lack of awareness about the Act in parts of India, inactive role of the Appropriate Authorities, ambiguity among some clinics that offer prenatal care services, and the role of a few medical practitioners in disregarding the law.[7] The Ministry of Health and Family Welfare of India has targeted education and media advertisements to reach clinics and medical professionals to increase awareness. The Indian Medical Association has undertaken efforts to prevent prenatal sex selection by giving its members Beti Bachao (save the daughter) badges during its meetings and conferences.[7][46] However, a recent study by Nandi and Deolalikar (2013) argues that the 1994 PNDT Act may have had a small impact by preventing 106,000 female foeticides over one decade.[47] According to a 2007 study by MacPherson, prenatal Diagnostic Techniques Act (PCPNDT Act) was highly publicized by NGOs and the government. Many of the ads used depicted abortion as violent, creating fear of abortion itself within the population. The ads focused on the religious and moral shame associated with abortion. MacPherson claims this media campaign was not effective because some perceived this as an attack on their character, leading to many becoming closed off, rather than opening a dialogue about the issue.[19] This emphasis on morality, claims MacPherson, increased fear and shame associated with all abortions, leading to an increase in unsafe abortions in India.[19] The government of India, in a 2011 report, has begun better educating all stakeholders about its MTP and PCPNDT laws. In its communication campaigns, it is clearing up public misconceptions by emphasizing that sex determination is illegal, but abortion is legal for certain medical conditions in India. The government is also supporting implementation of programs and initiatives that seek to reduce gender discrimination, including media campaign to address the underlying social causes of sex selection.[7][46] Given the dismal Child Sex Ratio in the country, and the Supreme Court directive of 2003 to State governments to enforce the law banning the use of sex determination technologies, the Ministry set up a National Inspection and Monitoring Committee (NIMC). Dr. Rattan Chand, Director (PNDT) was made the convenor of the NIMC. The NIMC under the guidance of Dr. Rattan Chand conducted raids in some of the districts in Maharashtra, Punjab, Haryana, Himachal Pradesh, Delhi and Gujarat. In April, it conducted raids on three clinics in Delhi. In its reports sent to the Chief Secretaries of the respective States, the committee observed that the Authorities had failed to monitor or supervise the registered clinics.[48] ### Laws passed in India to alleviate female foeticide[edit] Other Legislation Year Passed Goals Dowry Prohibition Act 1961 Prohibits families from taking a dowry, punishable with imprisonment Hindu Marriage Act 1955 Rules around marriage and divorce for Hindus Hindu Adoption and Maintenance Act 1956 Deals with the legal process of adopting children and the legal obligation to provide "maintenance" for other family members Immoral Traffic Prevention Act 1986 Stops sex trafficking and exploitation Equal Remuneration Act 1976 Prevents monetary discrimination between men and women in the workforce Female Infanticide Act 1870 Prevents female infanticide (Act passed in British India) Ban on ultrasound testing 1996 Bans prenatal sex determination Source:[49] ### Central and state government schemes to alleviate female foeticide and child mortality[edit] Other recent policy initiatives adopted by many states of India, claims Guilmoto,[50] attempt to address the assumed economic disadvantage of girls by offering support to girls and their parents. These policies provide conditional cash transfer and scholarships only available to girls, where payments to a girl and her parents are linked to each stage of her life, such as when she is born, completion of her childhood immunization, her joining school at grade 1, her completing school grades 6, 9 and 12, her marriage past age 21. Some states are offering higher pension benefits to parents who raise one or two girls. Different states of India have been experimenting with various innovations in their girl-driven welfare policies. For example, the state of Delhi adopted a pro-girl policy initiative (locally called Laadli scheme), which initial data suggests may be lowering the birth sex ratio in the state.[50][51] These types of government programs and schemes are a type of redistribution in an attempt to further development in the country. The central and state governments in India have noticed the country's failure to deal with female foeticide on its own and have come up with programs to deal with the problem at hand. A serious flaw that makes all of these programs ineffective is that they target only lower-income households, while ignoring the population of higher-income households also partaking in female foeticide. Sex determination tests and sex selective abortions are prevalent more amongst affluent families.[52] For example, upper-class families in Haryana have high rates of foeticide and infanticide and the programs do not target these families.[52] A study in Haryana found that the sex ratio at birth for upper caste women was 127 males for 100 females, compared with 105 with lower caste women.[52] While cash transfers successfully improve school enrollment and immunization rates for girls, they do not directly address parent's demand for sons and gender-biased sex selection. Additionally, a study conducted by Bijayalaxmi Nanda, an associate professor of political science at Delhi University, found that many of the beneficiaries of the Delhi Ladli Scheme wanted to use the money received for marriage rather than educational expenses.[53] Another problem with these government conditional cash transfers is that many of them only target the first two daughters in a family and have no incentive for families to have more than two daughters. These non-linear incentive models do not result in the same increase in benefits as the inputs and cash transfers put in by the government.[54] Additionally, they only incentivize a change in behavior until an age, educational, number of daughters threshold and do not prompt people to act beyond these guidelines. #### Select Schemes by the Central and State Governments[edit] Program Year Passed Central or State Government Benefits Balika Samriddhi Yojana 1997 Central Government Cash transfer to mother based on child meeting educational conditions and partaking in income generating activities Dhan Laxmi Scheme 2008 Central Government Cash transfers to family after meeting conditions (immunization, education, insurance) Kanya Jagriti Jyoti Scheme 1996 Punjab Cash transfers to 2 girl children in a family after meeting conditions (immunization, education, insurance) Beti Bachao, Beti Padhao Yojana 2015 Central Government Cash transfers based on educational attainment National Plan of Action 1992 Central Government For the survival, protection, and development of girl children. Goals include ending female feticide, reducing gender disparity, and giving girls better access to resources Devirupak 2002 Haryana Cash transfer to couple accepting terminal method of family planning (vasectomy, tubectomy) after birth of 1st or 2nd child Delhi Ladli Scheme 2008 Delhi Cash transfer based on educational attainment for first 2 daughters Apni Beti Apna Dhan 1994 Haryana Cash transfer if daughter reaches the age of 18 without being married Girl Child Protection Scheme 2005 Andhra Pradesh Cash transfer based on age and educational attainment. Family also has to partake in family planning Beti Hai Anmol Scheme 2010 Himachal Pradesh Interest earned on back account in daughter's name and cash scholarships for each year of school Bhagya Laxmi Scheme 2007 Karnataka Cash transfer based on age and educational attainment. Cash provided to families for natural death, health insurance, and scholarships Mukhyamantri Kanya Suraksha Yojna and Mukhyamantri Kanya Vivah Yojna 2008 Bihar Cash transfers to poor families with two daughters Indra Gandhi Balika Suraksha Yojana 2007 Himachal Pradesh Cash transfers based on age attainment Ladli Laxami Yojna 2006 Madhya Pradesh, Jharkhand Cash transfers based on educational attainment Rakshak Yojana 2005 Punjab Cash monthly transfers for families with 2 girls Mukhyamantri Kanyadan Yojna 2017 Madhya Pradesh Cash transfer for marriage assistance if the family waits until the legal age to marry off their daughter Sukanya Samriddhi Account 2015 Central Government Interest earned on bank account opened for daughter after she turns 21 Source:[55] ## Responds by others[edit] Increasing awareness of the problem has led to multiple campaigns by celebrities and journalists to combat sex-selective abortions. Aamir Khan devoted the first episode "Daughters Are Precious" of his show Satyamev Jayate to raise awareness of this widespread practice, focusing primarily on Western Rajasthan, which is known to be one of the areas where this practice is common. Its sex ratio dropped to 883 girls per 1,000 boys in 2011 from 901 girls to 1000 boys in 2001. Rapid response was shown by local government in Rajasthan after the airing of this show, showing the effect of media and nationwide awareness on the issue. A vow was made by officials to set up fast-track courts to punish those who practice sex-based abortion. They cancelled the licences of six sonography centres and issued notices to over 20 others.[56] This has been done on the smaller scale. Cultural intervention has been addressed through theatre. Plays such as 'Pacha Mannu', which is about female infanticide/foeticide, has been produced by a women's theatre group in Tamil Nadu. This play was showing mostly in communities that practice female infanticide/foeticide and has led to a redefinition of a methodology of consciousness raising, opening up varied ways of understanding and subverting cultural expressions.[57] The Mumbai High Court ruled that prenatal sex determination implied female foeticide. Sex determination violated a woman's right to live and was against India's Constitution.[9] The Beti Bachao, or Save girls campaign, has been underway in many Indian communities since the early 2000s. The campaign uses the media to raise awareness of the gender disparities creating, and resulting from, sex-selective abortion. Beti Bachao activities include rallies, posters, short videos and television commercials, some of which are sponsored by state and local governments and other organisations. Many celebrities in India have publicly supported the Beti Bachao campaign.[citation needed] ## See also[edit] India specific * Domestic violence in India * Dowry system in India * Feminism in India * Gender inequality in India * Gender pay gap in India * Men's rights movement in India * National Commission for Women * Pre-Conception and Pre-Natal Diagnostic Techniques Act, 1994 * Rape in India * Sexism in India * Welfare schemes for women in India * Women in agriculture in India * Women in India * Women in Indian Armed Forces * Women's Reservation Bill * Women's suffrage in India Other related * Sex-selective abortion * Bride burning * Foeticide * Gendercide * Sex selection * Sex Selective Abortions * Prenatal sex discernment * Bride buying * Intra-household bargaining ## References[edit] 1. ^ Data Highlights - 2001 Census Census Bureau, Government of India 2. ^ India at Glance - Population Census 2011 - Final Census of India, Government of India (2013) 3. ^ Census of India 2011: Child sex ratio drops to lowest since Independence The Economic Times, India 4. ^ a b Child Sex Ratio in India Archived 2013-12-03 at the Wayback Machine C Chandramouli, Registrar General & Census Commissioner, India (2011) 5. ^ Child Sex Ratio 2001 versus 2011 Census of India, Government of India (2013) 6. ^ "Sex ratio worsens in small families, improves with 3 or more children \| India News". The Times of India. 7. ^ a b c d IMPLEMENTATION OF THE PCPNDT ACT IN INDIA - Perspectives and Challenges Public Health Foundation of India, Supported by United Nations FPA (2010) 8. ^ a b James W.H. (July 2008). "Hypothesis:Evidence that Mammalian Sex Ratios at birth are partially controlled by parental hormonal levels around the time of conception". Journal of Endocrinology. 198 (1): 3–15. doi:10.1677/JOE-07-0446. PMID 18577567. 9. ^ a b c "UNICEF India". UNICEF. 10. ^ Therese Hesketh and Zhu Wei Xing, Abnormal sex ratios in human populations: Causes and consequences, PNAS, September 5, 2006, vol. 103, no. 36, pp 13271-13275 11. ^ a b c d e f Klausen Stephan; Wink Claudia (2003). "Missing Women: Revisiting the Debate". Feminist Economics. 9 (2–3): 263–299. doi:10.1080/1354570022000077999. S2CID 154492092. 12. ^ a b c Sen, Amartya (1990), More than 100 million women are missing, New York Review of Books, 20 December, pp. 61–66 13. ^ Kraemer, Sebastian. "The Fragile Male." British Medical Journal (2000): n. pag. British Medical Journal. Web. 20 Oct. 2013. 14. ^ a b Sen, Amartya (2001). "The Many Faces of Gender Inequality". The New Republic: 35–39. 15. ^ a b Donni, Olivier (2011). "Economic Approaches to Household Behavior: From the Unitary Model to Collective Decisions". Work, Gender, and Societies. 26: 67–83. 16. ^ a b Mazza V, Falcinelli C, Paganelli S, et al. (June 2001). "Sonographic early fetal gender assignment: a longitudinal study in pregnancies after in vitro fertilization". Ultrasound Obstet Gynecol. 17 (6): 513–6. doi:10.1046/j.1469-0705.2001.00421.x. PMID 11422974. 17. ^ Mevlude Akbulut-Yuksel and Daniel Rosenblum (January 2012), The Indian Ultrasound Paradox, IZA DP No. 6273, Forschungsinstitut zur Zukunft der Arbeit, Bonn, Germany 18. ^ "BBC NEWS - South Asia - India 'loses 10m female births'". bbc.co.uk. 2006-01-09. 19. ^ a b c d e MacPherson, Yvonne (November 2007). "Images and Icons: Harnessing the Power of Media to Reduce Sex-Selective Abortion in India". Gender and Development. 15 (2): 413–23. doi:10.1080/13552070701630574. 20. ^ A. Gettis, J. Getis, and J. D. Fellmann (2004). Introduction to Geography, Ninth Edition. New York: McGraw-Hill. pp. 200. ISBN 0-07-252183-X 21. ^ Johansson, Sten; Nygren, Olga (1991). "The missing girls of China: a new demographic account". Population and Development Review. 17 (1): 35–51. doi:10.2307/1972351. JSTOR 1972351. 22. ^ Merli, M. Giovanna; Raftery, Adrian E. (2000). "Are births underreported in rural China?". Demography. 37 (1): 109–126. doi:10.2307/2648100. JSTOR 2648100. PMID 10748993. S2CID 41085573. 23. ^ R. Jacobsen, H. Møller and A. Mouritsen, Natural variation in the human sex ratio, Hum. Reprod. (1999) 14 (12), pp 3120-3125 24. ^ Goodkind, Daniel (1999). "Should Prenatal Sex Selection be Restricted?: Ethical Questions and Their Implications for Research and Policy". Population Studies 53 (1): 49–61 25. ^ a b Das Gupta, Monica, "Explaining Asia's Missing Women": A New Look at the Data", 2005 26. ^ Mahalingam, R. (2007). "Culture, ecology, and beliefs about gender in son preference caste groups". Evolution and Human Behavior. 28 (5): 319–329. doi:10.1016/j.evolhumbehav.2007.01.004. 27. ^ a b c Beaman, Lori; Duflo, Esther; Pande, Rohini; Topalova, Petia (2012-02-03). "Female Leadership Raises Aspirations and Educational Attainment for Girls: A Policy Experiment in India". Science. 335 (6068): 582–586. doi:10.1126/science.1212382. PMC 3394179. PMID 22245740. 28. ^ a b "Women as Policy Makers: Evidence from a Randomized Policy Experiment in India". Gender Action Portal. Retrieved 2018-03-05. 29. ^ Duflo, Esther (2004). "Unappreciated service: performance, perceptions, and women: leaders in India" (PDF). Massachusetts Institute of Technology (MIT): Department of Economics. 30. ^ a b Jaggi, Tonushree (2001). "The Economics of Dowry: Causes and Effects of an Indian Tradition". University Avenue Undergraduate Journal of Economics. 5: 1–18. 31. ^ a b c d e Anderson, Siwan (Fall 2007). "The Economics of Dowry and Brideprice". Journal of Economic Perspectives. 21 (4): 151–174. doi:10.1257/jep.21.4.151. ISSN 0895-3309. S2CID 13722006. 32. ^ (PSC), Michigan Population Studies Center. "Rao: The Rising Price of Husbands: A Hedonic Analysis of Dowry Increases in Rural India". www.psc.isr.umich.edu. Retrieved 2018-03-05. 33. ^ Unnithan-Kumar, Maya (February 2010). "Female selective abortion - beyond 'culture': family making and gender inequality in a globalising India". Culture, Health & Sexuality. 12 (2): 153–166. doi:10.1080/13691050902825290. PMID 19437177. S2CID 39414131. 34. ^ Sen, Amartya (1990-12-20). "More Than 100 Million Women Are Missing". The New York Review of Books. ISSN 0028-7504. Retrieved 2018-03-05. 35. ^ Age Data C13 Table (India/States/UTs ) Final Population - 2011 Census of India, Ministry of Home Affairs, Government of India (2013) 36. ^ Gupta, Monica Das; Chung, Woojin; Shuzhuo, Li (2009-06-01). "Evidence for an Incipient Decline in Numbers of Missing Girls in China and India". Population and Development Review. 35 (2): 401–416. doi:10.1111/j.1728-4457.2009.00285.x. ISSN 1728-4457. 37. ^ a b c Age Data - Single Year Age Data - C13 Table (India/States/UTs ) Population Enumeration Data (Final Population) - 2011, Census of India, Ministry of Home Affairs, Government of India 38. ^ "A Treatise on the Family — Gary S. Becker \| Harvard University Press". www.hup.harvard.edu. Retrieved 2018-03-05. 39. ^ a b c Dube, Leela (1983). "Misadventures in Amniocentesis". Economic and Political Weekly. 18. 40. ^ a b "Female foeticide in India \| UNICEF". unicef.in. Retrieved 2018-03-05. 41. ^ Pandey, Sanjay. "Female foeticide, India's 'ticking bomb'". www.aljazeera.com. Retrieved 2018-03-05. 42. ^ Alston, Margaret (2014). Women, Political Struggles and Gender Equality in South Asia. Palgrave MacMillan. ISBN 978-1-137-39057-8. 43. ^ Ayres, Robert U.; Kneese, Allen V. (1969). "Production, Consumption, and Externalities". The American Economic Review. 59 (3): 282–297. JSTOR 1808958. 44. ^ a b Agnihotri, Satish (January 2001). "Declining Infant and Child Mortality in India: How Do Girl Children Fare?". Economic and Political Weekly. 36 (3): 228–233. JSTOR 4410198. 45. ^ "Medical Termination of Pregnancy Act 1971 - Introduction." Health News RSS. Med India, n.d. Web. 20 Oct. 2013. 46. ^ a b MTP and PCPNDT Initiatives Report Government of India (2011) 47. ^ Nandi, A.; Deolalikar, A. B. (2013). "Does a legal ban on sex-selective abortions improve child sex ratios? Evidence from a policy change in India". Journal of Development Economics. 103: 216–228. doi:10.1016/j.jdeveco.2013.02.007. 48. ^ Small gain for the girl child Front Line 49. ^ Tandon, Sneh (2006). "Female Foeticide and Infanticide in India: An Analysis of Crimes against Girl Children" (PDF). International Journal of Criminal Justice Sciences. 1. 50. ^ a b Christophe Z Guilmoto, Sex imbalances at birth Trends, consequences and policy implications United Nations Population Fund, Hanoi (October 2011) 51. ^ Delhi Laadli scheme 2008 Government of Delhi, India 52. ^ a b c Miller, B. D. (December 2001). "Female-selective abortion in Asia: patterns, policies, and debates". American Anthropologist. 103 (4): 1083–1095. doi:10.1525/aa.2001.103.4.1083. ISSN 0002-7294. PMID 12769123. 53. ^ "Government scheme to save girls in womb a flop: Study". India Today. 2011-12-28. Retrieved 2018-03-05. 54. ^ Brody, Samuel (2010). "Non-linear incentives, plan design, and flood mitigation: the case of the Federal Emergency Management Agency's community rating system". Journal of Environmental Planning and Management. 53 (2): 219–239. doi:10.1080/09640560903529410. S2CID 1634492. 55. ^ Sekher, T.V. (2010). "Special Financial Incentive Schemes for the Girl Child in India: A Review of Select Schemes" (PDF). International Institute for Population Sciences. 56. ^ Helen Pidd. "Indian campaign confronts prevalence of female foeticide". the Guardian. 57. ^ A. Mangai, "Cultural Intervention through Theatre: Case Study of a Play on Female Infanticide/Foeticide," Economic and Political Weekly, Vol. 33, No. 44 (Oct. 31 - Nov. 6, 1998), pp. WS70-WS72 https://www.jstor.org/stable/4407327 ## External links[edit] * UNICEF India * Female Foeticide in India: A Serious Challenge for the Society * Documentaries on Female Foeticide * Disappearing Daughters * Amartya Sen- More Than 100 Million Missing Women * Registrar General of India * v * t * e Social issues in India Economy * Communications * Famine * Farmers' suicides * Labour * Land reforms * Debt bondage * National Pension System * Poverty * BPL * Public distribution system * Remittances * Slums * Clearance * Standard of living * Street vendors * Transport * Urbanisation * Unemployment * Widening income gap Education * Literacy * Ragging Environment * Conservation * Climate change * Manual scavenging * Natural disasters * Water supply and sanitation * Water disputes Family * Cohabitation * Domestic violence * Dowry system * Family planning * Hindu joint family * Infertility * Nuclear family * Polyandry * Polygamy Children * Abortion * Child labour * Child marriage * Child prostitution * Child trafficking * Female foeticide * Female infanticide * Street children Women * Acid attack * Bride burning * Devadasi * Dowry death * Eve teasing * Women's health * Feminism * Menstrual taboo * Prostitution * Rape * Sati * Sexism Caste system * Caste politics * Caste-related violence * Dalit * Reservation Communalism * Proposed states and territories * Ethnic relations * Religious violence * Secularism * Separatist movements Crime * Corruption * Groom kidnapping * Human trafficking * Illegal housing * Illegal immigration * Illegal mining * Organised crime * Terrorism * Vigilantism * Cybercrime Health * Diabetes * Epidemics * HIV/AIDS * Leprosy * Malnutrition * Obesity * Suicide * Tuberculosis Media * Censorship * Internet * Films about social issues * Freedom of expression * Social impact of Indian soap opera * Fake news Other issues * Colourism * Feudalism * Gambling * Sexuality * LGBT * Homosexuality * Hijra * Human rights * Prohibition * Superstitions [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Female foeticide in India	None	3,270	wikipedia	https://en.wikipedia.org/wiki/Female_foeticide_in_India	2021-01-18T19:06:27	{"wikidata": ["Q5442759"]}
2q23.1 microdeletion syndrome is a rare chromosome disorder. Symptoms may include seizures, moderate to severe learning problems, speech delays, behavior problems, trouble sleeping, and developmental delays (learn to crawl, sit or walk later than other babies). Children affected by 2q23.1 microdeletion syndrome may also have low muscle tone (hypotonia), slow weight gain, and may be shorter than family members. 2q23.1 deletion syndrome is caused by the loss of a small piece of DNA in one copy of chromosome 2, one of the 23 pairs of chromosomes in each cell in our bodies. Most cases of 2q23.1 deletion syndrome are de novo, which means the deletion was not passed down from either parent. Diagnosis of 2q23.1 microdeletion syndrome may be suspected by symptoms but is confirmed by genetic testing. Treatment is based on the signs and symptoms of each person and may include seizure medication, speech therapy, behavior therapy, physical, and occupational therapy, and special education programs. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	2q23.1 microdeletion syndrome	c4304532	3,271	gard	https://rarediseases.info.nih.gov/diseases/10998/2q231-microdeletion-syndrome	2021-01-18T18:02:25	{"orphanet": ["228402"], "synonyms": ["Chromosome 2q23.1 microdeletion syndrome", "Monosomy 2q23.1", "Del(2)(q23.1)", "Pseudo-Angelman syndrome"]}
A bifid nose is a relatively uncommon malformation that is characterized by the nose being divided into two parts. There is a large degree of variability in the severity of the condition, ranging from a minimally noticeable groove down the center of the nasal tip to a complete clefting of the underlying bones and cartilage, resulting in 2 complete half noses. It is often associated with hypertelorbitism and midline clefts of the lip. The airway usually is adequate despite the cosmetic appearance associated with the condition. Both autosomal recessive and autosomal dominant inheritance of a bifid nose has been observed. It may also occur with frontonasal dysplasia (a condition in with several possible findings limited to the head and neck), for which several inheritance patterns have been reported. Treatment typically consists of surgical reconstruction to repair the malformation. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Bifid nose	c0221363	3,272	gard	https://rarediseases.info.nih.gov/diseases/884/bifid-nose	2021-01-18T18:01:48	{"mesh": ["C535441"], "omim": ["210400", "109740", "608980"], "umls": ["C0221363"], "orphanet": ["2695"], "synonyms": ["Median fissure of nose", "Nose, median cleft of"]}
A rare disorder of lipid metabolism characterized by childhood onset of steatorrhea due to isolated pancreatic colipase deficiency, while other exocrine pancreatic enzymes are normal. Early formation of gallstones, as well as vitamin B12 deficiency with megaloblastic anemia have also been reported. There have been no further descriptions in the literature since 1982. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Pancreatic colipase deficiency	c0268241	3,273	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=309108	2021-01-23T18:04:00	{"omim": ["614338"], "umls": ["C0268241"], "icd-10": ["K90.3"]}
Metaphyseal chondromatosis with D-2-hydroxyglutaric aciduria is an extremely rare genetic disorder characterized by the unique association of enchondromatosis with D-2 hydroxyglutaric aciduria (see these terms). Clinical features include enchondromatosis (with short stature, severe metaphyseal dysplasia and mild vertebral involvement), elevated levels of urinary 2-hydroxyglutaric acid and mild developmental delay. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Metaphyseal chondromatosis with D-2-hydroxyglutaric aciduria	c3553958	3,274	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=99646	2021-01-23T17:36:21	{"omim": ["614875"]}
Myelolipoma An adrenal myelolipoma SpecialtyOncology Myelolipoma (myelo-, from the ancient greek μυελός, marrow; lipo, meaning of, or pertaining to, fat; -oma, meaning tumor or mass) is a benign tumor-like lesion composed of mature adipose (fat) tissue and haematopoietic (blood-forming) elements in various proportions.[1] Myelolipomas can present in the adrenal gland,[2] or outside of the gland.[3] ## Contents * 1 Symptoms and signs * 2 Causes * 3 Pathology * 3.1 Macroscopic features * 3.2 Microscopic features * 4 Diagnosis * 5 Treatment * 6 Epidemiology * 7 References * 8 External links ## Symptoms and signs[edit] The majority of myelolipomas are asymptomatic. Most do not produce any adrenal hormones. Most are only discovered as a result of investigation for another problem.[4] When myelolipomas do produce symptoms, it is usually because they have become large, and are pressing on other organs or tissues nearby. Symptoms include pain in the abdomen or flank, blood in the urine, a palpable lump or high blood pressure.[1] As they are benign tumors, myelolipomas do not spread to other body parts. Larger myelolipomas are at risk of localised tissue death and bleeding, which may cause a retroperitoneal haemorrhage.[1] ## Causes[edit] Although several hypotheses have been proposed as to the cause of myelolipoma, the causative process is still not clearly understood.[5] Recent experimental evidence suggests that both the myeloid and lipomatous elements have a monoclonal origin, which strongly supports the hypothesis that myelolipomas are neoplastic lesions.[5] Older theories proposing a non-neoplastic origin include the following: * Adrenal cortical cells, or other cells within the stroma of the adrenal cortex that are able to differentiate, may reversibly change into fat or blood-forming cells. This might occur because of the actions of adrenal cortex hormones, or of hormones released by the pituitary gland that act on the adrenal glands, such as adrenocorticotropic hormone (ACTH).[6] * The blood-forming cells may arise by differentiation of cells within the capillaries of the adrenal gland.[4] * Myelolipoma simply represents a site of normal blood formation outside the bone marrow.[4] ## Pathology[edit] ### Macroscopic features[edit] Myelolipomas are usually found to occur alone in one adrenal gland, but not both. They can vary widely in size, from as small as a few millimetres to as large as 34 centimeters in diameter. The cut surface has colours varying from yellow to red to mahogany brown, depending on the distribution of fat, blood, and blood-forming cells. The cut surface of larger myelolipomas may contain haemorrhage or infarction.[1] * A macroscopic photograph of an adrenal myelolipoma. A remnant of the adrenal gland can be seen at the top * The cut surface shows colour variegation from yellow to red to brown depending on the distribution of fat, blood and myeloid elements ### Microscopic features[edit] The microscopic view of a myelolipoma shows the presence of normal adrenal cells, fat (adipose) cells, and the three lineages of the myeloid precursors The typical microscopic features of myelolipomas are shown in the image. There is a mixture of normal adrenal tissue, fat, and a full trilineage maturation of the three major blood-forming elements: myeloid (white blood cell forming), erythroid (red blood cell forming), and megakaryocytic (platelet forming) lines.[1] ## Diagnosis[edit] Myeloplipoma shown on a CT scan image Most myelolipomas are unexpected findings on CT scans and MRI scans of the abdomen. They may sometimes be seen on a plain X-ray films.[4] Fine needle aspiration may be performed to obtain cells for microscopic diagnosis.[1] ## Treatment[edit] Small myelolipomas generally do not produce symptoms, and do not require treatment. Ongoing surveillance of these lesions by a doctor is recommended. Surgical excision (removal) is recommended for large myelolipomas because of the risk of bleeding complications.[6] ## Epidemiology[edit] Incidences and prognoses of adrenal tumors,[7] with myelolipoma at right. Myelolipomas are rare. They have been reported to be found unexpectedly at autopsy in 0.08% to 0.4% of cases (i.e.: somewhere between 8 per 10,000 and 4 per 1,000 autopsies). They most commonly occur in the adrenal gland, and comprise about 8% of all adrenal tumours.[8] They may also occur in other sites, such as the mediastinum, the liver and the gastrointestinal tract.[1] There is no gender predilection, males and females are affected equally. The peak age range at diagnosis is between 40 and 79 years of age.[1] ## References[edit] 1. ^ a b c d e f g h Thompson, LDR (2006). Endocrine Pathology. Foundations in Diagnostic Pathology. ISBN 978-0-443-06685-6. 2. ^ Ong K, Tan KB, Putti TC (July 2007). "Myelolipoma within a non-functional adrenal cortical adenoma" (PDF). Singapore Med J. 48 (7): e200–2. PMID 17609815. 3. ^ Zieker D, Königsrainer I, Miller S, et al. (2008). "Simultaneous adrenal and extra-adrenal myelolipoma — an uncommon incident: case report and review of the literature". World J Surg Oncol. 6: 72. doi:10.1186/1477-7819-6-72. PMC 2474838. PMID 18601731. 4. ^ a b c d Ramchandani, P. Adrenal Myelolipoma Imaging at eMedicine 5. ^ a b McNicol AM (Winter 2008). "A diagnostic approach to adrenal cortical lesions". Endocr Pathol. 19 (4): 241–251. doi:10.1007/s12022-008-9055-x. PMID 19089656. 6. ^ a b Olobatuyi FA, Maclennan GT (September 2006). "Myelolipoma". J Urol. 176 (3): 1188. doi:10.1016/j.juro.2006.06.095. PMID 16890722. 7. ^ Data and references for pie chart are located at file description page in Wikimedia Commons. 8. ^ Mantero, Franco; Albiger, Nora (2004). "A comprehensive approach to adrenal incidentalomas". Arquivos Brasileiros de Endocrinologia & Metabologia. 48 (5): 583–591. doi:10.1590/S0004-27302004000500003. ISSN 0004-2730. ## External links[edit] Classification D * ICD-10: D17 * ICD-O: M8870/0 * MeSH: D018209 External resources * eMedicine: radiology/genitourinary/376700 * v * t * e Connective/soft tissue tumors and sarcomas Not otherwise specified * Soft-tissue sarcoma * Desmoplastic small-round-cell tumor Connective tissue neoplasm Fibromatous Fibroma/fibrosarcoma: * Dermatofibrosarcoma protuberans * Desmoplastic fibroma Fibroma/fibromatosis: * Aggressive infantile fibromatosis * Aponeurotic fibroma * Collagenous fibroma * Diffuse infantile fibromatosis * Familial myxovascular fibromas * Fibroma of tendon sheath * Fibromatosis colli * Infantile digital fibromatosis * Juvenile hyaline fibromatosis * Plantar fibromatosis * Pleomorphic fibroma * Oral submucous fibrosis Histiocytoma/histiocytic sarcoma: * Benign fibrous histiocytoma * Malignant fibrous histiocytoma * Atypical fibroxanthoma * Solitary fibrous tumor Myxomatous * Myxoma/myxosarcoma * Cutaneous myxoma * Superficial acral fibromyxoma * Angiomyxoma * Ossifying fibromyxoid tumour Fibroepithelial * Brenner tumour * Fibroadenoma * Phyllodes tumor Synovial-like * Synovial sarcoma * Clear-cell sarcoma Lipomatous * Lipoma/liposarcoma * Myelolipoma * Myxoid liposarcoma * PEComa * Angiomyolipoma * Chondroid lipoma * Intradermal spindle cell lipoma * Pleomorphic lipoma * Lipoblastomatosis * Spindle cell lipoma * Hibernoma Myomatous general: * Myoma/myosarcoma smooth muscle: * Leiomyoma/leiomyosarcoma skeletal muscle: * Rhabdomyoma/rhabdomyosarcoma: Embryonal rhabdomyosarcoma * Sarcoma botryoides * Alveolar rhabdomyosarcoma * Leiomyoma * Angioleiomyoma * Angiolipoleiomyoma * Genital leiomyoma * Leiomyosarcoma * Multiple cutaneous and uterine leiomyomatosis syndrome * Multiple cutaneous leiomyoma * Neural fibrolipoma * Solitary cutaneous leiomyoma * STUMP Complex mixed and stromal * Adenomyoma * Pleomorphic adenoma * Mixed Müllerian tumor * Mesoblastic nephroma * Wilms' tumor * Malignant rhabdoid tumour * Clear-cell sarcoma of the kidney * Hepatoblastoma * Pancreatoblastoma * Carcinosarcoma Mesothelial * Mesothelioma * Adenomatoid tumor * v * t * e Tumours of endocrine glands Pancreas * Pancreatic cancer * Pancreatic neuroendocrine tumor * α: Glucagonoma * β: Insulinoma * δ: Somatostatinoma * G: Gastrinoma * VIPoma Pituitary * Pituitary adenoma: Prolactinoma * ACTH-secreting pituitary adenoma * GH-secreting pituitary adenoma * Craniopharyngioma * Pituicytoma Thyroid * Thyroid cancer (malignant): epithelial-cell carcinoma * Papillary * Follicular/Hurthle cell * Parafollicular cell * Medullary * Anaplastic * Lymphoma * Squamous-cell carcinoma * Benign * Thyroid adenoma * Struma ovarii Adrenal tumor * Cortex * Adrenocortical adenoma * Adrenocortical carcinoma * Medulla * Pheochromocytoma * Neuroblastoma * Paraganglioma Parathyroid * Parathyroid neoplasm * Adenoma * Carcinoma Pineal gland * Pinealoma * Pinealoblastoma * Pineocytoma MEN * 1 * 2A * 2B [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Myelolipoma	c0206635	3,275	wikipedia	https://en.wikipedia.org/wiki/Myelolipoma	2021-01-18T18:33:00	{"mesh": ["D018209"], "umls": ["C0206635"], "icd-10": ["D17"], "wikidata": ["Q1956552"]}
Coolie itch SpecialtyDermatology Coolie itch is a cutaneous condition caused by Rhizoglyphus parasiticus, characterized by an intense pruritus. It is found in India on tea plantations and causes sore feet.[1]:454 Rhizoglyphus parasiticus is a type of mite.[2] ## See also[edit] * Copra itch * Skin lesion ## References[edit] 1. ^ James, William D.; Berger, Timothy G.; et al. (2006). Andrews' Diseases of the Skin: clinical Dermatology. Saunders Elsevier. ISBN 0-7216-2921-0. 2. ^ Alan B. Fleischer (15 January 2000). The clinical management of itching. Informa Health Care. pp. 62–. ISBN 978-1-85070-779-0. Retrieved 30 April 2010. * v * t * e Arthropods and ectoparasite-borne diseases and infestations Insecta Louse * Body louse (pediculosis corporis) / Head louse (head lice infestation) * Crab louse (phthiriasis) Hemiptera * Bed bug (cimicosis) Fly * Dermatobia hominis / Cordylobia anthropophaga / Cochliomyia hominivorax (myiasis) * Mosquito (mosquito-borne disease) Flea * Tunga penetrans (tungiasis) Crustacea Pentastomida * Linguatula serrata (linguatulosis) * Porocephalus crotali / Armillifer armillatus (porocephaliasis) * For ticks and mites, see Template:Tick and mite-borne diseases and infestations This infection-related cutaneous condition article is a stub. You can help Wikipedia by expanding it. * v * t * e [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Coolie itch	None	3,276	wikipedia	https://en.wikipedia.org/wiki/Coolie_itch	2021-01-18T18:57:17	{"wikidata": ["Q4036526"]}
For a discussion of genetic heterogeneity of quantitative trait loci for stature (STQTL), see STQTL1 (606255). Mapping Hirschhorn et al. (2001) analyzed genomewide scans in 4 populations using a variance-components method, using stature as a quantitative trait locus, and found strong evidence for linkage to chromosome 13q32-q33 in a Finnish population (maximum lod = 3.36 at markers D13S779-D13S797, p less than 0.05). [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	STATURE QUANTITATIVE TRAIT LOCUS 4	c1853474	3,277	omim	https://www.omim.org/entry/606258	2019-09-22T16:10:31	{"omim": ["606258"]}
## Description The electrocardiographic (ECG) QT interval, a measure of cardiac repolarization, is a genetically influenced quantitative trait with estimated heritability of approximately 30% (Arking et al., 2006). Very long or short QT intervals occur in a heterogeneous collection of mendelian disorders, the various forms of long QT syndrome (LQTS; see 192500) and short QT syndrome (SQTS; see 609620). These are usually due to rare, highly penetrant mutations in ion channel genes that are associated with increased risk of sudden cardiac death (SCD; see 115080). Familial clustering of SCD has been observed, but the vast majority of subjects who are at risk for SCD do not have mutations in the known genes for LQTS or SQTS. Mapping To identify genetic mechanisms by which an altered QT interval may contribute to SCD risk, Arking et al. (2006) examined the QT interval directly as opposed to the SCD phenotype, treating the QT interval as a quantitative trait that could be accurately and reliably measured in large samples from standard ECG recordings. In a genomewide study involving 200 individuals at the extremes of a population-based QT interval distribution of 3,966 subjects from the KORA cohort in Germany, the authors found an association between QT interval and common genetic variants in noncoding regions of the NOS1 regulator NOS1AP (605551) on chromosome 1q23.3. Post et al. (2007) replicated the association between variants in the NOS1AP gene and QT interval (p = 0.006) in a genetically homogeneous population of Old Order Amish. In a population-based prospective cohort of 5,374 Dutch individuals aged 55 years and older, Aarnoudse et al. (2007) determined the heart rate-corrected QT interval (QTc) and genotyped 2 SNPs in the NOS1AP gene. The authors found that the G allele of rs10494366 (36% frequency) was associated with a 3.8-ms increase in QTc for each additional allele copy (p = 7.8 x 10(-20)); and the G allele of rs10918594 (31% frequency) was associated with a 3.6-ms increase in QTc per allele copy (p = 6.9 x 10 (-17)). Over an 11.9-year follow-up period, there were 233 sudden cardiac deaths; no significant association was observed with sudden cardiac death. Aarnoudse et al. (2007) stated that the 2 SNPs, which are 55 kb apart, are not known to be functional and are not highly correlated with any known functional SNP. They suggested the existence of a causal untyped SNP that is correlated with both SNPs. Eijgelsheim et al. (2009) performed fine mapping of the association of the NOS1AP locus with QT interval within the Rotterdam Study, a population-based, prospective cohort study of individuals 55 years of age or older. The authors tested the association of SNPs in or within 100 kb of the NOS1AP gene with QT interval duration, using the combined set of SNPs present in the Affymetrix 500k and Illumina 550k chip arrays. A C-to-T SNP at chromosome 1 position 160300514 (rs12143842, T allele frequency = 24%) was associated with a QT interval duration increase of 4.4 ms per additional T allele (P = 4.4 x 10(-28)). For comparison, the most strongly associated variant to that time, rs10494366, was associated with a 3.5-ms increase (P = 1.6 x 10(-23)) per additional G allele. None of the inferred haplotypes showed a stronger effect than the individual rs12143842 SNP. Marroni et al. (2009) performed genomewide association scanning of 3 European genetically isolated populations from Italy, Scotland, and the Netherlands and confirmed an association between QT interval and the NOS1AP gene (rs10494366; p = 8.72 x 10(-8)). The strongest association signal was for a SNP rs2880058 located 25 kb upstream of NOS1AP (p = 2.0 x 10(-10)). They also identified a SNP rs2478333 on chromosome 13 located 100 kb from LOC730174 and 300 kb from the SUCLA2 gene (603921). ### Associations Pending Confirmation Kim et al. (2012) performed a genomewide association study of 6,805 Asian individuals (Korean, Japanese, and Chinese) and found significant association between a SNP (rs13017846) near the SLC8A1 gene (182305) and shorter QT intervals (p = 8.0 x 10(-14)). Using a genomewide association and replication study in up to 100,000 individuals, Arking et al. (2014) identified 35 common variant loci associated with QT interval that collectively explain approximately 8 to 10% of QT interval variation and highlight the importance of calcium regulation in myocardial repolarization. Rare variant analysis of 6 novel QT interval-associated loci in 298 unrelated probands with LQTS identified coding variants not found in controls but of uncertain causality and therefore requiring validation. Several newly identified loci encode proteins that physically interact with other recognized repolarization proteins. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	QT INTERVAL, VARIATION IN	c1857828	3,278	omim	https://www.omim.org/entry/610141	2019-09-22T16:05:01	{"omim": ["610141"]}
A number sign (#) is used with this entry because of evidence that the Revesz syndrome is caused by heterozygous mutation in the TINF2 gene (604319) on chromosome 14q12. For a discussion of genetic heterogeneity of dyskeratosis congenita, see DKCA1 (127550). Clinical Features Revesz et al. (1992) reported the case of a Sudanese male infant who was found to have bilateral exudative retinopathy at 6 months of age. A month later, severe aplastic anemia was found, which led to the child's death at the age of 19 months. The features of this syndrome were intrauterine growth retardation, fine sparse hair, fine reticulate skin pigmentation, ataxia because of cerebellar hypoplasia, cerebral calcifications, extensor hypertonia, and progressive psychomotor retardation. Kajtar and Mehes (1994) described similar findings in a 2-year-old Hungarian Gypsy girl who presented with thrombocytopenic purpura. Severe bone marrow hypoplasia was associated with bilateral progressive Coats retinopathy, nail dystrophy, fine hair, and apparent chromosome instability. Savage et al. (2008) described a patient with Revesz syndrome who had the characteristic bilateral exudative retinopathy, the dyskeratosis congenita triad of nail dystrophy, skin hyperpigmentation, and oral leukoplakia, as well as developmental delay, cerebellar hypoplasia, and very short telomere lengths. Severe aplastic anemia developed at age 1.5 years. The patient died after bone marrow transplant. Savage et al. (2008) considered Revesz syndrome to be part of the DKC disease spectrum. Sasa et al. (2012) reported a 21-month-old Hispanic boy with Revesz syndrome. He presented with severe aplastic anemia and was noted to have bilateral exudative retinopathy at age 9 months. He also had poor growth, nail dystrophy, oral leukoplakia, and delayed development with wide-based gait, suggesting cerebellar involvement. He underwent cord blood transplantation, but died 92 days later. Telomere lengths were shortened. Molecular Genetics In a patient with Revesz syndrome, Savage et al. (2008) identified a heterozygous mutation in the gene encoding TRF1-interacting nuclear factor-2 (TINF2; 604319.0002), a component of the shelterin telomere protection complex. His unaffected parents and 1 sister had normal telomere lengths and no mutation in TINF2. In a 21-month-old Hispanic boy with Revesz syndrome, Sasa et al. (2012) identified a heterozygous truncating mutation in exon 6 of the TINF2 gene (604319.0006). A truncated protein was expressed, but at lower levels than wildtype, suggesting decreased stability. INHERITANCE \- Autosomal dominant GROWTH Other \- Intrauterine growth retardation \- Poor growth HEAD & NECK Eyes \- Leukocoria \- Exudative retinopathy \- Nystagmus \- Megalocornea \- Bilateral subretinal masses Mouth \- Leukoplakia (tongue) SKIN, NAILS, & HAIR Skin \- Fine, reticulate skin pigmentation (trunk, palm, and soles) Nails \- Nail dystrophy \- Ridged fingernails \- Nail pitting Hair \- Fine hair \- Sparse hair NEUROLOGIC Central Nervous System \- Psychomotor retardation \- Ataxia \- Cerebellar hypoplasia \- Cerebral calcifications \- Hypertonia \- Progressive neurologic deterioration HEMATOLOGY \- Aplastic anemia \- Bone marrow failure LABORATORY ABNORMALITIES \- Chromosome instability (hypo-/hyperdiploidy, chromosomal breaks, premature centromere division) \- Shortened telomeres MOLECULAR BASIS \- Caused by mutation in the TRF1-interacting nuclear factor 2 gene (TINF2, 604319.0002 ) ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	REVESZ SYNDROME	c1327916	3,279	omim	https://www.omim.org/entry/268130	2019-09-22T16:22:43	{"doid": ["0070026"], "mesh": ["C538371"], "omim": ["268130"], "orphanet": ["3088"], "synonyms": ["Alternative titles", "DYSKERATOSIS CONGENITA, AUTOSOMAL DOMINANT 5", "EXUDATIVE RETINOPATHY WITH BONE MARROW FAILURE"]}
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: "Very long-chain acyl-coenzyme A dehydrogenase deficiency" – news · newspapers · books · scholar · JSTOR (March 2017) (Learn how and when to remove this template message) Very long-chain acyl-coenzyme A dehydrogenase deficiency Other namesVLCADD Very long-chain acyl-coenzyme: A dehydrogenase deficiency has an autosomal recessive pattern of inheritance. Very long-chain acyl-coenzyme A dehydrogenase deficiency is a fatty-acid metabolism disorder which prevents the body from converting certain fats to energy, particularly during periods without food.[1][2][3] Those affected by this disorder have inadequate levels of an enzyme that breaks down a group of fats called very long-chain fatty acids.[citation needed][4] ## Contents * 1 Signs and symptoms * 2 Causes * 3 Genetics * 4 Diagnosis * 5 Treatment * 6 Prognosis * 7 References * 8 External links ## Signs and symptoms[edit] Signs and symptoms can include:[5][6] * hypoglycemia * lethargy * hepatomegaly * muscle pain * cardiomyopathy * Early onset-pericardial effusion * heart arrhythmias * vomiting * coma death * Rhabdomyolysis * Hypoketotic Hypoglycemia ## Causes[edit] VLCAD (very long-chain-acyl-dehydrogenase) deficiency is exclusively linked to genetic mutations in DNA. A change of the gene that codes for very long-chain-acyl-CoA-dehydrogenase (VLCAD) results in a deficiency or malfunction of the produced VLCAD enzyme.[7] This mutation occurs on chromosome 17 and can be altered via a variety of pathways.[4] These can range from frameshift mutations, deletion mutations, insertion mutations, and missense mutations. All of which cause the enzyme to function differently in the mitochondria, or in some cases not at all.[4] Due to this mutation, effective levels of very long-chain-acyl-CoA-dehydrogenase are low or absent in the body, giving rise to the array of symptoms listed above.[4][7] ## Genetics[edit] Mutations in the ACADVL gene lead to inadequate levels of an enzyme called very long-chain acyl-coenzyme A (CoA) dehydrogenase. Without this enzyme, long-chain fatty acids from food and fats stored in the body cannot be degraded and processed. As a result, these fatty acids are not converted into energy, which can lead to characteristic signs and symptoms of this disorder, such as lethargy and hypoglycemia. Levels of very long-chain fatty acids or partially degraded fatty acids may build up in tissues and can damage the heart, liver, and muscles, causing more serious complications.[citation needed] VLCAD deficiency is characterized as an inherited genetic disorder. The mutations that occur within the gene itself are recessive, meaning that an individual has to acquire both recessive mutated genes in order for the disease to manifest.[4] There are various forms of the disease that can be manifested in infancy, adolescence, and adulthood.[8] However, it is still unknown at to what causes the disease to manifest itself in the different life stages. ## Diagnosis[edit] Typically, initial signs and symptoms of this disorder occur during infancy and include low blood sugar (hypoglycemia), lack of energy (lethargy), and muscle weakness. There is also a high risk of complications such as liver abnormalities and life-threatening heart problems. Symptoms that begin later in childhood, adolescence, or adulthood tend to be milder and usually do not involve heart problems. Episodes of very long-chain acyl-coenzyme A dehydrogenase deficiency can be triggered by periods of fasting, illness, and exercise. It is common for babies and children with the early and childhood types of VLCAD to have episodes of illness known as metabolic crises. Some of the first symptoms of a metabolic crisis are: extreme sleepiness, behavior changes, irritable mood, poor appetite. Some of these other symptoms of VLCAD in infants may also follow: fever, nausea, diarrhea, vomiting, hypoglycemia. Evaluation of symptom combinations can aid in a positive diagnosis of VLCAD.[9] Since symptoms vary depending on age and onset of the patient, consultation with a metabolic specialist should be considered. Diagnosis is further confirmed through genetic analysis of the VLCAD gene.[9] ## Treatment[edit] Treatment and management of VLCAD deficiency involve dietary restrictions as well as implementation of proper hydration to avoid further complications. Hospitalization due to VLCAD deficiency can be treated with intravenous (IV) glucose for hydration and alkalization of urine and prevention of renal malfunction or failure.[10] Avoidance of fasting periods, high-fat diets, and dehydration is recommended for those who are affected. A diet consisting of low-fat intake and supplemental calories is common for management of VLCAD deficiency. If a metabolic crisis is not treated, a child with VLCAD can develop: breathing problems, seizures, coma, sometimes leading to death.[citation needed] ## Prognosis[edit] Medical screening can confirm occurrences of VLCAD most often in neonatal and infancy stages. Approximately half of all patients show signs of VLCAD deficiency during the neonatal period, one-fourth present later in the first year of infancy, and the final quarter is split between manifestations in childhood and adulthood.[citation needed] Comorbidity of cardiomyopathy, arrhythmias[3] and rhabdomyolysis are extremely common in patients under 1 year old which can lead to complications later in life[citation needed]. Loss of awareness or seizure can occur from hypoketotic hypoglycemia,[3] which is often fatal if not caught in screening. However, prompt treatment shows high promise for improvement. Late-onset myopathic sufferers may only experience muscle-related, vague, sporadic symptoms, and may never be diagnosed.[3] There is an extremely high genotype-phenotype correlation in a presentation. Mitigation of VLCAD symptoms can be achieved through dietary management[citation needed]. ## References[edit] 1. ^ Leslie, Nancy D.; Valencia, C. Alexander; Strauss, Arnold W.; Connor, Jessica A.; Zhang, Kejian (1993-01-01). "Very Long-Chain Acyl-Coenzyme a Dehydrogenase Deficiency". In Pagon, Roberta A.; Adam, Margaret P.; Ardinger, Holly H.; Wallace, Stephanie E.; Amemiya, Anne; Bean, Lora J.H.; Bird, Thomas D.; Ledbetter, Nikki; Mefford, Heather C. (eds.). GeneReviews. Seattle (WA): University of Washington, Seattle. PMID 20301763.update 2014 2. ^ Reference, Genetics Home. "VLCAD deficiency". Genetics Home Reference. Retrieved 2017-02-27. 3. ^ a b c d "VLCAD deficiency \| Genetic and Rare Diseases Information Center (GARD) – an NCATS Program". rarediseases.info.nih.gov. Retrieved 2018-04-17. 4. ^ a b c d e Reference, Genetics Home. "VLCAD deficiency". Genetics Home Reference. Retrieved 2018-04-17. 5. ^ "Very Long Chain Acyl CoA Dehydrogenase Deficiency (LCAD)". 6. ^ https://rarediseases.info.nih.gov/diseases/5508/vlcad-deficiency 7. ^ a b "VLCAD deficiency \| Genetic and Rare Diseases Information Center (GARD) – an NCATS Program". rarediseases.info.nih.gov. Retrieved 2019-11-13. 8. ^ Very Long-Chain Acyl-CoA Dehydrogenase (VLCAD) Deficiency Information for Healthcare Professionals" (PDF). Kansas Department of Health and Environment. 8/13/2014. Retrieved October 16, 2019 9. ^ a b "American College of Medical Genetics ACT Sheet" (PDF). American College of Medical Genetics. 2010. Retrieved October 8, 2019. 10. ^ Leslie, N. D.; Valencia, C. A.; Strauss, A. W.; Zhang, K.; Adam, M. P.; Ardinger, H. H.; Pagon, R. A.; Wallace, S. E.; Bean LJH; Stephens, K.; Amemiya, A. (1993). "Very Long-Chain Acyl-Coenzyme A Dehydrogenase Deficiency". PMID 20301763. Cite journal requires `\|journal=` (help) ## External links[edit] Classification D * ICD-9-CM: 277.85 * SNOMED CT: 237997005 * v * t * e Inborn error of lipid metabolism: fatty-acid metabolism disorders Synthesis * Biotinidase deficiency (BTD) Degradation Acyl transport * Carnitine * CPT1 * CPT2 * CDSP * CACTD * Adrenoleukodystrophy (ALD) Beta oxidation General * Acyl CoA dehydrogenase * Short-chain SCADD * Medium-chain MCADD * Long-chain 3-hydroxy LCHAD * Very long-chain VLCADD * Mitochondrial trifunctional protein deficiency (MTPD): Acute fatty liver of pregnancy Unsaturated * 2,4 Dienoyl-CoA reductase deficiency (DECRD) Odd chain * Propionic acidemia (PCC deficiency) Other * 3-hydroxyacyl-coenzyme A dehydrogenase deficiency (HADHD) * Glutaric acidemia type 2 (MADD) To acetyl-CoA * Malonic aciduria (MCD) Aldehyde * Sjögren–Larsson syndrome (SLS) * 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 [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Very long-chain acyl-coenzyme A dehydrogenase deficiency	c3887523	3,280	wikipedia	https://en.wikipedia.org/wiki/Very_long-chain_acyl-coenzyme_A_dehydrogenase_deficiency	2021-01-18T18:34:47	{"gard": ["5508"], "mesh": ["C536353"], "umls": ["C3887523"], "icd-9": ["277.85"], "orphanet": ["26793"], "wikidata": ["Q7923095"]}
Most cases are sporadic. Some families have affected relatives, suggesting a complex genetic etiology. Bermejo-Sanchez et al. (2011) described the epidemiology of congenital amelia using data gathered from 20 surveillance programs on congenital anomalies, all International Clearinghouse for Birth Defects Surveillance and Research members, from all continents but Africa, from 1968 to 2006, depending on the program. Reported clinical information on cases was thoroughly reviewed to identify those strictly meeting the definition of amelia. Those with amniotic bands or limb-body wall complex were excluded. The primary epidemiologic analyses focused on isolated cases (about one-third) and those with multiple congenital anomalies (MCA) (two-thirds). A total of 326 amelia cases were ascertained among 23,110,591 live births, stillbirths, and, for some programs, elective terminations of pregnancy for fetal anomalies. The overall total prevalence was 1.41 per 100,000 (95% confidence interval 1.26-1.57). Only China, Beijing, and Mexico RYVEMCE had total prevalences, which were significantly higher than this overall total prevalence. Some underregistration could have influenced the total prevalence in some programs. Liveborn cases represented 54.6% of the total. Among monomelic cases (representing 65.2% of nonsyndromic amelia cases), both sides were equally involved, and the upper limbs (53.9%) were slightly more frequently affected. One of the most interesting findings was a higher prevalence of amelia among offspring of mothers younger than 20 years. Sixty-nine percent of the cases had MCA or syndromes. The most frequent defects associated with amelia were other types of musculoskeletal defects, intestinal defects, some renal and genital defects, oral clefts, defects of cardiac septa, and anencephaly. Limbs \- Amelia \- Terminal transverse hemimelia Inheritance \- Autosomal dominant vs. multifactorial \- most cases sporadic ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	AMELIA AND TERMINAL TRANSVERSE HEMIMELIA	c1863014	3,281	omim	https://www.omim.org/entry/104400	2019-09-22T16:45:16	{"mesh": ["C566294"], "omim": ["104400"]}
A number sign (#) is used with this entry because spherocytosis type 4 (SPH4) is caused by heterozygous mutation in the band 3 gene (SLC4A1, EPB3; 109270) on chromosome 17q21. For a general description and a discussion of genetic heterogeneity of spherocytosis, see SPH1 (182900). Clinical Features Prchal et al. (1991) studied a family with autosomal dominant hereditary spherocytosis associated with deficiency of erythrocyte band 3 protein. Del Giudice et al. (1992) reported a family in which a dominantly inherited form of hereditary spherocytosis was associated with deficiency of band 3, resulting in an increased spectrin/band 3 ratio. Since deficiency of spectrin is a much more frequent cause of hereditary spherocytosis, the usual finding is a decreased spectrin/band 3 ratio. An increased spectrin/band 3 ratio, pointing to a band 3 defect, was found in 2 families with hereditary spherocytosis studied by Lux et al. (1990). Del Giudice et al. (1993) described a family in which both hereditary spherocytosis due to band 3 deficiency and beta-0-thalassemia trait due to codon 39 (C-T) mutation (141900.0312) were segregating. Two subjects with HS alone had a typical clinical form of spherocytosis with anemia, reticulocytosis, and increased red cell osmotic fragility. Two who coinherited HS and beta-thalassemia trait were not anemic and showed a slight, well-compensated hemolysis. Thus, the beta-thalassemic trait partially corrected or 'silenced' HS caused by band 3 deficiency. Pathogenesis Saad et al. (1991) examined the mechanism underlying band 3 deficiency in a subset of patients with hereditary spherocytosis. Mapping Prchal et al. (1991) performed linkage analysis in a family with autosomal dominant hereditary spherocytosis associated with deficiency of erythrocyte band 3 protein. They excluded linkage with alpha-spectrin (182860), beta-spectrin (182870), and ankyrin (612641), but found a suggestion of linkage to EPB3 (SLC4A1). They used RFLPs not only in the EPB3 gene but also in the NGFR gene (162010) which, like EPB3, maps to 17q21-q22. A maximum lod score of 11.40 at theta = 0.00 was observed. Study of 42 members from 4 generations revealed a consistent linkage of spherocytosis with 1 particular haplotype generated by the 4 probes that were used. Molecular Genetics In a 28-year-old female with congenital spherocytic hemolytic anemia, Jarolim et al. (1991) identified a missense mutation in the band 3 gene (109270.0003). In a 33-year-old woman with pregnancy-associated hemolytic anemia and spherocytosis, Rybicki et al. (1993) identified a G40K mutation in band 3 (109270.0004). In a 3-generation Czech family in which 5 affected members exhibited compensated hemolytic disease, Jarolim et al. (1994) identified a 10-bp duplication in the SLC4A1 gene (109270.0005) that segregated with disease. Before splenectomy, affected individuals had reticulocytosis, hyperbilirubinemia, and increased osmotic fragility. In affected members of a large Swiss family with spherocytosis, Maillet et al. (1995) identified heterozygosity for a G771D mutation in band 3 (109270.0007). In an 18-year-old French man with moderate hereditary spherocytosis, Alloisio et al. (1996) identified an R150X mutation in band 3 (109270.0009). The proband's mother, who also carried the mutation, had a milder clinical presentation. Further investigation revealed a second, paternally inherited band 3 mutation in the proband (109270.0010). Eber et al. (1996) found that band 3 frameshift and nonsense null mutations occurred in dominant hereditary spherocytosis. In studies of 46 HS families, 12 ankyrin-1 (612614) mutations and 5 band 3 mutations were identified. Among 80 hereditary spherocytosis kindreds studied using denaturing electrophoretic separation of solubilized erythrocyte membrane proteins, Dhermy et al. (1997) recognized 3 prominent subsets: HS with isolated spectrin deficiency, HS with combined spectrin and ankyrin deficiency, and HS with band 3 deficiency. These 3 subsets represented more than 80% of the HS kindreds studied. In 8 dominant HS kindreds with band 3 deficiency mutations were sought. In each, linkage analysis confirmed the band 3 gene as the culprit gene. Five different mutations were found in the 8 kindreds. Dhermy et al. (1997) found that the amount of band 3 appeared to be slightly, but significantly, more reduced in HS patients with missense mutations and presence of the mutant transcripts than in HS patients with premature termination of translation and absence of mutant transcripts. This led to speculation that missense mutations may have a dominant negative effect. In a 29-year-old Japanese man with compensated hemolytic anemia and spherocytosis, Inoue et al. (1998) identified homozygosity for an SLC4A1 G130R mutation (109270.0018). In a 22-year-old Japanese man who presented with cholelithiasis and hemolysis and had a history of jaundice since early childhood, Iwase et al. (1998) identified a T837A mutation in SLC4A1 (109270.0019). Bruce et al. (2005) identified 11 human pedigrees with dominantly inherited hemolytic anemias in both the hereditary stomatocytosis (see 185020) and spherocytosis classes. Affected individuals in these families had an increase in membrane permeability to sodium and potassium ion that was particularly marked at zero degree centigrade. They found that disease in these pedigrees was associated with a series of single amino acid substitutions in the intramembrane domain of the band 3 anion exchanger, AE1. Anion movements were reduced in the abnormal red cells. The 'leak' cation fluxes were inhibited by chemically diverse inhibitors of band 3. Expression of the mutated genes in Xenopus laevis oocytes induced abnormal NA and K fluxes in the oocytes, and the induced chloride transport was low. These data were considered consistent with the suggestion that the substitutions convert the protein from an anion exchanger into an unregulated cation channel. Only 1 of the gene changes, R760Q (109270.0028), had previously been reported (Jarolim et al., 1995). All the mutations were in exon 17 of the AE1 gene. INHERITANCE \- Autosomal dominant ABDOMEN Liver \- Jaundice Spleen \- Splenomegaly SKIN, NAILS, & HAIR Skin \- Jaundice, neonatal or in early childhood HEMATOLOGY \- Hemolytic anemia \- Increased reticulocyte count \- Spherocytosis \- Increased red cell osmotic fragility \- Increased red cell membrane cation permeability at cold temperatures (in some patients) LABORATORY ABNORMALITIES \- Hyperbilirubinemia \- Pseudohyperkalemia (in some patients) MISCELLANEOUS \- Increased risk of post-splenectomy thrombotic complications (in some patients) MOLECULAR BASIS \- Caused by mutation in the red cell membrane band 3 gene (SLC4A1, 109270.0003 ) ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	SPHEROCYTOSIS, TYPE 4	c0221409	3,282	omim	https://www.omim.org/entry/612653	2019-09-22T16:00:52	{"doid": ["0110919"], "mesh": ["C536356"], "omim": ["612653"], "orphanet": ["822"], "synonyms": ["Alternative titles", "SPHEROCYTOSIS, HEREDITARY, 4"]}
A rare inherited cancer-predisposing syndrome characterized by predisposition to a wide variety of cancers, including neoplasms of the digestive tract, urinary tract, kidney, endometrium, ovary, brain, and prostate, as well as sebaceous skin tumors, depending on the gene involved. Tumors may occur at any age but often arise in young people. Factors influencing individual tumor risk include sex, age, affected gene, and personal history of cancer. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Lynch syndrome	c1333990	3,283	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=144	2021-01-23T17:27:13	{"gard": ["9905"], "mesh": ["D003123"], "omim": ["120435", "609310", "613244", "614331", "614337", "614350", "614385"], "umls": ["C1112155", "C1333990"], "icd-10": ["D48.9"]}
Moniz sign Differential diagnosisPyramidal tract lesions Moniz sign is a clinical sign in which forceful passive plantar flexion of the ankle elicits an extensor plantar reflex. It is found in patients with pyramidal tract lesions, and is one of a number of Babinski-like responses.[1] It is named after Portuguese neurologist António Egas Moniz.[2] ## References[edit] 1. ^ Kumar SP, Ramasubramanian D (December 2000). "The Babinski sign--a reappraisal". Neurol India. 48 (4): 314–8. PMID 11146592. Retrieved 2009-04-13. 2. ^ Buzzi, Alfredo E. (January 2004). "Egas Moniz" (PDF). The Invisible Light: the Journal of the Radiology History and Heritage Charitable Trust (20): 5–24. ISSN 1479-6945. Retrieved 2019-06-19. 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 [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Moniz sign	None	3,284	wikipedia	https://en.wikipedia.org/wiki/Moniz_sign	2021-01-18T19:08:30	{"wikidata": ["Q6900535"]}
A number sign (#) is used with this entry because of evidence that pancreatic and cerebellar agenesis (PACA) is caused by homozygous mutation in the PTF1A gene (607194) on chromosome 10p12. A form of isolated pancreatic agenesis (PAGEN2; 615935) is caused by mutation in a distal enhancer of the PTF1A gene. Clinical Features Hoveyda et al. (1999) described neonatal diabetes mellitus with cerebellar hypoplasia/agenesis, and dysmorphism. The patients they observed were referred to as Asian (specifically Pakistani). There was a strong family history of noninsulin-dependent diabetes mellitus (see 125853) in the absence of obesity. Three cases were described, 2 sisters and a female first cousin. All 3 had dysmorphic facial features consisting of beaked nose and low set, dysplastic ears. A wizened triangular face and presence of very little subcutaneous fat were noted. Prenatal diagnosis of the condition was possible in this family by demonstration of the absence of the cerebellum on imaging studies and severe intrauterine growth retardation (IUGR). Sellick et al. (2004) studied an individual from a consanguineous northern European family with a phenotype identical to that of the patients of Hoveyda et al. (1999). Severe IUGR, flexion contractures of arms and legs, very little subcutaneous fat, and optic nerve hypoplasia were seen. A computed tomography scan of the brain demonstrated agenesis of cerebellum and vermis. No pancreas was present at autopsy, and detailed macroscopic and microscopic examination failed to detect any pancreatic tissue in the abdominal cavity. Al-Shammari et al. (2011) described a male infant, the first child of healthy first-cousin Saudi parents, with this syndrome. Antenatal ultrasound showed intrauterine growth retardation and atrophic cerebellum. At birth, his growth parameters were below the third percentile. Dysmorphic features included triangular face, small chin, generalized joint stiffness, and bilateral talipes equinovarus. He had meconium ileus and was found to have diabetes mellitus. Brain MRI showed cerebellar agenesis. Ophthalmologic examination showed bilateral optic atrophy. The pancreas could not be visualized on abdominal ultrasound. The infant died at 4 months of age. Molecular Genetics In the consanguineous Pakistani family which Hoveyda et al. (1999) first described the syndrome of pancreatic and cerebellar agenesis, Sellick et al. (2004) found by positional candidate gene approach a mutation in the PTF1A gene (607194.0001). They found a different PTF1A mutation in a consanguineous family of northern European descent (607194.0002). Tutak et al. (2009) reported a male infant, born of consanguineous Turkish parents, who had cerebellar agenesis and neonatal diabetes mellitus and died at 1.5 months of age. The parents declined permission for necropsy, but the authors identified heterozygosity for a frameshift mutation in the PTF1A gene (Gly240fsTer276) in both parents. Tutak et al. (2009) stated that this was the fifth patient with cerebellar agenesis and diabetes mellitus reported to date. In a male infant with PACA, whose parents were healthy first cousins, Al-Shammari et al. (2011) identified a homozygous truncating mutation in the PTF1A gene (607194.0003). INHERITANCE \- Autosomal recessive HEAD & NECK Head \- Microcephaly Face \- Triangular face \- Small chin Ears \- Low-set ears \- Dysplastic ears Eyes \- Optic nerve hypoplasia \- Small pale optic discs Nose \- Beaked nose CARDIOVASCULAR Heart \- Secundum atrial septal defect (in some patients) RESPIRATORY \- Irregular respiratory pattern \- Episodic apnea CHEST Ribs Sternum Clavicles & Scapulae \- Pectus carinatum (in some patients) ABDOMEN Pancreas \- Pancreatic hypoplasia or agenesis SKELETAL \- Joint stiffness Limbs \- Flexion contractures of upper and lower extremities Hands \- Overlapping fingers (in some patients) NEUROLOGIC Central Nervous System \- Cerebellar hypoplasia or agenesis \- Seizures \- Hypotonicity (in some patients) \- Decreased reflexes (in some patients) ENDOCRINE FEATURES \- Neonatal diabetes mellitus \- Intermittent severe hypoglycemia \- Low C-peptide levels \- Low to undetectable insulin levels in the presence of hyperglycemia HEMATOLOGY \- Anemia requiring transfusions MISCELLANEOUS \- Death in infancy MOLECULAR BASIS \- Caused by mutation in the pancreas transcription factor 1, alpha subunit gene (PTF1A, 607094.0001 ) ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	PANCREATIC AND CEREBELLAR AGENESIS	c1836780	3,285	omim	https://www.omim.org/entry/609069	2019-09-22T16:06:48	{"mesh": ["C563796"], "omim": ["609069"], "orphanet": ["65288"], "synonyms": ["Alternative titles", "DIABETES MELLITUS, PERMANENT NEONATAL, WITH CEREBELLAR AGENESIS"]}
Hemophilia B is a bleeding disorder that slows the blood clotting process. People with this disorder experience prolonged bleeding or oozing following an injury or surgery. In severe cases of hemophilia, heavy bleeding occurs after minor injury or even in the absence of injury. Serious complications can result from bleeding into the joints, muscles, brain, or other internal organs. Milder forms may not become apparent until abnormal bleeding occurs following surgery or a serious injury. People with an unusual form of hemophilia B, known as hemophilia B Leyden, experience episodes of excessive bleeding in childhood but have few bleeding problems after puberty. Hemophilia B is inherited in an X-linked recessive pattern and is caused by mutations in the F9 gene.[719] [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Hemophilia B	c0008533	3,286	gard	https://rarediseases.info.nih.gov/diseases/8732/hemophilia-b	2021-01-18T18:00:06	{"mesh": ["D002836"], "omim": ["306900"], "umls": ["C0008533"], "orphanet": ["98879"], "synonyms": ["Christmas disease", "Factor IX deficiency", "HEM B"]}
## Summary ### Clinical characteristics. Pendred syndrome/nonsyndromic enlarged vestibular aqueduct (PDS/NSEVA) comprises a phenotypic spectrum of sensorineural hearing loss (SNHL) that is usually congenital and often severe to profound (although mild-to-moderate progressive hearing impairment also occurs), vestibular dysfunction, and temporal bone abnormalities (bilateral enlarged vestibular aqueduct with or without cochlear hypoplasia). PDS also includes development of euthyroid goiter in late childhood to early adulthood whereas NSEVA does not. ### Diagnosis/testing. In at least 50% of probands with Pendred syndrome and/or NSEVA, the molecular diagnosis is established by identification of biallelic pathogenic variants in SLC26A4 or double heterozygosity for one pathogenic variant in SLC26A4 and one pathogenic variant in either FOXI1 or KCNJ10. The clinical diagnosis of Pendred syndrome is established in a proband with SNHL, characteristic temporal bone abnormalities identified on thin-cut CT, and euthyroid goiter. In comparison, the clinical diagnosis of nonsyndromic enlarged vestibular aqueduct (NSEVA) is established in a proband with SNHL and the temporal bone finding of enlargement of the vestibular aqueducts. It is important to note that in PDS, the temporal bone abnormality can include both EVA and cochlear hypoplasia, an anomaly in which the cochlea has only 1.5 turns instead of the expected 2.75 turns. In NSEVA, the temporal bone abnormality is restricted to EVA, defined as a vestibular aqueduct that exceeds 1.5 mm in width at its midpoint. This distinction is relevant because thyroid enlargement is variably present, depending on methods used to assess thyroid size and nutritional iodine intake. Some studies have suggested that a goiter is present in only 50% of affected individuals. ### Management. Treatment of manifestations: Hearing habituation, hearing aids, and educational programs designed for the hearing impaired; consideration of cochlear implantation in individuals with severe-to-profound deafness; standard treatment of abnormal thyroid function. Surveillance: Repeat audiometry every three to six months initially if hearing loss is progressive, then semiannually or annually. Baseline ultrasound examination of the thyroid with periodic physical examination and/or ultrasonography to monitor volumetric changes; thyroid function tests every two to three years. Agents/circumstances to avoid: Some evidence suggests that dramatic increases in intracranial pressure can be associated with a sudden drop in hearing. For this reason, advisability of weightlifting and/or contact sports should be discussed with a physician/health care provider prior to participation. ### Genetic counseling. PDS/NSEVA is inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. When the family-specific pathogenic variants are known, carrier testing for at-risk family members, prenatal testing for pregnancies at increased risk, and preimplantation genetic diagnosis are possible. ## Diagnosis ### Suggestive Findings The diagnosis of Pendred syndrome/nonsyndromic enlarged vestibular aqueduct (PDS/NSEVA) spectrum is suggested by the following clinical, temporal bone imaging, and endocrine findings. #### Clinical Findings Sensorineural hearing impairment is usually congenital (or prelingual), non-progressive, and severe to profound as measured by auditory brain stem response (ABR) testing or pure tone audiometry. For evaluation of hearing loss, see Deafness and Hereditary Hearing Loss Overview. #### Temporal Bone Imaging Findings The identification and interpretation of temporal bone defects require both the appropriate test (i.e., thin-cut CT as a routine CT of the temporal bones typically will not suffice) and detailed familiarity with cochlear anatomy: * Mondini malformation or dysplasia (bilateral enlarged vestibular aqueduct [EVA] with cochlear hypoplasia) is detected on thin-cut CT of the temporal bones. The cochlea is hypoplastic and has 1.5 cochlear turns instead of the expected 2.75 turns, and the vestibular aqueduct is enlarged, with a midpoint width exceeding 1.5 mm. The presence of both cochlear hypoplasia and EVA is known as a Mondini malformation or dysplasia. * While the temporal bones are abnormal radiologically in all persons with PDS [Goldfeld et al 2005], a range of findings can be present. In a study of individuals homozygous for the same SLC26A4 pathogenic variant, high-resolution CT revealed that 100% had deficiency of the modiolus (i.e., the bony polyhedral structure centered on the cochlea was not apparent on a mid-modiolar section); 80% had EVA (i.e., width in the middle portion of the descending limb of the vestibular aqueduct >1.5 mm); and 75% had absence of the upper turn of the cochlea (i.e., the interscalar septum was not seen between the upper and middle turns) [Goldfeld et al 2005] (Figure 1). * Note: A radiologic diagnosis of EVA with or without cochlear hypoplasia does not equate to a clinical diagnosis of Pendred syndrome as there are other causes of these types of temporal bone malformations without associated thyroid abnormality (see Differential Diagnosis). * Nonsyndromic enlarged vestibular aqueduct (NSEVA) is detected on thin-cut CT of the temporal bones. The vestibular aqueduct is enlarged when its midpoint width exceeds 1.5 mm. #### Figure 1. Computed tomography in a proband with PDS shows absence of the upper turn of the cochlea and deficiency of the modiolus (white arrow). EVA is also present (black arrow). Inset shows a normal right cochlea and no enlargement of the vestibular aqueduct, (more...) #### Endocrine Findings * Euthyroid goiter, the typical thyroid defect of Pendred syndrome resulting from an organification defect of iodide, can be detected by volumetric studies to assess thyroid size; however, the ability to document thyroid enlargement depends on the method used to assess thyroid size. In addition, nutritional iodine intake may prevent thyroid enlargement. Some studies suggest that a goiter develops in only 50% of individuals with PDS [Reardon et al 1999, Wémeau & Kopp 2017]. If the thyroid is enlarged, thyroid hormone levels can be checked. * Goiter generally becomes apparent after age ten years [Suzuki et al 2007, Reardon et al 1999] and continues to increase 2.6-fold with each decade [Madeo et al 2009]. The thyroid status of these individuals should be monitored throughout their lifetime by physical examination and ultrasonography [Madeo et al 2009]. (See Management.) Note: In the past, an iodine perchlorate discharge test was used to diagnose an organification defect of iodide. Click here (pdf) for details of the perchlorate discharge test. ### Establishing the Diagnosis The clinical diagnosis of PDS is established in a proband with SNHL, characteristic temporal bone abnormalities identified on thin-cut CT and euthyroid goiter; the clinical diagnosis of NSEVA is established in a proband with SNHL and the temporal bone finding of enlargement of the vestibular aqueducts (see Suggestive Findings). The molecular diagnosis of PDS/NSEVA is established by identification of biallelic pathogenic variants in SLC26A4 or double heterozygosity for one pathogenic variant in SLC26A4 and one pathogenic variant in either FOXI1 or KCNJ10 (Table 1). The outcome of testing varies by ethnicity and phenotype. Ethnicity: * In Korean and Japanese probands, more than 80% have two pathogenic variants in SLC26A4, slightly more than 10% have one pathogenic variant, and fewer than 10% have no pathogenic variants [Tsukamoto et al 2003, Park et al 2005]. * In North American or European Caucasians with PDS/NSEVA only about 25% have two pathogenic variants in SLC26A4, as would be expected for autosomal recessive inheritance [Pryor et al 2005, Ito et al 2011]. About half have no detectable SLC26A4 pathogenic variants, and in 25%, only one pathogenic variant is found [Choi et al 2009a]. Phenotype: * The number of pathogenic variants in Caucasians is strongly correlated with the auditory and thyroid phenotypes: those with PDS are more likely than those with NSEVA to have biallelic pathogenic variants [Azaiez et al 2007]. * The degree of hearing loss in persons with NSEVA is greater if two (as opposed to 1 or 0) SCL26A4 pathogenic variants are identified [King et al 2010, Rose et al 2017]. An explanation for these molecular findings has been described by Chattaraj et al [2017], who identified a haplotype Caucasian EVA (CEVA) – comprising 12 variants upstream of SLC26A4 – which is frequently found in persons with NSEVA in trans with a coding or splice site variant. Approach to molecular genetic testing. For all persons with hearing loss, the use of a multigene panel for hearing loss and deafness maximizes the diagnostic rate while minimizing the diagnostic expense. Hearing loss and deafness multigene panels typically include SLC26A4, FOXI1, KCNJ10, and other genes of interest (see Differential Diagnosis). Note: (1) The genes included in panels of this type and the diagnostic sensitivity of the testing vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview; thus, clinicians need to determine which multigene panel provides the best opportunity to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. (3) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests. For more information on multigene panels click here. Note: Comprehensive genome sequencing (i.e., exome sequencing and genome sequencing) is currently not justified as a primary screen for genetic causes of deafness [Sloan-Heggen et al 2016]. ### Table 1. Molecular Genetic Testing Used in Pendred Syndrome (PDS) and Nonsyndromic Enlarged Vestibular Aqueduct (NSEVA) View in own window Gene 1, 2Proportion of PDS and NSEVA Attributed to Pathogenic Variants in GeneProportion of Pathogenic Variants 3 Detectable by Method PDSNSEVASequence analysis 4Gene-targeted deletion/duplication analysis 5 FOXI1None described<1% 62/2 6Unknown KCNJ10None described<1% 72/2 7Unknown SLC26A4~90% 850%-90% 8~90%~10% 9 UnknownUnknown~50%NA 1\. Genes are listed alphabetically. 2\. See Table A. Genes and Databases for chromosome locus and protein. 3\. See Molecular Genetics for information on allelic variants detected in this gene. 4\. 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. 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\. In two families, persons with NSEVA had a heterozygous pathogenic variant in both SLC26A4 and FOXI1 [Yang et al 2007]. 7\. In two families, persons with NSEVA had a heterozygous pathogenic variant in both KCNJ10 and SLC26A4 [Yang et al 2009]. 8\. The proportion of PDS and NSEVA attributable to SLC26A4 varies by ascertainment, inheritance, and ethnicity. In patients ascertained for inner ear malformations (specifically enlarged vestibular aqueduct with or without cochlear hypoplasia), the proportion of cases attributable to SLC26A4 is ~40%-50% in the European-American population and higher in multiplex families and Asian populations [Campbell et al 2001, Tsukamoto et al 2003, Berrettini et al 2005, Huang et al 2011, Chattaraj et al 2017, Rose et al 2017]. 9\. Single-exon and multiexon SLC26A4 deletions have been reported [Pera et al 2008]. ## Clinical Characteristics ### Clinical Description Pendred syndrome/nonsyndromic enlarged vestibular aqueduct (PDS/NSEVA) comprises a phenotypic spectrum of sensorineural hearing loss (SNHL), vestibular dysfunction, and temporal bone abnormalities. PDS also includes development of euthyroid goiter in late childhood to early adulthood whereas NSEVA does not. #### Pendred Syndrome (PDS) Variability in hearing loss and thyroid disease is considerable, even within the same family [Tsukamoto et al 2003, Napiontek et al 2004]. Hearing impairment. The degree of hearing impairment and its presentation vary. Classically, the hearing loss is bilateral, severe to profound, and congenital (or prelingual). However, hearing loss may be later in onset and progressive. The progression can be rapid in early childhood [Stinckens et al 2001] and may be associated with head injury, infection, or delayed secondary hydrops [Luxon et al 2003]. Vertigo can precede or accompany fluctuations in hearing [Sugiura et al 2005a, Sugiura et al 2005b]. The often-observed low-frequency air-bone gap in combination with normal tympanometry may represent a "third window" effect caused by the dilated vestibular aqueduct [Merchant et al 2007]. Vestibular dysfunction. Objective evidence of vestibular dysfunction can be demonstrated in 66% of individuals with PDS and ranges from mild unilateral canal paresis to gross bilateral absence of function. Vestibular dysfunction should be suspected in infants with normal motor development who episodically experience difficulty walking. Temporal bone abnormalities. The temporal bones are abnormal radiologically in all persons with PDS [Goldfeld et al 2005]; however, universal agreement as to the type of abnormality is lacking. (See Suggestive Findings.) Affected sibs may be discordant for temporal bone anomalies [Goldfeld et al 2005]. Goiter. Approximately 75% of individuals with PDS have evidence of goiter on clinical examination. Goiter is incompletely penetrant and develops in late childhood or early puberty in approximately 40% of individuals; in the remainder, it develops in early adult life. Marked intrafamilial variability exists [Reardon et al 1999, Madeo et al 2009], making the distinction between NSEVA and PDS difficult during childhood. While many individuals with PDS are started on thyroxine, only approximately 10% have abnormal thyroid function as defined by a serum TSH level >5 mU/L. Abnormal thyroid function studies in the absence of a goiter have not been reported. #### Nonsyndromic Enlarged Vestibular Aqueduct (NSEVA) NSEVA is characterized by sensorineural hearing impairment in the absence of other obvious abnormalities (i.e., nonsyndromic hearing loss), although CT or MRI of the temporal bones reveals enlarged vestibular aqueduct (EVA). Thyroid defects are not seen. Hearing impairment. The degree of hearing impairment and its presentation vary. Many persons with NSEVA are born with normal hearing and progressively become hearing impaired during childhood. The majority of persons with NSEVA (~80%) report fluctuations in hearing [Rose et al 2017]. Although several reports have described a correlation between the size of the EVA and the degree of hearing loss, a strict correlation has not been established [Berrettini et al 2005]. Vestibular dysfunction. Persons with EVA may deny vestibular disturbances, although vestibular deficits can be demonstrated by caloric testing. When EVA is unilateral, there is no strict correlation between the side of the vestibular deficit and the side of the vestibular enlargement [Berrettini et al 2005]. Temporal bone abnormalities. EVA is the most common imaging finding in persons with sensorineural hearing loss dating from infancy or childhood. EVA can be bilateral or unilateral. ### Genotype-Phenotype Correlations An understanding of the relationship between genotype and phenotype in the PDS/NSEVA spectrum is helpful in patient care. The phenotypes PDS and NSEVA are distinguishable based on the presence of thyroid dysfunction in PDS. The thyroid phenotype is dependent on the degree of residual iodide transport function in pendrin, the protein encoded by SLC26A4 [Pryor et al 2005, Pera et al 2008]. The correlation between variant type (missense vs nonsense) and development of thyroid enlargement is not robust and individuals who have biallelic pathogenic/likely pathogenic variants in SLC26A4 are at increased risk of developing thyroid-related manifestations regardless of variant type [Pryor et al 2005, Ladsous et al 2014, Suzuki et al 2007]. (See Management.) Pathogenic variants can occur anywhere in the 780-amino-acid protein. If a novel missense pathogenic variant is identified, it can be very difficult to predict the phenotype (i.e., hearing loss, whether moderate, severe, or profound; thyroid enlargement) in the absence of additional in vitro functional testing. ### Nomenclature Pendred syndrome (PDS) and nonsyndromic enlarged vestibular aqueduct (NSEVA) should be considered part of a disease continuum [Reardon et al 1999, Azaiez et al 2007]. PDS is also referred to as autosomal recessive sensorineural hearing impairment, enlarged vestibular aqueduct, and goiter. NSEVA is also referred to as: * Nonsyndromic enlarged vestibular aqueduct hearing loss; * Autosomal recessive nonsyndromic deafness 4 (DFNB4); * DFNB4 nonsyndromic hearing impairment and EVA. EVA is also referred to as dilation of the vestibular aqueduct (DVA). ### Prevalence When PDS/NSEVA are considered part of the same disease spectrum, prevalence rates are very high as pathogenic variants in SLC26A4 are the third most frequent cause of hearing loss (Figure 2). #### Figure 2. In an unbiased screen of 2434 persons who underwent comprehensive genetic testing for hearing loss, Pendred syndrome/nonsyndromic enlarged vestibular aqueduct (PDS/NSEVA) caused by biallelic pathogenic variants in SLC26A4 was the third most common diagnosis (more...) ## Differential Diagnosis Congenital inherited hearing impairment. Congenital (or prelingual) inherited hearing impairment affects approximately one in 1,000 newborns; 30% of these infants have additional anomalies, making the diagnosis of a syndromic form of hearing impairment possible (see Deafness and Hereditary Hearing Loss Overview). Although enlarged vestibular aqueduct (EVA) with or without cochlear hypoplasia are seen in virtually all individuals with Pendred syndrome (PDS), neither EVA nor cochlear hypoplasia is specific for PDS. Other causes of these types of temporal bone malformations include congenital cytomegalovirus and branchiootorenal syndrome, in which there is no associated thyroid abnormality. Congenital hypothyroidism with sensorineural hearing loss. Sporadic and endemic congenital hypothyroidism associated with sensorineural hearing impairment is clinically similar to PDS but genetically distinct. Resistance to thyroid hormone. Although the syndrome of resistance to thyroid hormone (RTH) is typically inherited in an autosomal dominant manner, one exceptional consanguineous kindred in which RTH was inherited in an autosomal recessive manner has been described. Two of six children had severe sensorineural hearing impairment and goiter and a large deletion (detected by karyotyping) on chromosome 3 that included the thyroid hormone receptor β gene (THRB; OMIM 190160). Autoimmune thyroid diseases. Autoimmune thyroid diseases, including Graves' disease, Hashimoto thyroiditis, and primary idiopathic myxedema, are caused by multiple genetic and environmental factors. Candidate genes involved in this group of diseases include genes that regulate immune response and/or thyroid physiology. See Deafness, Autosomal Recessive: OMIM Phenotypic Series to view genes associated with this phenotype in OMIM. ## Management ### Evaluations Following Initial Diagnosis To establish the extent of involvement in an individual with molecularly confirmed Pendred syndrome/nonsyndromic enlarged vestibular aqueduct (PDS/NSEVA) or clinically confirmed Pendred syndrome, the following evaluations are recommended if they have not already been completed: * Assessment of auditory acuity (ABR emission testing, pure tone audiometry) * Thyroid ultrasonography to measure the size of the thyroid and thyroid function tests (T3, T4, and TSH) * Consultation with an endocrinologist as needed * Consultation with a clinical geneticist and/or genetic counselor ### Treatment of Manifestations The following are appropriate: * Hearing habilitation (hearing aids as early as possible) * Consideration of cochlear implantation in individuals with severe to profound deafness * Educational programs designed for individuals with hearing impairment * Medical and/or surgical treatment of thyromegaly and/or abnormal thyroid function (requires consultation with an endocrinologist) ### Surveillance Surveillance includes the following: * Lifelong monitoring of hearing and thyroid function * Annual examination by a physician familiar with hereditary hearing impairment * Repeat audiometric testing initially every three to six months and then annually * Annual or biennial examination by an endocrinologist familiar with PDS * Assessment of thyroid size by physical examination and/or ultrasonography to monitor volumetric changes * Thyroid function tests (T3, T4, and TSH) every 2-3 years [Choi et al 2011b] ### Agents/Circumstances to Avoid Based on anecdotal reports that increased intracranial pressure in individuals with enlarged vestibular aqueduct (EVA) can occasionally trigger a decline in hearing, some physicians recommend avoiding activities like weightlifting and contact sports. The value of this approach is debatable and should be considered on an individual basis. ### Evaluation of Relatives at Risk At-risk relatives should be evaluated for hearing loss, vestibular dysfunction, and thyroid abnormality in the same manner as an affected individual at initial diagnosis (see Evaluations Following Initial Diagnosis). If the pathogenic variants in the family are known, molecular genetic testing of sibs is indicated shortly after birth so that appropriate and early support and management can be provided to the child and family. See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes. ### Therapies Under Investigation Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Pendred Syndrome/Nonsyndromic Enlarged Vestibular Aqueduct	None	3,287	gene_reviews	https://www.ncbi.nlm.nih.gov/books/NBK1467/	2021-01-18T21:04:02	{"synonyms": ["PDS/NSEVA", "PDS/DFNB4"]}
A number sign (#) is used with this entry because glucocorticoid-remediable aldosteronism (GRA), also referred to as glucocorticoid-suppressible hyperaldosteronism (GSH) or familial hyperaldosteronism type I (HALD1), is the result of an anti-Lepore-type fusion of the CYP11B2 (124080) and CYP11B1 genes (see 610613.0002). Description Glucocorticoid-remediable aldosteronism is an autosomal dominant disorder characterized by hypertension, variable hyperaldosteronism, and abnormal adrenal steroid production, including 18-oxocortisol and 18-hydroxycortisol (Lifton et al., 1992). There is significant phenotypic heterogeneity, and some individuals never develop hypertension (Stowasser et al., 2000). ### Genetic Heterogeneity of Familial Hyperaldosteronism Familial hyperaldosteronism type II (HALD2; 605635) is caused by mutation in the CLCN2 gene (600570) on chromosome 3q27. Familial hyperaldosteronism type III (HALD3; 613677) is caused by mutation in the KCNJ5 gene (600734) on chromosome 11q24. Familial hyperaldosteronism type IV (HALD4; 617027) is caused by mutation in the CACNA1H gene (607904) on chromosome 16p13. Clinical Features Sutherland et al. (1966) and Salti et al. (1969) described a father and son with hypertension, low plasma renin activity, and increased aldosterone secretion. The symptoms were responsive to dexamethasone treatment. Growth and sexual development were normal. The father was found to have multiple adrenocortical adenomas. New and Peterson (1967) described 2 cases in a family. Giebink et al. (1973) studied 2 brothers and their mother who had glucocorticoid-remediable aldosteronism. Ganguly et al. (1981) reported a kindred with GRA spanning 3 generations. The presumptive diagnosis was first made in a 7-year-old boy and led to the identification in his mother and grandmother. Urinary analysis did not identify a putative 'aldosterone-stimulating factor,' suggesting that GRA is a distinct disorder from idiopathic aldosteronism. Bilateral adrenal hyperplasia was present. Ganguly et al. (1981) reported another affected family. The diagnosis of hyperaldosteronism was established by failure of saline infusion to suppress plasma aldosterone normally and by the failure of furosemide or a low sodium diet to stimulate plasma renin activity. One family had basal serum potassium levels below 3.5 mmol per liter, whereas values were normal in the second family. Ganguly et al. (1981) showed that the paradoxic decline in plasma aldosterone when the patient is in the upright posture, usually observed in aldosterone-producing adenoma, is also seen in GRA. Thus, in patients with primary aldosteronism in whom GSH is suspected on the basis of young age and family history and a postural decline in plasma aldosterone is demonstrated, treatment with glucocorticoid should be given for 4 to 6 weeks before localization procedures are begun. Gordon (1995) reported phenotypic heterogeneity of GRA in at least 21 members of a large kindred encompassing approximately 1,000 descendants of an English convict transported to Australia in 1837 for highway robbery in Northamptonshire. Affected individuals were often normokalemic, and some remained normotensive until late in life. Gordon (1995) referred to the disorder as 'familial hyperaldosteronism type I.' Gates et al. (1996) described 2 large pedigrees with GRA confirmed by genetic analysis. Most of the affected members, who had only mild hypertension and normal biochemistry, were clinically indistinguishable from patients with essential hypertension. The authors suggested that GRA is an underdiagnosed condition. Stowasser et al. (1999) found that 10 normotensive individuals with GRA who did not take antihypertensive medication had normal plasma levels and normal upright aldosterone levels. However, plasma aldosterone failed to rise by at least 50% during 2 hours of upright posture in 5 of 7 subjects, or during a 1-hour infusion of angiotensin II (2 ng/kg-min) in each of 6 subjects so studied. Serial, second-hourly (day-curve) aldosterone levels correlated tightly with cortisol (r of 0.79 to 0.97, P less than 0.01 to 0.001) but not with plasma renin activity (PRA) (r of 0.13 to 0.40, not significant) levels in each of 6 subjects, and plasma aldosterone suppressed to less than 110 pmol/L during 4 days of dexamethasone administration (0.5 mg 6 hourly) in each of 2 patients studied, consistent with ACTH-regulated aldosterone production. The authors concluded that biochemical evidence of excessive, abnormally regulated aldosterone production is present not only in hypertensive individuals with GSH, but also in those who are normotensive. Stowasser et al. (2000) studied 9 GRA individuals with mild hypertension (normotensive or onset of hypertension after 15 years of age, blood pressure never greater than 160/100 mm Hg, 1 medication or less required to control hypertension, no history of stroke, age greater than 18 years when studied) and 17 GRA individuals with severe hypertension (onset before 15 years of age, or systolic blood pressure greater than 180 mm Hg or diastolic blood pressure greater than 120 mm Hg at least once, or more than 2 medications, or history of stroke). Severe hypertension was more frequent in males (11 of 13 males vs 6 of 13 females; P less than 0.05). Four subjects still normotensive after age 18 years were females. Of 10 other affected, deceased individuals (7 males and 3 females) from a single family, 6 who died before 60 years of age (4 by stroke) were males. Aldosterone was unresponsive (rose by less than 50%) to angiotensin II in all subjects. Day-curve studies (blood collected every 2 hours for 24 hours; n = 2 mild and 7 severe) demonstrated abnormal regulation of aldosterone by ACTH rather than by angiotensin II in both groups. The authors concluded that the degree of hybrid gene-induced aldosterone overproduction may have contributed to the severity of hypertension. Mulatero et al. (2002) reported a 5-generation pedigree from Sardinia in which the presence of the chimeric gene was demonstrated in affected members of 4 generations. This family displayed a mild phenotype, with average blood pressure levels of 131/86 mm Hg for GRA patients. The occurrence of stroke was very low, and preeclampsia was not observed in 29 pregnancies from 8 GRA mothers. Mulatero et al. (2002) found a significant correlation between blood pressure and 18-hydroxycortisol, 18-oxocortisol, and plasma aldosterone levels, but not with kallikrein (KLK1; 147910). However, other biochemical or genetic parameters investigated could not explain the mild phenotype in this family. Clinical Management In 8 GRA patients who were rendered normotensive for 1.3 to 4.5 years by glucocorticoid treatment, Stowasser et al. (2000) found that urinary 18-oxocortisol levels remained above normal, although they were lower than before treatment. Other biochemical findings during treatment included higher upright plasma potassium, decreased aldosterone, increased renin activity, and decreased aldosterone-to-renin ratios. However, 4 patients had uncorrected renin levels and aldosterone-to-renin ratios. For each of the 8 patients, day-curve aldosterone levels during treatment correlated more tightly with cortisol than with PRA. The findings indicated that control of hypertension by glucocorticoid treatment was associated with only partial suppression of ACTH-regulated hybrid steroid and aldosterone production. Stowasser et al. (2000) concluded that normalization of urinary hybrid steroid levels and abolition of ACTH-regulated aldosterone production may not be a requisite for hypertension control in patients with GRA and cautioned against the risk of cushingoid side effects. Mapping By analysis of a large kindred with glucocorticoid-remediable aldosteronism, Lifton et al. (1992) demonstrated complete linkage to chromosome 8q (maximum lod score of 5.23). Molecular Genetics In affected members of a family with GRA, Lifton et al. (1992) identified a chimeric gene in which the 5-prime regulatory sequences of the CYP11B1 gene were fused to the coding region of the CYP11B2 gene (610613.0002), resulting in ectopic expression of aldosterone synthase in the zona fasciculata. In Australian GRA patients, Miyahara et al. (1992) found that the chimeric gene encoded a fused P-450 protein consisting of the amino-terminal portion (exons 1-4) of CYP11B1 and the carboxyl-terminal part (exons 5-9) of CYP11B2. The chimeric gene responsible for GRA is an example of an 'anti-Lepore-type fusion.' The various hemoglobins Lepore (e.g., 142000.0019) have a fusion beta-type subunit that is delta globin at the NH2 end and beta globin at the COOH end. This chimeric structure results from nonhomologous pairing and unequal crossing-over between the contiguous delta and beta globin genes. The hemoglobins Lepore result from delta-beta fusion because the delta globin gene (142000) is located upstream from the beta globin gene (141900). The hemoglobins anti-Lepore, e.g., Hb Miyada (141900.0179) and Hb P(Nilotic) (141900.0215), are the reciprocal product of nonhomologous pairing and unequal crossing-over between the HBD and HBB genes; they are beta-delta fusion globins. In GRA, the 5-prime portion of the downstream gene is the 5-prime portion of the fusion gene; hence, it is an anti-Lepore fusion. Diagnosis MacConnachie et al. (1998) used a multiplex PCR protocol that allowed amplification of the control aldosterone synthase and chimeric gene to be carried out in the same tube. They described the regions of crossover in each of 10 GRA kindreds identified in Scotland. To identify crossover regions in each of the kindreds, the chimeric long PCR products were cloned and sequenced. Five crossover sites were identified ranging from intron 2 to exon 4, indicating the reliability of the method in identifying chimeric genes resulting from different sites of crossover. In 8 patients with idiopathic hyperaldosteronism, a positive dexamethasone suppression test, and a negative genetic test for the chimeric CYP11B1/CYP11B2 gene, Fardella et al. (2001) did not find any abnormalities in exons 3 through 9 of CYP11B1. The authors suggested that a positive dexamethasone suppression test could lead to an incorrect diagnosis of GRA. Pathogenesis White (1989) noted that an enzyme required for aldosterone synthase can be recovered from the zona granulosa of rats that have been sodium-deprived and potassium-loaded. He suggested that glucocorticoid-suppressible hyperaldosteronism might be due to abnormal regulation of CYP11B2 or abnormal structure, such as gene conversion, of CYP11B1. In glucocorticoid-suppressible hyperaldosteronism, CYP11B2 activity is under the control of ACTH (which normally regulates CYP11B1), which results from an unequal crossing-over involving the CYP11B1 and CYP11B2 genes. These genes are normally in the following orientation: 5-prime--CYP11B2--CYP11B1--3-prime; the hybrid anti-Lepore gene lies between CYP11B2 and CYP11B1 and has B1 sequence at its 5-prime end and B2 sequence at its 3-prime end. The breakpoints of the various hybrid genes that have been studied have been found to be 5-prime of intron 4. Pascoe et al. (1992) demonstrated that hybrid cDNAs containing 5-prime sequences from CYP11B1 and 3-prime sequences from CYP11B2, when transfected into COS-1 cells, resulted in aldosterone synthesis at near normal levels when the constructs contained up to the first 3 exons of CYP11B1, while those with 5 or more exons from CYP11B1 produced no detectable aldosterone. Pascoe et al. (1995) studied a French kindred in which 7 members had GSH; of the 7, 2 also had adrenal tumors and 2 other members of the family had micronodular adrenal hyperplasia. RT-PCR and Northern blot analysis of 1 of the adrenal tumors and the surrounding adrenal tissue showed that the hybrid CYP11B1/CYP11B2 gene causing the disease was expressed at higher levels than either CYP11B1 or CYP11B2 in the adrenal cortex. In situ hybridization showed that both CYP11B1 and the hybrid chain were expressed in all 3 zones of the cortex. Cell culture experiments demonstrated that hybrid gene expression was stimulated by ACTH, leading to increased production of aldosterone and the hybrid steroids characteristic of GSH. The genetic basis of the tumors and hyperplasia in this family was not known, but may have been related to the duplication causing the hyperaldosteronism. In glucocorticoid-suppressible hyperaldosteronism, there are increased levels of 18-hydroxycortisol and 18-oxocortisol due to exposure of cortisol to abnormal CYP11B2 activity in the zona fasciculata. These products have been implicated as having a local inhibitory effect on 11-beta-hydroxylase activity (Jamieson et al., 1996). However, in Chinese hamster ovary cells transfected with human CYP11B1 and CYP11B2, Fisher et al. (2001) found that neither 18-hydroxycortisol nor 18-oxocortisol affected the 11-beta-hydroxylase activity of either enzyme. By contrast, 18-hydroxydeoxycorticosterone significantly reduced the conversion rate of 11-deoxycorticosterone to corticosterone and that of 11-deoxycortisol to cortisol by both enzymes, and increased the production rate of 18-hydroxycorticosterone and aldosterone by CYP11B2. Aldosterone synthase was also able to convert 18-hydroxydeoxycorticosterone to 18-hydroxycorticosterone and aldosterone, although its affinity for this substrate was much lower (4.76 micromol/liter) than that for 11-deoxycorticosterone (0.11 micromol/liter). History Mulrow (1981) speculated that the primary defect in GSH resides in the anterior pituitary gland. Experiments in animals had suggested the existence of another aldosterone-regulating hormone, possibly originating in the pituitary. Mulrow (1981) asked: 'Is it possible that in the familial disorder of glucocorticoid-suppressible hyperaldosteronism, the pituitary gland is synthesizing or processing a more potent form of (a fragment of proopiomelanocortin, POMC; 176830) that enhances the response of the adrenal glomerulosa cell to normal concentrations of ACTH?' This hypothesis later proved to be untrue. INHERITANCE \- Autosomal dominant CARDIOVASCULAR Vascular \- Hypertension (suppressible by glucocorticoid treatment) GENITOURINARY Kidneys \- Adrenal hyperplasia ENDOCRINE FEATURES \- Increased aldosterone LABORATORY ABNORMALITIES \- Normal or decreased serum potassium \- Increased aldosterone \- Low plasma renin activity \- Increased 18-oxocortisol \- Increased 18-hydroxycortisol MISCELLANEOUS \- Variable phenotypic expression \- Variable age at onset (childhood to adult) \- Chimeric CYP11B1/CYP11B2 gene is an anti-Lepore-like fusion product MOLECULAR BASIS \- Caused by fusion of the cytochrome P450, subfamily XIB, polypeptide 1 gene (CYP11B1, 610613 ) and the cytochrome P450, subfamily XIB, polypeptide 2 gene (CYP11B2, 124080 ) ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	HYPERALDOSTERONISM, FAMILIAL, TYPE I	c1260386	3,288	omim	https://www.omim.org/entry/103900	2019-09-22T15:41:16	{"doid": ["14080"], "mesh": ["C563177"], "omim": ["103900"], "icd-9": ["255.11"], "icd-10": ["E26.02"], "orphanet": ["403"], "synonyms": ["Alternative titles", "GLUCOCORTICOID-REMEDIABLE ALDOSTERONISM", "FH I", "GLUCOCORTICOID-SUPPRESSIBLE HYPERALDOSTERONISM", "ALDOSTERONISM, SENSITIVE TO DEXAMETHASONE", "ACTH-DEPENDENT HYPERALDOSTERONISM SYNDROME"]}
## Description Dermochondrocorneal dystrophy, or Francois syndrome, is a rare disorder characterized by the development of skin nodules, acquired deformities of the extremities, and a corneal dystrophy. The corneal dystrophy is central and superficial with whitish subepithelial opacities (summary by Bierly et al., 1992). Clinical Features Francois (1949) observed 2 affected sibs with skeletal deformity of the hands and feet; xanthoma-like nodules on the pinnae, dorsal surface of the metacarpophalangeal and interphalangeal joints, posterior surface of the elbows, nose, and ears; and corneal dystrophy. The parents were related in the case reported by Jensen (1958). Remky and Engelbrecht (1967) described the disorder in both of unlike-sex twins. They identified a hypercholesterolemic early stage, involvement of the entire skeleton except the vertebrae and skull, and abnormal EEG with seizures. Ruiz-Maldonado et al. (1977) described the disorder in Mexican brothers, aged 3 and 5 years. Bierly et al. (1992) restudied the Mexican brothers reported by Ruiz-Maldonado et al. (1977). Photographs of the nodules on the elbows and on the outer part of the ear were provided. Bierly et al. (1992) found that the brothers had developed confluent opacification of their central corneas with anterior stromal involvement and peculiar anterior cortical cataracts. Bierly et al. (1992) could find reports of only 9 cases of this disorder. Caputo et al. (1988) described a nonfamilial case in a 45-year-old woman who also had severe involvement of the gingival and palatal mucous membranes. The similarities to histiocytic dermatoarthritis (142730), a probable dominant disorder, should be noted. Hidalgo-Bravo et al. (2015) reported a 10-year-old girl of Mexican mestizo origin who had onset of pain in her hands at age 23 months and soon after developed nodules of the interphalangeal joints and soles bilaterally. At 6 years of age, osteochondral lesions emerged symmetrically on her hands and feet, causing progressive deformity. Soon after, small rounded corneal opacities were detected bilaterally. Examination showed bilateral symmetric dermatosis over the surface of multiple joints, as well as 0.5- to 2-cm soft, smooth, movable, skin-colored nodules with regular borders on her nose, ear lobes, helix, and antihelix. She had flexion contractures of the interphalangeal joints of both hands, bilateral hallux valgus, and xanthomatous-appearing lesions on the hands, feet, ears, and nose. Ophthalmologic examination revealed central punctate opacities of the cornea, involving all layers except the epithelium. Biopsy of a hand nodule showed deposits of extracellular hyaline material in the papillary and reticular dermis, corresponding to dense collagen fibers on staining. X-rays showed decreased bone mineralization, metaphyseal widening typical of dysplasia, bilateral coxa vara with left hip osteoarthritis, metacarpal deformity with apparent sclerosis of interphalangeal joints, and apparent dislocation of the distal phalanges from metatarsals. Hidalgo-Bravo et al. (2015) stated that fewer than 15 patients had been reported with dermochondrocorneal dystrophy, and that this was the third patient of Mexican mestizo origin. The authors reviewed previously reported patients and tabulated their clinical features. Inheritance The transmission pattern of dermochondrocorneal dystrophy in the families reported by Francois (1949) and Jensen (1958) was consistent with autosomal recessive inheritance. INHERITANCE \- Autosomal recessive HEAD & NECK Eyes \- Corneal dystrophy (onset early in childhood) \- Subepithelial corneal opacities \- Anterior cortical cataracts \- Anterior stromal haziness Mouth \- Gingival hypertrophy SKELETAL Hands \- Limited hand motion \- Joint subluxation Feet \- Limited feet motion \- Joint subluxation \- Defective, irregular tarsal ossification SKIN, NAILS, & HAIR Skin \- Skin nodules - fingers, elbows, nose, ears (onset infancy-childhood) ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	DERMOCHONDROCORNEAL DYSTROPHY	c0432288	3,289	omim	https://www.omim.org/entry/221800	2019-09-22T16:28:52	{"mesh": ["C535375"], "omim": ["221800"], "orphanet": ["79149"], "synonyms": ["Alternative titles", "FRANCOIS SYNDROME"]}
Nasal ganglioglioma is a rare tumor, presenting in newborns, containing both neuronal and astrocytic components and that can be endonasal, extranasal or both. It is usually identified as a nasal mass that may cause feeding difficulties and nasal obstruction. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Nasal ganglioglioma	None	3,290	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=141115	2021-01-23T18:30:00	{}
Heparin-induced thrombocytopenia (HIT) is an adverse reaction to the drug heparin resulting in an abnormally low amount of platelets (thrombocytopenia). HIT is usually an immune response which typically occurs 4-10 days after exposure to heparin; it can lead to serious complications and be life-threatening. This condition occurs in up to 5% of those who are exposed to heparin. Characteristic signs of HIT are a drop in platelet count of greater than 50% and/or the formation of new blood clots during heparin therapy. The first step of treatment is to discontinue and avoid all heparin products immediately. Often, affected individuals require another medicine to prevent blood clotting (anticoagulants). [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Heparin-induced thrombocytopenia	c0272285	3,291	gard	https://rarediseases.info.nih.gov/diseases/2650/heparin-induced-thrombocytopenia	2021-01-18T18:00:05	{"umls": ["C0272285"], "orphanet": ["3325"], "synonyms": ["HIT", "Heparin-induced thrombocytopenia"]}
Cheirospondyloenchondromatosis is an extremely rare type of enchondromatosis of very early onset (from neonatal period to infancy) characterized by symmetrical multiple enchondromas with metacarpal and phalangeal involvement resulting in short hands and feet, platyspondyly, mild to moderate short stature and intellectual disability. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Cheirospondyloenchondromatosis	c4510810	3,292	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=99647	2021-01-23T18:54:24	{"synonyms": ["Generalized enchondromatosis with platyspondyly"]}
A number sign (#) is used with this entry because of evidence that ovarian dysgenesis-1 (ODG1) is caused by homozygous or compound heterozygous mutation in the gene encoding follicle-stimulating hormone receptor (FSHR; 136435) on chromosome 2p16. Description Hypergonadotropic ovarian failure is a heterogeneous disorder that, in the most severe forms, is a result of ovarian dysgenesis. Ovarian dysgenesis accounts for about half the cases of primary amenorrhea (Timmreck and Reindollar, 2003). ### Genetic Heterogeneity of Ovarian Dysgenesis Even in its isolated form, 46,XX ovarian dysgenesis is etiologically heterogeneous. See ODG2 (300510), caused by mutation in the BMP15 gene (300247); ODG3 (614324), caused by mutation in the PSMC3IP gene (608665); ODG4 (616185), caused by mutation in the MCMDC1 gene (610098); ODG5 (617690), caused by mutation in the SOHLH1 gene (610224); ODG6 (618078), caused by mutation in the NUP107 gene (607617); ODG7 (618117), caused by mutation in the MRPS22 gene (605810); and ODG8 (618187), caused by mutation in the ESR2 gene (601663). See also ovarian dysgenesis with sensorineural deafness, or Perrault syndrome (233400). Clinical Features Elliott et al. (1959) reported the condition in 3 sisters who had normal stature and sex chromatin but had never menstruated and had severe osteoporosis. The parents were first cousins in the case of the 2 affected sisters (with normal stature and sex-chromatin positivity) reported by Klotz et al. (1956). Christakos et al. (1969) observed gonadal dysgenesis in 3 sisters whose parents were second cousins. Each had a normal female 46,XX karyotype. Somatic features of Turner syndrome were not found. All 3 had elevated gonadotropins, and laparotomy on the 2 older sisters showed streak gonads and unstimulated mullerian structures. Gonadal dysgenesis, often with somatic abnormalities, has been reported in sibs by several other authors and in some of these reports the parents were consanguineous. Simpson et al. (1971) pointed out that only affected sibs have been described and parental consanguinity is frequent. Vesely et al. (1980) reported 3 affected sisters and expressed the opinion that only the family reported by Elliott et al. (1959) was similar in having sisters above 152 cm in height, with no associated congenital anomalies. Aleem (1981) described affected sisters, aged 16 and 17, who presented with secondary amenorrhea. In a nationwide population-based study of women born between 1950 and 1976 in Finland, Aittomaki (1994) identified 75 patients with XX gonadal dysgenesis. In 1 family, 4 daughters were affected; in 6 families, 2 daughters were affected; and 57 cases were isolated. In 1 additional family, there were 2 affected females in successive generations. Consanguinity was detected in 8 of 66 families (12%). When only females were considered, the segregation analysis yielded a proportion of 0.23 affected. The relatively high incidence of 1 in 8,300 liveborn girls implied a high gene frequency in the Finnish population. The geographic distribution was highly uneven, with most families originating in the sparsely populated north-central part of Finland. The findings supported the existence of an autosomal recessive XXGD gene, which Aittomaki (1994) symbolized ODG1 (for ovarian dysgenesis-1), that is highly enriched in Finland. This is, thus, one of the examples of 'Finnish diseases' of which some 30 have been defined (de la Chapelle, 1993). To elucidate the proportion of cases due to an autosomal recessive gene or genes, Meyers et al. (1996) analyzed 17 published and 8 unpublished pedigrees with at least 2 female offspring. To minimize ascertainment bias, the analysis was restricted to cases in which ovarian failure was documented by the presence of streak ovaries (published cases) or elevated gonadotropins (unpublished cases), and published cases included only those reported before 1982. Meyers et al. (1996) showed that 32% of these cases were sporadic and 68% segregated in an autosomal recessive pattern. Mapping By linkage studies in Finnish multiplex families with hypergonadotropic ovarian dysgenesis and normal karyotype, Aittomaki et al. (1995) mapped the ODG1 locus to chromosome 2p. Molecular Genetics In the Finnish population in which ovarian dysgenesis with normal XX karyotype is relatively common (approximately 1 in 8,300 females), Aittomaki et al. (1995) demonstrated that affected females are homozygous for a missense mutation in the FSHR gene (A189V; 136435.0001). In a 30-year-old Armenian woman with oligomenorrhea followed by secondary amenorrhea, who had high FSH levels and normal-sized ovaries without maturing follicles or corpus luteum, Beau et al. (1998) identified compound heterozygosity for missense mutations in the FSHR gene (136435.0003-136435.0004). In a Finnish woman with primary amenorrhea and hypergonadotropic ovarian failure, Doherty et al. (2002) identified compound heterozygosity for A189V and another missense mutation in the FSHR gene (136435.0007). Kuechler et al. (2010) studied a 17-year-old girl with primary amenorrhea and incomplete pubertal development, who had elevated FSH and LH levels with low estradiol levels. Diagnostic laparoscopy revealed normal-sized ovaries and small uterus. Histologic examination of ovarian tissue showed disturbed folliculogenesis with a high number of primordial follicles, but complete absence of secondary or tertiary follicles. In this patient, Kuechler et al. (2010) identified compound heterozygosity for a missense mutation in the FSHR gene (136435.0014) and a seemingly balanced translocation in which analysis of the breakpoints demonstrated a 162.7-kb deletion encompassing exons 9 and 10 of FSHR gene. Skel \- Osteoporosis GU \- Gonadal dysgenesis \- Primary amenorrhea \- Streak gonads Endo \- Elevated gonadotropins Inheritance \- Autosomal recessive ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	OVARIAN DYSGENESIS 1	c0685837	3,293	omim	https://www.omim.org/entry/233300	2019-09-22T16:27:24	{"doid": ["0080493"], "mesh": ["D023961"], "omim": ["233300"], "orphanet": ["243"], "synonyms": ["Alternative titles", "OVARIAN DYSGENESIS, HYPERGONADOTROPIC, AUTOSOMAL RECESSIVE", "OVARIAN DYSGENESIS, HYPERGONADOTROPIC, WITH NORMAL KARYOTYPE", "GONADAL DYSGENESIS, XX TYPE", "XX GONADAL DYSGENESIS", "OVARIAN FAILURE, HYPERGONADOTROPIC"]}
Klippel-Feil syndrome is a bone disorder characterized by the abnormal joining (fusion) of two or more spinal bones in the neck (cervical vertebrae). The vertebral fusion is present from birth. Three major features result from this vertebral fusion: a short neck, the resulting appearance of a low hairline at the back of the head, and a limited range of motion in the neck. Most affected people have one or two of these characteristic features. Less than half of all individuals with Klippel-Feil syndrome have all three classic features of this condition. In people with Klippel-Feil syndrome, the fused vertebrae can limit the range of movement of the neck and back as well as lead to chronic headaches and muscle pain in the neck and back that range in severity. People with minimal bone involvement often have fewer problems compared to individuals with several vertebrae affected. The shortened neck can cause a slight difference in the size and shape of the right and left sides of the face (facial asymmetry). Trauma to the spine, such as a fall or car accident, can aggravate problems in the fused area. Fusion of the vertebrae can lead to nerve damage in the head, neck, or back. Over time, individuals with Klippel-Feil syndrome can develop a narrowing of the spinal canal (spinal stenosis) in the neck, which can compress and damage the spinal cord. Rarely, spinal nerve abnormalities may cause abnormal sensations or involuntary movements in people with Klippel-Feil syndrome. Affected individuals may develop a painful joint disorder called osteoarthritis around the areas of fused bone or experience painful involuntary tensing of the neck muscles (cervical dystonia). In addition to the fused cervical bones, people with this condition may have abnormalities in other vertebrae. Many people with Klippel-Feil syndrome have abnormal side-to-side curvature of the spine (scoliosis) due to malformation of the vertebrae; fusion of additional vertebrae below the neck may also occur. People with Klippel-Feil syndrome may have a wide variety of other features in addition to their spine abnormalities. Some people with this condition have hearing difficulties, eye abnormalities, an opening in the roof of the mouth (cleft palate), genitourinary problems such as abnormal kidneys or reproductive organs, heart abnormalities, or lung defects that can cause breathing problems. Affected individuals may have other skeletal defects including arms or legs of unequal length (limb length discrepancy), which can result in misalignment of the hips or knees. Additionally, the shoulder blades may be underdeveloped so that they sit abnormally high on the back, a condition called Sprengel deformity. Rarely, structural brain abnormalities or a type of birth defect that occurs during the development of the brain and spinal cord (neural tube defect) can occur in people with Klippel-Feil syndrome. In some cases, Klippel-Feil syndrome occurs as a feature of another disorder or syndrome, such as Wildervanck syndrome or hemifacial microsomia. In these instances, affected individuals have the signs and symptoms of both Klippel-Feil syndrome and the additional disorder. ## Frequency Klippel-Feil syndrome is estimated to occur in 1 in 40,000 to 42,000 newborns worldwide. Females seem to be affected slightly more often than males. ## Causes Mutations in the GDF6, GDF3, or MEOX1 gene can cause Klippel-Feil syndrome. These genes are involved in proper bone development. The protein produced from the GDF6 gene is necessary for the formation of bones and joints, including those in the spine. While the protein produced from the GDF3 gene is known to be involved in bone development, its exact role is unclear. The protein produced from the MEOX1 gene, called homeobox protein MOX-1, regulates the process that begins separating vertebrae from one another during early development. GDF6 and GDF3 gene mutations that cause Klippel-Feil syndrome likely lead to reduced function of the respective proteins. MEOX1 gene mutations lead to a complete lack of homeobox protein MOX-1. Although the GDF6, GDF3, and homeobox protein MOX-1 proteins are involved in bone development, particularly formation of vertebrae, it is unclear how a shortage of one of these proteins leads to incomplete separation of the cervical vertebrae in people with Klippel-Feil syndrome. When Klippel-Feil syndrome is a feature of another disorder, it is caused by mutations in genes involved in the other disorder. ### Learn more about the genes associated with Klippel-Feil syndrome * GDF3 * GDF6 * MEOX1 ## Inheritance Pattern When Klippel-Feil syndrome is caused by mutations in the GDF6 or GDF3 genes, it is inherited in an autosomal dominant pattern, which means one copy of the altered gene in each cell is sufficient to cause the disorder. When caused by mutations in the MEOX1 gene, Klippel-Feil syndrome 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. As a feature of another disorder, Klippel-Feil syndrome is inherited in whatever pattern the other disorder follows. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Klippel-Feil syndrome	c1861689	3,294	medlineplus	https://medlineplus.gov/genetics/condition/klippel-feil-syndrome/	2021-01-27T08:25:06	{"gard": ["10280"], "mesh": ["C536887"], "omim": ["118100", "214300", "613702"], "synonyms": []}
Tuftsin, which is derived from the heavy chain of human immunoglobulin, is a tetrapeptide (Thr--Lys--Pro--Arg) that stimulates the phagocytic activity of polymorphonuclear leukocytes. (Tuftsin was named for Tufts University where the tetrapeptide was discovered.) It is activated in the spleen and bound to a carrier leukokinin molecule, a gamma-globulin which coats the polymorph. Tuftsin is absent in splenectomized humans and dogs. Its absence after splenectomy leads to problems with infection. Congenital familial deficiency of tuftsin with a history of repeated and severe infections has been observed in at least 4 families (Constantopoulos and Najjar, 1973; Najjar, 1981). In each of the 2 families reported by Constantopoulos et al. (1972), 1 child had recurrent infections and 1 parent had low tuftsin levels but was asymptomatic. Constantopoulos et al. (1972) observed affected father and son. In 1 patient, a mutant peptide was identified as Thr-Glu-Pro-Arg, representing a transition mutation (A-to-G) such that AAA or AAG = lysine is converted to GAA or GAG = glutamic acid (Konopinska et al., 1981). Bump et al. (1986) isolated the tuftsin receptor. Najjar (1987) indicated that in all instances only 1 parent of tuftsin-deficient individuals has also been deficient and that in no instances have both parents been normal. It is noteworthy that although this seems to be an autosomal dominant trait, the deficiency is complete. This suggests that allelic exclusion may be operative. Some of the tuftsin deficiency cases, which in Najjar's experience total 20, have been discovered as a result of studying patients with recurrent infections in whom no immune abnormality could be demonstrated, but in whom gamma globulin, administered for lack of anything else to do, resulted in great benefit (Najjar, 1987). Cases have been reported in Japan. In attempts to produce an antibody against tuftsin for diagnostic use, Naim et al. (1989) found that tuftsin appears to be nonantigenic to mammals even when coupled to various carrier proteins. Thus, the only reliable analytical assays are physical methods such as RP-HPLC and mass spectrometry. Misc \- Repeated severe infections \- Tuftsin is absent after splenectomy \- Post-splenectomy problems with infection Lab \- Congenital tuftsin deficiency 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 [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	TUFTSIN DEFICIENCY	c0398741	3,295	omim	https://www.omim.org/entry/191150	2019-09-22T16:32:14	{"mesh": ["C562872"], "omim": ["191150"]}
A rare autosomal recessive connective tissue disorder characterized by tortuosity and elongation of the large and medium-sized arteries and a propensity towards aneurysm formation, vascular dissection, and stenosis of the pulmonary arteries. ## Epidemiology Approximately 100 patients have been described in the literature so far. The male to female ratio is 1:1. ## Clinical description The clinical manifestations are variable, depending on the arteries affected. Onset usually occurs in infancy or early childhood. The cardiovascular anomalies may lead to right ventricular hypertension, acute respiratory symptoms, ventricular hypertrophy and cardiac failure. Patients are prone to aneurysm formation, dissection and ischemic events. Other typical manifestations include facial dysmorphism (features variably include an long face, hypertelorism, downslanting palpebral fissures, beaked nose, sagging cheeks, a high palate, and micrognathia), soft and hyperextensible skin, cutis laxa, hernias (inguinal, diaphragmatic, or hiatal), skeletal abnormalities, joint hypermobility, congenital contractures, keratoconus and generalized hypotonia. ## Etiology The disease is caused by loss-of-function mutations in the SLC2A10 gene (20q13.12), encoding the glucose/dehydroascorbic acid transporter 10 (GLUT10). So far, 35 SLC2A10 pathogenic variants have been reported in approximately 80 families. The exact role of GLUT10 in the pathogenesis of the disorder remains to be fully clarified. Previous evidences revealed that the deficiency of GLUT10 perturbs the canonical transforming growth factor beta (TGFbeta) pathway, activates a non-canonical alphavbeta3 integrin-TGF beta receptor II signaling and causes the disorganization of different extracellular matrix proteins (i.e. collagens, elastin, fibronectin, decorin), which are essential for the structural integrity of several connective tissues including blood vessels wall. Moreover, as GLUT10 acts as an intracellular transporter of dehydroascorbic acid, the shortage of ascorbate might impair collagen and elastin crosslinking in the endoplasmic reticulum, redox homeostasis in the mitochondria and global and gene-specific methylation/hydroxymethylation affecting the epigenetic regulation in the nucleus. ## Diagnostic methods Diagnosis requires further examination by echocardiography (ECG), angiography, and magnetic resonance angiography (MRA) and/or CT scan. Histology shows disruption of elastic fibers of the medial layer of the arterial wall. Detection of mutations in the SLC2A10 gene allows confirmation of the clinical diagnosis, and allows adapted genetic counseling and prognostic information to be provided to the patients. ## Differential diagnosis The differential diagnosis should include Loeys-Dietz syndrome, Ehlers-Danlos syndromes (particularly the vascular-like classical Ehlers-Danlos syndrome), Marfan syndrome, occipital horn syndrome, and autosomal recessive cutis laxa (particularly the EFEMP2-, FBLN5-, and LTBP4-related Cutis laxa. ## Antenatal diagnosis Prenatal diagnosis may be suspected by echocardiography and ultrasonography, and can be confirmed by prenatal molecular diagnosis performed on chorionic villi or amniocytes. Pregnancy requires intensive monitoring of both mother and fetus, cesarean delivery, and multidisciplinary postpartum care. ## Genetic counseling The pattern of inheritance is autosomal recessive. The risk of inheriting the disease is 25% where both parents are unaffected carriers. ## Management and treatment All patients require regular follow-up (periodic EGC, and MRA and/or CT scan) and may benefit from surgical interventions (aortic root replacement for aortic aneurysms and pulmonary artery reconstruction). ## Prognosis The prognosis can be severe and the first few years of life, usually before 5 years of age, might be critical for potentially life-threatening events. The main causes of premature death are respiratory insufficiency due to pulmonary artery stenosis, and heart failure due to either right ventricular hypertension and hypertrophy, myocarditis, and organ failure due to ischemic events. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Arterial tortuosity syndrome	c1859726	3,296	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=3342	2021-01-23T17:18:08	{"gard": ["774"], "mesh": ["C565942"], "omim": ["208050"], "umls": ["C1859726"], "icd-10": ["I77.1"], "synonyms": ["ATS"]}
Natural variation in gene expression is extensive, and variation in the baseline expression level of many genes has a heritable component. To localize the genetic determinants of these quantitative traits (gene expression phenotypes), Morley et al. (2004) used microarray analysis to measure gene expression levels and performed genomewide linkage analysis for expression levels of 3,554 genes in 14 large CEPH families. They identified 142 expression phenotypes with evidence of linkage to a regulatory region that exceeded a P value of less than 4.3 x 10(-7), which corresponds to a lod score of about 5.3. Of these 142, 27 (19%) had only a cis-acting transcriptional regulator, 110 (77.5%) had only a trans-acting regulator, and 5 (3.5%) had 2 regulators (2 phenotypes with a cis- and a trans-acting regulator, and 3 phenotypes with 2 trans-acting regulators). When Morley et al. (2004) lowered the threshold of linkage to a P value of less than 3.7 x 10(-5), which corresponds to a lod score of about 3.4, they identified 984 expression phenotypes. Among these 984, 164 (16%) had multiple regulators of expression level, a much higher percentage than the 3.5% found using the more stringent threshold. Furthermore, Morley et al. (2004) identified hotspots of transcriptional regulation where significant evidence of linkage for several expression phenotypes coincided, and expression levels of many genes sharing the same regulatory region were significantly correlated. They identified 2 hotspots for transcriptional regulation with 6 or more hits (P less than 0.03 after Bonferroni correction): chromosome 14q32 (GEVQ1), where 7 phenotypes mapped, and chromosome 20q13 (GEVQ2; 608878), where 6 phenotypes mapped. Using the less stringent criteria, 31 of the 984 expression phenotypes mapped to the 5-Mb window on chromosome 14, and regulation for 25 phenotypes mapped to the 5-Mb window on chromosome 20. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	GENE EXPRESSION, VARIATION IN, QUANTITATIVE TRAIT LOCUS ON CHROMOSOME 14	c1837209	3,297	omim	https://www.omim.org/entry/608875	2019-09-22T16:07:05	{"omim": ["608875"], "synonyms": ["Alternative titles", "GEVQ1"]}
## Description Alzheimer disease (AD) is a neurodegenerative disorder characterized by subtle onset of memory loss followed by a slowly progressive dementia. The great majority of AD cases are of late onset (LOAD) after age 65 years. LOAD shows complex, nonmendelian patterns of inheritance, and most likely results from the combined effects of variation in a number of genes as well as from environmental factors (summary by Grupe et al., 2006). The Alzheimer disease-6 (AD6) designation refers to a susceptibility locus on chromosome 10q. Although significant associations with several candidate genes on chromosome 10 have been reported, these findings have not been consistently replicated, and they remain controversial (Grupe et al., 2006). For a discussion of genetic heterogeneity of Alzheimer disease, see 104300. Clinical Features Bassett et al. (2005) performed functional magnetic resonance imaging (fMRI) of 9 asymptomatic female offspring from AD families linked to the chromosome 10q region and 6 females from AD families unlinked to this region. These individuals were on average 11.3 years younger than the onset age of their parents. All were APOE4-(107741) negative. During memory encoding tasks, individuals from the 10q-linked families showed more extensive activation in the bilateral temporal and frontal lobes as well as in the thalamus and right parahippocampal gyrus, compared to offspring from the unlinked families who showed only unilateral frontal and temporal lobe activation. These differences were seen despite similar memory performance. Bassett et al. (2005) suggested that there may be different cognitive strategies representing different regional limitations in the brain between AD families linked and unlinked to 10q. Mapping Bertram et al. (2000) performed parametric and nonparametric linkage analyses of 7 genetic markers on chromosome 10q, 6 of which map near the insulin-degrading enzyme gene (IDE; 146680), in 435 multiplex Alzheimer disease families. These analyses revealed significant evidence of linkage for adjacent markers (D10S1671, D10S583, D10S1710, and D10S566), which was most pronounced in late-onset AD (LOAD) families. Furthermore, Bertram et al. (2000) found evidence for allele-specific association between the putative disease locus and marker D10S583, which is located within 195 kb of the IDE gene. Using an autosomal dominant model, the maximum 2-point parametric lod score was 3.3 at theta of 0.22 at marker D10S583. In late-onset families, the highest lod score was 3.4 with theta of 0.16 at marker D10S1671. Myers et al. (2000) performed a 2-stage genomewide screen in sib pairs with late-onset Alzheimer disease to detect susceptibility loci other than APOE and identified an Alzheimer disease locus on chromosome 10q. Using multiple stages of analysis, they achieved a lod score of 3.83 using 429 sib pairs, close to marker D10S1225. This locus modifies risk for Alzheimer disease independent of APOE genotype. Myers et al. (2000) estimated a relative risk to sibs for this locus to be about equivalent to that for APOE. Ertekin-Taner et al. (2000) found that there is a quantitative trait locus for high plasma amyloid beta-42 levels that maps to the same region of 10q24 as Alzheimer disease. Plasma amyloid beta-42 is invariably elevated in early-onset familial Alzheimer disease, and it is also increased in first-degree relatives of patients with typical late-onset Alzheimer disease. To detect LOAD loci that increase amyloid beta-42, Ertekin-Taner et al. (2000) used plasma amyloid beta-42 as a surrogate trait and performed linkage analysis on extended Alzheimer disease pedigrees identified through a LOAD patient with extremely high plasma amyloid beta. Ertekin-Taner et al. (2000) reported linkage to chromosome 10 with a maximum lod score of 3.93 at 81 cm, close to D10S1225. They noted that linkage to the same region was obtained in a genomewide screen of LOAD sib pairs by Myers et al. (2000). These results provided strong evidence for a novel LOAD locus on chromosome 10 that acts to increase amyloid beta. By linkage analysis of 5 Amish families from the midwestern U.S. in which 49 individuals had late-onset dementia or mild cognitive impairment, Hahs et al. (2006) obtained 2-point lod scores greater than 1.5 at marker D10S2327 on 10q22 (lod scores of 2.42 and 1.42). The results were obtained under a model assuming autosomal recessive inheritance. Grupe et al. (2006) reported evidence suggesting a genetic association between SNP rs498055 on 10q24, upstream of the SORBS1 gene (605264) and located near a putative homolog of ribosomal protein S3a (RPS3A; 180478), and risk of LOAD in 4 of 6 independent case-control samples. However, Bertram et al. (2006) could not corroborate this association in 2 independent family samples. Furthermore, analysis of 3 family-based and 1 case-control datasets by Liang et al. (2008) showed that rs498055 was not associated with an increased risk of late-onset Alzheimer disease. In a genome screen of individuals from an isolated population from the southwestern area of the Netherlands, ascertained as part of the Genetic Research in Isolated Populations (GRIP) program, Liu et al. (2007) confirmed the AD locus at 10q22-q24 (AD6). Overall, multipoint analysis revealed 4 significant and 1 suggestive linkage peak. Liu et al. (2007) next tested for association between cognitive function as an endophenotype of AD and 4,173 single-nucleotide polymorphisms in the linked regions in an independent sample consisting of 197 individuals from the GRIP region. After adjusting for multiple testing, they detected significant association with cognitive function at 10q22-q24. A study of potential disease-causing genes in the region pointed to the HTR7 (182137), MPHOSPH1 (605498), and CYP2C (124020) cluster. By genomewide analysis of 3 large cohorts totaling 723 affected relative pairs with late-onset AD, Hamshere et al. (2007) found linkage to a locus on chromosome 10q21.2 (lod score of 3.3 at D10S464). There was no evidence to suggest that more than 1 locus was responsible for the linkage to 10q21.2, although this region may harbor more than 1 susceptibility gene. Evidence for an interaction was observed between loci on chromosomes 10 and 19. By genotyping SNPs spanning 80.2 Mb on chromosome 10q in a family-based data set containing 1,337 discordant sib pairs from 567 multiplex families and an independent case-control data set containing 483 cases and 879 controls, Liang et al. (2007) found that 22 SNPs in 5 candidate genes yielded significant association results in at least 1 data set, including SNPs in CTNNA2 (p = 0.03) in both data sets. However, the results did not converge with linkage analysis, suggesting that there is more extensive heterogeneity on chromosome 10 than had been appreciated. Liang et al. (2009) examined 28 genes on chromosome 10 for association with LOAD in a Caucasian case-control cohort of 506 cases and 558 controls. Two SNPs in 2 genes remained significant after correction for multiple testing: rs10508533 in PTPLA (610467) on 10p14-p13 (p = 0.0022) and rs17277986 in SORCS1 (606283) on 10q23 (p = 0.0025). The SORC1 association was not replicated in the validation and family-trio data sets. Multifactor dimensionality reduction yielded a significant association with the SORCS1 SNP rs17277986 in females (p = 0.00002; OR, 1.7). Reitz et al. (2011) analyzed genotypic data for 16 SNPs in the SORCS1 gene from 6 independent data sets totaling 2,809 patients and 3,482 controls. Inherited variants in SORCS1 were associated with AD in 5 of the 6 datasets, but the specific alleles and direction of association differed. Metaanalysis of single-SNP association data yielded significant associations in all datasets (p = 0.001 to 0.049). Using microarray gene expression and RT-PCR, Reitz et al. (2011) found decreased expression of SORCS1 in the amygdala of 19 AD brains compared to 10 controls. Expression levels appeared to correlate with certain disease-associated SNPs. In HEK293 cells with an AD-associated APP mutation (104760.0008), overexpression of SORCS1 resulted in a significant decrease in amyloid-beta-40 and -beta-42 secretion, whereas suppression of SORCS1 in HEK293 cells increased beta-amyloid-40 levels. The findings indicated that SORCS1 can influence APP processing, and Reitz et al. (2011) suggested that variation in the SORCS1 gene may be associated with risk of LOAD. Molecular Genetics ### IDE Gene Abraham et al. (2001) identified 8 single-nucleotide polymorphisms (SNPs) in the IDE gene. They found no association between late-onset Alzheimer disease and any of the individual SNPs or with any haplotypes. Prince et al. (2003) used a SNP genetic association strategy to investigate Alzheimer disease in relation to a 480-kb region encompassing the IDE gene. They interpreted the results as providing 'substantial' evidence that genetic variation within or very close to IDE impacts both disease risk and traits related to the severity of Alzheimer disease. Grupe et al. (2006) reported no association between AD and the IDE gene. In 176 patients with LOAD, Zou et al. (2010) measured cerebellar expression levels of 12 LOAD candidate genes. Genomewide association analysis using 564 cis-SNPs identified a significant association between rs7910977, located 4.2 kb beyond the 3-prime end of the IDE gene, and 2-fold higher cerebellar expression levels of IDE (p = 2.7 x 10(-8)). In the combined group of 565 patients with LOAD, the minor allele of rs7910977 was associated with 1.45-fold increased cerebellar expression of IDE (p = 2.6 x 10(-5)). When results from 7 independent case-control series involving 2,280 LOAD cases and 2,396 controls were combined, the minor allele of rs7910977 yielded a protective effect (OR, 0.81; p = 0.0046). ### PLAU Gene Finckh et al. (2003) noted that the urokinase gene (PLAU; 191840) maps to the AD6 critical region on chromosome 10. They genotyped a frequent C/T SNP of the PLAU gene, which results in a pro141-to-leu (P141L) mutation (rs2227564; 191840.0001), in 347 patients with LOAD and 291 control subjects. LOAD was associated with a CC genotype in the whole sample as well as in all subsamples stratified by gender or APOE4 (107741) carrier status. The odds ratio for LOAD due to a CC genotype was 1.89. Finckh et al. (2003) suggested that PLAU is a susceptibility gene for LOAD, with allele C (P141) being a recessive risk allele and allele T (L141) conferring protection. Ertekin-Taner et al. (2005) found significant association between PLAU 5-SNP haplotypes and LOAD in 3 independent series of 204, 148, and 113 AD patients with matched controls. Plasma A-beta-42 levels among individuals over 50 years old in 10 extended LOAD families were also significantly associated with PLAU haplotypes (p = 0.005). The CT and TT genotypes of rs2227564 were associated with LOAD (p = 0.05) and with age-dependent elevation of plasma A-beta-42 in 24 extended LOAD families (p = 0.0006). In Plau-knockout mice, plasma A-beta-42 and A-beta-40 levels, but not levels in brain, were significantly elevated in an age-dependent manner. Grupe et al. (2006) reported no association between AD and the PLAU gene. ### CTNNA3 Gene Alpha-T-catenin (CTNNA3; 607667) is a binding partner of beta-catenin (CTNNB1; 116806). In turn, CTNNB1 interacts with PSEN1 (104311), which has many mutations that elevate A-beta-42 and cause early-onset familial AD. The CTNNA3 gene maps to the AD6 region for which Ertekin-Taner et al. (2000) previously reported significant linkage to LOAD. Ertekin-Taner et al. (2003) identified 2 intronic CTNNA3 SNPs in strong linkage disequilibrium that showed highly significant association with plasma A-beta-42 levels in 10 extended LOAD families. Grupe et al. (2006) reported no association between AD and the CTNNA3 gene. In a study of 363 Japanese LOAD patients, with validation in a second set of 336 Japanese LOAD patients, Miyashita et al. (2007) found that 7 SNPs, spanning about 38 kb in intron 9 of the CTNNA3 gene, were associated with late-onset AD in females (p values of 5.95 x 10(-6) to 7.66 x 10(-4) after correction). Multiple logistic regression analysis of a total of 2,762 subjects (1,313 LOAD patients and 1,449 controls) demonstrated significant interaction between rs713250 and female patients but not with male patients. The data suggested that variation in the CTNNA3 gene may affect LOAD through a female-specific mechanism independent of the APOE4 allele. ### CALHM1 Gene Dreses-Werringloer et al. (2008) identified a 394C-T SNP (rs2986017), resulting in a pro86-to-leu (P86L) substitution, in the CALHM1 gene (612234) on chromosome 10q24.33. In 5 independent case-control populations including a total of 2,043 patients with late-onset AD and 1,361 controls, the authors observed an association between the T allele of this SNP and disease (odds ratio of 1.44, p = 2 x 10(-10)). In vitro functional expression studies showed that the polymorphic P86L channel exhibited decreased CALHM1-induced calcium permeability, resulting in decreased cytosolic calcium levels, as well as impaired ability to inhibit generation of insoluble beta-amyloid. The findings indicated a role for calcium signaling in APP (104760) processing and suggested that variations in the CALHM1 gene may influence susceptibility to late-onset AD. Beecham et al. (2009) were unable to replicate the findings of Dreses-Werringloer et al. (2008) in a case-control study of 510 patients with late-onset AD and 524 controls. Beecham et al. (2009) found no association with rs2986017 despite adequate power. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	ALZHEIMER DISEASE 6	c0276496	3,298	omim	https://www.omim.org/entry/605526	2019-09-22T16:11:12	{"doid": ["0110038"], "mesh": ["D000544"], "omim": ["605526"], "orphanet": ["1020"], "synonyms": ["Alternative titles", "AD6", "ALZHEIMER DISEASE 6, LATE-ONSET"]}
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. (February 2013) Inflammatory myeloblastic tumor Inflammatory myeloblastic tumor (IMT), also known as an "inflammatory pseudotumor", is a rare benign tumor occurring in the liver and/or bile ducts.[1] ## References[edit] 1. ^ Faraj W., Ajouz H., Mukherji D. et al. World J Surg Oncol 2011; 9:5. This oncology article is a stub. You can help Wikipedia by expanding it. * v * t * e [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Inflammatory myeloblastic tumor	c0334121	3,299	wikipedia	https://en.wikipedia.org/wiki/Inflammatory_myeloblastic_tumor	2021-01-18T19:05:48	{"mesh": ["D006104"], "umls": ["C0334121"], "wikidata": ["Q6030096"]}

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