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Spinal muscular atrophy with progressive myoclonic epilepsy (SMA-PME) is a neurological condition that causes muscle weakness and wasting (atrophy) and a combination of seizures and uncontrollable muscle jerks (myoclonic epilepsy). In individuals with SMA-PME, spinal muscular atrophy results from a loss of specialized nerve cells, called motor neurons, in the spinal cord and the part of the brain that is connected to the spinal cord (the brainstem). After a few years of normal development, affected children begin experiencing muscle weakness and atrophy in the lower limbs, causing difficulty walking and frequent falls. The muscles in the upper limbs are later affected, and soon the muscle weakness and atrophy spreads throughout the body. Once weakness reaches the muscles used for breathing and swallowing, it leads to life-threatening breathing problems and increased susceptibility to pneumonia. A few years after the muscle weakness begins, affected individuals start to experience recurrent seizures (epilepsy). Most people with SMA-PME have a variety of seizure types. In addition to myoclonic epilepsy, they may have generalized tonic-clonic seizures (also known as grand mal seizures), which cause muscle rigidity, convulsions, and loss of consciousness. Affected individuals can also have absence seizures, which cause loss of consciousness for a short period that may or may not be accompanied by muscle jerks. In SMA-PME, seizures often increase in frequency over time and are usually not well-controlled with medication. Individuals with SMA-PME may also have episodes of rhythmic shaking (tremors), usually in the hands; these tremors are not thought to be related to epilepsy. Some people with SMA-PME develop hearing loss caused by nerve damage in the inner ear (sensorineural hearing loss). Individuals with SMA-PME have a shortened lifespan; they generally live into late childhood or early adulthood. The cause of death is often respiratory failure or pneumonia. ## Frequency SMA-PME is a rare disorder; approximately a dozen affected families have been described in the scientific literature. ## Causes SMA-PME is caused by mutations in the ASAH1 gene. This gene provides instructions for making an enzyme called acid ceramidase. This enzyme is found in lysosomes, which are cell compartments that digest and recycle materials. Within lysosomes, acid ceramidase breaks down fats called ceramides into a fat called sphingosine and a fatty acid. These two breakdown products are recycled to create new ceramides for the body to use. Ceramides have several roles within cells. For example, they are a component of a fatty substance called myelin that insulates and protects nerve cells. ASAH1 gene mutations that cause SMA-PME result in a reduction of acid ceramidase activity to a level less than one-third of normal. Inefficient breakdown of ceramides and impaired production of its breakdown products likely play a role in the nerve cell damage that leads to the features of SMA-PME, but the exact mechanism is unknown. ### Learn more about the gene associated with Spinal muscular atrophy with progressive myoclonic epilepsy * ASAH1 ## 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	Spinal muscular atrophy with progressive myoclonic epilepsy	c1834569	1,700	medlineplus	https://medlineplus.gov/genetics/condition/spinal-muscular-atrophy-with-progressive-myoclonic-epilepsy/	2021-01-27T08:25:29	{"gard": ["3875"], "mesh": ["C537563"], "omim": ["159950"], "synonyms": []}
Lip licker's dermatitis Other namesIrritant contact cheilitis, perioral irritant contact dermatitis, perioral dermatitis Lip licker's dermatitis from a child repeatedly licking lips CausesRepeated lip licking Diagnostic methodBased on symptoms Differential diagnosisPerioral dermatitis MedicationEmollient Lip licker's dermatitis, also called irritant contact cheilitis, is a type of skin inflammation around the lips due to saliva from repetitive lip licking. The resulting scaling, redness, chapping and crusting make a well-defined ring around the lips. The rash may extend as far as the tongue can reach and frequently spares the angle of the mouth. It is treated with simple moisturisers, emollients, and sometimes topical steroids.[1][2][3] It is different to perioral dermatitis, which spares the vermillion border and is worsened by topical steroids.[4][3] Children are affected more often than adults. ## Contents * 1 Signs and symptoms * 2 Causes * 3 Diagnosis * 4 Treatment * 5 References ## Signs and symptoms[edit] lip licker's dermatitis Redness around the lips in circumoral distribution with dryness and scale is typical.[3][5] Chapping may also occur, especially in cold weather.[6] ## Causes[edit] Repeated licking resulting in a cycle of wetting and drying causes the redness, fissuring, and scale.[4] It can also occur with lip chewing, thumb sucking, or excessive drooling.[7] Wind instrument players may also experience lip licker's dermatitis.[8] Compulsive licking of lips causing lip licker's dermatitis is also seen as psychological disorder.[9] Persistent and continuous breathing from the mouth can cause dry lips and result in the temptation to repeatedly lick the lips with the aim to keep them moist.[10] ## Diagnosis[edit] The diagnosis of lip licker's dermatitis is from the history and inspection of the rash. It is important to distinguish it from allergic contact dermatitis and perioral dermatitis which are characterised by papules in the perioral area and sparing of the vermillion border, and worsened by topical steroids.[11][3] ## Treatment[edit] Generous application of bland emollients can improve the rash. However, complete resolution will not occur until the lip licking stops.[4] Breaking the cycle (dryness, then licking, followed by more dryness) is key to treatment. Sometimes, unlike in perioral dermatitis, topical steroids may be used for few days only.[12] ## References[edit] 1. ^ Dyall-Smith, Delwyn. "Eczematous cheilitis \| DermNet NZ". dermnetnz.org. Retrieved 4 January 2020. 2. ^ "EK02.21 Irritant contact dermatitis due to saliva". icd.who.int. ICD-11 - Mortality and Morbidity Statistics. Retrieved 4 January 2020. 3. ^ a b c d Paller, Amy S.; Mancini, Anthony J. (2016). "3. Eczematous Eruptions in Childhood". Hurwitz Clinical Pediatric Dermatology: A Textbook of Skin Disorders of Childhood and Adolescence (5th ed.). Edinburgh: Elsevier. pp. 62–63. ISBN 9780323244756. 4. ^ a b c Cohen, Bernard C (2013). "9. Oral Cavity". Paediatric Dermatology. Saunders Elsevier. pp. 240–263. ISBN 978-0-7234-3655-3. 5. ^ Tolaymat, Leila; Hall, Matthew R. (2019), "Perioral Dermatitis", StatPearls, StatPearls Publishing, PMID 30247843, retrieved 4 January 2020 6. ^ Rudikoff, Donald; Cohen, Steven R.; Scheinfeld, Noah (2014). Atopic Dermatitis and Eczematous Disorders. CRC Press. p. 51. ISBN 978--1-84076-195-5. 7. ^ Leung, Donald; Szefler, Stanley; Bonilla, Francisca; Akdis, Cezmi A; Sampson, Hugh (2016). "Contact Dermatitis". Paediatric Allergy (third ed.). pp. 467–481. ISBN 978-0-323-29875-9. 8. ^ Bolognia, Jean L; Schaffer, Julie V; Cerroni, Lorenzo (2018). "Environmental and Sports-Related Skin Diseases". Dermatology (4th ed.). Elsevier. pp. 1569–1594. ISBN 978-0-7020-6275-9. 9. ^ Harth, Wolfgang; Gieler, Uwe; Kusnir, Daniel; Tausk, Francisco A. (2008). "Part II: Specific Pattern of Diseases". Clinical Management in Psychodermatology. Springer. p. 20. ISBN 9783540347187. 10. ^ Robert Kliegman (2016). Nelson Textbook of Pediatrics. Elsevier. p. 1078–1082. ISBN 978-0-323-44919-9. 11. ^ Vanderweil, Stefan; Levin, Nikki A. (2009). "Periorbital Dermatitis: It's Not Every Rash That Occurs Around the Mouth". Medscape. Retrieved 4 January 2020. 12. ^ Braun-Falco, Otto; Plewig, Gerd; Wolff, Helmut Heinrich; Burgdorf, Walter (2000). "12. Dermatitis". Dermatology. Berlin: Springer. p. 510. ISBN 3-540-59452-3. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor *[BMI]: body mass index	Lip licker's dermatitis	None	1,701	wikipedia	https://en.wikipedia.org/wiki/Lip_licker%27s_dermatitis	2021-01-18T19:04:53	{"wikidata": ["Q48988826"]}
Asterixis Other namesFlapping tremor, liver flap SpecialtyNeurology Asterixis is a tremor of the hand when the wrist is extended, sometimes said to resemble a bird flapping its wings. This motor disorder is characterized by an inability to maintain a position, which is demonstrated by jerking movements of the outstretched hands when bent upward at the wrist. The tremor is caused by abnormal function of the diencephalic motor centers in the brain, which regulate the muscles involved in maintaining position. Asterixis is associated with various encephalopathies due especially to faulty metabolism.[1] The term derives from the Greek a, "not" and stērixis, "fixed position". Asterixis is the inability to maintain posture due to a metabolic encephalopathy. This can be elicited on physical exam by having the patient extend their arms and bend their hands back. With a metabolic encephalopathy, the patient is unable to hold their hands back resulting in a “flapping” motion consistent with asterixis. It can be seen in any metabolic encephalopathy e.g. chronic kidney failure, severe congestive heart failure, acute respiratory failure and commonly in decompensated liver failure. ## Contents * 1 Associated conditions and presentation * 2 History * 3 References * 4 External links ## Associated conditions and presentation[edit] Usually there are brief, arrhythmic interruptions of sustained voluntary muscle contraction causing brief lapses of posture, with a frequency of 3–5 Hz. It is bilateral, but may be asymmetric. Unilateral asterixis may occur with structural brain disease.[2] * It can be a sign of hepatic encephalopathy, damage to brain cells presumably due to the inability of the liver to metabolize ammonia to urea. The cause is thought to be predominantly related to abnormal ammonia metabolism.[3] * Asterixis is seen most often in drowsy or stuporous patients with metabolic encephalopathies, especially in decompensated cirrhosis or acute liver failure. * It is also seen in some patients with kidney failure and azotemia. * It can also be a feature of Wilson's disease. * Asterixis is also seen in respiratory failure due to carbon dioxide toxicity (hypercapnia). * Some drugs are known to cause asterixis, particularly phenytoin (when it is known as phenytoin flap). Other drugs implicated include benzodiazepines,salicylates, barbiturates, valproate, gabapentin, lithium, ceftazidime, and metoclopramide. ## History[edit] R.D. Adams and J.M. Foley first described asterixis in 1949 in patients with severe liver failure and encephalopathy.[4] Initially Foley and Adams referred to asterixis simply as "tremor" but realized that they needed a more appropriate term. On a literature search they found a poorly described phenomenon in similar patients mentioned by German physicians called “jactitations” but the reference was vague. Foley consulted Father Cadigan, a Jesuit classics scholar, who suggested “anisosterixis” (an "negative"–iso "equal"–sterixis "firmness") but Foley shortened this to asterixis due to the former being too difficult to pronounce. They introduced the term in 1953 by way of a medical abstract and later Adams solidified its medical use as he was an author and editor of the widely influential Harrison's Principles of Internal Medicine.[5] ## References[edit] 1. ^ "Asterixis – Definition". Retrieved 2014-11-30. 2. ^ Agarwal R, Baid R. Asterixis. J Postgrad Med 2016;62:115-7. Available from: http://www.jpgmonline.com/text.asp?2016/62/2/115/180572 3. ^ Anne M. Larson, Diagnosis and management of acute liver failure, Curr Opin Gastroenterol., 2010, 26(3):212:221, 2010 4. ^ Adams RD, Foley JM. The neurological changes in the more common types of severe liver disease. Trans American Neurology Association 1949; 74: 217–219. 5. ^ Pal G, Lin, Laureno R. Asterixis: a study of 103 patients. Metabolic Brain Disease [serial online]. September 2014;29(3):813–824. ## External links[edit] Classification D * ICD-10: R27.8 * ICD-9-CM: 781.3 * MeSH: D020820 * DiseasesDB: 33950 * Diagram * v * t * e Symptoms and signs relating to movement and gait Gait * Gait abnormality * CNS * Scissor gait * Cerebellar ataxia * Festinating gait * Marche à petit pas * Propulsive gait * Stomping gait * Spastic gait * Magnetic gait * Truncal ataxia * Muscular * Myopathic gait * Trendelenburg gait * Pigeon gait * Steppage gait * Antalgic gait Coordination * Ataxia * Cerebellar ataxia * Dysmetria * Dysdiadochokinesia * Pronator drift * Dyssynergia * Sensory ataxia * Asterixis Abnormal movement * Athetosis * Tremor * Fasciculation * Fibrillation Posturing * Abnormal posturing * Opisthotonus * Spasm * Trismus * Cramp * Tetany * Myokymia * Joint locking Paralysis * Flaccid paralysis * Spastic paraplegia * Spastic diplegia * Spastic paraplegia * Syndromes * Monoplegia * Diplegia / Paraplegia * Hemiplegia * Triplegia * Tetraplegia / Quadruplegia * General causes * Upper motor neuron lesion * Lower motor neuron lesion Weakness * Hemiparesis Other * Rachitic rosary * Hyperreflexia * Clasp-knife response [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor *[BMI]: body mass index	Asterixis	c0232766	1,702	wikipedia	https://en.wikipedia.org/wiki/Asterixis	2021-01-18T18:51:37	{"mesh": ["D020820"], "icd-9": ["781.3"], "icd-10": ["R27.8"], "wikidata": ["Q748444"]}
A number sign (#) is used with this entry because of evidence that cardiomyopathy of the dilated (CMD1KK), hypertrophic (CMH22), or restrictive (RCM4) type can be caused by heterozygous mutation in the myopalladin gene (MYPN; 608517) on chromosome 10q21. For a general phenotypic description and a discussion of genetic heterogeneity of dilated cardiomyopathy, see 115200; for hypertrophic cardiomyopathy, see 192600; for familial restrictive cardiomyopathy, see 115210. Clinical Features Duboscq-Bidot et al. (2008) studied 6 patients from 2 families, as well as 2 sporadic patients, with isolated dilated cardiomyopathy due to mutations in the myopalladin gene (see MOLECULAR GENETICS). Mean age at diagnosis was 40 years. Of the 8 patients, 4 had incomplete left bundle branch block (BBB) on electrocardiogram, 1 had complete left BBB, and 1 had right BBB; 3 patients had left ventricular hypertrophy. There were 3 cardiac deaths due to refractory congestive heart failure, at 20, 29, and 55 years of age. Immunofluorescence analysis of explanted cardiac tissue from 1 of the patients demonstrated labeling of the functionally normal right ventricle that was indistinguishable from controls, whereas the dilated left ventricle showed reduced localization of myopalladin to the Z-band region. Molecular Genetics Duboscq-Bidot et al. (2008) screened 114 probands with dilated cardiomyopathy (CMD) for mutations in the MYPN gene (608517) and identified 4 heterozygous mutations, in 2 (3%) of 65 familial cases and 2 (4%) of 49 sporadic cases, respectively (see, e.g., 608517.0001-608517.0003). The familial mutations segregated fully with disease in 1 pedigree and with variable penetrance in the other, and none of the mutations were found in 400 ethnically matched controls. Purevjav et al. (2012) screened the MYPN gene in 900 unrelated patients with cardiomyopathy, including 484 with hypertrophic cardiomyopathy (CMH), 348 with CMD, and 68 with restrictive cardiomyopathy (RCM), and identified 15 rare sequence variants. A P1112L missense mutation (608517.0002), previously identified in a CMD patient by Duboscq-Bidot et al. (2008), was detected in a patient with CMH; another missense mutation, Y20C (608517.0004), was identified in 1 patient with CMD and another with CMH; and a nonsense mutation (Q529X; 608517.0005) was identified in 2 sibs with RCM. The overall prevalence of MYPN mutations was 1.66%, with 1.72% for CMD, 1.86% for CMH, and 1.45% for RCM; the authors noted that this relatively high prevalence compared to other reported disease genes suggests that MYPN is likely to be clinically important. Meyer et al. (2013) analyzed the MYPN and ANKRD1 (609599) genes in 255 unrelated consecutive patients with CMD and identified 2 heterozygous missense mutations in the MYPN gene (see, e.g., 608517.0006) in 2 patients, for a prevalence of 0.8%. No disease-related mutations were found in ANKRD1. INHERITANCE \- Autosomal dominant CARDIOVASCULAR Heart \- Cardiomyopathy, dilated (in some patients) \- Cardiomyopathy, hypertrophic (in some patients) \- Cardiomyopathy, restrictive (in some patients) \- Congestive heart failure (in some patients) \- Left ventricular hypertrophy (in some patients) \- Thickened interventricular septum (in some patients) \- Reduced left ventricular ejection fraction (in some patients) \- Mitral valve regurgitation (in some patients) \- Atrial fibrillation (in some patients) \- Left or right bundle branch block, complete or incomplete (in some patients) MISCELLANEOUS \- Some patients exhibit features of more than 1 type of cardiomyopathy \- Patients often require cardiac transplantation MOLECULAR BASIS \- Caused by mutation in the myopalladin gene (MYPN, 608517.0001 ) ▲ 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	CARDIOMYOPATHY, DILATED, 1KK	c0340427	1,703	omim	https://www.omim.org/entry/615248	2019-09-22T15:52:45	{"doid": ["0110445"], "mesh": ["C536231"], "omim": ["615248"], "icd-10": ["I42.5"], "orphanet": ["75249", "154"], "synonyms": ["Familial or idiopathic restrictive cardiomyopathy"]}
A rare, genetic, neonatal epilepsy syndrome disease characterized by onset in the first 6 months of life of almost continuous migrating polymorphous focal seizures with corresponding multifocal ictal electroencephalographic discharges, progressive deterioration of psychomotor development, and usually early mortality. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor *[BMI]: body mass index	Malignant migrating focal seizures of infancy	c3150988	1,704	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=293181	2021-01-23T18:41:17	{"gard": ["12919"], "omim": ["613722", "614959", "615338", "616645"], "synonyms": ["Epilepsy of infancy with migrating focal seizures", "MMPEI", "MMPSI", "MPEI", "MPSI", "Malignant migrating partial epilepsy of infancy", "Malignant migrating partial seizures of infancy", "Migrating partial epilepsy of infancy", "Migrating partial seizures of infancy"]}
## Clinical Features Peiffer et al. (1999) reported a large consanguineous family in which 6 children had congenital primary microcephaly, severe mental retardation, and seizures. Variable features included hyperreflexia, mild spasticity, and cortical blindness. Neuroradiologic studies documented microcephaly and a simplified gyral pattern with no pachygyria. Genetic studies excluded linkage in this family to the LIS1 gene (601545) on chromosome 17p13.3 or to the MCPH1 gene (607117) on chromosome 8p23. Rajab et al. (2007) reported a consanguineous family from Oman in which 4 sibs had congenital primary microcephaly and died within hours to weeks after birth from central apnea. Variable features included seizures, truncal hypotonia, hyperreflexia, and cortical blindness. Brain imaging showed simplified gyral pattern, thin corpus callosum, mild brainstem hypoplasia, and cerebellar atrophy. There were no other obvious abnormalities. The authors noted the phenotypic similarities to the Amish form of microcephaly (MCPHA; 607196), but excluded this locus in the Omani family. Rajab et al. (2007) suggested that the Omani family had a different disorder from that reported by Peiffer et al. (1999) because of the longer survival in that family. Desir et al. (2008) reported a girl, born of consanguineous Moroccan parents, with microcephaly (-3.5 SD), delayed language, and 2 seizure episodes at age 4 years. Brain MRI showed a simplified gyral pattern, more severe in the frontal lobes, with a decreasing severity toward the parietal and temporal regions. At age 6, she had hyperactivity and an IQ of 50. Fetal sonography of a second pregnancy in this family showed recurrence of microcephaly. Fetal brain MRI at 30 weeks' gestation showed decreased cortical gyri in an anterior to posterior gradient. The frontal lobes were small and squared off. Genetic analysis detected homozygosity for a truncation mutation in the ASPM gene (605481.0009). The data indicated that at least 1 form of primary microcephaly (MCPH5; 608716) is allelic to a form of microcephaly with simplified gyral pattern. However, Desir et al. (2008) noted that prenatal and postnatal brain imaging of patients with microcephaly has rarely been reported, suggesting that the 2 disorders may actually represent a phenotypic continuum. Diagnosis Based on a study of 12 infants born with microcephaly and simplified gyral pattern and 5 controls, Vermeulen et al. (2010) developed a simple and reliable MRI rating scale that could reliably distinguish between affected and unaffected individuals. The 'gyration score' correlated well with visual scoring. Other brain abnormalities in addition to simplified gyral pattern were also found, most commonly dilatation of the lateral ventricles (in 75%) and partial or complete agenesis of the corpus callosum (in 58%). [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor *[BMI]: body mass index	MICROCEPHALY WITH SIMPLIFIED GYRAL PATTERN	c3711387	1,705	omim	https://www.omim.org/entry/603802	2019-09-22T16:12:42	{"mesh": ["C579935"], "omim": ["603802"], "orphanet": ["2512"]}
A number sign (#) is used with this entry because of evidence that external ophthalmoplegia with rib and vertebral anomalies (EORVA) is caused by homozygous mutation in the MYF5 gene (159990) on chromosome 12q21. Description External ophthalmoplegia with rib and vertebral anomalies is characterized by congenital nonprogressive external ophthalmoplegia and ptosis, with torticollis and scoliosis developing during childhood. In addition, patients exhibit hypoplastic or missing ribs with fusion anomalies (Di Gioia et al., 2018). Clinical Features Traboulsi et al. (2000) described 2 Yemeni girls, born of first-cousin parents, with bilateral congenital nonprogressive external ophthalmoplegia. Examination of the 15-month-old proband showed bilateral large-angle exotropia and mild left hypotropia in primary gaze with the head held straight. She had severely limited ocular motility, consisting of moderate bilateral abduction with minimal adduction and depression. She underwent corrective surgery, with recession of the bilateral lateral rectus and resection of the left medial rectus; microscopic examination of muscle biopsies showed normal muscle tendon. Intraoperative forced duction testing was positive, with limitation in all directions of attempted movement. The proband's affected 4-year-old sister had a very small exotropia in primary gaze and severely limited ocular motility similar to the proband's, with no upgaze and minimal residual abduction, adduction, and depression. Di Gioia et al. (2018) restudied the Yemeni sisters reported by Traboulsi et al. (2000) (family BX) and observed scoliosis in the older sister that had developed between age 4 and young adulthood, and mild left ptosis in the younger sister. The authors also reported 3 additional similarly affected individuals from 2 Turkish families (ALO and CHO). In family ALO, an affected sister and brother were born with nonprogressive ptosis and ophthalmoplegia, and developed torticollis and scoliosis by 6 years of age. In family CHO, the proband was a 16-year-old boy who had nonprogressive bilateral ptosis and ophthalmoplegia from birth, and developed torticollis in infancy and pectus carinatum in childhood, both of which progressed with age. MRI of his orbits showed absence of the extraocular muscles. Chest x-rays and CT images in the Turkish patients revealed a spectrum of dysmorphic ribs, including hypoplasia, fusion anomalies, pseudoarthrosis, missing ribs, and failure of some remaining ribs to extend anteriorly toward the sternum. Mapping Di Gioia et al. (2018) performed genomewide linkage analysis in the Yemeni family (BX) with external ophthalmoplegia originally reported by Traboulsi et al. (2000), as well as homozygosity mapping in 2 similarly affected Turkish families (ALO and CHO), and identified a 42.6-Mb overlapping region of homozygosity on chromosome 12. Within that region, the Turkish families shared a 1.2-Mb region of haploidentity (chr12:80,696,475-81,927,644; GRCh37). Molecular Genetics In affected individuals from the Yemeni family (BX) originally reported by Traboulsi et al. (2000) and 2 Turkish families (ALO and CHO) with external ophthalmoplegia and rib and vertebral anomalies mapping to chromosome 12, Di Gioia et al. (2018) performed whole-exome sequencing and identified homozygosity for mutations in the MYF5 gene: the 2 Yemeni sisters were homozygous for a missense mutation (R95C; 159990.0001) and the 3 affected individuals from the 2 Turkish families were homozygous for the same 10-bp deletion (159990.0002). The mutations segregated with disease in the families and were not found in public variant databases. Analysis of the MYF5 gene in probands from 28 recessive, 26 dominant, and 51 simplex pedigrees with congenital ophthalmoplegia did not reveal any rare homozygous or compound heterozygous variants. Noting the phenotypic variability exhibited by affected individuals, even among the 3 Turkish patients with the same mutation, the authors suggested that genetic or environmental modifiers might play a role. INHERITANCE \- Autosomal recessive HEAD & NECK Eyes \- Ptosis, congenital \- External ophthalmoplegia, congenital \- Exotropia \- Hypotropia \- Restriction of passive eye movements Neck \- Torticollis CHEST External Features \- Pectus excavatum (in 1 patient) Ribs Sternum Clavicles & Scapulae \- Shortened ribs \- Hypoplastic ribs \- Missing ribs \- Fusion anomalies \- Pseudoarthrosis \- Fused sternum SKELETAL Skull \- Clivus malformations (in some patients) \- Basilar invagination (in some patients) Spine \- Scoliosis \- Cervical fusion (in some patients) \- Atlantooccipital fusion (in 1 patient) MISCELLANEOUS \- Variable phenotype MOLECULAR BASIS \- Caused by mutation in the myogenic factor-5 gene (MYF5, 159990.0001 ) ▲ 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	OPHTHALMOPLEGIA, EXTERNAL, WITH RIB AND VERTEBRAL ANOMALIES	None	1,706	omim	https://www.omim.org/entry/618155	2019-09-22T15:43:21	{"omim": ["618155"]}
Polycystic liver disease Micrograph showing a von Meyenburg complex, a bile duct hamartoma associated with polycystic liver disease. Trichrome stain. SpecialtyMedical genetics Polycystic liver disease (PLD) usually describes the presence of multiple cysts scattered throughout normal liver tissue.[1] PLD is commonly seen in association with autosomal-dominant polycystic kidney disease, with a prevalence of 1 in 400 to 1000, and accounts for 8–10% of all cases of end stage renal disease.[2] The much rarer autosomal-dominant polycystic liver disease will progress without any kidney involvement.[2] ## Contents * 1 Pathophysiology * 2 Diagnosis * 3 Treatment * 4 References * 5 Further reading * 6 External links ## Pathophysiology[edit] Associations with PRKCSH and SEC63 have been described.[3] Polycystic liver disease comes in two forms as autosomal dominant polycystic kidney disease (with kidney cysts) and autosomal dominant polycystic liver disease (liver cysts only). ## Diagnosis[edit] Most patients with PLD are asymptomatic with simple cysts found following routine investigations. After confirming the presence of cysts in the liver, laboratory tests may be ordered to check for liver function including bilirubin, alkaline phosphatase, alanine aminotransferase, and prothrombin time.[2] Patients with PLD often have an enlarged liver which will compress adjacent organs, leading to nausea, respiratory issues, and limited physical ability. Classification of the progression of the disease takes into consideration the amount of remaining liver parenchyma compared to the amount and size of cysts.[2] ## Treatment[edit] Many patients are asymptomatic and thus are not candidates for surgery. For patients with pain or complications from the cysts, the goal of treatment is to reduce the size of cysts while protecting the functioning liver parenchyma.[2] Cysts may be removed surgically or by using aspiration sclerotherapy.[2] ## References[edit] 1. ^ Kelly, Deirdre A. (2009). Diseases of the Liver and Biliary System in Children. John Wiley & Sons. p. 239. ISBN 9781444300543. Retrieved 7 March 2018. 2. ^ a b c d e f Poston, Graeme J.; D’Angelica, Michael; Adam, René (2010). Surgical Management of Hepatobiliary and Pancreatic Disorders, Second Edition. CRC Press. p. 303. ISBN 9781841847603. Retrieved 7 March 2018. 3. ^ Online Mendelian Inheritance in Man (OMIM): 174050 ## Further reading[edit] * Everson, Gregory T. (2008). "Polycystic Liver Disease". Gastroenterology & Hepatology. 4 (3): 179–181. ISSN 1554-7914. PMC 3088294. PMID 21904493. ## External links[edit] Classification D * ICD-10: Q44.6 * OMIM: 174050 * MeSH: C536330 * DiseasesDB: 33340 * v * t * e Congenital malformations and deformations of digestive system Upper GI tract Tongue, mouth and pharynx * Cleft lip and palate * Van der Woude syndrome * tongue * Ankyloglossia * Macroglossia * Hypoglossia Esophagus * EA/TEF * Esophageal atresia: types A, B, C, and D * Tracheoesophageal fistula: types B, C, D and E * esophageal rings * Esophageal web (upper) * Schatzki ring (lower) Stomach * Pyloric stenosis * Hiatus hernia Lower GI tract Intestines * Intestinal atresia * Duodenal atresia * Meckel's diverticulum * Hirschsprung's disease * Intestinal malrotation * Dolichocolon * Enteric duplication cyst Rectum/anal canal * Imperforate anus * Rectovestibular fistula * Persistent cloaca * Rectal atresia Accessory Pancreas * Annular pancreas * Accessory pancreas * Johanson–Blizzard syndrome * Pancreas divisum Bile duct * Choledochal cysts * Caroli disease * Biliary atresia Liver * Alagille syndrome * Polycystic liver disease * v * t * e Deficiencies of intracellular signaling peptides and proteins GTP-binding protein regulators GTPase-activating protein * Neurofibromatosis type I * Watson syndrome * Tuberous sclerosis Guanine nucleotide exchange factor * Marinesco–Sjögren syndrome * Aarskog–Scott syndrome * Juvenile primary lateral sclerosis * X-Linked mental retardation 1 G protein Heterotrimeic * cAMP/GNAS1: Pseudopseudohypoparathyroidism * Progressive osseous heteroplasia * Pseudohypoparathyroidism * Albright's hereditary osteodystrophy * McCune–Albright syndrome * CGL 2 Monomeric * RAS: HRAS * Costello syndrome * KRAS * Noonan syndrome 3 * KRAS Cardiofaciocutaneous syndrome * RAB: RAB7 * Charcot–Marie–Tooth disease * RAB23 * Carpenter syndrome * RAB27 * Griscelli syndrome type 2 * RHO: RAC2 * Neutrophil immunodeficiency syndrome * ARF: SAR1B * Chylomicron retention disease * ARL13B * Joubert syndrome 8 * ARL6 * Bardet–Biedl syndrome 3 MAP kinase * Cardiofaciocutaneous syndrome Other kinase/phosphatase Tyrosine kinase * BTK * X-linked agammaglobulinemia * ZAP70 * ZAP70 deficiency Serine/threonine kinase * RPS6KA3 * Coffin-Lowry syndrome * CHEK2 * Li-Fraumeni syndrome 2 * IKBKG * Incontinentia pigmenti * STK11 * Peutz–Jeghers syndrome * DMPK * Myotonic dystrophy 1 * ATR * Seckel syndrome 1 * GRK1 * Oguchi disease 2 * WNK4/WNK1 * Pseudohypoaldosteronism 2 Tyrosine phosphatase * PTEN * Bannayan–Riley–Ruvalcaba syndrome * Lhermitte–Duclos disease * Cowden syndrome * Proteus-like syndrome * MTM1 * X-linked myotubular myopathy * PTPN11 * Noonan syndrome 1 * LEOPARD syndrome * Metachondromatosis Signal transducing adaptor proteins * EDARADD * EDARADD Hypohidrotic ectodermal dysplasia * SH3BP2 * Cherubism * LDB3 * Zaspopathy Other * NF2 * Neurofibromatosis type II * NOTCH3 * CADASIL * PRKAR1A * Carney complex * PRKAG2 * Wolff–Parkinson–White syndrome * PRKCSH * PRKCSH Polycystic liver disease * XIAP * XIAP2 See also intracellular signaling peptides and 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	Polycystic liver disease	c0158683	1,707	wikipedia	https://en.wikipedia.org/wiki/Polycystic_liver_disease	2021-01-18T19:05:27	{"gard": ["9457"], "mesh": ["C536330"], "umls": ["C0158683"], "icd-10": ["Q44.6"], "orphanet": ["2924"], "wikidata": ["Q246002"]}
A multiple congenital anomalies syndrome characterized by wormian bones, dextrocardia and short stature due to a growth hormone deficiency. Additional manifestations that have been reported include brachycamptodactyly, kidney hypoplasia, bilateral cryptorchidism, midshaft hypospadias, imperforate anus/anorectal agenesis, body asymmetry, mild developmental delay, hemimegalencephaly and facial dysmorphism (hypotelorism, downslanting palpebral fissures, low-set and posteriorly angulated ears, depressed nasal bridge, and microstomia). [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor *[BMI]: body mass index	Short stature-wormian bones-dextrocardia syndrome	c1861448	1,708	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=2863	2021-01-23T17:07:06	{"gard": ["4856"], "mesh": ["C566105"], "omim": ["185120"], "umls": ["C1861448"], "icd-10": ["Q87.1"], "synonyms": ["Stratton-Parker syndrome"]}
A rare hemophagocytic syndrome characterized by excessive activation and proliferation of macrophages and T cells occurring in the context of a variety of diseases, including infections, neoplasms, rheumatic disorders, and leading to sudden onset of persistent fever, lymphadenopathy, and hepatosplenomegaly. Complications include profound depression of one or more blood cell lines with coagulopathy and pancytopenia, and impaired liver and renal function. Bone marrow examination reveals numerous well differentiated macrophages actively phagocytosing hematopoietic elements. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor *[BMI]: body mass index	Macrophage activation syndrome	c1096155	1,709	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=158061	2021-01-23T18:28:38	{"gard": ["12124"], "mesh": ["D055501"], "umls": ["C1096155"]}
A number sign (#) is used with this entry because of evidence that trichohepatoneurodevelopmental syndrome (THNS) is caused by homozygous or compound heterozygous mutation in the CCDC47 gene (618260) on chromosome 17q23. Description Trichohepatoneurodevelopmental syndrome is a complex multisystem disorder characterized by woolly or coarse hair, liver dysfunction, pruritus, dysmorphic features, hypotonia, and severe global developmental delay (Morimoto et al., 2018). Clinical Features Morimoto et al. (2018) reported 4 unrelated children with a complex multisystem disorder. All 4 probands exhibited dysmorphic facial features, with coarse facies, ptosis, downturned mouth, and simple ears, as well as unusual hair that was coarse and/or woolly and/or curly. Other features present in all included microcephaly, brachycephaly, severe global developmental delay, liver dysfunction, pruritus, hypotonia, joint laxity or distal arthrogryposis, nipple hypoplasia, and overlapping toes. Most probands also showed midface hypoplasia, hypertelorism, dental abnormalities, plagiocephaly, narrow chest, hip dysplasia, and bilateral clubfoot. The patients also exhibited severe developmental delay and were nonverbal with generalized hypotonia at 5 to 8 years of age; neuroimaging revealed cerebral atrophy in all 4 patients, with abnormal ventricular morphology in 3 of them. Two of the patients were immunodeficient and experienced recurrent infections. Molecular Genetics In 4 unrelated children with woolly hair, liver dysfunction, pruritus, dysmorphic features, and developmental delay, Morimoto et al. (2018) performed whole-exome sequencing and identified homozygosity or compound heterozygosity for mutations in the CCDC47 gene (618260.0001-618260.0004). INHERITANCE \- Autosomal recessive GROWTH Weight \- Low weight HEAD & NECK Head \- Microcephaly \- Brachycephaly \- Plagiocephaly \- Bitemporal narrowing Face \- Coarse facies \- Midface hypoplasia Ears \- Simple ears \- Otitis media, bilateral Eyes \- Ptosis \- Hypertelorism \- Synophrys \- Cortical visual impairment \- Hyperopia Nose \- Unusual nose \- Hypoplasia of nasal bones \- Bulbous nasal tip Mouth \- Downturned mouth \- Full or thick lips \- High-arched palate \- Macroglossia Teeth \- Widely spaced teeth \- Dental crowding \- Small teeth \- Underbite RESPIRATORY Airways \- Obstructive sleep apnea CHEST External Features \- Hypertrichosis \- Narrow chest (in some patients) \- Pectus excavatum (in some patients) Breasts \- Hypoplastic nipples ABDOMEN Liver \- Liver dysfunction \- Hepatomegaly (in some patients) Biliary Tract \- Elevated bile acids \- Gallstones (in some patients) Spleen \- Splenomegaly (in some patients) Gastrointestinal \- Gastroesophageal reflux \- Feeding difficulties requiring gastrostomy tube \- Steatorrhea (in some patients) \- Chronic diarrhea (in some patients) SKELETAL \- Distal arthrogryposis \- Joint laxity Skull \- Microcephaly \- Brachycephaly \- Plagiocephaly Spine \- Scoliosis (in some patients) Pelvis \- Hip dysplasia \- Bilateral hip dislocation \- Bilateral coxa valga Hands \- Fifth digit hypoplasia \- Fifth digit clinodactyly Feet \- Small feet \- Overlapping toes \- Club feet, bilateral SKIN, NAILS, & HAIR Skin \- Pruritus \- Hypertrichosis on chest area Hair \- Woolly hair \- Coarse hair \- Curly hair MUSCLE, SOFT TISSUES \- Hypotonia NEUROLOGIC Central Nervous System \- Severe global developmental delay \- No speech development \- Generalized hypotonia \- Cerebral atrophy \- Abnormal electroencephalogram \- Abnormal ventricular morphology \- Abnormal corpus callosum (in some patients) \- Central sleep apnea IMMUNOLOGY \- Immunodeficiency (in some patients) \- Recurrent infections (in some patients) LABORATORY ABNORMALITIES \- Elevated alanine aminotransferase (ALT) \- Elevated aspartate aminotransferase (AST) \- Elevated alkaline phosphatase \- Elevated cholic acid \- Elevated chenodeoxycholic acid \- Elevated total bile acids \- Elevated total bilirubin \- Elevated direct bilirubin \- Low fecal elastase (in some patients) MISCELLANEOUS \- Multiple miscarriages in families of affected individuals MOLECULAR BASIS \- Caused by mutation in the coiled-coil domain containing-47 gene (CCDC47, 618260.0001 ) ▲ 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	TRICHOHEPATONEURODEVELOPMENTAL SYNDROME	None	1,710	omim	https://www.omim.org/entry/618268	2019-09-22T15:42:46	{"omim": ["618268"]}
A number sign (#) is used with this entry because of evidence that keratoconus-1 (KTCN1) is caused by heterozygous mutation in the VSX1 gene (605020) on chromosome 20p11. Description Keratoconus, the most common corneal dystrophy, is a bilateral, noninflammatory progressive corneal ectasia. Clinically, the cornea becomes progressively thin and conical, resulting in myopia, irregular astigmatism, and corneal scarring. The disease usually arises in the teenage years, eventually stabilizing in the third and fourth decades. The incidence of keratoconus is 1 in 2,000 in the general population; it occurs with no ethnic or gender preponderance, and causes significant visual impairment in young adults. No specific treatment exists except to replace the corneal tissue by surgery (corneal transplantation) when visual acuity can no longer be corrected by contact lenses (summary by Dash et al., 2006). Ihalainen (1986) reviewed various conditions with which keratoconus is at times associated. Keratoconus is frequent in cases of amaurosis congenita of Leber (204000). ### Genetic Heterogeneity of Keratoconus Also see KTCN2 (608932), mapped to 16q22.3-q23.1; KTCN3 (608586), mapped to 3p14-q13; KTCN4 (609271), mapped to 2p24; KTCN5 (614622), mapped to 5q14.1-q21.3; KTCN6 (614623), mapped to 9q34; KTCN7 (614629), mapped to 13q32; KTCN8 (614628), mapped to 14q24; and KTCN9 (617928), caused by mutation in the TUBA3D gene (617878) on 2q21. Clinical Features In a study of large number of patients with keratoconus in Finland, Ihalainen (1986) found that symptoms usually began in young adults. Pregnancy seemed to precipitate keratoconus in some instances. Nielsen et al. (2003) used gene microarrays to investigate differential gene expression in corneal epithelium from samples with and without keratoconus. Keratoconus epithelium appeared to be characterized by massive changes of the cytoskeleton, reduced extracellular matrix remodeling, altered transmembrane signaling, and modified cell-to-cell and cell-to-matrix interactions. Validation of gene expression with dChip analysis and real-time PCR indicated Gene Chip to be a valid technique for investigation of epithelium from single dissected corneal samples. Dogru et al. (2003) reviewed the ocular surface disease in keratoconus. Keratoconus patients showed disorders of tear quality, lowered tear film breakup time (BUT), squamous metaplasia of the corneal epithelium, and goblet cell loss, all of which seemed to relate to the extent of keratoconus progression. Li et al. (2004) examined 778 patients with keratoconus and found that 116 (14.9%) had clinically unilateral keratoconus at baseline. These 116 patients were followed for a period ranging from 6 months to 8 years. Approximately 50% of clinically normal fellow eyes progressed to keratoconus within 16 years. The greatest risk was during the first 6 years. Li et al. (2004) also described quantitative indices and qualitative patterns that might predict this progression. Individuals with keratoconus are not candidates for LASIK (laser-assisted in situ keratomileusis) for correction of their myopia and/or astigmatism. Jabbur et al. (2001) described the clinical course and histopathology of an individual with suspected keratoconus who underwent bilateral simultaneous LASIK. She required penetrating keratoplasty due to progressively worsening vision from corneal ectasia after LASIK. Classically, corneal allograft rejection was thought to be a Th1-mediated phenomenon. However, Th2-mediated allograft rejection has been reported in heart and kidney transplanted systems. Hargrave et al. (2003) reviewed the records of 84 consecutive patients who underwent penetrating keratoplasty for keratoconus. Because an association between keratoconus and atopic disease had been documented in the literature and had been considered significant since 1937, careful attention was paid to the clinical history of atopy (147050) in this study. Atopic patients have been shown to have a 'Th2 immune bias.' Of the 7 patients who rejected their corneal allografts, 4 had repeat penetrating keratoplasty. Of these 4 repeat corneal allografts, 3 showed eosinophilia when compared with rejected grafts in control (nonkeratoconic, nonatopic) patients. Atopic keratoconus patients had a mixed inflammatory cellular infiltrate in the rejected corneal tissue specimen with a significantly greater density of eosinophils compared with patients who did not have a preexisting Th2 bias. The histopathology was comparable to the authors' murine model of rejection in Th2 mice, characterized by a predominantly eosinophilic infiltrate when compared with wildtype (Th1) mice that had a predominantly mononuclear infiltrate in the rejected corneal graft bed. Fuentes et al. (2015) noted that acute corneal hydrops, a condition characterized by marked corneal edema after a break in the Descemet membrane, typically affects young individuals with progressive disease and occurs in approximately 3% of patients with keratoconus. In data collected from 191 patients with advanced keratoconus during a minimum 24-month follow-up, the authors found that increased epithelial thickening, stromal thinning at the keratoconus cone, anterior hyperreflexives at the Bowman layer level, and the absence of stromal scarring were associated with a high risk of corneal hydrops. All 11 cases of corneal hydrops (5.8%) in their series occurred in young males. Inheritance Hamilton (1938) claimed that certain of his pedigrees in Tasmania strongly supported autosomal recessive inheritance. Irregular autosomal dominant inheritance was suggested by Falls and Allen (1969), who observed affected aunt and niece. The mother, who presumably transmitted the trait, had astigmatism and other features the authors interpreted as forme fruste of keratoconus. They cited several instances of multigeneration involvement including the family of Staehli (1925) with transmission through 3 generations. From study of a large series, Hallermann and Wilson (1977) favored multifactorial inheritance but could not exclude isolated instances of dominant or recessive inheritance. Ihalainen (1986) found multiple cases in 19 of 101 families studied in the north of Finland and in 5 of 58 families in the south. Mean family size was 4.9 in the north as compared with 3.5 in the south. In 24 of 28 multiplex families the pattern of inheritance was autosomal dominant. The disorder was inherited from the mother in 15 cases and from the father in 9. Incomplete penetrance was indicated. Corneal transplant was carried out in 65 of the 144 patients coming from the area served by Oulu University Central Hospital in Finland. Among 212 patients, 63% were male. Kennedy et al. (1986) found keratoconus in less than 6% of the relatives of affected probands. Wang et al. (2000) conducted a family study to investigate genetic contributions to the development of keratoconus. The estimated prevalence in first-degree relatives was 3.34% (41/1,226), which is 15 to 67 times higher than that in the general population (0.23-0.05%). The correlation in sib and parent-offspring pairs (r = 0.30 and 0.22, respectively) was significantly greater than that in marital pairs (r = 0.14) and the latter was not significantly different from zero. Segregation analysis in 95 families did not reject a major gene model; the most parsimonious model was autosomal recessive inheritance. Mapping In patients with keratoconus-1 (KTCN1), Heon et al. (2002) identified mutations in the VSX1 gene (605020), which maps to chromosome 20p11.2. ### Associations Pending Confirmation Hamilton (1938) conducted studies of hereditary eye diseases in Tasmania where, in the coastal town of Burnie, keratoconus is present at a 5-fold increased incidence. Based on the assumption that individuals with keratoconus from this town are likely to be related through a founder effect, Fullerton et al. (2002) conducted a 10-cM interval genome scan on 6 patients of undefined genetic relationship and 1 affected sib pair to identify commonly shared chromosomal segments for the elucidation of candidate gene loci. Analysis of allele sharing revealed 4 markers on 3 chromosomes where all 8 individuals shared a common allele on at least 1 chromosome and 13 markers where all but 1 patient shared common alleles. No excess of allele sharing was observed at any marker tested on chromosome 21, a suggested candidate chromosome for keratoconus because of the occurrence of keratoconus with a 150-fold increased incidence in Down syndrome (Shapiro and France, 1985; van Allen et al., 1999). Further analysis of positive loci revealed suggestive association at 20q12, where significant deviation in frequency of the allele D20S119 was observed. The nearby candidate gene matrix metalloproteinase-9 (MMP9; 120361), which is located at 20q11.2-q13.1, was excluded. Pathogenesis Lema and Duran (2005) determined the levels of a panel of inflammatory molecules and matrix metalloproteinases in the tears of patients with keratoconus. Patients with keratoconus had significantly higher levels of IL6 (147620), TNFA (191160), and MMP9 (120361) than control subjects. The extent of the increase was associated with the severity of keratoconus. Lema and Duran (2005) suggested that the pathogenesis of keratoconus may involve chronic inflammatory events. Atilano et al. (2005) found that keratoconus-affected corneas showed a trend of lower mtDNA-to-nDNA ratio than did control corneas, had decreased cytochrome c oxidase subunit I (MTCO1; 516030) in areas of corneal thinning, and had significantly increased numbers of mtDNA deletions compared to control corneas. Atilano et al. (2005) suggested that increased oxidative stress and altered integrity of mtDNA may be related to each other, contributing to keratoconus pathogenesis. Kenney et al. (2005) found that keratoconus corneas exhibited a 2.20-fold increase in catalase (115500) mRNA and 1.8-fold increase in enzyme activity; a 1.5-fold increase in cathepsis V/L2 (603308) mRNA and abnormal protein distribution; and a 1.8-fold decrease in TIMP1 (305370) mRNA and a 2.8-fold decrease in protein compared with normal (physiologic) corneas. Kenney et al. (2005) concluded that keratoconus corneas had elevated levels of cathepsins V/L2, B (116810), and G (116830), which could stimulate hydrogen peroxide production, which, in turn, could upregulate catalase, an antioxidant enzyme. In addition, decreased TIMP1 and increased cathepsin V/L2 levels might play a role in the matrix degradation that is a hallmark of keratoconus corneas. These findings supported the hypothesis that keratoconus corneas undergo oxidative stress and tissue degradation. Because matrix degrading enzymes could potentially influence keratoconus progression, Matthews et al. (2007) studied the effects of TIMP1 and TIMP3 (188826) on stromal cell viability. Overexpression of TIMP3 induced apoptosis in corneal stromal cell cultures. Upregulated TIMP1 production or the addition of exogenous TIMP1 protein prevented stromal cell overgrowth, changed stromal cell morphology, and reduced the extent of TIMP3 induced apoptosis. Localized relative concentrations of TIMP1/TIMP3 could thus determine whether cells remained viable or became apoptotic. Matthews et al. (2007) concluded that this might be relevant to keratoconus because significantly more apoptotic cells were identified in the anterior stroma of keratoconic corneas than in normal corneas and the majority of the TIMP1 and TIMP3 producing stromal cells were located in that region. Shetty et al. (2015) studied the expression of select genes associated with corneal structure in a large cohort of patients with keratoconus (90 eyes) compared with patients undergoing photorefractive keratectomy who did not have keratoconus (52 eyes). Shetty et al. (2015) observed a significant reduction in lysyl oxidase (LOX; 153455) transcript levels in KTCN corneal epithelia, and LOX activity in KCTN tears correlated with disease severity. Collagen transcript levels (COL1A1, 120150; COL4A1, 120130) were also reduced in KCTN, whereas MMP9 (120361) transcript levels were upregulated and correlated with disease severity. IL6 (147620) transcript levels were moderately increased in KCTN patients. Immunohistochemistry demonstrated a reduction in the protein expression levels of LOX in the epithelium and COL4A1 in the basement membrane of KCTN patients (27 eyes) compared to healthy donor corneas (15 eyes). Shetty et al. (2015) concluded that the structural deformity of the KCTN cornea may be dependent on reduced expression of collagens and LOX, as well as on the concomitant increased expression of MMP9. Molecular Genetics Heon et al. (2002) analyzed the VSX1 gene in 63 patients with keratoconus (see KTCN1, 148300) and identified missense mutations in 2 probands (R166W, 605020.0001 and L159M, 605020.0003). They also screened VSX1 in 22 patients with posterior polymorphous corneal dystrophy (PPCD; see 122000), and identified a different missense mutation in 4 sibs (G160D; 605020.0002). The pathogenicity of 2 of these variants G160D and L159M, were later called into question. Bisceglia et al. (2005) evaluated the role of the VSX1 gene in a series of 80 keratoconus-affected Italian subjects. They found 3 previously described missense changes (see, e.g., 605020.0002) and a novel mutation (605020.0005) in 7 of 80 unrelated patients (8.7%); they also found 2 previously undescribed intronic polymorphisms. The authors concluded that the VSX1 gene plays an important role in a significant proportion of patients affected by keratoconus inherited as an autosomal dominant trait with variable expressivity and incomplete penetrance. In a case-control panel of 77 sporadic keratoconus patients and 71 controls and a keratoconus family panel involving 444 individuals from 75 families, Tang et al. (2008) screened for 3 keratoconus-associated VSX1 mutations, L159M, R166W, and H244R. The R166W and H244R variants were not found in the case-control panel, and L159M was detected in heterozygosity in 1 control. In the family panel, R166W was not found; L159M was detected in 5 individuals, 3 affected and 2 unaffected, and H244R was detected in 3 individuals, 2 affected and 1 unaffected. Tang et al. (2008) concluded that their results did not support a role for variation in the VSX1 gene in the pathogenesis of keratoconus. Dash et al. (2010) analyzed the entire coding region, intron-exon junctions, and 5- and 3-prime UTR of the VSX1 gene in 66 unrelated patients with keratoconus, including 27 familial cases and 39 sporadic cases. The G160D change (605020.0002), previously detected in a family with posterior polymorphous corneal dystrophy (PPCD1; 122000) and in a family with keratoconus, was identified in 2 sporadic keratoconus patients and not found in 100 controls; however, other variants that were found did not segregate with disease and/or did not demonstrate pathogenicity. Dash et al. (2010) concluded that VSX1 plays a minor role in keratoconus pathogenesis. Stabuc-Silih et al. (2010) analyzed the coding regions and intron-exon junctions of the VSX1 gene in 113 unrelated Slovenian patients with keratoconus, but identified no disease-causing mutations; they concluded that other genetic factors are involved in the development of keratoconus. De Bonis et al. (2011) analyzed the VSX1 gene in 222 unrelated Italian probands with keratoconus and reviewed previously published results. De Bonis et al. (2011) found 1 novel and 3 previously identified VSX1 missense variants in 6 keratoconus patients (see, e.g., 605020.0002 and 605020.0005), none of which had been found in controls. They concluded that VSX1 has a possible pathogenic role in keratoconus, although in a small number of patients. ### Associations Pending Confirmation In 15 unrelated probands with keratoconus, Udar et al. (2006) analyzed the candidate gene SOD1 (147450) and found a heterozygous splice site variant (IVS2+50del7) in 2 probands. The 7-bp deletion segregated with disease in 1 family, being present in an affected father and daughter and absent from 3 unaffected family members; DNA was not available from the other proband's family members. The variant was not found in 312 control chromosomes or in the ALS (see 105400) database either as a mutation or polymorphism. Analysis of the daughter's RNA showed that in addition to wildtype, 2 other SOD1 transcripts were expressed: 1 lacking all of exon 2, and 1 lacking all of exons 2 and 3. Udar et al. (2006) concluded that further studies would be required to determine whether a causal relationship existed between the splice variants and the keratoconus phenotype. Stabuc-Silih et al. (2010) analyzed the coding regions and intron-exon junctions of the SOD1, COL4A3 (120070), and COL4A4 (120131) genes in 113 unrelated Slovenian patients with keratoconus, but identified no disease-causing mutations in any of the genes. However, 1 polymorphism in COL4A3 showed significant association with keratoconus (D326Y; odds ratio, 14.703 for the 976G allele) as well as 2 polymorphisms in COL4A4, M1327V (OR, 0.3969 for 3979A) and F1644F (OR, 1.751 for 4932C). Stabuc-Silih et al. (2010) concluded that other genetic factors are involved in the development of keratoconus. De Bonis et al. (2011) analyzed the SOD1 and SPARC (182120) genes in 302 unrelated Italian probands with keratoconus, 80 of whom were previously studied by Bisceglia et al. (2005). The 7-bp deletion in intron 2, previously found in keratoconus patients by Udar et al. (2006), was identified in 2 sporadic patients and was not found in 200 controls. Six missense variants in the SPARC gene were detected in 1 familial and 5 sporadic cases, respectively; none was found in 200 controls, but the variant in the familial case did not segregate with disease in the family, and no relatives of the sporadic patients were available for study. De Bonis et al. (2011) concluded that the role played by SOD1 and SPARC in keratoconus was not definitively clarified. Al-Muammar et al. (2015) sequenced the entire coding region, exon-intron boundaries, and intron 2 encompassing the previously reported 7-bp deletion in the SOD1 gene in 55 Saudi patients with clinically confirmed keratoconus and identified no pathogenic mutations. Lechner et al. (2014) analyzed the ZNF469 gene (612078) in 112 European probands with keratoconus and in 96 unaffected and unrelated European individuals, and found significant enrichment of potentially pathogenic ZNF469 alleles in the keratoconus patients compared to controls (p = 0.00102; odds ratio, 13.6; relative risk, 12.0). The authors noted that the allele frequency differences showed that the rare ZNF469 alleles were not in linkage disequilibrium with a known common variant strongly associated with corneal thickness (but not keratoconus), located within a 53-kb linkage disequilibrium block 117 kb from the 5-prime end of ZNF46. Lechner et al. (2014) stated that the enrichment of rare potentially pathogenic ZNF469 alleles in 12.5% of keratoconus patients represented a significant mutational load and highlighted ZNF469 as the most significant genetic factor responsible for keratoconus yet reported. ### Exclusion Studies De Bonis et al. (2011) analyzed the LOX (153455) and TIMP3 (188826) genes in 302 unrelated Italian probands with keratoconus, 80 of whom were previously studied by Bisceglia et al. (2005), and did not find any disease-causing variants. Animal Model Tachibana et al. (2002) established an inbred line of spontaneous mutant mice with keratoconus-affected corneas (SKC mice). The SKC mouse cornea resembled corneas of human eyes with keratoconus: both corneas were conical and showed similar changes, including apoptosis of keratocytes and increased expression of Fos protein (164810). The SKC mouse phenotype was transmitted in an autosomal recessive manner, but it was observed almost exclusively in males. Female mice showed the phenotype when injected with testosterone, whereas male incidence of the phenotype diminished drastically when the mice were castrated. Linkage analysis localized a predisposition locus to a major histocompatibility complex (MHC) region on mouse chromosome 17 that includes the gene encoding 'sex-limited protein,' or Slp. The authors proposed that the SKC mouse may be a potential model for a subset of human keratoconus. INHERITANCE \- Autosomal dominant HEAD & NECK Eyes \- Keratoconus \- Astigmatism \- Predictors of acute corneal hydrops \- Increased epithelial thickening \- Stromal thinning at the cone \- Anterior hyperreflective anomalies at the Bowman layer level \- Absence of stromal scarring MISCELLANEOUS \- Young adult onset \- Precipitation by pregnancy MOLECULAR BASIS \- Caused by mutation in the visual system homeobox 1 gene (VSX1, 148300.0001 ) ▲ 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	KERATOCONUS 1	c1835677	1,711	omim	https://www.omim.org/entry/148300	2019-09-22T16:39:20	{"mesh": ["C563649"], "omim": ["148300"]}
## Summary ### Clinical characteristics. Retinoblastoma is a malignant tumor of the developing retina that occurs in children, usually before age five years. Retinoblastoma develops from cells that have cancer-predisposing variants in both copies of RB1. Retinoblastoma may be unifocal or multifocal. About 60% of affected individuals have unilateral retinoblastoma with a mean age of diagnosis of 24 months; about 40% have bilateral retinoblastoma with a mean age of diagnosis of 15 months. Heritable retinoblastoma is an autosomal dominant susceptibility for retinoblastoma. Individuals with heritable retinoblastoma are also at increased risk of developing non-ocular tumors. ### Diagnosis/testing. The diagnosis of retinoblastoma is usually established by examination of the fundus of the eye using indirect ophthalmoscopy. Imaging studies can be used to support the diagnosis and stage the tumor. The diagnosis of heritable retinoblastoma is established in a proband with retinoblastoma or retinoma and a family history of retinoblastoma or by identification of a heterozygous germline pathogenic variant in RB1. The following staging has been recommended for individuals with retinoblastoma and/or risk of heritable retinoblastoma to include "H" to describe the genetic risk for an individual to have a germline pathogenic variant in RB1: * HX. Unknown or insufficient evidence of a constitutional (germline) RB1 pathogenic variant * H0. Normal RB1 alleles in blood tested with demonstrated high-sensitivity assays * (H0. Normal RB1 in blood with <1% residual risk for mosaicism) H1. Bilateral retinoblastoma, trilateral retinoblastoma (retinoblastoma with intracranial CNS midline embryonic tumor), family history of retinoblastoma, or RB1 pathogenic variant identified in blood ### Management. Treatment of manifestations: Early diagnosis and treatment of retinoblastoma and non-ocular tumors can reduce morbidity and increase longevity; care is best provided by multidisciplinary teams of specialists including ophthalmology, pediatric oncology, pathology, and radiation oncology. Treatment options depend on tumor stage, number of tumor foci (unifocal, unilateral multifocal, or bilateral), localization and size of the tumor(s) within the eye(s), presence of vitreous seeding, the potential for useful vision, the extent and kind of extraocular extension, and the resources available. Treatment options include enucleation; cryotherapy; laser, systemic, or local ocular chemotherapy including intra-arterial chemotherapy, combined with or followed by laser or cryotherapy; radiation therapy using episcleral plaques; and, as a last resort, external beam radiotherapy. Prevention of secondary manifestations: If possible, radiation (including x-ray, CT scan, and external beam radiation) should be avoided in H1 individuals with heritable retinoblastoma to minimize the lifetime risk of developing late-onset second cancers. Surveillance: Children known to have an RB1 germline pathogenic variant (H1) have eye examination under anesthesia every three to four weeks until age six months, then less frequently until age three years, in order to identify retinoblastoma tumors as early and small as possible. Clinical examinations with cooperative children are performed every three to six months until age seven years, then annually and eventually biennially for life. Individuals who have unilateral retinoblastoma without an identified heterozygous germline RB1 pathogenic variant (H0) are still at risk for low-level mosaicism and should have regular clinical examination of the eyes, including clinical ultrasound. Individuals with retinomas are followed with retinal examinations and imaging every one to two years. To detect second non-ocular tumors in H1 individuals with retinoblastoma, physicians and parents should promptly evaluate complaints of bone pain or lumps because of the high risk for sarcomas and other cancers; however, effective screening protocols have not yet been developed. Agents/circumstances to avoid: Limiting exposure to DNA-damaging agents (radiation, tobacco, and UV light) may reduce the excess cancer risks in H1 survivors of heritable retinoblastoma. Evaluation of relatives at risk: Molecular genetic testing for early identification of asymptomatic at-risk children in a family reduces the need for costly screening procedures in those family members who have not inherited the pathogenic variant (i.e., H0). ### Genetic counseling. Heritable retinoblastoma is inherited in an autosomal dominant manner. Individuals with heritable retinoblastoma (H1) have a heterozygous de novo or inherited germline RB1 pathogenic variant. Offspring of H1 individuals have a 50% chance of inheriting the pathogenic variant. Prenatal testing for pregnancies at increased risk is possible if the RB1 pathogenic variant has been identified in an affected family member. ## Diagnosis Guidelines for diagnosis and care of children and families affected by retinoblastoma have been published [Canadian Retinoblastoma Society 2009]. ### Suggestive Findings Retinoblastoma should be suspected in children with any of the following: Leukocoria (white pupil) * Strabismus * Change in eye appearance * Reduced visual acuity Heritable retinoblastoma should be suspected in an individual with any of the following: * A diagnosis of retinoblastoma, including unilateral (unifocal and multifocal) and bilateral involvement * A retinoma * A family history of retinoblastoma ### Establishing the Diagnosis The diagnosis of retinoblastoma is established in a proband by retinal examination with full pupillary dilation by an ophthalmologist or optometrist. Confirmation of the diagnosis and determination of the disease extent is accomplished by examination under anesthesia. Ocular imaging can help confirm the diagnosis. Pathology is not required. Note: Biopsy may cause the tumor to spread beyond the eye, endangering the life of the individual. The diagnosis of heritable retinoblastoma is established in a proband with retinoblastoma or retinoma and a family history of retinoblastoma. However, the majority of individuals with retinoblastoma do not have a family history of the disorder. These patients require identification of a heterozygous germline RB1 pathogenic variant on molecular genetic testing (see Table 1) to determine if the retinoblastoma is heritable. Identification of an RB1 pathogenic variant in the proband allows for early diagnosis and screening for relatives at risk for retinoblastoma. The following staging has been recommended to clarify genetic risk of a germline RB1 pathogenic variant [Mallipatna et al 2017, Soliman et al 2017a]: * HX. Individual with unknown or insufficient evidence of a constitutional (germline) RB1 pathogenic variant * H0. Individual who did not inherit a known familial germline RB1 pathogenic variant confirmed by molecular genetic testing * (H0. Individual with retinoblastoma or retinoma with no germline RB1 pathogenic variant identified on molecular genetic testing; residual risk of mosaicism is <1%.) H1. Individual with bilateral retinoblastoma, trilateral retinoblastoma (retinoblastoma with intracranial CNS midline embryonic tumor), retinoblastoma and a family history of retinoblastoma, or identification of a germline RB1 pathogenic variant Molecular genetic testing approaches to identify individuals with heritable retinoblastoma can include single-gene testing and chromosomal microarray (CMA). Single-gene testing * Individuals with bilateral, unilateral familial, or unilateral multifocal retinoblastoma. Sequence analysis and gene-targeted deletion/duplication analysis of RB1 are performed on peripheral blood DNA. Note: Targeted analysis for recurrent pathogenic variants may be offered by some laboratories (see Table 1). * Individuals with unilateral unifocal retinoblastoma and a negative family history * If tumor tissue is not available, sequence analysis and gene-targeted deletion/duplication analysis of RB1 are performed on peripheral blood DNA. * If tumor tissue is available, sequence analysis and gene-targeted deletion/duplication analysis of RB1 are performed on tumor DNA. If pathogenic variants are identified, DNA from blood is tested for the presence of these variants. If no pathogenic variants are identified, methylation analysis of the RB1 promoter CpG island is performed to identify epigenetic inactivation of RB1 due to hypermethylation of the RB1 promoter. If no hypermethylation is identified at the promoter, DNA from tumor is tested for the amplification of MYCN, which is the cause of retinoblastoma in the absence of RB1 pathogenic variants in about 1.5% of individuals with isolated unilateral retinoblastoma. CMA uses oligonucleotide or SNP arrays to detect genome-wide large deletions/duplications (including RB1) that cannot be detected by sequence analysis. CMA may be considered in individuals with retinoblastoma associated with developmental delay and/or other congenital anomalies [Mitter et al 2011, Castéra et al 2013]. ### Table 1. Molecular Genetic Testing Used in Heritable Retinoblastoma View in own window Gene 1MethodSampleProportion of Probands with a Germline Pathogenic Variant 2 Detectable by Method RB1Sequence analysis 3Germline, tumor80%-84% Gene-targeted deletion/duplication analysis 4Germline, tumor16%-20% CMA 5Germline6%-8% 6 Targeted analysis for pathogenic variantsGermline, tumor25% 7 Methylation analysisTumorSee footnote 8. Allele loss analysisTumorSee footnote 9. MYCNGene-targeted deletion/duplication analysis 4TumorSee footnote 10. 1\. See Table A. Genes and Databases for chromosome locus and protein. 2\. See Molecular Genetics for information on allelic variants detected in this gene. 3\. Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here. 4\. 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. Gene-targeted deletion/duplication testing will detect deletions ranging from a single exon to the whole gene; however, breakpoints of large deletions and/or deletion of adjacent genes (e.g., those described by Mitter et al [2011], Castéra et al [2013]) may not be detected by these methods. 5\. Chromosomal microarray analysis (CMA) uses oligonucleotide or SNP arrays to detect genome-wide large deletions/duplications (including RB1) that cannot be detected by sequence analysis. The ability to determine the size of the deletion/duplication depends on the type of microarray used and the density of probes in the 13q14 region. CMA designs in current clinical use target the 13q14 region. 6\. Approximately 6%-8% of individuals with retinoblastoma have a chromosome deletion of 13q14. Such chromosome abnormalities are often associated with developmental delay and birth defects [Mitter et al 2011; Castéra et al 2013; Author, unpublished data]. 7\. Pathogenic variants that result in premature termination due to CpG-transitions account for 25% of all germline pathogenic variants [Rushlow et al 2009; Author, unpublished data]. 8\. Hypermethylation of RB1 promoter (which silences gene expression) is observed in approximately 15% of tumors from individuals with sporadic, unilateral retinoblastoma [Zeschnigk et al 2004; Author, unpublished data]. In these individuals, analysis of the promoter methylation status in DNA from tumor is needed to identify the two inactive RB1 alleles that triggered tumor development. 9\. Testing for loss of heterozygosity in tumors. Comparative genotyping of polymorphic loci within and flanking RB1 in DNA from peripheral blood and tumor can reveal that loss of the normal allele (hemizygosity) with or without duplication (homozygosity) of the mutated allele constitutes the somatic pathogenic variant. Observed in 60%-70% of tumors from patients with isolated unilateral retinoblastoma. 10\. About 1.5% of children with sporadic unilateral retinoblastoma have high-level MYCN amplification on tumor tissue testing but no pathogenic variants leading to inactivation of RB1 [Rushlow et al 2013]. The genetic interpretation of high-level MYCN amplification in the context of routine genetic testing is not yet established. ### Table 2. Probability of a Germline Pathogenic Variant Being Present in a Proband with Retinoblastoma Based on Family History and Tumor Presentation View in own window Family HistoryRetinoblastoma PresentationProbability That an RB1 Germline Pathogenic Variant Is Present UnilateralBilateral MultifocalUnifocal Positive 1+100% +100% +100% Negative 2+Close to 100% 3 +14%-95% +~14% 1\. Positive = more than one affected family member (10% of retinoblastoma) 2\. Negative = only one affected individual in the family (90% of retinoblastoma) 3\. RB1 pathogenic variants are identified by conventional molecular testing in 90%-97% of simplex cases with bilateral involvement; the remaining 5% may have translocations, deep intronic splice variants, or low-level mosaic pathogenic variants that may or may not be in the germline. Note: (1) If neither RB1 pathogenic variant identified in tumor tissue is found in the DNA of non-tumor cells (constitutional DNA), the affected individual has a low probability of having an RB1 germline pathogenic variant. (2) Because blood mosaicism as low as 20% can usually be detected by conventional molecular analysis such as sequencing, the failure to detect an RB1 pathogenic variant in constitutional DNA reduces but cannot eliminate the probability that the individual has an RB1 pathogenic variant in his/her germline. ## Clinical Characteristics ### Clinical Description Retinoblastoma. The most common presenting sign is a white pupillary reflex (leukocoria). Strabismus is the second most common presenting sign and may accompany or precede leukocoria [Abramson et al 2003]. Unusual presenting signs include glaucoma, orbital cellulitis, uveitis, hyphema, or vitreous hemorrhage. Most affected children are diagnosed before age five years. Atypical manifestations are more frequent in older children. Probands with retinoblastoma usually present in one of the following clinical settings: * Negative family history and unilateral retinoblastoma (60% of probands) * Negative family history and bilateral retinoblastoma (30% of probands) * Positive family history and unilateral or bilateral retinoblastoma (~10% of probands). For H1 individuals (see Establishing the Diagnosis) with a positive family history who undergo clinical surveillance via serial retinal examinations, tumors are often identified in the first month of life. * Chromosome deletion involving band 13q14. Up to 5% of all index cases with unifocal retinoblastoma and 7.5% of all index cases with multifocal retinoblastoma have a chromosome deletion of 13q14. Such chromosome abnormalities are often associated with developmental delay and birth defects [Mitter et al 2011, Castéra et al 2013]. Retinoblastoma is: * Unilateral if only one eye is affected by retinoblastoma. About 60% of affected individuals have unilateral retinoblastoma with a mean age at diagnosis of 24 months. Usually, in individuals with unilateral retinoblastoma the tumor is also unifocal (i.e., only a single tumor is present). Some individuals have multifocal tumors in one eye (unilateral multifocal retinoblastoma). Intraocular seeding may mimic primary multifocal tumor growth. In most persons with unilateral retinoblastoma without a family history, the tumor is large and it is not possible to determine if a single tumor is present. * Bilateral if both eyes are affected by retinoblastoma. About 40% of affected individuals have bilateral retinoblastoma with a mean age at diagnosis of 15 months. In most children with bilateral tumors, both eyes are affected at the time of initial diagnosis. In individuals with bilateral retinoblastoma both eyes may show multiple tumors. Some children who are initially diagnosed with unilateral retinoblastoma later develop a tumor in the contralateral unaffected eye. * Trilateral if bilateral (or, rarely, unilateral) retinoblastoma and a pinealoblastoma develop (see Pinealoblastomas). Retinoma and associated eye lesions. Benign retinal tumors (called retinoma) that have undergone spontaneous growth arrest may present within retinal scars [Dimaras et al 2008]. Calcified phthisic eyes may result from spontaneous regression of retinoblastoma associated with vascular occlusion [Valverde et al 2002]. The spectrum of RB1 pathogenic variants in individuals with retinoma and a family history for retinoblastoma and individuals who had retinoma in one eye and either retinoma or retinoblastoma in the other eye appears to be indistinct from that of individuals with bilateral retinoblastoma [Abouzeid et al 2009]. Pinealoblastomas occur in "retina-like" tissue in the pineal gland of the brain. Concurrence of pinealoblastomas or primitive neuroectodermal tumors and retinoblastoma is referred to as trilateral retinoblastoma. Pinealoblastoma is rare and usually fatal, unlike retinoblastoma of the eye, which is generally curable [de Jong et al 2014]. Other tumors. There is an increased risk for other specific extraocular primary neoplasms (collectively called second primary tumors). Most of the second primary tumors are osteosarcomas, soft tissue sarcomas (mostly leiomyosarcomas and rhabdomyosarcomas), or melanomas [Kleinerman et al 2007, Marees et al 2008, Kleinerman et al 2012]. These tumors usually manifest in adolescence or adulthood. The incidence of second primary tumors is increased to more than 50% in individuals with retinoblastoma who have received external beam radiation therapy [Wong et al 1997]. Survivors of heritable retinoblastoma who are not exposed to high-dose radiotherapy also have a high lifetime risk of developing a late-onset cancer [Dommering et al 2012b, Kleinerman et al 2012, MacCarthy et al 2013, Temming et al 2015]. ### Genotype-Phenotype Correlations In the majority of families with heritable retinoblastoma, all members who have inherited the germline pathogenic variant develop multiple tumors in both eyes. It is not unusual to find, however, that the founder (i.e., the first person in the family to have retinoblastoma) has only unilateral retinoblastoma. Most of these families segregate RB1 null alleles that are altered by frameshift or nonsense variants. With few exceptions, RB1 null alleles show nearly complete penetrance (>99%) [Taylor et al 2007, Dommering et al 2014, Frenkel et al 2016]. Fewer than 10% of families show a "low-penetrance" phenotype with reduced expressivity (i.e., increased prevalence of unilateral retinoblastoma) and incomplete penetrance (i.e., ≤25%). This low-penetrance phenotype is usually associated with RB1 in-frame, missense, or distinct splice site variants, certain indel variants in exon 1, or pathogenic variants in the promoter region. A third category of families shows differential penetrance depending on the parental origin of the pathogenic allele (parent-of-origin effect) [Klutz et al 2002, Eloy et al 2016, Imperatore et al 2018]. Cytogenetically visible deletions involving 13q14 that also result in deletions of additional genes in the same chromosome region as RB1 may cause developmental delay [Castéra et al 2013] and mild-to-moderate facial dysmorphism. As sizeable deletions of 13q14 show reduced expressivity, a considerable proportion of individuals with such deletions show unilateral retinoblastoma only; some of these children do not develop any tumors [Mitter et al 2011]. Contiguous loss of MED4, which is located centromeric to RB1, explains reduced expressivity in individuals with large deletions that include both RB1 and MED4 [Dehainault et al 2014]. ### Penetrance See Genotype-Phenotype Correlations. ### Nomenclature Glioma retinae is a historical name for retinoblastoma. ### Prevalence The incidence of retinoblastoma is estimated at between 1:15,000 and 1:20,000 live births [Moll et al 1997, Seregard et al 2004]. ## Differential Diagnosis Several ocular conditions of childhood can clinically simulate retinoblastoma: * Sporadic congenital disorders including persistent hyperplastic primary vitreous and Coats disease (OMIM 300216) * Hereditary disorders including tuberous sclerosis complex, Norrie disease (OMIM 310600), incontinentia pigmenti, familial exudative vitreoretinopathy (see Phenotypic Series: Exudative vitreoretinopathy), and von Hippel-Lindau syndrome * Ocular infestation by Toxocara canis ## Management Guidelines for retinoblastoma care have been developed [Canadian Retinoblastoma Society 2009]. ### Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with retinoblastoma, the evaluations summarized in this section (if not performed as part of the evaluation that led to the diagnosis) are recommended: * Prior to planning therapy, the extent of the tumor within and outside the eye should be determined. Each affected eye is assigned a cancer stage, depending on the extent of disease and the risk that the cancer has spread outside the eye [Mallipatna et al 2017]. Extent of the tumor is estimated by clinical examination under anesthetic and ultrasound or MRI, particularly focusing on the tumor - optic nerve relationship. Brain MRI is also useful to evaluate for a pinealoblastoma, indicating trilateral retinoblastoma. CT examination is NOT recommended because of the increased risk for second primary cancer potentially induced by radiation. * For very large tumors with risk factors for extraocular disease, bone marrow aspiration and examination of cerebrospinal fluid may also be performed at diagnosis, or performed when pathologic examination of the enucleated eye reveals optic nerve invasion or significant risks for extraocular extension. * If retinoblastoma has spread outside the eye, the stage of cancer will be evaluated to determine the most appropriate care of the child. * In individuals with a family history of retinoblastoma, and in uncommon circumstances in which the child presents with strabismus or poor vision, the retinal tumors may be small and detected by optical coherent tomography [Soliman et al 2017b]. * Consultation with a clinical geneticist and/or genetic counselor is appropriate. ### Treatment of Manifestations Goals of treatment in order of priority are preservation of life and then of sight. As optimal treatment may be complex, specialists skilled in the treatment of retinoblastoma from various fields including ophthalmology, pediatric oncology, pathology, and radiation oncology collaborate to deliver optimized care. In addition to eye and tumor stage, choice of treatment depends on many factors, including the number of tumor foci (unifocal, unilateral multifocal, or bilateral), localization and size of the tumor(s) within the eye(s), presence of vitreous seeding, the potential for useful vision, the extent and kind of extraocular extension, and the resources available. Treatment options for the eye include enucleation; cryotherapy; laser, systemic, or local ocular chemotherapy including intra-arterial chemotherapy, combined with or followed by laser or cryotherapy; radiation therapy using episcleral plaques; and, as a last resort, external beam radiotherapy. ### Prevention of Secondary Complications If possible, any radiation (including x-ray, CT scan, and external beam radiation) are avoided to minimize the lifetime risk of developing late-onset second cancers. Such tests should only be used if absolutely necessary in essential health care. ### Surveillance Further information regarding medical surveillance for those who have had or are at risk of developing retinoblastoma is available in the guidelines for retinoblastoma care. Guidelines for clinical screening for children at risk are published [Skalet et al 2018]. Detection of subsequent retinoblastoma after initial diagnosis. Following successful treatment, children require frequent follow-up examination for early detection of newly arising intraocular tumors, as indicated in guidelines [Skalet et al 2018]: * It is recommended that children known to have an RB1 germline pathogenic variant (H1) have an eye examination under anesthesia every three to four weeks until age six months, then less frequently until age three years. Clinical examinations with cooperative children are performed every three to six months until age seven years, then annually and eventually biennially for life. * Individuals who have unilateral retinoblastoma without an identified heterozygous germline RB1 pathogenic variant are at risk for low-level mosaicism (H0) and can develop a tumor in the other eye [Temming et al 2013]. This risk is small enough that examination under anesthesia may be replaced with regular clinical examination of the eyes, including clinical ultrasound (a simple, noninvasive procedure). Individuals with retinomas (premalignant retinal lesions associated with retinoblastoma) are followed with retinal examinations and imaging every one to two years, to detect any change early. Detection of second non-ocular tumors in individuals with retinoblastoma. Because of the high risk for second cancers, including sarcomas, melanoma, and specific other cancers, prompt investigation of any signs or symptoms is indicated. Total-body MRI at regular intervals is under investigation to determine when the technology will be specific and sensitive enough for screening for second cancers in persons with a heterozygous germline RB1 pathogenic variant. ### Agents/Circumstances to Avoid It has been suggested by Fletcher et al [2004] that cancer risks in survivors of heritable retinoblastoma may be reduced by limiting exposure to DNA-damaging agents (radiotherapy, tobacco, and UV light). It is plausible that cancer risks in these individuals may be reduced by limiting exposure to chemotherapy. ### Evaluation of Relatives at Risk The American Society of Clinical Oncologists identifies heritable retinoblastoma as a Group 1 disorder – i.e., a hereditary syndrome for which genetic testing is considered part of the standard management for at-risk family members [American Society of Clinical Oncology 2003]. It is appropriate to evaluate apparently asymptomatic at-risk relatives of an affected individual in order to identify as early as possible those who would benefit from eye examination by an experienced ophthalmologist and allow for early identification of a retinoblastoma. Evaluations can include: * Molecular genetic testing if the pathogenic variant in the family is known, which reduces the need for costly screening procedures in those at-risk family members who have not inherited the pathogenic variant [Noorani et al 1996, Richter et al 2003]; * Eye examinations by an ophthalmologist experienced in the treatment of retinoblastoma starting directly after birth as described above (see Surveillance, Detection of subsequent retinoblastoma after initial diagnosis. Young or uncooperative children may require examination under anesthesia. 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 are not many 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	Retinoblastoma	c0035335	1,712	gene_reviews	https://www.ncbi.nlm.nih.gov/books/NBK1452/	2021-01-18T21:00:10	{"mesh": ["D012175"], "synonyms": []}
Primary central nervous system lymphoma (primary CNS lymphoma) is a rare form of non-Hodgkin lymphoma in which cancerous cells develop in the lymph tissue of the brain and/or spinal cord. Because the eye is so close to the brain, primary CNS lymphoma can also start in the eye (called ocular lymphoma). The signs and symptoms vary based on which parts of the central nervous system are affected, but may include nausea and vomiting; seizures; headaches; arm or leg weakness; confusion; double vision and/or hearing loss. The exact underlying cause of primary CNS lymphoma is poorly understood; however, people with a weakened immune system (such as those with acquired immunodeficiency syndrome) or who have had an organ transplant appear to have an increased risk of developing the condition. Treatment varies based on the severity of the condition and location of the cancerous cells. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor *[BMI]: body mass index	Primary central nervous system lymphoma	c0280803	1,713	gard	https://rarediseases.info.nih.gov/diseases/9318/primary-central-nervous-system-lymphoma	2021-01-18T17:58:11	{"umls": ["C0280803"], "orphanet": ["46135"], "synonyms": ["Primary lymphoma, CNS", "PCNSL", "Primary brain lymphoma", "Primary CNS lymphoma"]}
Connolly et al. (1979) stated that urinary taurine excretion values show three modes in normals, consistent with a polymorphic codominant 2-allele system regulating renal reabsorption. They estimated frequencies of 0.35 and 0.65 for the high and low reabsorption, respectively. Beta-alanine competitively inhibits reabsorption of taurine and BAIB (beta-aminoisobutyric acid; see 210100). Thus, the postulated system is probably homologous to the beta-amino acid renal transport system found in mice and rats. Taurine excretion is, on the average, low in the Down syndrome, suggesting to Connolly et al. (1979) that the gene encoding this system is on human chromosome 21. At HGM6 (Oslo, 1981), a tentative assignment of a locus for this function to chromosome 21 was made on the basis of dosage effect in Down syndrome. Goodman (1981) concluded that a polymorphic codominant pair of alleles, symbolized T(R) and T(S), for rapid and slow uptake of taurine, are the prime regulators of taurine reabsorption at the renal level. The subtlety of the difference (only about 20% in reabsorption between the two homozygous genotypes) makes taurine loading essential to rigorous demonstration. In Down syndrome subjects, four genotypes occur in frequencies suggesting that the gene is on chromosome 21. A correlation between primary taurine excretion and IQ in Down syndrome was observed by Thomas et al. (1965). Thus, the same variability in uptake may occur in brain cells. Goodman et al. (1980) claimed that taurine metabolism may be important in epilepsy. Taurine, like gamma-aminobutyric acid (GABA), is probably neuroinhibitory and serves a role in modulation of neurotransmission (Barbeau and Huxtable, 1978). Taurine accounts for more than half of the total free amino acids in brain and platelet. Variability in platelet taurine may be a useful way to examine this polymorphism. Goodman (1981) estimated that the frequency of the rapid absorption gene is about 0.338. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor *[BMI]: body mass index	BETA-AMINO ACIDS, RENAL TRANSPORT OF	c1862289	1,714	omim	https://www.omim.org/entry/109660	2019-09-22T16:44:27	{"omim": ["109660"], "synonyms": ["Alternative titles", "TAURINE RENAL REABSORPTION"]}
For the alternative medicine practice similar to homeopathy, see tautopathy. Tauopathy Diagram of a normal microtubule and one affected by tauopathy SpecialtyNeurology Tauopathy belongs to a class of neurodegenerative diseases involving the aggregation of tau protein into neurofibrillary or gliofibrillary tangles (NFTs) in the human brain. Tangles are formed by hyperphosphorylation of the microtubule protein known as tau, causing the protein to dissociate from microtubules and form insoluble aggregates.[1] (These aggregations are also called paired helical filaments.) The mechanism of tangle formation is not well understood, and whether tangles are a primary cause of Alzheimer's disease or play a peripheral role is unknown. ## Contents * 1 Detection and imaging * 2 Alzheimer's disease * 3 Other diseases * 4 See also * 5 References * 6 External links ## Detection and imaging[edit] Post-mortem Tau tangles are seen microscopically in stained brain samples. Pre-mortem In living patients tau tangle locations can be imaged with a PET scan using a suitable radio-emissive agent.[2] ## Alzheimer's disease[edit] Abnormal accumulation of tau protein in neuronal cell bodies (arrow) and neuronal extensions (arrowhead) in the neocortex of a patient who died with Alzheimer's disease. The bar = 25 microns (0.025 millimeters). Neurofibrillary tangles were first described by Alois Alzheimer in one of his patients suffering from Alzheimer's disease (AD). The tangles are considered a secondary tauopathy. AD is also classified as an amyloidosis because of the presence of senile plaques.[3] When tau becomes hyperphosphorylated, the protein dissociates from the microtubules in axons.[4] Then, tau becomes misfolded and the protein begins to aggregate, which eventually forms the neurofibrillary tangles seen in Alzheimer’s patients.[1] Microtubules also destabilize when tau is dissociated. The combination of the neurofibrillary tangles and destabilized microtubules result in disruption of processes such as axonal transport and neural communication.[5] The degree of NFT involvement in AD is defined by Braak stages. Braak stages I and II are used when NFT involvement is confined mainly to the transentorhinal region of the brain, stages III and IV when there's also involvement of limbic regions such as the hippocampus, and V and VI when there's extensive neocortical involvement. This should not be confused with the degree of senile plaque involvement, which progresses differently.[6] ## Other diseases[edit] * Primary age-related tauopathy (PART)/Neurofibrillary tangle-predominant senile dementia, with NFTs similar to AD, but without plaques.[3][7][8] * Chronic traumatic encephalopathy (CTE)[9][10] * Progressive supranuclear palsy (PSP)[11] * Corticobasal degeneration (CBD) * Frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17)[12] * Lytico-bodig disease (Parkinson-dementia complex of Guam)[13] * Ganglioglioma and gangliocytoma[14] * Meningioangiomatosis[15] * Postencephalitic parkinsonism * Subacute sclerosing panencephalitis (SSPE)[16] * As well as lead encephalopathy, tuberous sclerosis, Pantothenate kinase-associated neurodegeneration, and lipofuscinosis[17] In both Pick's disease and corticobasal degeneration, tau proteins are deposited as inclusion bodies within swollen or "ballooned" neurons.[medical citation needed] Argyrophilic grain disease (AGD), another type of dementia,[18][19][20] is marked by an abundance of argyrophilic grains and coiled bodies upon microscopic examination of brain tissue.[21] Some consider it to be a type of Alzheimer's disease.[21] It may co-exist with other tauopathies such as progressive supranuclear palsy and corticobasal degeneration,[3] and also Pick's disease.[22] Tauopathies are often overlapped with synucleinopathies, possibly due to interaction between the synuclein and tau proteins.[23] The non-Alzheimer's tauopathies are sometimes grouped together as "Pick's complex" due to their association with frontotemporal dementia, or frontotemporal lobar degeneration.[24] ## See also[edit] * Proteopathy ## References[edit] 1. ^ a b Goedert M, Spillantini MG (May 2017). "Propagation of Tau aggregates". Molecular Brain. 10 (1): 18. doi:10.1186/s13041-017-0298-7. PMC 5450399. PMID 28558799. 2. ^ Alzheimer 'tau' protein far surpasses amyloid in predicting toll on brain tissue 3. ^ a b c Dickson DW (August 2009). "Neuropathology of non-Alzheimer degenerative disorders". International Journal of Clinical and Experimental Pathology. 3 (1): 1–23. PMC 2776269. PMID 19918325. 4. ^ Wang JZ, Xia YY, Grundke-Iqbal I, Iqbal K (2013). "Abnormal hyperphosphorylation of tau: sites, regulation, and molecular mechanism of neurofibrillary degeneration". Journal of Alzheimer's Disease. 33 Suppl 1: S123-39. doi:10.3233/JAD-2012-129031. PMID 22710920. 5. ^ Wang Y, Mandelkow E (January 2016). "Tau in physiology and pathology". Nature Reviews. Neuroscience. 17 (1): 5–21. doi:10.1038/nrn.2015.1. PMID 26631930. S2CID 30614958. 6. ^ Braak H, Braak E (1991). "Neuropathological stageing of Alzheimer-related changes". Acta Neuropathologica. 82 (4): 239–59. doi:10.1007/BF00308809. PMID 1759558. S2CID 668690. 7. ^ Santa-Maria I, Haggiagi A, Liu X, Wasserscheid J, Nelson PT, Dewar K, Clark LN, Crary JF (November 2012). "The MAPT H1 haplotype is associated with tangle-predominant dementia". Acta Neuropathologica. 124 (5): 693–704. doi:10.1007/s00401-012-1017-1. PMC 3608475. PMID 22802095. 8. ^ Jellinger KA, Attems J (February 2007). "Neurofibrillary tangle-predominant dementia: comparison with classical Alzheimer disease". Acta Neuropathologica. 113 (2): 107–17. doi:10.1007/s00401-006-0156-7. PMID 17089134. S2CID 5655388. 9. ^ McKee AC, Cairns NJ, Dickson DW, Folkerth RD, Keene CD, Litvan I, Perl DP, Stein TD, Vonsattel JP, Stewart W, Tripodis Y, Crary JF, Bieniek KF, Dams-O'Connor K, Alvarez VE, Gordon WA (January 2016). "The first NINDS/NIBIB consensus meeting to define neuropathological criteria for the diagnosis of chronic traumatic encephalopathy" (PDF). Acta Neuropathologica. 131 (1): 75–86. doi:10.1007/s00401-015-1515-z. PMC 4698281. PMID 26667418. 10. ^ Roberts GW (1988). "Immunocytochemistry of neurofibrillary tangles in dementia pugilistica and Alzheimer's disease: evidence for common genesis". Lancet. 2 (8626–8627): 1456–8. doi:10.1016/S0140-6736(88)90934-8. PMID 2904573. S2CID 32662671. 11. ^ Williams DR, Lees AJ (March 2009). "Progressive supranuclear palsy: clinicopathological concepts and diagnostic challenges". The Lancet. Neurology. 8 (3): 270–9. doi:10.1016/S1474-4422(09)70042-0. PMID 19233037. S2CID 1417930. 12. ^ Selkoe DJ, Podlisny MB (2002). "Deciphering the genetic basis of Alzheimer's disease". Annual Review of Genomics and Human Genetics. 3: 67–99. doi:10.1146/annurev.genom.3.022502.103022. PMID 12142353. 13. ^ Hof PR, Nimchinsky EA, Buée-Scherrer V, Buée L, Nasrallah J, Hottinger AF, Purohit DP, Loerzel AJ, Steele JC, Delacourte A (1994). "Amyotrophic lateral sclerosis/parkinsonism-dementia complex of Guam: quantitative neuropathology, immunohistochemical analysis of neuronal vulnerability, and comparison with related neurodegenerative disorders". Acta Neuropathologica. 88 (5): 397–404. doi:10.1007/BF00389490. PMID 7847067. S2CID 2821768. 14. ^ Brat DJ, Gearing M, Goldthwaite PT, Wainer BH, Burger PC (June 2001). "Tau-associated neuropathology in ganglion cell tumours increases with patient age but appears unrelated to ApoE genotype". Neuropathology and Applied Neurobiology. 27 (3): 197–205. doi:10.1046/j.1365-2990.2001.00311.x. PMID 11489139. S2CID 36482221. 15. ^ Halper J, Scheithauer BW, Okazaki H, Laws ER (July 1986). "Meningio-angiomatosis: a report of six cases with special reference to the occurrence of neurofibrillary tangles". Journal of Neuropathology and Experimental Neurology. 45 (4): 426–46. doi:10.1097/00005072-198607000-00005. PMID 3088216. S2CID 663552. 16. ^ Paula-Barbosa MM, Brito R, Silva CA, Faria R, Cruz C (November 1979). "Neurofibrillary changes in the cerebral cortex of a patient with subacute sclerosing panencephalitis (SSPE)". Acta Neuropathologica. 48 (2): 157–60. doi:10.1007/BF00691159. PMID 506699. S2CID 36105401. 17. ^ Wisniewski K, Jervis GA, Moretz RC, Wisniewski HM (March 1979). "Alzheimer neurofibrillary tangles in diseases other than senile and presenile dementia". Annals of Neurology. 5 (3): 288–94. doi:10.1002/ana.410050311. PMID 156000. S2CID 25649751. 18. ^ Ferrer I, Santpere G, van Leeuwen FW (June 2008). "Argyrophilic grain disease". Brain. 131 (Pt 6): 1416–32. doi:10.1093/brain/awm305. PMID 18234698. 19. ^ Josephs KA, Whitwell JL, Parisi JE, Knopman DS, Boeve BF, Geda YE, Jack CR, Petersen RC, Dickson DW (April 2008). "Argyrophilic grains: a distinct disease or an additive pathology?". Neurobiology of Aging. 29 (4): 566–73. doi:10.1016/j.neurobiolaging.2006.10.032. PMC 2727715. PMID 17188783. 20. ^ Wallon D, Sommervogel C, Laquerrière A, Martinaud O, Lecourtois M, Hannequin D (April 2010). "[Argyrophilic grain disease: synergistic component of dementia?]" [Argyrophilic grain disease: synergistic component of dementia?]. Revue Neurologique (in French). 166 (4): 428–32. doi:10.1016/j.neurol.2009.10.012. PMID 19963233. 21. ^ a b Tolnay M, Monsch AU, Staehelin HB, Probst A (May 1999). "[Argyrophilic grain disease: differentiation from Alzheimer disease]". Der Pathologe. 20 (3): 159–68. doi:10.1007/s002920050339. PMID 10412175. S2CID 2026154. 22. ^ Jellinger KA (April 1998). "Dementia with grains (argyrophilic grain disease)". Brain Pathology. 8 (2): 377–86. doi:10.1111/j.1750-3639.1998.tb00161.x. PMID 9546294. S2CID 22872309. 23. ^ Moussaud S, Jones DR, Moussaud-Lamodière EL, Delenclos M, Ross OA, McLean PJ (October 2014). "Alpha-synuclein and tau: teammates in neurodegeneration?". Molecular Neurodegeneration. 9: 43. doi:10.1186/1750-1326-9-43. PMC 4230508. PMID 25352339. 24. ^ Kertesz A, McMonagle P, Jesso S (November 2011). "Extrapyramidal syndromes in frontotemporal degeneration". Journal of Molecular Neuroscience. 45 (3): 336–42. doi:10.1007/s12031-011-9616-1. PMID 21887521. S2CID 13315112. ## External links[edit] Classification D * MeSH: D024801 * v * t * e Diseases of the nervous system, primarily CNS Inflammation Brain * Encephalitis * Viral encephalitis * Herpesviral encephalitis * Limbic encephalitis * Encephalitis lethargica * Cavernous sinus thrombosis * Brain abscess * Amoebic Brain and spinal cord * Encephalomyelitis * Acute disseminated * Meningitis * Meningoencephalitis Brain/ encephalopathy Degenerative Extrapyramidal and movement disorders * Basal ganglia disease * Parkinsonism * PD * Postencephalitic * NMS * PKAN * Tauopathy * PSP * Striatonigral degeneration * Hemiballismus * HD * OA * Dyskinesia * Dystonia * Status dystonicus * Spasmodic torticollis * Meige's * Blepharospasm * Athetosis * Chorea * Choreoathetosis * Myoclonus * Myoclonic epilepsy * Akathisia * Tremor * Essential tremor * Intention tremor * Restless legs * Stiff-person Dementia * Tauopathy * Alzheimer's * Early-onset * Primary progressive aphasia * Frontotemporal dementia/Frontotemporal lobar degeneration * Pick's * Dementia with Lewy bodies * Posterior cortical atrophy * Vascular dementia Mitochondrial disease * Leigh syndrome Demyelinating * Autoimmune * Inflammatory * Multiple sclerosis * For more detailed coverage, see Template:Demyelinating diseases of CNS Episodic/ paroxysmal Seizures and epilepsy * Focal * Generalised * Status epilepticus * For more detailed coverage, see Template:Epilepsy Headache * Migraine * Cluster * Tension * For more detailed coverage, see Template:Headache Cerebrovascular * TIA * Stroke * For more detailed coverage, see Template:Cerebrovascular diseases Other * Sleep disorders * For more detailed coverage, see Template:Sleep CSF * Intracranial hypertension * Hydrocephalus * Normal pressure hydrocephalus * Choroid plexus papilloma * Idiopathic intracranial hypertension * Cerebral edema * Intracranial hypotension Other * Brain herniation * Reye syndrome * Hepatic encephalopathy * Toxic encephalopathy * Hashimoto's encephalopathy Both/either Degenerative SA * Friedreich's ataxia * Ataxia–telangiectasia MND * UMN only: * Primary lateral sclerosis * Pseudobulbar palsy * Hereditary spastic paraplegia * LMN only: * Distal hereditary motor neuronopathies * Spinal muscular atrophies * SMA * SMAX1 * SMAX2 * DSMA1 * Congenital DSMA * Spinal muscular atrophy with lower extremity predominance (SMALED) * SMALED1 * SMALED2A * SMALED2B * SMA-PCH * SMA-PME * Progressive muscular atrophy * Progressive bulbar palsy * Fazio–Londe * Infantile progressive bulbar palsy * both: * Amyotrophic lateral sclerosis * v * t * e 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 [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor *[BMI]: body mass index	Tauopathy	c0949664	1,715	wikipedia	https://en.wikipedia.org/wiki/Tauopathy	2021-01-18T19:00:08	{"mesh": ["D024801"], "umls": ["C0949664"], "orphanet": ["98527"], "wikidata": ["Q2397106"]}
A number sign (#) is used with this entry because spastic paraplegia-7 is caused by homozygous or compound heterozygous mutation in the paraplegin gene (SPG7; 602783) on chromosome 16q24. Some patients with the disorder carry heterozygous SPG7 mutations. Description Hereditary spastic paraplegia (SPG) is characterized by progressive weakness and spasticity of the lower limbs due to degeneration of corticospinal axons. There is considerable genetic heterogeneity. Inheritance is most often autosomal dominant (see 182600), but X-linked (see 312920) and autosomal recessive (see 270800) forms occur. SPG7 shows phenotypic variability between families. Some cases are pure, whereas other are complicated with additional neurologic features (Warnecke et al., 2007). Clinical Features De Michele et al. (1998) reported a large consanguineous family with autosomal recessive spastic paraplegia with age of onset between 25 and 42 years (mean 30 +/- 8 years). Abnormal gait was the presenting symptom in all cases, and it was associated with leg pains in 1 patient. Weakness and extensor plantar response were absent in 1 patient with the shortest duration of disease at the time of observation. Vibration sense was frequently decreased in the lower limbs. Hypernasal and slowed speech was present in 2 patients and dysphagia in 1. Urinary urgency was present in 3 patients, scoliosis and pes cavus in 2, and pale optic disc in 2. There were no cerebellar or extrapyramidal signs in any of the 6 affected individuals (3 persons in each of 2 sibships who were related as double first cousins, having been born from brothers married to sisters). Casari et al. (1998) reported 2 affected brothers from a small village in southern Italy who showed typical signs of pure SPG with an age of onset of 26 years. Casari et al. (1998) reported a French family with autosomal recessive complicated SPG characterized by progressive weakness and spasticity of the lower limbs, decreased perception of sharp stimulation, diminished vibratory sense, and urinary incontinence. Mean age of onset was 34 years. These patients also had optic atrophy (3 of 3 examined), cortical atrophy (1 of 3 examined), and cerebellar atrophy (2 of 3 examined). Muscle biopsies showed ragged-red fibers and abnormal mitochondrial structure with no reaction to cytochrome c oxidase, consistent with a defect in mitochondrial respiration. Elleuch et al. (2006) reported a Moroccan family in which 4 sibs had SPG7. Age at onset ranged from 28 to 32 years with instability and stiff legs, which rapidly progressed to lower limb spasticity and weakness with hyperreflexia. Three patients could not run, and 1 could walk only with help. All had pes cavus, but none had extensor plantar responses. One patient had nystagmus, another had cerebellar signs, and a third had bladder dysfunction; none had decreased visual acuity. Two patients had impaired sensation at the ankles. Warnecke et al. (2007) reported a consanguineous Turkish family in which 3 sibs had a complicated form of SPG7. Age at onset ranged from 10 to 25 years, with gait disturbances in 2 sibs and dysarthria in 1. Clinical features included lower limb spasticity, pyramidal signs, lower limb hyperreflexia, supranuclear palsy, nystagmus, and cerebellar dysarthria. Two of the sibs, who were more severely affected, also had ataxia and extensor plantar responses, and 1 had urinary incontinence. Neuropsychologic evaluations showed severe deficits in attention and executive function in all sibs. The more severely affected sibs also showed impaired working memory and verbal learning. However, none of the sibs reported cognitive deficits. Brain MRI showed cerebellum atrophy and mild frontal cortical atrophy. Diffusion tensor imaging showed decreased white matter in the corticospinal tracts, frontal lobes, and midbrain. There was no evidence of peripheral neuropathy or optic atrophy. Molecular analysis identified a homozygous mutation in the SPG7 gene (602783.0006). Warnecke et al. (2007) suggested that the diffuse involvement may reflect mitochondrial dysfunction. Inheritance Although SPG7 has classically been considered to show an autosomal recessive mode of inheritance, there is also evidence for autosomal dominant transmission in some families (Sanchez-Ferrero et al., 2013). Mapping In a large consanguineous family with SPG, De Michele et al. (1998) demonstrated linkage to 16q24.3, with markers D16S413 (maximum lod score 3.37 at a recombination fraction of 0.00) and D16S303 (maximum lod score 3.74 at a recombination fraction of 0.00). Multipoint analysis localized the disease gene in the most telomeric region, with a lod score of 4.2. Molecular Genetics Casari et al. (1998) found that all affected individuals from the SPG7 family reported by De Michele et al. (1998) were homozygous for a 9.5-kb deletion (602783.0003) in the SPG7 gene. In 1 of 2 brothers from a small village in southern Italy who had autosomal recessive hereditary pure spastic paraplegia, Casari et al. (1998) identified a homozygous 2-bp deletion in the paraplegin cDNA (602783.0001), resulting in a frameshift that abolished approximately 60% of the protein. In a French family with SPG, they identified homozygosity for a 1-bp insertion (602783.0002) in all affected sibs; the mother was heterozygous for the mutation. In 4 affected sibs from a Moroccan family with SPG7, Elleuch et al. (2006) identified compound heterozygosity for 2 mutations in the SPG7 gene (602783.0004-602783.0005). In 1 (0.7%) of 136 index patients with autosomal recessive SPG, Elleuch et al. (2006) identified 2 mutations in the SPG7 gene. Twenty families had at least 1 variant in the SPG7 gene that was not found in 550 control chromosomes. In 4 of these families, mutations were predicted to be highly deleterious, suggesting that they may have contributed to the phenotype. The authors identified several additional rare variants in the SPG7 gene, which were of undetermined significance. Arnoldi et al. (2008) identified 7 different SPG7 mutations (see, e.g., 602783.0007-602783.0009) in 6 (4.4%) of 135 Italian patients with spastic paraplegia. Four of the patients were heterozygous for the mutations, which fell within conserved domains of the protein and were not found in controls. In 7 of 98 Dutch patients with apparently sporadic upper motor neuron disease symptoms, Brugman et al. (2008) identified homozygosity or compound heterozygosity for 6 mutations in the SPG7 gene that were of known or probable pathogenicity. Six patients had lower limb involvement only, and 1 patient had both upper and lower limb involvement. Three patients developed cerebellar signs, including dysarthria and gait ataxia, late in the disease course. None had bulbar involvement. Two patients with pure spastic paraparesis carried a single pathogenic mutation in the SPG7 gene. Sanchez-Ferrero et al. (2013) sequenced the SPG7 gene in 285 Spanish patients with spastic paraplegia who were negative for mutations in the SPAST (604277) and ATL1 (606439) genes. Fourteen SPG7 mutations, including 12 novel mutations, were identified in 14 patients. The mutations included 2 large deletions, 5 missense changes, 4 nonsense mutations, 2 frameshift insertion/deletions, and 1 splice site mutation. Thirteen patients had only a single heterozygous mutation, suggesting a dominant effect for some SPG7 mutations. Functional studies were not performed to assess the biologic significance. An A510V (rs61755320) substitution (602783.0012) was found in 8 patients (3%): 4 carried A510V in compound heterozygous state with another SPG7 mutation, 1 was homozygous for A510V, and 3 patients were heterozygous for A510V. The A510V substitution was also identified in 1% of controls. All patients had adult onset of the disorder, but only 35% had a complicated phenotype. INHERITANCE \- Autosomal recessive \- Autosomal dominant HEAD & NECK Eyes \- Optic atrophy \- Supranuclear palsy \- Nystagmus ABDOMEN Gastrointestinal \- Dysphagia (rare) GENITOURINARY Bladder \- Urinary urgency \- Urinary incontinence \- Sphincter disturbances SKELETAL Spine \- Scoliosis Feet \- Pes cavus NEUROLOGIC Central Nervous System \- Lower limb spasticity \- Lower limb weakness \- Spastic gait \- Ataxic gait \- Hyperreflexia \- Extensor plantar responses \- Pyramidal signs \- Decreased vibratory sense in the lower limbs \- Degeneration of the lateral corticospinal tracts \- Cerebral white matter lesions \- Dysarthria \- Cognitive defects in executive function and attention \- Memory deficits \- Cortical atrophy \- Cerebellar atrophy MISCELLANEOUS \- Mean age of onset 30 years (range 25-42) \- Complicated and pure forms \- Some patients carry heterozygous mutations MOLECULAR BASIS \- Caused by mutation in the paraplegin gene (SPG7, 602783.0001 ) ▲ 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	SPASTIC PARAPLEGIA 7, AUTOSOMAL RECESSIVE	c1846564	1,716	omim	https://www.omim.org/entry/607259	2019-09-22T16:09:29	{"doid": ["0110816"], "mesh": ["C564599"], "omim": ["607259"], "orphanet": ["99013"], "genereviews": ["NBK1107"]}
Palmoplantar keratoderma (PPK) is a group of skin conditions characterized by thickening of the skin on the palms of the hands and soles of the feet. PPK can also be a feature of various underlying syndromes. In rare forms of PPK, organs other than the skin may also be affected. PPK can be either acquired during the lifetime (more commonly) or inherited. Acquired PPKs may arise due to changes in a person's health or environment. Inherited PPKs are caused by genetic mutations that result in abnormalities of keratin, a skin protein. Depending on the genetic cause, inheritance can be autosomal dominant or autosomal recessive. Treatment is aimed at softening the thickened skin to make it less noticeable and relieve discomfort. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor *[BMI]: body mass index	Palmoplantar keratoderma	c0022596	1,717	gard	https://rarediseases.info.nih.gov/diseases/8167/palmoplantar-keratoderma	2021-01-18T17:58:28	{"umls": ["C0022596"], "synonyms": ["Keratoderma, Palmoplantar"]}
This article is an orphan, as no other articles link to it. Please introduce links to this page from related articles; try the Find link tool for suggestions. (October 2016) 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: "Eruptive hypomelanosis" – news · newspapers · books · scholar · JSTOR (October 2016) (Learn how and when to remove this template message) Eruptive hypomelanosis SpecialtyDermatology, Infectious disease Eruptive hypomelanosis is a novel paraviral exanthem suspected to be related to viral infections. Most patients are young children aged two to ten. Most children develop prodromal symptoms similar to common cold or influenza. Small, monomorphous, and hypopigmented macules then erupt. There could be systemic manifestations like pharyngitis or enlargement of lymph nodes. Most children with eruptive hypomelanosis develop no complications. The epidemiology, aetiology, clinical manifestations, complication, infectivity, and management of eruptive hypomelanosis leave much space to be investigated.[1][2] ## References[edit] 1. ^ Zawar, Vijay; Bharatia, Pravin; Chuh, Antonio (2014). "Eruptive hypomelanosis: a novel exanthem associated with viral symptoms in children". JAMA Dermatology. 150 (11): 1197–201. doi:10.1001/jamadermatol.2014.1499. PMID 25229328. 2. ^ Chuh, Antonio; Bharatia, Pravin; Zawar, Vijay (2016). "Eruptive Hypomelanosis in a Young Child as a Paraviral Exanthem". Pediatric Dermatology. 33 (1): e38–e39. doi:10.1111/pde.12736. PMID 26646426. ## External links[edit] 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	Eruptive hypomelanosis	None	1,718	wikipedia	https://en.wikipedia.org/wiki/Eruptive_hypomelanosis	2021-01-18T18:45:57	{"wikidata": ["Q24882796"]}
A number sign (#) is used with this entry because cranioectodermal dysplasia-3 (CED3) is caused by homozygous mutation in the IFT43 gene (614068) on chromosome 14q24. One such family has been reported. Description Cranioectodermal dysplasia (CED), also known as Sensenbrenner syndrome, is a rare autosomal recessive heterogeneous ciliopathy that is primarily characterized by skeletal abnormalities, including craniosynostosis, narrow rib cage, short limbs, and brachydactyly, and ectodermal defects. Nephronophthisis leading to progressive renal failure, hepatic fibrosis, heart defects, and retinitis pigmentosa have also been described (summary by Arts et al., 2011). For discussion of genetic heterogeneity of cranioectodermal dysplasia, see CED1 (218330). Clinical Features Arts et al. (2011) reported a sister and brother from a consanguineous family of Moroccan descent with cranioectodermal dysplasia. Both sibs had short stature, narrow thorax, rhizomelic shortening of limbs, hypoplastic and widely spaced teeth, and nephronophthisis. The 7-year-old sister, who lacked the typical craniofacial features of Sensenbrenner syndrome, had bilateral 2-3-4 toe syndactyly, and brachydactyly with webbing of fingers and short, broad nails. Her 5-year-old brother displayed macrocephaly, scaphocephaly, sagittal suture synostosis, frontal bossing, telecanthus, everted lower lip, micrognathia, and sparse, fine hair. In addition, he had bilateral postaxial polydactyly of hands and feet, brachydactyly and webbing of fingers with short, broad nails, bilateral 2-3 and 5-6 toe syndactyly, and sandal gap between toes 1-2. The brother also had peripheral pulmonary stenosis, neonatal cholestasis and cirrhosis, and end-stage renal disease requiring dialysis. Mapping In a consanguineous family of Moroccan descent in which a brother and sister had cranioectodermal dysplasia, Arts et al. (2011) performed genomewide homozygosity mapping and found that the 2 largest regions of homozygosity overlapped in a 25.2-Mb region on chromosome 14. Molecular Genetics In a brother and sister from a consanguineous family of Moroccan descent with cranioectodermal dysplasia mapping to chromosome 14, Arts et al. (2011) analyzed 2 candidate genes and identified homozygosity for a mutation in the translation initiation codon of the IFT43 gene (614068.0001). The first-cousin parents were each heterozygous for the mutation. Arts et al. (2011) noted that IFT43 directly binds to WDR35 (613602) in the intraflagellar transport (IFT)-A protein complex. No mutations in the IFT43 gene were detected in 4 additional unrelated patients with CED who were known to be negative for mutation in WDR35, and homozygosity mapping in 2 consanguineous CED families revealed no major intervals of homozygosity in regions containing the 3 known CED-related genes, indicating the likelihood of further genetic heterogeneity in the disorder. Pathogenesis Consistent with disruption of a member of the IFTA protein complex, fibroblasts from 1 of the affected sibs and from a previously studied patient (Gilissen et al., 2010) with CED2 (613610) and mutations in WDR35 showed similar ciliary defects, with accumulation of IFTB-complex proteins in the ciliary tip. In addition, cilia in mutant IFT43 fibroblasts were somewhat shorter than those of control fibroblasts, as had previously been reported (Walczak-Sztulpa et al., 2010) in patients with CED1 (218330) and mutation in the IFT122 gene (606045). Arts et al. (2011) concluded that their findings demonstrated that CED results from defects in retrograde intraflagellar transport. INHERITANCE \- Autosomal recessive GROWTH Height \- Short stature HEAD & NECK Head \- Scaphocephaly (in some patients) \- Macrocephaly (in some patients) Face \- Frontal bossing (in some patients) \- Micrognathia (in some patients) Eyes \- Telecanthus (in some patients) Mouth \- Everted lower lip (in some patients) Teeth \- Hypoplastic teeth \- Widely spaced teeth CARDIOVASCULAR Vascular \- Peripheral pulmonary stenosis (in some patients) CHEST External Features \- Narrow thorax ABDOMEN Liver \- Neonatal cholestasis (in some patients) \- Cirrhosis (in some patients) GENITOURINARY Kidneys \- Nephronophthisis \- End-stage renal disease (in some patients) SKELETAL Skull \- Sagittal suture synostosis (in some patients) Limbs \- Rhizomelic limbs \- Shortening or bowing of humeri \- Joint laxity Hands \- Brachydactyly \- Webbing of fingers \- Postaxial polydactyly, bilateral (in some patients) Feet \- Postaxial polydactyly, bilateral (in some patients) \- Syndactyly \- Sandal gap, bilateral (in some patients) SKIN, NAILS, & HAIR Skin \- Skin laxity \- Dry skin Nails \- Short, broad nails Hair \- Sparse, fine hair MOLECULAR BASIS \- Caused by mutation in the intraflagellar transport 43 gene (ITF43, 614068.0001 ) ▲ 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	CRANIOECTODERMAL DYSPLASIA 3	c0432235	1,719	omim	https://www.omim.org/entry/614099	2019-09-22T15:56:29	{"doid": ["0080033"], "mesh": ["C562966"], "omim": ["614099"], "orphanet": ["1515"], "genereviews": ["NBK154653"]}
A rare chromosomal disorder, characterized by childhood onset drug resistant epilepsy with typical electroencephalographic findings (EEG), mild to severe intellectual disability and behavioral problems. ## Epidemiology The overall birth prevalence of ring chromosomes is 1/30-60,000 and ring 20 (r20) is one of the most common and is probably underdiagnosed. ## Clinical description Initial psychomotor development is usually unaffected. Age of seizure onset varies between 1-24 years (frequently 4-10 years) and are typically recurrent focal motor seizures during sleep or whilst awake with alteration of consciousness, staring, automatisms, ictal visual, affective behavior and periods of intense fear. Seizures can progress to generalized tonic or tonic-clonic seizures. Non-convulsive status epilepticus (NCSE) is common, recognizable by an altered state of vigilance, staring, reduced motor activity and speech. R20 syndrome is considered a developmental epileptic encephalopathy since epilepsy onset is followed by an early cognitive-behavioral decline which seems to be focused on frontal lobe dysfunction. Language and learning disabilities, attention problems, aggressive and obsessive behavior, and apathy are frequently reported. The electroencephalogram (EEG) shows frontal spikes within runs of bilateral slow high voltage activity. Age-related patterns of sleep deterioration, ranging from normal to destructured non-rapid eye movement/rapid eye movement, is also typical. There are no distinct dysmorphisms although microcephaly, strabismus, micrognathia, down-slanting palpebral fissures, ear abnormalities and poor somatic growth can be present. Associated brain, cardiac and renal malformations are rare. ## Etiology A ring chromosome is an aberrant chromosome whose ends have fused together. Ring chromosomes are unstable: during mitosis, the ring may be lost or duplicated. Patients carrying a ring chromosome often have mosaic karyotypes with normal cells, cells with a ring chromosome, cells with monosomy and/or cells with reorganized/duplicated rings. Some patients with r20 lose the terminal part of 20q. The epileptogenic mechanism remains unknown. Currently there is no evidence to support a correlation between the level of mosaicism and the severity of the phenotype, although non-mosaic cases present with the most severe symptoms/comorbidities. ## Diagnostic methods Diagnosis is suspected in patients with childhood onset recurrent seizures with a cognitive deterioration, behavioral changes and typical EEG findings. As mosaicism is frequent, r20 chromosome should be confirmed by karyotyping with at least 100 metaphases on blood lymphocytes. Diagnosis may be missed using other genetic techniques including aCGH. ## Differential diagnosis Differential diagnosis includes primarily Lennox Gastaut syndrome. Moreover, frontal lobe epilepsy, continuous spike and wave during slow wave sleep and NCSE of other etiologies should be considered. ## Genetic counseling R20 mosaicism could be sporadic or inherited: parent-to child transmission has been reported in a few exceptional families. Genetic counseling is recommended. ## Management and treatment Seizures associated with r20 are often refractory to medications and there is no specific treatment regimen for the disorder. A more favorable outcome has been reported with the combination of valproate and lamotrigine. Ketogenic diet can be helpful, with better results if introduced at seizure onset. Resective brain surgery is not a therapeutic option. Mild improvement with vagus nerve stimulation is reported. ## Prognosis Prognosis is generally poor since epilepsy is drug resistant, remaining into adulthood. Cognitive performance can remain locked at the time of epilepsy onset or worsen over time. * European Reference Network [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor *[BMI]: body mass index	Ring chromosome 20 syndrome	c0265482	1,720	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=1444	2021-01-23T17:10:21	{"gard": ["1334"], "mesh": ["C580424", "C535369"], "umls": ["C0265482", "C2930886"], "icd-10": ["Q93.2"], "synonyms": ["Ring 20", "Ring chromosome 20"]}
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(January 2019) (Learn how and when to remove this template message) (Learn how and when to remove this template message) Ergophobia SpecialtyPsychology Ergophobia, ergasiophobia or ponophobia is an abnormal and persistent fear of work (manual labor, non-manual labor, etc.) or fear of finding employment. It may be a form of social phobia or performance anxiety. People with ergophobia experience undue anxiety about the workplace environment even though they realize their fear is irrational. Their fear may actually be a combination of fears, such as fear of failing at assigned tasks, speaking before groups at work (both of which are types of performance anxiety), socializing with co-workers (a type of social phobia), and other fears of emotional, psychological and/or physiological injuries.[1] The term ergophobia comes from the Greek "ergon" (work) and "phobos" (fear).[2] ## Contents * 1 Phobias * 2 Symptoms * 3 History and measurement * 4 Clinical assessment * 5 Similar syndromes * 6 In culture * 7 Notes and references ## Phobias[edit] A phobia is a psychological condition in which an individual has a persisting fear of situations or objects, disproportionate to the threat they actually pose.[3] Once the fearful individual encounters the situation or object of their phobia, the emotional, cognitive and physical reaction is almost immediate. This condition creates immense distress that stems from the need to constantly be alert and to be able to avoid the triggering source of the phobia. Phobias can be specific to a certain stimulus or general to social situations. The most effective treatment for phobias is exposure therapy.[4] ## Symptoms[edit] Ergophobia can manifest itself in somatic symptoms in addition to psychological ones. There have been several studies focusing on burnout among teachers, and it has been found that those experiencing ergophobia performed significantly worse on a physical health index compared to their colleagues.[1][5] Physical symptoms include rapid heartbeat, dry mouth, excessive sweating, general uneasiness, and panic attacks.[1] ## History and measurement[edit] Ergophobia was defined by William Upson in 1905 as “the art of laziness”.[6] The New York Medical Journal claimed to be the first to define this condition, but the publication later found the name had been used by a hospital in New Jersey as early as in the 1860s.[5] Ergophobia is a corollary of Occupational Burnout, which is thought to be the result of long-term unresolvable job stress. The term “burnout” did not come to be used with regularity until the 1970s in the United States. Freudenberger, for example, used it to describe the phenomenon of physical and emotional exhaustion with associated negative attitudes arising from intense interactions when working with people.[7] Later studies on ergophobia and occupational burnout build upon the existing conception of Freudenberger’s research and found the phenomenon was quite common in a variety of human service occupations. These occupations include health care and mental health care professionals, social welfare workers, lawyers, and business organization employees.[1] Even though there is no formal diagnosis procedure, the Maslach Burnout Inventory, a series of introspective occupational burnout questions, is used together with Areas of Worklife Survey (AWS) to assess levels of burnout. These tests measure emotional burnout, depersonalization, and personal achievements and are suitable for an individual as well as group assessment.[1] ## Clinical assessment[edit] Ergophobia is not defined as a phobia in the DSM 5 manual, but it may be a subset of performance anxiety. There may be a connection between executive dysfunction and work-related anxiety because there is a known connection between dysfunction and general anxiety disorder. It is unclear which one causes the other.[8] ## Similar syndromes[edit] Generalized Anxiety disorder might be a similar syndrome, in it one experiences uncontrollably elevated levels of anxiety and worries over varying issues and events.[9] As with phobia, the anxiety and individual with Generalized Anxiety Disorder experiences is disproportionate to the actual threat that the events or situations pose. Adults with GAD can feel stressed by work-related concerns regarding everyday tasks, evaluations, and presentations.[9] Social anxiety disorder, also known as social phobia, is characterized by feelings of anxiety caused by social interactions or situations in which the individual can be scrutinized or rejected by others.[10] This anxiety is easily exacerbated by work-related situations such as presentations and professional and friendly social interactions at the workplace.[9] A similar condition is “Other specified Anxiety Disorder”, in which there is distress and significant levels of anxiety, but not in a manner that fully embodies the diagnostic symptoms of anxiety disorders.[9] This disorder greatly influences performance in social, occupational or other important situations, and as such may seem similar to Ergophobia or occupational burnout.[9] ## In culture[edit] Ergophobia is being displayed and discussed in pop culture as suffering from burnout. Being burnt out is conceptualized as encompassing three components: emotional exhaustion, depersonalization, and reduced personal accomplishment. When people are seen as characteristically “burnt-out”, their attitudes towards others change, becoming more cynical and retracted from normal social dynamics.[1] Specifically, these traits are shown in two parts externally, emotional exhaustion refers to the feeling of being emotionally drained after interacting with other people and depersonalization is expressed in negative attitudes or unsympathetic responses towards other people.[1] When an individual perceives their sense of competence as lesser than their co-workers, or view their intelligence as greater than their colleagues who are being elevated to higher roles, there is a higher chance that their sense of personal accomplishment gets diminished.[1] With the decline of at first the agricultural, and later manufacturing sectors in the United States, the service industry has come to be the dominant industry in the economy in North America.[11] Currently, 79.45 percent of people in the U.S are employed in the service industry.[11] A service-based economy has the potential to exacerbate emotional exhaustion as there are simply more people employed in this sector. Because burnout or ergophobia is most commonly found in service sector roles, it is easy to see how it is becoming a more prevalent issue in contemporary society.[12] The more people employed in an environment that is conducive to ergophobia, the greater the number of cases of ergophobia, regardless of changes in the rates reported of ergophobia itself.[13] The changing nature of employer-employee relations has also itself been significantly altered by this evolution to a service-based economy.[14] Performance appraisal systems are now a popular tool within organizations to enhance employee commitment and productivity.[1] Such a system, in which the relationship between employee and boss is much closer, and thus the employee is subsequent to more face-to-face scrutiny which can exacerbate emotional exhaustion among employees and subsequently feelings of ergophobia.[1] Prevalence of ergophobia and occupational burnout is also increasing, as there is increasing diagnosis of the condition.[1] Performance appraisal systems are now a popular tool within organizations to enhance employee commitment and productivity.[1] Mental health has become a much less taboo subject in recent years, and there is a proliferation of mental health awareness discourses in popular North American culture. An example of such a mental-health-initiatives led by the private sphere, is the Canadian campaign, Bell Let’s Talk. Such worldwide and pervasive initiatives may, however, lead to misdiagnosis.[13] As the fear of work itself is such a general catchall term, many may believe that they suffer from ergophobia when in fact the root issue is a plethora of other mental health issues such as Generalized Anxiety Disorder or social anxiety disorder.[14] * Medicine portal Look up Ergophobia in Wiktionary, the free dictionary. ## Notes and references[edit] 1. ^ a b c d e f g h i j k l Belcastro, Philip A.; Hays, Leon C. (1984). "Ergophilia . . . ergophobia . . . ergo . . . burnout?". Professional Psychology: Research and Practice. 15 (2): 260–270. doi:10.1037/0735-7028.15.2.260. ISSN 1939-1323. 2. ^ "Ergo" is also used to form other English words, including "ergometer" (a device that measures the amount of work done by muscles) and "ergonomics" (an applied science that designs interfaces and working environments with the aim of maximizing functionality and improving worker comfort). 3. ^ Agras, S.; Sylvester, D.; Oliveau, D. (1969). "The epidemiology of common fears and phobia". Comprehensive Psychiatry. 10 (2): 151–156. doi:10.1016/0010-440x(69)90022-4. PMID 5774552. 4. ^ Wolitzky-Taylor, Kate B.; Horowitz, Jonathan D.; Powers, Mark B.; Telch, Michael J. (July 2008). "Psychological approaches in the treatment of specific phobias: A meta-analysis". Clinical Psychology Review. 28 (6): 1021–1037. doi:10.1016/j.cpr.2008.02.007. ISSN 0272-7358. PMID 18410984. 5. ^ a b Guglielmi, R Sergio; Tatrow, Kristin (March 1998). "Occupational Stress, Burnout, and Health in Teachers: A Methodological and Theoretical Analysis". Review of Educational Research. 68 (1): 61–99. doi:10.3102/00346543068001061. ISSN 0034-6543. 6. ^ Upson, William Hazlett (1933). Ergophobia (Manuscript). University of Vermont Libraries, Special Collections. Archived from the original on 2018-12-05. Retrieved 2018-12-04. 7. ^ Freudenberger, Herbert J. (1974-01-01). "Staff Burn-Out". Journal of Social Issues. 30 (1): 159–165. doi:10.1111/j.1540-4560.1974.tb00706.x. ISSN 1540-4560. 8. ^ Eysenck, M. W.; Derakshan, N.; Santos, R.; Calvo, M. G. (2007). "Anxiety and cognitive performance: attentional control theory". Emotion. 7 (2): 336–53. doi:10.1037/1528-3542.7.2.336. PMID 17516812. S2CID 33462708. 9. ^ a b c d e Rada, R. E.; Johnson-Leong, C. (2004). "Stress, burnout, anxiety and depression among dentists". The Journal of the American Dental Association. 135 (6): 788–794. doi:10.14219/jada.archive.2004.0279. PMID 15270165. S2CID 1707474. 10. ^ Pereira-Lima, K.; Loureiro, S. R. (2015). "Burnout, anxiety, depression, and social skills in medical residents". Psychology, Health & Medicine. 20 (3): 353–362. doi:10.1080/13548506.2014.936889. PMID 25030412. 11. ^ a b Hsu, H. Y.; Chen, S. H.; Yu, H. Y.; Lou, J. H. (2010). "Job stress, achievement motivation and occupational burnout among male nurses". Journal of Advanced Nursing. 66 (7): 1592–1601. doi:10.1111/j.1365-2648.2010.05323.x. PMID 20492017. 12. ^ Gabris, G. T.; Ihrke, D. M. (2001). "Does performance appraisal contribute to heightened levels of employee burnout?". Public Personnel Management. 30 (2): 157–172. doi:10.1177/009102600103000203. 13. ^ a b Ahola, Kirsi (2007). Occupational burnout and health. People and Work Research Reports. Helsinki: Finnish Institute of Occupational Health. ISBN 978-951-802-794-5. ISSN 1237-6183. 14. ^ a b Brown, Michelle; Benson, John (2003). "Rated to exhaustion? Reactions to performance appraisal processes". Industrial Relations. 34 (1): 67–81. doi:10.1111/1468-2338.00259. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor *[BMI]: body mass index	Ergophobia	None	1,721	wikipedia	https://en.wikipedia.org/wiki/Ergophobia	2021-01-18T18:53:02	{"wikidata": ["Q2724163"]}
Chromhidrosis Other namesColored sweat[1] SpecialtyDermatology 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. (March 2011) (Learn how and when to remove this template message) Chromhidrosis is a rare condition characterized by the secretion of colored sweat.[2] It is caused by the deposition of lipofuscin in the sweat glands. Cases of red, blue, green, yellow, pink, and black sweat have been reported.[by whom?] Usually chromhidrosis affects the apocrine glands, mainly on the face and underarms. A limited number of treatment options exist, including regular application of Capsaicin cream and prolonged relief may be provided by botulinum toxin treatment. Chromogenic pigments produced by bacteria (Corynebacterium in particular) are implicated in this condition but their exact role still requires careful microbiological elucidation. Chromhidrosis of the eccrine glands is rare, it occurs mainly after the ingestion of certain dyes or drugs. ## Contents * 1 See also * 2 References * 3 Further reading * 4 External links ## See also[edit] * List of cutaneous conditions ## References[edit] 1. ^ James, William; Berger, Timothy; Elston, Dirk (2005). Andrews' Diseases of the Skin: Clinical Dermatology (10th ed.). Saunders. p. 179. ISBN 978-0-7216-2921-6. 2. ^ Freedberg, Irwin M.; Eisen, Arthur Z.; Wolff, Klauss; Austen, K. Frank; Katz, Lowell A.; Katz, Stephen, eds. (2003). Fitzpatrick's Dermatology in General Medicine (6th ed.). New York: McGraw-Hill. p. 708. ISBN 978-0-07-138076-8. ## Further reading[edit] * Schwarz, T; Neumann, R; Duschet, P; Brückler, B; Klein, W; Oppolzer, G; Bardach, H; Gschnait, F (1989). "Apokrine Chromhidrose" [Apocrine chromhidrosis]. Der Hautarzt (in German). 40 (2): 106–9. PMID 2714985. * Marksjr, J (1989). "Treatment of apocrine chromhidrosis with topical capsaicin". Journal of the American Academy of Dermatology. 21 (2 Pt 2): 418–20. doi:10.1016/S0190-9622(89)80050-7. PMID 2474015. * Bartels, Eva (2008). "Farbkodierte Dopplersonographie der Vertebralarterien. Vergleich mit der konventionellen Duplexsonographie" [Color coded Doppler sonography of the vertebral arteries. Comparison with conventional duplex sonography]. Ultraschall in der Medizin. 13 (2): 59–66. doi:10.1055/s-2007-1005277. PMID 1604294. * Musel, Andrea (2005). "Chromhidrosis and Pseudochromhidrosis" (PDF). DermatologyReview.com Journal: 1–3. (dead link 20191006) ## External links[edit] Classification D * ICD-10: L75.1 * ICD-9-CM: 705.89 * DiseasesDB: 30737 External resources * eMedicine: derm/596 * v * t * e Disorders of skin appendages Nail * thickness: Onychogryphosis * Onychauxis * color: Beau's lines * Yellow nail syndrome * Leukonychia * Azure lunula * shape: Koilonychia * Nail clubbing * behavior: Onychotillomania * Onychophagia * other: Ingrown nail * Anonychia * ungrouped: Paronychia * Acute * Chronic * Chevron nail * Congenital onychodysplasia of the index fingers * Green nails * Half and half nails * Hangnail * Hapalonychia * Hook nail * Ingrown nail * Lichen planus of the nails * Longitudinal erythronychia * Malalignment of the nail plate * Median nail dystrophy * Mees' lines * Melanonychia * Muehrcke's lines * Nail–patella syndrome * Onychoatrophy * Onycholysis * Onychomadesis * Onychomatricoma * Onychomycosis * Onychophosis * Onychoptosis defluvium * Onychorrhexis * Onychoschizia * Platonychia * Pincer nails * Plummer's nail * Psoriatic nails * Pterygium inversum unguis * Pterygium unguis * Purpura of the nail bed * Racquet nail * Red lunulae * Shell nail syndrome * Splinter hemorrhage * Spotted lunulae * Staining of the nail plate * Stippled nails * Subungual hematoma * Terry's nails * Twenty-nail dystrophy Hair Hair loss/ Baldness * noncicatricial alopecia: Alopecia * areata * totalis * universalis * Ophiasis * Androgenic alopecia (male-pattern baldness) * Hypotrichosis * Telogen effluvium * Traction alopecia * Lichen planopilaris * Trichorrhexis nodosa * Alopecia neoplastica * Anagen effluvium * Alopecia mucinosa * cicatricial alopecia: Pseudopelade of Brocq * Central centrifugal cicatricial alopecia * Pressure alopecia * Traumatic alopecia * Tumor alopecia * Hot comb alopecia * Perifolliculitis capitis abscedens et suffodiens * Graham-Little syndrome * Folliculitis decalvans * ungrouped: Triangular alopecia * Frontal fibrosing alopecia * Marie Unna hereditary hypotrichosis Hypertrichosis * Hirsutism * Acquired * localised * generalised * patterned * Congenital * generalised * localised * X-linked * Prepubertal Acneiform eruption Acne * Acne vulgaris * Acne conglobata * Acne miliaris necrotica * Tropical acne * Infantile acne/Neonatal acne * Excoriated acne * Acne fulminans * Acne medicamentosa (e.g., steroid acne) * Halogen acne * Iododerma * Bromoderma * Chloracne * Oil acne * Tar acne * Acne cosmetica * Occupational acne * Acne aestivalis * Acne keloidalis nuchae * Acne mechanica * Acne with facial edema * Pomade acne * Acne necrotica * Blackhead * Lupus miliaris disseminatus faciei Rosacea * Perioral dermatitis * Granulomatous perioral dermatitis * Phymatous rosacea * Rhinophyma * Blepharophyma * Gnathophyma * Metophyma * Otophyma * Papulopustular rosacea * Lupoid rosacea * Erythrotelangiectatic rosacea * Glandular rosacea * Gram-negative rosacea * Steroid rosacea * Ocular rosacea * Persistent edema of rosacea * Rosacea conglobata * variants * Periorificial dermatitis * Pyoderma faciale Ungrouped * Granulomatous facial dermatitis * Idiopathic facial aseptic granuloma * Periorbital dermatitis * SAPHO syndrome Follicular cysts * "Sebaceous cyst" * Epidermoid cyst * Trichilemmal cyst * Steatocystoma * simplex * multiplex * Milia Inflammation * Folliculitis * Folliculitis nares perforans * Tufted folliculitis * Pseudofolliculitis barbae * Hidradenitis * Hidradenitis suppurativa * Recurrent palmoplantar hidradenitis * Neutrophilic eccrine hidradenitis Ungrouped * Acrokeratosis paraneoplastica of Bazex * Acroosteolysis * Bubble hair deformity * Disseminate and recurrent infundibulofolliculitis * Erosive pustular dermatitis of the scalp * Erythromelanosis follicularis faciei et colli * Hair casts * Hair follicle nevus * Intermittent hair–follicle dystrophy * Keratosis pilaris atropicans * Kinking hair * Koenen's tumor * Lichen planopilaris * Lichen spinulosus * Loose anagen syndrome * Menkes kinky hair syndrome * Monilethrix * Parakeratosis pustulosa * Pili (Pili annulati * Pili bifurcati * Pili multigemini * Pili pseudoannulati * Pili torti) * Pityriasis amiantacea * Plica neuropathica * Poliosis * Rubinstein–Taybi syndrome * Setleis syndrome * Traumatic anserine folliculosis * Trichomegaly * Trichomycosis axillaris * Trichorrhexis (Trichorrhexis invaginata * Trichorrhexis nodosa) * Trichostasis spinulosa * Uncombable hair syndrome * Wooly hair nevus Sweat glands Eccrine * Miliaria * Colloid milium * Miliaria crystalline * Miliaria profunda * Miliaria pustulosa * Miliaria rubra * Occlusion miliaria * Postmiliarial hypohidrosis * Granulosis rubra nasi * Ross’ syndrome * Anhidrosis * Hyperhidrosis * Generalized * Gustatory * Palmoplantar Apocrine * Body odor * Chromhidrosis * Fox–Fordyce disease Sebaceous * Sebaceous hyperplasia 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	Chromhidrosis	c0263473	1,722	wikipedia	https://en.wikipedia.org/wiki/Chromhidrosis	2021-01-18T19:08:05	{"gard": ["10749"], "umls": ["C0263473"], "icd-9": ["705.89"], "icd-10": ["L75.1"], "wikidata": ["Q2966706"]}
## Summary ### Clinical characteristics. Autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) is characterized by clusters of nocturnal motor seizures, which are often stereotyped and brief (5 seconds to 5 minutes). They vary from simple arousals from sleep to dramatic, often bizarre hyperkinetic events with tonic or dystonic features. Affected individuals may experience aura. Retained awareness during seizures is common. A minority of individuals experience daytime seizures. Onset ranges from infancy to adulthood. About 80% of individuals develop ADNFLE in the first two decades of life; mean age of onset is ten years. Clinical neurologic examination is normal and intellect is usually preserved, but reduced intellect, psychiatric comorbidity, or cognitive deficits may occur. Within a family, the manifestations of the disorder may vary considerably. ADNFLE is lifelong but not progressive. As an individual reaches middle age, attacks may become milder and less frequent. ### Diagnosis/testing. The diagnosis of ADNFLE is established in a proband who has suggestive clinical findings combined with a family history that is positive for other affected individuals and/or by the identification of a heterozygous pathogenic variant in CHRNA4, CHRNB2, CHRNA2, KCNT1, DEPDC5, or CRH on molecular genetic testing. ### Management. Treatment of manifestations: Carbamazepine is associated with remission in about 70% of individuals, often in relatively low doses. Individuals with ADNFLE associated with the CHRNA4 pathogenic variant p.Ser284Leu are more responsive to zonisamide than carbamazepine. Resistance to AEDs, present in about 30% of affected individuals, requires a trial of all appropriate AEDs. Adjunctive fenofibrate therapy or vagal nerve stimulation may be considered for individuals resistant to AEDs. Surveillance: Reevaluation of EEGs at regular intervals to monitor disease progression. Evaluation of relatives at risk: A medical history from relatives at risk can identify those with ADNFLE so that treatment can be initiated promptly. Pregnancy management: Discussion of the risks and benefits of using a given antiepileptic drug during pregnancy should ideally take place prior to conception. Transitioning to a lower-risk medication prior to pregnancy may be possible. ### Genetic counseling. ADNFLE is inherited in an autosomal dominant manner. Most individuals diagnosed with ADNFLE have an affected parent. The proportion of cases caused by de novo pathogenic variants is unknown, as the frequency of subtle signs of the disorder in parents has not been thoroughly evaluated and molecular genetic data are insufficient. Penetrance is estimated at 70% and the risk to each offspring of inheriting the pathogenic variant is 50%; thus, the chance that the offspring will manifest ADNFLE is (50% x 70% =) 35%. Prenatal testing for pregnancies at increased risk is possible. ## Diagnosis ### Suggestive Findings No formal diagnostic criteria for autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) have been published. ADNFLE should be suspected in individuals with the following clinical features, EEG findings, neuroimaging, and family history. Clinical features * Clusters of brief (5-second to 5-minute) nocturnal motor seizures that are often stereotyped and may include: * Nightmares * Verbalizations * Sudden limb movements * Parasomnias (undesirable phenomena that occur mainly or only during sleep) * Preserved intellect, although reduced intellect, cognitive deficits, or psychiatric comorbidity may occur * Normal clinical neurologic examination Note: The clinical features of ADNFLE are indistinguishable from those of nonfamilial NFLE [Hayman et al 1997, Tenchini et al 1999, Steinlein et al 2000]. EEG findings * Clusters of seizures with a frontal semiology * Ictal EEG that may be normal or obscured by movement artifact * Interictal EEG that shows infrequent epileptiform discharges Neuroimaging. Normal findings Family history * Consistent with autosomal dominant inheritance [Tassinari & Michelucci 1997, Provini et al 1999, Combi et al 2004] * Note: Absence of a known family history of ADNFLE does not preclude the diagnosis. ### Establishing the Diagnosis The diagnosis of ADNFLE is established in a proband with the clinical features and findings detailed in Suggestive Findings combined with a family history that is positive for other affected individuals and/or by identification of a heterozygous pathogenic variant in one of the genes listed in Table 1. Molecular genetic testing approaches can include serial single-gene testing, use of a multigene panel, and more comprehensive genomic testing: * Serial single-gene testing is based on the order in which pathogenic variants most commonly occur (i.e., CHRNA4, CHRNB2, KCNT1, DEPDC5, CHRNA2, and CRH). If no pathogenic variant is found, deletion/duplication analysis may be considered. * A multigene panel that includes CHRNA4, CHRNB2, CHRNA2, KCNT1, DEPDC5, CRH, and other genes of interest (see Differential Diagnosis) is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests. For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here. * More comprehensive genomic testing (when available) including exome sequencing and genome sequencing may be considered. Such testing may provide or suggest a diagnosis not previously considered (e.g., mutation of a different gene or genes that results in a similar clinical presentation). 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 Autosomal Dominant Nocturnal Frontal Lobe Epilepsy View in own window Gene 1, 2Proportion of ADNFLE Attributed to Pathogenic Variants in GeneProportion of Pathogenic Variants 3 Detectable by Method Sequence analysis 4Gene-targeted deletion/duplication analysis 5 CHRNA2Rare 6Rare 6None reported 7 CHRNA410%-15% 810%-15% 8 CHRNB2Lower than in CHRNA4 8Lower than in CHRNA4 8 CRHRare 9Rare 9 DEPDC510% 1010% 10 KCNT1<5% 11<5% 11 1\. Genes are listed in alphabetic order. 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\. Reported in two families [Aridon et al 2006, Conti et al 2015] 7\. To date, exon or whole-gene deletions/duplications have not been detected in ADNFLE. 8\. 10%-15% of individuals with a family history have pathogenic variants in subunits of nicotinic acetylcholine receptor [Ferini-Strambi et al 2012]. 9\. Combi et al [2005], Sansoni et al [2013] 10\. Picard et al [2014] 11\. Heron et al [2012] ## Clinical Characteristics ### Clinical Description Autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) is characterized by clusters of nocturnal motor seizures with a range of manifestations. Nocturnal seizures. The history may be obtained from the affected individual and witnesses, and supplemented if necessary by video-EEG monitoring. Seizures may occur in any stage of sleep, although typically in clusters in non-REM (NREM) sleep, most commonly in stage 2 sleep [Picard & Scheffer 2012]. The affected individual often goes back to sleep rapidly after a seizure, only to be awakened by another event. The seizures are often stereotyped and brief (5 seconds to 5 minutes); they vary from simple arousals from sleep to dramatic hyperkinetic events with tonic or dystonic features. The hyperkinetic manifestations may appear bizarre, sometimes with ambulation, bicycling movements, ballism (flinging or throwing arm movements), and pelvic thrusting movements. The three distinct sub-classifications of seizure types based on clinical features of the seizures (semiology) and their duration are "paroxysmal arousals," "paroxysmal dystonia," and "episodic wandering." * Paroxysmal arousal is characterized by abrupt recurrent arousals from NREM sleep associated with a stereotypic motor pattern. * Paroxysmal dystonia is characterized by recurrent motor attacks with dystonic-dyskinetic features arising from NREM sleep and usually lasting less than two minutes. * Episodic wandering is somnambulic agitated behavior arising from NREM sleep. The reported frequency ranges from one to 20 attacks each night, a mean of 20 seizures per month; about 60% of the affected individuals reported more than 15 seizures per month. Retained awareness during seizures is common and may cause affected individuals to fear falling asleep. A sense of difficulty breathing and hyperventilation may occur, as well as vocalization, clonic features, urinary incontinence, and secondary generalization. Some individuals experience an aura preceding the seizure during sleep and are aware of the onset. Aura may be nonspecific or may consist of numbness in one limb, fear, a shiver, vertigo, or a feeling of falling or being pushed. Note: A minority of individuals experience daytime seizures, typically during a period of poor seizure control. Some of the seizures reported are paroxysmal dystonia similar to those during sleep, and others are generalized tonic-clonic seizures, generalized atonic seizures, and focal seizures with impairment of consciousness or awareness. EEG findings * Ictal EEG recordings may be normal or may be obscured by movement artifact. Ictal rhythms, if present, are usually sharp waves or repetitive 8- to 11-Hz spikes. Recruiting patterns and rhythmic theta (bifrontal, unilateral frontal, or with diffuse desynchronization) are occasionally seen [Picard & Scheffer 2012]. El Helou et al [2008] suggest that seizures may be initiated by K-complexes. * Interictal waking EEG shows anterior quadrant epileptiform activity in very few affected individuals. * Interictal sleep EEG may show infrequent epileptiform discharges. Cognitive findings. Clinical neurologic examination is normal and intellect is usually preserved [Oldani et al 1996, Nakken et al 1999]; however, in some individuals neuropsychological assessment reveals reduced intellect, cognitive deficits, or psychiatric comorbidity [Khatami et al 1998, Provini et al 1999, Picard et al 2000, Cho et al 2003, Wood et al 2010]. Picard et al [2009] found below-normal general intellect in five (45%) of 11 subjects with special difficulty in executive tasks and concluded that cognitive dysfunction is an integral part of ADNFLE caused by a heterozygous pathogenic variant in the nicotinic receptor (see Phenotype Correlations by Gene). Magnusson et al [2003] reported an increase in psychiatric symptoms in families with ADNFLE (see Phenotype Correlations by Gene). Familial variation. Within a family, the manifestations of the disorder may vary considerably; individuals with subtle manifestations may not present for medical attention. A high incidence of true parasomnias has been reported in relatives of those with ADNFLE [Provini et al 1999]. True parasomnias were distinguished from epileptic seizures because of their age-dependent course, the rarity of episodes, and their being not violent and often not disturbing for the affected individual. They often ended well before the onset of the clear-cut epileptic seizures. Onset and prognosis. ADNFLE is lifelong but not progressive. Onset ranges from infancy to adulthood. About 80% of affected individuals develop ADNFLE in the first two decades of life; mean age of onset is ten years. As an individual reaches middle age, attacks may become milder and less frequent. Seizures may vary over time; for example, tonic attacks appearing in early childhood may evolve into seizures with dystonic or hyperkinetic components in later childhood. ### Phenotype Correlations by Gene KCNT1. Individuals with heterozygous pathogenic variants in KCNT1 may have a more severe phenotype than those with neuronal nicotinic acetylcholine receptor (nAChR) pathogenic variants [Heron et al 2012]: * Affected individuals are more likely to display psychiatric and behavioral problems. * Affected individuals are more likely to have a lower age of onset, complete penetrance, and cognitive comorbidities. ### Genotype-Phenotype Correlations Steinlein et al [2012] suggested that certain nAchR pathogenic variants may be associated with an increased risk for cognitive dysfunction. Marked intrafamilial variation in severity is seen, the reasons for which are unknown. ### Penetrance Penetrance is estimated at 70%. KCNT1-related ADNFLE demonstrates complete penetrance compared to 60%-80% in nAChR-related ADNFLE. ### Prevalence The number of families with ADNFLE reported exceeds 100 [Picard & Brodtkorb 2007], but no accurate data concerning the prevalence of ADNFLE exist. It is likely that the disorder is underdiagnosed, or in some cases misdiagnosed. Families with the disorder have been identified worldwide [Steinlein 2014]. ## Differential Diagnosis The differential diagnosis of autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) includes conditions of varied etiology. Normal sleep is characterized by periodic arousals, and occasionally other sleep-related movements or phenomena including nightmares [Phillips et al 1998]. Parasomnias (disorders in which undesirable physical and mental phenomena occur mainly or exclusively during sleep [American Academy of Sleep Medicine 2001]) including the following may be considered: * Pavor nocturnus (night terrors), a common childhood syndrome, is characterized by attacks of extreme fear and distress that occur one or two hours after the child falls asleep. The child is unaware during the attack, which lasts five to ten minutes, and is amnesic for the event the following day [Schenck & Mahowald 2000]. * Benign somnambulism (sleep walking) is not accompanied by abnormal motor behavior or dystonia and is usually a self-limiting disorder of childhood. Somnambulism is often familial. Hysteria is often considered because the individual retains awareness during the attacks, which can be bizarre. Clues to the organic nature of attacks are the occurrence during sleep and the stereotyped semiology (sequence of observed events during the attack). Periodic limb movement disorder (nocturnal myoclonus) affects the flexor muscles of the lower limbs and is characterized by segmental motor activity in muscles that recurs every 20-30 seconds. Brief stationary movements may be followed by myoclonic or repetitive clonic jerks that coincide with the periodic K-complexes of light sleep. Restless legs syndrome is often accompanied by segmental motor activity and may be a spinal cord-mediated disorder. REM sleep disorders may include prominent motor and verbal manifestations that are often of unknown cause or secondary to other neurologic disorders. REM sleep disorders typically occur in men ages 55-60 years. Polysomnography is a useful diagnostic tool. Respiratory disorders such as asthma may be considered because of difficulty breathing. Obstructive sleep apnea may be considered in individuals complaining of daytime sleepiness who are not aware of their nocturnal attacks. ## Management ### Evaluations Following Initial Diagnosis To establish the extent of disease and needs of an individual diagnosed with autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) the following evaluations are recommended if they have not already been completed: * In addition to the evaluation for epilepsy, cognitive and behavioral assessment to help determine the extent of disease * Consultation with a clinical geneticist and/or genetic counselor ### Treatment of Manifestations In about 70% of individuals with ADNFLE, carbamazepine is associated with remission of seizures, often with relatively low doses. However, individuals with ADNFLE associated with the CHRNA4 pathogenic variant p.Ser284Leu respond only partially to carbamazepine and are more responsive to zonisamide [Provini et al 1999, Ito et al 2000, Combi et al 2004]. Exposure to quinidine significantly reduces gain of function for KCNT1 pathogenic variants implicated in ADNFLE and EIMFS [Milligan et al 2014]. Clinical treatment with quinidine was reported in a child with EIMFS [Bearden et al 2014], and correlated with a marked reduction in seizure frequency. In the future, it may be also possible to treat KCNT1-related ADNFLE with quinidine. Resistance to AEDs occurs in about 30% of affected individuals. Intrafamilial variation in pharmaco-responsiveness occurs; therefore, all appropriate AEDs should be tried. Adjunctive therapy with fenofibrate reduced seizure frequency in individuals with pharmacoresistant ADNFLE/NFLE in one study [Puligheddu et al 2017]. Vagal nerve stimulation may be considered for individuals with resistance to AEDs [Carreño et al 2010]. #### Caregivers For information on non-medical interventions and coping strategies for parents or caregivers of children diagnosed with epilepsy, see Epilepsy & My Child Toolkit. ### Prevention of Secondary Complications Prompt diagnosis and appropriate treatment for ADNFLE can help prevent morning tiredness and daytime somnolence resulting from sleep fragmentation due to seizure-related arousals. ### Surveillance Serial evaluation of EEGs to monitor disease progression is appropriate. ### Evaluation of Relatives at Risk It is appropriate to evaluate relatives at risk in order to identify as early as possible those who would benefit from initiation of treatment: * If the pathogenic variant in the family is known, molecular genetic testing can be used to clarify the genetic status of at-risk relatives. * If the pathogenic variant in the family is not known, a medical history to seek evidence of affected status should be elicited from relatives at risk. See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes. ### Pregnancy Management In general, women with epilepsy or a seizure disorder from any cause are at greater risk for mortality during pregnancy than pregnant women without a seizure disorder; use of antiepileptic medication during pregnancy reduces this risk. However, exposure to antiepileptic medication may increase the risk for adverse fetal outcome (depending on the drug used, the dose, and the stage of pregnancy at which medication is taken). Nevertheless, the risk of an adverse outcome to the fetus from antiepileptic medication exposure is often less than that associated with exposure to an untreated maternal seizure disorder. Therefore, use of antiepileptic medication to treat a maternal seizure disorder during pregnancy is typically recommended. Discussion of the risks and benefits of using a given antiepileptic drug during pregnancy should ideally take place prior to conception. Transitioning to a lower-risk medication prior to pregnancy may be possible [Sarma et al 2016]. See MotherToBaby for further information on medication use during pregnancy. ### Therapies Under Investigation Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor *[BMI]: body mass index	Autosomal Dominant Nocturnal Frontal Lobe Epilepsy	c3696898	1,723	gene_reviews	https://www.ncbi.nlm.nih.gov/books/NBK1169/	2021-01-18T21:41:33	{"mesh": ["C579932"], "synonyms": ["ADNFLE"]}
A number sign (#) is used with this entry because of evidence that glomuvenous malformations are caused by heterozygous mutation in the glomulin gene (601749) on chromosome 1p22. Description Glomuvenous malformations, also known as 'venous malformations with glomus cells' or glomangiomas, are similar to mucocutaneous venous malformations (VMCM; 600195), but clinically are distinguishable: they have a cobble-stone appearance, have a consistency harder than that of venous malformations, and are painful on palpation. Histologically, GVMs are distinguishable by the presence of pathognomonic rounded cells (glomus cells) around the distended vein-like channels. The term glomus (Latin for ball) stems from the morphologically similar contractile cells of the Sucquet-Hoyer arteriovenous anastomoses in glomus bodies that are involved in cutaneous thermoregulation. Glomus cells in GVMs appear to be incompletely or improperly differentiated vascular smooth muscle cells, since they stain positively with smooth muscle cell alpha-actin (102620) and vimentin (193060) (summary by Brouillard et al., 2002). The genetic distinctness of glomuvenous malformations from mucocutaneous venous malformations is indicated by the fact that mutations have been found in the TIE2/TEK gene (600221) in mucocutaneous venous malformations and not in glomuvenous malformations. Clinical Features Glomus tumors are benign cutaneous neoplasms that are derived from specialized arteriovenous shunts that occur normally in many parts of the body. Gorlin et al. (1960) reported 5 affected members in 2 generations of a family. The lesions tend to resemble cavernous hemangiomas. The distinctive feature is the presence of multiple layers of glomus cells lining the blood-filled cavities. The tumors are present at birth or appear in the first 2 decades. Isolated glomus tumor usually develops later (at about age 33 years on the average), is more frequently subungual than is the case with multiple tumors, and has no particular familial occurrence. Reed (1970) presented a pedigree of 4 persons with multiple glomus tumors in 2 generations. Beasley et al. (1986) reported 4 patient with GVMs in 3 generations. The 9-year-old proposita had had 6 soft, blue-black skin lesions from birth, on the forearm, thigh, and buttocks. All but one were raised. As pointed out by Boon et al. (1999), glomus tumors, or glomangiomas, are a clinical and radiologic subtype of venous malformations. Their pathognomonic characteristic is the presence of undifferentiated smooth muscle cells (glomus cells) surrounding convoluted venous channels. Although clinically they look like any venous malformation, they are more painful on palpation, only partially compressible, and usually not found in mucosa. In addition, familial aggregation is more common than in venous malformations generally, and several pedigrees showing autosomal dominant inheritance have been reported. Iqbal et al. (1998) estimated that penetrance rises from 70% at age 5 years to 100% by age 30 years. Inheritance The inheritance of the cutaneous disorder discussed here is uncomplicated autosomal dominant with many instances of male-to-male transmission. It is not to be confused with multiple paragangliomata (168000), which is often referred to as glomus tumors. In various autosomal dominant skin disorders, segmental forms reflecting mosaicism have been reported. Happle (1997) delineated 2 different types of mosaic manifestation. Type 1 reflects heterozygosity for the underlying mutation and shows the same degree of severity as that observed in the corresponding nonmosaic phenotype. In the case of cutaneous disorders, the skin other than that in the segmental area is normal. Type 2 originates from loss of heterozygosity and shows an excessively severe involvement in a segmental area, usually superimposed on the disseminated lesions of the ordinary trait. Happle and Konig (1999) surveyed the literature on multiple glomus tumors and found 5 cases suggesting a type 2 segmental involvement. In all of these cases, a unilateral band-like or patchy arrangement of excessively pronounced glomus tumors was associated with disseminated lesions corresponding to the ordinary phenotype, and in 3 cases other family members were affected with disseminated glomus tumors. The unilateral agminated (i.e., gathered in clusters) lesions were reported to be present in early childhood, whereas the disseminated lesions appeared later. Mapping Boon et al. (1999) demonstrated that 5 families with inherited cutaneous venous malformations with glomus cells showed linkage to 1p22-p21 (lod score = 12.7 at recombination fraction = 0.00). They designated the locus VMGLOM. Irrthum et al. (2001) reported 7 additional families with glomangioma showing linkage to 1p22-p21. Combined with the families reported by Boon et al. (1999), they found a lod score of 18.41 at theta = 0.0 at marker D1S188. Haplotype analysis revealed evidence for a founder effect in some of the families. In 4 glomangioma families, Calvert et al. (2001) found linkage of the trait to 1p22-p21. Brouillard et al. (2000) reported a physical map based on 18 overlapping YAC clones spanning the 5-Mb VMGLOM locus. They also reported a sequence-ready PAC map of 46 clones covering 1.48 Mb within the YAC contig, a region to which they restricted VMGLOM. They identified several positional candidate genes within a narrowed region on 1p and found that one of these, designated originally FAP48 (601749), contained mutations in cases of GVMs. Molecular Genetics In connection with the demonstration of mutations in glomulin as the cause of this disorder, Brouillard et al. (2002) found a somatic 'second hit' mutation (601749.0002) in affected tissue of a patient with an inherited genomic deletion (601749.0001). Furthermore, since all but one (601749.0004) of the 14 different germline mutations identified in patients with GVMs resulted in premature stop codons, and since the localized nature of the lesions could be explained by the Knudson 2-hit model, GVMs are likely caused by complete loss of function of glomulin. Amyere et al. (2013) hypothesized that a Knudson '2-hit' model could explain the multifocality and partial penetrance of GVMs, and performed a systematic analysis using multiple approaches, including a sensitive allele-specific pairwise SNP-chip method. Amyere et al. (2013) identified 16 somatic mutations, most of which were not intragenic but were cases of acquired uniparental isodisomy (aUPID) involving chromosome 1p. The breakpoint of each aUPID is located in an A- and T-rich high DNA flexibility region (1p13.1-1p12). This region corresponds to a possible fragile site. Occurrences of these mutations render the inherited glomulin variant in 1p22.1 homozygous in the affected tissues without loss of genetic material. Amyere et al. (2013) concluded that this finding demonstrates that a double hit is needed to trigger formation of a GVM. Nomenclature Strauchen (2002) noted 'a common point of confusion,' namely the interchangeable use of 'paraganglioma' and 'glomus tumor.' He emphasized that the glomus tumor is a tumor of modified perivascular smooth muscle, which frequently presents as a painful subungual mass, and is unrelated to tumors of the adrenal and extraadrenal paraganglia. Jugulotympanic paraganglioma is often referred to as a 'glomus jugulare tumor.' This tumor arises from minute, anatomically dispersed paraganglia located at the base of the skull and temporal bone and is closely related to similar tumors of the carotid body and other extraadrenal paraganglia. It is unrelated to the much more common glomus tumor of skin and soft tissue. Inheritance \- Autosomal dominant Lab \- Multiple layers of glomus cells lining blood-filled cavities Skin \- Multiple glomus tumors ▲ 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	GLOMUVENOUS MALFORMATIONS	c1841984	1,724	omim	https://www.omim.org/entry/138000	2019-09-22T16:40:41	{"mesh": ["C536827"], "omim": ["138000"], "orphanet": ["83454"], "synonyms": ["Alternative titles", "VENOUS MALFORMATIONS WITH GLOMUS CELLS", "GLOMUS TUMORS, MULTIPLE", "GLOMANGIOMAS, MULTIPLE"]}
Flexion teardrop fracture Teardrop fracture of the cervical spine before and after treatment with metal fixation SpecialtyOrthopedic A flexion teardrop fracture is a fracture of the anteroinferior aspect of a cervical vertebral body due to flexion of the spine along with vertical axial compression.[1] The fracture continues sagittally through the vertebral body, and is associated with deformity of the body and subluxation or dislocation of the facet joints at the injured level.[2] A flexion teardrop fracture is usually associated with a spinal cord injury, often a result of displacement of the posterior portion of the vertebral body into the spinal canal.[3] The flexion teardrop fracture should not be confused with a similar-looking vertebral fracture called "extension teardrop fracture". Both usually occur in the cervical spine, but as their names suggest, they result from different mechanisms (flexion-compression vs. hyperextension). Both are associated with a small fragment being broken apart from the anteroinferior corner of the affected vertebra. Flexion teardrop fractures usually involve instability in all elements of the spine at the injured level, commonly occur at the C4-C7 vertebra, and have a high association with spinal cord injury (in particular anterior cord syndrome). In comparison, the extension-type fracture occurs more commonly at C2 or C3, causes less if any disruption to the middle and posterior elements, and does not usually result in spinal cord injury (however it may co-occur with more dangerous spine injuries). [4][5] ## References[edit] 1. ^ eMedicine > Fracture, Cervical Spine By Moira Davenport. Updated: Apr 30, 2010 2. ^ https://radiopaedia.org/articles/flexion-tear-drop-fracture; retrieved 05-23-2018 3. ^ Brant W, Helms C. "Fundamentals of Diagnostic Radiology" (Third Edition): 1110. Cite journal requires `\|journal=` (help) 4. ^ https://radiopaedia.org/articles/flexion-tear-drop-fracture; retrieved 05-23-2018 5. ^ https://radiopaedia.org/articles/extension-tear-drop-fracture-1; retrieved 05-23-2018 * v * t * e Fractures and cartilage damage General * Avulsion fracture * Chalkstick fracture * Greenstick fracture * Open fracture * Pathologic fracture * Spiral fracture Head * Basilar skull fracture * Blowout fracture * Mandibular fracture * Nasal fracture * Le Fort fracture of skull * Zygomaticomaxillary complex fracture * Zygoma fracture Spinal fracture * Cervical fracture * Jefferson fracture * Hangman's fracture * Flexion teardrop fracture * Clay-shoveler fracture * Burst fracture * Compression fracture * Chance fracture * Holdsworth fracture Ribs * Rib fracture * Sternal fracture Shoulder fracture * Clavicle * Scapular Arm fracture Humerus fracture: * Proximal * Supracondylar * Holstein–Lewis fracture Forearm fracture: * Ulna fracture * Monteggia fracture * Hume fracture * Radius fracture/Distal radius * Galeazzi * Colles' * Smith's * Barton's * Essex-Lopresti fracture Hand fracture * Scaphoid * Rolando * Bennett's * Boxer's * Busch's Pelvic fracture * Duverney fracture * Pipkin fracture Leg Tibia fracture: * Bumper fracture * Segond fracture * Gosselin fracture * Toddler's fracture * Pilon fracture * Plafond fracture * Tillaux fracture Fibular fracture: * Maisonneuve fracture * Le Fort fracture of ankle * Bosworth fracture Combined tibia and fibula fracture: * Trimalleolar fracture * Bimalleolar fracture * Pott's fracture Crus fracture: * Patella fracture Femoral fracture: * Hip fracture Foot fracture * Lisfranc * Jones * March * Calcaneal This human musculoskeletal 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	Flexion teardrop fracture	None	1,725	wikipedia	https://en.wikipedia.org/wiki/Flexion_teardrop_fracture	2021-01-18T18:47:58	{"umls": ["CL379836"], "wikidata": ["Q5459010"]}
Atrioventricular block SpecialtyCardiology Atrioventricular block (AV block) is a type of heart block that occurs when the electrical signal traveling from the atria, or the upper chambers of the heart, to ventricles, or the lower chambers of the heart, is impaired. Normally, the sinoatrial node (SA node) produces an electrical signal to control the heart rate. The signal travels from the SA node to the ventricles through the atrioventricular node (AV node). In an AV block, this electrical signal is either delayed or completely blocked. When the signal is completely blocked, the ventricles produce their own electrical signal to control the heart rate. The heart rate produced by the ventricles is much slower than that produced by the SA node.[1] Some AV blocks are benign, or normal, in certain people, such as in athletes or children. Other blocks are pathologic, or abnormal, and have several causes, including ischemia, infarction, fibrosis, and drugs. ## Contents * 1 Anatomy * 2 Diagnosis * 3 Classification * 3.1 First-degree Atrioventricular Block * 3.2 Second-degree Atrioventricular Block * 3.2.1 Mobitz I * 3.2.2 Mobitz II * 3.3 Third-degree Atrioventricular Block * 4 Etiology * 5 Management * 6 References * 7 External links ## Anatomy[edit] Electrical conduction pathway of the heart. Normal ECG tracing for a single contraction of the heart. The synchronized contraction of the heart occurs through a well coordinated electrical signal pathway. The initial electrical signal originates from the SA node located in the upper portion of the right atrium. The electrical signal then travels through both the right and left atrium, and causes the two atria to contract at the same time. This simultaneous contraction results in the P wave seen in an ECG tracing. The electrical signal then travels to the AV node located on the lower portion of the interatrial septum. At the AV node there is a delay in the electrical signal, which allows the atria to contract and blood to flow from the atria to the ventricles. This delay accounts for the ECG period between the P wave and the QRS complex, and creates the PR interval. From the AV nodes, the electrical signal travels through Bundle of His and divides into the right bundle and left bundle, which are located within the interventricular septum. Finally, the electrical signal travels into the Purkinje fibers. The division of the signal into a right and left bundle and then into the Purkinje fibers allows for a simultaneous depolarization and contraction of the right and left ventricles. The contraction of the ventricles results in the QRS complex seen on an ECG tracing. ECG tracing in relation to normal depolarization and contraction of the heart. Red tracing indicates pathway of electrical depolarization. Blue tracing indicates resulting ECG tracing. After contraction, the ventricles must repolarize, or reset themselves, in order to allow for a second depolarization and contraction. The repolarization creates the T wave in the ECG tracing.[2][3] ## Diagnosis[edit] An electrocardiogram, or ECG, is used to differentiate between the different types of AV block. In AV block, there is a disruption between the signal traveling from the atria to the ventricles. This results in abnormalities in the PR interval, as well as the relationship between P waves and QRS complexes on the ECG tracing.[1][4] If the patient is symptomatic from their suspected AV block, it is important that an ECG is also obtained while having symptoms. Physicians may also order a continuous ECG (i.e. Holter monitor or implanted cardiac monitor) to monitor the patient for symptoms and conduction abnormalities over a longer period of time, as AV blocks can be intermittent.[5] Because some types of AV block can be associated with underlying structural heart disease, patients may also undergo echocardiogram to look at the heart and assess the function.[5] Laboratory diagnosis for AV blocks include electrolyte, drug level and cardiac enzyme level tests.[6] Based upon clinical suspicion, the physician may do lab tests to assess for reversible causes of AV block, such as hypothyroidism, rheumatologic disorders, and infections (such as Lyme disease).[5] ## Classification[edit] There are three types, or degrees, of AV block: (1) first-degree, (2) second-degree, and (3) third-degree, with third-degree being the most severe. An ECG is used to differentiate between the different types of AV block. However, one important consideration when diagnosing AV blocks from ECGs is the possibility of pseudo- AV blocks which are due to concealed junctional extrasystoles. It is important to diagnose AV-blocks precisely because unnecessary pacemaker placement in patients with pseudo-AV blocks can worsen symptoms and create complications.[7] Representative electrocardiogram recordings of the different degrees of heart block. ### First-degree Atrioventricular Block[edit] First-degree AV block occurs when there is a delay, but not disruption, as the electrical signal moves between the atrium and the ventricles through the AV node.[8] On ECG, this is defined by a PR interval greater than 200 msec. Additionally, there are no dropped, or skipped, beats.[1][4] ### Second-degree Atrioventricular Block[edit] Second-degree AV block occurs when the electrical signal between the atria and ventricles is even more impaired than in a first-degree AV block. In a second-degree AV block, the impairment results in a failure to conduct an impulse, which causes a skipped beat.[9] #### Mobitz I[edit] Mobitz I is characterized by a progressive, yet, reversible block of the AV node. On ECG, this is defined by a progressive prolongation of the PR interval, with a resulting dropped beat (the PR interval gets longer and longer until a beat is finally dropped, or skipped).[4][9] Some patients are asymptomatic; those who have symptoms respond to treatment effectively. There is low risk of a Mobitz I AV block leading to heart attack and complete heart block.[9] #### Mobitz II[edit] Mobitz II is caused by a sudden, unexpected failure of the His-Purkinje cells to conduct the electrical impulse. On ECG, the PR interval is unchanged from beat to beat, but there is a sudden failure to conduct the signal to the ventricles, and a resulting random skipped beat.[4] The risks and possible effects of Mobitz II are much more severe than Mobitz I in that it can lead to severe heart attack.[9][10] ### Third-degree Atrioventricular Block[edit] Third-degree AV block occurs when the signal between the atria and ventricles is completely blocked, and there is no communication between the two. None of the signals from the upper chambers make it to the lower chambers. On ECG, there is no relationship between P waves and QRS complexes, meaning the P waves and QRS complexes are not in a 1:1 ratio. Third-degree AV block is the most severe of the AV blocks. Persons suffering third-degree AV block need emergency treatment including but not limited to a pacemaker.[11] ## Etiology[edit] There are many causes of AV block, ranging from a normal variant among people to the result of a heart attack. First-degree AV block and Mobitz I second-degree block are often thought to be just normal, benign, conditions in patients, and do not often result from a severe underlying condition.[1] Mobitz II second-degree block and third-degree AV block are not normal variants, and are associated with an underlying condition. Common causes include ischemia (lack of blood flow and oxygen to the heart muscle) or progressive fibrosis (excessive scaring) of the heart. It is also possible that high degree block can result after cardiac surgery during which the surgeon was in close proximity to the electrical conduction system and accidentally injured it. Reversible causes of Mobitz II and third-degree heart block include untreated Lyme disease, hypothyroidism, hyperkalemia (high levels of potassium), and drug toxicity. Drugs that slow the conduction of the electrical signal through AV node, such as beta-blockers, digoxin, calcium channel blockers, and amiodarone, can cause heart block if they are taken in excessive amounts, or the levels in the blood get too high.[1][9][11] ## Management[edit] Management is dependent upon the severity, or degree, of the blockage, the consistency of symptoms, as well as the cause of the AV block. Patients with first-degree AV block do not have any resulting severe or life-threatening symptoms, such as symptomatic bradycardia or hypotension, and, thus, do not require treatment.[1] Similarly, patients with second-degree Mobitz I AV block rarely develop life-threatening symptoms, and patients who are asymptomatic do not require treatment. However, in some cases, patients with Mobtz I block can develop life-threatening symptoms that requires intervention. These patients often respond well to atropine, but make require temporary transcutaneous pacing or transvenous pacing until they are not longer symptomatic.[9] Patients with second-degree Mobitz II and third-degree heart block are much more likely to have symptomatic bradycardia and hemodynamic instability, such as hypotension. Additionally, there is an increased risk of patients with Mobitz II heart block developing third-degree heart block. Therefore, these patients often require temporary pacing with transcutaneous or transvenous pacing wires, and many will ultimately require a permanent implanted pacemaker.[5][9][11] If the heart block is found to be caused by a reversible condition, such as Lyme disease, the underlying condition should first be treated. Often, this will lead to resolution of the heart block and the associated symptoms.[5] ## References[edit] 1. ^ a b c d e f Kashou, Anthony H.; Goyal, Amandeep; Nguyen, Tran; Chhabra, Lovely (2019), "Atrioventricular Block", StatPearls, StatPearls Publishing, PMID 29083636, retrieved 2019-11-12 2. ^ Lilly, Leonard (2006). Pathophysiology of Heart Disease. Lippincott Williams & Wilkins. ISBN 978-0-7817-6321-9.[page needed] 3. ^ Klabunde, Richard E. (2012). Cardiovascular physiology concepts (2nd ed.). Philadelphia, PA: Lippincott Williams & Wilkins/Wolters Kluwer. ISBN 9781451113846. OCLC 712765593. 4. ^ a b c d Dubin, Dale, 1940- (2000). Rapid interpretation of EKG's : an interactive course (6th ed.). Tampa, Fla.: Cover Pub. Co. ISBN 9780912912066. OCLC 45498043.CS1 maint: multiple names: authors list (link) 5. ^ a b c d e Kusumoto, Fred M.; Schoenfeld, Mark H.; Barrett, Coletta; Edgerton, James R.; Ellenbogen, Kenneth A.; Gold, Michael R.; Goldschlager, Nora F.; Hamilton, Robert M.; Joglar, José A.; Kim, Robert J.; Lee, Richard (2019-08-20). "2018 ACC/AHA/HRS Guideline on the Evaluation and Management of Patients With Bradycardia and Cardiac Conduction Delay: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society". Circulation. 140 (8): e382–e482. doi:10.1161/CIR.0000000000000628. ISSN 1524-4539. PMID 30586772. 6. ^ "Atrioventricular Block: Practice Essentials, Background, Pathophysiology". 2017-01-06. Cite journal requires `\|journal=` (help) 7. ^ Golchha, Sandeep; Bachani, Neeta; Lokhandwala, Yash. "Premature complexes and pauses". ncbi. PMC. Retrieved 2020-12-03. 8. ^ "Types of Heart Block - NHLBI, NIH". www.nhlbi.nih.gov. Retrieved 2017-03-22. 9. ^ a b c d e f g Mangi, Muhammad Asif; Jones, Wesley M.; Napier, Laura (2019), "Atrioventricular Block Second-Degree", StatPearls, StatPearls Publishing, PMID 29493981, retrieved 2019-11-12 10. ^ Wogan, J. M.; Lowenstein, S. R.; Gordon, G. S. (1993-01-01). "Second-degree atrioventricular block: Mobitz type II". The Journal of Emergency Medicine. 11 (1): 47–54. doi:10.1016/0736-4679(93)90009-v. ISSN 0736-4679. PMID 8445186. 11. ^ a b c Knabben, Vinicius; Chhabra, Lovely; Slane, Matthew (2019), "Third-Degree Atrioventricular Block", StatPearls, StatPearls Publishing, PMID 31424783, retrieved 2019-11-12 ## External links[edit] Classification D * ICD-10: I44.0-I44.3 * ICD-9-CM: 426.0-426.1 * MeSH: D054537 * SNOMED CT: 233917008 External resources * eMedicine: med/189 * Second-Degree Atrioventricular Block at eMedicine * v * t * e Cardiovascular disease (heart) Ischaemic Coronary disease * Coronary artery disease (CAD) * Coronary artery aneurysm * Spontaneous coronary artery dissection (SCAD) * Coronary thrombosis * Coronary vasospasm * Myocardial bridge Active ischemia * Angina pectoris * Prinzmetal's angina * Stable angina * Acute coronary syndrome * Myocardial infarction * Unstable angina Sequelae * hours * Hibernating myocardium * Myocardial stunning * days * Myocardial rupture * weeks * Aneurysm of heart / Ventricular aneurysm * Dressler syndrome Layers Pericardium * Pericarditis * Acute * Chronic / Constrictive * Pericardial effusion * Cardiac tamponade * Hemopericardium Myocardium * Myocarditis * Chagas disease * Cardiomyopathy * Dilated * Alcoholic * Hypertrophic * Tachycardia-induced * Restrictive * Loeffler endocarditis * Cardiac amyloidosis * Endocardial fibroelastosis * Arrhythmogenic right ventricular dysplasia Endocardium / valves Endocarditis * infective endocarditis * Subacute bacterial endocarditis * non-infective endocarditis * Libman–Sacks endocarditis * Nonbacterial thrombotic endocarditis Valves * mitral * regurgitation * prolapse * stenosis * aortic * stenosis * insufficiency * tricuspid * stenosis * insufficiency * pulmonary * stenosis * insufficiency Conduction / arrhythmia Bradycardia * Sinus bradycardia * Sick sinus syndrome * Heart block: Sinoatrial * AV * 1° * 2° * 3° * Intraventricular * Bundle branch block * Right * Left * Left anterior fascicle * Left posterior fascicle * Bifascicular * Trifascicular * Adams–Stokes syndrome Tachycardia (paroxysmal and sinus) Supraventricular * Atrial * Multifocal * Junctional * AV nodal reentrant * Junctional ectopic Ventricular * Accelerated idioventricular rhythm * Catecholaminergic polymorphic * Torsades de pointes Premature contraction * Atrial * Junctional * Ventricular Pre-excitation syndrome * Lown–Ganong–Levine * Wolff–Parkinson–White Flutter / fibrillation * Atrial flutter * Ventricular flutter * Atrial fibrillation * Familial * Ventricular fibrillation Pacemaker * Ectopic pacemaker / Ectopic beat * Multifocal atrial tachycardia * Pacemaker syndrome * Parasystole * Wandering atrial pacemaker Long QT syndrome * Andersen–Tawil * Jervell and Lange-Nielsen * Romano–Ward Cardiac arrest * Sudden cardiac death * Asystole * Pulseless electrical activity * Sinoatrial arrest Other / ungrouped * hexaxial reference system * Right axis deviation * Left axis deviation * QT * Short QT syndrome * T * T wave alternans * ST * Osborn wave * ST elevation * ST depression * Strain pattern Cardiomegaly * Ventricular hypertrophy * Left * Right / Cor pulmonale * Atrial enlargement * Left * Right * Athletic heart syndrome Other * Cardiac fibrosis * Heart failure * Diastolic heart failure * Cardiac asthma * Rheumatic fever [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor *[BMI]: body mass index	Atrioventricular block	c0004245	1,726	wikipedia	https://en.wikipedia.org/wiki/Atrioventricular_block	2021-01-18T18:32:24	{"mesh": ["D054537"], "umls": ["C0004245", "C1841659"], "wikidata": ["Q300121"]}
Flea-borne spotted fever SpecialtyInfectious disease Flea-borne spotted fever or California pseudotyphus[1] is a condition characterized by a rash of maculopapules or furuncles.[2] It is caused by Rickettsia felis.[3] ## See also[edit] * American tick bite fever * Japanese spotted fever * List of cutaneous conditions ## References[edit] 1. ^ Gideon Guide to Outbreaks: 2019 edition, p. 1522, at Google Books 2. ^ Rapini, Ronald P.; Bolognia, Jean L.; Jorizzo, Joseph L. (2007). Dermatology: 2-Volume Set. St. Louis: Mosby. ISBN 978-1-4160-2999-1. 3. ^ Didier Raoult; Philippe Parola (2007). Rickettsial diseases. CRC Press. pp. 87–. ISBN 978-0-8493-7611-5. Retrieved 23 May 2010. ## External links[edit] Classification D * ICD-10: A77.8 * v * t * e Proteobacteria-associated Gram-negative bacterial infections α Rickettsiales Rickettsiaceae/ (Rickettsioses) Typhus * Rickettsia typhi * Murine typhus * Rickettsia prowazekii * Epidemic typhus, Brill–Zinsser disease, Flying squirrel typhus Spotted fever Tick-borne * Rickettsia rickettsii * Rocky Mountain spotted fever * Rickettsia conorii * Boutonneuse fever * Rickettsia japonica * Japanese spotted fever * Rickettsia sibirica * North Asian tick typhus * Rickettsia australis * Queensland tick typhus * Rickettsia honei * Flinders Island spotted fever * Rickettsia africae * African tick bite fever * Rickettsia parkeri * American tick bite fever * Rickettsia aeschlimannii * Rickettsia aeschlimannii infection Mite-borne * Rickettsia akari * Rickettsialpox * Orientia tsutsugamushi * Scrub typhus Flea-borne * Rickettsia felis * Flea-borne spotted fever Anaplasmataceae * Ehrlichiosis: Anaplasma phagocytophilum * Human granulocytic anaplasmosis, Anaplasmosis * Ehrlichia chaffeensis * Human monocytotropic ehrlichiosis * Ehrlichia ewingii * Ehrlichiosis ewingii infection Rhizobiales Brucellaceae * Brucella abortus * Brucellosis Bartonellaceae * Bartonellosis: Bartonella henselae * Cat-scratch disease * Bartonella quintana * Trench fever * Either B. henselae or B. quintana * Bacillary angiomatosis * Bartonella bacilliformis * Carrion's disease, Verruga peruana β Neisseriales M+ * Neisseria meningitidis/meningococcus * Meningococcal disease, Waterhouse–Friderichsen syndrome, Meningococcal septicaemia M− * Neisseria gonorrhoeae/gonococcus * Gonorrhea ungrouped: * Eikenella corrodens/Kingella kingae * HACEK * Chromobacterium violaceum * Chromobacteriosis infection Burkholderiales * Burkholderia pseudomallei * Melioidosis * Burkholderia mallei * Glanders * Burkholderia cepacia complex * Bordetella pertussis/Bordetella parapertussis * Pertussis γ Enterobacteriales (OX−) Lac+ * Klebsiella pneumoniae * Rhinoscleroma, Pneumonia * Klebsiella granulomatis * Granuloma inguinale * Klebsiella oxytoca * Escherichia coli: Enterotoxigenic * Enteroinvasive * Enterohemorrhagic * O157:H7 * O104:H4 * Hemolytic-uremic syndrome * Enterobacter aerogenes/Enterobacter cloacae Slow/weak * Serratia marcescens * Serratia infection * Citrobacter koseri/Citrobacter freundii Lac− H2S+ * Salmonella enterica * Typhoid fever, Paratyphoid fever, Salmonellosis H2S− * Shigella dysenteriae/sonnei/flexneri/boydii * Shigellosis, Bacillary dysentery * Proteus mirabilis/Proteus vulgaris * Yersinia pestis * Plague/Bubonic plague * Yersinia enterocolitica * Yersiniosis * Yersinia pseudotuberculosis * Far East scarlet-like fever Pasteurellales Haemophilus: * H. influenzae * Haemophilus meningitis * Brazilian purpuric fever * H. ducreyi * Chancroid * H. parainfluenzae * HACEK Pasteurella multocida * Pasteurellosis * Actinobacillus * Actinobacillosis Aggregatibacter actinomycetemcomitans * HACEK Legionellales * Legionella pneumophila/Legionella longbeachae * Legionnaires' disease * Coxiella burnetii * Q fever Thiotrichales * Francisella tularensis * Tularemia Vibrionaceae * Vibrio cholerae * Cholera * Vibrio vulnificus * Vibrio parahaemolyticus * Vibrio alginolyticus * Plesiomonas shigelloides Pseudomonadales * Pseudomonas aeruginosa * Pseudomonas infection * Moraxella catarrhalis * Acinetobacter baumannii Xanthomonadaceae * Stenotrophomonas maltophilia Cardiobacteriaceae * Cardiobacterium hominis * HACEK Aeromonadales * Aeromonas hydrophila/Aeromonas veronii * Aeromonas infection ε Campylobacterales * Campylobacter jejuni * Campylobacteriosis, Guillain–Barré syndrome * Helicobacter pylori * Peptic ulcer, MALT lymphoma, Gastric cancer * Helicobacter cinaedi * Helicobacter cellulitis 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	Flea-borne spotted fever	None	1,727	wikipedia	https://en.wikipedia.org/wiki/Flea-borne_spotted_fever	2021-01-18T18:59:51	{"icd-10": ["A77.8"], "orphanet": ["83316"], "synonyms": [], "wikidata": ["Q5458307"]}
Luxating patella Other namesTrick knee, subluxation of patella, floating patella, floating kneecap Patellar luxation on radiograph: Left before, right after reduction; after reduction, the patella is still displaced. SpecialtyOrthopedics A luxating patella, sometimes called a trick knee, is a condition in which the patella, or kneecap, dislocates or moves out of its normal location. Patellar luxation is a common condition in dogs, particularly small and miniature breeds. The condition usually becomes evident between the ages of 4 and 6 months. It can occur in cats, as well, especially domestic short-haired cats.[1] It also occurs in humans, where it can be associated with damage to the anterior cruciate ligament.[2] There have been several reports of patella luxation in other species such as miniature pigs, alpacas, llamas, cattle and goats.[3] ## Contents * 1 Causes * 2 Diagnosis * 2.1 Grade I * 2.2 Grade II * 2.3 Grade III * 2.4 Grade IV * 3 Treatment * 4 Dog & cat breeds affected * 5 References * 6 External links ## Causes[edit] Rarely, it can be caused by some form of blunt trauma, but most frequently, it is a developmental, congenital defect. In congenital cases, it is frequently bilateral. The condition can also be inherited through genetics. This can also be caused by obesity. ## Diagnosis[edit] MRI after luxation of the right patella: A bone bruise is at the medial surface of the patella (axial image) and in the corresponding surface of the lateral condyle of the femur (coronal). The medial retinaculum of the patella is at least partially disrupted. Diagnosis is made through palpation of the knee, to see whether it slips inside the joint more than would normally be expected. Often, a dog owner might be told that his or her pet has "loose knee", but this is not a medical term, and it is not correct to use it interchangeably with luxating patella.[4] Luxating patella cannot be present without the knee being loose, but a loose knee is not necessarily slipping out of the joint. Even with luxating patella, symptoms such as intermittent limping in the rear leg might be mild or absent. Physical examination and manual manipulation are the preferred methods for diagnosis. More extreme cases can result in severe lameness. Osteoarthritis typically develops secondarily.[4] The four recognized diagnostic grades of patellar luxation include, in order of severity:[4] ### Grade I[edit] * Grade I - the patella can be manually luxated but is reduced (returns to the normal position) when released. ### Grade II[edit] * Grade II - the patella can be manually luxated or it can spontaneously luxate with flexion of the stifle joint. The patella remains luxated until it is manually reduced or when the animal extends the joint and derotates the tibia in the opposite direction of luxation. ### Grade III[edit] * Grade III - the patella remains luxated most of the time, but can be manually reduced with the stifle joint in extension. Flexion and extension of the stifle results again in luxation of the patella. ### Grade IV[edit] * Grade IV - the patella is permanently luxated and cannot be manually repositioned, with up to 90° of rotation of the proximal tibial plateau. The femoral trochlear groove is shallow or absent, with displacement of the quadriceps muscle group in the direction of luxation. ## Treatment[edit] Grades II, III, and IV require surgery to correct, if the animal has difficulty walking. The surgery required is governed by the type of abnormality present, but often involves a sulcoplasty, a deepening of the trochlear sulcus where the patella sits, a realignment of the attachment of the patella tendon on the tibia, and tightening or releasing of the capsule on either side of the patella, according to which side the patella is slipping. Some grade IV conditions may require more involved surgery to realign the femur and/or tibia. A therapeutic dosage of glucosamine can be used as a preliminary treatment to strengthen ligaments and the surrounding tissues of the joint and can delay or prevent surgery.[5] Additional help can be given with the use of pet ramps, stairs, or steps. These can help the animal travel from one place to another, especially up and down, without adding any pain or damage to the patella. ## Dog & cat breeds affected[edit] Most cases of patellar luxation are medial, and this is frequently a congenital problem in toy- and miniature-breed dogs. Breeds showing a predisposition for medial patellar luxation include miniature and toy Poodles, Maltese, Jack Russell Terriers, Yorkshire Terriers, Pomeranians, Pekingese, Patterdale Terriers, Chihuahuas, Cavalier King Charles Spaniels, Papillons, Boston Terriers, Plummer Terriers and Teddy Roosevelt Terriers. Large-breed dogs are also affected, and the Labrador retriever seems particularly predisposed. Patellar luxation is less common in cats than in dogs. Predisposed breeds include the Devon Rex and the Abyssinian. Although the specific cause of patellar luxation is unknown in these cases, a defect in hind limb conformation is generally agreed to be the underlying cause.[6] ## References[edit] 1. ^ Ettinger, Stephen J.; Feldman, Edward C. (1995). Textbook of Veterinary Internal Medicine (4th ed.). W.B. Saunders Company. ISBN 0-7216-6795-3. 2. ^ "The Knee and Shoulder Centers - [PRINTABLE] Anterior Cruciate Ligament Surgery". Retrieved 2007-11-27. 3. ^ "Trochlear wedge sulcoplasty, tibial tuberosity transposition, and lateral imbrication for correction of a traumatic patellar luxation in a miniature companion pig: A case report and visual description". 4. ^ a b c "Patellar Luxation". Orthopedic Foundation for Animals. Archived from the original (text/html) on 2007-08-26. Retrieved 2007-09-04. 5. ^ Ward, DVM, Ernest. "Cruciate Ligament Rupture in Dogs". VCA. Retrieved 2020-01-23. 6. ^ Patellar Luxation, canine and feline (cat and dog) veterinary factsheets Archived 2008-04-27 at the Wayback Machine ## External links[edit] Classification D * ICD-10: M22.1 * ICD-9-CM: 836.3, 836.4 * v * t * e Acquired musculoskeletal deformities Upper limb shoulder * Winged scapula * Adhesive capsulitis * Rotator cuff tear * Subacromial bursitis elbow * Cubitus valgus * Cubitus varus hand deformity * Wrist drop * Boutonniere deformity * Swan neck deformity * Mallet finger Lower limb hip * Protrusio acetabuli * Coxa valga * Coxa vara leg * Unequal leg length patella * Luxating patella * Chondromalacia patellae * Patella baja * Patella alta foot deformity * Bunion/hallux valgus * Hallux varus * Hallux rigidus * Hammer toe * Foot drop * Flat feet * Club foot knee * Genu recurvatum Head * Cauliflower ear General terms * Valgus deformity/Varus deformity * Joint stiffness * Ligamentous laxity [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor *[BMI]: body mass index	Luxating patella	None	1,728	wikipedia	https://en.wikipedia.org/wiki/Luxating_patella	2021-01-18T18:46:47	{"icd-9": ["836.3", "836.4"], "icd-10": ["M22.1"], "wikidata": ["Q381444"]}
A number sign (#) is used with this entry because of evidence that anencephaly (ANPH) is caused by homozygous mutation in the TRIM36 gene (609317) on chromosome 5q22. One such patient has been reported. Description Anencephaly is characterized by the absence of cranial vault and brain tissues in the fetus. It is considered an extreme form of neural tube defect (182940) (summary by Singh et al., 2017). Inheritance Penrose (1957) concluded that recessive inheritance of anencephaly exists. Multiple affected sibs were reported by several authors, e.g., Iffy (1963), who observed 3 affected sibs and quoted the description by Martin (1840) of 6 affected sibs. Record and McKeown (1950) estimated that the empiric risk of recurrence is about 2%. Concordantly affected presumably monozygotic twins were reported by Taber and Elwell (1960), Josephson and Waller (1933), and Labate and Calvelli (1952). Discordance in monozygotic twins was reported by Grebe (1949), Pedlow (1961), and Litt and Strauss (1935). Horne's patient (1958) had 4 anencephalic offspring of which the last was sired by a man other than the husband. Stevenson (1960) described 6 affected sibs. Dumoulin and Gordon (1959) reported a patient who, in addition to producing 3 normal and 2 anencephalic infants, had uniovular twins, one of whom was anencephalic. Yen and MacMahon (1968) studied the recurrence of anencephaly in families and concluded that the findings were explained by a persistent environmental factor as adequately as by genetic factors. Christakos and Simpson (1969) described anencephaly in 3 sibs. Fuhrmann et al. (1971) described 5 of 8 children of 2 related families with spina bifida or anencephaly. The 2 fathers had married 2 sisters and each union was a third-cousin marriage. Farag et al. (1986) reported 3 sibships in 2 kindreds with multiple cases of 'nonsyndromal' anencephaly, including 2 instances of like-sex twins concordantly affected. In 1 kindred, 2 affected sibships were offspring of consanguineous parents. Prompted by the case of a 21-year-old woman who sought counseling after the birth of 2 consecutive anencephalic male fetuses with complete rachischisis and discordant renal dysplasia, and because of the presence of parental consanguinity, Shaffer et al. (1990) analyzed segregation in 23 additional consanguineous cases and compared the findings with those in 294 presumably nonconsanguineous families previously reported. Using classical segregation analysis, the segregation ratios in the nonsporadic cases were consistent with a major autosomal recessive locus in both groups. Zlotogora (1995) suggested the existence of a major autosomal recessive gene responsible for anencephaly among Iranian Jews. Molecular Genetics In a 20-week-old fetus, born of consanguineous Indian parents, with anencephaly, Singh et al. (2017) identified a homozygous missense mutation in the TRIM36 gene (P508T; 609317.0001). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Cellular transfection of the mutation led to disrupted microtubules, disorganized spindles, loosely arranged chromosomes, abnormal cytokinesis, decreased cell proliferation, and increased apoptosis compared to controls. Similar results were obtained by cellular knockdown of TRIM36 using siRNA. Singh et al. (2017) concluded that mutant TRIM36 adversely affects neural cell proliferation during neural tube formation, leading to anencephaly. Population Genetics A striking geographic variation may in part be due to ethnic genetic differences (Masterson, 1962). Farag et al. (1989) reported a marked fall in the frequency of anencephaly among Bedouins in the last 20 years, which they attributed to a better maternal diet. A mass educational dietetic program to the Bedouin women had emphasized the importance of fresh vegetables and fruit, rich in folic acid, in addition to their traditional foods, rice and meat. Zlotogora (1995) stated that among families originating in Iran or Iraq, anencephaly is the most prevalent neural tube defect. Singh et al. (2017) stated that anencephaly has a prevalence of 2.1 per 1,000 births in India. Animal Model Zhao et al. (1996) reported that mice that are homozygous for deficiency in the paired class homeobox-containing gene Cart1 (601527, see Zhao et al., 1993) are born alive with acrania and meroanencephaly but die soon after birth. They noted that the phenotype observed in these mice resembles strikingly a corresponding human syndrome caused by a neural tube closure defect. Prenatal treatment of Cart1-deficient mutant mice with folic acid suppressed the acrania/meroanencephaly phenotype, suggesting to Zhao et al. (1996) that these mice may provide a useful animal model for developing therapeutic protocols for neural tube defects. They further reported that on the C57BL/6 x 129 hybrid genetic background approximately 65% of the Cart1-mutant mice developed the acrania/meroanencephaly, while the other 35% had fully formed heads. They also examined mutant mice on a 129/SvEv inbred genetic background. On this genetic background Zhao et al. (1996) reported that all Cart1-deficient mutants had the acrania /meroanencephaly phenotype. These results suggested to them that the penetrance of the acrania/meroanencephaly phenotype is modified by differences in genetic background. INHERITANCE \- Autosomal recessive NEUROLOGIC Central Nervous System \- Anencephaly \- Rachischisis \- Neural tube defect MISCELLANEOUS \- Onset in utero \- Death in utero or perinatally \- One patient with a confirmed TRIM36 mutation has been reported (last curated July 2017) MOLECULAR BASIS \- Caused by mutation in the tripartite motif-containing protein 36 gene (TRIM36, 609317.0001 ) ▲ 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	ANENCEPHALY	c0002902	1,729	omim	https://www.omim.org/entry/206500	2019-09-22T16:31:06	{"doid": ["0060668"], "mesh": ["D000757"], "omim": ["206500"], "icd-9": ["740.0"], "icd-10": ["Q00.0"], "orphanet": ["1048"], "synonyms": []}
A number sign (#) is used with this entry because corticosterone methyloxidase type I deficiency (CMO I deficiency) is caused by mutation in the CYP11B2 gene (124080). Description CMO type I deficiency is an autosomal recessive disorder caused by a defect in the penultimate biochemical step of aldosterone biosynthesis, the 18-hydroxylation of corticosterone (B) to 18-hydroxycorticosterone (18-OHB). This enzymatic defect results in decreased aldosterone and salt-wasting. In CMO I deficiency, aldosterone is undetectable, whereas its immediate precursor, 18-OHB, is low or normal. These patients have an increased ratio of corticosterone to 18-OHB (Portrat-Doyen et al., 1998). The CYP11B2 gene product also catalyzes the final step in aldosterone biosynthesis: the 18-oxidation of 18-OHB to aldosterone. A defect in that enzymatic step results in CMO type II deficiency (610600), an allelic disorder with an overlapping phenotype but distinct biochemical features. In CMO II deficiency, aldosterone can be low or normal, but at the expense of increased secretion of 18-OHB. These patients have a low ratio of corticosterone to 18-OHB (Portrat-Doyen et al., 1998). Clinical Features Visser and Cost (1964) and Degenhart et al. (1966) reported 3 Dutch infants, from a large consanguineous family, who presented in early infancy with dehydration, failure to thrive, poor feeding, vomiting, and intermittent fever. Laboratory studies showed hyponatremia and hyperkalemia, consistent with salt-wasting. Urinary aldosterone was undetectable and corticosterone and 11-deoxycorticosterone were increased. Total urinary excretion of 17-ketosteroids, 17-ketogenic steroids, and 17-hydroxycorticosteroids was normal. Mineralocorticoid (deoxycorticosterone acetate) supplementation was successful. Postmortem examination of 1 affected infant who died of infection showed grossly normal adrenals, but microscopic examination showed poor development of the zona glomerulosa and hyperplasia of the juxtaglomerular apparatus. The findings suggested a metabolic defect affecting biosynthesis of aldosterone at the step between corticosterone and aldosterone. All 6 parents of the 3 patients shared a great-grandparental ancestral couple in common. In a follow-up of the family reported by Visser and Cost (1964), Peter et al. (1997) found decreased plasma levels of aldosterone and 18-OH-corticosterone and increased plasma corticosterone and 11-deoxycorticosterone. Cortisol and its precursors were in the normal range. The findings were consistent with a defect in 18-hydroxylation of corticosterone, thus confirming the diagnosis of CMO type I deficiency. Drop et al. (1982) knew of 6 reported cases. Kayes-Wandover et al. (2001) reported a 47-year-old man who first presented with CMO type I deficiency after developing hyperkalemia in preparation for a barium enema. Past medical history was notable for failure to thrive in infancy. Laboratory analysis showed increased serum renin with low serum and urinary levels of aldosterone, increased urinary corticosterone, and decreased urinary 18-hydroxycorticosterone. Molecular Genetics In 3 Amish patients with CMO type I deficiency, Mitsuuchi et al. (1993) identified a homozygous 5-bp deletion in the CYP11B2 gene (124080.0003). In 2 individuals with CMO I deficiency reported by Visser and Cost (1964), Peter et al. (1997) identified a homozygous mutation in the CYP11B2 gene (124080.0006). All 4 unaffected parents were heterozygous for the mutation. In a man who presented in middle age with CMO type I deficiency, Kayes-Wandover et al. (2001) identified a homozygous 6-bp duplication in the CYP11B2 gene (124080.0009). INHERITANCE \- Autosomal recessive GROWTH Other \- Failure to thrive \- Growth retardation CARDIOVASCULAR Vascular \- Hypotension ABDOMEN Gastrointestinal \- Poor feeding \- Vomiting GENITOURINARY Kidneys \- Salt-wasting METABOLIC FEATURES \- Dehydration \- Intermittent fever ENDOCRINE FEATURES \- Hypoaldosteronism LABORATORY ABNORMALITIES \- Decreased serum aldosterone \- Increased serum corticosterone \- Increased serum ratio of corticosterone to 18-hydroxycorticosterone (18-OHB) \- Decreased serum 18-OHB \- Hyponatremia \- Hyperkalemia \- Increased serum renin \- Normal urinary 17-ketosteroids MISCELLANEOUS \- Onset in neonatal period \- Infants may have acute life-threatening crises \- Symptoms ameliorate with age \- Adults may be asymptomatic \- Allelic disorder to corticosterone methyloxidase type II deficiency ( 610600 ) MOLECULAR BASIS \- Caused by mutation in the cytochrome p450 subfamily XIB, polypeptide 2 gene (CYP11B2, 124080.0002 ) ▲ 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	CORTICOSTERONE METHYLOXIDASE TYPE I DEFICIENCY	c0268293	1,730	omim	https://www.omim.org/entry/203400	2019-09-22T16:31:24	{"mesh": ["C537806"], "omim": ["203400"], "orphanet": ["427"], "synonyms": ["18-HYDROXYLASE DEFICIENCY", "Alternative titles", "ALDOSTERONE DEFICIENCY I", "CMO I DEFICIENCY", "STEROID 18-HYDROXYLASE DEFICIENCY", "ALDOSTERONE DEFICIENCY DUE TO DEFECT IN STEROID 18-HYDROXYLASE", "HYPERRENINEMIC HYPOALDOSTERONISM, FAMILIAL, 1"]}
A carcinoid tumor is a type of neuroendocrine tumor that usually develops in the digestive (GI) tract (such as the stomach or intestines) or in the lungs. In some cases, a carcinoid tumor develops in another part of the body, such as the pancreas, testicle (in men), or ovary (in women). It is a slow-growing tumor that typically does not cause symptoms in the early stages, so a person may have the tumor for years before being diagnosed. In later stages, symptoms may vary depending on where the tumor is located. Symptoms of a GI carcinoid tumor may only develop if the tumor has spread to the liver. The tumor may produce hormone-like substances that spread to the body and cause symptoms of carcinoid syndrome, such as flushing of the face and chest, diarrhea, and trouble breathing. People with a lung carcinoid tumor are less likely to have carcinoid syndrome, but may experience coughing, wheezing, or pneumonia. The tumor may also cause various symptoms if it has spread to other parts of the body. The cause of carcinoid tumors is unknown, but certain unavoidable risk factors may increase a person's chance of developing a carcinoid tumor. In general, cancer develops when a cell randomly develops mutations in its DNA. Surgery to remove the tumor is the main treatment and can typically cure the tumor if it has not spread to other parts of the body. Other treatment options may include radiation therapy, chemotherapy, and targeted therapy. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor *[BMI]: body mass index	Carcinoid tumor	c0007095	1,731	gard	https://rarediseases.info.nih.gov/diseases/9316/carcinoid-tumor	2021-01-18T18:01:38	{"mesh": ["D002276"], "umls": ["C0007095"], "synonyms": []}
A group of neoplasms arising from precursor cells committed to the myeloid cell-line differentiation. All of them are characterized by clonal expansion of myeloid blasts. They manifest by fever, pallor, anemia, hemorrhages and recurrent infections. ## Epidemiology Annual incidence rate of AML is estimated to be 1/33,000-1/25,000 in Europe. ## Clinical description Although, AML can occur at any age, it is typically a disease affecting elder people, usually more than 65 years. The main clinical picture consists of a short time period with pallor, fatigue, fever, infections and hemorrhages. Presence of all these features is not compulsory. Central nervous system infiltration is uncommon and mainly related with monocytic variants. Extramedullary accumulation of myeloid blasts in different tissues, mainly skin, can be observed and is known as myeloid sarcoma (see this term). Testes are usually not affected. ## Etiology Pathogenesis of AML is still unclear but a two-hit model has been suggested as the probable mechanism for leukemogenesis. That means that AML could be the consequence of at least 2 different types of gene mutations. Class I mutations resulting in proliferative advantage while the class II mutations alter the normal hematopoietic differentiation. Examples of class I mutations are those of FLT3-ITD or KIT mutations. Class II mutations include CEBPA mutations. Controversy is also still in the type of cell from which AML arises. While data supporting progenitor cells committed to specific myeloid cell type has been reported, other studies argue in favor for a more immature stem. ## Diagnostic methods Diagnosis relies on laboratory findings showing anemia, thrombocytopenia and leucopenia or leukocytosis which result from disturbed hematopoietic function due to bone marrow and peripheral blood infiltration by immature blast cells. Diagnosis of AML also relies on bone marrow aspirate or biopsy after the disease has been suspected. Bone marrow should have at least 20% of myeloid blasts to be considered as AML. After morphological examination, immunophenotyping of leukemic cells, cytogenetic and molecular analysis should be performed. ## Differential diagnosis Differential diagnosis includes megaloblastic anaemia, myelodysplastic syndromes, acute lymphoblastic leukemia, acute biphenotypic leukemia, chronic myeloid leukemia (myeloid blast phase), and metastases of tumors such rhabdomyosarcoma and neuroblastoma (see these terms). ## Management and treatment For young patients, treatment consists of an induction cycle with cytarabine plus idarubicin or daunorubicin in a typical 3 + 7 schedule with the first objective to reach complete response (CR). About 75% of the patients achieve CR, but virtually all of them will relapse if additional treatment (consolidation therapy) is not given. Based on stratification, patients can be treated with chemotherapy consolidation or allogenic hematopoietic stem cell transplantation (HSCT). Refractory or relapsed AML is treated with a second induction course adding new drugs (such gemtuzumab ozogamicin) to the standard treatment. Some drugs such as azacitidine or decitabine are available for the treatment of elderly AML patients under specific circumstances. ## Prognosis Prognosis varies widely according to cytogenetics, molecular findings, response to induction treatment and age, between others. Overall, long-term survivors account for 40% of young patients. For children less than 15 years, overall survival rates are 60-70%. Prognosis of elder patients is rather poor. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor *[BMI]: body mass index	Acute myeloid leukemia	c0023467	1,732	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=519	2021-01-23T18:36:36	{"gard": ["12757"], "mesh": ["D015470"], "omim": ["601626"], "umls": ["C0023467", "C1879321"], "icd-10": ["C92.0"], "synonyms": ["AML", "Acute myelogenous leukemia"]}
Soviet poster circa 1925. Title translation: "Abortions induced by grandma or self-taught midwives not only maim the woman, they also often lead to death" An unsafe abortion is the termination of a pregnancy by people lacking the necessary skills, or in an environment lacking minimal medical standards, or both.[1] An unsafe abortion is a life-threatening procedure. It includes self-induced abortions, abortions in unhygienic conditions, and abortions performed by a medical practitioner who does not provide appropriate post-abortion attention.[2] About 25 million unsafe abortions occur a year, of which most occur in the developing world.[3] Unsafe abortions results in complications for about 7 million women a year.[3] Unsafe abortions are also one of the leading causes of deaths during pregnancy and childbirth (about 5-13% of all deaths during this period).[3] Most unsafe abortions occur where abortion is illegal,[4] or in developing countries where affordable and well-trained medical practitioners are not readily available,[5][6] or where modern birth control is unavailable.[7] Unsafe abortion was and is a public health crisis.[8] More specifically, lack of access to safe abortion was and is a public health risk.[8] The more restrictive the law, the higher the rates of death and other complications.[8] ## Contents * 1 Overview * 2 Conflating illegal and unsafe abortion * 3 Frequency by continent * 3.1 Abortion in the U.S. before 1973 (Roe v. Wade) * 3.2 Rates in the U.S. after 1973 * 4 Methods * 5 Health risks * 5.1 Treatment of complications * 6 See also * 7 References * 8 External links ## Overview[edit] The World Health Organization (WHO) estimated that for the time period of 2010-14 there were 55.7 million abortions worldwide each year. Out of these abortions, approximately 54% were safe, 31% were less safe, and 14% were least safe. That means that 25 million (45%) abortions each year between 2010 and 2014 were unsafe, with 24 million (97%) of these in developing countries.[9] In 2003 approximately 42 million pregnancies were voluntarily terminated, of which 20 million were unsafe.[10] According to WHO and the Guttmacher Institute, at least 22,800[11] women die annually as a result of complications of unsafe abortion, and between two million and seven million women each year survive unsafe abortion but sustain long-term damage or disease (incomplete abortion, infection, sepsis, bleeding, and injury to the internal organs, such as puncturing or tearing of the uterus). They also concluded abortion is safer in countries where it is legal, but dangerous in countries where it is outlawed and performed clandestinely. The WHO reports that in developed regions, nearly all abortions (92%) are safe, whereas in developing countries, more than half (55%) are unsafe. According to WHO statistics, the risk rate for unsafe abortion is 1/270; according to other sources, unsafe abortion is responsible for at least 8% of maternal deaths.[12][11] Worldwide, 48% of all induced abortions are unsafe. The British Medical Bulletin reported in 2003 that 70,000 women a year die from unsafe abortion.[13] Incidence of such abortions may be difficult to measure because they can be reported variously as miscarriage, "induced miscarriage", "menstrual regulation", "mini-abortion", and "regulation of a delayed/suspended menstruation".[14][15] An article pre-printed by the WHO called safe, legal abortion a "fundamental right of women, irrespective of where they live" and unsafe abortion a "silent pandemic".[14] The article states "ending the silent pandemic of unsafe abortion is an urgent public-health and human-rights imperative." It also states "access to safe abortion improves women’s health, and vice versa, as documented in Romania during the regime of President Nicolae Ceaușescu" and "legalisation of abortion on request is a necessary but insufficient step toward improving women’s health" citing that in some countries, such as India, where abortion has been legal for decades, access to competent care remains restricted because of other barriers. WHO’s Global Strategy on Reproductive Health, adopted by the World Health Assembly in May 2004, noted: "As a preventable cause of maternal mortality and morbidity, unsafe abortion must be dealt with as part of the MDG on improving maternal health and other international development goals and targets."[16] The WHO's Development and Research Training in Human Reproduction (HRP), whose research concerns people's sexual and reproductive health and lives,[17] has an overall strategy to combat unsafe abortion that comprises four interrelated activities:[16] * to collate, synthesize and generate scientifically sound evidence on unsafe abortion prevalence and practices; * to develop improved technologies and implement interventions to make abortion safer; * to translate evidence into norms, tools and guidelines; * and to assist in the development of programmes and policies that reduce unsafe abortion and improve access to safe abortion and highquality postabortion care. A 2007 study published in The Lancet found that, although the global rate of abortion declined from 45.6 million in 1995 to 41.6 million in 2003, unsafe procedures still accounted for 48% of all abortions performed in 2003. It also concluded that, while the overall incidence of abortion in both developed and developing countries is approximately equal, unsafe abortion occurs more often in less-developed nations.[18] According to a new study in The Lancet that focused on data from 2010 to 2014, nearly 55 million pregnancies are terminated early and of that 55 million, nearly half, 25.5 million are deemed as unsafe.[19] The WHO and the Guttmacher Institute stress the need for access to a safe abortion for all women and that unsafe methods must be replaced. Africa, Asia and Latin America account for almost 97 percent of them of unsafe abortions. These regions are often poorer and underdeveloped and lack the access to safe abortion methods. Out of all abortions in these regions only 25% are considered safe. In developed countries these numbers improve drastically. Nearly all abortions in North America (99%) are considered safe. Overall nearly 88% of abortions in developed countries were actually considered safe, with the number of safe abortions in Europe slightly lower. ## Conflating illegal and unsafe abortion[edit] Unsafe abortions often occur where abortion is illegal.[4] However, the prevalence of unsafe abortion may also be determined by other factors, such as whether it occurs in a developing country that has a low level of competent medical care.[20] Unsafe abortions sometimes occur where abortion is legal, and safe abortions sometimes occur where abortion is illegal.[21] Legalization is not always followed by elimination of unsafe abortion.[5][22] Affordable safe services may be unavailable despite legality, and conversely, women may be able to afford medically competent services despite illegality.[23] When abortion is illegal, that generally contributes to the prevalence of unsafe abortion, but it is not the only contributor. In addition, a lack of access to safe and effective contraception contributes to unsafe abortion. It has been estimated that the incidence of unsafe abortion could be reduced by as much as 73% without any change in abortion laws if modern family planning and maternal health services were readily available globally.[7] Illegality of abortion contributes to maternal mortality, but that contribution is not as great as it once was, due to medical advances including penicillin and the birth control pill.[24] ## Frequency by continent[edit] Region Number of unsafe abortions (thousands) Number of unsafe abortions per 100 live births Number of unsafe abortions per 1000 women Africa 4200 14 24 Asia* 10500 14 13 Europe 500 7 3 Latin America and the Caribbean 3700 32 29 North America Negligible incidence Negligible incidence Negligible incidence Oceania ** 30 12 17 World 19000 14 14 * Excluding Japan ** Excluding Australia and New Zealand Source: WHO 2006[25] ### Abortion in the U.S. before 1973 (Roe v. Wade)[edit] In 1973, the Supreme Court ruled 7–2 that laws prohibiting an abortion violated a woman’s right to privacy. The landmark case, Roe v. Wade, changed abortion in the United States. Early abortion laws really only prohibited the use of toxic chemicals that were used to cause a miscarriage.[26] The first such law was passed in Connecticut in 1821.[26] Prior to 1973, the authority to legalize abortion rested with the state governments. Up through the 1960s 44 states had laws that outlawed abortions unless the health of the pregnant patient was at stake.[27] In the 1940s, records show that more than 1,000 women died each year from abortions that were labeled as unsafe. Many of these abortions were self-induced. Unsafe abortion practices were such a concern in the United States that nearly every large hospital had some type of “septic abortion ward” that was responsible for dealing with the complications that accompanied an incomplete abortion. Incomplete abortions were the leading cause for OB-GYN services across the United States.[28] In the 1960s, the National Opinion Research Center found that hundreds of women were attempting to self-abort with coat hangers, knitting needles and ballpoint pens, and by swallowing toxic chemicals like bleach and laundry detergent.[28] However, the number of deaths declined significantly into the 1960s and 1970s. The Centers for Disease Control and Prevention estimates that in 1972, 130,000 women attempted self-induced abortions or obtained illegal abortions, resulting in 39 deaths.[29] ### Rates in the U.S. after 1973[edit] In 2005, the Detroit News reported that a 16-year-old boy beat his pregnant, under-age girlfriend with a bat at her request to abort a fetus. The young couple lived in Michigan, where parental consent is required to receive an abortion.[30][31][32] In Indiana, where there are also parental consent laws, a girl by the name of Becky Bell died from an unsafe abortion rather than discuss her pregnancy and wish for an abortion with her parents.[33][34] In 2011, Kermit Gosnell, a licensed doctor who provided abortion services in the American state of Pennsylvania, was indicted by a grand jury on murder charges after a woman died in his clinic. The grand jury found that the conditions in Gosnell's clinic were not only unsanitary and that Gosnell staffed his clinic with unlicensed individuals, he had also commonly conducted the lesser known practice of severing the spinal cords of newly born babies.[35] ## Methods[edit] Methods of unsafe abortion include: * Trying to break the amniotic sac inside the womb with a sharp object or wire (for example an unbent wire clothes hanger or knitting needle). This method can cause infection or injury to internal organs (for example perforating the uterus or intestines), resulting in death.[36] The uterus softens during pregnancy and is very easy to pierce, so one traditional method was to use a large feather.[37] * Pumping toxic mixtures, such as chili peppers and chemicals like alum, Lysol, permanganate, or plant poison into the body of the woman. This method can cause the woman to go into toxic shock and die.[38] * Inducing an abortion without medical supervision by self-administering abortifacient over-the-counter drugs or drugs obtained illegally or by using drugs not indicated for abortion but known to result in miscarriage or uterine contraction. Drugs that cause uterine contractions include oxytocin (synthetic forms are Pitocin and Syntocinon), prostaglandins, and ergot alkaloids. Risks include uterine rupture, irregular heartbeat, a rise in blood pressure (hypertension), a drop in blood pressure (hypotension), anemia requiring transfusion, cardiovascular problems, pulmonary edema, and death, as well as intense bronchospasms in women with asthma.[39] ## Health risks[edit] Unsafe abortion is a major cause of injury and death among women worldwide. It is estimated that nearly 25 million unsafe abortions take place annually.[40] WHO estimates that at least 7.9% of maternal deaths are due to unsafe abortion, with a greater proportion occurring in Latin America, the Caribbean, and sub-Saharan Africa and a lesser proportion in East Asia were access to abortion is generally legal.[41] 97% of these abortions take place in developing countries.[42] Unsafe abortion is believed to result in at least 22,800 deaths and millions of injuries annually.[42] The legal status of abortion is believed to play a major role in the frequency of unsafe abortion.[43][44] For example, the 1996 legalization of abortion in South Africa had an immediate positive impact on the frequency of abortion-related complications,[45] with abortion-related deaths dropping by more than 90%.[46] Groups such as the World Health Organization have advocated a public-health approach to addressing unsafe abortion, emphasizing the legalization of abortion, the training of medical personnel, and ensuring access to reproductive-health services.[44] An unsafe abortion can lead to wide range of health risks that can affect the well-being of women. The major and most life-threatening complications that stem from unsafe abortions are infection, hemorrhaging and injury to internal organs.[47] Abortion symptoms that can lead to additional health risks: * To provide the necessary treatment, an accurate assessment of an unsafe abortion is critical. Some signs and symptoms that require immediate attention by a licensed health care provider include: abdominal pain, vaginal infection, abnormal vaginal bleeding, shock (collapse of the circulatory system).[47] * It is difficult to diagnose complications that result from an unsafe abortion. A woman with an extra-uterine or ectopic pregnancy may have symptoms similar to those of incomplete abortion. Therefore, it is important for health care providers to refer individuals they are unsure about to a facility where a definitive diagnosis can be made and care can be provided.[48] Complications and their treatments include: * Infection: antibiotics prescribed by a health care provider and removing tissue from the affected area. * Hemorrhage: swift treatment by a health care provider is imperative, as delays can be fatal. Damage to the genital tract or internal organs: Admission to a health care facility is imperative, any delay can be fatal.[49] ### Treatment of complications[edit] Regardless if an abortion was legal or illegal, health care providers are required by law to provide medical care to patients, as it may be life-saving. In some cases, treatment for abortion complications may be administered only when the woman provides information about the abortion and any and all persons that were involved.[50] It is difficult to get a confession from women seeking emergency medical care as a result of an illegal abortion because it puts women's lives at risk. However, it is a legal requirement for doctors to report cases of women who have undergone any type of abortion. Any delay in care increases the risks to women’s health and lives.[50] ## See also[edit] * Reproductive health * Reproductive rights * Gerri Santoro ## References[edit] 1. ^ Safe Abortion: Technical and Policy Guidance for Health Systems, page 12 (World Health Organization 2003): "a procedure for terminating an unwanted pregnancy either by persons lacking the necessary skill or in an environment lacking the minimum medical standards, or both." 2. ^ "Unsafe abortion: Global and regional estimates of the incidence of unsafe abortion and associated mortality in 2003" (PDF). World Health Organization. 2007. Retrieved March 7, 2011. "The estimates given in this document are intended to reflect induced abortions that carry greater risk than those carried out officially for reasons accepted in the laws of a country." 3. ^ a b c "Preventing unsafe abortion". www.who.int. Retrieved 19 April 2019. 4. ^ a b Rosenthal E (October 2007). "Legal or Not, Abortion Rates Compare". New York Times. Retrieved 2009-06-30. 5. ^ a b Blas, Erik et al. Equity, social determinants and public health programmes, pages 182-183 (World Health Organization 2010). 6. ^ Chaudhuri, S.K. Practice Of Fertility Control: A Comprehensive Manual, 7th Edition, page 259 (Elsevier India, 2007). 7. ^ a b Singh, Susheela et al. Adding it Up: The Costs and Benefits of Investing in Family Planning and Newborn Health (New York: Guttmacher Institute and United Nations Population Fund 2009): "If women’s contraceptive needs were addressed...the number of unsafe abortions would decline by 73% from 20 million to 5.5 million." A few of the findings in that report were subsequently changed, and are available at: "Facts on Investing in Family Planning and Maternal and Newborn Health Archived 2012-03-24 at the Wayback Machine" (Guttmacher Institute 2010). 8. ^ a b c Haddad LB, Nour NM (2009). "Unsafe abortion: unnecessary maternal mortality". Reviews in Obstetrics & Gynecology. 2 (2): 122–6. PMC 2709326. PMID 19609407. 9. ^ Ganatra B, Gerdts C, Rossier C, Johnson BR, Tunçalp Ö, Assifi A, Sedgh G, Singh S, Bankole A, Popinchalk A, Bearak J, Kang Z, Alkema L (November 2017). "Global, regional, and subregional classification of abortions by safety, 2010-14: estimates from a Bayesian hierarchical model". Lancet. 390 (10110): 2372–2381. doi:10.1016/S0140-6736(17)31794-4. PMC 5711001. PMID 28964589. 10. ^ "Unsafe abortion Global and regional estimates of the incidence of unsafe abortion and associated mortality in 2008, pg2" (World Health Organization 2011): "It was estimated that in 2003 approximately 42 million pregnancies were voluntarily terminated: 22 million safely and 20 million unsafely." 11. ^ a b "Induced Abortion Worldwide". Guttmacher Institute. 2016-05-10. Retrieved 2018-03-08. 12. ^ Nour NM (2008). "An Introduction to Maternal Mortality". Reviews in Obstetrics & Gynecology. 1 (2): 77–81. PMC 2505173. PMID 18769668. 13. ^ Grimes DA (2003-12-01). "Unsafe Abortion: The Silent Scourge". British Medical Bulletin. 67 (1): 99–113. doi:10.1093/bmb/ldg002. PMID 14711757. 14. ^ a b Grimes DA. "Unsafe Abortion - The Preventable Pandemic". Retrieved 2010-01-16. 15. ^ Nations MK, Misago C, Fonseca W, Correia LL, Campbell OM (June 1997). "Women's hidden transcripts about abortion in Brazil". Social Science & Medicine. 44 (12): 1833–45. doi:10.1016/s0277-9536(96)00293-6. PMID 9194245. 16. ^ a b "Preventing unsafe abortion". WHO. Retrieved 2014-03-28. 17. ^ "New findings from the WHO Multicountry Survey on Maternal and Newborn Health". WHO. Retrieved 2014-03-28. 18. ^ Sedgh G, Henshaw S, Singh S, Ahman E, Shah IH (October 2007). "Induced abortion: estimated rates and trends worldwide". Lancet. 370 (9595): 1338–45. CiteSeerX 10.1.1.454.4197. doi:10.1016/S0140-6736(07)61575-X. PMID 17933648. S2CID 28458527. 19. ^ Welch, A. (2017, September 27). Report finds nearly half of all abortions worldwide are unsafe. Retrieved December 05, 2017, from https://www.cbsnews.com/news/report-finds-nearly-half-of-all-abortions-worldwide-are-unsafe/ 20. ^ Chaudhuri, S.K. Practice Of Fertility Control: A Comprehensive Manual, 7th Edition, page 259 (Elsevier India, 2007). 21. ^ Faúndes, Aníbal and Barzelatto, José. The Human Drama of Abortion: a Global Search for Consensus, page 21 (Vanderbilt University Press 2006). 22. ^ "Unsafe abortion: Global and regional estimates of the incidence of unsafe abortion and associated mortality in 2003" (PDF). World Health Organization. 2007. Retrieved March 7, 2011. "In several countries, the legalization of abortion has not been followed by elimination of unsafe abortion." 23. ^ Safe Abortion: Technical and Policy Guidance for Health Systems, page 15 (World Health Organization 2003). 24. ^ "Abortion Distortions: Senators from both sides make false claims about Roe v. Wade" Archived 2011-07-26 at the Wayback Machine, FactCheck.org (2005-08-22): "Sen. Boxer claimed that overturning Roe v. Wade would cost the lives of more than 5,000 pregnant women a year. That might have been true before the invention of penicillin and the birth control pill, but it's not true now. The best evidence indicates that the annual deaths from illegal abortions would number in the hundreds, not thousands." 25. ^ WHO pre-print copy of Grimes DA, Benson J, Singh S, Romero M, Ganatra B, Okonofua FE, Shah IH (November 2006). "Unsafe abortion: the preventable pandemic". Lancet. 368 (9550): 1908–19. doi:10.1016/s0140-6736(06)69481-6. PMID 17126724. S2CID 6188636. 26. ^ a b Wilson J (22 January 2013). "Before and after Roe v. Wade - CNN". CNN. Retrieved 7 December 2017. 27. ^ Kliff S (22 January 2013). "CHARTS: How Roe v. Wade changed abortion rights". Retrieved 7 December 2017 – via www.WashingtonPost.com. 28. ^ a b "What Americans Have Forgotten About The Era Before Roe v. Wade". ThinkProgress.org. Retrieved 7 December 2017. 29. ^ "Lessons from Before Roe: Will Past be Prologue?". 22 September 2004. 30. ^ Cardenas E, Hunter G (5 January 2005). "Boy Faces Felony in Baseball Bat Abortion". Detroit News. 31. ^ White P (January 13–21, 2005). "Baseball Bat Abortion". Boulder Weekly. Retrieved 2009-05-31. 32. ^ "Michigan: Restrictions on Young Women's Access to Abortion". NARAL Pro-Choice America. Retrieved 2009-05-31. 33. ^ "Pacifica Radio". 2003-01-22. Retrieved 2009-05-31. 34. ^ Platner J (2006-09-15). "Remembering Becky Bell". Planned Parenthood Golden Gate. Retrieved 2009-05-31. 35. ^ "Investigation of the Women's Medical Society Grand Jury Report". Phila.gov. Retrieved 7 December 2017. 36. ^ Soubiran A (1969). Diary of a Woman in White (English ed.). Avon Books. pp. 98–99. citing Henri Modnor (1935). Fatal Abortions. 37. ^ Avery M (1939). "My Family Speaks". Confessions of an Abortionist: Intimate Sidelights on the Secret Human, Sorrow, Drama and Tragedy in the Experience of a Doctor Whose Profession it is to Perform Illegal Operations (First ed.). Haldeman-Julius Company.. Accessed 14 December 2012. 38. ^ Andrew Walker (7 April 2008). "Saving Nigerians from risky abortions". BBC News. Retrieved 31 May 2009. 39. ^ Rastegari E.C., Uretsky S. Encyclopedia of Surgery: Uterine stimulants. Accessed 14 December 2012. 40. ^ Ganatra B, Gerdts C, Rossier C, Johnson Jr B R, Tuncalp Ö, Assifi A, Sedgh G, Singh S, Bankole A, Popinchalk A, Bearak J, Kang Z, Alkema L. Global, regional, and subregional classification of abortions by safety, 2010–14: estimates from a Bayesian hierarchical model. The Lancet. 2017 Sep 41. ^ Say, L; Chou, D; Gemmill, A; Tunçalp, Ö; Moller, AB; Daniels, J; Gülmezoglu, AM; Temmerman, M; Alkema, L (June 2014). "Global causes of maternal death: a WHO systematic analysis". The Lancet. Global Health. 2 (6): e323-33. doi:10.1016/S2214-109X(14)70227-X. PMID 25103301. 42. ^ a b Grimes DA, Benson J, Singh S, Romero M, Ganatra B, Okonofua FE, Shah IH (November 2006). "Unsafe abortion: the preventable pandemic" (PDF). Lancet. 368 (9550): 1908–19. doi:10.1016/S0140-6736(06)69481-6. PMID 17126724. S2CID 6188636. 43. ^ Berer M (November 2004). "National laws and unsafe abortion: the parameters of change". Reproductive Health Matters. 12 (24 Suppl): 1–8. doi:10.1016/S0968-8080(04)24024-1. PMID 15938152. S2CID 33795725. 44. ^ a b Berer M (2000). "Making abortions safe: a matter of good public health policy and practice". Bulletin of the World Health Organization. 78 (5): 580–92. PMC 2560758. PMID 10859852. 45. ^ Jewkes R, Rees H, Dickson K, Brown H, Levin J (March 2005). "The impact of age on the epidemiology of incomplete abortions in South Africa after legislative change". BJOG. 112 (3): 355–9. doi:10.1111/j.1471-0528.2004.00422.x. PMID 15713153. S2CID 41663939. 46. ^ Bateman C (December 2007). "Maternal mortalities 90% down as legal TOPs more than triple". South African Medical Journal = Suid-Afrikaanse Tydskrif vir Geneeskunde. 97 (12): 1238–42. PMID 18264602. 47. ^ a b "Preventing unsafe abortion". World Health Organization. Retrieved 7 December 2017. 48. ^ Vlassoff et al. Economic impact of unsafe abortion-related morbidity and mortality: evidence and estimation challenges. Brighton, Institute of Development Studies, 2008 (IDS Research Reports 59). 49. ^ L Haddad. Unsafe Abortion: Unnecessary Maternal Mortality. Rev Obstet Gynecol. 2009 Spring; 2(2): 122–126. 50. ^ a b Human Rights Committee; Committee Against Torture; Committee on the Elimination of Discrimination Against Women. ## External links[edit] World Health Organization, index for Sexual and reproductive health * Preventing Unsafe Abortion and its Consequences: Priorities for Research and Action, New York: Guttmacher Institute, 2006 * My Back-Alley Abortion, via BeliefNet * v * t * e Abortion Main topics * Definitions * History * Methods * Abortion debate * Philosophical aspects * Abortion law Movements * Abortion-rights movements * Anti-abortion movements Issues * Abortion and mental health * Beginning of human personhood * Beginning of pregnancy controversy * Abortion-breast cancer hypothesis * Anti-abortion violence * Abortion under communism * Birth control * Crisis pregnancy center * Ethical aspects of abortion * Eugenics * Fetal rights * Forced abortion * Genetics and abortion * Late-term abortion * Legalized abortion and crime effect * Libertarian perspectives on abortion * Limit of viability * Malthusianism * Men's rights * Minors and abortion * Natalism * One-child policy * Paternal rights and abortion * Prenatal development * Reproductive rights * Self-induced abortion * Sex-selective abortion * Sidewalk counseling * Societal attitudes towards abortion * Socialism * Toxic abortion * Unsafe abortion * Women's rights By country Africa * Algeria * Angola * Benin * Botswana * Burkina Faso * Burundi * Cameroon * Cape Verde * Central African Republic * Chad * Egypt * Ghana * Kenya * Namibia * Nigeria * South Africa * Uganda * Zimbabwe Asia * Afghanistan * Armenia * Azerbaijan * Bahrain * Bangladesh * Bhutan * Brunei * Cambodia * China * Cyprus * East Timor * Georgia * India * Iran * Israel * Japan * Kazakhstan * South Korea * Malaysia * Nepal * Northern Cyprus * Philippines * Qatar * Saudi Arabia * Singapore * Turkey * United Arab Emirates * Vietnam * Yemen Europe * Albania * Andorra * Austria * Belarus * Belgium * Bosnia and Herzegovina * Bulgaria * Croatia * Czech Republic * Denmark * Estonia * Finland * France * Germany * Greece * Hungary * Iceland * Ireland * Italy * Kazakhstan * Latvia * Liechtenstein * Lithuania * Luxembourg * Malta * Moldova * Monaco * Montenegro * Netherlands * North Macedonia * Norway * Poland * Portugal * Romania * Russia * San Marino * Serbia * Slovakia * Slovenia * Spain * Sweden * Switzerland * Ukraine * United Kingdom North America * Belize * Canada * Costa Rica * Cuba * Dominican Republic * El Salvador * Guatemala * Mexico * Nicaragua * Panama * Trinidad and Tobago * United States Oceania * Australia * Micronesia * Fiji * Kiribati * Marshall Islands * New Zealand * Papua New Guinea * Samoa * Solomon Islands * Tonga * Tuvalu * Vanuatu South America * Argentina * Bolivia * Brazil * Chile * Colombia * Ecuador * Guyana * Paraguay * Peru * Suriname * Uruguay * Venezuela Law * Case law * Constitutional law * History of abortion law * Laws by country * Buffer zones * Conscientious objection * Fetal protection * Heartbeat bills * Informed consent * Late-term restrictions * Parental involvement * Spousal consent Methods * Vacuum aspiration * Dilation and evacuation * Dilation and curettage * Intact D&X * Hysterotomy * Instillation * Menstrual extraction * Abortifacient drugs * Methotrexate * Mifepristone * Misoprostol * Oxytocin * Self-induced abortion * Unsafe abortion Religion * Buddhism * Christianity * Catholicism * Hinduism * Islam * Judaism * Scientology * Category [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor *[BMI]: body mass index	Unsafe abortion	None	1,733	wikipedia	https://en.wikipedia.org/wiki/Unsafe_abortion	2021-01-18T18:29:11	{"wikidata": ["Q1342132"]}
Not to be confused with Bronchiolitis obliterans syndrome. Cryptogenic organizing pneumonia Micrograph showing a Masson body (off center left/bottom of the image – pale circular and paucicellular), as may be seen in cryptogenic organizing pneumonia. The Masson body plugs the airway. The artery associated with the obliterated airway is also seen (far left of the image). H&E stain. SpecialtyPulmonology Cryptogenic organizing pneumonia (COP), formerly known as bronchiolitis obliterans organizing pneumonia (BOOP), is an inflammation of the bronchioles (bronchiolitis) and surrounding tissue in the lungs.[1][2] It is a form of idiopathic interstitial pneumonia.[3] It is often a complication of an existing chronic inflammatory disease such as rheumatoid arthritis, dermatomyositis, or it can be a side effect of certain medications such as amiodarone. COP was first described by Gary Epler in 1985.[4] The clinical features and radiological imaging resemble infectious pneumonia. However, diagnosis is suspected after there is no response to multiple antibiotics, and blood and sputum cultures are negative for organisms. ## Contents * 1 Terminology * 2 Signs and symptoms * 3 Causes * 4 Diagnosis * 4.1 Imaging * 5 Unusual presentations of organizing pneumonia * 6 Complications * 7 Treatment * 8 References * 9 External links ## Terminology[edit] "Organizing" refers to unresolved pneumonia (in which the alveolar exudate persists and eventually undergoes fibrosis) in which fibrous tissue forms in the alveoli. The phase of resolution and/or remodeling following bacterial infections is commonly referred to as organizing pneumonia, both clinically and pathologically. The American Thoracic Society and the European Respiratory Society hold that "cryptogenic organizing pneumonia" is the preferred clinical term for this disease for multiple reasons:[5][6] * Avoid confusion with bronchiolitis obliterans, which may not be visualized in every case of this disease. * Avoid confusion with constrictive bronchiolitis * Emphasize the cryptogenic nature of the disease ## Signs and symptoms[edit] The classic presentation of COP is the development of nonspecific systemic (e.g., fevers, chills, night sweats, fatigue, weight loss) and respiratory (e.g. difficulty breathing, cough) symptoms in association with filling of the lung alveoli that is visible on chest x-ray.[7] This presentation is usually so suggestive of an infection that the majority of patients with COP have been treated with at least one failed course of antibiotics by the time the true diagnosis is made.[7] ## Causes[edit] * Pulmonary infection by bacteria, viruses and parasites * Drugs: antineoplastic drugs, erlotinib, amiodarone * Chemical exposure, most notably to diacetyl[8] * Vaping: On October 17, 2019, the American Journal of Clinical Pathology reported that lung biopsies from patients with vaping-associated pulmonary illness show acute lung injury patterns, including organizing pneumonia.[9] * Ionizing radiations[10][11] * Inflammatory diseases * Systemic lupus * Rheumatoid arthritis (RA-associated COP) * Scleroderma * Bronchial obstruction * Proximal bronchial squamous cell carcinoma[12] * SARS-CoV-2 * Analysis of COVID-19 CT imaging along with postmortem lung biopsies and autopsies suggest that the majority of patients with COVID-19 pulmonary involvement also have secondary organizing pneumonia (OP) or its histological variant, acute fibrinous and organizing pneumonia, which are both well-known complications of viral infections. [13] It was identified in 1985, although its symptoms had been noted before but not recognised as a separate lung disease. The risk of COP is higher for people with inflammatory diseases like lupus, dermatomyositis, rheumatoid arthritis, and scleroderma.[14] ## Diagnosis[edit] On clinical examination, crackles are common, and more rarely, patients may have clubbing (<5% of cases). Laboratory findings are nonspecific. Almost 75% of people have symptoms for less than two months before seeking medical attention. A flu-like illness, with a cough, fever, a feeling of illness (malaise), fatigue, and weight loss heralds the onset in about 40% of patients. Doctors do not find any specific abnormalities on routine laboratory tests or on a physical examination, except for the frequent presence of crackling sounds (called rales) upon auscultation with a stethoscope by the care provider. Pulmonary function tests usually show that the amount of air the lungs can hold is below normal. The amount of oxygen in the blood is often low at rest and is even lower with exercise. ### Imaging[edit] CT scan showing cryptogenic organizing pneumonia (biopsy-proven) The reversed halo sign is seen in about 20% of individuals with COP.[15] The chest x-ray is distinctive with features that appear similar to an extensive pneumonia, with both lungs showing widespread white patches. The white patches may seem to migrate from one area of the lung to another as the disease persists or progresses. Computed tomography (CT) may be used to confirm the diagnosis. Often the findings are typical enough to allow the doctor to make a diagnosis without ordering additional tests.[16] To confirm the diagnosis, a doctor may perform a lung biopsy using a bronchoscope. Many times, a larger specimen is needed and must be removed surgically. Plain chest radiography shows normal lung volumes, with characteristic patchy unilateral or bilateral consolidation. Small nodular opacities occur in up to 50% of patients and large nodules in 15%. On high resolution computed tomography, airspace consolidation with air bronchograms is present in more than 90% of patients, often with a lower zone predominance. A subpleural or peribronchiolar distribution is noted in up to 50% of patients. Ground glass appearance or hazy opacities associated with the consolidation are detected in most patients. Pulmonary physiology is restrictive with a reduced diffusion capacity of the lung for carbon monoxide (DLCO). Airflow limitation is uncommon; gas exchange is usually abnormal and mild hypoxemia is common. Bronchoscopy with bronchoalveolar lavage reveals up to 40% lymphocytes, along with more subtle increases in neutrophils and eosinophils. In patients with typical clinical and radiographic features, a transbronchial biopsy that shows the pathologic pattern of organizing pneumonia and lacks features of an alternative diagnosis is adequate to make a tentative diagnosis and start therapy. On surgical lung biopsy, the histopathologic pattern is organizing pneumonia with preserved lung architecture; this pattern is not exclusive to COP and must be interpreted in the clinical context. Histologically, cryptogenic organizing pneumonia is characterized by the presence of polypoid plugs of loose organizing connective tissue (Masson bodies) within alveolar ducts, alveoli, and bronchioles. ## Unusual presentations of organizing pneumonia[edit] While patchy bilateral disease is typical, there are unusual variants of organizing pneumonia where it may appear as multiple nodules or masses. One rare presentation, focal organizing pneumonia, may be indistinguishable from lung cancer based on imaging alone, requiring biopsy or surgical resection to make the diagnosis.[17] ## Complications[edit] Rare cases of COP have induced with lobar cicatricial atelectasis.[18] ## Treatment[edit] Most patients recover with corticosteroid therapy.[19] A standardized approach to dosing starting at 0.75 mg/kg and weaning over 24 weeks has been shown to reduce total corticosteroid exposure without affecting outcome. About two thirds of patients recover with corticosteroid therapy: the usual corticosteroid administered is prednisolone in Europe and prednisone in the US; these differ by only one functional group and have the same clinical effect. The corticosteroid is initially administered in high dosage, typically 50 mg per day tapering down to zero over a six-month to one-year period.[citation needed] If the corticosteroid treatment is halted too quickly the disease may return. ## References[edit] 1. ^ "bronchiolitis obliterans with organizing pneumonia" at Dorland's Medical Dictionary 2. ^ White, Eric J. Stern, Charles S. (1999). Chest radiology companion. Philadelphia: Lippincott Williams & Wilkins. p. 76. ISBN 978-0-397-51732-9. 3. ^ https://www.merckmanuals.com/professional/pulmonary-disorders/interstitial-lung-diseases/cryptogenic-organizing-pneumonia 4. ^ Epler GR (June 2011). "Bronchiolitis obliterans organizing pneumonia, 25 years: a variety of causes, but what are the treatment options?". Expert Rev Respir Med. 5 (3): 353–61. doi:10.1586/ers.11.19. PMID 21702658. S2CID 207222916. 5. ^ [https://books.google.se/books?id=j-eYLc1BA3oC&pg=PA64 Page 64 in: Joseph F. Tomashefski, Carol Farver, Armando E. Fraire (2009). Dail and Hammar's Pulmonary Pathology: Volume I: Nonneoplastic Lung Disease (3 ed.). Springer Science & Business Media. ISBN 9780387687926.CS1 maint: multiple names: authors list (link) 6. ^ Geddes DM (August 1991). "BOOP and COP". Thorax. 46 (8): 545–7. doi:10.1136/thx.46.8.545. PMC 463266. PMID 1926020. 7. ^ a b "Pulmonary Question 27: Diagnose cryptogenic organizing pneumonia". MKSAP 5 For Students Online. American College of Physicians. Retrieved 23 November 2012. 8. ^ Levy, Barry S.; Wegman, David H.; Baron, Sherry L.; Sokas, Rosemary K., eds. (2011). Occupational and environmental health recognizing and preventing disease and injury (6th ed.). New York: Oxford University Press. p. 414. ISBN 9780199750061. Retrieved June 23, 2015. 9. ^ Mukhopadhyay, Sanjay; Mehrad, Mitra; Dammert, Pedro; Arrossi, Andrea V; Sarda, Rakesh; Brenner, David S; Maldonado, Fabien; Choi, Humberto; Ghobrial, Michael (2019). "Lung Biopsy Findings in Severe Pulmonary Illness Associated With E-Cigarette Use (Vaping): A Report of Eight Cases". American Journal of Clinical Pathology. 153 (1): 30–39. doi:10.1093/ajcp/aqz182. ISSN 0002-9173. PMID 31621873. 10. ^ Nogi, S; Nakayama, H; Tajima, Y; Okubo, M; Mikami, R; Sugahara, S; Akata, S; Tokuuye, K (2014). "Cryptogenic organizing pneumonia associated with radiation: A report of two cases". Oncology Letters. 7 (2): 321–324. doi:10.3892/ol.2013.1716. PMC 3881924. PMID 24396439. 11. ^ Oie, Y; Saito, Y; Kato, M; Ito, F; Hattori, H; Toyama, H; Kobayashi, H; Katada, K (2013). "Relationship between radiation pneumonitis and organizing pneumonia after radiotherapy for breast cancer". Radiation Oncology. 8: 56. doi:10.1186/1748-717X-8-56. PMC 3605133. PMID 23497657. 12. ^ Radzikowska, E; Nowicka, U; Wiatr, E; Jakubowska, L; Langfort, R; Chabowski, M; Roszkowski, K (2007). "Organising pneumonia and lung cancer - case report and review of the literature". Pneumonologia I Alergologia Polska. 75 (4): 394–7. PMID 18080991. 13. ^ Kory, Pierre; Kanne, Jeffrey P (2020-09-22). "SARS-CoV-2 organizing pneumonia:'Has there been a widespread failure to identify and treat this prevalent condition in COVID-19?'". BMJ. 7 (1). doi:10.1136/bmjresp-2020-000724. 14. ^ Al-Ghanem Sara; Al-Jahdali Hamdan; Bamefleh Hanaa; Khan Ali Nawaz (Apr–Jun 2008). "Bronchiolitis obliterans organizing pneumonia: Pathogenesis, clinical features, imaging and therapy review". Ann Thorac Med. 3 (2): 67–75. doi:10.4103/1817-1737.39641. PMC 2700454. PMID 19561910. 15. ^ Radswiki; et al. "Reversed halo sign (lungs)". Radiopaedia. Retrieved 2018-01-02. 16. ^ Zare Mehrjardi, Mohammad; Kahkouee, Shahram; Pourabdollah, Mihan (March 2017). "Radio-pathological correlation of organizing pneumonia (OP): a pictorial review". The British Journal of Radiology. 90 (1071): 20160723. doi:10.1259/bjr.20160723. ISSN 1748-880X. PMC 5601538. PMID 28106480. 17. ^ Oikonomou, A; Hansell, DM (2001). "Organizing pneumonia: the many morphological faces". European Radiology. 12 (6): 1486–96. doi:10.1007/s00330-001-1211-3. PMID 12042959. S2CID 10180778. 18. ^ Yoshida, K; Nakajima, M; Niki, Y; Matsushima, T (2001). "Atelectasis of the right lower lobe in association with bronchiolitis obliterans organizing pneumonia". Nihon Kokyuki Gakkai Zasshi = the Journal of the Japanese Respiratory Society. 39 (4): 260–5. PMID 11481825. 19. ^ Oymak FS, Demirbaş HM, Mavili E, et al. (2005). "Bronchiolitis obliterans organizing pneumonia. Clinical and roentgenological features in 26 cases". Respiration. 72 (3): 254–62. doi:10.1159/000085366. PMID 15942294. S2CID 71769382. ## External links[edit] Classification D * ICD-10: J84.0 * ICD-9-CM: 516.8 * MeSH: D018549 * DiseasesDB: 31684 External resources * eMedicine: radio/117 * "Idiopathic Interstitial Pneumonias". Merck Manual Professional. May 2008. * v * t * e Diseases of the respiratory system Upper RT (including URTIs, common cold) Head sinuses Sinusitis nose Rhinitis Vasomotor rhinitis Atrophic rhinitis Hay fever Nasal polyp Rhinorrhea nasal septum Nasal septum deviation Nasal septum perforation Nasal septal hematoma tonsil Tonsillitis Adenoid hypertrophy Peritonsillar abscess Neck pharynx Pharyngitis Strep throat Laryngopharyngeal reflux (LPR) Retropharyngeal abscess larynx Croup Laryngomalacia Laryngeal cyst Laryngitis Laryngopharyngeal reflux (LPR) Laryngospasm vocal cords Laryngopharyngeal reflux (LPR) Vocal fold nodule Vocal fold paresis Vocal cord dysfunction epiglottis Epiglottitis trachea Tracheitis Laryngotracheal stenosis Lower RT/lung disease (including LRTIs) Bronchial/ obstructive acute Acute bronchitis chronic COPD Chronic bronchitis Acute exacerbation of COPD) Asthma (Status asthmaticus Aspirin-induced Exercise-induced Bronchiectasis Cystic fibrosis unspecified Bronchitis Bronchiolitis Bronchiolitis obliterans Diffuse panbronchiolitis Interstitial/ restrictive (fibrosis) External agents/ occupational lung disease Pneumoconiosis Aluminosis Asbestosis Baritosis Bauxite fibrosis Berylliosis Caplan's syndrome Chalicosis Coalworker's pneumoconiosis Siderosis Silicosis Talcosis Byssinosis Hypersensitivity pneumonitis Bagassosis Bird fancier's lung Farmer's lung Lycoperdonosis Other * ARDS * Combined pulmonary fibrosis and emphysema * Pulmonary edema * Löffler's syndrome/Eosinophilic pneumonia * Respiratory hypersensitivity * Allergic bronchopulmonary aspergillosis * Hamman-Rich syndrome * Idiopathic pulmonary fibrosis * Sarcoidosis * Vaping-associated pulmonary injury Obstructive / Restrictive Pneumonia/ pneumonitis By pathogen * Viral * Bacterial * Pneumococcal * Klebsiella * Atypical bacterial * Mycoplasma * Legionnaires' disease * Chlamydiae * Fungal * Pneumocystis * Parasitic * noninfectious * Chemical/Mendelson's syndrome * Aspiration/Lipid By vector/route * Community-acquired * Healthcare-associated * Hospital-acquired By distribution * Broncho- * Lobar IIP * UIP * DIP * BOOP-COP * NSIP * RB Other * Atelectasis * circulatory * Pulmonary hypertension * Pulmonary embolism * Lung abscess Pleural cavity/ mediastinum Pleural disease * Pleuritis/pleurisy * Pneumothorax/Hemopneumothorax Pleural effusion Hemothorax Hydrothorax Chylothorax Empyema/pyothorax Malignant Fibrothorax Mediastinal disease * Mediastinitis * Mediastinal emphysema Other/general * Respiratory failure * Influenza * Common cold * SARS * Coronavirus disease 2019 * Idiopathic pulmonary haemosiderosis * Pulmonary alveolar proteinosis * v * t * e Pneumonia Infectious pneumonias * Bacterial pneumonia * Viral pneumonia * Fungal pneumonia * Parasitic pneumonia * Atypical pneumonia * Community-acquired pneumonia * Healthcare-associated pneumonia * Hospital-acquired pneumonia * Ventilator-associated pneumonia * Severe acute respiratory syndrome Pneumonias caused by infectious or noninfectious agents * Aspiration pneumonia * Lipid pneumonia * Eosinophilic pneumonia * Bronchiolitis obliterans organizing pneumonia Noninfectious pneumonia * Chemical pneumonitis * Idiopathic pneumonia 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	Cryptogenic organizing pneumonia	c0242770	1,734	wikipedia	https://en.wikipedia.org/wiki/Cryptogenic_organizing_pneumonia	2021-01-18T18:51:23	{"gard": ["1620", "5961"], "mesh": ["D018549"], "umls": ["C0242770"], "orphanet": ["1302"], "wikidata": ["Q2012642"]}
## Summary ### Clinical characteristics. For the purposes of this chapter, NFIA-related disorder is defined as heterozygous inactivation or disruption of only NFIA without involvement of adjacent or surrounding genes. NFIA-related disorder comprises central nervous system abnormalities (most commonly abnormalities of the corpus callosum) with or without urinary tract defects, such as unilateral or bilateral vesicoureteral reflux and hydronephrosis. Additional features include macrocephaly, seizures, developmental delay and/or cognitive impairment, nonspecific dysmorphic features, ventriculomegaly, and hypotonia, which can exacerbate motor delay and feeding issues in infancy. Rarer features may include strabismus, cutis marmorata, or craniosynostosis of the metopic, lambdoid, or sagittal suture. ### Diagnosis/testing. The diagnosis of NFIA-related disorder is established in a proband by detection of one of the following: a heterozygous intragenic NFIA pathogenic variant; a heterozygous deletion of the 1p31.3 region that includes part or all of NFIA with surrounding genes intact; or a chromosome translocation/other rearrangement with a 1p31.3 breakpoint that disrupts NFIA. ### Management. Treatment of manifestations: Standard treatment of seizure disorder, tethered spinal cord, recurrent urinary tract infections, hydronephrosis, strabismus, craniosynostosis, and developmental delays. Surveillance: Affected individuals should be followed by the appropriate specialists (e.g., neurologist, urologist, and/or clinical geneticist) as needed based on their particular features. ### Genetic counseling. NFIA-related disorder is inherited in an autosomal dominant manner. Each child of an individual with NFIA-related disorder has a 50% chance of inheriting the causative genetic alteration. The proportion of NFIA-related disorder caused by de novo variants is approximately 75%-80%. Prenatal diagnosis for a pregnancy at increased risk is possible if the causative genetic alteration in an affected family member is known. ## Diagnosis NFIA-related disorder is defined here as heterozygous inactivation or disruption of only NFIA; larger, nonrecurrent chromosome 1p32-p31 deletions are discussed in Genetically Related Disorders. ### Suggestive Findings An NFIA-related disorder should be suspected in individuals with the following clinical and radiographic findings. Clinical features * Macrocephaly * Seizures including: * Generalized tonic-clonic * Pseudo-seizures * Nonspecific seizure disorders * Hypotonia (generalized/neonatal) * Developmental delay * Frequent urinary tract infections * Nonspecific dysmorphic features (see Clinical Characteristics) * Other, less common findings, including eye abnormalities (e.g., strabismus) or cutis marmorata Radiographic abnormalities * Brain * Abnormalities of the corpus callosum including agenesis or hypoplasia of the corpus callosum * Ventriculomegaly (typically non-progressive) * Hydrocephalus * Less commonly, Chiari type I malformation and/or subarachnoid hemorrhage * Urinary tract * Vesicoureteral reflux * Hydronephrosis * Renal cysts * Spine. Tethered spinal cord * Skull. Rarely, craniosynostosis, which may involve the metopic, lambdoid, or sagittal sutures ### Establishing the Diagnosis The diagnosis of NFIA-related disorder (defined here as heterozygous inactivation or disruption of only NFIA) is established in a proband by detection of one of the following (see Table 1): * Heterozygous intragenic NFIA pathogenic variant * Heterozygous deletion of the 1p31.3 region that includes part or all of NFIA with surrounding genes intact * Chromosome translocation / other rearrangement with a 1p31.3 breakpoint that disrupts NFIA Note: Molecular testing by CMA or karyotyping may detect a large and/or complex heterozygous rearrangement that inactivates NFIA and one or more (often adjacent) genes. Because individuals with such rearrangements (sometimes termed the chromosome 1p32-p31 deletion syndrome) have additional features, they are not the focus of this GeneReview and are described in Genetically Related Disorders. Molecular genetic testing approaches can include a combination of chromosomal microarray analysis (CMA), a multigene panel, and exome or genome sequencing: * If not already performed, CMA may be obtained to detect genome-wide deletions that include NFIA. The ability to determine the size of the deletion depends on the type of microarray used, the density of the probes in the 1p31.3 region, and the size cutoff for reporting. The genomic size of the NFIA locus is 380 kb. * A multigene panel that includes NFIA and other genes of interest (see Differential Diagnosis) may be considered. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview; thus, clinicians need to determine which multigene panel is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. (3) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests. For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here. * More comprehensive genomic testing (when available) including exome sequencing and genome sequencing may be considered. Such testing may provide or suggest a diagnosis not previously considered (e.g., mutation of a different gene or genes that results in a similar clinical presentation). For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here. Karyotype. If clinical suspicion is high and other molecular genetic testing methods have not identified a pathogenic variant involving NFIA, a high-resolution karyotype to detect a balanced chromosomal rearrangement involving the 1p31 region, followed by custom MLPA to confirm deletion of NFIA, or sequencing of the breakpoints to confirm disruption of NFIA, could be considered. ### Table 1. Molecular Genetic Testing Used in NFIA-Related Disorder View in own window Gene 1MethodProportion of Probands with a Pathogenic Variant 2 Detectable by Method NFIASequence analysis 35/13 4, 5 Gene-targeted deletion/duplication analysis 6See footnotes 7 & 8 CMA 95/13 5, 10 Karyotype 113/13 12 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\. Iossifov et al [2012], Negishi et al [2015], Revah-Politi et al [2017] 5\. The number of probands is 13; some probands have other affected family members. The total number of individuals reported with NFIA-related disorder is 20 (see Revah-Politi et al [2017], Table 2). 6\. Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. 7\. Intragenic deletions that affect one or multiple exons within NFIA but disrupt no other genes have been identified in five probands [Mikhail et al 2011, Rao et al 2014, Nyboe et al 2015, Bayat et al 2017, Hollenbeck et al 2017]. 8\. Gene-targeted methods will detect single-exon up to whole-gene deletions; however, breakpoints of large deletions and/or deletion of adjacent genes may not be determined. 9\. Chromosomal microarray analysis (CMA) using oligonucleotide arrays or SNP arrays. CMA designs in current clinical use typically cover the 1p31.3 region. 10\. Lu et al [2007], Mikhail et al [2011], Rao et al [2014], Nyboe et al [2015], Coci et al [2016], Bayat et al [2017], Hollenbeck et al [2017] 11\. Karyotype can detect balanced chromosome rearrangements that are not detectable through chromosomal microarray analysis. 12\. Chromosome rearrangements, including translocations and inversions, which disrupt NFIA (in some cases, shown to result in deletions at the breakpoints), have been identified in three probands [Lu et al 2007, Coci et al 2016]. Note: For NFIA somatic variants, see Genetically Related Disorders, Cancer and benign tumors. ## Clinical Characteristics ### Clinical Description NFIA-related disorder comprises central nervous system abnormalities (see Suggestive Findings) with or without urinary tract defects. Additional features include macrocephaly, seizures, developmental delay, dysmorphic features (see below), ventriculomegaly, and hypotonia. Central nervous system (CNS) abnormalities. Abnormalities of the corpus callosum are the most consistent feature of this disorder, present in virtually all affected individuals (all but one published individual to date). These abnormalities can include agenesis of the corpus callosum, hypoplasia of the corpus callosum, or other defects (including dysgenesis of the corpus callosum, agenesis of the rostral part of the corpus callosum, or thin corpus callosum). Other CNS phenotypes that may be present include non-progressive ventriculomegaly, hydrocephalus, Chiari type I malformation, and tethered spinal cord. Less common CNS findings include polymicrogyria and decreased periventricular white matter. There appears to be variable expressivity of the CNS phenotype, with no one affected individual presenting with all of the different features listed here. Seizures are present in approximately half of reported individuals. The types of seizures range from tonic-clonic seizures [Lu et al 2007] to pseudo-seizures [Revah-Politi et al 2017] to nonspecific seizure disorders [Lu et al 2007, Revah-Politi et al 2017]. Developmental delay, ranging from mild to severe, includes both motor and speech delays. Some affected individuals also have hypotonia, which can exacerbate motor delays and feeding issues (particularly in infancy). Despite early delays, most affected individuals are able to walk and use verbal language to communicate. The oldest reported affected individual was a male age 42 years (father of the proband in Nyboe et al [2015]) who was not reported to have any developmental delays. Of probands with developmental delay, the oldest reported individual was a female age 25 years, who at the time of evaluation was experiencing some cognitive delays and behavioral issues [Mikhail et al 2011]. Behavioral abnormalities reported in affected individuals include autism [Iossifov et al 2012, Revah-Politi et al 2017] and bipolar disorder / depression [Mikhail et al 2011, Revah-Politi et al 2017]. Intellectual disability (which may be mild) has also been reported [Mikhail et al 2011, Coci et al 2016, Hollenbeck et al 2017]. Urinary tract defects described in individuals with NFIA-related disorder most commonly include vesicoureteral reflux and hydronephrosis (which may be unilateral or bilateral); additional phenotypes include pyelonephritis, ureterovesical junction diverticulum, dysplastic kidneys, and renal cysts. Sometimes the defects manifest as recurrent urinary tract infections. Urinary tract defects are present in approximately half of affected individuals [Revah-Politi et al 2017], with reported intrafamilial variation [Nyboe et al 2015, Revah-Politi et al 2017]. Dysmorphic features associated with NFIA-related disorder are typically described as mild and have variable penetrance. Recurrent features include relative macrocephaly, frontal bossing / prominent forehead, low-set ears, and proximally placed first digits [Revah-Politi et al 2017]. Eye abnormalities have been reported in rare instances and include strabismus divergens in two individuals [Coci et al 2016], ptosis in two individuals [Coci et al 2016, Hollenbeck et al 2017], and esotropia in one individual [Hollenbeck et al 2017]. Dermatologic findings. Cutis marmorata has been reported in one individual with an intragenic deletion of NFIA [Rao et al 2014]. Note: Cutis marmorata has been described in multiple individuals with deletions that include NFIA and surrounding genes (see Genetically Related Disorders), suggesting the existence of another rare phenotype associated with NFIA haploinsufficiency. Craniosynostosis has been seen in a minority of individuals with NFIA pathogenic variants [Rao et al 2014, Nyboe et al 2015]. Types of craniosynostosis reported include metopic, lambdoid, and sagittal. Prognosis. It is unknown if life span in NF1A-related disorder is abnormal. One reported individual is alive at age 42 years [Nyboe et al 2015], demonstrating that survival into adulthood is possible. Since many adults with disabilities have not undergone advanced genetic testing, it is likely that adults with this condition are underrecognized and underreported. ### Genotype-Phenotype Correlations No genotype-phenotype correlations have been identified to date, with the exception of individuals who have larger, nonrecurrent 1p31.3 deletions that include NFIA and other, often adjacent, genes (see Genetically Related Disorders) [Lu et al 2007, Koehler et al 2010, Chen et al 2011, Ji et al 2014, Labonne et al 2016]. ### Nomenclature Early reports that identified deletions affecting NFIA referred to the phenotypic presentation as "chromosome 1p32-p31 deletion syndrome" or "chromosome 1p31 deletion." The identification of intragenic deletions and single-nucleotide variants within NFIA that lead to a similar phenotypic presentation have demonstrated that loss of function of NFIA is responsible for most of the phenotypes associated with the 1p31 deletion. NFIA-related disorder is referred to as "brain malformations with or without urinary tract defects" (BRMUTD) in OMIM (613735). ### Prevalence NFIA-related disorder is rare, having been described in only 13 families representing 20 affected individuals. ## Differential Diagnosis ### Table 2. Disorders to Consider in the Differential Diagnosis of NFIA-Related Disorder View in own window Differential Diagnosis DisorderGene(s)MOIClinical Features of the Differential Diagnosis Disorder Overlapping w/NFIA-related disorderDistinguishing from NFIA-related disorder Sotos syndrome 1NSD1AD * Macrocephaly * Ventriculomegaly * DD * Brain malformations incl partial-to-complete agenesis of corpus callosum * No urinary tract defects * Sotos syndrome typically includes distinctive facial appearance & overgrowth. Acquired macrocephaly w/impaired intellectual development (OMIM 618286)NFIBAD * Macrocephaly * DD * Minor dysmorphic features * Brain malformations incl dysgenesis of corpus callosum * Neurodevelopmental phenotypes No urinary tract defects (in affected individuals reported to date) Malan syndrome 2 (OMIM 614753)NFIXAD * Macrocephaly * Ventriculomegaly * DD * Brain malformations incl hypoplasia of corpus callosum Individuals w/Malan syndrome generally have an overgrowth phenotype. Joubert syndrome 9CC2D2AAR * Ventriculomegaly w/seizures in some affected individuals * Agenesis of corpus callosum * Hydrocephalus * Renal disease * Typically more severe than NFIA-related disorder * Characteristic MRI findings ("molar tooth sign") * Eye abnormalities Stromme syndrome (OMIM 243605)CENPFAR * Hydrocephalus * Agenesis of corpus callosum * Renal abnormalities incl hydronephrosis * Typically more severe than NFIA-related disorder * Intestinal atresia * Ocular abnormalities * Microcephaly * Cardiac involvement AD = autosomal dominant; AR = autosomal recessive; DD = developmental delay; MOI = mode of inheritance 1\. Because Sotos syndrome and Malan syndrome have overlapping features, Sotos syndrome is sometimes referred to as Sotos syndrome 1. 2\. Malan syndrome is also referred to as Sotos syndrome 2. ## Management ### Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with NFIA-related disorder, the evaluations summarized in Table 3 (if not performed as part of the evaluation that led to diagnosis) are recommended. ### Table 3. Recommended Evaluations Following Initial Diagnosis in Individuals with NFIA-Related Disorder View in own window System/ConcernEvaluationComment NeurologicBrain MRITo evaluate for brain anomalies, incl Chiari type I malformation Spinal imaging 1To evaluate for tethered cord EEGIf seizures are suspected; referral to neurologist if EEG is abnormal or if strong suspicion of seizures DevelopmentDevelopmental assessmentTo incl motor, adaptive, cognitive, & speech/language evaluation Evaluation for early intervention / special education Psychiatric/ BehavioralNeuropsychiatric evaluationFor individuals age >12 mos: screen for behavior concerns incl sleep disturbances, ADHD, anxiety, &/or traits suggestive of ASD. Gastrointestinal/ FeedingConsider feeding evaluation for feeding problems related to hypotonia.1 reported individual w/NFIA-related disorder was able to tolerate only a soft diet at age 5 yrs but could eat other foods by age 8 yrs. 2 GenitourinaryRenal ultrasoundTo detect renal anomalies Consider voiding cystourethrogram.In those w/suggestive renal ultrasound findings or w/urinary tract infections EyesOphthalmologic evaluationFor possible strabismus CraniofacialConsider craniofacial 3D-computed tomographic scanning in those w/abnormal head shape.Consider referral to craniofacial team if concern for craniosynostosis. Miscellaneous/ OtherConsultation w/clinical geneticist &/or genetic counselorTo incl genetic counseling Family support/resourcesUse of community or online resources such as Parent to Parent ADHD = attention-deficit/hyperactivity disorder; ASD = autism spectrum disorder 1\. The choice of imaging depends on the age of the affected individuals. In infants <3 months of age, spinal ultrasound may be used. In those >3 months of age, typically spinal MRI is required. 2\. Shanske et al [2004], Lu et al [2007] ### Treatment of Manifestations ### Table 4. Treatment of Manifestations in Individuals with NFIA-Related Disorder View in own window Manifestation/ConcernTreatmentConsiderations/Other SeizuresStandard treatment w/AEDs by experienced neurologistMany different AEDs may be effective; no one AED has been demonstrated effective specifically for this disorder. Tethered spinal cordStandard treatment per neurosurgeon Developmental delay / intellectual disabilitySee Developmental Delay / Intellectual Disability Management Issues. Recurrent urinary tract infections &/or hydronephrosisStandard treatment per urologist StrabismusStandard treatment per ophthalmologist CraniosynostosisStandard treatmentConsider referral to a craniofacial team w/experience in treating craniosynostosis. AEDs = antiepileptic drugs #### Developmental Delay / Intellectual Disability Management Issues The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States (US); 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. In the US, early intervention is a federally funded program available in all states. Ages 3-5 years. In the US, developmental preschool through the local public school district is recommended. Before placement, an evaluation is made to determine needed services and therapies and an individualized education plan (IEP) is developed. Ages 5-21 years * In the US, an IEP based on the individual's level of function should be developed by the local public school district. Affected children are permitted to remain in the public school district until age 21. * Discussion about transition plans including financial, vocation/employment, and medical arrangements should begin at age 12 years. Developmental pediatricians can provide assistance with transition to adulthood. All ages. Consultation with a developmental pediatrician is recommended to ensure the involvement of appropriate community, state, and educational agencies 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. 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. If feeding difficulty is present, particularly in infancy, referral to an occupational or speech therapist for evaluation and treatment, including feeding therapy, is recommended. At least one individual with NFIA-related disorder has been reported with a history of feeding issues [Shanske et al 2004, Lu et al 2007]. Communication issues. Consider evaluation for alternative means of communication (e.g., Augmentative and Alternative Communication [AAC]) for individuals who have expressive language difficulties. #### Social/Behavioral Concerns Children may qualify for and benefit from interventions used in treatment of autism spectrum disorder, including applied behavior analysis (ABA). ABA therapy is targeted to the individual child's behavioral, social, and adaptive strengths and weaknesses and is typically performed one on one with a board-certified behavior analyst. Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications, such as medication used to treat ADHD, when necessary. ### Surveillance Following initial evaluation, affected individuals should be followed by the appropriate specialists (e.g., neurologist, urologist, and/or clinical geneticist) as needed based on their particular features. ### Evaluation of Relatives at Risk It is appropriate to clarify the genetic status of apparently asymptomatic older and younger at-risk relatives of an affected individual by molecular genetic testing for the genetic alteration identified in the proband in order to identify as early as possible those who would benefit from prompt initiation of treatment. 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	NFIA-Related Disorder	None	1,735	gene_reviews	https://www.ncbi.nlm.nih.gov/books/NBK542336/	2021-01-18T21:09:14	{"synonyms": ["NFIA Haploinsufficiency"]}
A number sign (#) is used with this entry because of evidence that autosomal dominant medullary cystic kidney disease-1 (MCKD1) is caused by heterozygous mutation in the MUC1 gene (158340) on chromosome 1q22. Description Medullary cystic kidney disease (MCKD) is an autosomal dominant form of tubulointerstitial nephropathy characterized by formation of renal cysts at the corticomedullary junction. It is characterized by adult onset of impaired renal function and salt wasting resulting in end-stage renal failure by the sixth decade (Wolf et al., 2004). Although early reports suggested that medullary cystic kidney disease and familial juvenile nephronophthisis (NPHP1; 256100) represented the same disease entity because of the overlapping phenotype (Chamberlin et al., 1977), they are now considered to be distinct disorders. MCKD has adult onset and shows autosomal dominant inheritance, whereas NPHP1 has juvenile onset and shows autosomal recessive inheritance (Christodoulou et al., 1998). NPHP1 is caused by mutation in the nephrocystin gene (NPHP1; 607100) on chromosome 2q13. ### Genetic Heterogeneity of Medullary Cystic Kidney Disease See also MCKD2 (603860), which is caused by mutation in the UMOD gene (191845) on chromosome 16p. Clinical Features Thorn et al. (1944) are credited with the first description of medullary cystic renal disease under the designation 'salt-losing nephritis.' They noted an association with red and blond hair. Rayfield and McDonald (1972) also recognized the association between medullary cystic disease and red and blond hair. Smith and Graham (1945) reported an isolated case. Goldman et al. (1966) described a kindred with 17 affected members spanning 5 generations. Fifteen had died in the second decade of life with rapid clinical deterioration after the onset of symptoms. The kidneys showed thin cortices, prominent glomerular hyalinization, numerous corticomedullary and intramedullary cysts lined by low cuboidal epithelium, and increase in medullary connective tissue. The authors noted differences from polycystic kidney disease (see 173900), such as the absence of flank pain, and the presence of hypertension and small kidneys. Gardner (1971) reported 2 extensively affected sibships. The average age of onset of symptoms was 23 years in one and 35 years in the second. The average duration of illness was only 2.2 years. Wrigley et al. (1973) described a family with somewhat later onset of medullary cystic kidney disease. Whelton et al. (1974) reported another affected family. Giangiacomo et al. (1975) presented a family in which the onset of autosomal dominant MCKD was unusually early. Stavrou et al. (1998) reported a large Cypriot family in which at least 23 members spanning 4 generations had interstitial nephropathy inherited in an autosomal dominant pattern. Ten patients were deceased. Clinical features were variable and included renal medullary cysts, hypertension, hyperuricemia, and gout. Urinalysis of 10 patients showed no hematuria, pyuria, or casts. The mean age at onset of end-stage renal disease (ESRD) was 62 years. Two renal biopsies showed interstitial fibrosis and severe tubular atrophy consistent with a primary tubulointerstitial process. There was also periglomerular fibrosis with a few sclerotic glomeruli. Linkage analysis excluded the NPHP1 locus on 2q13 and the PKD1 locus (601313) on 16p. Ala-Mello et al. (1999) used the term 'nephronophthisis' for both the dominant disorder called medullary cystic disease and recessive juvenile nephronophthisis (NPHP1). The dominant form was characterized by later age at onset of first symptoms, at start of dialysis, and at transplantation. In a survey of 59 cases ascertained in Finland, 17 came from 4 families showing dominant inheritance and 37 came from apparently recessive families; 2 were considered new dominant mutations, and 3 sporadic cases could not be classified. Parvari et al. (2001) studied a family of Jewish ancestry in which 15 members spanning 4 generations had chronic renal failure with onset between 18 and 38 years of age. Hypertension was often the presenting sign, followed by progressive renal insufficiency. No polyuria, anemia, gout, hematuria, or proteinuria were seen. An average of 4.5 years elapsed between diagnosis and end-stage renal disease. Renal pathology at early stages of the disease showed extensive tubulointerstitial fibrosis and global glomerulosclerosis. Wolf et al. (2004) reported a Belgian kindred with MCKD. Age at presentation ranged from 29 to 53 years, and age at ESRD varied between 34 and 49 years. First symptoms included polyuria, polydipsia, and anemia. One patient had hypertension and 2 had hyperuricemia. Gout was not reported. Variable ultrasound findings included small kidneys and small medullary cysts. Kiser et al. (2004) reported a large Native American kindred in which 12 living members had MCKD1 confirmed by linkage analysis. Age at onset of renal insufficiency ranged from 34 to 65 years and age at development of ESRD ranged from 35 to 66 years. No patient presented with polyuria, polydipsia, or urinary salt wasting; most presented with abnormal laboratory data obtained for other reasons. Other features included gout (61%), hypertension (55%), and anemia (39%). Ultrasound detected renal cysts in 44% of patients, and renal biopsies of 4 patients showed interstitial fibrosis, interstitial inflammation, tubular atrophy, and glomerulosclerosis. Only 2 patients had significant proteinuria on urinalysis. Kirby et al. (2013) reported 6 unrelated families with MCKD1, including the families previously reported by Kiser et al. (2004) and Kimmel et al. (2005). Affected individuals had slowly progressive kidney dysfunction beginning in adulthood, absent or low grade proteinuria with bland urinary sediments, decreased glomerular filtration rate, and absence of other association signs or symptoms of systemic disease. Hypertension tended to occur only after onset of chronic renal failure. Hematuria was typically not present. Renal biopsies showed tubulointerstitial fibrosis and tubular atrophy, and renal ultrasounds occasionally showed cortical cysts, but cysts were often not present. Diagnosis Kiser et al. (2004) noted that the diagnosis of MCKD is difficult because initial signs and symptoms may be mild or vague, symptoms of frank renal failure occur late, renal cysts may be absent in over 50% of patients, and renal histologic abnormalities are nonspecific. Inheritance The transmission pattern of MCKD1 in the families reported by Kirby et al. (2013) was consistent with autosomal dominant inheritance. Mapping By genomewide linkage analysis of 2 Cypriot families with adult-onset autosomal dominant MCKD, including the family reported by Stavrou et al. (1998), Christodoulou et al. (1998) identified a candidate disease locus, MCKD1, on chromosome 1q21 (2-point lod score of 6.45 and multipoint lod score of 9.41 at marker D1S1595). Analysis of haplotypes and of critical recombinants refined the locus to an 8-cM interval between D1S498 and D1S2125. The 2 families shared the same disease haplotype, suggesting a common ancestor. Parvari et al. (2001) found linkage to the MCKD1 locus on 1q21 (maximum 2-point lod score of 3.82 at D1S394) in a family of Jewish ancestry in which 15 members spanning 4 generations had chronic renal failure. The report established a relationship between an autosomal dominant nephropathy characterized by hypertension and progressive renal failure and autosomal dominant medullary cystic kidney disease associated with macroscopic corticomedullary cysts, salt-losing tubulointerstitial nephropathy, and anemia. By haplotype analysis of a British kindred with MCKD, Fuchshuber et al. (2001) refined the MCKD1 locus to a 4-cM (3.3-Mb) interval between D1S305 and D1S2635. Molecular analysis excluded mutations in the HAX1 gene (605998) in 1 family. By high-resolution haplotype analysis of 3 families with MCKD, including the original Arizona kindred reported by Gardner (1971), the Welsh family reported by Fuchshuber et al. (2001), and a family from the Dutch/German border, Wolf et al. (2003) detected extensive haplotype sharing across the MCKD1 critical gene region. The data enabled refinement of the disease interval to less than 650 kb. Genealogy of the Arizona kindred showed that they originated from Germany in the 17th century, thereby providing historical data for haplotype sharing by descent at the MCKD1 locus. By analysis of an affected Belgian kindred, Wolf et al. (2004) further refined the MCKD1 critical region to a 2.1-Mb interval on 1q21 with a telomeric marker at D1S2624. Kimmel et al. (2005) reported a large family in which bipolar disorder (MAFD1; 125480) appeared to cosegregate with autosomal dominant medullary cystic kidney disease. Of the 7 members with kidney disease, 5 had bipolar I disorder, one had unipolar depression, and 1 had a hyperthymic phenotype. The authors noted that the 2 known loci of medullary cystic kidney disease are in regions of chromosome 1 (MCKD1) and 16 (MCDK2; 603860) that had previously been linked to bipolar disorder and schizophrenia. Molecular Genetics In 16 kindreds with MCKD, Wolf et al. (2006) failed to identify pathogenic sequence changes in 37 genes within the MCKD1 critical region. In affected members of 6 unrelated families with autosomal dominant medullary cystic kidney disease-1, Kirby et al. (2013) identified a heterozygous 1-bp insertion of a cytosine in 1 copy of an extremely long (1.5-5.0 kb) GC-rich coding variable number tandem repeat (VNTR) sequence in the MUC1 gene (158340.0001). The insertion was within a stretch of 7 cytosines occurring at positions 53-59 in a single copy of the canonical 60-mer repeat. The insertion of cytosine occurred in a different VNTR size in each family, indicating independent occurrence of the mutations. Some of the families had previously been reported (e.g., by Kiser et al., 2004). The insertion was predicted to cause a frameshift, resulting in a mutant protein with many copies of a novel repeat sequence, but lacking a downstream self-cleavage module and both the transmembrane and intracellular domains characteristic of the wildtype MUC1 precursor protein. Full genotyping of this region showed that the mutation segregated with the risk-associated haplotype in each family, but was not found in over 500 controls from various populations. A similar cytosine insertion was found in 13 of 21 additional families with the disorder who were studied, consistent with it being a fully penetrant cause of disease. Antibodies against a peptide synthesized to correspond to the predicted mutant VNTR sequence showed specific intracellular staining in epithelial cells from the loop of Henle, distal tubule, and collecting duct of patients that was not seen in controls. The mutant MUC1 showed partial colcalization with wildtype MUC1 in the collecting duct of a patient. Kirby et al. (2013) emphasized that the mutation was missed by massively parallel sequencing and was found only by diligent analysis of the linked region using cloning, Southern blot analysis, long-range PCR, and reconstruction of the VNTR allele in patients and controls. INHERITANCE \- Autosomal dominant CARDIOVASCULAR Vascular \- Hypertension \- Hypotension may occur late in disease due to salt wasting GENITOURINARY Kidneys \- Impaired renal function \- Impaired renal creatinine clearance \- Impaired renal uric acid clearance \- Salt wasting \- Small kidneys \- Tubulointerstitial nephritis \- Tubulointerstitial fibrosis \- Interstitial inflammation \- Glomerulosclerosis \- Renal biopsy shows medullary cysts \- Corticomedullary cysts \- Cysts may be absent in over 50% of patients \- Tubular atrophy \- Cortical atrophy \- Disintegration of the tubular basement membrane \- Progression to end stage renal failure in late adulthood (fifth to seventh decade) METABOLIC FEATURES \- Gout HEMATOLOGY \- Anemia LABORATORY ABNORMALITIES \- Hyperuricemia \- Increased serum creatinine \- Decreased glomerular filtration rate (GFR) MISCELLANEOUS \- Adult onset (range 34 to 66 years) MOLECULAR BASIS \- Caused by mutation in the transmembrane mucin 1 gene (MUC1, 158340.0001 ). ▲ 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	MEDULLARY CYSTIC KIDNEY DISEASE 1	c1868139	1,736	omim	https://www.omim.org/entry/174000	2019-09-22T16:36:03	{"mesh": ["C536137"], "omim": ["174000"], "icd-10": ["Q61.5"], "orphanet": ["88949", "34149"], "synonyms": ["ADTKD-MUC1", "MUC1-related autosomal dominant medullary cystic kidney disease", "POLYCYSTIC KIDNEYS, MEDULLARY TYPE", "Alternative titles", "MUCI-related ADTKD", "Medullary cystic kidney disease type 1", "ADTKD", "Autosomal dominant medullary cystic kidney disease", "MEDULLARY CYSTIC KIDNEY DISEASE, AUTOSOMAL DOMINANT", "MCKD1", "MCKD"], "genereviews": ["NBK153723"]}
Morgagni Stewart Morel syndrome Other namesHyperostosis frontalis interna,' Metabolic craniopathy Morgagni Stewart Morel syndrome is inherited in an X-linked recessive manner(or autosomal dominant).[1] SpecialtyEndocrinology Morgagni-Stewart-Morel syndrome is a condition with a wide range of associated endocrine problems including: diabetes mellitus, diabetes insipidus, and hyperparathyroidism.[2] Other signs and symptoms include headaches, vertigo, hirsutism, menstrual disorder, galactorrhoea, obesity, depression, and seizures.[2] Thickening of the inner table of the frontal part of the skull a usually benign condition known as hyperostosis frontalis interna.[2][3] The syndrome was first described in 1765.[3] It is named after the Italian anatomist and pathologist Giovanni Battista Morgagni, the British neurologist Roy Mackenzie Stewart, and the Swiss psychiatrist Ferdinand Morel. ## Contents * 1 Diagnosis * 2 Treatment * 3 References * 4 External links ## Diagnosis[edit] The diagnosis of Morgagni-Stewart-Morel is based upon a radiological finding of hyperostosis frontalis interna. Diagnosis considers a combination of clinical features including obesity,[4] virilism, and mental disturbances.[5] ## Treatment[edit] Treatment is based upon the symptoms, and generally includes medication, diet and lifestyle modification for weight control. Seizures and headaches associated with hyperostosis frontalis interna (HFI) are treated with standard medications.[6] ## References[edit] 1. ^ INSERM US14. "Morgagni Stewart Morel syndrome". Orphanet. Retrieved 1 November 2017. 2. ^ a b c Nallegowda M, Singh U, Khanna M, Yadav SL, Choudhary AR, Thakar A (March 2005). "Morgagni Stewart Morel syndrome—additional features". Neurol India. 53 (1): 117–9. doi:10.4103/0028-3886.15078. hdl:1807/7758. PMID 15805672. 3. ^ a b She R, Szakacs J (2004). "Hyperostosis frontalis interna: case report and review of literature". Ann. Clin. Lab. Sci. 34 (2): 206–8. PMID 15228235. 4. ^ "Obesity: MedlinePlus Medical Encyclopedia". medlineplus.gov. Retrieved 2018-04-17. 5. ^ "Morgagni-Stewart-Morel syndrome \| Genetic and Rare Diseases Information Center (GARD) – an NCATS Program". rarediseases.info.nih.gov. Retrieved 2018-04-17. 6. ^ "Morgagni-Stewart-Morel syndrome \| Genetic and Rare Diseases Information Center (GARD) – an NCATS Program". rarediseases.info.nih.gov. Retrieved 2018-04-17. ## External links[edit] Classification D * ICD-10: M85.2 * OMIM: 144800 External resources * Orphanet: 77296 [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor *[BMI]: body mass index	Morgagni Stewart Morel syndrome	c0020494	1,737	wikipedia	https://en.wikipedia.org/wiki/Morgagni_Stewart_Morel_syndrome	2021-01-18T18:48:11	{"gard": ["8593"], "mesh": ["D006957"], "umls": ["C0020494"], "orphanet": ["77296"], "wikidata": ["Q9178742"]}
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) Some of this article's listed sources may not be reliable. Please help this article by looking for better, more reliable sources. Unreliable citations may be challenged or deleted. (July 2012) (Learn how and when to remove this template message) 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. (July 2012) (Learn how and when to remove this template message) (Learn how and when to remove this template message) Acute inhalation injury may result from frequent and widespread use of household cleaning agents and industrial gases (including chlorine and ammonia). The airways and lungs receive continuous first-pass exposure to non-toxic and irritant or toxic gases via inhalation. Irritant gases are those that, on inhalation, dissolve in the water of the respiratory tract mucosa and provoke an inflammatory response, usually from the release of acidic or alkaline radicals.[1][2] Smoke, chlorine, phosgene, sulfur dioxide, hydrogen chloride, hydrogen sulfide, nitrogen dioxide, ozone, and ammonia are common irritants. Depending on the type and amount of irritant gas inhaled, victims can experience symptoms ranging from minor respiratory discomfort to acute airway and lung injury and even death. A common response cascade to a variety of irritant gases includes inflammation, edema and epithelial sloughing, which if left untreated can result in scar formation and pulmonary and airway remodeling. Currently, mechanical ventilation remains the therapeutic mainstay for pulmonary dysfunction following acute inhalation injury. ## Contents * 1 Causes * 1.1 Smoke inhalation * 1.2 Chlorine * 1.3 Phosgene * 1.4 Ammonia * 1.5 Mustard gas * 1.6 Chloramine * 1.7 Methyl isocyanate * 2 Pathophysiology * 2.1 Acute lung injury * 2.2 Acute respiratory distress syndrome * 3 Treatment strategies * 4 Preclinical development of pulmonary protective strategies * 4.1 In vitro * 4.2 In vivo * 5 References ## Causes[edit] ### Smoke inhalation[edit] Smoke inhalation injury, either by itself but more so in the presence of body surface burn, can result in severe lung-induced morbidity and mortality.[3] The most common cause of death in burn centers is now respiratory failure. The September 11 attacks in 2001 and forest fires in U.S. states such as California and Nevada are examples of incidents that have caused smoke inhalation injury.[4][5] Injury to the lungs and airways is not only due to deposition of fine particulate soot but also due to the gaseous components of smoke, which include phosgene, carbon monoxide, and sulfur dioxide. ### Chlorine[edit] Chlorine is a relatively common gas in industry with a variety of uses. It is used to disinfect water as well as being a part of the sanitation process for sewage and industrial waste. Chlorine is also used as a bleaching agent during the production of paper and cloth. Many household cleaning products, including bleach, contain chlorine. Given the volume and ease of chlorine for industrial and commercial use, exposure could occur from an accidental spill or a deliberate attack. The National Institute for Occupational Safety and Health recommends that a person wear splash proof goggles, a face shield and a respirator mask when working in the vicinity of chlorine gas. Because chlorine is a gas at room temperature, most exposure occurs via inhalation. Exposure may also occur through skin or eye contact or by ingesting chlorine-contaminated food or water. Chlorine is a strong oxidizing element causing the hydrogen to split from water in moist tissue, resulting in nascent oxygen and hydrogen chloride that cause corrosive tissue damage. Additionally oxidation of chlorine may form hypochlorous acid, which can penetrate cells and react with cytoplasmic proteins destroying cell structure.[6][7] Chlorine’s odor provides early warning signs of exposure but causes olfactory fatigue or adaptations, reducing awareness of exposure at low concentrations. With increased exposure, symptoms may progress to labored respirations, severe coughing, chest tightness, wheezing, dyspnea, and bronchospasm associated with a decrease in oxygen saturation level. .[8] Severe exposure may result in changes in upper and lower airways resulting in an acute lung injury, which may not be present until several hours after exposure. A recent chlorine gas leak in Pune, India, landed 20 individuals in the hospital.[9] Though that was an accidental exposure, chlorine gas has been used as a weapon of warfare since World War I, most recently in 2007 in Iraq.[10][11][citation needed] ### Phosgene[edit] Phosgene, notably used as a chemical weapon during World War I, is also used as an industrial reagent and building block in synthesis of pharmaceuticals and other organic compounds. Because of safety issues, phosgene is almost always produced and consumed within the same plant and extraordinary measures are made to contain this gas. In low concentrations, phosgene’s odor resembles freshly cut hay or grass. Because of this, the gas may not be noticed and symptoms may appear slowly. Phosgene directly reacts with amine, sulfhydryl, and alcohol groups, adversely affecting cell macromolecules and metabolism. The direct toxicity to the cells leads to an increase in capillary permeability.[12][13] Furthermore, when phosgene hydrolyzes it forms hydrochloric acid, which can damage the cell surface and cause cell death in the alveoli and bronchioles. The hydrochloric acid triggers an inflammatory response that attracts neutrophils to the lungs, which causes pulmonary edema.[14] ### Ammonia[edit] Ammonia is generally used in household cleaning products, as well as on farms and in some industrial and commercial locations, and this makes it easy for accidental or deliberate exposure to occur.[15][16][17] Ammonia interacts with moist surfaces to form ammonium hydroxide, which causes necrosis of tissues. Exposure to high concentrations can cause bronchiolar and alveolar edema and airway destruction resulting in respiratory distress or failure. Although ammonia has a pungent odor, it also causes olfactory fatigue or adaptation, reducing awareness of prolonged exposure. ### Mustard gas[edit] Sulfur mustard, commonly known as mustard gas, was used as a chemical weapon in World War I and more recently in the Iran–Iraq War. Sulfur mustard is a vesicant alkylating agent with strong cytotoxic, mutagenic, and carcinogenic properties. After exposure, victims show skin irritations and blisters.[18][19] This agent also causes respiratory tract lesions, bone marrow depression, and eye damage, the epithelial tissues of these organs being predominately affected. Inhalation of high doses of this gas causes lesions in the larynx, trachea, and large bronchi with inflammatory reactions and necrosis. The alkylating agent affects more the upper parts of the respiratory tract, and only intensely exposed victims showed signs like bronchiolitis obliterans in the distal part. Secondary effects of sulfur mustard exposure lead to chronic lung diseases such as chronic bronchitis. ### Chloramine[edit] A common exposure involves accidental mixing of household ammonia with cleansers containing bleach, causing the irritant gas monochloramine to be released. ### Methyl isocyanate[edit] Methyl isocyanate is an intermediate chemical in the production of carbamate pesticides (such as carbaryl, carbofuran, methomyl, and aldicarb).[20][21] It has also been used in the production of rubbers and adhesives. As a highly toxic and irritating material, it is hazardous to human health, and was involved in the Bhopal disaster—which killed nearly 8,000 people initially and approximately 17,000 people in total.[22] When inhaled the vapor produces a direct inflammatory effect on the respiratory tract. ## Pathophysiology[edit] Respiratory damage is related to the concentration of the gas and its solubility. Irritant gas exposures predominantly affect the airways, causing tracheitis, bronchitis, and bronchiolitis. Other inhaled agents may be directly toxic (e.g. cyanide, carbon monoxide), or cause harm simply by displacing oxygen and producing asphyxia (e.g. methane, carbon dioxide). The effect of inhaling irritant gases depends on the extent and duration of exposure and on the specific agent[23][24][25] Chlorine, phosgene, sulfur dioxide, hydrogen chloride, hydrogen sulfide, nitrogen dioxide, ozone, and ammonia are among the most important irritant gases. Hydrogen sulfide is also a potent cellular toxin, blocking the cytochrome system and inhibiting cellular respiration. More water-soluble gases (e.g. chlorine, ammonia, sulfur dioxide, hydrogen chloride) dissolve in the upper airway and immediately cause mucous membrane irritation, which may alert people to the need to escape the exposure. Permanent damage to the upper respiratory tract, distal airways, and lung parenchyma occurs only if escape from the gas source is impeded. Less soluble gases (e.g. nitrogen dioxide, phosgene, ozone) may not dissolve until they are well into the respiratory tract, often reaching the lower airways.[26] These agents are less likely to produce early warning signs (phosgene in low concentrations has a pleasant odor), are more likely to cause severe bronchiolitis, and often have a lag of ≥ 12 h before symptoms of pulmonary edema develop. ### Acute lung injury[edit] Acute lung injury (ALI), also called non-cardiogenic pulmonary edema, is characterized by the abrupt onset of significant hypoxemia and diffuse pulmonary infiltrates in the absence of cardiac failure. The core pathology is disruption of the capillary-endothelial interface: this actually refers to two separate barriers – the endothelium and the basement membrane of the alveolus.[27][28][29][30] In the acute phase of ALI, there is increased permeability of this barrier and protein rich fluid leaks out of the capillaries. There are two types of alveolar epithelial cells – Type 1 pneumocytes represent 90% of the cell surface area, and are easily damaged. Type 2 pneumocytes are more resistant to damage, which is important as these cells produce surfactant, transport ions and proliferate and differentiate into Type 1 cells. The damage to the endothelium and the alveolar epithelium results in the creation of an open interface between the lung and the blood, facilitating the spread of micro-organisms from the lung systemically, stoking up a systemic inflammatory response. Moreover, the injury to epithelial cells handicaps the lung’s ability to pump fluid out of airspaces. Fluid filled airspaces, loss of surfactant, microvascular thrombosis and disorganized repair (which leads to fibrosis) reduces resting lung volumes (decreased compliance), increasing ventilation-perfusion mismatch, right to left shunt and the work of breathing. In addition, lymphatic drainage of lung units appears to be curtailed—stunned by the acute injury—which contributes to the build-up of extravascular fluid. Some patients rapidly recover from ALI and have no permanent sequelae. Prolonged inflammation and destruction of pneumocytes leads to fibroblastic proliferation, hyaline membrane formation, tracheal remodeling and lung fibrosis. This fibrosing alveolitis may become apparent as early as five days after the initial injury. Subsequent recovery may be characterized by reduced physiologic reserve, and increased susceptibility to further lung injuries. Extensive microvascular thrombosis may lead to pulmonary hypertension, myocardial dysfunction and systemic hypotension. ### Acute respiratory distress syndrome[edit] Clinically, the most serious and immediate complication is acute respiratory distress syndrome (ARDS), which usually occurs within 24 h.[31][32][33] Those with significant lower airway involvement may develop bacterial infection. Importantly, victims suffering body surface burn and smoke inhalation are the most susceptible. Thermal injury combined with inhalation injury compromises pulmonary function, producing microvascular hyperpermeability that leads to a significant increase in lung lymph flow and pulmonary edema. The terrorist attack on the World Trade Center on September 11, 2001 left many people with impaired lung function.[34][35][36] A study of firefighters and EMS workers enrolled in the FDNY WTC Medical Monitoring and Treatment Program, whose lung function was tested prior to 9/11, documented a steep decline in lung function in the first year after 9/11.[37] A new study that includes a thousand additional workers shows that the declines have persisted over time.[38] Prior to 9/11, 3% of firefighters had below-normal lung function, one year after 9/11 nearly 19% did, and six years later it stabilized at 13%. Ten to 14 days after acute exposure to some agents (e.g. ammonia, nitrogen oxides, sulfur dioxide, mercury), some patients develop bronchiolitis obliterans progressing to ARDS. Bronchiolitis obliterans with organized pneumonia can ensue when granulation tissue accumulates in the terminal airways and alveolar ducts during the body's reparative process. A minority of these patients develop late pulmonary fibrosis. Also at enhanced risk are persons with co-morbidities. Several studies report that both aged persons and smokers are especially vulnerable to the adverse effects of inhalation injury. ## Treatment strategies[edit] Specific pretreatments, drugs to prevent chemically induced lung injuries due to respiratory airway toxins, are not available. Analgesic medications, oxygen, humidification, and ventilator support currently constitute standard therapy. In fact, mechanical ventilation remains the therapeutic mainstay for acute inhalation injury.[39][40] The cornerstone of treatment is to keep the PaO2 > 60 mmHg (8.0 kPa), without causing injury to the lungs with excessive O2 or volutrauma. Pressure control ventilation is more versatile than volume control, although breaths should be volume limited, to prevent stretch injury to the alveoli. Positive end-expiratory pressure (PEEP) is used in mechanically ventilated patients with ARDS to improve oxygenation. Hemorrhaging, signifying substantial damage to the lining of the airways and lungs, can occur with exposure to highly corrosive chemicals and may require additional medical interventions. Corticosteroids are sometimes administered, and bronchodilators to treat bronchospasms. Drugs that reduce the inflammatory response, promote healing of tissues, and prevent the onset of pulmonary edema or secondary inflammation may be used following severe injury to prevent chronic scarring and airway narrowing.[41] Although current treatments can be administered in a controlled hospital setting, many hospitals are ill-suited for a situation involving mass casualties among civilians. Inexpensive positive-pressure devices that can be used easily in a mass casualty situation, and drugs to prevent inflammation and pulmonary edema are needed. Several drugs that have been approved by the FDA for other indications hold promise for treating chemically induced pulmonary edema. These include β2-agonists, dopamine, insulin, allopurinol, and non-steroidal anti-inflammatory drugs (NSAIDs), such as ibuprofen. Ibuprofen is particularly appealing because it has an established safety record and can be easily administered as an initial intervention.[42] Inhaled and systemic forms of β2-agonists used in the treatment of asthma and other commonly used medications, such as insulin, dopamine, and allopurinol have also been effective in reducing pulmonary edema in animal models but require further study. A recent study documented in the AANA Journal discussed the use of volatile anesthetic agents, such as sevoflurane, to be used as a bronchodilator that lowered peak airway pressures and improved oxygenation.[43][44] Other promising drugs in earlier stages of development act at various steps in the complex molecular pathways underlying pulmonary edema. Some of these potential drugs target the inflammatory response or the specific site(s) of injury. Others modulate the activity of ion channels that control fluid transport across lung membranes or target surfactant, a substance that lines the air sacs in the lungs and prevents them from collapsing. Mechanistic information based on toxicology, biochemistry, and physiology may be instrumental in determining new targets for therapy. Mechanistic studies may also aid in the development of new diagnostic approaches. Some chemicals generate metabolic byproducts that could be used for diagnosis, but detection of these byproducts may not be possible until many hours after initial exposure. Additional research must be directed at developing sensitive and specific tests to identify individuals quickly after they have been exposed to varying levels of chemicals toxic to the respiratory tract. Currently there are no clinically approved agents that can reduce pulmonary and airway cell dropout and avert the transition to pulmonary and /or airway fibrosis. ## Preclinical development of pulmonary protective strategies[edit] Given the constant threat of bioterrorist related events, there is an urgent need to develop pulmonary protective and reparative agents that can be used by first responders in a mass casualty setting. Use in such a setting would require administration via a convenient route for e.g. intramuscular via epipens.[45] Other feasible routes of administration could be inhalation and perhaps to a lesser extent oral – swallowing can be difficult in many forms of injury especially if accompanied by secretions or if victim is nauseous. A number of in vitro and in vivo models lend themselves to preclinical evaluation of novel pulmonary therapies. ### In vitro[edit] In vitro, exposure of human bronchial epithelial cells or human pulmonary alveolar epithelial cells to agents such as hydrogen peroxide or bleach produces a time and toxin-dose-dependent decrease in cellular viability.[46][47][48] Cells exposed to these agents demonstrate significant ATP depletion, DNA damage, and lipid peroxidation, followed by death allowing for evaluation of novel cytoprotective agents. Potential tissue reparative agents can be evaluated in vitro by determining their effects on stimulation of pulmonary and airway epithelial cell proliferation. ### In vivo[edit] Test articles passing muster in vitro can be evaluated in a number of in vivo models (usually in mice) of ALI including chlorine inhalation, intratracheal instillation of bleomycin and in transforming growth factor β1 (TGF β1) overexpressing transgenic mice exposed to high dose doxycycline.[49][50][51][52][53][54][55] Acute exposure to high concentrations of chlorine gas induces pathological and functional changes in the lungs of rodents. Histological changes consist of epithelial necrosis and detachment, increase in the area of smooth muscle, epithelial regeneration and mucous cell hyperplasia.[56] Most of these abnormalities resolve with time. Functional changes (increased RL and/or bronchial responsiveness to inhaled methacholine) last for mean intervals of 3 and 7 days after exposure, but can persist up to 30 and 90 days, respectively. The functional changes are related to the overall abnormal airway epithelial damage and there is a significant correlation between RL and bronchoalveolar lavage ( BAL) neutrophilia. Bleomycin is an antineoplastic antibiotic drug isolated in 1966 from the actinomycete Streptomyces verticillus. Bleomycin forms a complex with oxygen and metals such as Fe2+, leading to the production of oxygen radicals, DNA breaks, and ultimately cell death.[57][58] Doxycycline driven overexpression of TGF β1 in the lungs of transgenic mice result in a time-dependent inflammatory response characterized by massive infiltration of F4/80+ monocytic/macrophage-like cells and a wave of apoptotic pulmonary cell death. Mice that survive this initial onslaught go on to demonstrate an increase in lung collagen content, and decreased lung compliance.[59][60] A large animal model of ALI is the ovine model of body surface burn + heated smoke inhalation.[61][62] It has been established that combined burn and smoke inhalation injury impairs hypoxic pulmonary vasoconstriction (HPV), the vasoconstrictive response to hypoxia, thereby mismatching ventilation with perfusion. Gas exchange is affected by increases in the dispersion of both alveolar ventilation and cardiac output because bronchial and vascular functions are altered by injury-related factors, such as the effects of inflammatory mediators on airway and vascular smooth muscle tone. As a rule of thumb, all these models are characterized by high mortality, inflammation of the airways and pulmonary parenchyma, edema and flooding of the alveolar spaces by a proteinaceous exudate, sloughing of the airway and pulmonary epithelium, scarring and transition to airway and pulmonary remodeling. ## References[edit] 1. ^ Bessac BF, Jordt SE. (2010) Sensory detection and responses to toxic gases: mechanisms, health effects, and countermeasures. Proc Am Thorac Soc. 7: 269-77. 2. ^ do Pico GA. (1995) Toxic gas inhalation. Curr Opin Pulm Med. 1:102-8. 3. ^ Clark WR Jr. (1992) Smoke inhalation: diagnosis and treatment. World J Surg. 16: 24-9. 4. ^ Mauer MP, Cummings KR. (2010) Impulse oscillometry and respiratory symptoms in World Trade Center responders, 6 years post-9/11. Lung 188:107-13. 5. ^ Buyantseva LV, Tulchinsky M, Kapalka GM, Chinchilli VM, Qian Z, Gillio R, Roberts A, Bascom. (2007) Evolution of lower respiratory symptoms in New York police officers after 9/11: a prospective longitudinal study. Occup Environ Med. 49:310-7. 6. ^ Martin JG, Campbell HR, Iijima H, Gautrin D, Malo JL, Eidelman DH, Hamid Q, Maghni K. (2003). Chlorine-induced injury to the airways in mice, Am J Respir Crit Care Med. 168:568-74. 7. ^ Matalon S, Maull EA. (2010) Understanding and treating chlorine-induced lung injury. Proc Am Thorac Soc. 7: 253 8. ^ Kennedy SM, Enarson DA, Janssen RG, Chan-Yeung M. (1991) Lung health consequences of reported accidental chlorine gas exposures among pulpmill workers. Am Rev Respir Dis. 143:74-9. 9. ^ [1] 10. ^ "Chemical Warfare in World War I". webharvest.gov. Archived from the original on 2004-10-17. Retrieved 2016-06-13. 11. ^ Cave, Damien; Fadam, Ahmad (2007-02-21). "Iraqi Militants Use Chlorine in 3 Bombings". The New York Times. ISSN 0362-4331. Retrieved 2016-06-13. 12. ^ Grainge C, Rice P. (2010) Management of phosgene-induced acute lung injury. Clin Toxicol. 48:497-508. 13. ^ Gift JS, McGaughy R, Singh DV, Sonawane B. (2008)Health assessment of phosgene: approaches for derivation of reference concentration. Regul Toxicol Pharmacol. 51:98-107 14. ^ Lazarus AA, Devereaux A. (2002) Potential agents of chemical warfare. Worst-case scenario protection and decontamination methods. Postgrad Med. 112:133-40. 15. ^ Lalić H, Djindjić-Pavicić M, Kukuljan M. (2009) Ammonia intoxication on workplace--case report and a review of literature. Coll Antropol. 33:945-9. 16. ^ Weiss SM, Lakshminarayan S. (1994) Acute inhalation injury. Clin Chest Med. 15:103-16. 17. ^ Witschi H. (1977) Environmental agents altering lung biochemistry. Fed Proc. 36:1631-4. 18. ^ Adelipour M, Imani Fooladi AA, Yazdani S, Vahedi E, Ghanei M, Nourani MR. (2011) Smad molecules expression pattern in human bronchial airway induced by sulfur mustard. Iran J Allergy Asthma Immunol. 10:147-54. 19. ^ Ghabili K, Agutter PS, Ghanei M, Ansarin K, Panahi Y, Shoja MM. (2011) Sulfur mustard toxicity: history, chemistry, pharmacokinetics, and pharmacodynamics. Crit Rev Toxicol. 41:384-403. 20. ^ Mansour SA. (2004) Pesticide exposure--Egyptian scene. Toxicology 198: 91-115. 21. ^ Beckett WS. (1998) Persistent respiratory effects in survivors of the Bhopal disaster. Thorax 53:S43-6. 22. ^ Beckett WS. (1998) Persistent respiratory effects in survivors of the Bhopal disaster. Thorax 53:S43-6. 23. ^ Demnati R, Fraser R, Ghezzo H, Martin JG, Plaa G, Malo JL. (1998) Time-course of functional and pathological changes after a single high acute inhalation of chlorine in rats, Eur Respir J. 11:922-8. 24. ^ Kirkhorn SR, Garry VF. (2008) Agricultural lung diseases. Environ Health Perspect 108:705-12. 25. ^ Hlastala MP, Ralph DD, Babb AL, Influence of gas physical properties on pulmonary gas exchange, Adv Exp Med Biol. 227 (1988) 33-8. 26. ^ Anderson JC, Hlastala MP. (2007) Breath tests and airway gas exchange. Pulm Pharmacol Ther. 20:112-7. 27. ^ Luh SP, Chiang CH. (2007) Acute lung injury/acute respiratory distress syndrome (ALI/ARDS): the mechanism, present strategies and future perspectives of therapies. J Zhejiang Univ Sci B 8:60-9. 28. ^ Flick MR. (1986) Mechanisms of acute lung injury. What have we learned from experimental animal models? Crit Care Clin. 2:455-70. 29. ^ Uchida T, Makita K. (2008) Acute lung injury and alveolar epithelial function. Masui. 57:51-9. 30. ^ Tang PS, Mura M, Seth R, Liu M. (2008) Acute lung injury and cell death: how many ways can cells die? Am J Physiol 294:L632-41. 31. ^ Lynch JE, Cheek JM, Chan EY, Zwischenberger JB. (2006) Adjuncts to mechanical ventilation in ARDS. Semin Thorac Cardiovasc Surg. 18:20-7. 32. ^ Meduri GU, Yates CR. (2004) Systemic inflammation-associated glucocorticoid resistance and outcome of ARDS. Ann N Y Acad Sci. 1024:24-53. 33. ^ Morrison RJ, Bidani A. (2002) Acute respiratory distress syndrome epidemiology and pathophysiology. Chest Surg Clin N Am. 12:301-23. 34. ^ Banauch GI, Izbicki G, Christodoulou V, Weiden MD, Webber MP, Cohen H, Gustave J, Chavko R, Aldrich TK, Kelly KJ, Prezant DJ. (2008) Trial of prophylactic inhaled steroids to prevent or reduce pulmonary function decline, pulmonary symptoms, and airway hyperreactivity in firefighters at the world trade center site. Disaster Med Public Health Prep. 2:33-9. 35. ^ Berninger A, Webber MP, Weakley J, Gustave J, Zeig-Owens R, Lee R, Al-Othman F, Cohen HW, Kelly K, Prezant DJ. (2010) Quality of life in relation to upper and lower respiratory conditions among retired 9/11-exposed firefighters with pulmonary disability. Qual Life Res. 19:1467-76. 36. ^ Crowley LE, Herbert R, Moline JM, Wallenstein S, Shukla G, Schechter C, Skloot GS, Udasin I, Luft BJ, Harrison D, Shapiro M, Wong K, Sacks HS, Landrigan PJ, Teirstein AS. (2011) Sarcoid like granulomatous pulmonary disease in World Trade Center disaster responders. Am J Ind Med. 54:175-84. 37. ^ Banauch GI, Izbicki G, Christodoulou V, Weiden MD, Webber MP, Cohen H, Gustave J, Chavko R, Aldrich TK, Kelly KJ, Prezant DJ. (2008) Trial of prophylactic inhaled steroids to prevent or reduce pulmonary function decline, pulmonary symptoms, and airway hyperreactivity in firefighters at the world trade center site. Disaster Med Public Health Prep. 2:33-9. 38. ^ Berninger A, Webber MP, Weakley J, Gustave J, Zeig-Owens R, Lee R, Al-Othman F, Cohen HW, Kelly K, Prezant DJ. (2010) Quality of life in relation to upper and lower respiratory conditions among retired 9/11-exposed firefighters with pulmonary disability. Qual Life Res. 19:1467-76. 39. ^ Matthay MA, Zemans RL. (2011) The acute respiratory distress syndrome: pathogenesis and treatment. Annu Rev Pathol. 6:147-63. 40. ^ [2] 41. ^ Johnson ER, Matthay MA. (2010) Acute lung injury: epidemiology, pathogenesis, and treatment, J Aerosol Med Pulm Drug Deliv. 23:243-52. 42. ^ [3] 43. ^ Meesun, Vera (June 2014). "CRNA". AANA Journal. 82 (3): 226. 44. ^ [4] 45. ^ [5] 46. ^ Rappeneau S, Baeza-Squiban A, Jeulin C, Marano F. (2000) Protection from cytotoxic effects induced by the nitrogen mustard mechlorethamine on human bronchial epithelial cells in vitro. Toxicol Sci. 54:212-21. 47. ^ Arita Y, Harkness SH, Kazzaz JA, Koo HC, Joseph A, Melendez JA, Davis JM, Chander A, Li Y. (2006) Mitochondrial localization of catalase provides optimal protection from H2O2-induced cell death in lung epithelial cells. Am J Physiol. 290:L978-86. 48. ^ Song W, Wei S, Zhou Y, Lazrak A, Liu G, Londino JD, Squadrito GL, Matalon S. (2010) Inhibition of lung fluid clearance and epithelial Na+ channels by chlorine, hypochlorous acid, and chloramines. J Biol Chem. 285:9716-28. 49. ^ Matute-Bello G, Frevert CW, Martin TR. (2008) Animal models of acute lung injury. Am J Physiol. 295:L379-99. 50. ^ Li X, Li S, Zhang M, Li X, Zhang X, Zhang W, Li C. (2010) Protective effects of a bacterially expressed NIF-KGF fusion protein against bleomycin-induced acute lung injury in mice. Acta Biochim Biophys Sin 42: 548-57. 51. ^ Hoshino T, Okamoto M, Sakazaki Y, Kato S, Young HA, Aizawa H. (2009) Role of proinflammatory cytokines IL-18 and IL-1beta in bleomycin-induced lung injury in humans and mice. Am J Respir Cell Mol Biol. 41:661-70 52. ^ Zarogiannis SG, Jurkuvenaite A, Fernandez S, Doran SF, Yadav AK, Squadrito GL, Postlethwait EM, Bowen L, Matalon S. (2011) Am J Respir Cell Mol Biol. 45:386-92 53. ^ Song W, Wei S, Liu G, Yu Z, Estell K, Yadav AK, Schwiebert LM, Matalon S. (2011) Post Exposure Administration of a {beta}2-Agonist Decreases Chlorine Induced Airway Hyper-Reactivity in Mice. Am J Respir Cell Mol Biol. 45:88-94. 54. ^ Kang HR, Cho SJ, Lee CG, Homer RJ, Elias JA. (2007) Transforming growth factor (TGF)-beta1 stimulates pulmonary fibrosis and inflammation via a Bax-dependent, bid-activated pathway that involves matrix metalloproteinase-12. J Biol Chem. 282 :7723-32. 55. ^ Pulichino AM, Wang IM, Caron A, Mortimer J, Auger A, Boie Y, Elias JA, Kartono A, Xu L, Menetski J, Sayegh CE. (2008) Identification of transforming growth factor beta1-driven genetic programs of acute lung fibrosis. Am J Respir Cell Mol Biol. 39:324-36. 56. ^ Zarogiannis SG, Jurkuvenaite A, Fernandez S, Doran SF, Yadav AK, Squadrito GL, Postlethwait EM, Bowen L, Matalon S. (2011) Am J Respir Cell Mol Biol. 45:386-92 57. ^ Li X, Li S, Zhang M, Li X, Zhang X, Zhang W, Li C. (2010) Protective effects of a bacterially expressed NIF-KGF fusion protein against bleomycin-induced acute lung injury in mice. Acta Biochim Biophys Sin 42: 548-57. 58. ^ Hoshino T, Okamoto M, Sakazaki Y, Kato S, Young HA, Aizawa H. (2009) Role of proinflammatory cytokines IL-18 and IL-1beta in bleomycin-induced lung injury in humans and mice. Am J Respir Cell Mol Biol. 41:661-70 59. ^ Kang HR, Cho SJ, Lee CG, Homer RJ, Elias JA. (2007) Transforming growth factor (TGF)-beta1 stimulates pulmonary fibrosis and inflammation via a Bax-dependent, bid-activated pathway that involves matrix metalloproteinase-12. J Biol Chem. 282 :7723-32. 60. ^ Pulichino AM, Wang IM, Caron A, Mortimer J, Auger A, Boie Y, Elias JA, Kartono A, Xu L, Menetski J, Sayegh CE. (2008) Identification of transforming growth factor beta1-driven genetic programs of acute lung fibrosis. Am J Respir Cell Mol Biol. 39:324-36. 61. ^ Hamahata A, Enkhbaatar P, Sakurai H, Nozaki M, Traber DL. (2010) Sclerosis therapy of bronchial artery attenuates acute lung injury induced by burn and smoke inhalation injury in ovine model. Burns. 36:1042-9. 62. ^ Esechie A, Enkhbaatar P, Traber DL, Jonkam C, Lange M, Hamahata A, Djukom C, Whorton EB, Hawkins HK, Traber LD, Szabo C. (2009) Beneficial effect of a hydrogen sulphide donor (sodium sulphide) in an ovine model of burn- and smoke-induced acute lung injury. Br J Pharmacol. 158:1442-53. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor *[BMI]: body mass index	Acute inhalation injury	c1997538	1,738	wikipedia	https://en.wikipedia.org/wiki/Acute_inhalation_injury	2021-01-18T18:35:09	{"umls": ["C1997538"], "wikidata": ["Q1663497"]}
A rare, X-linked leukodystrophy characterized primarily by spastic gait and autonomic dysfunction. When additional central nervous system (CNS) signs, such as intellectual deficit, ataxia, or extrapyramidal signs, are present, the syndrome is referred to as complicated SPG. ## Epidemiology The prevalence and incidence of SPG2 have not been reported, but as part of the Pelizaeus-Merzbacher (PMD; see this term) spectrum, SPG2 roughly accounts for about 20 % of cases. There have been approximately 20 cases published on SPG2. SPG2 affects males but some female heterozygotes presenting in adulthood with a milder phenotype have also been reported. ## Clinical description SPG2 spans a continuum of phenotypes that goes from pure to complicated SPG2. Pure SPG2 manifests as early as infancy or early childhood (<5 years) but may be delayed until early adulthood. It presents with weakness, hyperreflexia, Babinski sign and spastic gait due to spastic paraparesis. Autonomic dysfunction (spastic urinary bladder and possibly bowel, with increased urinary and fecal frequency and incontinence) is frequent. Patients are able to walk and their speech is normal. There is no CNS involvement and no cognitive decline. Complicated SPG2 shares the same features as SPG2 but also shows additional CNS involvement like nystagmus, and ataxia that present in the first years of life. Optic atrophy may be present. Patients can also show a mild intellectual deficit. ## Etiology SPG2 is due to missense substitutions affecting the PLP1 gene. PLP1 encodes the proteolipid protein (PLP), the most abundant protein of the myelin sheath in the central nervous system, and its alternatively spliced isoform (DM20). SPG2 is allelic to Pelizaeus-Merzbacher disease (PMD; see this term) that is also due to PLP1 mutations. ## Diagnostic methods Diagnosis is based on clinical, electrophysiologic, and neuroradiological findings. White matter N-acetyl aspartate levels are reduced. Brain magnetic resonance imaging (MRI) reveals patchy or diffuse hypomyelination on T2-weighted images. Patients with pure SPG2 can have very subtle T2 hyperintensity. Other MR techniques, including MR spectroscopy and diffusion tensor imaging are useful in the diagnosis of the disease. Molecular genetic testing of PLP1 confirms the diagnosis. ## Differential diagnosis Differential diagnosis includes other forms of hereditary spastic paraplegia (see this tem). Complicated SPG2 is not clearly distinguishable from mild Pelizaeus-Merzbacher disease (PMD) and null syndrome (see these terms). ## Antenatal diagnosis Prenatal genetic testing is possible when a family's underlying PLP1 mutation has been identified. ## Genetic counseling Transmission is X-linked recessive. ## Management and treatment A son born to a female carrier has a 50% risk of inheriting the mutation and developing the disease, while a daughter has a 50% risk of being a carrier. All daughters of an affected male will be carriers but none of his sons will be affected. Management is multidisciplinary and involves neurologists, physical therapists, and orthopedic doctors. Treatment may include antiepileptic drugs for seizures, and physical therapy with antispasticity drugs (baclofen, diazepam, tizanidine, botulinum toxin, dantrolene) for spasticity. Regular surveillance is necessary. ## Prognosis Pure SPG2 patients show a normal life expectancy. In complicated SPG2 cases, patients deteriorate neurologically leading to a shorter life expectancy (between the fourth and seventh decade) typically from aspiration pneumonia, pulmonary embolism and other complications of generalized weakness. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor *[BMI]: body mass index	Spastic paraplegia type 2	c1839264	1,739	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=99015	2021-01-23T17:02:56	{"gard": ["4923"], "mesh": ["C536857"], "omim": ["312920"], "umls": ["C1839264"], "icd-10": ["G11.4"], "synonyms": ["SPG2", "Spastic gait type 2", "Spastic paraparesis type 2", "X-linked spastic paraplegia type 2"]}
A pure form of hereditary spastic paraplegia characterized by a childhood- to adulthood-onset of slowly progressive lower limb spasticity and hyperreflexia of lower extremities, extensor plantar reflexes, distal sensory impairment, variable urinary dysfunction and pes cavus. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor *[BMI]: body mass index	Autosomal dominant spastic paraplegia type 12	c1858106	1,740	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=100993	2021-01-23T17:04:12	{"gard": ["9586"], "mesh": ["C537484"], "omim": ["604805"], "umls": ["C1858106"], "icd-10": ["G11.4"], "synonyms": ["SPG12"]}
Cerebral folate transport deficiency is a disorder that develops from a shortage (deficiency) of the B-vitamin folate (also called vitamin B9) in the brain. Affected children have normal development during infancy, but around age 2 they begin to lose previously acquired mental and movement abilities (psychomotor regression). They develop intellectual disability, speech difficulties, and recurrent seizures (epilepsy). Movement problems such as tremors and difficulty coordinating movements (ataxia) can be severe, and some affected individuals need wheelchair assistance. Affected individuals have leukodystrophy, which is a loss of a type of brain tissue known as white matter. White matter consists of nerve fibers covered by a fatty substance called myelin that promotes the rapid transmission of nerve impulses. Leukodystrophy contributes to the neurological problems that occur in cerebral folate transport deficiency. Without treatment, these neurological problems worsen over time. ## Frequency The prevalence of cerebral folate transport deficiency is unknown. Fewer than 20 affected individuals have been described in the scientific literature. ## Causes Mutations in the FOLR1 gene cause cerebral folate transport deficiency. The FOLR1 gene provides instructions for making a protein called folate receptor alpha. This protein is found within the cell membrane where it attaches (binds) to folate, allowing the vitamin to be brought into the cell. Folate receptor alpha is produced in largest amounts in the brain, specifically in an area of the brain called the choroid plexus. This region releases cerebrospinal fluid (CSF), which surrounds and protects the brain and spinal cord. Folate receptor alpha is thought to play a major role in bringing folate from the bloodstream into brain cells. It transports folate across the choroid plexus and into the CSF, ultimately reaching the brain. In the brain, folate is needed for making myelin and chemical messengers called neurotransmitters. Both of these substances play essential roles in transmitting signals in the nervous system. Additionally, folate is involved in the production and repair of DNA, regulation of gene activity (expression), and protein production. FOLR1 gene mutations result in a lack of protein or malfunctioning protein. As a result, folate from the bloodstream cannot be transported into the CSF. Without folate, many processes in the brain are impaired, leading to the neurological problems typical of cerebral folate transport deficiency. The signs and symptoms of cerebral folate transport deficiency do not begin until late infancy because other mechanisms can compensate for this loss. For example, another protein called folate receptor beta is responsible for folate transport before birth and in early infancy. ### Learn more about the gene associated with Cerebral folate transport deficiency * FOLR1 ## 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	Cerebral folate transport deficiency	c2751584	1,741	medlineplus	https://medlineplus.gov/genetics/condition/cerebral-folate-transport-deficiency/	2021-01-27T08:24:58	{"gard": ["10594"], "mesh": ["C567791"], "omim": ["613068"], "synonyms": []}
A number sign (#) is used with this entry because combined pituitary hormone deficiency-4 (CPHD4) is caused by heterozygous mutation in the LHX4 gene (602146) on chromosome 1q25. For discussion of phenotypic and genetic heterogeneity of combined pituitary hormone deficiency, see CPHD1 (613038). Clinical Features Machinis et al. (2001) reported a French family in which 2 sibs, born of a consanguineous marriage, were found to have combined pituitary hormone deficiency (CPHD) involving growth hormone (GH; 139250), thyrotropin (TSH; 188540) and adrenocorticotropic hormone (ACTH; 202200). MRI imaging showed that both had small sella turcicas, persistent craniopharyngeal canals, hypoplastic anterior hypophyses with associated pointed cerebellar tonsils (Chiari malformation; 118420), and ectopic posterior hypophyses. Their mother was 148 cm tall and had a small sella turcica and a hypoplastic anterior hypophysis associated with a deformation of the cerebellar tonsils. Their maternal grandfather was 150 cm tall and had a small sella turcica. Tajima et al. (2007) described a 16-month-old Japanese girl who presented with severe respiratory distress and hypoglycemia at birth; subsequent evaluation revealed CPHD, with deficiency of TSH, ACTH, GH, prolactin (PRL; 176760), follicle-stimulating hormone (FSH; 136530), and luteinizing hormone (LH; 152780). At age 15 months, she had short stature (-5.6 SD for a normal Japanese girl), and brain MRI demonstrated hypoplastic anterior pituitary, ectopic posterior lobe, a poorly developed sella turcica, and Chiari malformation. Pfaeffle et al. (2008) identified 5 patients with CPHD and pituitary dysmorphology. The patients had GH deficiency and reduction in TSH, LH, FSH, or ACTH. One patient had hypoglycemia, and 2 had delayed bone age. In contrast to previously reported patients with LHX4 mutations, no cerebellar hypoplasia reminiscent of Arnold-Chiari malformation was seen. Molecular Genetics In 4 affected members over 3 generations of a French family with combined pituitary hormone deficiency, who displayed short stature, pituitary and cerebellar defects, and abnormalities of the sella turcica of the central skull base, Machinis et al. (2001) identified heterozygosity for a splice site mutation in the LHX4 gene (602146.0001). In a 16-month-old Japanese girl with severe CPHD, pituitary defects, small sella turcica, and Chiari malformation, Tajima et al. (2007) identified heterozygosity for a de novo missense mutation in the LHX4 gene (602146.0005). From a mutation screen of pituitary transcription factor genes in 253 patients from 245 pedigrees with CPHD, Pfaeffle et al. (2008) identified 3 heterozygous missense mutations in LHX4 (602146.0002-602146.0004) in 5 patients with CPHD and pituitary dysmorphology, but without cerebellar hypoplasia. History Ferrier and Stone (1969) described an apparently distinct form of familial pituitary insufficiency in 2 sisters, aged 10 and 11 years. The features were severe growth retardation from infancy, tendency to hypoglycemia, deficient production of growth hormone, TSH, and ACTH, marked retardation in skeletal maturation, and very small sella turcica with abnormal morphology of the petrous bone. Ozer (1974) reported a case of pituitary dwarfism with small sella turcica. Retinitis pigmentosa was an additional feature. INHERITANCE \- Autosomal dominant GROWTH Height \- Short stature SKELETAL \- Delayed bone age Skull \- Very small sella turcica (some) \- Abnormal petrous bone METABOLIC FEATURES \- Hypoglycemia ENDOCRINE FEATURES \- Hypothyroidism (if untreated) LABORATORY ABNORMALITIES \- Low or absent growth hormone (GH) \- Low or absent thyroid-stimulating hormone (TSH) \- Low or absent luteinizing hormone (LH) \- Low or absent follicle stimulating hormone (FSH) \- Low or absent adrenocorticotropic hormone (ACTH) MISCELLANEOUS \- Laboratory findings are variable MOLECULAR BASIS \- Caused by mutation in the LIM homeo box gene 4 (LHX4, 602146.0001 ) ▲ 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	PITUITARY HORMONE DEFICIENCY, COMBINED, 4	c2678408	1,742	omim	https://www.omim.org/entry/262700	2019-09-22T16:23:20	{"doid": ["9406"], "mesh": ["C567492"], "omim": ["262700"], "orphanet": ["85442"], "synonyms": ["Alternative titles", "PITUITARY HORMONE DEFICIENCY, COMBINED, WITH OR WITHOUT CEREBELLAR DEFECTS", "SHORT STATURE, PITUITARY AND CEREBELLAR DEFECTS, AND SMALL SELLA TURCICA"]}
Oil derived from the tissues of oily fish For Omegaven, see Fish oil (medical use). See also: Omega-3 acid ethyl esters Fish oil capsules Fish oil is oil derived from the tissues of oily fish. Fish oils contain the omega-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), precursors of certain eicosanoids that are known to reduce inflammation in the body[1][2] and improve hypertriglyceridemia. There has been a great deal of controversy in recent years about the role of fish oil in cardiovascular disease, with recent meta-analyses reaching different conclusions about its potential impact. The most promising evidence supports supplementation for prevention of cardiac death.[3] Fish oil and omega-3 fatty acids have also been studied in a wide variety of other conditions such as clinical depression,[4][5] anxiety,[6][7][8] cancer, and macular degeneration, yet their benefit in these conditions has also not been verified.[9] The fish used as sources do not actually produce omega-3 fatty acids, but instead accumulate them by consuming either microalgae or prey fish that have accumulated omega-3 fatty acids. Fatty predatory fish like sharks, swordfish, tilefish, and albacore tuna may be high in omega-3 fatty acids but, due to their position at the top of the food chain, these species may also accumulate toxic substances through biomagnification. For this reason, the United States Environmental Protection Agency recommends limiting consumption (especially for women of childbearing age) of certain (predatory) fish species (e.g. albacore tuna, shark, king mackerel, tilefish and swordfish) due to high levels of the toxic contaminant mercury. Dioxins, PCBs and chlordane, as well as other chlorinated cyclodiene insecticides are also present.[10] Fish is rich in protein and other vitamins aquaculture feed. More than 50 percent of the world's fish oil used in aquaculture feed is fed to farmed salmon.[11] Marine and freshwater fish oil vary in contents of arachidonic acid, EPA and DHA.[12] The various species range from lean to fatty and their oil content in the tissues has been shown to vary from 0.7% to 15.5%.[13] They also differ in their effects on organ lipids.[12] Studies have revealed that there is no relation between total fish intake or estimated omega−3 fatty acid intake from all fish, and serum omega−3 fatty acid concentrations.[14] Only fatty fish intake, particularly salmonid, and estimated EPA + DHA intake from fatty fish has been observed to be significantly associated with increase in serum EPA + DHA.[14] As of 2019, the US Food and Drug Administration has approved four fish oil-based prescription drugs, namely Lovaza, Omtryg (both omega-3 acid ethyl esters), Vascepa (ethyl eicosapentaenoic acid), and Epanova (omega-3 carboxylic acids).[15] ## Contents * 1 Uses * 2 Nutritional details * 3 Health effects * 3.1 Various recommendations * 3.2 Prostate cancer * 3.3 Cardiovascular * 3.4 Hypertension * 3.5 Mental health * 3.6 Alzheimer's disease * 3.7 Psoriasis * 3.8 Pregnancy * 3.9 Crohn's disease * 4 Supplement quality and concerns * 4.1 Contamination * 4.2 Dioxins and PCBs * 4.3 Spoilage * 4.4 EPA and DHA content * 4.5 Formulation * 4.6 Prescription fish oil * 5 Dangers * 5.1 Maximum intake * 5.2 Vitamins * 5.3 Toxic pollutants * 6 See also * 7 References * 8 Further reading * 9 External links ## Uses[edit] Often marketed and sold for consumption as part of the diet or in dietary supplements in contemporary societies, fish oils also have found roles in external use, as emollients[16] or as general ointments[17] as well as in body art,[18] or for alleged insulation against cold temperatures.[19] Fish oil rendering in Port Dover, Ontario, 1918 ## Nutritional details[edit] The most widely available dietary source of EPA and DHA is cold-water oily fish, such as salmon, herring, mackerel, anchovies, and sardines. Oils from these fish have a profile of around seven times as much omega-3 oils as omega-6 oils. Other oily fish, such as tuna, also contain omega-3 in somewhat lesser amounts. Although fish is a dietary source of omega-3 oils, fish do not synthesize them; they obtain them from the algae (microalgae in particular) or plankton in their diets.[20] Grams of omega-3 fatty acids per 3oz (85g) serving of popular fish.[21][22] Common name grams Herring, sardines 1.3–2 Spanish mackerel, Atlantic, Pacific 1.1–1.7 Salmon 1.1–1.9 Halibut 0.60–1.12 Tuna 0.21–1.1 Swordfish 0.97 Greenshell/lipped mussels 0.95[23] Tilefish 0.9 Tuna (canned, light) 0.17–0.24 Pollock 0.45 Cod 0.15–0.24 Catfish 0.22–0.3 Flounder 0.48 Grouper 0.23 Mahi mahi 0.13 Orange roughy 0.028 Red snapper 0.29 Shark 0.83 King mackerel 0.36 Hoki (blue grenadier) 0.41 Silver gemfish 0.40 Blue eye cod 0.31 Sydney rock oyster 0.30 Tuna, canned 0.23 Snapper 0.22 Barramundi, saltwater 0.100 Giant tiger prawn 0.100 For comparison, note the omega-3 levels in some common non-fish foods: Grams of omega-3 fatty acids per 3oz (85g) serving of common non-fish foods.[21] Name grams Flaxseeds 19.55 Chia seeds 14.8 Hemp seeds 7.4 Walnut 1.7 Soybean 1.1 Butter 0.27 Eggs, large regular 0.109[23] Lean red meat 0.031 Turkey 0.030 Cereals, rice, pasta, etc. 0.00 Fruit 0.00 Milk, regular 0.00 Bread, regular 0.00 Vegetables 0.00 ## Health effects[edit] Kepler Cod Liver Oil with Malt Extract ### Various recommendations[edit] In a 2009 letter on a pending revision to the Dietary Guidelines for Americans, the American Heart Association recommended 250–500 mg/day of EPA and DHA.[24] The Guidelines were revised again for 2015–2020; included is a recommendation that adults consume at least eight ounces of a variety of types of fish per week, equating to at least 250 mg/day of EPA + DHA.[citation needed] The Food and Drug Administration recommends not exceeding 3 grams per day of EPA + DHA from all sources, with no more than 2 grams per day from dietary supplements.[25] ### Prostate cancer[edit] The effect of fish oil consumption on prostate cancer is controversial,[26][27] as one study showed decreased risk with higher blood levels of DPA, whereas another reported increased risk of more aggressive prostate cancer with higher blood levels of combined EPA and DHA.[28] Some evidence indicated an association between high blood levels of omega-3 fatty acids and an increased prostate cancer risk.[29] ### Cardiovascular[edit] There has been a great deal of controversy in recent years about the role of fish oil in cardiovascular disease, with recent meta-analyses reaching different conclusions about its potential impact.[3] Multiple evaluations suggest fish oil has little or no reduction in cardiovascular mortality, in distinction to earlier observational data, though there appears to be a small reduction in the incidence of actual cardiac events and strokes with its use.[30][31][32][33] In 2007, the American Heart Association had recommended the consumption of 1 gram of fish oil daily,[34] preferably by eating fish, for patients with coronary artery disease, but cautioned pregnant and nursing women to avoid eating fish with high potential for mercury contaminants including mackerel, shark, and swordfish.[35] (Optimal dosage was related to body weight.) The US National Institutes of Health lists three conditions for which fish oil and other omega-3 sources are most highly recommended: hypertriglyceridemia (high triglyceride level), preventing secondary cardiovascular disease, and hypertension (high blood pressure). It then lists 27 other conditions for which there is less evidence. It also lists possible safety concerns: "Intake of 3 grams per day or greater of omega-3 fatty acids may increase the risk of bleeding, although there is little evidence of significant bleeding risk at lower doses. Very large intakes of fish oil/omega-3 fatty acids may increase the risk of hemorrhagic (bleeding) stroke."[9] There is also some evidence that fish oil may have a beneficial effect on certain abnormal heart rhythms.[36][37] However, a 2012 meta-analysis found no such significant benefit.[38] A 2008 meta-study by the Canadian Medical Association Journal found fish oil supplementation did not demonstrate any preventative benefit to cardiac patients with ventricular arrhythmias.[39] A 2012 meta-analysis published in the Journal of the American Medical Association, covering 20 studies and 68,680 patients, found that Omega-3 Fatty Acid supplementation did not reduce the chance of death, cardiac death, heart attack or stroke.[40] A 2018 meta-analysis of randomized trials with a total of 77,000 participants published in JAMA found a 3% reduction in the relative risk for those who supplemented fish oil; however, this effect was not statistically significant, but suggested a very minor benefit.[41] In 2018, Cochrane conducted their own meta-analysis with a total of 79 studies and 112,000 participants and found a 5% reduction in the relative risk for cardiovascular mortality and a 7% reduction in the relative risk for coronary heart disease for those who supplemented with Omega-3s.[42] ### Hypertension[edit] There have been some human trials that have concluded that consuming omega-3 fatty acids slightly reduces blood pressure (DHA could be more effective than EPA). It is important to note that because omega-3 fatty acids can increase the risk of bleeding, a qualified healthcare provider should be consulted before supplementing with fish oil.[43] ### Mental health[edit] A 2008 Cochrane systematic review found that limited data is available. In the one eligible study, omega-3s were an effective adjunctive therapy for depressed but not manic symptoms in bipolar disorder. The authors found an "acute need" for more randomised controlled trials.[44] A 2009 metastudy found that patients taking omega-3 supplements with a higher EPA:DHA ratio experienced fewer depressive symptoms. The studies provided evidence that EPA may be more efficacious than DHA in treating depression. However, this metastudy concluded that due to the identified limitations of the included studies, larger, randomized trials are needed to confirm these findings.[45] In a 2011 meta-analysis of PubMed articles about fish oil and depression from 1965 to 2010, researchers found that "nearly all of the treatment efficacy observed in the published literature may be attributable to publication bias."[46] A 2014 meta-analysis of eleven trials conducted respectively on patients with a DSM-defined diagnosis of major depressive disorder (MDD) and of eight trials with patients with depressive symptomatology but no diagnosis of MDD demonstrated significant clinical benefit of omega-3 PUFA treatment compared to placebo. The study concluded that: "The use of omega-3 PUFA is effective in patients with diagnosis of MDD and on depressive patients without diagnosis of MDD."[47] ### Alzheimer's disease[edit] A Cochrane meta-analysis published in June 2012 found no significant protective effect for cognitive decline for those aged 60 and over and who started taking fatty acids after this age. A co-author of the study said to Time, "Our analysis suggests that there is currently no evidence that omega-3 fatty acid supplements provide a benefit for memory or concentration in later life".[48] ### Psoriasis[edit] Diets supplemented with cod liver oil have shown beneficial effects on psoriasis.[49] ### Pregnancy[edit] Some studies reported better psychomotor development at 30 months of age in infants whose mothers received fish oil supplements for the first four months of lactation.[50] In addition, five-year-old children whose mothers received modest algae based docosahexaenoic acid supplementation for the first 4 months of breastfeeding performed better on a test of sustained attention. This suggests that docosahexaenoic acid intake during early infancy confers long-term benefits on specific aspects of neurodevelopment.[50] In addition, provision of fish oil during pregnancy may reduce an infant's sensitization to common food allergens and reduce the prevalence and severity of certain skin diseases in the first year of life. This effect may persist until adolescence with a reduction in prevalence and/or severity of eczema, hay fever and asthma.[51] ### Crohn's disease[edit] A 2014 Cochrane review found that, based on two large studies, fish oil supplements did not appear to be effective for maintenance of remission in Crohn's disease.[52] ## Supplement quality and concerns[edit] Fish oil is a commonly used dietary supplement, with sales in the U.S. alone reaching $976 million in 2009.[53] Problems of quality have been identified in periodic tests by independent researchers of marketed supplements containing fish oil and other marine oils. These problems include contamination, inaccurate listing of EPA and DHA levels, spoilage and formulation issues.[54] ### Contamination[edit] Fish can accumulate toxins such as mercury, dioxins, and polychlorinated biphenyls (PCBs), and spoiled fish oil may produce peroxides.[55] There appears to be little risk of contamination by microorganisms, proteins, lysophospholipids, cholesterol, and trans-fats.[56] ### Dioxins and PCBs[edit] Dioxins and PCBs may be carcinogenic at low levels of exposure over time. These substances are identified and measured in one of two categories, dioxin-like PCBs and total PCBs. While the U.S. FDA has not set a limit for PCBs in supplements, the Global Organization for EPA and DHA (GOED) has established a guideline allowing for no more than 3 picograms of dioxin-like PCBs per gram of fish oil. In 2012, samples from 35 fish oil supplements were tested for PCBs. Trace amounts of PCBs were found in all samples, and two samples exceeded the GOED's limit.[57] Although trace amounts of PCBs contribute to overall PCB exposure, Consumerlab.com claims the amounts reported by tests it ordered on fish oil supplements are far below those found in a single typical serving of fish.[57] ### Spoilage[edit] Peroxides can be produced when fish oil spoils. A study commissioned by the government of Norway concluded there would be some health concern related to the regular consumption of oxidized (rancid) fish/marine oils, particularly in regards to the gastrointestinal tract, but there is not enough data to determine the risk. The amount of spoilage and contamination in a supplement depends on the raw materials and processes of extraction, refining, concentration, encapsulation, storage and transportation.[56] ConsumerLab.com reports in its review that it found spoilage in test reports it ordered on some fish oil supplement products.[57] ### EPA and DHA content[edit] According to ConsumerLab.com tests, the concentrations of EPA and DHA in supplements can vary from between 8 and 80% fish oil content. The concentration depends on the source of the omega-3s, how the oil is processed, and the amounts of other ingredients included in the supplement.[57] A 2012 report claims 4 of 35 fish oil supplements it covered contained less[quantify] EPA or DHA than was claimed on the label, and 3 of 35 contained more.[quantify][57] A ConsumerLab.com publication in 2010 claims 3 of 24 fish oil supplements it covered contained less[quantify] EPA and/or DHA than was claimed on the label.[53] However, the bioavailability of EPA and DHA from both capsular and emulsified fish oils has been shown to be high.[58] ### Formulation[edit] Fish oil supplements are available as liquids or capsules. Some capsules are enteric-coated to pass through the stomach before dissolving in the small intestine, thus helping prevent indigestion and "fish burps". Poorly manufactured enteric-coated products have the potential to release ingredients too early. ConsumerLab.com, a for-profit supplement testing company, reported that 1 of the 24 enteric-coated fish oil supplements it evaluated released ingredients prematurely.[53] Fish oil products may use other techniques to hide the fishy taste. For example, added lemon or strawberry flavor tends to produce a more agreeable product.[59] ### Prescription fish oil[edit] See also: Omega-3 acid ethyl esters and Fish oil (medical use) Fish oil preparations that are only available with a doctor's prescription undergo the same US Food and Drug Administration (FDA) regulatory requirements as other prescription pharmaceuticals, with regard to both efficacy and safety.[60] The prescription fish oil drugs differ from over-the-counter fish oil supplements. They should not be confused with each other.[61] Prescription fish oil is considered a safe and effective option to reduce triglycerides. There are various prescription fish oil products that have been approved and permitted by the FDA for increasing triglyceride levels. Prescription fish oil products having DHA raise up the LDL-C levels to reduce triglycerides, like fibrates.[62] Heart experts advise that prescription fish oil helps in decreasing additional levels of blood fats. Prescription fish oils might only help when triglycerides reach a specific upper level.[63] Prescription fish oil pills, capsules and tablets have more omega-3 fatty acids than those which are non-prescription. The FDA regularly monitors prescription fish oil for standards, quality and safety.[64] As of 2019, four fish oil-based prescription drugs have been approved in the United States for the treatment of hypertriglyceridemia,[15] namely: 1. Epanova (omega-3 carboxylic acids) was approved on 23 April 2014.[65][66][67] Clinical trial on mixed dyslipidaemia (hypertriglyceridemia with hypocholesterolemia) started in 2014[68] found that it has no medical benefits, and the clinical trial was called off on 13 January 2019.[69] 2. Lovaza (omega-3 acid ethyl esters) was approved on 10 November 2004.[70][71][72][73] 3. Omtryg (omega-3 acid ethyl esters) was approved on 23 April 2014.[74][75][76] 4. Vascepa (ethyl eicosapentaenoic acid) was approved on 26 July 2012.[77][78][79] On 13 December 2019, the FDA also approved it as the first drug specifically "to reduce cardiovascular risk among patients with elevated triglyceride levels."[80] Some fish-oil products are approved for parenteral nutrition: 1. Omegaven, approved in July 2018, is indicated as a source of calories and fatty acids in children with parenteral nutrition-associated cholestasis (PNAC).[81][82][83] 2. Smoflipid, approved in July 2016, is indicated in adults as a source of calories and essential fatty acids for parenteral nutrition when oral or enteral nutrition is not possible, insufficient, or contraindicated.[84][85][86] ## Dangers[edit] A 2013 review concluded that the potential for adverse events amongst older adults taking fish oil "appear mild–moderate at worst and are unlikely to be of clinical significance".[87] ### Maximum intake[edit] The FDA recommends that consumers do not exceed more than three grams per day of EPA and DHA combined, with no more than 2 grams from a dietary supplement.[88] This is not the same as 3000 mg of fish oil. A 1000 mg pill typically has only 300 mg of omega-3; 10 such pills would equal 3000 mg of omega-3. According to the European Food Safety Authority's (EFSA) Panel on Dietetic Products, Nutrition and Allergies, supplementation of 5 grams of EPA and DHA combined does not pose a safety concern for adults.[89] A 1987 study found that healthy Greenlandic Inuit had an average intake of 5.7 grams of omega-3 EPA per day which had many effects including prolonged bleeding times, such as slower blood clotting.[90] ### Vitamins[edit] The liver and liver products (such as cod liver oil) of fish and many animals (such as seals and whales) contain omega-3, but also the active form of vitamin A. At high levels, this form of the vitamin can be dangerous (Hypervitaminosis A).[91] ### Toxic pollutants[edit] Consumers of oily fish should be aware of the potential presence of heavy metals and fat-soluble pollutants like PCBs and dioxins, which are known to accumulate up the food chain. After extensive review, researchers from Harvard's School of Public Health in the Journal of the American Medical Association (2006) reported that the benefits of fish intake generally far outweigh the potential risks. Fish oil supplements came under scrutiny in 2006, when the Food Standards Agency in the UK and the Food Safety Authority of Ireland reported PCB levels that exceeded the European maximum limits in several fish oil brands,[92][93] which required temporary withdrawal of these brands. To address the concern over contaminated fish oil supplements, the International Fish Oil Standards (IFOS) Program, a third-party testing and accreditation program for fish oil products, was created by Nutrasource Diagnostics Inc. in Guelph, Ontario, Canada.[94] A March 2010 lawsuit filed by a California environmental group claimed that eight brands of fish oil supplements contained excessive levels of PCB's, including CVS/pharmacy, Nature Made, Rite Aid, GNC, Solgar, Twinlab, Now Health, Omega Protein and Pharmavite. The majority of these products were either cod liver or shark liver oils. Those participating in the lawsuit claim that because the liver is the major filtering and detoxifying organ, PCB content may be higher in liver-based oils than in fish oil produced from the processing of whole fish.[95][96] An analysis based on data from the Norwegian Women and Cancer Study (NOWAC) with regards to the dangers of persistent organic pollutants (POPs) in cod liver came to the conclusion that "in Norwegian women, fish liver consumption was not associated with an increased cancer risk in breast, uterus, or colon. In contrast, a decreased risk for total cancer was found."[97] A report by the Harvard Medical School studied five popular brands of fish oil, including Nordic Ultimate, Kirkland and CVS. They found that the brands had "negligible amounts of mercury, suggesting either that mercury is removed during the manufacturing of purified fish oil or that the fish sources used in these commercial preparations are relatively mercury-free".[98] Microalgae oil is a vegetarian alternative to fish oil. Supplements produced from microalgae oil provide a balance of omega-3 fatty acids similar to fish oil, with a lower risk of pollutant exposure.[99] ## See also[edit] * Algae * Cod liver oil * Docosahexaenoic acid * Eicosapentaenoic acid * Krill oil * Lovaza * Shark liver oil ## References[edit] 1. ^ Moghadasian, Mohammed H. (2008). "Advances in Dietary Enrichment with N-3 Fatty Acids". Critical Reviews in Food Science and Nutrition. 48 (5): 402–10. doi:10.1080/10408390701424303. PMID 18464030. S2CID 41311376. 2. ^ Cleland, Leslieg; James, Michaelj; Proudman, Susannam (2006). "Fish oil: What the prescriber needs to know". Arthritis Research & Therapy. 8 (1): 679–81. doi:10.1186/ar1876. 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ISSN 1460-2105. PMC 4188122. PMID 25210201. 28. ^ Chua, Michael E.; Sio, Maria Christina D.; Sorongon, Mishell C.; Morales Jr, Marcelino L. Jr. (May–June 2013). "The relevance of serum levels of long chain omega-3 polyunsaturated fatty acids and prostate cancer risk: a meta-analysis". Canadian Urological Association Journal. 7 (5–6): E333–43. doi:10.5489/cuaj.1056. PMC 3668400. PMID 23766835. 29. ^ Brasky TM, Darke AK, Song X, et al. (August 2013). "Plasma phospholipid fatty acids and prostate cancer risk in the SELECT trial". J. Natl. Cancer Inst. 105 (15): 1132–41. doi:10.1093/jnci/djt174. PMC 3735464. PMID 23843441. 30. ^ Abdelhamid, Asmaa S.; Brown, Tracey J.; Brainard, Julii S.; Biswas, Priti; Thorpe, Gabrielle C.; Moore, Helen J.; Deane, Katherine Ho; Summerbell, Carolyn D.; Worthington, Helen V.; Song, Fujian; Hooper, Lee (29 February 2020). "Omega-3 fatty acids for the primary and secondary prevention of cardiovascular disease". The Cochrane Database of Systematic Reviews. 3: CD003177. doi:10.1002/14651858.CD003177.pub5. ISSN 1469-493X. PMC 7049091. PMID 32114706. 31. ^ Abdelhamid, AS; Martin, N; Bridges, C; Brainard, JS; Wang, X; Brown, TJ; Hanson, S; Jimoh, OF; Ajabnoor, SM; Deane, KH; Song, F; Hooper, L (November 2018). "Polyunsaturated fatty acids for the primary and secondary prevention of cardiovascular disease". The Cochrane Database of Systematic Reviews. 11: CD012345. doi:10.1002/14651858.CD012345.pub3. PMC 6517012. PMID 30484282. 32. ^ Goel, A; Pothineni, NV; Singhal, M; Paydak, H; Saldeen, T; Mehta, JL (22 November 2018). "Fish, Fish Oils and Cardioprotection: Promise or Fish Tale?". International Journal of Molecular Sciences. 19 (12): 3703. doi:10.3390/ijms19123703. PMC 6321588. PMID 30469489. 33. ^ John M. Eisenberg Center for Clinical Decisions Communications Science (2007). "Omega-3 Fatty Acids and Cardiovascular Disease: Current State of the Evidence". PMID 30763028. Cite journal requires `\|journal=` (help) 34. ^ "Fish oil supplements provide some benefit after heart attack, heart failure". American Heart Association. Retrieved 6 October 2020. 35. ^ "Fish and Omega-3 Fatty Acids". American Heart Association. Retrieved 9 February 2007. 36. ^ Charnock John S (1999). "The role of omega-3 polyunsaturated fatty acid-enriched diets in the prevention of ventricular fibrillation" (PDF). Asia Pacific Journal of Clinical Nutrition. 8 (3): 226–30. doi:10.1046/j.1440-6047.1999.00115.x. PMID 24394167. 37. ^ Li GR, Sun HY, Zhang XH, Cheng LC, Chiu SW, Tse HF, Lau CP (2009). "Omega-3 polyunsaturated fatty acids inhibit transient outward and ultra-rapid delayed rectifier K+currents and Na+current in human atrial myocytes". Cardiovasc Res. 81 (2): 286–93. doi:10.1093/cvr/cvn322. PMID 19029136. 38. ^ Khawaja, Owais; Gaziano, J. Michael; Djoussé, Luc (1 February 2012). "A meta-analysis of omega-3 fatty acids and incidence of atrial fibrillation". Journal of the American College of Nutrition. 31 (1): 4–13. doi:10.1080/07315724.2012.10720003. ISSN 1541-1087. PMID 22661621. S2CID 30454093. 39. ^ Nair, G. M.; Connolly, S. J. (2008). "Should patients with cardiovascular disease take fish oil?". Canadian Medical Association Journal. 178 (2): 181–82. doi:10.1503/cmaj.071654. PMC 2174997. PMID 18195293. 40. ^ Rizos, E. C.; Ntzani, E. E.; Bika, E; Kostapanos, MS; Elisaf, MS (2012). "Association Between Omega-3 Fatty Acid Supplementation and Risk of Major Cardiovascular Disease Events: A Systematic Review and Meta-analysis". Journal of the American Medical Association. 308 (10): 1024–33. doi:10.1001/2012.jama.11374. PMID 22968891. 41. ^ Aung, Theingi; Halsey, Jim; Kromhout, Daan; Gerstein, Hertzel C.; Marchioli, Roberto; Tavazzi, Luigi; Geleijnse, Johanna M.; Rauch, Bernhard; Ness, Andrew; Galan, Pilar; Chew, Emily Y. (1 March 2018). "Associations of Omega-3 Fatty Acid Supplement Use With Cardiovascular Disease Risks: Meta-analysis of 10 Trials Involving 77 917 Individuals". JAMA Cardiology. 3 (3): 225–233. doi:10.1001/jamacardio.2017.5205. ISSN 2380-6583. PMC 5885893. PMID 29387889. 42. ^ Abdelhamid, Asmaa S; Brown, Tracey J; Brainard, Julii S; Biswas, Priti; Thorpe, Gabrielle C; Moore, Helen J; Deane, Katherine HO; AlAbdulghafoor, Fai K; Summerbell, Carolyn D; Worthington, Helen V; Song, Fujian (18 July 2018). "Omega-3 fatty acids for the primary and secondary prevention of cardiovascular disease". Cochrane Database of Systematic Reviews. 7: CD003177. doi:10.1002/14651858.cd003177.pub3. ISSN 1465-1858. PMC 6513557. PMID 30019766. 43. ^ "Omega-3 fatty acids, fish oil, alpha-linolenic acid". Retrieved 4 February 2014. 44. ^ Montgomery P, Richardson AJ (2008). Montgomery P (ed.). "Omega-3 fatty acids for bipolar disorder". Cochrane Database of Systematic Reviews (2): CD005169. doi:10.1002/14651858.CD005169.pub2. PMID 18425912. 45. ^ Martins, Julian G (2009). "EPA but Not DHA Appears to Be Responsible for the Efficacy of Omega-3 Long Chain Polyunsaturated Fatty Acid Supplementation in Depression: Evidence from a Meta-Analysis of Randomized Controlled Trials". Journal of the American College of Nutrition. 28 (5): 525–42. doi:10.1080/07315724.2009.10719785. PMID 20439549. S2CID 26466917. 46. ^ Bloch, M H; Hannestad, J (2011). "Omega-3 fatty acids for the treatment of depression: Systematic review and meta-analysis". Molecular Psychiatry. 17 (12): 1272–82. doi:10.1038/mp.2011.100. PMC 3625950. PMID 21931319. 47. ^ Grosso, G.; Pajak, A.; Marventano, S.; Castellano, S.; Galvano, F.; Bucolo, C.; Caraci, F. (2014). "Role of Omega-3 Fatty Acids in the Treatment of Depressive Disorders: A Comprehensive Meta-Analysis of Randomized Clinical Trials". PLOS ONE. 9 (5): e96905. Bibcode:2014PLoSO...996905G. doi:10.1371/journal.pone.0096905. PMC 4013121. PMID 24805797. 48. ^ Sifferlin, Alexandra (13 June 2012). "Fish Oil Fail: Omega-3s May Not Protect Brain Health After All". Time. Retrieved 19 June 2012. 49. ^ Wolters, M. (2005). "Diet and psoriasis: experimental data and clinical evidence". British Journal of Dermatology. 153 (4): 706–14. doi:10.1111/j.1365-2133.2005.06781.x. PMID 16181450. S2CID 1426074. 50. ^ a b Jensen, Craig L.; Voigt, Robert G.; Llorente, Antolin M.; Peters, Sarika U.; Prager, Thomas C.; Zou, Yali L.; Rozelle, Judith C.; Turcich, Marie R.; Fraley, J. Kennard; Anderson, Robert E.; Heird, William C. (2010). "Effects of Early Maternal Docosahexaenoic Acid Intake on Neuropsychological Status and Visual Acuity at Five Years of Age of Breast-Fed Term Infants". The Journal of Pediatrics. 157 (6): 900–05. doi:10.1016/j.jpeds.2010.06.006. PMID 20655543. 51. ^ Calder, Philip C.; Kremmyda, Lefkothea-Stella; Vlachava, Maria; Noakes, Paul S.; Miles, Elizabeth A. (2010). "Is there a role for fatty acids in early life programming of the immune system?". Proceedings of the Nutrition Society. 69 (3): 373–80. doi:10.1017/S0029665110001552. PMID 20462467. 52. ^ Lev-Tzion, R; Griffiths, AM; Leder, O; Turner, D (28 February 2014). "Omega 3 fatty acids (fish oil) for maintenance of remission in Crohn's disease". The Cochrane Database of Systematic Reviews. 2 (2): CD006320. doi:10.1002/14651858.CD006320.pub4. PMID 24585498. 53. ^ a b c "ConsumerLab.com Finds Quality Problems with Nearly Thirty Percent of Fish Oil Supplements Reviewed; "Fishy" Claims Identified: Softgels and Liquids for Adults, Children and Pets Tested, Including Krill Oil and Algal Oil Supplements". ConsumerLab.com. 28 September 2010. Retrieved 20 October 2012.[dubious – discuss] 54. ^ Reviews of Supplements and Health Products ConsumerLab. 55. ^ Schecter, A.; Cramer, P.; Boggess, K.; Stanley, J.; Olson, J. R. (1 April 1997). "Levels of dioxins, dibenzofurans, PCB and DDE congeners in pooled food samples collected in 1995 at supermarkets across the United States". Chemosphere. 34 (5–7): 1437–47. Bibcode:1997Chmsp..34.1437S. doi:10.1016/s0045-6535(97)00440-2. ISSN 0045-6535. PMID 9134677. 56. ^ a b Aursand, Marit; Mozuraityte, Revilija; Hamre, Kristin; Knutsen, Helle; Maage, Amund; Arukwe, Augustine (2011). Description of the processes in the value chain and risk assessment of decomposition substances and oxidation products in fish oils (PDF). Norwegian Scientific Committee for Food Safety. ISBN 978-82-8259-035-8. Archived from the original (PDF) on 9 September 2016. Retrieved 19 October 2012.[page needed] 57. ^ a b c d e "ConsumerLab.com Review: Fish Oil and Omega-3 Fatty Acid Supplements Review (Including Krill, Algae, and Calamari Oil)". ConsumerLab.com. 13 August 2012. Retrieved 19 October 2012.(registration required) 58. ^ Raatz, SK; Redmon, JB; Wimmergren, N; Donadio, JV; Bibus, DM (2009). "Enhanced absorption of omega-3 fatty acids after emulsified compared with encapsulated fish oil". Journal of the American Dietetic Association. 109 (6): 1076–81. doi:10.1016/j.jada.2009.03.006. PMC 2701654. PMID 19465191. 59. ^ Yılmaz, Emin; Öǧütcü, Mustafa; Arifoglu, Nazan (2015). "Assessment of Thermal and Textural Characteristics and Consumer Preferences of Lemon and Strawberry Flavored Fish Oil Organogels". Journal of Oleo Science. 64 (10): 1049–1056. doi:10.5650/jos.ess15113. PMID 26369597. 60. ^ Bays H E (19 March 2007). "Safety Considerations with Omega-3 Fatty Acid Therapy". The American Journal of Cardiology. 99 (6 (Supplement 1)): S35–S43. doi:10.1016/j.amjcard.2006.11.020. PMID 17368277. 61. ^ "Prescription fish oil pill lowers heart attack risk in those already on statins". medicalxpress.com. Retrieved 25 September 2019. 62. ^ "AHA Endorses Prescription Fish Oil for High Triglycerides". www.medpagetoday.com. 20 August 2019. Retrieved 25 September 2019. 63. ^ "Heart Experts Support Use of Prescription Fish Oil". WebMD. Retrieved 25 September 2019. 64. ^ "Omega-3 Fish Oil: Supplements and Prescriptions". WebMD. Retrieved 25 September 2019. 65. ^ "Epanova (omega-3-carboxylic acids) capsules, for oral use". DailyMed. 8 September 2014. Retrieved 12 May 2020. 66. ^ "Drug Approval Package: Epanova (Omega-3-carboxylic acids)". U.S. Food and Drug Administration (FDA). 28 March 2016. Retrieved 12 May 2020. 67. ^ "Epanova". Drug Information Portal. Retrieved 12 May 2020. 68. ^ Nicholls, Stephen J.; Lincoff, A. Michael; Bash, Dianna; Ballantyne, Christie M.; Barter, Philip J.; Davidson, Michael H.; Kastelein, John J. P.; Koenig, Wolfgang; et al. (2018). "Assessment of omega-3 carboxylic acids in statin-treated patients with high levels of triglycerides and low levels of high-density lipoprotein cholesterol: Rationale and design of the STRENGTH trial". Clinical Cardiology. 41 (10): 1281–1288. doi:10.1002/clc.23055. PMC 6489732. PMID 30125052. 69. ^ "AstraZeneca to discontinue Epanova trial, expects $100 million writedown". Reuters. 13 January 2020. Retrieved 15 January 2020. 70. ^ "Lovaza- omega-3-acid ethyl esters capsule, liquid filled". DailyMed. 3 April 2019. Retrieved 12 May 2020. 71. ^ "Lovaza: FDA-Approved Drugs". U.S. Food and Drug Administration (FDA). Retrieved 15 January 2020. 72. ^ "Drug Approval Package: Omacor (Omega-3-Acid Ethyl Esters) NDA #021654". U.S. Food and Drug Administration (FDA). Retrieved 12 May 2020. 73. ^ "Lovaza". Drug Information Portal. Retrieved 12 May 2020. 74. ^ "Omtryg- omega-3-acid ethyl esters capsule". DailyMed. 31 March 2016. Retrieved 12 May 2020. 75. ^ "Drug Approval Package: Brand Omtryg capsules NDA 204977". U.S. Food and Drug Administration (FDA). 18 December 2014. Retrieved 12 May 2020. 76. ^ "Omtryg". Drug Information Portal. Retrieved 12 May 2020. 77. ^ "Vascepa- icosapent ethyl capsule". DailyMed. 30 January 2020. 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"Hypervitaminosis a and Fractures". New England Journal of Medicine. 348 (4): 347–49. doi:10.1056/NEJMe020167. PMID 12540650. 92. ^ Jess Halliday (13 April 2006). "Dioxins prompt second UK fish oil withdrawal". Retrieved 8 February 2007. 93. ^ "Pollutants found in fish oil capsules". BBC News. 6 April 2002. Retrieved 8 February 2007. 94. ^ International Fish Oil Standards Archived 18 May 2012 at the Wayback Machine. 95. ^ Elisabeth Leamy (3 March 2010). "Lawsuit Raises Fish Oil Supplement Concerns". Retrieved 5 March 2010. 96. ^ "Lawsuit says fish oil supplements contain PCB", San Francisco Chronicle, 3 March 2010. 97. ^ Brustad, Magritt; Sandanger, Torkjel Manning; Andersen, Vegard; Lund, Eiliv (2007). "POP exposure from fish liver consumption and risk of cancer?the Norwegian Women and Cancer Study". Journal of Environmental Monitoring. 9 (7): 682–6. doi:10.1039/B706302B. PMID 17607388. 98. ^ Foran, Stacy E.; Flood, James G.; Lewandrowski, Kent B. (2003). "Measurement of Mercury Levels in Concentrated Over-the-Counter Fish Oil Preparations: Is Fish Oil Healthier Than Fish?". Archives of Pathology & Laboratory Medicine. 127 (12): 1603–05. doi:10.1043/1543-2165(2003)127<1603:MOMLIC>2.0.CO;2 (inactive 10 January 2021). PMID 14632570.CS1 maint: DOI inactive as of January 2021 (link) 99. ^ Doughman, Scott D.; Krupanidhi, Srirama; Sanjeevi, Carani B. (2007). "Omega-3 Fatty Acids for Nutrition and Medicine: Considering Microalgae Oil as a Vegetarian Source of EPA and DHA". Current Diabetes Reviews. 3 (3): 198–203. doi:10.2174/157339907781368968. PMID 18220672. ## Further reading[edit] * FAO (1986) The production of fish meal and oil FAO Fishery Technical Paper 142. ISBN 92-5-102464-2. ## External links[edit] Wikimedia Commons has media related to Fish oil. * International Fish Oil Standards — An organization concerned with the quality of omega-3 products as it relates to the international standards established by the World Health Organization and the Council For Responsible Nutrition for purity and concentration. * Joyce A. Nettleton, ed. "PUFA Newsletter". Retrieved 20 February 2006.CS1 maint: extra text: authors list (link) Two newsletters, both quarterly, reviewing recent publications in essential fatty acids. One is written for researchers, the second is for consumers. Industry sponsored, academic contributors. * Omega-3 Fatty Acids American Cancer Society. Updated 11 January 2008. * v * t * e Seafood Fish * Anchovy * Barramundi * Billfish * Carp * Catfish * Cod * Eel * Flatfish * Flounder * Herring * Mackerel * Salmon * Sardine * Shark * Sturgeon * Swordfish * Tilapia * Trout * Tuna * Whitebait Shellfish * Abalone * Cockles * Conch * Crab meat * Crayfish * Geoduck * Krill * Lobster * Mussels * Oysters * Scallops * Shrimp * Sea urchins * Crustaceans * Molluscs Other seafood * Edible seaweed * Jellyfish * Marine mammals * Octopus * Sea cucumber * Squid * Whale meat * Sea vegetables * Algae * List of seafoods * more... Processed seafood * Caviar * Dried fish * Hutki Shira * Canned fish * Cod liver oil * Cured fish * Fermented fish * Fish fillet * Fish head * Fish oil * Fish sauce * Fish paste * Fish steak * Fish stock * Lutefisk * Salted fish * Salted squid * Shark liver oil * Shrimp paste * Smoked fish * Stockfish * Surimi * Roe * more... 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Morel's ear is the complete or partial absence of the helix or antihelix of the outer ear. Named after Bénédict Morel, a French psychiatrist who regarded it as one of the hereditary "stigmata of degeneration" that allowed medical professions to identify the mentally ill.[1] Marcel Proust referenced Morel's ear in In Search of Lost Time. When Charles Morel says he would like to seduce a virgin, his companion responds first of all with a gesture: "M. de Charlus could not refrain from pinching Morel's ear."[2] ## References[edit] 1. ^ Erwin J. Haeberle, "'Stigmata of Degeneration': Prisoner Markings in Nazi Concentration Camps," Journal of Homosexuality, vol. 6, 1980/81, 135-139, available online Archived 2011-04-21 at the Wayback Machine, accessed January 3, 2012 2. ^ Patrick Alexander, Marcel Proust's Search for Lost Time: A Reader's Guide (), 88, availbel online, accessed January 3, 2012 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	Morel's ear	None	1,744	wikipedia	https://en.wikipedia.org/wiki/Morel%27s_ear	2021-01-18T18:49:17	{"wikidata": ["Q6911278"]}
Donnai and Winter (1989) presented examples of 5 fetuses and 1 newborn with abnormalities difficult to explain on the basis of amniotic bands (see 217100) and suggested that these may result from a mutant gene, the homolog of the mouse mutant 'disorganization' (Ds). The mouse mutant is a semidominant with variable expression in heterozygotes and lethality in homozygotes (Hummel, 1959). Donnai and Winter (1989) reviewed the features of the mouse mutation including the high frequency of limb duplications, usually involving a single limb; polydactyly, sometimes of high degree and undifferentiated; and limbs originating from abnormal sites. Human cases of the same nature were collected from the literature and a new case was added. Winter and Donnai (1989), in reporting a patient with striking congenital defects including 9 toes on the right leg and a fingerlike structure arising from the abdomen, suggested that such cases may represent the human homolog of mice heterozygous for the single 'disorganisation' (Ds) semidominant gene. Lin (1991) presented another proposed example. Petzel and Erickson (1991) suggested that the 'disorganisation' mutation is responsible for the findings in patients with duplications of internal organs and external structures of the lower half of the body that have traditionally been explained as incomplete twinning. A statistical analysis suggested to Crosby et al. (1993) that occurrence of anomalies in mice with the Ds mutation follows a Poisson distribution. Their results further suggested that congenital anomalies in mice with this mutation occur independently of each other. Crosby et al. (1993) proposed that Ds causes a heritable predisposition to congenital anomalies and that Ds combined with appropriate somatic events compromises normal development. They also proposed that some sporadic, nonheritable congenital anomalies involve somatic mutations at Ds-like loci. They pictured some typical anomalies including polydactyly of the limb of the duplication type (135750, 188740). The parallelism to the Knudson hypothesis for cancer is obvious. In that case also, the statistical approach demonstrating a Poisson distribution for the number of tumors per eye for retinoblastoma (Knudson, 1971) or per kidney for Wilms tumor (Knudson and Strong (1972)) supported a random distribution for a second hit. Lowry and Yong (1991) described 2 Chinese brothers with cleft lip/palate, profound sensorineural deafness, and a sacral lipoma. One had aberrant digital appendages on the heel and thigh, whereas the other had an anterior sacral meningocele and dislocated hip. Intelligence was normal in both. Both boys suffered from functional constipation, but biopsy studies showed no evidence of Hirschsprung disease. The parents were normal and unrelated. Lowry and Yong (1991) suggested that this mutation might be homologous to 'disorganisation,' located on chromosome 14 of the mouse (Hummel (1958, 1959)). Robin et al. (1993) reported 2 unrelated patients with malformations similar to those in mice with the Ds mutation. The first case had a body wall defect, limb malformations and hamartoma, while the second case had a partially duplicated foot, as well as other anomalies. They discussed the findings in relation to the 2-hit hypothesis of Crosby et al. (1993): that there is a heritable predisposition and that a 'second hit,' either somatic mutation or an epigenetic event, determines the type of malformation. They considered the hypothesis attractive because it explained both the low penetrance and the variable expression of the Ds mutation. Woods et al. (1995) described a male infant with a partial foot with 2 toes arising from the right buttock, hypoplasia of the right leg and right foot, absence of the right kidney, and severe hypoplasia of the right common iliac artery. The infant's karyotype was 47,XXY. Woods et al. (1995) discussed a possible role of arterial hypoplasia in the origin of limb underdevelopment. Onal et al. (2005) reported a newborn infant with defects similar to those seen in mice heterozygous for the mutant Ds gene. The child had left popliteal webbing, left iliac bone hypoplasia, bifid scrotum, hypospadias, chordee deformity of the penis, and a sacral dimple. Other anomalies included absence of the right kidney and a hamartomatous tubular skin pedicle on the left thigh. No obvious amniotic bands or oligohydramnios were noted. The similarity between the proband's anomalies, those in previously reported cases, and those found in mice supported the possibility of a human homolog of the Ds gene. Isidor et al. (2009) reported 6 patients with congenital pedicle skin hamartomatous lesions. Two patients showed a single skin pedicle lesion; 1 of these was shown to have 22q11.2 deletion, and 4 patients had, in addition to the single skin pedicle, severe limb anomalies for which they were originally diagnosed with amniotic band sequence (217100). Isidor et al. (2009) proposed that all of these infants instead showed various forms of a phenotype resembling Ds in the mouse and suggested that this phenotype may be associated with apparent amniotic band syndrome. They proposed calling this 'amniotic band syndrome plus.' All patients were the children of nonconsanguineous parents. Patient 1 of Isidor et al. (2009) had multiple anomalies including limb defects, constriction rings, partial syndactyly, and a pedicle skin lesion on the occipital region. The skin pedicle was removed at 12 months of age and showed a tuberous hamartomatous lesion. Patient 2 had multiple anomalies including limb defects and a pedicle skin lesion on the vertex; a pedicular skin lesion on the vertex had also been present in the maternal grandfather and great-grandfather. Constriction rings were present on the proximal phalanx of the second, third, and fourth digits of the left hand, with distal amputation of the last phalanx of the index finger. Lower limbs were normal except for equinovarus feet. Patient 3 had multiple limb anomalies, constriction rings, and a pedicle skin lesion on the back. A pedicular skin lesion was also present at the external side of the right ankle with a hemicircumferential constriction ring. Patient 4 had a right cleft lip, detected by ultrasound at 20 weeks' gestation, as well as limb defects, constriction rings, partial syndactyly, and a pedicle skin lesion on the head. Patient 5 had a lumbar fingerlike pedicle and bifid uvula. Spinal cord MRI was normal apart from this pedicle skin lesion at the level of L2-L3 which seemed to be linked to L4 by a fibrous tract. At 6 years of age, nasal speech and speech delay were noted. Physical exam showed small round ears, small mouth, and iris heterochromia. Brain MRI showed frontal polymicrogyria. Chromosome and FISH analyses were performed and showed a 46,XX karyotype with 22q11.2 microdeletion. Patient 6 had a dorsal fingerlike pedicle. Examination was otherwise normal apart from a single palmar crease on the left hand. Axial skeleton x-ray showed 11 pairs of ribs. MRI showed absence of fusion of the posterior arch of S1. Except for the patient with 22q11.2 microdeletion, neurologic examination and psychomotor development was normal. Purandare et al. (2009) reported 4 patients with developmental anomalies seen in amniotic band sequence, with additional anomalies that could not be explained by amniotic bands alone. The anomalies seen in their patients included facial malformation and clefting, brain anomalies (encephalocele, agenesis of the corpus callosum, holoprosencephaly), eye anomalies (anophthalmia, microphthalmia, and microcornea), and extremity and digit anomalies (talipes equinovarus, syndactyly). Other phenotypic features included genitourinary anomalies (hydronephrosis and abnormal testes, epididymis, and seminal vesicles) and skin appendages similar to those seen in Ds mice. Presence of amniotic bands in addition to malformations not attributed to amniotic bands were seen in 3 of 4 patients. Purandare et al. (2009) concluded that the 4 patients in their report had involvement of at least 4 organ systems, including the skin appendages, that had been reported in the Ds mouse, and had clinical findings that overlap the spectrum of Ds and amniotic band sequence. Patient 1 had anterior encephalocele, hypertelorism, Tessier 4-5 facial cleft, bilateral microphthalmia, and microcornea, rudimentary nose, talipes equinovarus, and skin appendages/hamartomas near the right eye and over the right forearm. The patient expired on day 4 of life due to respiratory complications. Patient 2 had left superior facial disruption of the nose and midline facial structures by amniotic bands including severe clefting of the midline external soft tissues and bony structures. There was amputation of the left upper extremity at the level of the distal humerus. Various brain anomalies included frontal encephalocele, periventricular leukomalacia, and agenesis of the corpus callosum. This patient survived a few hours. Patient 3, who survived for 57 minutes, had a large omphalocele with amniotic bands attached to the umbilical cord. This band attached at the opposite end to the tip of a cutaneous polyp on the inner surface of the right upper arm. Cleft lip and palate, disruption of the nose, and disruption and displacement of the eyes with anophthalmia/microphthalmia was also seen. The base of the skull was abnormal and had a shallow sella turcica with absent pituitary. An ectopic pituitary was present in the nasopharyngeal submucosa. The karyotype of the fourth patient, delivered as spontaneous intrauterine fetal demise, showed mosaicism for trisomy 3. There were severe facial clefts involving palate, lip, nose, and right eyelid. There was a left-sided body wall defect from left pleural apex to sacral level and from midline to posterior body wall with absence of the left chest wall. The left upper extremity was attached near the dorsal pelvis. Animal Model Robin et al. (1997) gave an extensive review of the Ds mutation in mice, pointing out that the range of malformations is so great that no 2 affected mice are identical. Most affected mice have only a single malformation, and most of these malformations are similar to both common (neural tube defects, orofacial clefting, gastroschisis, limb reductions) and rare (anophthalmia, duplicated rectum) human birth defects. Robin et al. (1997) suggested that the low penetrance (under 30%) and highly variable expression of Ds make it a paradigm for understanding the genetic basis for many seemingly sporadic birth defects of humans. Skel \- Limb duplication \- Polydactyly \- Limbs originating from abnormal sites \- Aberrant digital appendages \- Sacral lipoma \- Sacral meningocele \- Dislocated hip Inheritance \- Autosomal recessive Abdomen \- Duplication of internal organs HEENT \- Cleft lip/palate \- Sensorineural deafness ▲ 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	DISORGANIZATION, MOUSE, HOMOLOG OF	c1857230	1,745	omim	https://www.omim.org/entry/223200	2019-09-22T16:28:40	{"omim": ["223200"], "synonyms": ["Alternative titles", "DS"]}
A number sign (#) is used with this entry because spinal muscular atrophy type II (SMA2) is caused by homozygous or compound heterozygous mutation in the SMN1 gene (600354) on chromosome 5q13. The SMN1 gene is also involved in the more severe SMA type I (253300) and the less severe SMA type III (253400) and SMA type IV (271150). Description Spinal muscular atrophy refers to a group of autosomal recessive neuromuscular disorders characterized by degeneration of the anterior horn cells of the spinal cord, leading to symmetric muscle weakness and atrophy (summary by Wirth, 2000). Clinical Features Fried and Emery (1971) suggested the existence of a distinct form of spinal muscular atrophy intermediate in severity between the infantile form SMA type I and juvenile form SMA III. The intermediate form, which they designated SMA II, is characterized by onset usually between 3 and 15 months and survival beyond 4 years and usually until adolescence or later. Proximal muscle weakness is the cardinal feature as in other forms of spinal muscular atrophy. They presented 14 cases, of whom 2 were sibs. The parents were all unaffected and nonconsanguineous. Imai et al. (1995) demonstrated peripheral but not central conduction abnormalities in patients with SMA II. Pearn et al. (1973) used a method of sib-sib correlation introduced by Haldane (1941) to support the existence of separate 'acute' and 'chronic' forms of spinal muscular atrophy. Hanson and Bundey (1974) described 2 brothers in a sibship of 4. They suggested that SMA I and SMA III may be due to homozygosity of allelic genes, and SMA II could represent the genetic compound. Hausmanowa-Petrusewicz et al. (1985) referred to this as the infantile chronic form of SMA. Imai et al. (1995) demonstrated peripheral but not central conduction abnormalities in patients with SMA II. Mapping On the basis of 13 clinically heterogeneous SMA families, Brzustowicz et al. (1990) concluded that 'chronic' childhood-onset SMA (including intermediate SMA, or SMA type II, and Kugelberg-Welander syndrome, or SMA type III) is genetically homogeneous, mapping to chromosomal region 5q11.2-q13.3. Their data indicated that the acute childhood SMA (type I or Werdnig-Hoffmann disease) maps to the same or a closely linked locus on 5q. The findings suggested that all 3 forms of SMA, types I, II, and III, are allelic. In 24 multiplex families of distinct ethnic origin with chronic forms of proximal SMA, i.e., types II and III, Melki et al. (1990) demonstrated linkage to the DNA marker D5S39, thus mapping the locus to 5q12-q14. No evidence for genetic heterogeneity for types II and III was found. To confirm the localization of the chronic forms of SMA, types II and III, to 5q12-q14 and to test for genetic homogeneity in the French-Canadian population, Simard et al. (1992) studied 8 families. They showed tight linkage to marker locus D5S39 and loose linkage to D5S6. They also presented a family that appeared to be discordant for the localization on chromosome 5; however, the family contained an apparently asymptomatic individual who was shown to be homozygous for the mutant SMA alleles. ### Genetic Heterogeneity In a linkage study of 161 families in which individuals suffered from the intermediate or mild form of SMA, Merette et al. (1994) found support for the hypothesis of linkage heterogeneity, with 5% of the families unlinked to the region 5q11.2-q13.3. Nevo et al. (1998) presented evidence that there may be a form of type II SMA (intermediate SMA with onset between 3 and 18 months) that is unrelated to the SMN1 region on 5q13. Molecular Genetics Matthijs et al. (1996) used an SSCP assay for the molecular diagnosis of 58 patients with SMA, including 12 patients (7 Belgian and 5 Turkish) with SMA II. This assay discriminates between the SMN gene (600354) and the almost identical centromeric BCD541 repeating unit. In 11 of the 12 patients, homozygous deletion of exon 7 of the SMN gene was detected. Of these 11, the deletion was associated with homozygous deletion of exon 8 in 10 and with heterozygous deletion of exon 8 in 1. Deletion of the SMN gene was not found in 1 Turkish patient with atypical manifestations of SMA II. Samilchuk et al. (1996) carried out deletion analysis of the SMN gene and the neighboring NAIP (600355) gene in 11 cases of type I SMA and in 4 type II SMA cases. The patients were of Kuwaiti origin. They also analyzed samples from 41 healthy relatives of these patients and 44 control individuals of Arabic origin. Samilchuk et al. (1996) found homozygous deletions of exons 7 and 8 of the SMN gene in all SMA patients studied. Exon 5 of the NAIP gene was homozygously absent in all type I SMA patients but was retained in the type II patients. They noted that there findings were consistent with the previously reported observations that the incidence of NAIP deletion is much higher in the clinically more severe cases (type I SMA) than in the milder forms, and all of the type II SMA patients in their study had at least one copy of the intact NAIP gene. ### Modifying Factors Jedrzejowska et al. (2008) reported 3 unrelated families with asymptomatic carriers of the 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 (601627). 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. 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. Biochemical Features 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. 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. History Brzustowicz et al. (1990) noted that HEXB (606873) maps to the same region and that deficiency of the product of this gene (as well as of the product of the HEXA gene) has been found in association with chronic cases of SMA. INHERITANCE \- Autosomal recessive NEUROLOGIC Central Nervous System \- Muscle weakness, symmetric, proximal (lower limbs more affected than upper limbs) due to motor neuronopathy \- Muscle atrophy \- EMG shows neurogenic abnormalities \- Tongue fasciculation/fibrillation \- Degeneration of anterior horn cells \- Hand tremor MISCELLANEOUS \- Presentation between 6-18 months \- Death between 2 years of age and young adulthood \- Death secondary to respiratory infection or failure \- Child often can sit unsupported but never ambulates \- Deletions in NAIP gene ( 600355 ) found in 18% of SMAII patients MOLECULAR BASIS \- Caused by mutation in the survival of motor neuron 1 gene (SMN1, 600354.0002 ) ▲ 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	SPINAL MUSCULAR ATROPHY, TYPE II	c0393538	1,746	omim	https://www.omim.org/entry/253550	2019-09-22T16:24:55	{"doid": ["0050530"], "mesh": ["D014897"], "omim": ["253550"], "orphanet": ["70", "83418"], "synonyms": ["SMA II", "MUSCULAR ATROPHY, SPINAL, INFANTILE CHRONIC FORM", "Alternative titles", "SMA", "MUSCULAR ATROPHY, SPINAL, INTERMEDIATE TYPE"], "genereviews": ["NBK1352"]}
This article is about the condition. For the film, see Red Tears. For the VV Brown song, see Crying Blood. Haemolacria is a physical condition that causes a person to produce tears that are partially composed of blood. It can manifest as tears that are anything from merely red-tinged to appearing to be entirely made of blood. Haemolacria is a symptom of a number of diseases,[1] and may also be indicative of a tumor in the lacrimal apparatus. It is most often provoked by local factors such as bacterial conjunctivitis, environmental damage or injuries.[2] Acute haemolacria can occur in fertile women and seems to be induced by hormones,[2] similarly to what happens in endometriosis. ## Contents * 1 History * 2 See also * 3 References ## History[edit] Twinkle Dwivedi From Lucknow, India, Dwivedi presented a rare condition that appeared to cause her to spontaneously bleed from her eyes and other parts of her body without presenting any visible wounds.[3] Dwivedi was the subject of numerous medical research studies and TV shows including Body Shock[4] and a National Geographic documentary.[5] In the absence of a medical explanation for her condition, some religious explanations have been posed. It was suggested that she could have had an unknown disease, but more skeptical views hypothesized that the case might be explained by Münchausen syndrome by proxy, where her mother, seemingly the only one to witness her bleeding actually starting, was fabricating the story and somehow inducing the effect on the girl.[6] Sanal Edamaruku observed in 2010 that the pattern seemed to match her menstrual cycle and believed that she was faking the symptoms.[7] Calvino Inman Aged 22, reported to weep tears of blood 5 times a day.[8] Rashida Khatoon From India, was reportedly crying blood up to five times a day in 2009, and fainting with every weeping.[9] Débora Santos Age 17, from Brazil. Was reported to have cried tears of blood several times in her life.[10] Yaritza Oliva (not officially diagnosed) Age 21, from Chile. Was reported to have cried tears of blood several times a day in 2013.[11] Linnie Ikeda (not officially diagnosed) Age 25, from Waikele, Hawai'i on the island of 'O'ahu. She was diagnosed after 2008 with Gardner–Diamond syndrome for her random bruising, but in 2010 had symptoms of the splitting of her tongue which would bleed profusely. In 2011, Ikeda has started bleeding from her eyes.[12] Marnie-Rae Harvey (not officially diagnosed) Age 17, from the United Kingdom. Started in 2013 with initially coughing up blood but now persists in her tears since 2015.[13] Sakhina Khatun From BHAGWANGOLA, MURSHIDABAD, WEST BENGAL, India, was reportedly crying blood many times a day in 2019, and fainting with every weeping.[14] Nicole Nayan ( not officially diagnosed ) Grade School Student From Philippines Reportedly Crying blood Every Friday .,[1] ## See also[edit] * Le Chiffre, a fictional character who suffers from haemolacria in Casino Royale * Hematidrosis – blood in sweat ## References[edit] 1. ^ Ahluwalia, BK; Khurana AK; Sood S (Jan–Feb 1987). "Bloody tears (jddfcj)". Indian Journal of Ophthalmology. 35 (1): 41–43. PMID 3450614. 2. ^ a b Ottovay E, Norn M (August 1991). "Occult haemolacria in females". Acta Ophthalmol (Copenh). 69 (4): 544–6. doi:10.1111/j.1755-3768.1991.tb02038.x. PMID 1750328. S2CID 8298926. 3. ^ "Doctor probes mystery of girl who cries blood". MSNBC Today. 2009-09-11. Archived from the original on 2009-09-18. Retrieved 2010-04-29. 4. ^ "Girl Who Cries Blood". Bodyshock. Retrieved 2010-04-29. 5. ^ "Filming "The Girl Who Cries Blood"". National Geographic. Archived from the original on 2010-04-13. Retrieved 2010-04-29. 6. ^ Sutcliffe, Tom (2010-01-13). "Last Night's Television – Muslim Driving School, BBC2; Girl Who Cries Blood, Channel 4; The Man Who Couldn't Stop Hiccuping, BBC1". The Independent UK. London. Retrieved 2010-04-29. 7. ^ "When I met the 'girl who cries blood'". The Guardian. 12 May 2010. 8. ^ "Adolescente americano chora sangue até três vezes por dia, diz site". 9. ^ "Indian Girl Cries Tears of Blood". 2009-05-14. 10. ^ Kleber Tomaz (28 June 2011). "Médicos investigam caso de garota que 'chora' sangue no interior de SP". 11. ^ "WATCH: Tears Of Blood?". Huffington Post. 25 June 2013. 12. ^ Lynn Kawano (13 May 2015). "Woman with uncontrollable bleeding from eyes, mouth looking for 'a bit of hope'". Hawaii News Now. 13. ^ Tracy Ollerenshaw (10 March 2016). "The girl with bleeding eyes and ears – and no diagnosis". BBC News. 14. ^ "Indian Girl Cries Tears of Blood". 2019-09-21. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor *[BMI]: body mass index	Haemolacria	c2747932	1,747	wikipedia	https://en.wikipedia.org/wiki/Haemolacria	2021-01-18T18:46:21	{"umls": ["C2747932"], "wikidata": ["Q2703671"]}
Bleeding disorder due to P2RY12 defect affects the way the platelets function. Platelets are important for helping the blood to clot. Symptoms of a bleeding disorder due to P2RY12 defect include frequent nose bleeds, easy bruising, and excessive bleeding after surgery or an accident. These symptoms can vary from person to person. This condition is very rare and it's not clear how it changes over time. Bleeding disorder due to a P2RY12 defect occur due to a variant in the P2RY12 gene and is inherited in an autosomal recessive pattern. Diagnosis is based on the symptoms, clinical exam, and the results of specialized laboratory testing. Treatment is focused on managing the symptoms, and may involve blood transfusions, and/or medications that help the blood clot. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor *[BMI]: body mass index	Bleeding disorder due to P2RY12 defect	c1853278	1,748	gard	https://rarediseases.info.nih.gov/diseases/12478/bleeding-disorder-due-to-p2ry12-defect	2021-01-18T18:01:46	{"mesh": ["C565220"], "omim": ["609821"], "orphanet": ["36355"], "synonyms": ["ADP platelet receptor P2Y12 defect", "P2Y12 defect", "Bleeding disorder due to ADP platelet receptor P2Y12 defect", "Bleeding disorder due to P2Y12 defect", "Bleeding disorder, platelet-type 8", "Bleeding disorder due to P2RX1 defect, somatic"]}
Hawkinsinuria is an inborn error of tyrosine metabolism characterized by failure to thrive, persistent metabolic acidosis, fine and sparse hair, and excretion of the unusual cyclic amino acid metabolite, hawkinsin ((2-l-cystein-S-yl, 4-dihydroxycyclohex-5-en-1-yl)acetic acid), in the urine. ## Epidemiology The prevalence is unknown, but the disease appears to be very rare with only a small number of affected families reported in the literature. ## Clinical description Symptoms manifest in infants fed on formula or cow's milk or after weaning from breast milk. ## Etiology The disorder is transmitted as an autosomal dominant trait and is caused by an A33T mutation in 4-hydroxyphenylpyruvic acid dioxygenase (4-HPPD), an enzyme that catalyses the conversion of hydroxyphenylpyruvate to homogentisate. ## Diagnostic methods The diagnosis is confirmed by detection of characteristic tyrosine metabolites by organic acid analysis of the urine. ## Management and treatment Patients are treated with ascorbic acid and a low-protein diet (in particular, restricted phenylalanine and tyrosine intake). On this diet, the patients grow normally and the metabolic acidosis resolves. ## Prognosis The prognosis for hawkinsinuria patients is good: although patients continue to excrete hawkinsin in their urine, the symptoms improve significantly after the first year of life and the children appear to be asymptomatic by the time they reach late childhood. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor *[BMI]: body mass index	Hawkinsinuria	c2931042	1,749	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=2118	2021-01-23T19:08:04	{"gard": ["5668"], "mesh": ["C535845"], "omim": ["140350"], "umls": ["C2931042"], "icd-10": ["E70.2"], "synonyms": ["4-HPPD deficiency", "4-alpha-hydroxyphenylpyruvate hydroxylase deficiency", "4-hydroxyphenylpyruvic acid dioxygenase deficiency"]}
Spondyloepimetaphyseal dysplasia, aggrecan type is a new form of skeletal dysplasia characterized by severe short stature, facial dysmorphism and characteristic radiographic findings. ## Epidemiology To date, three cases have been described, all originating from the same family. ## Clinical description Facial features include midface hypoplasia with almost absent nasal cartilage, and relative prognathism and macrocephaly. Radiographic findings include irregular epiphyses of long bones with widened metaphyses, platyspondyly, multiple cervical-vertebral clefts and brachydactyly. ## Etiology The disease results from a missense mutation affecting the C-type lectin domain of aggrecan (AGC1 gene; chromosome 15) which regulates endochondral ossification. Transmission is autosomal-recessive. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor *[BMI]: body mass index	Spondyloepimetaphyseal dysplasia, aggrecan type	c2748544	1,750	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=171866	2021-01-23T17:14:45	{"gard": ["10513"], "mesh": ["C567558"], "omim": ["612813"], "umls": ["C2748544"], "icd-10": ["Q77.7"], "synonyms": ["SEMD, aggrecan type"]}
Tyrosinemia type 2 is an inborn error of tyrosine metabolism characterized by hypertyrosinemia with oculocutaneous manifestations and, in some cases, intellectual deficit. ## Epidemiology Prevalence is unknown but less than 150 cases have been reported in the literature so far. The disease appears to be more common in Arab and Mediterranean populations. ## Clinical description Skin lesions occur in 80% of cases, ocular involvement in 75% of cases and neurologic findings and some degree of intellectual deficit in up to 60% of cases. Onset is variable but the ocular symptoms (redness, photophobia, excessive tearing and pain) usually develop in the first year of life. Ocular signs include corneal clouding with bilateral dendritiform corneal lesions (pseudodendritic keratitis), neovascularization, corneal ulceration and scarring, which may lead to decreased visual acuity. Cutaneous manifestations usually begin after the first year of life but may develop at the same time as the ocular symptoms. The skin lesions consist of nonpruritic, hyperkeratotic papules and plaques principally located on the palms and soles (palmoplantar hyperkeratosis). These lesions are painful and progressive and are often associated with hyperhidrosis. Central nervous system (CNS) involvement is highly variable with intellectual deficit (ranging from mild to severe) being the most common manifestation. Other signs of CNS involvement include behavioral problems, nystagmus, tremor, ataxia, and convulsions. ## Etiology Tyrosinemia type 2 is caused by mutations in the TAT gene (16q22.1) encoding tyrosine aminotransferase (TAT). The elevated levels of tyrosine caused by TAT deficiency appear to result in deposition of tyrosine crystals leading to an inflammatory response and the oculocutaneous findings. It has also been suggested that there is a correlation between the extent of the CNS involvement and the levels of tyrosine in the plasma. ## Diagnostic methods Diagnosis is established on the basis of the clinical findings and detection of high levels of plasma and urinary tyrosine, and elevated levels of urinary tyrosine metabolites (such as 4-hydroxyphenylpyruvate, 4-hydroxyphenyllactate, 4-hydroxyphenylacetate and N-acetyltyrosine). TAT assays on liver biopsy samples are usually not necessary for diagnosis. Some patients with tyrosinemia type 2 may be identified through neonatal screening program studies. ## Differential diagnosis As the ocular findings are often the initial manifestations of the disease, the pseudodendritic keratitis is often mistaken for herpes simplex keratitis (see this term). ## Antenatal diagnosis Molecular genetic prenatal diagnosis has been reported in families in which the TAT mutation had already been identified. ## Genetic counseling Tyrosinemia type 2 is transmitted as an autosomal recessive trait ## Management and treatment Management revolves around dietary restriction of phenylalanine and tyrosine. Oral retinoids may also be administered for treatment of the skin lesions. ## Prognosis The controlled diet results in lowering of plasma tyrosine levels and rapid resolution of the oculocutaneous manifestations. However, the extent to which this controlled diet prevents the CNS involvement is unclear. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor *[BMI]: body mass index	Tyrosinemia type 2	c0268487	1,751	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=28378	2021-01-23T18:34:22	{"gard": ["3105"], "mesh": ["D020176"], "omim": ["276600"], "umls": ["C0268487"], "icd-10": ["E70.2"], "synonyms": ["Keratosis palmoplantaris-corneal dystrophy syndrome", "Oculocutaneous tyrosinemia", "Richner-Hanhart syndrome", "Tyrosinemia due to TAT deficiency", "Tyrosinemia due to tyrosine aminotransferase deficiency", "Tyrosinemia type II"]}
Myotonia permanens is a very rare, persistent and more severe form of potassium-aggravated myotonia (PAM, see this term). ## Epidemiology Prevalence is unknown. ## Clinical description Continuous and severe myotonia begins during childhood (usually before 10 years of age) and involves mainly the face, neck, limbs, and thoracic muscles. It can be aggravated by exercise or potassium ingestion and less often by cold. Occasionally, patients have muscle hypertrophy, especially of the neck and shoulders. Paralysis is never observed. Severe stiffness of the pharyngeal and respiratory muscles may provoke episodes of hypoxia and acidosis that can compromise the respiratory function. Close monitoring is necessary during surgery as rigidity and rhabdomyolysis may occur. Depolarizing agents can cause severe ventilation problems due to a paradoxical increase of stiffness in respiratory muscles and must be avoided. ## Etiology Myotonia permanens is a muscle sodium channelopathy due to missense mutations of the SCN4A gene encoding the alpha subunit of the skeletal muscle voltage-gated sodium channel Nav1.4. ## Genetic counseling Transmission is autosomal dominant. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor *[BMI]: body mass index	Myotonia permanens	c2931826	1,752	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=99735	2021-01-23T16:59:11	{"mesh": ["C538353"], "omim": ["608390"], "icd-10": ["G71.1"]}
Autoimmune thyroiditis Other namesChronic Autoimmune thyroiditis SpecialtyEndocrinology Autoimmune thyroiditis, is a chronic disease in which the body interprets the thyroid glands and its hormone products T3, T4 and TSH as threats, therefore producing special antibodies that target the thyroid's cells, thereby destroying it. It may present with hypothyroidism or hyperthyroidism and with or without a goiter.[1] ## Contents * 1 Signs and symptoms * 2 Causes * 2.1 High iodine consumption * 2.2 Age * 3 Mechanism * 4 Diagnosis * 4.1 Categories * 5 Treatment * 6 References * 7 External links ## Signs and symptoms[edit] The symptoms may vary depending on the thyroid function, i.e. hyperthyroidism or hypothyroidism. Hyperthyroidism can cause sweating, rapid heart rate, anxiety, tremors, fatigue, difficulty sleeping, sudden weight loss, and protruding eyes.[2] Hypothyroidism can cause weight gain, fatigue, dry skin, hair loss, intolerance to cold, and constipation.[2] The effects of this disease may be permanent but can sometimes be transient. Symptoms may come and go depending on whether the person receives treatment, and whether the treatment takes effect.[citation needed] ## Causes[edit] Thyroid autoimmunity is familial.[1] The disease is said to be inherited as a dominant trait since it has been reported that as many as fifty percent of the first degree relatives of patients with some type of autoimmune thyroiditis present with thyroid antibodies in serum.[1] Some studies have even related it to chromosome 21 because of its high correlation with patients with Down syndrome and familial Alzheimer disease. This theory is controversial, since patients with Turner syndrome also present a high prevalence of autoimmune thyroiditis (up to fifty percent).[1] ### High iodine consumption[edit] Autoimmune thyroiditis has a higher prevalence in societies that have a higher intake of iodine in their diet, such as the United States and Japan. Also, the rate of lymphocytic infiltration increased in areas where the iodine intake was once low, but increased due to iodine supplementation. “The prevalence of positive serum tests in such areas rises to over 40 percent within 0.5 to 5 years.” [1] ### Age[edit] It has been shown that “the prevalence of positive tests for thyroid antibodies increases with age, with a frequency as high as 33 percent in women 70 years old or older.”[1] The mean age of prevalence in women is higher than in men by one year, (58 and 59 years old respectively).[citation needed]Autoimmune thyroiditis can affect children. It is very rare in children under the age of five, but can occur;it accounts for around 40 percent of cases in adolescents with goiters.[citation needed] People with hypothyroidism over the age of 40 have an increased chance of developing autoimmune thyroiditis.[1] ## Mechanism[edit] Thyroid autoantibodies appear mostly with the presence of lymphocytes in the targeted organ.[1][3] Lymphocytes produce antibodies targeting three different thyroid proteins: Thyroid peroxidase Antibodies (TPOAb), Thyroglobulin Antibodies (TgAb), and Thyroid stimulating hormone receptor Antibodies (TRAb).[1][2] The antibody attacks ultimately lead to hypothyroidism, which is caused by replacement of follicular cells with parenchymatous tissue.[4] Some patients who are healthy may be positive for more than one of these antibodies. Doctors who attend to such patients will most likely do routine follow-ups on the patient's health since, even though it is highly unlikely that they will present any thyroid problems, there is still a chance that they will develop some type of dysfunction with time.[2] ## Diagnosis[edit] Various tests can be chosen depending on the presenting symptoms. Doctors may search for Thyroid peroxidase Antibodies (TPOAb) when a person has symptoms of hypothyroidism, or when a person will be started on a drug therapy associated with risks of developing hypothyroidism,[2] such as lithium or Interferon alfa.[1] This antibody is related to Hashimoto's thyroiditis and Graves' disease. If the person presents symptoms of hyperthyroidism, doctors are more likely to test for Thyroid stimulating hormone receptor Antibodies (TRAb), and monitor the effects of anti-thyroid therapy, also associated with Graves' disease.[1] Doctors may check Thyroglobulin Antibodies (TgAb) also, whenever a thyroglobulin test is performed to see if the antibody is interfering. TgAb may also be ordered in regular intervals after a person has been diagnosed with thyroid cancer, and just like TPOAb, it can be associated with Hashimoto's thyroiditis.[2] ### Categories[edit] Specialists separate autoimmune thyroiditis into two clinical categories. 1. If goiters are present, it is understood as Hashimoto's thyroiditis. 2. If the thyroid is atrophic, and does not present goiters, it is called atrophic thyroiditis.[1] It can also refer to Graves' disease. If the symptoms of thyroiditis appear in women after giving birth, it is called postpartum thyroiditis.[1] ## Treatment[edit] The usual therapy is Levothyroxine.[5] ## References[edit] 1. ^ a b c d e f g h i j k l m Dayan, Dayan, Colin M; Dayan, Colin M.; Gilbert H. Daniels (1996). "Chronic Autoimmune Thyroiditis". The New England Journal of Medicine. 335 (2): 99–107. doi:10.1056/nejm199607113350206. PMID 8649497. 2. ^ a b c d e f "Thyroid Antibodies". Retrieved 4 April 2012. 3. ^ Weetman, A. P.; A. M. McGregor; H. Lazarus; R. Hall (April 1982). "Thyroid Antibodies are Produced by Thyroid- Derived Lymphocytes". Clin Exp Immunol. 48 (1): 196–200. PMC 1536583. PMID 7044629. 4. ^ Berghi, N. (2017). "Immunological Mechanisms Implicated in the Pathogenesis of Chronic Urticaria and Hashimoto Thyroiditis". Iranian Journal of Allergy, Asthma and Immunology. 16 (4): 358–366. Retrieved 3 December 2020. 5. ^ https://www.btf-thyroid.org/thyroiditis ## External links[edit] Classification D * ICD-10: E06.3 * MeSH: D013967 * SNOMED CT: 66944004 * 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	Autoimmune thyroiditis	c0920350	1,753	wikipedia	https://en.wikipedia.org/wiki/Autoimmune_thyroiditis	2021-01-18T18:30:03	{"gard": ["6570"], "mesh": ["D013967"], "umls": ["C0920350"], "wikidata": ["Q187842"]}
A number sign (#) is used with this entry because of evidence that complete achromatopsia and some cases of incomplete achromatopsia are caused by homozygous or compound heterozygous mutation in the CNGA3 gene (600053), which encodes the alpha subunit of the cone photoreceptor cGMP-gated cation channel, on chromosome 2q11. Description Total colorblindness, also referred to as rod monochromacy or complete achromatopsia, is a rare congenital autosomal recessive disorder characterized by photophobia, reduced visual acuity, nystagmus, and the complete inability to discriminate between colors. Electroretinographic recordings show that in achromatopsia the rod photoreceptor function is normal, whereas cone photoreceptor responses are absent (summary by Kohl et al., 1998). ### Genetic Heterogeneity of Total Achromatopsia A form of achromatopsia previously designated achromatopsia-1 (ACHM1) was later found to be the same as achromatopsia-3 (ACHM3; 262300), caused by mutation in the CNGB3 gene (605080). ACHM4 (613856) is caused by mutation in the GNAT2 gene (139340); ACHM5 (613093) is caused by mutation in the PDE6C gene (600827); ACHM6 (see 610024) is caused by mutation in the PDE6H gene (601190); and ACHM7 (616517) is caused by mutation in the ATF6 gene (605537). Clinical Features Patients with achromatopsia have poor visual acuity, photophobia, congenital nystagmus, and colorblindness. Photophobia is striking, even in light of ordinary intensity. Vision in ordinary light is severely restricted, and relatively better in dim light. The fundus appears normal (summary by Zlotogora, 1995). The largest pedigree reported with achromatopsia is that of a family residing on the Island of Fuur in the Limfjord in the north of Denmark (Holm and Lodberg, 1940; Franceschetti et al., 1963). Mantyjarvi (1978) described affected brothers and a sister with first-cousin parents. Sloan (1954) observed second-cousin parents in 2 instances. Voke-Fletcher (1978) described affected brother and sister with first-cousin parents. Both sibs had marked lateral nystagmus and photophobia. Typical rod monochromats have normal levels of rhodopsin and normal rod function but lack all sensitivity mediated by cone pigments. Some atypical rod monochromats behave as if they have only rod vision; however, reflection densitometry shows that their retinas contain normal quantities of cone pigments (Alpern, 1974), suggesting that the defect is located distal to the point of light absorption. Presumably the site of the mutation in this disorder is different from that in total colorblindness. Simunovic et al. (2001) examined red-green color-deficient subjects, a small sample of monochromats, and age-matched color-normal control subjects to determine whether color vision deficiency confers a selective advantage under scotopic conditions. They found no evidence that red-green color deficiency or monochromatism confers a selective advantage under scotopic conditions, including dark adaptation, scotopic visual field sensitivity, or performance on a scotopic perceptual task. Using optical coherence tomography, Varsanyi et al. (2007) examined in vivo the anatomic structure of the retina in patients with achromatopsia and controls. In patients with achromatopsia, statistically significant reductions were found in total macular volume and in the thickness of the central retina compared with controls. Varsanyi et al. (2007) stated that a possible reason for the structural alteration is the qualitative and/or quantitative disorder of the cone photoreceptors, as the morphologic change is most expressed in the foveola. Liang et al. (2015) reported 15 Chinese patients with achromatopsia from 10 unrelated families. All patients had poor visual acuity since birth, congenital nystagmus, photophobia, color vision disturbances, and absent or residual cone responses with normal rod responses on electroretinography. Best corrected visual acuity ranged from 20/100 to 10/400. Spectral-domain optical coherence tomography (SD-OCT) revealed disruption or loss of the macular inner-outer segment junction of the photoreceptors. Zelinger et al. (2015) found that most of the Israeli and Palestinian patients from 41 families with ACHM2 in their cohort showed severely reduced visual acuity, photoaversion, nystagmus, nondetectable cone ERG responses, and impaired color discrimination. Visual acuity usually ranged from finger counting to 0.2 and refractive errors ranged from high myopia to high hypermetropia, with hypermetropia being most common. Population Genetics Zlotogora (1995) stated that this usually very rare disorder is relatively frequent among Moroccan, Iraqi, and Iranian Jews. Zelinger et al. (2015) found that the prevalence of ACHM was 1:5,000 among Arab Muslims residing in Jerusalem. The most common mutations in this population were 2 founder mutations in the CNGA3 gene (c.1585G-A, 600053.0008 and c.940_942delATC). Inheritance Achromatopsia-2 is an autosomal recessive disorder (Kohl et al., 1998). Clinical Management Park and Sunness (2004) reported that red contact lenses successfully alleviated photophobia in patients with cone disorders. Mapping Arbour et al. (1997) performed a genomewide search for linkage with total colorblindness using an inbred Jewish kindred from Iran. They used a DNA-pooling strategy that took advantage of the likelihood that the disease in this inbred kindred was inherited by all affected individuals from a common founder. Equal molar amounts of DNA from all affected individuals were pooled and used as a PCR template for short tandem repeat polymorphic markers (STRPs). Pooled DNA from unaffected members of the kindred was used as a control. A reduction in the number of alleles in the affected versus control pools was observed at several loci. Upon genotyping of individual family members, significant linkage was established between the disease phenotype and markers localized on chromosome 2. The highest lod score observed was 5.4 (theta = 0.0). When 4 additional small unrelated families were genotyped, the combined peak lod score was 8.2. Analysis of recombinant chromosomes revealed that the disease gene lies within a 30-cM interval that spans the centromere. Additional fine-mapping studies identified a region of homozygosity in all affected individuals, narrowing the region to 14 cM. Linkage analysis in this kindred initially involved an examination of markers on chromosome 14 because Pentao et al. (1992) had found maternal isodisomy of chromosome 14 in a patient with rod monochromacy. No linkage with chromosome 14 markers was found in the Iranian Jewish kindred. The chromosomal assignment for the achromatopsia locus was given as 2p11.2-q12. Wissinger et al. (1998) refined the map location for rod monochromacy to an approximately 3-cM interval between markers D2S2175 and D2S373 on 2q11 and showed that this interval includes the gene encoding the alpha-subunit of the cGMP-gated cation channel in cone photoreceptors (CNGA3; 600053). Nomenclature The British expression 'day blindness' is a good one because the cones are defective and the subjects see better at night. This term is parallel to night blindness (McKusick, 1992). Molecular Genetics Kohl et al. (1998) identified missense mutations (600053.0001-600053.0005) in CNGA3 in 5 families with rod monochromacy. In 2 families the mutations were homozygous, whereas the remaining families showed compound heterozygous mutations. In all cases, the segregation pattern was consistent with autosomal recessive inheritance of the disease. This was the first report of a color vision disorder caused by defects other than mutations in the cone pigment genes, and implied, at least in this instance, a common genetic basis for phototransduction in the 3 different cone photoreceptors of the human retina. Wissinger et al. (2001) screened for CNGA3 mutations in 258 independent families with hereditary cone photoreceptor disorders and found CNGA3 mutations not only in patients with the complete form of achromatopsia, but also in patients with incomplete achromatopsia and even in a few patients diagnosed with severe progressive cone dystrophy. Mutations were identified in 53 families and included 8 previously described mutations and 38 novel mutations. These mutations comprised 39 amino acid substitutions, 4 stop-codon mutations, two 1-bp insertions, and one 3-bp in-frame deletion. Most of the amino acid substitutions affected residues conserved in the CNG channel family and were clustered at the cytoplasmic face of transmembrane domains (TM) S1 and S2, in TM S4, and in the cGMP-binding domain. Four mutations, arg277 to cys (R277C; 600053.0009), arg283 to trp (R283W; 600053.0002), arg436 to trp (R435W; 600053.0010), and phe547 to leu (F547L; 600053.0006), accounted for 41.8% of all the detected mutations. Wiszniewski et al. (2007) analyzed the CNGA3, CNGB3, and GNAT2 (139340) genes in 16 unrelated patients with autosomal recessive ACHM: 10 patients had mutations in CNGB3, 3 had mutations in CNGA3, and no coding region mutations were found in 3 patients. The authors concluded that CNGA3 and CNGB3 mutations are responsible for the substantial majority of achromatopsia. Zelinger et al. (2010) identified a mutation in the CNGA3 gene (V529M; 600053.0008) in Arab Muslim and Oriental Jewish families with achromatopsia; the mutation was also identified in 3 previously unreported Christian European families. The European patients were all compound heterozygous for V529M and another CNGA3 mutation, whereas most of the Arab Muslim and Jewish patients were homozygous for V529M. Haplotype analysis revealed a shared Muslim-Jewish haplotype, which was different from the haplotypes detected in European patients; microsatellite analysis of the surrounding 21.5-cM interval on chromosome 2 revealed a unique and extremely rare haplotype associated with the V529M mutation. The shared mutation was calculated to have arisen about 200 generations earlier, in an ancient common ancestor who lived approximately 5,000 years ago. In a study of 15 Chinese patients from 10 unrelated families with ACHM, Liang et al. (2015) identified CNGA3 mutations in 13 patients from 8 families. INHERITANCE \- Autosomal recessive HEAD & NECK Eyes \- Day blindness \- Infantile nystagmus \- Photophobia \- Colors indistinguishable \- Funduscopy normal \- Rod monochromacy \- Decreased foveolar thickness MOLECULAR BASIS \- Caused by mutation in the cyclic nucleotide-gated channel, alpha-3 gene (CNGA3, 600053.0001 ) ▲ 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	ACHROMATOPSIA 2	c0152200	1,754	omim	https://www.omim.org/entry/216900	2019-09-22T16:29:30	{"doid": ["0110007"], "mesh": ["D003117"], "omim": ["216900"], "orphanet": ["49382"], "synonyms": ["Alternative titles", "COLORBLINDNESS, TOTAL", "ROD MONOCHROMATISM 2", "ROD MONOCHROMACY 2"], "genereviews": ["NBK1418"]}
A rare neurometabolic disease, due to a lipoic acid biosynthesis defect, with a highly variable phenotype, typically characterized by early-onset acute or subacute developmental delay or regression frequently associated with feeding difficulties. Clinical severity is variable and may range from mild cases which present a later onset with slow neurological deterioration and general improvement over time to severe cases with clinical signs since birth and leading to early death. Associated manifestations include hypotonia, vision loss, respiratory failure, seizures, and intellectual disability. Brain magnetic resonance imaging frequently shows cavitating leukoencephalopathy with lesions in the periventricular/central white matter and parieto-occiîtal lobes. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor *[BMI]: body mass index	Multiple mitochondrial dysfunctions syndrome type 3	c3809165	1,755	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=363424	2021-01-23T18:26:08	{"omim": ["615330"], "icd-10": ["E88.8"], "synonyms": ["IBA57 deficiency", "MMDS3"]}
A number sign (#) is used with this entry because of evidence that Brunner syndrome (BRNRS) is caused by mutation in the gene encoding monoamine oxidase A (MAOA; 309850) on chromosome Xp11. Description Brunner syndrome is a recessive X-linked disorder characterized by impulsive aggressiveness and mild mental retardation associated with MAOA deficiency (Brunner et al., 1993). Clinical Features In a large Dutch kindred, Brunner et al. (1993) identified a novel form of X-linked nondysmorphic mild mental retardation. All affected males in the family showed characteristic abnormal behavior, in particular aggressive and sometimes violent behavior. Other types of impulsive behavior included arson, attempted rape, and exhibitionism. Attempted suicide was reported in a single case. Results of urinalysis in 3 affected males indicated a marked disturbance of monoamine metabolism. These data were considered consistent with a primary defect in the structural gene for MAOA and/or MAOB (309860). Normal platelet MAOB activity suggested that the unusual behavior pattern in this family may be caused by isolated MAOA deficiency. Piton et al. (2014) reported a French family in which several affected males manifested a cognitive disorder similar to Brunner syndrome. The 7-year-old proband had autism as well as impulsive and autoaggressive behavior, and showed anger when frustrated. Other features included feeding and sleep difficulties in early life, delayed motor development, and amimic facial expressions. Laboratory studies showed increased urinary levels of the MAOA substrates normetanephrine and metanephrine, as well as decreased serum levels of MAOA products. The proband's 2 maternal uncles had severely delayed psychomotor development requiring placement in a school for special needs in childhood. They had autistic features and auto- and heteroaggressive outbursts, could not read or write, and had poor autonomy. Both suffered from familial neglect and had been maltreated and sexually abused in early childhood. Two deceased maternal great-uncles of the proband reportedly had encephalopathy and had been institutionalized their whole lives. The maternal grandmother of the proband had depression and psychotic disturbances; the proband's mother was unaffected. Palmer et al. (2016) reported 2 unrelated families from Australia with Brunner syndrome. All patients were adults at the time of the report. In family H, 2 brothers had mild intellectual disability with limited literacy and a history of impulsivity, school expulsions, violent episodes, explosive tempers, limited interests with obsessive behavior, disturbed wake/sleep cycle, occasional body twitches, and essential tremor. The patients did not receive psychopharmacologic treatment, and no specific serotonergic symptoms or worsening of behavior with high tyramine foods or medication were noted. In family R, previously reported by Cheung and Earl (2001), 2 brothers had mild intellectual disability with poor or absent literacy and attention deficit-hyperactivity disorder (ADHD). The patients were generally 'placid,' but 1 had a history of impulsive and aggressive behavior when ingesting high tyramine foods, severe night terrors, and episodic flushing, diarrhea, and headache. The other patient had difficulty sustaining friendships and some obsessive traits, but only occasional episodes of flushing, diarrhea, and headache. Both also had essential tremor. Their mother had normal intelligence with paroxysmal episodes of flushing, diarrhea, headache, and palpitations. All affected members of family R had exacerbation of serotonergic symptoms when consuming food and drink high in tyramine, and responded favorably to treatment with a selective serotonin reuptake inhibitor (SSRI). Biochemical studies of patient tissue samples showed high serum serotonin and urinary metanephrines and low urinary 5-hydroxyindoleacetic acid (5-HIAA) and vanillylmandelic acid (VMA). Clinical Management Palmer et al. (2016) found that treatment of a mother and her 2 sons (family R) with Brunner syndrome using a selective serotonin reuptake inhibitor (SSRI) resulted in a reduction of symptoms. The patients did have initial exacerbation of symptoms, but after some time showed a reduction of symptoms, including normalization of biochemical parameters. Palmer et al. (2016) noted the paradoxical response to SSRI treatment, which theoretically would increase serotonin levels and thus exacerbate symptoms. The authors recommended that patients with Brunner syndrome avoid food and medications contraindicated in patients on MAO inhibitors and that they be issued medical alert bracelets. Inheritance The transmission pattern of Brunner syndrome in the families reported by Brunner et al. (1993) and Piton et al. (2014) was consistent with X-linked recessive inheritance. Mapping By genetic linkage analysis using markers spanning the X chromosome, Brunner et al. (1993) assigned the locus for Brunner syndrome to chromosome Xp21-p11 between DXS7 and DXS77. A maximal multipoint lod score of 3.69 was obtained for linkage to MAOA at chromosome Xp11.4-p11.23. Molecular Genetics Brunner et al. (1993) reported that each of 5 affected males with Brunner syndrome had a point mutation in exon 8 of the MAOA gene, which changed a glutamine to a termination codon (309850.0001). In a boy and his 2 maternal uncles with Brunner syndrome, Piton et al. (2014) identified a hemizygous mutation in the MAOA gene (C266F; 309850.0003). The mutation, which was found by high-throughput sequencing of coding exons of intellectual disability genes in the proband, was also present in the proband's unaffected mother. The mutation was present in cis with a low activity promoter polymorphism in the MAOA gene (309850.0002) that has been associated with decreased MAOA activity and with behavioral disturbances after childhood neglect. In vitro studies of the proband's cells showed a significant reduction of MAOA activity as well as decreased levels of MAOA protein. Piton et al. (2014) suggested that the promoter polymorphism may have exacerbated the effect of the C266F mutation, and that the protective familial environment of the proband may have mitigated his phenotype compared to that of his uncles. In affected members of 2 unrelated Australian families with Brunner syndrome, Palmer et al. (2016) identified hemizygous or heterozygous mutations in the MAOA gene (309850.0004 and 309850.0005). Functional studies of the variants were not performed, but patient samples showed increased serotonin and metanephrines and decreased HVA, VMA, and 5-HIAA, consistent with the diagnosis. ### Antisocial Behavior, Susceptibility to Caspi et al. (2002) studied a large sample of male children from birth to adulthood to determine why some children who are maltreated grow up to develop antisocial behavior whereas others do not. A functional promoter polymorphism (309850.0002) in the MAOA gene was found to moderate the effect of maltreatment. Maltreated children with a genotype conferring high levels of MAOA expression were less likely to develop antisocial problems. Caspi et al. (2002) concluded that their findings may partly explain why not all victims of maltreatment grow up to victimize others, and they provided epidemiologic evidence that genotypes can moderate children's sensitivity to environmental insults. In a large sample of healthy volunteers, Meyer-Lindenberg et al. (2006) found that those with the low-expression MAOA polymorphism (MAOA-L; 2R, 3R, or 5R) showed an approximately 8% decrease of gray matter volumes in the cingulate gyrus and amygdala, as well as the insula and hypothalamus, compared to those with the high-expression polymorphism (MAOA-H; 3.5R or 4R). MAOA-L males had an approximately 14% increase in volumes in the lateral orbitofrontal cortex compared to MAOA-H males; no such difference in this area was seen in women, suggesting a sex-by-genotype interaction. Functional MRI studies during emotional arousal showed that MAOA-L carriers demonstrated increased amygdala arousal as well as diminished reactivity of regulatory prefrontal regions compared to MAOA-H carriers. Studies of aversive emotional memory retrieval showed that male, but not female, MAOA-L carriers had increased activity in the amygdala and hippocampus and impaired cingulate activation during cognitive inhibition compared to MAOA-H carriers. The findings suggested that sex- and genotype-specific differences in limbic circuitry for emotion regulation and cognitive control may be involved in the association of MAOA with impulsive aggression and/or violence. Among 2,524 participants in a longitudinal study of delinquent behavior in adolescence and young adulthood, Guo et al. (2008) found a significant association between the rare MAOA2R polymorphism and serious delinquency and violent delinquency. Men with the MAOA2R variant had about twice the levels of delinquency compared to those with the other MAOA promoter variants. The results for women were similar, but weaker. In vitro functional expression studies in human brain-derived cell lines showed that the 2R promoter exhibited much lower levels of promoter activity than the 3R or 4R promoters, with about 25 to 30% of activity exhibited by the 4R promoter. Genotype/Phenotype Correlations The difficulties in relating a cognitive or behavioral phenotype to a specific genotype were indicated by the criticism of Brunner et al. (1993) leveled by Hebebrand and Klug (1995) that the 'clinical delineation of the phenotype appears so vague that it can be questioned whether it indeed results from the mutation.' (A similar question existed about the phenotype/karyotype relationships in the XYY 'syndrome.') Their criticism pertained to (1) inadequate delineation of the cognitive and behavioral phenotype, (2) the assumed X-linked inheritance of the phenotype, and (3) the lod score calculation, which was performed without assuming a phenocopy rate. Brunner and Ropers (1995) responded that 'Hebebrand and Klug's desire for phenotypes that are specific enough to allow recognition in the general population is somewhat unrealistic given the complex basis of any behaviour in humans, both normal and abnormal. Although the genes may be simple, the behaviour they affect is necessarily much more complex.' They stated further that 'there has always been a clear dichotomy between affected and unaffected males, both from the perspective of the family, as well as from our interviews with affected and unaffected family members.' In a response to the response, Hebebrand and Klug (1995) stated that the psychiatric and forensic evaluations seemed inadequate. 'Thus, did the affected males (n = ?) with exhibitionism fulfill the DSM-III-R or DSM-IV criteria for exhibitionism? What exactly did the individuals do who had a history of voyeurism or arson? Can it be excluded that some of the 'unaffected' males, who perhaps have a high intelligence level, refused to disclose their socially unacceptable behavior to the interviewer (or other family members)?' INHERITANCE \- X-linked recessive ABDOMEN Gastrointestinal \- Diarrhea, episodic (in some patients) SKIN, NAILS, & HAIR Skin \- Flushing, episodic (in some patients) NEUROLOGIC Central Nervous System \- Intellectual disability, mild to severe \- Learning disabilities \- Literacy difficulties \- Essential tremor \- Delayed motor development (in some patients) \- Disturbed sleep/wake cycle \- Night terrors \- Headache, episodic \- Body twitches Behavioral Psychiatric Manifestations \- Autism \- Attention-deficit hyperactivity disorder \- Auto- and hetero-aggressive behavior \- Angry outbursts \- Easily frustrated \- Antisocial behavior \- Obsessive tendencies \- Impulsivity \- Temper tantrums \- Limited interests LABORATORY ABNORMALITIES \- Decreased monoamine oxidase A activity \- Increased serotonin \- Increased urinary levels of MAOA substrates (endogenous bioamines) \- Decreased serum levels of MAOA products \- Increased urinary metanephrines \- Low urinary 5-hydroxyindoleacetic acid (5-HIAA) \- Low urinary vanillylmandelic acid (VMA) MISCELLANEOUS \- Female carriers may be mildly affected \- Variable manifestations \- Some patients may show symptoms of serotonin syndrome \- Phenotype may be exacerbated by ingestion of foods high in tyramine \- Phenotype may be exacerbated by maltreatment in childhood MOLECULAR BASIS \- Caused by mutation in the monoamine oxidase A gene (MAOA, 309850.0001 ) ▲ 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	BRUNNER SYNDROME	c0796275	1,756	omim	https://www.omim.org/entry/300615	2019-09-22T16:20:04	{"doid": ["0060693"], "mesh": ["C563156"], "omim": ["300615"], "orphanet": ["3057"]}
A number sign (#) is used with this entry because pentosuria (PNTSU) is caused by homozygous or compound heterozygous mutation in the DCXR gene (608347) on chromosome 17q25. Description Essential pentosuria is an inborn error of metabolism in which 1 to 4 gm of the pentose L-xylulose is excreted in the urine each day. It is a benign condition that occurs principally in individuals of Ashkenazi Jewish descent (summary by Hiatt, 2001). Biochemical Features Levene and La Forge (1914) showed that the excreted pentose in pentosuria is L-xylulose. By direct biochemical means applied to erythrocytes, Wang and Van Eys (1970) demonstrated that the basic fault in pentosuria concerns NADP-linked xylitol dehydrogenase, the enzyme that catalyzes the conversion of L-xylulose to xylitol. Although the glucuronic acid pathway, in which metabolic block is situated, was elucidated in the 1950s (Touster, 1959) and the site of the metabolic block became evident, actual demonstration of the responsible enzyme deficiency required the finding of L-xylulose reductase activity in normal red cells. Biopsy of liver and kidney, which had the highest enzyme activity, could not be justified in this benign condition. Lane (1985) found that 2 distinct L-xylulose reductases are produced in human tissues. The major isozyme is missing in pentosuria, whereas the minor isozyme, which presumably is coded by a separate gene, is retained. The major isozyme occurs in both the cytosol and the mitochondria, whereas the minor isozyme is limited to the cytosol (Lane and Jenkins, 1985). Heterozygotes can be recognized by demonstrating either an intermediate level of erythrocyte activity of xylitol dehydrogenase or increased urinary or serum L-xylulose, or both, in a glucuronolactone loading test (Hiatt, 2001). Inheritance The inheritance pattern of pentosuria is autosomal recessive (Pierce et al., 2011). Politzer and Fleischmann (1962) suggested dominant inheritance for pentosuria in 1 Lebanese family. Lane and Jenkins (1985) restudied the family, using an improved assay for red cell enzyme in the identification of heterozygotes, and concluded that pseudodominance of the usual recessive trait was actually the case. They discussed the possibility that the Lebanese and Ashkenazim gene may have the same mutation, i.e., descended from a single mutation in the past. The minimum estimate of the frequency of the pentosuria allele in Ashkenazim was calculated to be 0.0127. Molecular Genetics In 9 probands of Ashkenazi Jewish descent with pentosuria, Pierce et al. (2011) identified homozygous or compound heterozygous loss-of-function mutations in the DCXR gene (608347.0001 and 608347.0002). Patient cells showed a complete lack of the DCXR protein. The allele frequency of the 2 alleles combined among 1,067 individuals of Ashkenazi Jewish descent was 0.0173, leading to an expected frequency of pentosuria of 1 in 3,300 individuals in this population. These families had originally been studied by Margaret Lasker in the mid-20th century. Population Genetics Pentosuria occurs almost exclusively in individuals of Ashkenazi Jewish descent. The frequency in American Jews is estimated at 1 in 2,000 to 2,500 (Hiatt, 2001). Khachadurian (1962) and Politzer and Fleischmann (1962) described pentosuria in Lebanese families. Soyama and Furukawa (1985) described a Japanese case of pentosuria. History Pentosuria was one of the original 4 inborn errors of metabolism discussed by Garrod (1908) in his famous lectures. In the early- and mid-20th century, pentosuria was often confused with diabetes mellitus. Some individuals were inappropriately treated with insulin, leading to hypoglycemic reactions (summary by Pierce et al., 2011). INHERITANCE \- Autosomal recessive LABORATORY ABNORMALITIES \- Increased urinary excretion of L-xylulose MISCELLANEOUS \- Benign trait \- High frequency among individuals of Ashkenazi Jewish descent (1 in 3,300) MOLECULAR BASIS \- Caused by mutation in the dicarbonyl/L-xylulose reductase gene (DCXR, 608347.0001 ) ▲ 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	PENTOSURIA	c0268162	1,757	omim	https://www.omim.org/entry/260800	2019-09-22T16:23:36	{"doid": ["0111258"], "mesh": ["C536652"], "omim": ["260800"], "icd-10": ["E74.8"], "orphanet": ["2843"], "synonyms": ["Alternative titles", "L-XYLULOSURIA", "XYLITOL DEHYDROGENASE DEFICIENCY", "L-XYLULOSE REDUCTASE DEFICIENCY"]}
A number sign (#) is used with this entry because of evidence that Timothy syndrome (TS) is caused by heterozygous mutation in the CACNA1C gene (114205) on chromosome 12p13. Mutation in the CACNA1C gene can also cause Brugada syndrome (BRGDA3; 611875) and long QT syndrome (LQT8; 618447). Description Timothy syndrome (TS) is characterized by multiorgan dysfunction, including lethal arrhythmias, webbing of fingers and toes, congenital heart disease, immune deficiency, intermittent hypoglycemia, cognitive abnormalities, and autism (Splawski et al., 2004). Clinical Features Reichenbach et al. (1992) and Marks et al. (1995) described 3 male and 2 female infants with long QT syndrome, syndactyly, and a high risk of sudden death. Four died suddenly at an early age. All 5 had transient 2:1 atrioventricular block. AV block had previously been reported in long QT syndrome and results from prolonged ventricular repolarization rather than an intrinsic conduction disturbance. The family history was negative in each case. New dominant mutation, recessive inheritance, or a contiguous gene syndrome were considered possibilities. The first patient had a small patent ductus arteriosus (see 607411) by echocardiogram; the second had a tiny membranous ventricular septal defect and patent foramen ovale by echocardiogram. Marks et al. (1995) commented that atrioventricular block occurs in patients with long QT syndrome as a result of prolonged ventricular repolarization rather than an intrinsic conduction abnormality. Splawski et al. (2004) referred to the disorder reported by Reichenbach et al. (1992) and Marks et al. (1995) as Timothy syndrome (TS) and described 17 affected children. Inheritance was sporadic in all but 1 family in which 2 of 3 sibs were affected. None of the parents was affected. Ten of the 17 children with TS died, and the average age of death was 2.5 years. All affected individuals had severe prolongation of the QT interval on electrocardiogram, syndactyly, and abnormal teeth and were bald at birth. Arrhythmias were the most serious aspect of TS, and 12 of 17 children had life-threatening episodes. Individuals with TS also had congenital heart disease, including patent ductus arteriosus, patent foramen ovale, ventricular septal defects, and tetralogy of Fallot. Some children had dysmorphic facial features, including flat nasal bridge, small upper jaw, low-set ears, or small or misplaced teeth. Episodic serum hypocalcemia was described in 4 individuals. Many of the surviving children showed developmental delays consistent with language, motor, and generalized cognitive impairment, and Splawski et al. (2004) demonstrated a significant association between autism spectrum disorders and TS. Splawski et al. (2005) studied 2 children with Timothy syndrome without syndactyly. The first was a girl who had bradycardia, biventricular hypertrophy, and moderate biventricular dysfunction noted at 25 weeks' gestation, with 2:1 atrioventricular block and QTc of 730 ms noted at birth. Despite placement of an implantable pacemaker, she had multiple episodes of severe arrhythmias requiring cardioversion or resuscitation in infancy. Cervical sympathetic ganglionectomy and ventricular pacemaker placement at 4 months of age were unsuccessful in reducing arrhythmias. She had bilateral congenitally dislocated hips and joint hyperextensibility, and muscle biopsy at age 5 months revealed nemaline myopathy. By age 6 years, a discrepancy of body development was apparent, with her lower body typical of a 2- to 3-year-old child. Facial dysmorphism included protruding forehead, depressed nasal bridge, and protruding tongue, and severe caries resulted in the extraction of most teeth. She also experienced seizures with increasing frequency, static encephalopathy, and severe developmental delay. She died at age 6 years due to ventricular fibrillation. The second child was a boy who was apparently well until age 4 years, when he experienced cardiac arrest while at play and was diagnosed with long QT syndrome. Over the next 6 years, he had 3 more episodes of cardiac arrest, all triggered by auditory stimuli, and underwent pacemaker implantation. At age 11, he experienced cardiac arrest after antibiotic therapy and was in a coma for 2 weeks, following which significant brain damage remained. An implantable cardioverter defibrillator (ICD) was placed that subsequently fired more than 20 times. At age 21, he was still experiencing weekly cardiac arrhythmias, which were associated with night terrors, and he exhibited signs of depression and obsessive-compulsive behavior. Hiippala et al. (2015) studied a 13-year-old Finnish girl who was resuscitated from ventricular fibrillation after collapsing at home and was found to have a slightly prolonged QTc interval of 480 ms. She had a history of 2 similar events in the previous year while walking with friends, from which she recovered spontaneously. Cardiac evaluation showed normal structure and function, with a peak heart rate of 176 bpm on exercise testing, which did not trigger any ventricular arrhythmias. Flecainide provocation and adrenaline infusion tests were negative. An ICD was inserted, but over a follow-up period of 3.5 years, no shocks occurred, and her QTc intervals were in the high-normal range (440 to 460 ms). She had no learning difficulties or psychiatric disorders, no craniofacial dysmorphism, and no musculoskeletal abnormalities. Molecular Genetics Splawski et al. (2004) showed that, in all available patients, TS resulted from an identical de novo gly406-to-arg (G406R; 114205.0001) mutation in exon 8A of the CACNA1C gene. They found that CACNA1C was expressed in all tissues affected in TS. Functional expression revealed that the G406R mutation produced maintained inward Ca(2+) currents by causing nearly complete loss of voltage-dependent channel inactivation. Splawski et al. (2004) stated that this likely induces intracellular Ca(2+) overload in multiple cell types. They noted that, in the heart, prolonged Ca(2+) current delays cardiomyocyte repolarization and increases risk of arrhythmia, the ultimate cause of death in TS. These findings established the importance of CACNA1C in human physiology and development and implicated Ca(2+) signaling in autism. Splawski et al. (2005) reported 2 individuals with a severe variant of TS in whom they identified de novo missense mutations in exon 8 of the CACNA1C gene (G406R, and G402S, 114205.0002). They found that the exon 8 splice variant was highly expressed in heart and brain, accounting for about 80% of CACNA1C mRNA. In contrast to previously reported TS patients with a mutation in exon 8A, these 2 patients did not have syndactyly, had an average QT interval that was 60 ms longer, and had multiple episodes of unprovoked arrhythmia; multiple arrhythmias were rare in the patients with mutations in exon 8A, and most were associated with medications and/or anesthesia. Splawski et al. (2005) concluded that gain-of-function mutations in CACNA1C exons 8 and 8A cause distinct forms of TS; they designated the atypical, more severe form due to exon 8 mutations 'TS2' (Timothy syndrome type 2). To explore the effect of the Timothy syndrome G406R mutation in the CaV1.2 channel on the electrical activity and contraction of human cardiomyocytes, Yazawa et al. (2011) reprogrammed human skin cells from Timothy syndrome patients to generate induced pluripotent stem cells, and differentiated those cells into cardiomyocytes. Electrophysiologic recording and calcium imaging studies of these cells revealed irregular contraction, excess calcium influx, prolonged action potentials, irregular electrical activity, and abnormal calcium transients in ventricular-like cells. Yazawa et al. (2011) found that roscovitine, a compound that increases the voltage-dependent inactivation of CaV1.2, restored the electrical and calcium signaling properties of cardiomyocytes from Timothy syndrome patients. Yazawa et al. (2011) concluded that their study provided new opportunities for studying the molecular and cellular mechanisms of cardiac arrhythmias in humans and provided a robust assay for developing drugs to treat these diseases. Etheridge et al. (2011) studied a severely affected infant with Timothy syndrome and his mildly affected father. The father never experienced syncope or seizure, but had cutaneous syndactyly of the toes and was found to have a prolonged QTc (480 ms). The authors also studied an unrelated, moderately affected 14-year-old girl; she experienced cardiac arrest with documented ventricular fibrillation and a QTc of 560 ms in adolescence, and had bilateral syndactyly of the hands and feet. All 3 patients were heterozygous for the G406R mutation in the CACNA1C gene; however, the 2 more mildly affected individuals were both found to be mosaic for the mutation, showing only a minor peak for the mutant allele. Analysis of the father's gametes revealed that approximately 16% of his sperm carried the mutant allele; cardiac tissue was not available for study. Etheridge et al. (2011) noted that previously described 'de novo' mutations in Timothy syndrome might also represent cases of parental mosaicism, with implications for genetic counseling. By targeted sequencing of channelopathy- and arrhythmogenic right ventricular cardiomyopathy (see 107970)-associated genes in a 13-year-old Finnish girl who had cardiac arrest due to ventricular fibrillation and QTc intervals in the upper limits of normal, and who was negative for the 4 most common Finnish LQTS mutations, Hiippala et al. (2015) identified heterozygosity for the G402S mutation in the CACNA1C gene. Her unaffected parents, who had normal electrocardiograms, did not carry the mutation. To evaluate the possibility of mosaicism, Hiippala et al. (2015) calculated the ratio of mutated and normal alleles from the next-generation sequencing (NGS) reads, and found that 37% of the reads represented the mutated allele and 61% showed the normal allele. Sanger sequencing of blood- and saliva-derived DNA confirmed the mutation; in both samples, the mutation peak was slightly weaker than the normal genotype, consistent with the allele distribution detected by NGS. Pathogenesis Erxleben et al. (2006) noted that the CaV1 family of calcium channels has a second mode of gating, termed 'mode 2,' that involves frequent openings of much longer duration than 'mode 1.' Cyclosporin, a calcineurin (see 114105) inhibitor, and a mutation associated with Timothy syndrome independently resulted in increased mode 2 activity in recombinant rabbit CaV1.2 channels. Stimulation of mode 2 activity was blocked by inhibition of calcium/calmodulin-dependent protein kinase-2 (CAMK2A; 114078) and by mutating putative phosphoacceptor serine residues at the cytoplasmic end of the S6 helix in domain I (Timothy syndrome) or domain IV (cyclosporin), which both contain consensus sequences for CAMK2A. Erxleben et al. (2006) concluded that aberrant phosphorylation and increased cellular calcium entry contribute to the neurotoxicity observed in some transplant patients with chronic cyclosporin use, and that a similar excitotoxic mechanism is at work in patients with Timothy syndrome. History Splawski et al. (2004) named this disorder Timothy syndrome in honor of Dr. Katherine W. Timothy, who was among the first to identify a case of severe long QT syndrome and syndactyly and performed much of the phenotypic analysis that revealed other abnormalities (Keating, 2004). INHERITANCE \- Autosomal dominant HEAD & NECK Face \- Round face Nose \- Flat nasal bridge Mouth \- Receding upper jaw \- Thin upper lip Teeth \- Small teeth CARDIOVASCULAR Heart \- Cardiac arrhythmias resulting in sudden death \- Long QT interval, severe \- Ventricular tachyarrhythmia \- Bradycardia, atrioventricular block \- Patent foramen ovale (in some patients) \- Ventricular septal defects (in some patients) \- Tetralogy of Fallot (rare) \- Cardiomegaly (in some patients) Vascular \- Patent ductus arteriosus (in some patients) \- Pulmonary hypertension (in some patients) RESPIRATORY Airways \- Bronchitis (in some patients) Lung \- Pneumonia (in some patients) SKELETAL Hands \- Cutaneous syndactyly Feet \- Cutaneous syndactyly SKIN, NAILS, & HAIR Hair \- No hair at birth MUSCLE, SOFT TISSUES \- Hypotonia (in some patients) NEUROLOGIC Central Nervous System \- Autism or autism spectrum disorder \- Mental retardation (in some patients) \- Developmental delay \- Seizures (in some patients) ENDOCRINE FEATURES \- Hypothyroidism (in some patients) IMMUNOLOGY \- Recurrent infections LABORATORY ABNORMALITIES \- Hypocalcemia (in some patients) \- Hypoglycemia (in some patients) MISCELLANEOUS \- De novo mutation, most patients have a GLY406ARG mutation in CACNA1C ( 114205.0001 ) \- Some patients with milder phenotypes exhibit somatic mosaicism MOLECULAR BASIS \- Caused by mutation in the calcium channel, voltage-dependent, L type, alpha 1C subunit gene (CACNA1C, 114205.0001 ) ▲ 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	TIMOTHY SYNDROME	c1832916	1,758	omim	https://www.omim.org/entry/601005	2019-09-22T16:15:31	{"doid": ["0060173"], "mesh": ["C536962"], "omim": ["601005"], "orphanet": ["65283", "768"], "synonyms": ["Alternative titles", "LONG QT SYNDROME WITH SYNDACTYLY"], "genereviews": ["NBK1403", "NBK1129"]}
Emergence delirium Other namesAgitated emergence, emergence agitation, emergence excitement, postanesthetic excitement SpecialtyAnesthesia Emergence delirium is a condition in which emergence from general anesthesia is accompanied by psychomotor agitation. Some see a relation to pavor nocturnus[1] while others see a relation to the excitement stage of anesthesia. ## Contents * 1 Children * 2 Elderly * 3 Epidemiology * 4 References * 5 Further reading * 6 External links ## Children[edit] The pediatric anesthesia emergence delirium scale may be used to measure the severity of this condition in children.[2] ## Elderly[edit] Elderly people are more likely to experience confusion or problems with thinking following surgery, which can occur up to several days postoperatively. These cognitive problems can last for weeks or months, and can affect the patients’ ability to plan, focus, remember, or undertake activities of daily living. a review of Intravenous versus inhalational maintenance of anaesthesia for postoperative cognitive outcomes in elderly people undergoing non-cardiac surgery showed little or no difference in postoperative delirium according to the type of anaesthetic maintenance agents from five studies (321 participants). The authors of this review were uncertain whether maintenance of anaesthesia with propofol-based total intravenous anaesthesia (TIVA) or with inhalational agents can affect incidences of postoperative delirium.[3] ## Epidemiology[edit] The overall incidence of emergence delirium is 5.3%, with a significantly greater incidence (12–13%) in children. The incidence of emergence delirium after halothane, isoflurane, sevoflurane or desflurane ranges from 2–55%.[4] Most emergence delirium in the literature describes agitated emergence. Unless a delirium detection tool is used, it is difficult to distinguish if the agitated emergence from anesthesia was from delirium or pain or fear, etc. A research study of 400 adult patients emerging from general anesthesia in the PACU were assessed for delirium using the Confusion Assessment Method for the ICU (CAM-ICU) found rates of emergence delirium of 31% at PACU admission with rates declining to 8% by 1 hour.[5] ## References[edit] 1. ^ http://www.asa2012.com/PDFs_abstracts/davidson.pdf[permanent dead link] 2. ^ Sikich, N; Lerman, J (2004). "Development and psychometric evaluation of the pediatric anesthesia emergence delirium scale". Anesthesiology. 100 (5): 1138–45. doi:10.1097/00000542-200405000-00015. PMID 15114210. 3. ^ Miller, David; Lewis, Sharon R; Pritchard, Michael W; Schofield-Robinson, Oliver J; Shelton, Cliff L; Alderson, Phil; Smith, Andrew F (21 August 2018). "Intravenous versus inhalational maintenance of anaesthesia for postoperative cognitive outcomes in elderly people undergoing non‐cardiac surgery". Cochrane Database of Systematic Reviews. 2018 (8): CD012317. doi:10.1002/14651858.CD012317.pub2. PMC 6513211. PMID 30129968. 4. ^ Mason, LJ (2004). "Pitfalls of Pediatric Anesthesia: Emergence Delirium" (PDF). Richmond, Virginia: Society for Pediatric Anestheisa. Archived from the original (PDF) on 2016-03-27. Retrieved 2012-06-21. 5. ^ E. Card, P. Pandharipande, C. Tomes, C. Lee, J. Wood, D. Nelson, A. Graves, A. Shintani, E. W. Ely and C. Hughes (2014) Emergence from general anaesthesia and evolution of delirium signs in the post-anaesthesia care unit. Br. J. Anaesth. (2014) doi: 10.1093/bja/aeu442 First published online: December 23, 2014 ## Further reading[edit] * Vlajkovic GP, Sindjelic RP (Jan 2007). "Emergence delirium in children: many questions, few answers". Anesth. Analg. 104 (1): 84–91. doi:10.1213/01.ane.0000250914.91881.a8. PMID 17179249. * Lepouse C, Lautner CA, Liu L, Gomis P, Leon A (Jun 2006). "Emergence delirium in adults in the post-anaesthesia care unit". Br. J. Anaesth. 96 (6): 747–53. doi:10.1093/bja/ael094. PMID 16670111. ## External links[edit] Classification D * ICD-10: F13.4 * ICD-9-CM: 292.81 * MeSH: D000071257 * v * t * e Anesthesia and anesthesiology Types * General * Sedation * Twilight anesthesia * Local * Topical * Intercostal nerve block * Neuraxial blockade * Spinal * Epidural * Dental * Inferior alveolar nerve Techniques * Airway management * Anesthesia provision in the US * Arterial catheter * Bronchoscopy * Capnography * Dogliotti's principle * Drug-induced amnesia * Intraoperative neurophysiological monitoring * Nerve block * Penthrox inhaler * Tracheal intubation Scientific principles * Blood–gas partition coefficient * Concentration effect * Fink effect * Minimum alveolar concentration * Second gas effect Measurements * ASA physical status classification system * Baricity * Bispectral index * Entropy monitoring * Fick principle * Goldman index * Guedel's classification * Mallampati score * Neuromuscular monitoring * Thyromental distance Instruments * Anaesthetic machine * Anesthesia cart * Boyle's machine * Gas cylinder * Laryngeal mask airway * Laryngeal tube * Medical monitor * Odom's indicator * Relative analgesia machine * Vaporiser * Double-lumen endotracheal tube * Endobronchial blocker Complications * Emergence delirium * Allergic reactions * Anesthesia awareness * Local anesthetic toxicity * Malignant hyperthermia * Perioperative mortality * Postanesthetic shivering * Postoperative nausea and vomiting * Postoperative residual curarization Subspecialties * Cardiothoracic * Critical emergency medicine * Geriatric * Intensive care medicine * Obstetric * Oral sedation dentistry * Pain medicine Professions * Anesthesiologist * Anesthesiologist assistant * Nurse anesthetist * Operating department practitioners * Certified Anesthesia Technician * Certified Anesthesia Technologist * Anaesthetic technician * Physicians' assistant (anaesthesia) History * ACE mixture * Helsinki Declaration for Patient Safety in Anaesthesiology * History of general anesthesia * History of neuraxial anesthesia * History of tracheal intubation Organizations * American Association of Nurse Anesthetists * American Society of Anesthesia Technologists & Technicians * American Society of Anesthesiologists * Anaesthesia Trauma and Critical Care * Association of Anaesthetists of Great Britain and Ireland * Royal College of Anaesthetists * Association of Veterinary Anaesthetists * Australian and New Zealand College of Anaesthetists * Australian Society of Anaesthetists * International Anesthesia Research Society * Category * 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	Emergence delirium	c0920253	1,759	wikipedia	https://en.wikipedia.org/wiki/Emergence_delirium	2021-01-18T18:50:03	{"mesh": ["D000071257"], "icd-9": ["292.81"], "icd-10": ["F13.4"], "wikidata": ["Q394116"]}
Bruns apraxia SpecialtyNeurology Bruns apraxia, or frontal ataxia is a gait apraxia[1] found in patients with bilateral frontal lobe disorders. It is characterised by an inability to initiate the process of walking, despite the power and coordination of the legs being normal when tested in the seated or lying position. The gait is broad-based with short steps with a tendency to fall backwards. It was originally described in patients with frontal lobe tumours, but is now more commonly seen in patients with cerebrovascular disease.[2] It is named after Ludwig Bruns.[3][4] ## Contents * 1 Symptoms * 2 Cause * 3 Diagnosis * 4 Treatment * 5 References * 6 External links ## Symptoms[edit] Unlike ataxias of cerebellar origin, Bruns apraxia exhibits many frontal lobe ataxia characteristics, with some or all present. * Difficulty in initiating movement * Poor truncal mobility * Falls due to minor balance disturbances * Greatly hindered postural responses * Characteristic magnetic gait, the inability to raise one's foot off of the floor. * Wide base, poor balance control when in stance * Short stride * En bloc turns Often patients with frontal lobe ataxia may experience minute cognitive changes that accompany the gait disturbances, such as frontal dementia and presentation of frontal release signs (Plantar reflex). Urinary incontinence may also be present.[5] [6] Bruns apraxia can be distinguished from Parkinsonian ataxia and cerebellar ataxia in a number of ways. Patients typically afflicted with Parkinsonian ataxia typically have irregular arm swing, a symptom not typically present in frontal ataxia. Walking stride in cerebellar ataxia varies dramatically, accompanied by erratic foot placement and sudden, uncontrolled lurching, not generally characteristic of Bruns apraxia.[7] ## Cause[edit] Frontal lobe ataxia is often associated with damage to the frontopontocerebellar tract (Arnold's bundle) that connects the frontal lobe to the cerebellum. This pathway normally sends information from the cortical regions to the cerebellum, particularly information used to initiate planned movement.[8] Many neurologists describe frontal lobe ataxia as really an apraxia, in which voluntary control of initiating movement is greatly hindered, but normal movement is present when elicited involuntarily or reflexively.[9] This indicates that cerebellar function is intact and that the presented symptoms of Bruns apraxia are due to damage located within frontal lobe regions and pathways leading from there to the cerebellum.[10] ## Diagnosis[edit] Diagnosis consists of a variety of tests, including but not limited to: * Measurement of orthostatic blood pressure * Coordination * rapid, alternating movements * stroking of heel along the opposite shin from knee to ankle * finger-to-nose testing. * Primary sensory modalities are examined with the following methods, searching for focal sensory loss, graded distal sensory loss, or levels of decreased sensation, hyperesthesia or dysesthesia. * light touch * pin-prick * temperature * position * vibration [11] * Focused gait examination, which examines stationary position and walking abnormalities. Walking generally exposes any faults within the complex neurological communication between systems as weight is shifted from one foot to the other.[12] ## Treatment[edit] Treatment consists of physical rehabilitation programs designed to improve overall function, increase strength and improve balance. The ultimate goal is to increase the patient's degree of independence, thus improving the patient's quality of life. Exercise typically begins with simple movements, gradually transitioning into more complex actions. Various aspects of treatment are assessed based on the individual patient's condition, utilizing many assessment tools: * Functional Reach Test * External Perturbation Test – Push, Release * External Perturbation Test – Pull * Clinical Sensory Integration Test * Single Leg Stance Test * Five Times Sit to Stand Test [13] Various scales are also utilized * Brief Ataxia Rating Scale * Friedreich's ataxia Impact Scale * Scale For Assessment and Rating of Ataxia [14] ## References[edit] 1. ^ Dorland's (2012). Dorland's Illustrated Medical Dictionary (32nd ed.). Elsevier. p. 256. ISBN 978-0-19-856878-0. 2. ^ William Pryse-Phillips. Companion to clinical neurology. Oxford University Press, 2003, page 136. ISBN 978-0-19-515938-7. 3. ^ Barry G. Firkin, Judith A. Whitworth. Dictionary of Medical Eponyms. Informa Health Care, 2001, page 51. ISBN 978-1-85070-333-4. 4. ^ Bruns' ataxia at Who Named It? 5. ^ Frontal lobe ataxia; Thompson, PD. Handbook Clinical Neurology. 2012;103:619-22. doi: 10.1016/B978-0-444-51892-7.00044-9. 6. ^ Ataxia: Physical Therapy and Rehabilitation Applications for Ataxic Patients, 2014. http://cirrie.buffalo.edu/encyclopedia/en/article/112/#s4 7. ^ Jody Corey-Bloom; Ronald B. David. “Clinical Adult Neurology”. Demos Medical Publishing, 2009, 3rd ed, pages 115-116. ISBN 978-1-933864-35-8. 8. ^ David McDougal; Dave Van-Lieshout; John Harting. “Pontine Nuclei and Middle Cerebellar Peduncle” Medical Neurosciences 731. UW-Madison Medical School. "Archived copy". Archived from the original on 2013-03-30. Retrieved 2013-04-28.CS1 maint: archived copy as title (link) 9. ^ Jody Corey-Bloom; Ronal B. David. “Clinical Adult Neurology”. Demos Medical Publishing, 2009, 3rd ed, page 115. ISBN 978-1-933864-35-8. 10. ^ George Milbry Gould; James Hendrie Lloyd. “The Philadelphia Medical Journal, Volume 6”. The Philadelphia Medical Publishing Company, 1900, page 374. 11. ^ Jody Corey-Bloom; Ronal B. David. “Clinical Adult Neurology”. Demos Medical Publishing, 2009, 3rd ed, page 114. ISBN 978-1-933864-35-8. 12. ^ Jody Corey-Bloom; Ronal B. David. “Clinical Adult Neurology”. Demos Medical Publishing, 2009, 3rd ed, page 114. ISBN 978-1-933864-35-8. 13. ^ Ataxia: Physical Therapy and Rehabilitation Applications for Ataxic Patients, 2014. http://cirrie.buffalo.edu/encyclopedia/en/article/112/#s4 14. ^ Ataxia: Physical Therapy and Rehabilitation Applications for Ataxic Patients, 2014. http://cirrie.buffalo.edu/encyclopedia/en/article/112/#s4 ## External links[edit] Classification D * MeSH: D020235 [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor *[BMI]: body mass index	Bruns apraxia	None	1,760	wikipedia	https://en.wikipedia.org/wiki/Bruns_apraxia	2021-01-18T18:38:49	{"wikidata": ["Q4979461"]}
Bannayan-Riley-Ruvalcaba syndrome is a genetic condition characterized by a large head size (macrocephaly), multiple noncancerous tumors and tumor-like growths called hamartomas, and dark freckles on the penis in males. The signs and symptoms of Bannayan-Riley-Ruvalcaba syndrome are present from birth or become apparent in early childhood. At least half of affected infants have macrocephaly, and many also have a high birth weight and a large body size (macrosomia). Growth usually slows during childhood, so affected adults are of normal height and body size. About half of all children with Bannayan-Riley-Ruvalcaba syndrome have intellectual disability or delayed development, particularly the development of speech and of motor skills such as sitting, crawling, and walking. These delays may improve with age. About half of all people with Bannayan-Riley-Ruvalcaba syndrome develop hamartomas in their intestines, known as hamartomatous polyps. Other noncancerous growths often associated with Bannayan-Riley-Ruvalcaba syndrome include fatty tumors called lipomas and angiolipomas that develop under the skin. Some affected individuals also develop hemangiomas, which are red or purplish growths that consist of tangles of abnormal blood vessels. People with Bannayan-Riley-Ruvalcaba syndrome may also have an increased risk of developing certain cancers, although researchers are still working to determine the cancer risks associated with this condition. Other signs and symptoms that have been reported in people with Bannayan-Riley-Ruvalcaba syndrome include weak muscle tone (hypotonia) and other muscle abnormalities, and seizures. Some affected individuals have thyroid problems, such as an enlargement of the thyroid gland, known as multinodular goiter, or a condition called Hashimoto thyroiditis. Skeletal abnormalities have also been described with this condition, including an unusually large range of joint movement (hyperextensibility), abnormal side-to-side curvature of the spine (scoliosis), and a sunken chest (pectus excavatum). The features of Bannayan-Riley-Ruvalcaba syndrome overlap with those of another disorder called Cowden syndrome. People with Cowden syndrome develop hamartomas and other noncancerous growths; they also have an increased risk of developing certain types of cancer. Both conditions can be caused by mutations in the PTEN gene. Some people with Bannayan-Riley-Ruvalcaba syndrome have had relatives diagnosed with Cowden syndrome, and other individuals have had the characteristic features of both conditions. Based on these similarities, researchers have proposed that Bannayan-Riley-Ruvalcaba syndrome and Cowden syndrome represent a spectrum of overlapping features known as PTEN hamartoma tumor syndrome instead of two distinct conditions. ## Frequency The prevalence of Bannayan-Riley-Ruvalcaba syndrome is unknown, although it appears to be rare. Several dozen cases have been reported in the medical literature. Researchers suspect that the disorder is underdiagnosed because its signs and symptoms vary and some of them are subtle. ## Causes About 60 percent of all cases of Bannayan-Riley-Ruvalcaba syndrome result from mutations in the PTEN gene. Another 10 percent of cases are caused by a large deletion of genetic material that includes part or all of this gene. The protein produced from the PTEN gene is a tumor suppressor, which means that it normally prevents cells from growing and dividing (proliferating) too rapidly or in an uncontrolled way. If this protein is missing or defective, cell proliferation is not regulated effectively. Uncontrolled cell division can lead to the formation of hamartomas and other cancerous and noncancerous tumors. The protein produced from the PTEN gene likely has other important functions within cells; however, it is unclear how mutations in this gene can cause the other features of Bannayan-Riley-Ruvalcaba syndrome, such as macrocephaly, developmental delay, and muscle and skeletal abnormalities. When Bannayan-Riley-Ruvalcaba syndrome is not caused by mutations or deletions of the PTEN gene, the cause of the condition is unknown. ### Learn more about the gene associated with Bannayan-Riley-Ruvalcaba syndrome * PTEN ## Inheritance Pattern This condition is inherited in an autosomal dominant pattern, which means one copy of the altered gene in each cell is sufficient to cause the disorder. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor *[BMI]: body mass index	Bannayan-Riley-Ruvalcaba syndrome	c0391826	1,761	medlineplus	https://medlineplus.gov/genetics/condition/bannayan-riley-ruvalcaba-syndrome/	2021-01-27T08:25:49	{"gard": ["5887"], "mesh": ["D006223"], "omim": ["158350"], "synonyms": []}
Gross pathology of an ovarian carcinoma. Benign, borderline, or malignant neoplasm involving the ovary Ovarian tumors, or ovarian neoplasms, are tumors arising from the ovary. They can be benign or malignant (ovarian cancer). They consists of mainly solid tissue, while ovarian cysts contain fluid. ## Histopathologic classification[edit] Ovarian tumors by incidence and risk of ovarian cancer[1] Further information: Ovarian cancer Ovarian tumors are classified according to the histology of the tumor, obtained in a pathology report. Histology dictates many aspects of clinical treatment, management, and prognosis. The most common forms are: Type Subtype Relative incidence[2] Percent malignant[2] Comments Micrograph Germ cell tumor Mature cystic teratoma 46.0% 0.17% to 2%[3] Cystic, with elements of all 3 germ layers (endoderm, mesoderm and ectoderm).[4] Hair follicles. Immature teratoma 2.5% 100% A teratoma that contains anaplastic immature elements, and is often synonymous with malignant teratoma.[5] Other germ cell tumors 3.0% Others mainly include dysgerminoma, yolk sac tumor, struma ovarii and squamous cell carcinoma arising from a dermoid cyst, and malignant mixed germ cell tumor.[2] Surface epithelial-stromal tumor Serous tumor 25% 18.5% Benign serous tumors of the right ovarian cyst are thinwalled unilocular cysts that are lined by ciliated pseudostratified cuboidal or columnar epithelium.[6] Mucinous tumor 15% 8.8% Benign mucinous tumors of the ovary consist of simple, nonstratified columnar epithelium with basally-located hyperchromatic nuclei and resemble gastric foveolar epithelium.[6] Endometrioid tumor 1% Almost 100% Tubular glands, resembling endometrium.[7] Other surface-epithelial tumors 1.5% Others include mainly malignant mixed mullerian tumor, Brenner tumor and mixed epithelial tumor.[2] Brenner tumor. Sex cord-stromal tumor Ovarian fibroma 1.5% 0% Spindle-shaped fibroblastic cells and abundant collagen.[8] Adult granulosa cell tumor 1% Almost 100% Small, bland, cuboidal to polygonal cells in various patterns.[9] Other sex cord-stromal tumors 1% Others include mainly juvenile granulosa cell tumor, thecoma and sclerosing stromal tumor[2] Secondary/metastatic) tumor 2% 100% Usually from breast cancer, colon cancer, endometrial cancer, stomach cancer or cervical cancer.[10] Mixed tumors contain elements of more than one of the above classes of tumor histology. ## References[edit] 1. ^ \- Vaidya, SA; Kc, S; Sharma, P; Vaidya, S (2014). "Spectrum of ovarian tumors in a referral hospital in Nepal". Journal of Pathology of Nepal. 4 (7): 539–543. doi:10.3126/jpn.v4i7.10295. ISSN 2091-0908. \- Minor adjustment for mature cystic teratomas (0.17 to 2% risk of ovarian cancer): Mandal, Shramana; Badhe, Bhawana A. (2012). "Malignant Transformation in a Mature Teratoma with Metastatic Deposits in the Omentum: A Case Report". Case Reports in Pathology. 2012: 1–3. doi:10.1155/2012/568062. ISSN 2090-6781. 2. ^ a b c d e Unless otherwise specified in boxes, reference is: Vaidya, SA; Kc, S; Sharma, P; Vaidya, S (2014). "Spectrum of ovarian tumors in a referral hospital in Nepal". Journal of Pathology of Nepal. 4 (7): 539–543. doi:10.3126/jpn.v4i7.10295. ISSN 2091-0908. 3. ^ Mandal, Shramana; Badhe, Bhawana A. (2012). "Malignant Transformation in a Mature Teratoma with Metastatic Deposits in the Omentum: A Case Report". Case Reports in Pathology. 2012: 1–3. doi:10.1155/2012/568062. ISSN 2090-6781. 4. ^ Hillary Rose Elwood. "Skin nonmelanocytic tumor - Other tumors of skin - Benign (mature) cystic teratoma". pathology Outlines. Topic Completed: 1 November 2016. Revised: 4 April 2019 5. ^ Sun, Hang; Ding, Hongxin; Wang, Jianjun; Zhang, Emma; Fang, Yihua; Li, Zhenhua; Yu, Xiao; Wang, Chongren; Zhao, Yifan; Chen, Kan; Wen, Siwan; Li, Liang; Shan, Shan; Hong, Liu; Chen, Face; Su, Pu (2019). "The differences between gonadal and extra-gonadal malignant teratomas in both genders and the effects of chemotherapy". BMC Cancer. 19 (1). doi:10.1186/s12885-019-5598-0. ISSN 1471-2407. 6. ^ a b Baradwan, Saeed; Alalyani, Haneen; Baradwan, Amira; Baradwan, Afnan; Al-Ghamdi, Maram; Alnemari, Jameel; Al-Jaroudi, Dania (2018). "Bilateral ovarian masses with different histopathology in each ovary". Clinical Case Reports. 6 (5): 784–787. doi:10.1002/ccr3.1466. ISSN 2050-0904. 7. ^ Shahrzad Ehdaivand. "Ovary tumor - Endometrioid tumors - General". Pathology Outlines. Topic Completed: 1 December 2012. Revised: 6 March 2020 8. ^ Parwate, Nikhil Sadanand; Patel, Shilpa M.; Arora, Ruchi; Gupta, Monisha (2015). "Ovarian Fibroma: A Clinico-pathological Study of 23 Cases with Review of Literature". The Journal of Obstetrics and Gynecology of India. 66 (6): 460–465. doi:10.1007/s13224-015-0717-6. ISSN 0971-9202. PMC 5080219. 9. ^ Shahrzad Ehdaivand. "Ovary tumor - Sex cord stromal tumors - Granulosa cell tumor - adult". Pathology Outlines. Topic Completed: 1 December 2012. Revised: 9 March 2020 10. ^ Lisa Lee-Jones, University of Wales College of Medicine (2003-12-01). "Ovarian tumours : an overview". Atlas of Genetics and Cytogenetics in Oncology and Haematology. * 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	Ovarian tumor	c0919267	1,762	wikipedia	https://en.wikipedia.org/wiki/Ovarian_tumor	2021-01-18T18:54:18	{"mesh": ["D010051"], "umls": ["C0919267"], "wikidata": ["Q11793790"]}
Marie Unna hereditary hypotrichosis Other namesMarie Unna hypotrichosis[1] SpecialtyMedical genetics Marie Unna hereditary hypotrichosis is an autosomal dominant condition characterized by scalp hair that is sparse or absent at birth, with variable coarse, wiry hair regrowth in childhood, and potential loss again at puberty.[2]:639 ## See also[edit] * List of cutaneous conditions ## References[edit] 1. ^ Rapini, Ronald P.; Bolognia, Jean L.; Jorizzo, Joseph L. (2007). Dermatology: 2-Volume Set. St. Louis: Mosby. ISBN 978-1-4160-2999-1. 2. ^ Freedberg, et al. (2003). Fitzpatrick's Dermatology in General Medicine. (6th ed.). McGraw-Hill. ISBN 0-07-138076-0. ## External links[edit] Classification D * ICD-10: Q84.2 (ILDS Q84.230) * MeSH: C535912 C535912, C535912 This condition of the skin appendages 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	Marie Unna hereditary hypotrichosis	c2931059	1,763	wikipedia	https://en.wikipedia.org/wiki/Marie_Unna_hereditary_hypotrichosis	2021-01-18T18:56:27	{"gard": ["3390"], "mesh": ["C535912"], "umls": ["C2931059"], "orphanet": ["444"], "wikidata": ["Q1641486"]}
inability to achieve orgasm despite adequate stimulation Anorgasmia SpecialtyPsychiatry, gynecology, urology Anorgasmia is a type of sexual dysfunction in which a person cannot achieve orgasm despite adequate stimulation. Anorgasmia is far more common in females (4.6 percent)[1] than in males and is especially rare in younger men. The problem is greater in women who are post-menopause.[1] In males, it is most closely associated with delayed ejaculation. Anorgasmia can often cause sexual frustration. ## Contents * 1 Causes * 1.1 Drugs-induced * 1.2 Primary anorgasmia * 1.3 Secondary anorgasmia * 1.3.1 Prostatectomy * 1.4 Situational anorgasmia * 2 Diagnosis * 3 Treatment * 4 See also * 5 References * 6 External links ## Causes[edit] The condition is sometimes classified as a psychiatric disorder. However, it can also be caused by medical problems such as diabetic neuropathy, multiple sclerosis, genital mutilation on either gender, complications from genital surgery, pelvic trauma (such as from a straddle injury caused by falling on the bars of a climbing frame, bicycle or gymnastics beam), hormonal imbalances, total hysterectomy, spinal cord injury, cauda equina syndrome, uterine embolisation, childbirth trauma (vaginal tearing through the use of forceps or suction or a large or unclosed episiotomy), vulvodynia and cardiovascular disease.[2] ### Drugs-induced[edit] A common cause of anorgasmia, in both men and women, is the use of anti-depressants, particularly selective serotonin reuptake inhibitors (SSRIs). Though reporting of anorgasmia as a side effect of SSRIs is not precise, studies have found that 17–41% of users of such medications are affected by some form of sexual dysfunction.[3][4] Another cause of anorgasmia is cocaine use[5] and opiate addiction, particularly to heroin.[6] ### Primary anorgasmia[edit] Primary anorgasmia is a condition where one has never experienced an orgasm. This is significantly more common in women, although it can occur in men who lack the gladipudendal (bulbocavernosus) reflex.[7] Women with this condition can sometimes achieve a relatively low level of sexual excitement. Frustration, restlessness, and pelvic pain or a heavy pelvic sensation may occur because of vascular engorgement. On occasion, there may be no obvious reason why orgasm is unobtainable. In such cases, women report that they are unable to orgasm even if they have a caring, skilled partner, adequate time and privacy, and an absence of medical issues which would affect sexual satisfaction. About 15% of women report difficulties with orgasm, and as many as 10% of women in the United States have never climaxed.[8][9] Only 29% of women always have orgasms with their partner.[10] Some social theorists[who?] believe that inability to orgasm may be related to residual psychosocial perceptions that female sexual desire is somehow 'wrong', and that this stems from the age of Victorian repression. It is thought that this view may impede some women – perhaps those raised in a more repressed environment – from being able to experience natural and healthy sexual feeling.[11] ### Secondary anorgasmia[edit] Secondary anorgasmia is the loss of the ability to have orgasms (as opposed to primary anorgasmia which indicates a person who has never had an orgasm). Or loss of the ability to reach orgasm of past intensity. The cause may be alcoholism, depression, grief, pelvic surgery (such as total hysterectomy) or injuries, certain medications, death-grip, illness, estrogen deprivation associated with menopause, or rape. #### Prostatectomy[edit] The prostate and surrounding organs. Secondary anorgasmia is close to 50% among males undergoing prostatectomy;[12] 80% among radical prostatectomies.[13] This is generally caused by damage to the primary nerves serving the penile area, which pass near the prostate gland. Removal of the prostate frequently damages or even completely removes these nerves, making sexual response unreasonably difficult.[14] Radical prostatectomies are usually given to younger males who are expected to live more than 10 years. At more advanced ages, the prostate is less likely to grow during that person's remaining lifetime.[14] ### Situational anorgasmia[edit] People who are orgasmic in some situations may not be in others. A person may have an orgasm from one type of stimulation but not from another, achieve orgasm with one partner but not another, or have an orgasm only under certain conditions or only with a certain type or amount of foreplay. These common variations are within the range of normal sexual expression and should not be considered problematic. A person who is troubled by experiencing situational anorgasmia should be encouraged to explore alone and with their partner those factors that may affect whether or not they are orgasmic, such as fatigue, emotional concerns, feeling pressured to have sex when they are not interested, or a partner's sexual dysfunction. In the relatively common case of female situational anorgasmia during penile-vaginal intercourse, some sex therapists recommend that couples incorporate manual or vibrator stimulation during intercourse, or using the female-above position as it may allow for greater stimulation of the clitoris by the penis or pubic symphysis or both, and it allows the woman better control of movement. ## Diagnosis[edit] This article needs additional citations for verification. Please help improve this article by adding citations to reliable sources. Unsourced material may be challenged and removed. Find sources: "Anorgasmia" – news · newspapers · books · scholar · JSTOR (June 2007) (Learn how and when to remove this template message) Effective treatment for anorgasmia depends on the cause. In the case of women suffering from psychological sexual trauma or inhibition, psychosexual counselling might be advisable and could be obtained through general practitioner (GP) referral.[15] Women suffering from anorgasmia with no obvious psychological cause would need to be examined by their GP to check for absence of disease. Blood tests would also need to be done (full blood count, liver function, oestradiol/estradiol, total testosterone, SHBG, FSH/LH, prolactin, thyroid function, lipids and fasting blood sugar) to check for other conditions such as diabetes, lack of ovulation, low thyroid function or hormone imbalances.[2] The normal thresholds for these tests and timing in a woman's menstrual cycle is detailed in Berman et al., 2005. They would then need to be referred to a specialist in sexual medicine. The specialist would check the patient's blood results for hormonal levels, thyroid function and diabetes, evaluate genital blood flow and genital sensation, as well as giving a neurological work-up to determine the degree (if any) of nerve damage. Recently, it has been proposed to add a subtype of FOD, called reduced orgasmic intensity, and field trials are underway to assess the suitability of this proposal.[16] ## Treatment[edit] Just as with erectile dysfunction in men, lack of sexual function in women may be treated with hormonal patches or tablets to correct hormonal imbalances, clitoral vacuum pump devices and medication to improve blood flow, sexual sensation and arousal.[2] Many practitioners today treat both men and women who have SSRI-induced anorgasmia with sildenafil, more commonly known as Viagra. While this approach is known to work well in men with sexual dysfunction, it is only recently that the effectiveness of sildenafil in women with sexual dysfunction is coming to light. A recent study by H. G. Nurnberg et al. showed a complete or very significant reversal of their sexual dysfunction upon taking sildenafil one hour prior to sexual activity.[17] In this study, eight out of the nine women required 50 mg of sildenafil while the 9th woman required 100 mg of sildenafil. Another option for women who have SSRI-induced anorgasmia is the use of vardenafil. Vardenafil is a type 5 phosphodiesterase (PDE5) inhibitor that facilitates muscle relaxation and improves penile erection in men. However, there is much controversy about the efficiency of the drug used in the reversal of female sexual dysfunction.[18] Vardenafil is similar to sildenafil, but vardenafil is less expensive and may be covered under some insurance plans. A study by A.K. Ashton M.D. has shown that in the case of one particular woman, the effects of vardenafil as opposed to sildenafil have not only been comparable in the effectiveness, but that vardenafil is cheaper and reversal of sexual dysfunction requires a smaller dose.[19] So far, vardenafil has been approved by the Food and Drug administration only for use in men. The NIH states that yohimbine hydrochloride has been shown in human studies to be possibly effective in the treatment of male impotence resulting from erectile dysfunction or SSRI usage (e.g., anorgasmia).[20] Published reports have shown it to be effective in the treatment of orgasmic dysfunction in men.[21] Cabergoline, an agonist of dopamine D₂ receptors which inhibits prolactin production, was found in a small study to fully restore orgasm in one third of anorgasmic subjects, and partially restore orgasm in another third. Limited data has shown that the drug amantadine may help to relieve SSRI-induced sexual dysfunction.[22][23][24] Cyproheptadine, buspirone, stimulants such as amphetamines (including the antidepressant bupropion), nefazodone and yohimbine have been used to treat SSRI-induced anorgasmia.[25] Reducing the SSRI dosage may also resolve anorgasmia problems. ## See also[edit] * Delayed ejaculation * Sexual anhedonia * Sexual dysfunction * Death-grip syndrome * Dysorgasmia ## References[edit] 1. ^ a b Nolen-Hoeksema, Susan (2014). Abnormal Psychology Sixth Edition. New York, NY: McGraw-Hill Education. p. 368. ISBN 978-0-07-803538-8. 2. ^ a b c For Women Only, Revised Edition: A Revolutionary Guide to Reclaiming Your Sex Life by Berman, J. Bumiller, E. and Berman L. (2005), Owl Books, NY. ISBN 978-0-8050-7883-1 3. ^ Hu XH, Bull SA, Hunkeler EM, et al. (July 2004). "Incidence and duration of side effects and those rated as bothersome with selective serotonin reuptake inhibitor treatment for depression: patient report versus physician estimate". The Journal of Clinical Psychiatry. 65 (7): 959–65. doi:10.4088/JCP.v65n0712. PMID 15291685. 4. ^ Landén M, Högberg P, Thase ME (January 2005). "Incidence of sexual side effects in refractory depression during treatment with citalopram or paroxetine". The Journal of Clinical Psychiatry. 66 (1): 100–06. doi:10.4088/JCP.v66n0114. PMID 15669895. 5. ^ Woodhouse, Christopher (2019). "The effects of recreational drug use on the genitourinary tract". Trends in Urology & Men's Health. 10 (4): 18–20. doi:10.1002/tre.703. S2CID 199618320. 6. ^ http://www.atforum.com/pdf/europad/HeroinAdd6-3.pdf 7. ^ Bridley, G. S.; Gillan, P. (1982). "Men and women who do not have orgasms". The British Journal of Psychiatry. 140 (4): 351–6. doi:10.1192/bjp.140.4.351. PMID 7093610. 8. ^ Frank JE, Mistretta P, Will J (March 2008). "Diagnosis and treatment of female sexual dysfunction". American Family Physician. 77 (5): 635–42. PMID 18350761. 9. ^ Giustozzi AA. Sexual dysfunction in women. In: Ferri FF. Ferri's Clinical Advisor 2010. St. Louis, Mo.: Mosby; 2009. [1] 10. ^ http://www.iub.edu/~kinsey/resources/FAQ.html#orgasm 11. ^ Stern and Saunders "Psychosocial Sexual Impediment: a Victorian Legacy? (UNC Chapel Hill, 2007)[citation not found] 12. ^ Dunsmuir WD, Emberton M, Neal DE. "There is significant sexual dissatisfaction following TURP". British Journal of Urology (77): 161A. 13. ^ Koeman M, Van Driel MF, Weijmar Schultz WC, Mensink HJ (1996). "Orgasm after radical prostatectomy". British Journal of Urology. 77 (6): 861–64. doi:10.1046/j.1464-410x.1996.01416.x. PMID 8705222. 14. ^ a b "Radical Prostatectomy". WebMD. Retrieved 6 December 2011. 15. ^ Humphery, S.; Nazareth, I. (1 October 2001). "GPs' views on their management of sexual dysfunction". Family Practice. 18 (5): 516–518. doi:10.1093/fampra/18.5.516. ISSN 0263-2136. PMID 11604374. 16. ^ Brotto LA, Bitzer J, Laan E, Leiblum S, Luria M (2010). "Women's Sexual Desire and Arousal Disorders". Journal of Sexual Medicine. 7 (1 Pt 2): 586–614. doi:10.1111/j.1743-6109.2009.01630.x. PMID 20092454.CS1 maint: multiple names: authors list (link) 17. ^ H. Geore Nurnberg, M.D.; et al. (1999). "Sildenafil for Women Patients with Antidepressant-Induced Sexual Dysfunction". Psychiatric Services. 50 (8): 1076–78. doi:10.1176/ps.50.8.1076. PMID 10445658. 18. ^ J. Angulo; et al. (2003). "Vardenafil enhances clitoral and vaginal blood flow responses to pelvic nerve stimulation in female dogs". International Journal of Impotence Research. 15 (2): 137–141. doi:10.1038/sj.ijir.3900985. PMID 12789394. 19. ^ A.K. Ashton (2004). "Vardenafil Reversal of Female Anorgasmia". American Journal of Psychiatry. 161 (11): 2133. doi:10.1176/appi.ajp.161.11.2133. PMID 15514423. 20. ^ "Yohimbe: MedlinePlus Supplements". nlm.nih.gov. 19 November 2010. Archived from the original on 1 August 2010. Retrieved 13 December 2010. 21. ^ Adeniyi AA, Brindley GS, Pryor JP, Ralph DJ (May 2007). "Yohimbine in the treatment of orgasmic dysfunction". Asian Journal of Andrology. 9 (3): 403–07. doi:10.1111/J.1745-7262.2007.00276.x. PMID 17486282. 22. ^ Shrivastava RK, Shrivastava S, Overweg N, Schmitt M (1995). "Amantadine in the treatment of sexual dysfunction associated with selective serotonin reuptake inhibitors". Journal of Clinical Psychopharmacology. 15 (1): 83–84. doi:10.1097/00004714-199502000-00014. PMID 7714234. 23. ^ Balogh S, Hendricks SE, Kang J (1992). "Treatment of fluoxetine-induced anorgasmia with amantadine". The Journal of Clinical Psychiatry. 53 (6): 212–13. PMID 1607353. 24. ^ Keller Ashton A, Hamer R, Rosen RC (1997). "Serotonin reuptake inhibitor-induced sexual dysfunction and its treatment: a large-scale retrospective study of 596 psychiatric outpatients". Journal of Sex & Marital Therapy. 23 (3): 165–75. doi:10.1080/00926239708403922. PMID 9292832. 25. ^ Gitlin, Michael J. (1998). "Treatment of Antidepressant-Induced Sexual Dysfunction". Medscape Psychiatry & Mental Health eJournal. 3 (3). Retrieved 4 April 2018. * The original text for this article is taken from public domain CDC text. * Berman, J. Bumiller, E. and Berman L. (2005) For Women Only, Revised Edition: A Revolutionary Guide to Reclaiming Your Sex Life, Owl Books, NY ## External links[edit] Classification D * ICD-10: F52.3 * ICD-9-CM: 302.73, 302.74 * DiseasesDB: 23879 * SNOMED CT: 62607004 External resources * eMedicine: article/295376 article/295379 * Anorgasmia.net Anorgasmia: definition, causes, diagnosis and treatment * University of California, Santa Barbara's SexInfo includes statistics, causes, and treatments for anorgasmia * Definition of Anorgasmia, Mayo Clinic * v * t * e Mental and behavioral disorders Adult personality and behavior Gender dysphoria * Ego-dystonic sexual orientation * Paraphilia * Fetishism * Voyeurism * Sexual maturation disorder * Sexual relationship disorder Other * Factitious disorder * Munchausen syndrome * Intermittent explosive disorder * Dermatillomania * Kleptomania * Pyromania * Trichotillomania * Personality disorder Childhood and learning Emotional and behavioral * ADHD * Conduct disorder * ODD * Emotional and behavioral disorders * Separation anxiety disorder * Movement disorders * Stereotypic * Social functioning * DAD * RAD * Selective mutism * Speech * Stuttering * Cluttering * Tic disorder * Tourette syndrome Intellectual disability * X-linked intellectual disability * Lujan–Fryns syndrome Psychological development (developmental disabilities) * Pervasive * Specific Mood (affective) * Bipolar * Bipolar I * Bipolar II * Bipolar NOS * Cyclothymia * Depression * Atypical depression * Dysthymia * Major depressive disorder * Melancholic depression * Seasonal affective disorder * Mania Neurological and symptomatic Autism spectrum * Autism * Asperger syndrome * High-functioning autism * PDD-NOS * Savant syndrome Dementia * AIDS dementia complex * Alzheimer's disease * Creutzfeldt–Jakob disease * Frontotemporal dementia * Huntington's disease * Mild cognitive impairment * Parkinson's disease * Pick's disease * Sundowning * Vascular dementia * Wandering Other * Delirium * Organic brain syndrome * Post-concussion syndrome Neurotic, stress-related and somatoform Adjustment * Adjustment disorder with depressed mood Anxiety Phobia * Agoraphobia * Social anxiety * Social phobia * Anthropophobia * Specific social phobia * Specific phobia * Claustrophobia Other * Generalized anxiety disorder * OCD * Panic attack * Panic disorder * Stress * Acute stress reaction * PTSD Dissociative * Depersonalization disorder * Dissociative identity disorder * Fugue state * Psychogenic amnesia Somatic symptom * Body dysmorphic disorder * Conversion disorder * Ganser syndrome * Globus pharyngis * Psychogenic non-epileptic seizures * False pregnancy * Hypochondriasis * Mass psychogenic illness * Nosophobia * Psychogenic pain * Somatization disorder Physiological and physical behavior Eating * Anorexia nervosa * Bulimia nervosa * Rumination syndrome * Other specified feeding or eating disorder Nonorganic sleep * Hypersomnia * Insomnia * Parasomnia * Night terror * Nightmare * REM sleep behavior disorder Postnatal * Postpartum depression * Postpartum psychosis Sexual dysfunction Arousal * Erectile dysfunction * Female sexual arousal disorder Desire * Hypersexuality * Hypoactive sexual desire disorder Orgasm * Anorgasmia * Delayed ejaculation * Premature ejaculation * Sexual anhedonia Pain * Nonorganic dyspareunia * Nonorganic vaginismus Psychoactive substances, substance abuse and substance-related * Drug overdose * Intoxication * Physical dependence * Rebound effect * Stimulant psychosis * Substance dependence * Withdrawal Schizophrenia, schizotypal and delusional Delusional * Delusional disorder * Folie à deux Psychosis and schizophrenia-like * Brief reactive psychosis * Schizoaffective disorder * Schizophreniform disorder Schizophrenia * Childhood schizophrenia * Disorganized (hebephrenic) schizophrenia * Paranoid schizophrenia * Pseudoneurotic schizophrenia * Simple-type schizophrenia Other * Catatonia Symptoms and uncategorized * Impulse control disorder * Klüver–Bucy syndrome * Psychomotor agitation * Stereotypy [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor *[BMI]: body mass index	Anorgasmia	c0234022	1,764	wikipedia	https://en.wikipedia.org/wiki/Anorgasmia	2021-01-18T18:36:01	{"icd-9": ["302.74", "302.73"], "icd-10": ["F52.3"], "wikidata": ["Q1772397"]}
A rare, neural tube closure defect characterized by partial lacking of bone fusion, resulting in sac-like protrusions of the brain and the membranes that cover it through the openings in the skull. Protruding tissue may be located on any part of the head, but most often affects the occipital area. Depending in the size nad location, encephalocele are often associated with neurological problems including intellectual disability, seizures, vision impairment, ataxia, and hydrocephalus. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor *[BMI]: body mass index	Isolated encephalocele	c0014065	1,765	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=199647	2021-01-23T17:24:17	{"gard": ["6333"], "mesh": ["D004677"], "icd-10": ["Q01.0", "Q01.1", "Q01.2", "Q01.8", "Q01.9"]}
## Summary ### Clinical characteristics. Shprintzen-Goldberg syndrome (SGS) is characterized by: delayed motor and cognitive milestones and mild-to-moderate intellectual disability; craniosynostosis of the coronal, sagittal, or lambdoid sutures; distinctive craniofacial features; and musculoskeletal findings including olichostenomelia, arachnodactyly, camptodactyly, pectus excavatum or carinatum, scoliosis, joint hypermobility or contractures, pes planus, foot malposition, and C1-C2 spine malformation. Cardiovascular anomalies may include mitral valve prolapse, secundum atrial septal defect, and aortic root dilatation. Minimal subcutaneous fat, abdominal wall defects, and myopia are also characteristic findings. ### Diagnosis/testing. The diagnosis of SGS is established in a proband with a heterozygous pathogenic variant in SKI identified by molecular genetic testing. ### Management. Treatment of manifestations: Early intervention for developmental delay with placement in special education programs; standard management of cleft palate and craniosynostosis; surgical fixation may be necessary for cervical spine instability; routine management for scoliosis; surgical correction for pectus excavatum is rarely indicated; physiotherapy for joint contractures; clubfoot deformity may require surgical correction. If aortic dilatation is present, treatment with beta-adrenergic blockers or other medications should be considered in order to reduce hemodynamic stress; surgical intervention for aneurysms may be indicated; treatment of myopia as per ophthalmologist; surgical repair of abdominal hernias as indicated. Prevention of secondary complications: Subacute bacterial endocarditis prophylaxis is recommended for dental work or other procedures for individuals with cardiac complications. Surveillance: Developmental assessment with each visit; cervical spine evaluation and clinical evaluation for scoliosis as recommended by orthopedist; imaging per cardiologist familiar with this condition; ophthalmology exams as recommended by ophthalmologist. Agents/circumstances to avoid: Contact sports; use of agents that stimulate the cardiovascular system; activities that may lead to joint pain and/or injury. ### Genetic counseling. SGS, resulting from a heterozygous pathogenic variant in SKI, is an autosomal dominant disorder. Most individuals with SGS have unaffected parents, suggesting that the causative variant has occurred either as a de novo event in the affected individual or as a result of germline mosaicism in one of the parents. Affected sibs born to unaffected parents support the occurrence of germline mosaicism in some families with SGS. Once a SKI pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing are possible. ## Diagnosis Formal diagnostic criteria for Shprintzen-Goldberg syndrome (SGS) have not been established. ### Suggestive Findings SGS should be suspected in individuals with a combination of the following clinical (see Figure 1) and radiographic features: #### Figure 1. Clinical features of Shprintzen-Goldberg syndrome. Note craniosynostosis with typical craniofacial features including dolichocephaly, proptosis, hypertelorism, low-set ears, and retrognathia. Hand and foot images show arachnodactyly and camptodactyly. (more...) * Neurodevelopment. Hypotonia, delayed motor and cognitive milestones, mild-to-moderate intellectual disability * Craniosynostosis usually involving the coronal, sagittal, or lambdoid sutures * Craniofacial findings * Dolichocephaly with or without scaphocephaly * Tall or prominent forehead * Hypertelorism * Downslanting palpebral fissures * Ocular proptosis * Malar flattening * High narrow palate with prominent palatine ridges * Micrognathia and/or retrognathia * Apparently low-set and posteriorly rotated ears * Musculoskeletal findings * Dolichostenomelia * Arachnodactyly * Camptodactyly * Pectus excavatum or carinatum * Scoliosis * Joint hypermobility or contractures * Pes planus * Foot malposition/talipes equinovarus/club foot * C1-C2 spine malformation * Cardiovascular anomalies. Mitral valve prolapse/valvular anomalies, secundum atrial septal defect, aortic root dilatation * Brain anomalies. Chiari 1 malformation * Other. Minimal subcutaneous fat, abdominal wall defects, and myopia ### Establishing the Diagnosis The diagnosis of SGS is established in a proband with a heterozygous pathogenic variant in SKI identified by molecular genetic testing (see Table 1). Molecular genetic testing approaches can include a combination of gene-targeted testing (single-gene testing and multigene panel) and comprehensive genomic testing (exome sequencing, exome array, genome sequencing) depending on the phenotype. Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Because the phenotype of SGS 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 craniosynostosis and additional congenital anomalies are more likely to be diagnosed using genomic testing (see Option 2). #### Option 1 When the phenotypic and laboratory findings suggest the diagnosis of SGS, molecular genetic testing approaches can include single-gene testing or use of a multigene panel: * Single-gene testing. Sequence analysis of SKI to detect small intragenic deletions/insertions and missense, nonsense, and splice site variants. * A multigene panel that includes SKI and other genes of interest (see Differential Diagnosis) is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests. For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here. #### Option 2 When the phenotype is indistinguishable from many other inherited disorders characterized by craniosynostosis, 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 – and particularly when evidence supports autosomal dominant inheritance – exome array (when clinically available) may be considered to detect (multi)exon deletions or duplications that cannot be detected by sequence analysis. For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here. ### Table 1. Molecular Genetic Testing Used in Shprintzen-Goldberg Syndrome View in own window Gene 1MethodNumber of Probands with a Pathogenic Variant 2 Detectable by Method SKISequence analysis 344 4 Gene-targeted deletion/duplication analysis 5None reported 6 1\. See Table A. Genes and Databases for chromosome locus and protein. 2\. See Molecular Genetics for information on allelic variants detected in this gene. 3\. Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here. 4\. Carmignac et al [2012], Doyle et al [2012], Au et al [2014], Schepers et al [2015], Saito et al [2017], O'Dougherty et al [2019], Zhang et al [2019] 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\. Contiguous deletion of SKI and adjacent genes has been reported in individuals with a phenotype that appears to be distinct from SGS (see Genetically Related Disorders) ## Clinical Characteristics ### Clinical Description To date, 44 individuals have been identified with a pathogenic variant in SKI [Carmignac et al 2012, Doyle et al 2012, Au et al 2014, Schepers et al 2015, Saito et al 2017, O'Dougherty et al 2019, Zhang et al 2019]. The following description of the phenotypic features associated with this condition is based on these reports. ### Table 2. Select Features of Shprintzen-Goldberg Syndrome View in own window Feature# of Persons w/Feature / # Evaluated for Feature DD/ID41/44 Hypotonia16/19 Craniosynostosis 131/41 Dolichocephaly/scaphocephaly36/39 Hypertelorism42/43 Downslanting palpebral fissures38/41 Ocular proptosis34/42 Malar flattening24/24 High narrow palate23/23 Micrognathia36/40 Low-set, posteriorly rotated ears23/24 Arachnodactyly43/44 Camptodactyly24/38 Pectus deformity32/40 Scoliosis29/39 Joint hypermobility18/22 Joint contractures32/36 Foot malposition / talipes equinovarus / club foot / pes cavus23/31 C1-C2 spine malformation7/10 Aortic root dilatation14/41 Mitral valve prolapse / valvular anomalies12/38 Abdominal hernias14/23 Minimal subcutaneous fat / marfanoid habitus9/20 DD = developmental delay; ID = intellectual disability 1\. Typically coronal, sagittal, or lambdoid sutures Neurodevelopment. Motor and cognitive milestones are delayed and intellectual disability is usually mild to moderate. To date, three individuals with Shprintzen-Goldberg syndrome (SGS) and a confirmed SKI pathogenic variant were reported to have normal intelligence [Doyle et al 2012, Schepers et al 2015, Zhang et al 2019]. Craniosynostosis usually involves the coronal, sagittal, or lambdoid sutures. The sutures are fused at birth and craniosynostosis can usually be suspected from the abnormal skull shape. A single suture or multiple sutures may be involved [Au et al 2014]. Information on individuals with SGS who underwent surgery for craniosynostosis in unavailable. Characteristic craniofacial features include hypertelorism, downslanting palpebral fissures, ocular proptosis, high narrow palate, micrognathia, and low-set posteriorly rotated ears. Cleft palate was reported in three of 17 individuals with SGS [Doyle et al 2012, Schepers et al 2015, O'Dougherty et al 2019]. Broad/bifid uvula has been reported in two of 12 individuals [Doyle et al 2012, O'Dougherty et al 2019]. Musculoskeletal. Arachnodactyly, camptodactyly, pectus deformities, and clubfeet are common features and are present at birth. Joint contractures are often present at birth or in the neonatal period, with the ankle joint most frequently affected [Au et al 2014, Saito et al 2017]. Joint hypermobility also occurs in individuals with SGS and is typically present from birth. Joint dislocation and instability reported by O'Dougherty et al [2019] included involvement of the left patella, thumb, and foot and C1-C2 instability. Au et al [2014] reported subluxing patellae. Pes planus becomes evident later in childhood; one or both feet may be affected. Scoliosis may be severe [Au et al 2014]. Cardiovascular. Aortic root dilatation was present in three of 18 affected individuals reported by Carmignac et al [2012]. In the report of Doyle et al [2012], however, eight of ten individuals with SGS and confirmed pathogenic variants in SKI had aortic root dilatation with or without mitral valve prolapse/incompetence. Surgery at age 16 years for aortic dilatation (aortic root dilatation with Z score = 7.014) was reported in one individual with molecularly confirmed SGS [Carmignac et al 2012]. This individual also had vertebrobasilar and internal carotid tortuosity and a dilated pulmonary artery root. Among the affected individuals with molecularly confirmed SGS reported by Doyle et al [2012] one had arterial tortuosity and two had splenic artery aneurysm – one with spontaneous rupture. Ocular. Myopia was reported in ten of 19 individuals [Carmignac et al 2012, Au et al 2014, O'Dougherty et al 2019]. Ectopia lentis has not been reported in the 16 individuals with SGS who were evaluated for this finding [Doyle et al 2012, Schepers et al 2015]. Minimal subcutaneous fat and/or marfanoid habitus was reported in nine of 20 individuals [Carmignac et al 2012, Au et al 2014]. Abdominal wall defects were reported in 14 of 23 individuals [Carmignac et al 2012, Au et al 2014, Schepers et al 2015, Saito et al 2017, O'Dougherty et al 2019]. Other * Dural ectasia (5/8 individuals) [Doyle et al 2012, Schepers et al 2015, O'Dougherty et al 2019] * Chiari 1 malformation (2/3 individuals) [Au et al 2014, O'Dougherty et al 2019] * Cryptorchidism (1/1 male) [Saito et al 2017] ### Genotype-Phenotype Correlations No genotype-phenotype correlations have been identified. ### Penetrance Penetrance is unknown. ### Nomenclature Goldberg-Shprintzen syndrome and Shprintzen-Goldberg omphalocele syndrome are separate syndromes, not related to SGS. Other names that have been used to refer to SGS: * Craniosynostosis with arachnodactyly and abdominal hernias * Marfanoid-craniosynostosis syndrome * Shprintzen-Goldberg craniosynostosis syndrome * Shprintzen-Goldberg marfanoid syndrome The term Furlong syndrome has been used to describe one individual with craniosynostosis, features of SGS, normal intelligence, and aortic enlargement. Adès et al [2006] reported on two individuals with a phenotype similar to Furlong syndrome. They had the same pathogenic missense variant in TGFBR1, making a diagnosis of Loeys-Dietz syndrome type 1 most likely [B Loeys, personal communication]. In the absence of analysis for pathogenic variants in the original individual described as having Furlong syndrome, the existence of this as a separate entity remains unclear. ### Prevalence SGS is a rare disorder and the prevalence is unknown. A SKI pathogenic variant has been identified in 44 individuals with SGS to date. ## Differential Diagnosis Loeys-Dietz syndrome (LDS) and Marfan syndrome (MFS). The phenotype of Shprintzen-Goldberg syndrome (SGS) is distinctive but shows some overlap with LDS and MFS (see Table 3). Distinguishing features of SGS include the following: * Hypotonia and intellectual disability are rare findings in individuals with LDS and MFS but appear to be almost always present in those with SGS. * Some of the distinctive radiographic findings in SGS are rarely found in individuals with either LDS or MFS. These include: * C1/C2 abnormality (in 7/10 individuals with SGS) [Doyle et al 2012, Au et al 2014, Saito et al 2017, O'Dougherty et al 2019]; * Thirteen pairs of ribs (1/1) [O'Dougherty et al 2019]; * Chiari 1 malformation (2/3 ) [Au et al 2014, O'Dougherty et al 2019]. * Aortic root dilatation is less frequent in SGS than in LDS or MFS, but when present in individuals with SGS, it can be severe [Carmignac et al 2012]. One of the hallmarks of LDS is the occurrence of arterial tortuosity and aneurysms in arteries other than the aorta. Arterial tortuosity was found in two individuals with SGS; a further two individuals with SGS had splenic artery aneurysm [Carmignac et al 2012, Doyle et al 2012]. ### Table 3. Comparison of Clinical Features of SGS, TGFBR1-/TGFBR2-LDS, and MFS View in own window Clinical FeatureSGSTGFBR1-/TGFBR2-LDS 1MFS 2 DD++−− Ectopia lentis−−+++ Cleft palate / bifid uvula+++− Widely spaced eyes++++− Craniosynostosis+++++− Tall stature+++++ Arachnodactyly+++++++ Pectus deformity++++++ Clubfoot++++− Osteoarthritis−++ Aortic root aneurysm++++++ Arterial aneurysm+++− Arterial tortuosityRare++− Early dissection−++++ Bicuspid aortic valve−++− Mitral valve insufficiency++++ Striae−+++ Dural ectasia+++ \+ = feature is present; ++ = feature is more commonly present; +++ = feature is most commonly present; − = feature is absent; DD = developmental delay; LDS = Loeys-Dietz syndrome; MFS = Marfan syndrome; SGS = Shprintzen-Goldberg syndrome 1\. Approximately 75%-85% of Loeys-Dietz syndrome is attributed to pathogenic variants in TGFBR2 or TGFBR1. LDS is also known to be associated with heterozygous pathogenic variants in SMAD2, SMAD3, TGFB2, and TGFB3. LDS is inherited in an autosomal dominant manner. 2\. Marfan syndrome is caused by pathogenic variants in FBN1 and inherited in an autosomal dominant manner. Other disorders ### Table 4. Disorders of Interest in the Differential Diagnosis of Shprintzen-Goldberg Syndrome View in own window GeneDifferential DisorderMOIClinical Features of Differential Disorder Overlapping w/SGSDistinguishing from SGS FBN2Congenital contractural arachnodactylyAD * Dolichostenomelia, arachnodactyly * Kyphosis/scoliosis 1 * Aortic dilatation (occasionally present) Most individuals w/CCA have "crumpled" ears that present as a folded upper helix of the external ear. FLNAFrontometaphyseal dysplasia & Melnick-Needles syndrome (See Otopalatodigital Spectrum Disorders.)XLTall, square-shaped vertebrae; bowed tibiae; occasionally, fusion of upper cervical vertebraePresence of ID & craniosynostosis in SGS usually distinguishes it from MNS or FMD. B3GAT3B3GAT3-related disorder 2ARCraniosynostosis, midface hypoplasia, kyphoscoliosis, joint contractures, long fingers, foot deformity, cardiovascular abnormalitiesPresence of multiple neonatal fractures, hypoplasia of the nasal bones, femoral bowing, & overlapping fingers helps distinguish this disorder from SGS. HNRNPKAu-Kline syndromeAD * Aortic dilatation * Sagittal craniosynostosis, shallow orbits, palate abnormalities, &/or bifid uvula * ID (mild to moderate) * Skeletal anomalies * Marfanoid body habitus * Arachnodactyly & camptodactyly * Congenital heart disease * Hydronephrosis * Hearing loss * Seizures AD = autosomal dominant; AR = autosomal recessive; CCA = congenital contractural arachnodactyly; FMD = frontometaphyseal dysplasia; ID = intellectual disability; MNS = Melnick-Needles syndrome; MOI = mode of inheritance; SGS = Shprintzen-Goldberg syndrome; XL = X-linked 1\. Kyphosis/scoliosis in ~50% of individuals with CCA (begins as early as infancy, is progressive, & causes the greatest morbidity in CCA) 2\. Yauy et al [2018] ## Management ### Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with Shprintzen-Goldberg syndrome (SGS), the evaluations summarized in Table 5 (if not performed as part of the evaluation that led to the diagnosis) are recommended. ### Table 5. Recommended Evaluations Following Initial Diagnosis in Individuals with Shprintzen-Goldberg Syndrome View in own window System/ConcernEvaluationComment NeurodevelopmentAssessment for developmental disabilitiesReferral for early intervention services; consider referral to neurodevelopmental specialist. Craniofacial * Physical examination * Head CT to evaluate sutures if craniosynostosis suspected To identify cleft palate & craniosynostosis MusculoskeletalReferral to orthopedist &/or radiographs as indicatedTo evaluate for C1/C2 abnormality, scoliosis, severe pectus deformity, abnormal joint mobility, & foot malposition CardiovascularEchocardiogramTo evaluate for aortic root dilation Consider MRA or CT scan w/3D reconstruction from head to pelvis.To identify arterial aneurysms & arterial tortuosity throughout the arterial tree OphthalmologyExamination by ophthalmologist w/expertise in connective tissue disordersTo evaluate for myopia & complications of proptosis NeurologyBrain MRITo evaluate for Chiari 1 malformation OtherConsultation w/clinical geneticist &/or genetic counselor ### Treatment of Manifestations Management of SGS is best conducted through the coordinated input of a multidisciplinary team of specialists including a clinical geneticist, cardiologist, ophthalmologist, orthopedist, cardiothoracic surgeon, and craniofacial team. ### Table 6. Treatment of Manifestations in Individuals with Shprintzen-Goldberg Syndrome View in own window Manifestation/ ConcernTreatmentConsiderations/Other DDEarly intervention servicesConsider consultation w/developmental pediatrician or neurodevelopmental specialist. Craniosynostosis & cleft palateManagement by craniofacial teamTreatment as in other disorders w/these manifestations Cervical spine instabilityTreatment per orthopedistSurgical fixation may be necessary. ScoliosisTreatment per orthopedist Pectus excavatumTreatment per orthopedistMay be severe; rarely, surgical correction indicated for medical reasons Joint contracturesPhysiotherapy may help ↑ mobility. Clubfoot deformityTreatment per orthopedistMay require surgical correction Aortic dilatationTreatment w/beta-adrenergic blockers or other medications per cardiologistShould be considered in order to reduce hemodynamic stress AneurysmsSurgical intervention may be indicated; per vascular surgeon. MyopiaTreatment per ophthalmologist Abdominal herniaSurgical repair may be indicated. DD = developmental delay ### Prevention of Secondary Complications For individuals with cardiac complications, subacute bacterial endocarditis prophylaxis is recommended for dental work or other procedures expected to contaminate the bloodstream with bacteria. ### Surveillance ### Table 7. Recommended Surveillance for Individuals with Shprintzen-Goldberg Syndrome View in own window System/ConcernEvaluationFrequency NeurodevelopmentDevelopmental assessmentAt each visit Musculoskeletal * Cervical spine evaluation * Clinical evaluation for scoliosis Per orthopedist CardiologyImaging per cardiologist to screen for aortopathy, mitral valve anomalies, & aneurysmsPer cardiologist Vision issuesOphthalmologic examPer ophthalmologist ### Agents/Circumstances to Avoid The following should be avoided: * Contact sports, which may lead to catastrophic complications in those with cardiovascular issues or cervical spine anomalies/instability * Agents that stimulate the cardiovascular system, including routine use of decongestants * Activities that cause joint pain or injury ### 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	Shprintzen-Goldberg Syndrome	c1321551	1,766	gene_reviews	https://www.ncbi.nlm.nih.gov/books/NBK1277/	2021-01-18T20:57:05	{"mesh": ["C537328"], "synonyms": []}
A rare rheumatologic disease characterized by bilateral morning stiffness which lasts > 45-60 min of duration associated with a subacute-onset of severe pain with active movements, typically affecting the shoulders, proximal upper limbs, neck and/or, less commonly, the pelvic girdle and proximal aspects of thighs, which are exacerbated with inactivity and improve progressively over the day. Muscle tenderness, peripheral synovitis, arthritis, carpal tunnel syndrome or distal tenosynovitis, as well as non-specific symptoms, such as fatigue, asthenia, malaise, low-grade fever, anorexia and weight loss, may be associated. Acute phase reactants (erythrocyte sedimentation rate, C-reactive protein) are increased. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor *[BMI]: body mass index	Polymyalgia rheumatica	c0032533	1,767	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=93569	2021-01-23T17:11:43	{"gard": ["4704"], "mesh": ["D011111"], "umls": ["C0032533", "C1527406"], "icd-10": ["M35.3"], "synonyms": ["Rhizomelic pseudopolyarthritis"]}
Teebi and Kaurah (1996) described 3 Iranian sibs (2 boys and a girl), born of first-cousin parents, with the association of microcephaly (with normal intelligence), total anonychia, and transverse palmar creases. The same abnormalities were reportedly found in the proband's cousin; her parents were also consanguineous. Teebi and Kaurah (1996) proposed that this complex is a distinct autosomal recessive 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	ANONYCHIA, TOTAL, WITH MICROCEPHALY	c2931373	1,768	omim	https://www.omim.org/entry/607214	2019-09-22T16:09:31	{"mesh": ["C536948"], "omim": ["607214"], "orphanet": ["1094"]}
3-methylcrotonyl-CoA carboxylase deficiency (also known as 3-MCC deficiency) is an inherited disorder in which the body is unable to process certain proteins properly. People with this disorder have a shortage of an enzyme that helps break down proteins containing a particular building block (amino acid) called leucine. Infants with 3-MCC deficiency appear normal at birth but usually develop signs and symptoms in infancy or early childhood. The characteristic features of this condition, which can range from mild to life-threatening, include feeding difficulties, recurrent episodes of vomiting and diarrhea, excessive tiredness (lethargy), and weak muscle tone (hypotonia). If untreated, this disorder can lead to delayed development, seizures, and coma. Many of these complications can be prevented with early detection and lifelong management with a low-protein diet and appropriate supplements. Some people with gene mutations that cause 3-MCC deficiency never experience any signs or symptoms of the condition. The characteristic features of 3-MCC deficiency are similar to those of Reye syndrome, a severe disorder that develops in children while they appear to be recovering from viral infections such as chicken pox or flu. Most cases of Reye syndrome are associated with the use of aspirin during these viral infections. ## Frequency This condition is detected in an estimated 1 in 36,000 newborns worldwide. ## Causes Mutations in the MCCC1 or MCCC2 gene can cause 3-MCC deficiency. These two genes provide instructions for making different parts (subunits) of an enzyme called 3-methylcrotonyl-coenzyme A carboxylase (3-MCC). This enzyme plays a critical role in breaking down proteins obtained from the diet. Specifically, 3-MCC is responsible for the fourth step in processing leucine, an amino acid that is part of many proteins. Mutations in the MCCC1 or MCCC2 gene reduce or eliminate the activity of 3-MCC, preventing the body from processing leucine properly. As a result, toxic byproducts of leucine processing build up to harmful levels, which can damage the brain. This damage underlies the signs and symptoms of 3-MCC deficiency. ### Learn more about the genes associated with 3-methylcrotonyl-CoA carboxylase deficiency * MCCC1 * MCCC2 ## 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	3-methylcrotonyl-CoA carboxylase deficiency	c0268600	1,769	medlineplus	https://medlineplus.gov/genetics/condition/3-methylcrotonyl-coa-carboxylase-deficiency/	2021-01-27T08:25:30	{"gard": ["10954"], "mesh": ["C535308"], "omim": ["210200", "210210"], "synonyms": []}
Kondo et al. (2004) studied 3 patients from 2 pedigrees with an unusual form of cone dystrophy (see 180020) in which the peripheral cone system was more affected than the central cone system, and whose rod system was relatively normal. The fundus examination and fluorescein angiogram results were essentially normal except for mild temporal pallor of the optic disc in 2 patients. The corrected visual acuity ranged from 20/16 to 20/100. Color vision was normal in 1 patient, but abnormal in 2 patients. A relative paracentral scotoma was detected 2 patients (3 eyes). Full-field electroretinogram (ERG) cone responses were reduced significantly, but rod responses were normal in all patients, as in patients were typical cone dystrophy. However, the focal macular cone ERGs were well preserved in all patients. Psychophysical rod-cone perimetry demonstrated that the peripheral cone system was impaired, whereas the rod sensitivity was completely normal. The results of the multifocal ERG in 2 patients supported the findings made by the full-field and focal macular ERGs. These findings demonstrated that there was a subgroup of patients with cone dystrophy in whom the peripheral cone system was more affected than the central cone system. INHERITANCE \- Autosomal recessive HEAD & NECK Eyes \- Peripheral retinal cone degeneration \- Visual acuity loss (none to moderate (20/16 to 20/100)) \- Mild temporal pallor of the optic disc (partial optic atrophy) \- Defective color vision in some patients \- Preserved rod function \- Distinctive electroretinogram - focal macular cone ERG is well-preserved \- Relative paracentral scotoma in 2/3 of patients \- Rod-cone perimetry showed normal rod sensitivity, but impaired peripheral cone sensitivity MISCELLANEOUS \- 3 reported cases, 1 pedigree of affected sibs, neither parent affected ▲ 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	PERIPHERAL CONE DYSTROPHY	c1836946	1,770	omim	https://www.omim.org/entry/609021	2019-09-22T16:06:50	{"mesh": ["C563813"], "omim": ["609021"]}
A number sign (#) is used with this entry because congenital stationary night blindness type 1B is caused by mutation in the GRM6 gene (604096) on chromosome 5q35. For a general phenotypic description and discussion of the genetic heterogeneity of congenital stationary night blindness, see CSNB1A (310500). Clinical Features Gassler (1925) constructed an instructive pedigree of an inbred Swiss kindred with night blindness and myopia which was reproduced by Francois (1961). Merin et al. (1970) and Der Kaloustian and Baghdassarian (1972) reported instructive families. Weleber and Tongue (1987) emphasized the possible confusion of autosomal recessive congenital stationary night blindness with Leber congenital amaurosis (see 204000). Barnes et al. (2002) reported a 30-year-old Greek man with a history of night blindness. There was no known consanguinity, although his parents were from the same village in Greece. The patient's maximal dark-adapted response showed both a reduced a-wave and a markedly reduced b-wave as compared with that of a control individual. There was substantial reduction in a-wave amplitude, in contrast to CSNB1A (310500), in which little or no reduction in the amplitude of the ERG a-wave is seen (Miyake et al., 1986). Barnes et al. (2002) also noted that the patient's pedigree did not appear to be consistent with X-linked inheritance and the patient did not show the reduced visual acuity and myopia that are common in CSNB1A. The patient's mother had a severe retinitis pigmentosa (RP, see 268000)-like condition, but the diagnosis of a mild form of RP in the proband was ruled out because of the entirely normal appearance of the fundus at age 30 and the lack of other visual changes over time, such as peripheral visual field loss. Barnes et al. (2002) concluded that the overall pattern of findings distinguished this patient from previously described forms of CSNB. They suggested that 2 factors, a rod phototransduction defect and a postreceptoral defect, are likely to contribute to his night blindness, and also noted evidence of dysfunction within the cone ON pathway. Dryja et al. (2005) reexamined the patient reported by Barnes et al. (2002) at 37 years of age, at which time the patient reported that there had been no worsening of his night blindness. He had developed sparse midperipheral bone spicule-shaped pigment clumps, primarily in the nasal retina, and there was a temporal visual field defect that had not been apparent on his initial examination. ERGs to elicit cone ON and OFF responses showed prominent and normal a-waves but substantially reduced b-waves in the ON responses. Dryja et al. (2005) suggested that the signs of retinal degeneration in this patient might be related to his being a carrier of a mutation in an unidentified RP gene, since his mother had an apparently autosomal recessive form of RP. The authors also reported 2 other patients who had been night-blind from an early age. All 3 patients had visual acuities that were normal or only slightly reduced. When maximally dark-adapted, they could perceive lights only with an intensity 2 to 3 log units above normal. Abramowicz et al. (2005) described a son and daughter, born of first-cousin parents, with complete stationary night blindness. They considered several candidate genes and excluded the sidekick genes SDK1 (607216) and SDK2 (607217). Zeitz et al. (2005) reported 5 individuals with CSNB1B from 3 unrelated families. All patients displayed a distinctive abnormality of the rod pathway signals on scotopic 15-Hz flicker ERG, characterized by abnormal phase behavior with several minimum responses. Molecular Genetics Dryja et al. (2005) analyzed the GRM6 gene (604096) in 26 unrelated patients with a prior diagnosis of congenital stationary night blindness. A 37-year-old Greek man, previously reported by Barnes et al. (2002), was found be homozygous for a nonsense mutation (604096.0001). A 14-year-old girl was homozygous for a missense mutation (604096.0002), and a 31-year-old man was compound heterozygous for a nonsense mutation (604096.0003) and a missense mutation (604096.0004). In affected members of 3 unrelated families with CSNB1B, Zeitz et al. (2005) identified 5 different homozygous or compound heterozygous mutations in the GRM6 gene (see, e.g., 604096.0005-604096.0007). Nomenclature The term nyctalopia, which literally means 'seeing at night,' is a misnomer. Hemeralopia ('seeing in the day') is the proper term for night blindness. See 310500 for a discussion of the derivation of these 2 terms, including the idea that the syllable 'al,' coming from a Greek root for 'blind' or 'obscure,' actually makes nyctalopia mean night blindness. HEENT \- Hemeralopia \- Night blindness \- Myopia 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	NIGHT BLINDNESS, CONGENITAL STATIONARY, TYPE 1B	c0339535	1,771	omim	https://www.omim.org/entry/257270	2019-09-22T16:24:16	{"doid": ["0110865"], "mesh": ["C536122"], "omim": ["257270"], "orphanet": ["215"], "synonyms": ["Alternative titles", "NIGHT BLINDNESS, CONGENITAL STATIONARY, COMPLETE, AUTOSOMAL RECESSIVE", "CSNB, COMPLETE, AUTOSOMAL RECESSIVE"]}
A number sign (#) is used with this entry because of evidence that lymphatic malformation-1 (LMPHM1) is caused by heterozygous mutation in the FLT4 gene (136352) on chromosome 5q35. One patient with homozygous mutation in the FLT4 gene has been reported. Description Primary lymphedema is caused by anatomic or functional defects in the lymphatic system, resulting in chronic swelling of body parts. There may be accompanying nail and skin changes, such as nail dysplasia or papillomatosis. Onset is usually at birth or in early childhood but can occur later, and the severity is variable (summary by Gordon et al., 2013 and Balboa-Beltran et al., 2014). ### Genetic Heterogeneity of Lymphatic Malformation Primary lymphedema is genetically heterogeneous: see also LMPHM2 (611944), which maps to chromosome 6q16.2-q22.1; LMPHM3 (613480), caused by mutation in the GJC2 gene (608803) on chromosome 1q42; LMPHM4 (615907), caused by mutation in the VEGFC gene (601528) on chromosome 4q34; LMPHM5 (153200); LMPHM6 (616843), caused by mutation in the PIEZO1 gene (611184) on chromosome 16q24; and LMPHM7 (617300), caused by mutation in the EPHB4 gene (600011) on chromosome 7q22. Lymphedema can also be a feature of syndromic disorders such as lymphedema-distichiasis syndrome (153400), which is caused by mutation in the FOXC2 gene (602402). Nomenclature An early classification of primary lymphedema was based on age of onset. The first descriptions of familial lymphedema were published by Milroy (1892), who described early onset of the disorder, and Meige (1898), who described onset around the time of puberty. Lymphedema of early onset became classified as Milroy disease (type I), and lymphedema after puberty as Meige disease or lymphedema praecox (type II; see 153200). However, later reports showed that lymphedema could occur with early and late onset within the same family and that the features of the disorder could vary within a family. Primary lymphedema is here classified by molecular defect and mode of inheritance. Clinical Features Milroy (1892), a physician in Omaha, Nebraska, described the lymphedema in 6 generations of a family. Also see Milroy (1928). Rosen et al. (1962) observed congenital chylous ascites in an affected infant whose father had recurrent swelling of the scrotum beginning at the age of 20 years. Marked loss of albumin into the intestinal tract with consequent hypoproteinemia was demonstrated. In 2 patients, Hurwitz and Pinals (1964) observed persistent bilateral pleural effusion in which the protein content of the pleural fluid was high. Esterly (1965) described a family with 15 affected members of 3 generations. One child had striking congenital edema of the hands as a main feature and a second had similar swelling of the hands, as well as bilateral involvement of the legs and feet. A sib of the proposita had no apparent lymphedema, although 2 of his 4 children had bilateral swelling of the legs and feet. He was regarded at first as a 'skipped' generation similar to those noted in previous pedigrees of Milroy disease. Closer examination, however, demonstrated a definite 3 x 5 cm area of slight edema on the medial aspect of the left lower leg. This area was warm to the touch and could be pitted against the underlying tibia. High blood flow in the leg affected by congenital lymphedema has been thought to be due to accumulation of vasodilatory metabolites. Lymphedematous legs generally feel warm and the patients have warm feet. The proposita in the family reported by Esterly (1965) could recover the newspaper from her front walk in her bare feet in winter without discomfort. Esterly (1965) reviewed 22 previously documented pedigrees which, with his own family, gave a total of 152 affected persons. Ferrell et al. (1998) studied 13 lymphedema families from the U.S. and Canada. All members of these families were of western European ancestry. In the 13 families, 105 individuals were classified as affected, with a male:female ratio of 1:2.3. The age of onset of lymphedema ranged from prenatal (diagnosed by ultrasound) to age 55 years. When affected x normal matings were analyzed, 76 of 191 children were affected, yielding a penetrance of 80%. Brice et al. (2005) examined 211 individuals from 10 families with a history of congenital lymphedema and mutations in FLT4. Mutations were confirmed in 64 clinically affected individuals, and 7 clinically unaffected individuals were also found to have mutations. In all but 2 patients onset of swelling was from birth. Lymphedema was confined to the lower extremities in all patients and was associated with secondary changes including deep creases over the toes, small dysplastic ('ski jump') toenails, and papillomas. Brice et al. (2005) noted that these patients also had prominent, wide-caliber leg and foot veins not seen in other forms of congenital lymphedema. Apart from hydroceles and some urethral abnormalities, there were no major structural abnormalities or consistent dysmorphic features. Ghalamkarpour et al. (2006) reported 3 unrelated families with autosomal dominant lymphedema confirmed by genetic analysis (see, e.g., 136352.0008-136352.0009). In 1 family, the proband had severe elephantiasis up to the inguinal ligaments bilaterally associated with chronic venous ulcerations, cellulitis, and papillomatosis. In another family, a 22-week-old fetus was found to have fetal hydrops with bilateral leg edema, pleural effusions, hydrothorax, and pulmonary hypoplasia on ultrasound. The pregnancy was terminated. Other affected family members had congenital lymphedema of the legs with variable severity. One affected member from a third family had spontaneous resolution of the edema. Liu et al. (2012) examined 378 patients with primary lymphedema of the lower extremities using magnetic resonance lymphangiography. Defects of the inguinal lymph nodes were detected in 63 (17%) of the patients, with mild or moderate dilation of the afferent lymph vessels. Lymphatic abnormalities were present in 123 (32%) of the patients, including aplasia, hypoplasia, or hyperplasia, with no obvious defects of the drainage lymph nodes. Abnormalities of both lymph vessels and lymph nodes were observed in 192 (51%) of the patients. There was no significant difference in age at onset or severity of disease between the groups, including between patients exhibiting hypoplasia or hyperplasia. Inheritance Holberg et al. (2001) performed a complex segregation analysis and a genomewide search for linkage in 6 previously described families with Milroy congenital lymphedema. Results confirmed that Milroy lymphedema is generally inherited as a dominant condition, but this mode of inheritance did not account for all observed familial correlations. The authors suggested that shared environmental or additional genetic factors may also be important in explaining the observed familial aggregation. The possibility of an autosomal recessive form of congenital lymphedema was raised by Kajii and Tsukahara (1985), who described brother and sister. The parents were not known to be related but came from an island with a population of 1,500 in the Sea of Japan. Kajii and Tsukahara (1986) cited a similar experience of brother and sister with congenital lymphedema of the lower extremities and no associated malformations. Mapping In linkage studies of 3 multigeneration families demonstrating hereditary lymphedema segregating as an autosomal dominant with incomplete penetrance, Ferrell et al. (1998) demonstrated a 2-point lod score of 6.1 at theta = 0.0 for marker D5S1354 and a maximum multipoint lod score of 8.8 at marker D5S1354 located at 5q34-q35. Linkage analysis in 2 additional families using markers from the linked region showed 1 family consistent with linkage to distal chromosome 5; in the second family, linkage to 5q was excluded for all markers in the region. Evans et al. (1999) carried out a genomewide search in a 4-generation North American family with what they termed 'dominantly inherited primary congenital lymphedema.' They established linkage to markers from the 5q35.3 region in this family and in 4 additional British families. The locus appeared to be situated in the most telomeric region of 5q35.3. No recombination was observed with D5S408 (lod = 10.03) and D5S2006 (lod = 8.46), with a combined multipoint score of 16.55. Four unaffected subjects were identified as gene carriers and provided an estimated penetrance ratio of 0.84 for this disorder. Molecular Genetics In a family with hereditary lymphedema, Ferrell et al. (1998) identified a mutation in the FLT4 gene (136352.0005). In several families with autosomal dominant hereditary lymphedema, Karkkainen et al. (2000) identified different mutations in the FLT4 gene (see, e.g., 136352.0002). Evans et al. (2003) identified 8 different heterozygous mutations in the FLT4 gene (see, e.g., 136352.0011) in affected members of 12 different Caucasian families with hereditary lymphedema. All the mutations occurred in the tyrosine kinase domains. Several families showed incomplete penetrance of the phenotype. In 14 affected and 2 unaffected members of a 3-generation consanguineous Israeli family of Muslim Arab origin with hereditary lymphedema, Spiegel et al. (2006) identified heterozygosity for a missense mutation in the FLT4 gene (136352.0010). The mutation was not found in 110 control individuals. There was wide intrafamilial phenotypic variability including 2 asymptomatic individuals, a case of prenatal hydrothorax evolving to hydrops fetalis, and a late-onset complication of chronic degenerative joint disease of the knees. Connell et al. (2009) identified mutations in the FLT4 gene, including 14 novel mutations, in 22 (42%) of 52 patients with primary lymphedema. Mutation prevalence was 75% in patients with a typical Milroy phenotype and a positive family history, and 68% if positive family history was not a diagnostic criterion. No mutations were found outside the kinase domains, showing that analysis of nonkinase domains of FLT4 is not useful for Milroy disease patients. No mutations were identified in the VEGFC gene (601528), which encodes the FLT4 ligand. The findings indicated that a positive family history is not essential in Milroy disease, and that the likelihood of detecting FLT4 mutations in patients with a phenotype not typical for Milroy disease is less than 5%. ### Recessive Inheritance Ghalamkarpour et al. (2009) studied a Hispanic female, born of first-cousin parents, who had lymphedema at birth that extended below the knees bilaterally and was accompanied by a hypoplastic fourth toe. Her parents were unaffected, and there was no family history of lymphedema. The authors identified homozygosity for a missense mutation in the ATP-binding domain of the FLT4 gene (136352.0012) in the proband; her parents were heterozygous for the hypomorphic mutation, which was not found in 110 controls. Ghalamkarpour et al. (2009) suggested that there should be large-scale screening of the FLT4 gene in all primary lymphedema patients. Animal Model Congenital lymphedema is autosomal dominant in the pig (Van der Putte (1978, 1978)). INHERITANCE \- Autosomal dominant CARDIOVASCULAR Vascular \- Hemangioma GENITOURINARY External Genitalia (Male) \- Hydrocele SKIN, NAILS, & HAIR Skin \- Hyperkeratosis over edematous areas \- Papillomatosis over edematous areas \- Hemangioma Nails \- Upturned toenails MUSCLE, SOFT TISSUES \- Lymphedema, predominantly in the lower limbs \- Lymphography shows hypoplasia of lymphatic vessels PRENATAL MANIFESTATIONS Amniotic Fluid \- Non-immune fetal hydrops (rare) MISCELLANEOUS \- Onset usually at birth \- Later onset may occur \- Variable expression and severity \- More prevalent in females \- Spontaneous resorption (rare) \- Lymphedema that presents at puberty is called Meige disease ( 153200 ) MOLECULAR BASIS \- Caused by mutation in the FMS-like tyrosine kinase-4 gene (FLT4, 136352.0005 ) ▲ 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	LYMPHATIC MALFORMATION 1	c1704423	1,772	omim	https://www.omim.org/entry/153100	2019-09-22T16:38:47	{"doid": ["0070210"], "mesh": ["D008209"], "omim": ["153100"], "icd-10": ["Q82.0"], "orphanet": ["79452"], "synonyms": ["Alternative titles", "NONNE-MILROY LYMPHEDEMA", "MILROY DISEASE", "LYMPHEDEMA, EARLY-ONSET", "PRIMARY CONGENITAL LYMPHEDEMA", "LYMPHEDEMA, HEREDITARY, TYPE I, FORMERLY", "LYMPHEDEMA, HEREDITARY, IA, FORMERLY"], "genereviews": ["NBK1239"]}
A number sign (#) is used with this entry because focal segmental glomerulosclerosis-8 (FSGS8) is caused by heterozygous mutation in the ANLN gene (616027) on chromosome 7p14. For a general phenotypic description and a discussion of genetic heterogeneity of focal segmental glomerulosclerosis and nephrotic syndrome, see FSGS1 (603278). Clinical Features Gbadegesin et al. (2014) reported 2 unrelated families with proteinuria due to focal segmental glomerulosclerosis confirmed by renal biopsy. Some clinical details of 1 large 4-generation family were provided. The age at onset varied greatly, between 9 and 69 years, and end-stage renal disease occurred between 35 and 75 years. Five patients underwent renal transplant with no recurrence in the renal allograft. Inheritance The transmission pattern of FSGS8 in the families reported by Gbadegesin et al. (2014) was consistent with autosomal dominant inheritance. Molecular Genetics In affected members of a large 4-generation family with autosomal dominant FSGS8, Gbadegesin et al. (2014) identified a heterozygous missense mutation in the ANLN gene (R431C; 616027.0001). The mutation was found by a combination of linkage analysis and whole-exome sequencing focusing on genes known to be enriched in the podocyte. Mutational screening of the ANLN gene in 250 families with FSGS identified 1 missense mutation (G618C; 616027.0002) that segregated with the disorder in 1 family. Overexpression of the R431C mutant in HEK293 cells resulted in reduced and defective binding to CD2AP (604241) compared to wildtype, and cells carrying the mutation showed increased cell motility compared to wildtype in a wound-healing assay. The findings suggested that anillin may play a significant role in podocyte cell migration. Renal biopsy specimens from humans with idiopathic FSGS showed increased expression of anillin in the glomerulus, whereas synaptopodin (SYNPO; 608155) expression was downregulated. Gbadegesin et al. (2014) postulated that differentiated podocytes that express anillin are likely to be abnormal, since anillin is usually expressed in actively dividing cells. Animal Model Gbadegesin et al. (2014) found that morpholino-mediated knockdown of anillin in zebrafish caused severe edema. Transmission electron microscopy revealed fusion and almost complete effacement of podocyte foot processes as well as disorganization of the glomerular filtration barrier. INHERITANCE \- Autosomal dominant GENITOURINARY Kidneys \- Nephrotic syndrome \- Focal segmental glomerulosclerosis \- End-stage renal disease LABORATORY ABNORMALITIES \- Proteinuria MISCELLANEOUS \- Highly variable age at onset (range 9 to 69 years) \- Two unrelated families have been reported (last curated September 2014) MOLECULAR BASIS \- Caused by mutation in the actin-binding protein anillin gene (ANLN, 616027.0001 ) ▲ 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	FOCAL SEGMENTAL GLOMERULOSCLEROSIS 8	c1868672	1,773	omim	https://www.omim.org/entry/616032	2019-09-22T15:50:13	{"doid": ["0111133"], "mesh": ["C536404"], "omim": ["616032"], "orphanet": ["656"], "synonyms": ["Alternative titles", "GLOMERULOSCLEROSIS, FOCAL SEGMENTAL, 8"]}
Disorder that involves repeated thoughts (obsessions) that make a person feel driven to do something (compulsions) "OCD" redirects here. It is not to be confused with Obsessive–compulsive personality disorder. For other uses, see OCD (disambiguation). Parts of this article (those related to Article contains some spelling mistakes, typos, and other language mistakes.) need to be updated. Please update this article to reflect recent events or newly available information. (January 2021) Obsessive–compulsive disorder Frequent, excessive hand washing occurs in some people with OCD SpecialtyPsychiatry SymptomsFeel the need to check things repeatedly, perform certain routines repeatedly, have certain thoughts repeatedly[1] ComplicationsTics, anxiety disorder, suicide[2][3] Usual onsetBefore 35 years[1][2] CausesUnknown[1] Risk factorsChild abuse, stress[2] Diagnostic methodBased on the symptoms[2] Differential diagnosisAnxiety disorder, major depressive disorder, eating disorders, obsessive–compulsive personality disorder[2] TreatmentCounseling, selective serotonin reuptake inhibitors, clomipramine[4][5] Frequency2.3%[6] Obsessive–compulsive disorder (OCD) is a mental disorder in which a person has certain thoughts repeatedly (called "obsessions") or feels the need to perform certain routines repeatedly (called "compulsions") to an extent which generates distress or impairs general functioning.[1][2] The person is unable to control either the thoughts or activities for more than a short period of time.[1] Common compulsions include hand washing, counting of things, and checking to see if a door is locked.[1] These activities occur to such a degree that the person's daily life is negatively affected,[1] often taking up more than an hour a day.[2] Most adults realize that the behaviors do not make sense.[1] The condition is associated with tics, anxiety disorder, and an increased risk of suicide.[2][3] The cause is unknown.[1] There appear to be some genetic components, with both identical twins more often affected than both non-identical twins.[2] Risk factors include a history of child abuse or other stress-inducing event.[2] Some cases have been documented to occur following infections.[2] The diagnosis is based on the symptoms and requires ruling out other drug-related or medical causes.[2] Rating scales such as the Yale–Brown Obsessive Compulsive Scale (Y-BOCS) can be used to assess the severity.[7] Other disorders with similar symptoms include anxiety disorder, major depressive disorder, eating disorders, tic disorders, and obsessive–compulsive personality disorder.[2] Treatment involves psychotherapy, such as cognitive behavioral therapy (CBT), and sometimes antidepressants, such as selective serotonin reuptake inhibitors (SSRIs) or clomipramine.[4][5] CBT for OCD involves increasing exposure to what causes the problems while not allowing the repetitive behavior to occur.[4] Contrary to this, metacognitive therapy encourages the ritual behaviors as to alter the relationship to one's thoughts about them.[8] While clomipramine appears to work as well as SSRIs, it has greater side effects and thus is typically reserved as a second-line treatment.[4] Atypical antipsychotics may be useful when used in addition to an SSRI in treatment-resistant cases but are also associated with an increased risk of side effects.[5][9] Without treatment, the condition often lasts decades.[2] Obsessive–compulsive disorder affects about 2.3% of people at some point in their lives[6] while rates during any given year are about 1.2%.[2] It is unusual for symptoms to begin after the age of 35, and half of people develop problems before 20.[1][2] Males and females are affected about equally[1] and it occurs worldwide.[2] The phrase obsessive–compulsive is sometimes used in an informal manner unrelated to OCD to describe someone as being excessively meticulous, perfectionistic, absorbed, or otherwise fixated.[10] ## Contents * 1 Signs and symptoms * 1.1 Obsessions * 1.2 Compulsions * 1.3 Insight * 1.4 Overvalued ideas * 1.5 Cognitive performance * 1.6 Children * 1.7 Associated conditions * 2 Causes * 2.1 Drug-induced OCD * 2.2 Genetics * 2.3 Autoimmune * 3 Mechanisms * 3.1 Neuroimaging * 3.2 Cognitive models * 3.3 Neurobiological * 4 Diagnosis * 4.1 Differential diagnosis * 5 Management * 5.1 Therapy * 5.2 Medication * 5.3 Procedures * 5.4 Children * 6 Epidemiology * 7 Prognosis * 8 History * 8.1 Notable cases * 9 Society and culture * 9.1 Art, entertainment and media * 10 Research * 11 Other animals * 12 References * 13 External links ## Signs and symptoms OCD can present with a wide variety of symptoms. Certain groups of symptoms usually occur together. These groups are sometimes viewed as dimensions or clusters that may reflect an underlying process. The standard assessment tool for OCD, the Yale–Brown Obsessive Compulsive Scale (Y-BOCS), has 13 predefined categories of symptoms. These symptoms fit into three to five groupings.[11] A meta-analytic review of symptom structures found a four-factor structure (grouping) to be most reliable. The observed groups included a "symmetry factor", a "forbidden thoughts factor", a "cleaning factor", and a "hoarding factor". The "symmetry factor" correlated highly with obsessions related to ordering, counting, and symmetry, as well as repeating compulsions. The "forbidden thoughts factor" correlated highly with intrusive and distressing thoughts of a violent, religious, or sexual nature. The "cleaning factor" correlated highly with obsessions about contamination and compulsions related to cleaning. The "hoarding factor" only involved hoarding-related obsessions and compulsions and was identified as being distinct from other symptom groupings.[12] While OCD has been considered a homogeneous disorder from a neuropsychological perspective, many of the putative neuropsychological deficits may be due to comorbid disorders. Furthermore, some subtypes have been associated with improvement in performance on certain tasks such as pattern recognition (washing subtype) and spatial working memory (obsessive thought subtype). Subgroups have also been distinguished by neuroimaging findings and treatment response. Neuroimaging studies on this have been too few, and the subtypes examined have differed too much to draw any conclusions. On the other hand, subtype-dependent treatment response has been studied, and the hoarding subtype has consistently responded least to treatment.[13] ### Obsessions Main article: Intrusive thought See also: Primarily obsessional obsessive compulsive disorder People with OCD may face intrusive thoughts, such as thoughts about the devil (shown is a painted interpretation of Hell) Obsessions are thoughts that recur and persist despite efforts to ignore or confront them.[14] People with OCD frequently perform tasks, or compulsions, to seek relief from obsession-related anxiety. Within and among individuals, the initial obsessions, or intrusive thoughts, vary in their clarity and vividness. A relatively vague obsession could involve a general sense of disarray or tension accompanied by a belief that life cannot proceed as normal while the imbalance remains. A more intense obsession could be a preoccupation with the thought or image of someone close to them dying[15][16] or intrusions related to "relationship rightness".[17] Other obsessions concern the possibility that someone or something other than oneself—such as God, the devil, or disease—will harm either the person with OCD or the people or things that the person cares about. Other individuals with OCD may experience the sensation of invisible protrusions emanating from their bodies or have the feeling that inanimate objects are ensouled.[18] Some people with OCD experience sexual obsessions that may involve intrusive thoughts or images of "kissing, touching, fondling, oral sex, anal sex, intercourse, incest, and rape" with "strangers, acquaintances, parents, children, family members, friends, coworkers, animals, and religious figures", and can include "heterosexual or homosexual content" with persons of any age.[19] As with other intrusive, unpleasant thoughts or images, some disquieting sexual thoughts at times are normal, but people with OCD may attach extraordinary significance to the thoughts. For example, obsessive fears about sexual orientation can appear to the person with OCD, and even to those around them, as a crisis of sexual identity.[20][21] Furthermore, the doubt that accompanies OCD leads to uncertainty regarding whether one might act on the troubling thoughts, resulting in self-criticism or self-loathing.[19] Most people with OCD understand that their notions do not correspond with reality; however, they feel that they must act as though their notions are correct. For example, an individual who engages in compulsive hoarding might be inclined to treat inorganic matter as if it had the sentience or rights of living organisms, while accepting that such behavior is irrational on a more intellectual level. There is a debate as to whether or not hoarding should be considered with other OCD symptoms.[22] OCD sometimes manifests without overt compulsions, referred to as Primarily Obsessional OCD. OCD without overt compulsions could, by one estimate, characterize as many as 50 percent to 60 percent of OCD cases.[23] ### Compulsions Main article: Compulsive behavior Skin-picking disorder Some people with OCD perform compulsive rituals because they inexplicably feel they have to, while others act compulsively so as to mitigate the anxiety that stems from particular obsessive thoughts. The person might feel that these actions somehow either will prevent a dreaded event from occurring or will push the event from their thoughts. In any case, the individual's reasoning is so idiosyncratic or distorted that it results in significant distress for the individual with OCD or for those around them. Excessive skin picking, hair-pulling, nail biting, and other body-focused repetitive behavior disorders are all on the obsessive–compulsive spectrum.[2] Some individuals with OCD are aware that their behaviors are not rational, but feel compelled to follow through with them to fend off feelings of panic or dread.[2][24] Some common compulsions include hand washing, cleaning, checking things (e.g., locks on doors), repeating actions (e.g., turning on and off switches), ordering items in a certain way, and requesting reassurance.[25] Compulsions are different from tics (such as touching, tapping, rubbing, or blinking)[26] and stereotyped movements (such as head banging, body rocking, or self-biting), which usually are not as complex and are not precipitated by obsessions.[2] It can sometimes be difficult to tell the difference between compulsions and complex tics.[2] About 10% to 40% of individuals with OCD also have a lifetime tic disorder.[27] People rely on compulsions as an escape from their obsessive thoughts; however, they are aware that the relief is only temporary, that the intrusive thoughts will soon return. Some people use compulsions to avoid situations that may trigger their obsessions. Although some people do certain things over and over again, they do not necessarily perform these actions compulsively. For example, bedtime routines, learning a new skill, and religious practices are not compulsions. Whether or not behaviors are compulsions or mere habit depends on the context in which the behaviors are performed. For example, arranging and ordering books for eight hours a day would be expected of one who works in a library, but would seem abnormal in other situations. In other words, habits tend to bring efficiency to one's life, while compulsions tend to disrupt it.[28] In addition to the anxiety and fear that typically accompanies OCD, sufferers may spend hours performing such compulsions every day. In such situations, it can be hard for the person to fulfill their work, family, or social roles. In some cases, these behaviors can also cause adverse physical symptoms. For example, people who obsessively wash their hands with antibacterial soap and hot water can make their skin red and raw with dermatitis.[29] People with OCD can use rationalizations to explain their behavior; however, these rationalizations do not apply to the overall behavior but to each instance individually. For example, a person compulsively checking the front door may argue that the time taken and stress caused by one more check of the front door is much less than the time and stress associated with being robbed, and thus checking is the better option. In practice, after that check, the person is still not sure and deems it is still better to perform one more check, and this reasoning can continue for as long as necessary. In Cognitive Behavioral Therapy, OCD patients are asked to overcome intrusive thoughts by not doing any compulsions. They are taught that rituals keep OCD strong, while not performing them causes the OCD to become weaker.[30] For body focused repetitive behaviors (BFRB), such as trichotillomania, skin picking and onychophagia (nail biting), behavioral interventions such as habit reversal training[31] and decoupling[32] are recommended for the treatment of compulsive behaviors. ### Insight The DSM-V contains three specifiers for the level of insight in OCD. Good or fair insight is characterized by the acknowledgment that obsessive-compulsive beliefs are or may not be true. Poor insight is characterized by the belief that obsessive-compulsive beliefs are probably true. Absence of insight makes obsessive-compulsive beliefs delusional thoughts, and occurs in about 4% of people with OCD.[33] ### Overvalued ideas Some people with OCD exhibit what is known as overvalued ideas. In such cases, the person with OCD will truly be uncertain whether the fears that cause them to perform their compulsions are irrational or not. After some discussion, it is possible to convince the individual that their fears may be unfounded. It may be more difficult to do ERP therapy on such people because they may be unwilling to cooperate, at least initially. There are severe cases in which the person has an unshakable belief in the context of OCD that is difficult to differentiate from psychotic disorders.[34] ### Cognitive performance Though it was once believed to be associated with above-average intelligence, this does not appear to necessarily be the case.[35] A 2013 review reported that people with OCD may sometimes have mild but wide-ranging cognitive deficits; significantly regarding spatial memory, to a lesser extent with verbal memory, fluency, executive function, and processing speed, while auditory attention was not significantly affected.[36] People with OCD show impairment in formulating an organizational strategy for coding information, set-shifting, and motor and cognitive inhibition.[37] Specific subtypes of symptom dimensions in OCD have been associated with specific cognitive deficits.[38] For example, the results of one meta-analysis comparing washing and checking symptoms reported that washers outperformed checkers on eight out of ten cognitive tests.[39] The symptom dimension of contamination and cleaning may be associated with higher scores on tests of inhibition and verbal memory.[40] ### Children Approximately 1–2% of children are affected by OCD.[41] Obsessive–compulsive disorder symptoms tend to develop more frequently in children that are 10–14 years of age, with males displaying symptoms at an earlier age and a more severe level than females.[42] In children, symptoms can be grouped into at least four types.[11] ### Associated conditions People with OCD may be diagnosed with other conditions, as well as or instead of OCD, such as the aforementioned obsessive–compulsive personality disorder, major depressive disorder, bipolar disorder,[43] generalized anxiety disorder, anorexia nervosa, social anxiety disorder, bulimia nervosa, Tourette syndrome, transformation obsession, autism spectrum disorder, attention deficit hyperactivity disorder, dermatillomania (compulsive skin picking), body dysmorphic disorder and trichotillomania (hair pulling). More than 50 percent of people experience suicidal tendencies, and 15 percent have attempted suicide.[7] Depression, anxiety and prior suicide attempts increase the risk of future suicide attempts.[44] Individuals with OCD have also been found to be affected by delayed sleep phase syndrome at a substantially higher rate than the general public.[45] Moreover, severe OCD symptoms are consistently associated with greater sleep disturbance. Reduced total sleep time and sleep efficiency have been observed in people with OCD, with delayed sleep onset and offset and an increased prevalence of delayed sleep phase disorder.[46] Behaviorally, there is some research demonstrating a link between drug addiction and the disorder as well. For example, there is a higher risk of drug addiction among those with any anxiety disorder (possibly as a way of coping with the heightened levels of anxiety), but drug addiction among people with OCD may serve as a type of compulsive behavior and not just as a coping mechanism. Depression is also extremely prevalent among people with OCD. One explanation for the high depression rate among OCD populations was posited by Mineka, Watson and Clark (1998), who explained that people with OCD (or any other anxiety disorder) may feel depressed because of an "out of control" type of feeling.[47] Someone exhibiting OCD signs does not necessarily have OCD. Behaviors that present as (or seem to be) obsessive or compulsive can also be found in a number of other conditions as well, including obsessive–compulsive personality disorder (OCPD), autism spectrum disorder, disorders where perseveration is a possible feature (ADHD, PTSD, bodily disorders or habit problems)[48] or sub-clinically. Some with OCD present with features typically associated with Tourette's syndrome, such as compulsions that may appear to resemble motor tics; this has been termed "tic-related OCD" or "Tourettic OCD".[49][50] OCD frequently co-occurs with both bipolar disorder and major depressive disorder. Between 60–80% of those with OCD experience a major depressive episode in their lifetime. Comorbidity rates have been reported at between 19–90% due to methodological differences. Between 9–35% of those with bipolar disorder also have OCD, compared to the 1–2% in the general population. Around 50% of those with OCD experience cyclothymic traits or hypomanic episodes. OCD is also associated with anxiety disorders. Lifetime comorbidity for OCD has been reported at 22% for specific phobia, 18% for social anxiety disorder, 12% for panic disorder, and 30% for generalized anxiety disorder. The comorbidity rate for OCD and ADHD has been reported as high as 51%.[51] ## Causes Main article: Cause of obsessive-compulsive disorder The cause is unknown.[1] Both environmental and genetic factors are believed to play a role. Risk factors include a history of child abuse or other stress-inducing event.[2] ### Drug-induced OCD Many different types of medication can create/induce pure OCD in patients that have never had symptoms before. A new chapter about OCD in the DSM-5 (2013) now specifically includes drug-induced OCD. Atypical antipsychotics (second generation antipsychotics), such as olanzapine (Zyprexa), have been proven to induce de-novo OCD in patients.[52][53][54][55] ### Genetics There appear to be some genetic components with identical twins more often affected than non-identical twins.[2] Further, individuals with OCD are more likely to have first-degree family members exhibiting the same disorders than do matched controls. In cases where OCD develops during childhood, there is a much stronger familial link in the disorder than cases in which OCD develops later in adulthood. In general, genetic factors account for 45–65% of the variability in OCD symptoms in children diagnosed with the disorder.[56] A 2007 study found evidence supporting the possibility of a heritable risk for OCD.[57] A mutation has been found in the human serotonin transporter gene, hSERT, in unrelated families with OCD.[58] A systematic review found that while neither allele was associated with OCD overall, in caucasians the L allele was associated with OCD.[59] Another meta analysis observed an increased risk in those with the homozygous S allele, but found the LS genotype to be inversely associated with OCD.[60] A genome wide association study found OCD to be linked with SNPs near BTBD3 and two SNPs in DLGAP1 in a trio-based analysis, but no SNP reached significance when analyzed with case-control data.[61] One meta analysis found a small but significant association between a polymorphism in SLC1A1 and OCD.[62] The relationship between OCD and COMT has been inconsistent, with one meta analysis reporting a significant association, albeit only in men,[63] and another meta analysis reporting no association.[64] It has been postulated by evolutionary psychologists that moderate versions of compulsive behavior may have had evolutionary advantages. Examples would be moderate constant checking of hygiene, the hearth or the environment for enemies. Similarly, hoarding may have had evolutionary advantages. In this view OCD may be the extreme statistical "tail" of such behaviors, possibly due to a high amount of predisposing genes.[65] ### Autoimmune A controversial hypothesis[66] is that some cases of rapid onset of OCD in children and adolescents may be caused by a syndrome connected to Group A streptococcal infections, known as pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS).[66] OCD and tic disorders are hypothesized to arise in a subset of children as a result of a post-streptococcal autoimmune process.[67][68][69] The PANDAS hypothesis is unconfirmed and unsupported by data, and two new categories have been proposed: PANS (pediatric acute-onset neuropsychiatric syndrome) and CANS (childhood acute neuropsychiatric syndrome).[68][69] The CANS/PANS hypotheses include different possible mechanisms underlying acute-onset neuropsychiatric conditions, but do not exclude GABHS infections as a cause in a subset of individuals.[68][69] PANDAS, PANS and CANS are the focus of clinical and laboratory research but remain unproven.[67][68][69] Whether PANDAS is a distinct entity differing from other cases of tic disorders or OCD is debated.[70][71][72][73] A review of studies examining anti-basal ganglia antibodies in OCD found an increased risk of having anti-basal ganglia antibodies in those with OCD versus the general population.[74] ## Mechanisms Main article: Biology of obsessive–compulsive disorder ### Neuroimaging Some parts of the brain showing abnormal activity in OCD Functional neuroimaging during symptom provocation has observed abnormal activity in the orbitofrontal cortex, left dorsolateral prefrontal cortex, right premotor cortex, left superior temporal gyrus, globus pallidus externus, hippocampus and right uncus. Weaker foci of abnormal activity were found in the left caudate, posterior cingulate cortex and superior parietal lobule.[75] However, an older meta analysis of functional neuroimaging in OCD reported the only consistent functional neuroimaging findings have been increased activity in the orbital gyrus and head of the caudate nucleus, while ACC activation abnormalities were too inconsistent.[76] A meta analysis comparing affective and non affective tasks observed differences with controls in regions implicated in salience, habit, goal-directed behavior, self-referential thinking and cognitive control. For non affective tasks, hyperactivity was observed in the insula, ACC, and head of the caudate/putamen, while hypoactivity was observed in the medial prefrontal cortex (mPFC) and posterior caudate. Affective tasks were observed to relate to increased activation in the precuneus and posterior cingulate cortex(PCC), while decreased activation was found in the pallidum, ventral anterior thalamus and posterior caudate.[77] The involvement of the cortico-striato-thalamo-cortical loop in OCD as well as the high rates of comorbidity between OCD and ADHD have led some to draw a link in their mechanism. Observed similarities include dysfunction of the anterior cingulate cortex, and prefrontal cortex, as well as shared deficits in executive functions.[78] The involvement of the orbitofrontal cortex and dorsolateral prefrontal cortex in OCD is shared with bipolar disorder and may explain their high degree of comorbidity.[79] Decreased volumes of the dorsolateral prefrontal cortex related to executive function has also been observed in OCD.[80] People with OCD evince increased grey matter volumes in bilateral lenticular nuclei, extending to the caudate nuclei, with decreased grey matter volumes in bilateral dorsal medial frontal/anterior cingulate gyri.[81][82] These findings contrast with those in people with other anxiety disorders, who evince decreased (rather than increased) grey matter volumes in bilateral lenticular / caudate nuclei, as well as decreased grey matter volumes in bilateral dorsal medial frontal/anterior cingulate gyri.[82] Increased white matter volume and decreased fractional anisotropy in anterior midline tracts has been observed in OCD, possibly indicating increased fiber crossings.[83] ### Cognitive models Generally two categories of models for OCD have been postulated, the first involving deficits in executive function, and the second involving deficits in modulatory control. The first category of executive dysfunction is based on the observed structural and functional abnormalities in the dlPFC, striatum, and thalamus. The second category involving dysfunctional modulatory control primarily relies on observed functional and structural differences in the ACC, mPFC and OFC.[84][85] One proposed model suggests that dysfunction in the OFC leads to improper valuation of behaviors and decreased behavioral control, while the observed alterations in amygdala activations leads to exaggerated fears and representations of negative stimuli.[86] Due to the heterogeneity of OCD symptoms, studies differentiating between symptoms have been performed. Symptom specific neuroimaging abnormalities include the hyperactivity of caudate and ACC in checking rituals, while finding increased activity of cortical and cerebellar regions in contamination related symptoms. Neuroimaging differentiating between content of intrusive thoughts have found differences between aggressive as opposed to taboo thoughts, finding increased connectivity of the amygdala, ventral striatum, and ventromedial prefrontal cortex in aggressive symptoms, while observing increased connectivity between the ventral striatum and insula in sexual/religious intrusive thoughts.[87] Another model proposes that affective dysregulation links excessive reliance on habit based action selection[88] with compulsions. This is supported by the observation that those with OCD demonstrate decreased activation of the ventral striatum when anticipating monetary reward, as well as increase functional connectivity between the VS and the OFC. Furthermore, those with OCD demonstrate reduced performance in pavlovian fear extinction tasks, hyper responsiveness in the amygdala to fearful stimuli, and hypo-responsiveness in the amygdala when exposed to positively valanced stimuli. Stimulation of the nucleus accumbens has also been observed to effectively alleviate both obsessions and compulsions, supporting the role of affective dysregulation in generating both.[86] ### Neurobiological From the observation of the efficacy of antidepressants in OCD, a serotonin hypothesis of OCD has been formulated. Studies of peripheral markers of serotonin, as well as challenges with proserotonergic compounds have yielded inconsistent results, including evidence pointing towards basal hyperactivity of serotonergic systems.[89] Serotonin receptor and transporter binding studies have yielded conflicting results, including higher and lower serotonin receptor 5-HT2A and serotonin transporter binding potentials that were normalized by treatment with SSRIs. Despite inconsistencies in the types of abnormalities found, evidence points towards dysfunction of serotonergic systems in OCD.[90] Orbitofrontal cortex overactivity is attenuated in people who have successfully responded to SSRI medication, a result believed to be caused by increased stimulation of serotonin receptors 5-HT2A and 5-HT2C.[91] A complex relationship between dopamine and OCD has been observed. Although antipsychotics, which act by antagonizing dopamine receptors may improve some cases of OCD, they frequently exacerbate others. Antipsychotics, in the low doses used to treat OCD, may actually increase the release of dopamine in the prefrontal cortex, through inhibiting autoreceptors. Further complicating things is the efficacy of amphetamines, decreased dopamine transporter activity observed in OCD,[92] and low levels of D2 binding in the striatum.[93] Furthermore, increased dopamine release in the nucleus accumbens after deep brain stimulation correlates with improvement in symptoms, pointing to reduced dopamine release in the striatum playing a role in generating symptoms.[94] Abnormalities in glutamatergic neurotransmission have implicated in OCD. Findings such as increased cerebrospinal glutamate, less consistent abnormalities observed in neuroimaging studies and the efficacy of some glutamatergic drugs such as the glutamate-inhibiting riluzole have implicated glutamate in OCD.[93] OCD has been associated with reduced N-Acetylaspartic acid in the mPFC, which is thought to reflect neuron density or functionality, although the exact interpretation has not been established.[95] ## Diagnosis Formal diagnosis may be performed by a psychologist, psychiatrist, clinical social worker, or other licensed mental health professional. To be diagnosed with OCD, a person must have obsessions, compulsions, or both, according to the Diagnostic and Statistical Manual of Mental Disorders (DSM). The Quick Reference to the 2000 edition of the DSM states that several features characterize clinically significant obsessions and compulsions. Such obsessions, the DSM says, are recurrent and persistent thoughts, impulses or images that are experienced as intrusive and that cause marked anxiety or distress. These thoughts, impulses or images are of a degree or type that lies outside the normal range of worries about conventional problems.[96] A person may attempt to ignore or suppress such obsessions, or to neutralize them with some other thought or action, and will tend to recognize the obsessions as idiosyncratic or irrational. Compulsions become clinically significant when a person feels driven to perform them in response to an obsession, or according to rules that must be applied rigidly, and when the person consequently feels or causes significant distress. Therefore, while many people who do not suffer from OCD may perform actions often associated with OCD (such as ordering items in a pantry by height), the distinction with clinically significant OCD lies in the fact that the person who suffers from OCD must perform these actions, otherwise they will experience significant psychological distress. These behaviors or mental acts are aimed at preventing or reducing distress or preventing some dreaded event or situation; however, these activities are not logically or practically connected to the issue, or they are excessive. In addition, at some point during the course of the disorder, the individual must realize that their obsessions or compulsions are unreasonable or excessive. Moreover, the obsessions or compulsions must be time-consuming (taking up more than one hour per day) or cause impairment in social, occupational or scholastic functioning.[96] It is helpful to quantify the severity of symptoms and impairment before and during treatment for OCD. In addition to the person's estimate of the time spent each day harboring obsessive-compulsive thoughts or behaviors, concrete tools can be used to gauge the person's condition. This may be done with rating scales, such as the Yale–Brown Obsessive Compulsive Scale (Y-BOCS). With measurements like these, psychiatric consultation can be more appropriately determined because it has been standardized.[7] OCD is sometimes placed in a group of disorders called the obsessive–compulsive spectrum.[97] ### Differential diagnosis OCD is often confused with the separate condition obsessive–compulsive personality disorder (OCPD). OCD is egodystonic, meaning that the disorder is incompatible with the sufferer's self-concept.[98][99] Because egodystonic disorders go against a person's self-concept, they tend to cause much distress. OCPD, on the other hand, is egosyntonic—marked by the person's acceptance that the characteristics and behaviours displayed as a result are compatible with their self-image, or are otherwise appropriate, correct or reasonable. As a result, people with OCD are often aware that their behavior is not rational, are unhappy about their obsessions but nevertheless feel compelled by them.[100] By contrast, people with OCPD are not aware of anything abnormal; they will readily explain why their actions are rational, it is usually impossible to convince them otherwise, and they tend to derive pleasure from their obsessions or compulsions.[100] ## Management A form of psychotherapy called "cognitive behavioral therapy" (CBT) and psychotropic medications are first-line treatments for OCD.[1][101] Other forms of psychotherapy, such as psychodynamic and psychoanalysis may help in managing some aspects of the disorder, but in 2007 the American Psychiatric Association (APA) noted a lack of controlled studies showing their effectiveness "in dealing with the core symptoms of OCD".[102] ### Therapy One exposure and ritual prevention activity would be to check the lock only once, and then leave The specific technique used in CBT is called exposure and response prevention (ERP) which involves teaching the person to deliberately come into contact with the situations that trigger the obsessive thoughts and fears ("exposure"), without carrying out the usual compulsive acts associated with the obsession ("response prevention"), thus gradually learning to tolerate the discomfort and anxiety associated with not performing the ritualistic behavior. At first, for example, someone might touch something only very mildly "contaminated" (such as a tissue that has been touched by another tissue that has been touched by the end of a toothpick that has touched a book that came from a "contaminated" location, such as a school). That is the "exposure". The "ritual prevention" is not washing. Another example might be leaving the house and checking the lock only once (exposure) without going back and checking again (ritual prevention). The person fairly quickly habituates to the anxiety-producing situation and discovers that their anxiety level drops considerably; they can then progress to touching something more "contaminated" or not checking the lock at all—again, without performing the ritual behavior of washing or checking.[103] ERP has a strong evidence base, and it is considered the most effective treatment for OCD.[103] However, this claim was doubted by some researchers in 2000, who criticized the quality of many studies.[104] A 2018 review found that self-help metacognitive training improved symptoms in OCD.[105] A 2007 Cochrane review also found that psychological interventions derived from CBT models were more effective than treatment as usual consisting of no treatment, waiting list or non-CBT interventions.[106] For body focused repetitive behaviors (BFRB), behavioral interventions are recommended by reviews such as habit reversal training[31] and decoupling.[32] It has generally been accepted that psychotherapy in combination with psychiatric medication is more effective than either option alone.[107] ### Medication A blister pack of clomipramine under the brand name Anafranil The medications most frequently used are the selective serotonin reuptake inhibitors (SSRIs).[4] Clomipramine, a medication belonging to the class of tricyclic antidepressants, appears to work as well as SSRIs but has a higher rate of side effects.[4] SSRIs are a second line treatment of adult obsessive compulsive disorder (OCD) with mild functional impairment and as first line treatment for those with moderate or severe impairment. In children, SSRIs can be considered as a second line therapy in those with moderate-to-severe impairment, with close monitoring for psychiatric adverse effects.[101] SSRIs are efficacious in the treatment of OCD; people treated with SSRIs are about twice as likely to respond to treatment as those treated with placebo.[108][109] Efficacy has been demonstrated both in short-term (6–24 weeks) treatment trials and in discontinuation trials with durations of 28–52 weeks.[110][111][112] In 2006, the National Institute of Clinical and Health Excellence (NICE) guidelines recommended antipsychotics for OCD that does not improve with SSRI treatment.[5] For OCD there is tentative evidence for risperidone and insufficient evidence for olanzapine. Quetiapine is no better than placebo with regard to primary outcomes, but small effects were found in terms of YBOCS score. The efficacy of quetiapine and olanzapine are limited by the insufficient number of studies.[113] A 2014 review article found two studies that indicated that aripiprazole was "effective in the short-term" and found that "[t]here was a small effect-size for risperidone or anti-psychotics in general in the short-term"; however, the study authors found "no evidence for the effectiveness of quetiapine or olanzapine in comparison to placebo."[5] While quetiapine may be useful when used in addition to an SSRI in treatment-resistant OCD, these drugs are often poorly tolerated, and have metabolic side effects that limit their use. None of the atypical antipsychotics appear to be useful when used alone.[9] Another review reported that no evidence supports the use of first generation antipsychotics in OCD.[114] A guideline by the APA suggested that dextroamphetamine may be considered by itself after more well supported treatments have been tried.[115] ### Procedures Electroconvulsive therapy (ECT) has been found to have effectiveness in some severe and refractory cases.[116] Surgery may be used as a last resort in people who do not improve with other treatments. In this procedure, a surgical lesion is made in an area of the brain (the cingulate cortex). In one study, 30% of participants benefitted significantly from this procedure.[117] Deep-brain stimulation and vagus nerve stimulation are possible surgical options that do not require destruction of brain tissue. In the United States, the Food and Drug Administration approved deep-brain stimulation for the treatment of OCD under a humanitarian device exemption requiring that the procedure be performed only in a hospital with specialist qualifications to do so.[118] In the United States, psychosurgery for OCD is a treatment of last resort and will not be performed until the person has failed several attempts at medication (at the full dosage) with augmentation, and many months of intensive cognitive–behavioral therapy with exposure and ritual/response prevention.[119] Likewise, in the United Kingdom, psychosurgery cannot be performed unless a course of treatment from a suitably qualified cognitive–behavioral therapist has been carried out. ### Children Therapeutic treatment may be effective in reducing ritual behaviors of OCD for children and adolescents.[120] Similar to the treatment of adults with OCD, CBT stands as an effective and validated first line of treatment of OCD in children.[121] Family involvement, in the form of behavioral observations and reports, is a key component to the success of such treatments.[122] Parental interventions also provide positive reinforcement for a child who exhibits appropriate behaviors as alternatives to compulsive responses. In a recent meta-analysis of evidenced-based treatment of OCD in children, family-focused individual CBT was labeled as "probably efficacious", establishing it as one of the leading psychosocial treatments for youth with OCD.[121] After one or two years of therapy, in which a child learns the nature of his or her obsession and acquires strategies for coping, that child may acquire a larger circle of friends, exhibit less shyness, and become less self-critical.[123] Although the causes of OCD in younger age groups range from brain abnormalities to psychological preoccupations, life stress such as bullying and traumatic familial deaths may also contribute to childhood cases of OCD, and acknowledging these stressors can play a role in treating the disorder.[124] ## Epidemiology Age-standardized disability-adjusted life year estimated rates for obsessive-compulsive disorder per 100,000 inhabitants in 2004. no data <45 45–52.5 52.5–60 60–67.5 67.5–75 75–82.5 82.5–90 90–97.5 97.5–105 105–112.5 112.5–120 >120 Obsessive–compulsive disorder affects about 2.3% of people at some point in their life.[6] Rates during a given year are about 1.2% and it occurs worldwide.[2] It is unusual for symptoms to begin after the age of thirty five and half of people develop problems before twenty.[1][2] Males and females are affected about equally.[1] ## Prognosis Quality of life (QoL) is reduced across all domains in OCD. While psychological or pharmacological treatment can lead to a reduction of OCD symptoms and an increase in QoL, symptoms may persist at moderate levels even following adequate treatment courses, and completely symptom-free periods are uncommon.[125][126] In pediatric OCD, around 40% still have the disorder in adulthood, and around 40% qualify for remission.[127] ## History In the 7th century AD, John Climacus records an instance of a young monk plagued by constant and overwhelming "temptations to blasphemy" consulting an older monk,[128]:212 who told him, "My son, I take upon myself all the sins which these temptations have led you, or may lead you, to commit. All I require of you is that for the future you pay no attention to them whatsoever."[128]:212 The Cloud of Unknowing, a Christian mystical text from the late 14th century, recommends dealing with recurring obsessions by first attempting to ignore them,[128]:213 and, if that fails, "cower under them like a poor wretch and a coward overcome in battle, and reckon it to be a waste of your time for you to strive any longer against them",[128]:213 a technique now known as "emotional flooding".[128]:213 From the 14th to the 16th century in Europe, it was believed that people who experienced blasphemous, sexual or other obsessive thoughts were possessed by the devil.[98][128]:213 Based on this reasoning, treatment involved banishing the "evil" from the "possessed" person through exorcism.[129][130] The vast majority of people who thought they were possessed by the devil did not suffer from hallucinations or other "spectacular symptoms",[128]:213 but "complained of anxiety, religious fears, and evil thoughts."[128]:213 In 1584, a woman from Kent, England named Mrs. Davie, described by a justice of the peace as "a good wife",[128]:213 was nearly burned at the stake after she confessed that she experienced constant, unwanted urges to murder her family.[128]:213 The English term obsessive-compulsive arose as a translation of German Zwangsvorstellung ('obsession') used in the first conceptions of OCD by Carl Westphal. Westphal's description went on to influence Pierre Janet, who further documented features of OCD.[33] In the early 1910s, Sigmund Freud attributed obsessive–compulsive behavior to unconscious conflicts that manifest as symptoms.[129] Freud describes the clinical history of a typical case of "touching phobia" as starting in early childhood, when the person has a strong desire to touch an item. In response, the person develops an "external prohibition" against this type of touching. However, this "prohibition does not succeed in abolishing" the desire to touch; all it can do is repress the desire and "force it into the unconscious".[131] Freudian psychoanalysis remained the dominant treatment for OCD until the mid-1980s,[128]:210–211 even though medicinal and therapeutical treatments were known and available,[128]:210 because it was widely thought that these treatments would be detrimental to the effectiveness of the psychotherapy.[128]:210 In the mid-1980s, psychiatry made a sudden "about-face" on the subject[128]:210 and began treating OCD primarily through medicine and practical therapy rather than psychoanalysis.[128]:210 ### Notable cases John Bunyan (1628–1688), the author of The Pilgrim's Progress, displayed symptoms of OCD (which had not yet been named).[128]:53–54 During the most severe period of his condition, he would mutter the same phrase over and over again to himself while rocking back and forth.[128]:53–54 He later described his obsessions in his autobiography Grace Abounding to the Chief of Sinners,[128]:53–54 stating, "These things may seem ridiculous to others, even as ridiculous as they were in themselves, but to me they were the most tormenting cogitations."[128]:54 He wrote two pamphlets advising those suffering from similar anxieties.[128]:217–218 In one of them, he warns against indulging in compulsions:[128]:217–218 "Have care of putting off your trouble of spirit in the wrong way: by promising to reform yourself and lead a new life, by your performances or duties".[128]:218 British poet, essayist and lexicographer Samuel Johnson (1709–1784) also suffered from OCD.[128]:54–55 He had elaborate rituals for crossing the thresholds of doorways, and repeatedly walked up and down staircases counting the steps.[132][128]:55 He would touch every post on the street as he walked past,[128]:55 only step in the middles of paving stones,[128]:55 and repeatedly perform tasks as though they had not been done properly the first time.[128]:55 The American aviator and filmmaker Howard Hughes is known to have had OCD.[133] Friends of Hughes have also mentioned his obsession with minor flaws in clothing.[134] This was conveyed in The Aviator (2004), a film biography of Hughes.[135] ## Society and culture This ribbon represents Trichotillomania and other body focused repetitive behaviors. Concept for the ribbon was started by Jenne Schrader. Colors were voted on by the Trichotillomania Facebook community, and made official by Trichotillomania Learning Center in August 2013. ### Art, entertainment and media Movies and television shows may portray idealized or incomplete representations of disorders such as OCD. Compassionate and accurate literary and on-screen depictions may help counteract the potential stigma[136] associated with an OCD diagnosis, and lead to increased public awareness, understanding and sympathy for such disorders.[137] * In the film As Good as It Gets (1997), actor Jack Nicholson portrays a man "with Obsessive Compulsive Disorder (OCD)".[138] "Throughout the film, [he] engages in ritualistic behaviors (i.e., compulsions) that disrupt his interpersonal and professional life", a "cinematic representation of psychopathology [that] accurately depicts the functional interference and distress associated with OCD".[138] * The film Matchstick Men (2003), directed by Ridley Scott, portrays a con-man named Roy (Nicolas Cage) who has obsessive-compulsive disorder. The film "opens with Roy, at home, suffering with his numerous obsessive compulsive symptoms, which take the form of a need for order and cleanliness and a compulsion to open and close doors three times, whilst counting aloud, before he can walk through them".[139] * In the USA Network American comedy-drama detective mystery television series Monk (2002–2009), the titular Adrian Monk fears both human contact and dirt.[140][141] * In Turtles All the Way Down (2017), a young adult novel by author John Green, teenage main character Aza Holmes struggles with OCD. It manifests as a fear of the human microbiome. Throughout the story, she repeatedly opens a never-fully-healed callus on her finger in an effort to drain out what she believes are pathogens. The novel is based on author Green's own experiences of OCD. He explained that Turtles All the Way Down is intended to show how “most people with chronic mental illnesses also live long, fulfilling lives”.[142] ## Research The naturally occurring sugar inositol has been suggested as a treatment for OCD.[143] μ-Opioids, such as hydrocodone and tramadol, may improve OCD symptoms.[144] Administration of opiate treatment may be contraindicated in individuals concurrently taking CYP2D6 inhibitors such as fluoxetine and paroxetine.[145] Much current research is devoted to the therapeutic potential of the agents that affect the release of the neurotransmitter glutamate or the binding to its receptors. These include riluzole,[146] memantine, gabapentin, N-acetylcysteine, topiramate and lamotrigine.[citation needed] ## Other animals See also: Animal psychopathology § Obsessive compulsive disorder (OCD) ## References 1. ^ a b c d e f g h i j k l m n o The National Institute of Mental Health (NIMH) (January 2016). 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"WHAT IS OCD?". USA Network. Archived from the original on 17 December 2008. Retrieved 8 December 2008. 142. ^ Flood, Alison (14 October 2017). "John Green: 'Having OCD is an ongoing part of my life'". The Guardian. Retrieved 21 September 2019. 143. ^ Camfield DA, Sarris J, Berk M (1 June 2011). "Nutraceuticals in the treatment of obsessive compulsive disorder (OCD): a review of mechanistic and clinical evidence". Progress in Neuro-psychopharmacology & Biological Psychiatry. 35 (4): 887–95. doi:10.1016/j.pnpbp.2011.02.011. PMID 21352883. S2CID 30024004. 144. ^ Davidson J, Bjorgvinsson T (June 2003). "Current and potential pharmacological treatments for obsessive-compulsive disorder". Expert Opinion on Investigational Drugs. 12 (6): 993–1001. doi:10.1517/13543784.12.6.993. PMID 12783603. S2CID 35971588. 145. ^ Koran LM (2007). "Obsessive-Compulsive Disorder: An Update for the Clinician". Focus (5): 3. 146. ^ Wu K, Hanna GL, Rosenberg DR, Arnold PD (2012). "The role of glutamate signaling in the pathogenesis and treatment of obsessive–compulsive disorder". Pharmacology Biochemistry and Behavior. 100 (4): 726–735. doi:10.1016/j.pbb.2011.10.007. PMC 3437220. PMID 22024159. ## External links Classification D * ICD-10: F42 * ICD-9-CM: 300.3 * OMIM: 164230 * MeSH: D009771 * DiseasesDB: 33766 External resources * MedlinePlus: 000929 * eMedicine: article/287681 Wikimedia Commons has media related to Obsessive–compulsive disorder. * Obsessive–compulsive disorder at Curlie * National Institute Of Mental Health * American Psychiatric Association * APA Division 12 treatment page for obsessive-compulsive disorder * Davis, Lennard J. (2008). Obsession: A History. University of Chicago Press. ISBN 978-0-226-13782-7. * v * t * e Mental and behavioral disorders Adult personality and behavior Gender dysphoria * Ego-dystonic sexual orientation * Paraphilia * Fetishism * Voyeurism * Sexual maturation disorder * Sexual relationship disorder Other * Factitious disorder * Munchausen syndrome * Intermittent explosive disorder * Dermatillomania * Kleptomania * Pyromania * Trichotillomania * Personality disorder Childhood and learning Emotional and behavioral * ADHD * Conduct disorder * ODD * Emotional and behavioral disorders * Separation anxiety disorder * Movement disorders * Stereotypic * Social functioning * DAD * RAD * Selective mutism * Speech * Stuttering * Cluttering * Tic disorder * Tourette syndrome Intellectual disability * X-linked intellectual disability * Lujan–Fryns syndrome Psychological development (developmental disabilities) * Pervasive * Specific Mood (affective) * Bipolar * Bipolar I * Bipolar II * Bipolar NOS * Cyclothymia * Depression * Atypical depression * Dysthymia * Major depressive disorder * Melancholic depression * Seasonal affective disorder * Mania Neurological and symptomatic Autism spectrum * Autism * Asperger syndrome * High-functioning autism * PDD-NOS * Savant syndrome Dementia * AIDS dementia complex * Alzheimer's disease * Creutzfeldt–Jakob disease * Frontotemporal dementia * Huntington's disease * Mild cognitive impairment * Parkinson's disease * Pick's disease * Sundowning * Vascular dementia * Wandering Other * Delirium * Organic brain syndrome * Post-concussion syndrome Neurotic, stress-related and somatoform Adjustment * Adjustment disorder with depressed mood Anxiety Phobia * Agoraphobia * Social anxiety * Social phobia * Anthropophobia * Specific social phobia * Specific phobia * Claustrophobia Other * Generalized anxiety disorder * OCD * Panic attack * Panic disorder * Stress * Acute stress reaction * PTSD Dissociative * Depersonalization disorder * Dissociative identity disorder * Fugue state * Psychogenic amnesia Somatic symptom * Body dysmorphic disorder * Conversion disorder * Ganser syndrome * Globus pharyngis * Psychogenic non-epileptic seizures * False pregnancy * Hypochondriasis * Mass psychogenic illness * Nosophobia * Psychogenic pain * Somatization disorder Physiological and physical behavior Eating * Anorexia nervosa * Bulimia nervosa * Rumination syndrome * Other specified feeding or eating disorder Nonorganic sleep * Hypersomnia * Insomnia * Parasomnia * Night terror * Nightmare * REM sleep behavior disorder Postnatal * Postpartum depression * Postpartum psychosis Sexual dysfunction Arousal * Erectile dysfunction * Female sexual arousal disorder Desire * Hypersexuality * Hypoactive sexual desire disorder Orgasm * Anorgasmia * Delayed ejaculation * Premature ejaculation * Sexual anhedonia Pain * Nonorganic dyspareunia * Nonorganic vaginismus Psychoactive substances, substance abuse and substance-related * Drug overdose * Intoxication * Physical dependence * Rebound effect * Stimulant psychosis * Substance dependence * Withdrawal Schizophrenia, schizotypal and delusional Delusional * Delusional disorder * Folie à deux Psychosis and schizophrenia-like * Brief reactive psychosis * Schizoaffective disorder * Schizophreniform disorder Schizophrenia * Childhood schizophrenia * Disorganized (hebephrenic) schizophrenia * Paranoid schizophrenia * Pseudoneurotic schizophrenia * Simple-type schizophrenia Other * Catatonia Symptoms and uncategorized * Impulse control disorder * Klüver–Bucy syndrome * Psychomotor agitation * Stereotypy * v * t * e Obsessive–compulsive disorder History * Yale–Brown Obsessive Compulsive Scale Biology Neuroanatomy * Basal ganglia (striatum) * Orbitofrontal cortex * Cingulate cortex * Brain-derived neurotrophic factor Receptors * 5-HT1Dβ * 5-HT2A * 5-HT2C * μ Opioid * H2 * NK1 * M4 * NMDA Symptoms * Obsessions (associative * diagnostic * injurious * scrupulous * pathogenic * sexual) * Compulsions (impulses, rituals * tics) * Thought suppression (avoidance) * Hoarding (animals, books * possessions) Treatment Serotonergics Selective serotonin reuptake inhibitors * Escitalopram * Fluoxetine * Fluvoxamine * Paroxetine * Sertraline * Citalopram * Nefazodone Serotonin–norepinephrine reuptake inhibitors * Venlafaxine * Desvenlafaxine * Duloxetine Serotonin–norepinephrine–dopamine reuptake inhibitors * Nefazodone Monoamine oxidase inhibitors * Phenelzine * Tranylcypromine Tricyclic antidepressants * Clomipramine Serotonergic psychedelics * Lysergic acid diethylamide * Psilocin Atypical antipsychotics * Aripiprazole * Quetiapine Mu opioidergics * Hydrocodone * Morphine * Tramadol Anticholinergics * Diphenhydramine NMDA glutamatergics * Riluzole NK-1 tachykininergics * Aprepitant Other * Nicotine * Memantine * Tautomycin Behavioral * Cognitive behavioral therapy (Exposure and response prevention) * Inference-based therapy * Metacognitive therapy Organizations * International OCD Foundation Notable people * Edna B. Foa * Stanley Rachman * Adam S. Radomsky * Jeffrey M. Schwartz * Susan Swedo * Emily Colas * Vic Meyer Popular culture Literature/Comics Fictional * Matchstick Men * Plyushkin * Xenocide Nonfiction * Everything in Its Place * Just Checking Media * As Good as It Gets * The Aviator * Matchstick Men * Adrian Monk * "$pringfield" * Straight Up Related * Obsessive–compulsive personality disorder * Obsessional jealousy * PANDAS * Primarily Obsessional OCD * Relationship obsessive–compulsive disorder * Social anxiety disorder * Tourette syndrome * v * t * e OCD pharmacotherapies Antidepressants * SSRIs (e.g., fluoxetine, fluvoxamine, sertraline) * SNRIs (e.g., venlafaxine) * TCAs (e.g., clomipramine) * MAOIs (e.g., phenelzine) Others * Antiandrogens (e.g., cyproterone acetate, leuprorelin) * Antipsychotics (e.g., risperidone) * Benzodiazepines (e.g., clonazepam) * Lamotrigine * Memantine * Mirtazapine * N-Acetylcysteine * Ondansetron * Pregabalin * Psychedelics (e.g., psilocybin) * Riluzole * Topiramate Authority control * GND: 4234004-4 * LCCN: sh85093751 * NDL: 00991324 [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-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	Obsessive–compulsive disorder	c0028768	1,774	wikipedia	https://en.wikipedia.org/wiki/Obsessive%E2%80%93compulsive_disorder	2021-01-18T18:46:17	{"mesh": ["D009771"], "umls": ["C0028768"], "wikidata": ["Q178190"]}
A cerebral malformation characterized by symmetric, bilateral pachygyria with normal head circumference and without polymicrogyria. Clinical manifestations include developmental delay, moderate intellectual disability, normal or slightly decreased muscle tone and deep-tendon reflexes, telecanthus or hypertelorism. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors	Autosomal recessive frontotemporal pachygyria	c1853215	1,775	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=329329	2021-01-23T17:01:14	{"mesh": ["C538092"], "umls": ["C1853215"], "icd-10": ["Q04.3"]}
This article possibly contains original research. Please improve it by verifying the claims made and adding inline citations. Statements consisting only of original research should be removed. (July 2015) (Learn how and when to remove this template message) Iconophobia SpecialtyPsychology Iconophobia (literally fear of icons) refers to an aversion to images, especially religious icons. Iconophobia is differentiated from iconoclasm in that iconophobia refers to the aversion to or hatred of the images whereas iconoclasm refers to the actual destruction of images that may arise from iconophobia. Chari Larsson wrote: > “If iconophobia is defined as the suspicion and anxiety towards the power exerted by images, its history is an ancient one in all of its Platonic, Christian, and Judaic forms. At its most radical, iconophobia results in an act of iconoclasm, or the total destruction of the image. At the other end of the spectrum, contemporary iconophobia may be more subtle. Images are simply withdrawn from circulation with the aim of eliminating their visibility.”[1] The history of iconophobia begins with ancient Greece and Rome and continues with the violent iconoclasms of the period 726-842 in the Eastern Orthodox Church within the Byzantine Empire. But it is the Protestant Reformation that is most associated with iconophobia: “The Protestant Reformation, initiated by Martin Luther in 1517, brought iconophobia to the forefront of contemporary politics... Iconophobia was pushed to its extreme in the teachings of John Calvin... Protestant iconophobia had a huge and not exclusively negative impact on aesthetics and the history of art. It permanently affected the ways images were made, exhibited, and judged.”[2] ## Contents * 1 Iconophobia and the English Reformation * 2 References ## Iconophobia and the English Reformation[edit] The leading historian of English Protestantism, Patrick Collinson, applied the term iconophobia to a specific period in post-Reformation England in his 1985 Stenton Lecture, From Iconoclasm to Iconophobia: the Cultural Impact of the Second English Reformation.[3] The arguments also informed chapter 4 of his 1988 book, The Birthpangs of Protestant England.[4] Collinson’s work has shaped a generation of scholarly enquiry into the impact of religion on culture, and of culture on religion, in post-reformation England. Scholars have accepted, rejected, and modified Collinson’s arguments, but one way or another they continue to exert a powerful influence over reformation studies. Collinson carefully re-defined iconoclasm (generally defined as “the destruction of religious icons and other images or monuments for religious or political motives”) in his essay as follows: > “The first generation of Protestant publicists and propagandists, the Edwardian generation, made polemical and creative use of cultural vehicles which their spiritual children and grandchildren later repudiated, as part of their rather general programme of rejection. They wrote and staged Protestant plays. They sang Protestant songs and godly ballads to secular and popular tunes. And they made brilliant use of the graphic image, both to attack Catholicism and to commend their own religious convictions and values. These strategies constitute, for my purpose, what is meant by Iconoclasm ... Iconoclasm in this sense may imply the substitution of other, acceptable images, or the refashioning of some images for an altered purpose.”[3] Iconophobia, by comparison, is defined as “the total repudiation of all images”, which Collinson associates with a watershed moment around 1580, introducing a “sudden and drastic” change. This “secondary thrust” of reform “came close to dispensing with images and the mimetic altogether, while disparaging the tastes and capacities of the illiterate, the mass of the people”.[citation needed] Collinson describes the “age of extreme iconophobia” as “quite short, equivalent to little more than a single generation”.[4] Nevertheless, much subsequent scholarship has suggested that iconophobia characterised post-Reformation Protestantism from 1580 onwards.[citation needed] ## References[edit] 1. ^ Larsson, Chari (2012). "Suspicious Images: Iconophobia and the Ethical Gaze". Journal of Media and Culture. 15 (1). 2. ^ Kelly, Michael (1998). "Iconoclasm and Iconophobia". Encyclopedia of Aesthetics. p. 453. ISBN 9780195113075. 3. ^ a b Collinson, Patrick (1986). From Iconoclasm to Iconophobia: the Cultural Impact of the Second English Reformation. Stenton Lectures. 19. University of Reading. ISSN 0309-0469. 4. ^ a b Collinson, Patrick (1988). The Birthpangs of Protestant England: Religious and Cultural Change in the Sixteenth and Seventeenth Centuries. Macmillan. p. 120. ISBN 9780333543078. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-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	Iconophobia	None	1,776	wikipedia	https://en.wikipedia.org/wiki/Iconophobia	2021-01-18T18:28:33	{"wikidata": ["Q23808134"]}
Giant-cell tumor of bone Micrograph of a giant-cell tumor of bone showing the characteristic giant cells, H&E stain SpecialtyOncology Giant-cell tumor of the bone (GCTOB), is a relatively uncommon tumor of the bone. It is characterized by the presence of multinucleated giant cells (osteoclast-like cells). Malignancy in giant-cell tumor is uncommon and occurs in about 2% of all cases. However, if malignant degeneration does occur, it is likely to metastasize to the lungs. Giant-cell tumors are normally benign,[1] with unpredictable behavior.[2] It is a heterogeneous tumor composed of three different cell populations. The giant-cell tumour stromal cells (GCTSC) constitute the neoplastic cells,[3] which are from an osteoblastic origin and are classified based on expression of osteoblast cell markers such as alkaline phosphatase and osteocalcin. In contrast, the mononuclear histiocytic cells (MNHC) and multinucleated giant cell (MNGC) fractions are secondarily recruited and comprise the non-neoplastic cell population. They are derived from an osteoclast-monocyte lineage determined primarily by expression of CD68, a marker for monocytic precursor cells.[4][5][6] In most patients, the tumors are slow to develop, but may recur locally in as many as 50% of cases. ## Contents * 1 Signs and symptoms * 2 Diagnosis * 2.1 Imaging * 2.2 Differential diagnosis * 3 Treatment * 4 Epidemiology * 5 See also * 6 References * 7 External links ## Signs and symptoms[edit] Distribution of giant-cell tumors of bone Patients usually present with pain and limited range of motion caused by tumor's proximity to the joint space. Swelling may occur, as well, if the tumor has been growing for a long time. Some patients may be asymptomatic until they develop a pathologic fracture at the site of the tumor. They usually originate from the epiphysis of long bones, but in rare cases, they may arise from anterior arc of the ribs.[7] The symptoms may include muscular aches and pains in arms or legs and abdominal pain. Patients may also experience nerve pain which feels like an electric shock due to weight bearing.[citation needed] ## Diagnosis[edit] High magnification micrograph of giant cells in a giant-cell tumor of bone, H&E stain The diagnosis of giant-cell tumors is based on biopsy findings. The key histomorphologic feature is, as the name of the entity suggests, (multinucleated) giant cells with up to a hundred nuclei that have prominent nucleoli. Surrounding mononuclear and small multinucleated cells have nuclei similar to those in the giant cells; this distinguishes the lesion from other osteogenic lesions which commonly have (benign) osteoclast-type giant cells. Soap-bubble appearance is a characteristic feature.[citation needed] ### Imaging[edit] X-ray of a giant-cell bone tumor in the head of the fourth metacarpal of the left hand On X-ray, giant-cell tumors (GCTs) are lytic/lucent lesions that have an epiphyseal location and grow to the articular surface of the involved bone.[8] Radiologically the tumors may show characteristic 'soap bubble' appearance.[9] They are distinguishable from other bony tumors in that GCTs usually have a nonsclerotic and sharply defined border. About 5% of giant-cell tumors metastasize, usually to a lung, which may be benign metastasis,[10] when the diagnosis of giant-cell tumor is suspected, a chest X-ray or computed tomography may be needed. MRI can be used to assess intramedullary and soft tissue extension.[additional citation(s) needed] ### Differential diagnosis[edit] A number of tumors have giant cells, but are not true benign giant-cell tumors. These include, aneurysmal bone cyst, chondroblastoma, simple bone cyst, osteoid osteoma, osteoblastoma, osteosarcoma, giant-cell reparative granuloma, Giant-cell tumor of the tendon sheath and brown tumor of hyperparathyroidism. ## Treatment[edit] General treatment regimens have not changed much in the past 30 years, in part due to the lack of randomized clinical trials.[4] Surgery is the treatment of choice if the tumor is determined to be resectable. Curettage is a commonly used technique.[11] The situation is complicated in a patient with a pathological fracture. It may be best to immobilize the affected limb and wait for the fracture to heal before performing surgery. Patients with tumors that are not amenable to surgery are treated with radiation therapy.[12] However caution is employed since a majority of recurrent tumors with transformations to the malignant sarcoma phenotype have been in patients receiving radiotherapy for their primary benign lesion.[13] Pharmacotherapy for GCTOB, includes bisphosphonates such as Zoledronate, which are thought to induce apoptosis in the MNGC fraction, preventing tumor-induced osteolysis. Indeed, in vitro studies have shown zoledronate to be effective in killing osteoclast-like cells.[2][4] More recently, humanized monoclonal antibodies such as Denosumab targeting the RANK ligand have been employed in treatment of GCTOB in a phase II study. This is based on the notion that increased expression of RANK-ligands by stromal cells plays a role in tumor pathogenesis.[4] ## Epidemiology[edit] Giant-cell tumor of the bone accounts for 4-5% of primary bone tumors and about 20% of benign bone tumors.[14] However, significantly higher incidence rates are observed in Asia, where it constitutes about 20% of all primary bone tumors in China.[15] It is slightly more common in females, has a predilection for the epiphyseal/metaphyseal region of long bones,[2][16] and generally occurs in the third to fourth decade.[13] Although classified as a benign tumor, GCTOB has been observed to metastasize to the lungs in up to 5% of cases, and in rare instances (1-3%) can transform to the malignant sarcoma phenotype with equal disease outcome.[2][4][16] ## See also[edit] * Large cell * Aneurysmal bone cyst ## References[edit] 1. ^ Pai SB, Lalitha RM, Prasad K, Rao SG, Harish K (September 2005). "Giant cell tumor of the temporal bone—a case report". BMC Ear Nose Throat Disord. 5: 8. doi:10.1186/1472-6815-5-8. PMC 1253509. PMID 16162299. 2. ^ a b c d Werner M (2006). "Giant cell tumour of bone: morphological, biological and histogenetical aspects". Int Orthop. 30 (6): 484–489. doi:10.1007/s00264-006-0215-7. PMC 3172738. PMID 17013643. 3. ^ Huang , Xu J, Wood DJ, Zheng MH (2000). "Gene Expression of Osteoprotegerin Ligand, Osteoprotegerin, and REceptor Activator of NF-kB in Giant Cell Tumor of Bone". American Journal of Pathology. 156 (3): 761–767. doi:10.1016/s0002-9440(10)64942-5. PMC 1876848. PMID 10702390.CS1 maint: multiple names: authors list (link) 4. ^ a b c d e Thomas DM, Skubitz T (2009). "Giant-cell tumour of bone". Current Opinion in Oncology. 21 (4): 338–344. doi:10.1097/CCO.0b013e32832c951d. PMID 19444102. S2CID 41807503. 5. ^ Werner M (2006). "Giant-cell tumour of bone: morphological, biological and histogenetical aspects". Int Orthop. 30 (6): 484–489. doi:10.1007/s00264-006-0215-7. PMC 3172738. PMID 17013643. 6. ^ Wuelling M, Delling G, Kaiser E (2003). "The Origin of the Neoplastic Stromal Cell in Giant Cell Tumor of Bone". Human Pathology. 34 (10): 983–993. doi:10.1053/S0046-8177(03)00413-1. PMID 14608531.CS1 maint: multiple names: authors list (link) 7. ^ Dehghan A, Moaddab AH, Eskandarlou M, Moeeni A. Anterior chest wall giant cell tumor. Gen Thorac Cardiovasc Surg. 2010 Jan;58(1):39-41. 8. ^ Murphey M, Nomikos G, Flemming D, Gannon F, Temple H, Kransdorf M (2001). "From the archives of AFIP. Imaging of giant cell tumor and giant cell reparative granuloma of bone: radiologic-pathologic correlation". Radiographics. 21 (5): 1283–309. doi:10.1148/radiographics.21.5.g01se251283. PMID 11553835. 9. ^ essentials of skeletal radiology. Lippincott Williams & Wilkins. 2005. pp. 1–. GGKEY:29STUY0DQ70. Retrieved 21 June 2010. 10. ^ "Giant-cell tumor of bone - Wheeless' Textbook of Orthopaedics". 11. ^ Balke M, Schremper L, Gebert C, et al. (March 2008). "Giant cell tumor of bone: treatment and outcome of 214 cases". J. Cancer Res. Clin. Oncol. 134 (9): 969–78. doi:10.1007/s00432-008-0370-x. PMID 18322700. S2CID 2971150. 12. ^ Mendenhall W, Zlotecki R, Scarborough M, Gibbs C, Mendenhall N (2006). "Giant cell tumor of bone". Am J Clin Oncol. 29 (1): 96–9. doi:10.1097/01.coc.0000195089.11620.b7. PMID 16462511. S2CID 31907929. 13. ^ a b Mendenhall WM, Zlotecki RA, Scarborough MT, Gibbs PC, Mendenhall NP (2006). "Giant Cell Tumor of Bone". American Journal of Clinical Oncology. 29 (1): 96–99. doi:10.1097/01.coc.0000195089.11620.b7. PMID 16462511. S2CID 31907929.CS1 maint: multiple names: authors list (link) 14. ^ Gamberi G, Serra M, Ragazzini P, Magagnoli G, Pazzaglia L, Ponticelli F, Ferrari C, Zanasi M, Bertoni F, Picci P, Benassi M (2003). "Identification of markers of possible prognostic value in 57 giant-cell tumors of bone". Oncol Rep. 10 (2): 351–6. doi:10.3892/or.10.2.351. PMID 12579271. 15. ^ Thomas D. M., Skubitz T. (2009). "Giant-cell tumour of bone". Current Opinion in Oncology. 21 (4): 338–344. doi:10.1097/cco.0b013e32832c951d. PMID 19444102. S2CID 41807503. 16. ^ a b Dickson B. C., Li S.-Q., Wunder J. S., Ferguson P. C., Eslami B., Werier J. A.; et al. (2008). "Giant-cell tumor of bone express p63". Modern Pathology. 21 (4): 369–375. doi:10.1038/modpathol.2008.29. PMID 18311114.CS1 maint: multiple names: authors list (link) ## External links[edit] * "Symposium on Giant Cell Tumor". Indian Journal of Orthopaedics. 41 (2). 2007. Classification D * ICD-10: C40, C41 * ICD-O: 9250/1 * MeSH: D018212 * DiseasesDB: 9337 External resources * eMedicine: radio/307 * v * t * e Tumours of bone and cartilage Diaphysis * Multiple myeloma * Epithelia * Adamantinoma * Primitive neuroectodermal tumor * Ewing family * Ewing's sarcoma Metaphysis Osteoblast * Osteoid osteoma * Osteoblastoma * Osteoma/osteosarcoma Chondroblast * Chondroma/ecchondroma/enchondroma * Enchondromatosis * Extraskeletal chondroma * Chondrosarcoma * Mesenchymal chondrosarcoma * Myxoid chondrosarcoma * Osteochondroma * Osteochondromatosis * Chondromyxoid fibroma Fibrous * Ossifying fibroma * Fibrosarcoma Epiphysis Chondroblast * Chondroblastoma Myeloid * Giant-cell tumor of bone Other Notochord * Chordoma [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors	Giant-cell tumor of bone	c0206638	1,777	wikipedia	https://en.wikipedia.org/wiki/Giant-cell_tumor_of_bone	2021-01-18T18:31:45	{"gard": ["13046"], "mesh": ["D018212"], "umls": ["C0206638"], "icd-10": ["C41", "C40"], "orphanet": ["363976"], "wikidata": ["Q1785791"]}
Histiocytosis-lymphadenopathy plus syndrome (also known as SLC29A3 spectrum disorder) is a group of conditions with overlapping signs and symptoms that affect many parts of the body. This group of disorders includes H syndrome, pigmented hypertrichosis with insulin-dependent diabetes mellitus (PHID), Faisalabad histiocytosis, and familial Rosai-Dorfman disease (also known as sinus histiocytosis with massive lymphadenopathy or SHML). These conditions were once thought to be distinct disorders; however, because of the overlapping features and shared genetic cause, they are now considered to be part of the same disease spectrum. While some affected individuals have signs and symptoms characteristic of one of the conditions, others have a range of features from two or more of the conditions. The pattern of signs and symptoms can vary even within the same family. A feature common to the disorders in this spectrum is histiocytosis, which is the overgrowth of immune system cells called histiocytes. The cells abnormally accumulate in one or more tissues in the body, which can lead to organ or tissue damage. The buildup often occurs in the lymph nodes, leading to swelling of the lymph nodes (lymphadenopathy). Other areas of cell accumulation can include the skin, kidneys, brain and spinal cord (central nervous system), or digestive tract. This spectrum is known as histiocytosis-lymphadenopathy plus syndrome because the disorders that make up the spectrum can have additional signs and symptoms. A characteristic feature of H syndrome is abnormal patches of skin (lesions), typically on the lower body. These lesions are unusually dark (hyperpigmented) and have excessive hair growth (hypertrichosis). In addition, histiocytes accumulate at the site of the skin lesions. Other features of H syndrome include enlargement of the liver (hepatomegaly), heart abnormalities, hearing loss, reduced amounts of hormones that direct sexual development (hypogonadism), and short stature. Like H syndrome, PHID causes patches of hyperpigmented skin with hypertrichosis. PHID is also characterized by the development of type 1 diabetes (also known as insulin-dependent diabetes mellitus), which usually begins in childhood. Type 1 diabetes occurs when the body does not produce enough of the hormone insulin, leading to dysregulation of blood sugar levels. Faisalabad histiocytosis typically causes lymphadenopathy and swelling of the eyelids due to accumulation of histiocytes. Affected individuals can also have joint deformities called contractures in their fingers or toes and hearing loss. The most common feature of familial Rosai-Dorfman disease is lymphadenopathy, usually affecting lymph nodes in the neck. Histiocytes can also accumulate in other parts of the body. ## Frequency Histiocytosis-lymphadenopathy plus syndrome is a rare disorder, affecting approximately 100 individuals worldwide. ## Causes Histiocytosis-lymphadenopathy plus syndrome is caused by mutations in the SLC29A3 gene, which provides instructions for making a protein called equilibrative nucleoside transporter 3 (ENT3). ENT3 belongs to a family of proteins that transport molecules called nucleosides in cells. With chemical modification, nucleosides become the building blocks of DNA, its chemical cousin RNA, and molecules such as ATP and GTP, which serve as energy sources in the cell. Molecules derived from nucleosides play an important role in many functions throughout the body. ENT3 is found in cellular structures called lysosomes, which break down large molecules into smaller ones that can be reused by cells. Researchers believe that this protein transports nucleosides generated by the breakdown of DNA and RNA out of lysosomes into the cell so they can be reused. The protein is also thought to transport nucleosides into structures called mitochondria, which are the energy-producing centers of cells. In mitochondria, nucleosides are likely used in the formation or repair of DNA found in these structures, known as mitochondrial DNA. The SLC29A3 gene mutations involved in histiocytosis-lymphadenopathy plus syndrome reduce or eliminate the activity of the ENT3 protein. Researchers speculate that the resulting impairment of nucleoside transport leads to a buildup of nucleosides in lysosomes, which may be damaging to cell function. A lack of ENT3 activity may also lead to a reduction in the amount of nucleosides in mitochondria. This nucleoside shortage could impair cellular energy production, which would impact many body systems. It is unclear how the mutations lead to histiocytosis and other features of the condition or why affected individuals can have different patterns of signs and symptoms. ### Learn more about the gene associated with Histiocytosis-lymphadenopathy plus syndrome * SLC29A3 ## 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	Histiocytosis-lymphadenopathy plus syndrome	c1864445	1,778	medlineplus	https://medlineplus.gov/genetics/condition/histiocytosis-lymphadenopathy-plus-syndrome/	2021-01-27T08:24:49	{"gard": ["10239", "7588"], "mesh": ["C538322"], "omim": ["602782"], "synonyms": []}
A number sign (#) is used with this entry because of evidence that chilblain lupus-1 (CHBL1) is caused by heterozygous mutation in the TREX1 gene (606609) on chromosome 3p21. Description Chilblain lupus is a cutaneous form of systemic lupus erythematosus (SLE; 152700) characterized by the appearance of painful bluish-red papular or nodular lesions of the skin in acral locations (including the dorsal aspects of fingers and toes, heels, nose, cheeks, ears, and, in some cases, knees) precipitated by cold and wet exposure (summary by Lee-Kirsch et al., 2006). ### Genetic Heterogeneity of Chilblain Lupus See also CHBL2 (614415), caused by mutation in the SAMHD1 gene (606754) on chromosome 20q11. Mutations in the TREX1 and SAMHD1 genes also cause Aicardi-Goutieres syndrome (AGS1, 225750 and AGS5, 612952, respectively). Clinical Features Chilblain lupus, a rare cutaneous form of systemic lupus erythematosus (152700), was first described by Jonathan Hutchinson (1888). Lee-Kirsch et al. (2006) described a large nonconsanguineous German family with 18 members over 5 generations affected with chilblain lupus. Affected individuals presented with painful bluish-red papular or nodular lesions of the skin in acral locations (including the dorsal aspects of fingers and toes, heels, nose, cheeks, ears, and, in some cases, knees) precipitated by cold and wet exposure at temperatures less than 10 degrees centigrade. Sometimes a plaque-like appearance was noted, and ulceration was commonly seen. Although deep ulceration led to necrotic destruction of the distal interphalangeal joint of the left fifth finger in the index patient at age 15 years, the lesions usually healed without scars, occasionally leaving atrophic skin and pigmentary changes. The onset of the skin lesions was in early childhood, and, in most patients, the lesions tended to improve during summer. Mucous membranes and nails were not affected, although subungual lesions were sometimes seen. There was no associated Raynaud phenomenon (see 179600) or photosensitivity. There was no evidence of associated disease of any internal organ (including the CNS), immune deficiency, or malignancy. Arthralgias affected mainly large joints, such as knees and shoulders. There was no increased susceptibility to infection. Histologic findings included a deep inflammatory infiltrate with perivascular distribution and granular deposits of immunoglobulins and complement along the basement membrane. Some affected individuals showed antinuclear antibodies or immune complex formation, whereas cryoglobulins or cold agglutinins were absent. The family study suggested a highly penetrant trait with autosomal dominant inheritance. Chilblain lupus occurs predominantly in adult women and has only rarely been described in children. Before the report of Lee-Kirsch et al. (2006) there had been only one report of familial chilblain lupus, in 2 brothers (Weston and Morelli, 2000). Rice et al. (2007) reported a nonconsanguineous Bangladeshi family in which 2 brothers and a sister were affected; the father had been similarly affected throughout his life but was unavailable for study. The onset of the disorder in this family was in early childhood. The patients presented with painful bluish-red swelling of the skin affecting mainly the fingers, toes, ears, helices, and, occasionally, the nose. The lesions were induced by cold temperatures and were significantly worse in the winter months. The lesions could ulcerate; the father and 2 sons were affected. In the affected males, the ulcerations led to a loss of ear cartilage and destruction of the proximal interphalangeal joints and distal toes. Ulcerative lesions healed but left areas of atrophic and hypopigmented skin. Antinuclear antibodies were intermittently raised, and 1 patient exhibited persistently elevated erythrocyte-sedimentation rate. Mapping By single-nucleotide polymorphism (SNP)-based genomewide linkage analysis in the family described by them, Lee-Kirsch et al. (2006) mapped a locus for chilblain lupus to 3p. Haplotype analysis refined the locus to a 13.8-cM interval on chromosome 3p21-p14, flanked by markers rs704920 and D3S1300, with a lod score of 5.04. Other Features The locus to which Lee-Kirsch et al. (2006) established linkage of the isolated CHBL phenotype partially overlaps that for type 1 Aicardi-Goutieres syndrome (225750). Children affected with Aicardi-Goutieres syndrome suffer from progressive microcephaly and severe cerebral dysfunction associated with calcification of basal ganglia, chronic lymphocytosis, and elevated interferon-alpha (see 147660) in the spinal fluid. Some patients have chilblain-like lesions that resemble those found in the family reported by Lee-Kirsch et al. (2006), although unaffected parents of children with this autosomal recessive disorder do not show any cutaneous findings. Aicardi-Goutieres syndrome has been suggested to be a form of systemic lupus erythematosus because of the findings of hypocomplementemia and antinuclear autoantibodies in addition to lupus-like skin lesions in some patients. Therefore, Lee-Kirsch et al. (2006) suggested that chilblain lupus and Aicardi-Goutieres syndrome may be allelic phenotypes representing different spectrums of the same disease. In a large study of the clinical and molecular phenotype of Aicardi-Goutieres syndrome, Rice et al. (2007) discussed and illustrated chilblain lesions in patients with that disorder in patients from 127 pedigrees. Chilblain lesions were reported in 43% of patients and were associated with mutations in all 4 Aicardi-Goutieres syndrome causative genes: TREX1 (606609), RNASEH2A (606034), RNASEH2B (610326), and RNASEH2C (610330). The lesions were usually situated on the feet but sometimes also affected the hands and outer rim of the ears. Many parents reported a direct relationship with cold temperatures, with considerable worsening of the lesions during winter months. Molecular Genetics Rice et al. (2007) described a heterozygous mutation in the TREX1 gene (606609.0005) in affected members of a family with chilblain lupus. In affected members of the large 5-generation German family with chilblain lupus previously described by Lee-Kirsch et al. (2006), Lee-Kirsch et al. (2007) identified heterozygosity for a missense mutation in the TREX1 gene (D18N; 606609.0007). In a 16-year-old girl with relatively mild Aicardi-Goutieres syndrome (225750), who was negative for mutation in other known AGS genes, Haaxma et al. (2010) identified heterozygosity for the same D18N mutation in the TREX1 gene that had previously been found in the German family with chilblain lupus by Lee Kirsch et al. (2007). Haaxma et al. (2010) had no explanation for how the same mutation might cause such distinct phenotypes. History For a review of the career and clinical observations of Hutchinson, who first described chilblain lupus, see McKusick (1952, 2005). INHERITANCE \- Autosomal dominant CARDIOVASCULAR Vascular \- No Raynaud phenomenon SKELETAL \- Arthralgias (knees and shoulders) SKIN, NAILS, & HAIR Skin \- Painful bluish-red papules or nodules (fingers, toes, nose, cheek, ears) \- Cutaneous ulcers \- Healed areas are atrophic and hypopigmented \- No cutaneous photosensitivity Skin Histology \- Deep inflammatory perivascular infiltrate with granular deposits of immunoglobulins and complement along basement membrane Nails \- Subungual lesions (in some patients) IMMUNOLOGY \- Antinuclear antibody present (in some patients) MISCELLANEOUS \- Environmental triggers - cold and wet exposure \- Onset in early childhood \- Allelic to Aicardi-Goutieres syndrome ( 225750 ) MOLECULAR BASIS \- Caused by mutation in the 3-prime repair exonuclease-1 gene (TREX1, 606609.0005 ) ▲ 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	CHILBLAIN LUPUS 1	c0024145	1,779	omim	https://www.omim.org/entry/610448	2019-09-22T16:04:29	{"doid": ["0060386"], "mesh": ["C535924"], "omim": ["610448"], "orphanet": ["481662"], "synonyms": []}
A rare genetic syndromic intellectual disability characterized by global developmental delay, moderate to severe intellectual disability, motor and language impairment, behavioral abnormalities (with mood instability, aggression, and self-mutilation), and progressive hand tremor. Facial dysmorphism includes narrow palpebral fissures, large ears, long philtrum, and prominent chin. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-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	Progressive essential tremor-speech impairment-facial dysmorphism-intellectual disability-abnormal behavior syndrome	c4225395	1,780	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=457212	2021-01-23T16:55:55	{"omim": ["616269"]}
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 does not cite any sources. Please help improve this article by adding citations to reliable sources. Unsourced material may be challenged and removed. Find sources: "Penetration" weaponry – news · newspapers · books · scholar · JSTOR (September 2007) (Learn how and when to remove this template message) 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. (March 2011) (Learn how and when to remove this template message) (Learn how and when to remove this template message) Strictly speaking, penetration occurs when a projectile enters a target without passing through it and perforation occurs when the projectile completely passes through the target, but the word penetration is commonly used to refer to either. Penetration into a semi-infinite or massive target is penetration (in the strict sense of the word) of targets so thick that the level of penetration is not affected by the target's thickness. There is a transition region between semi-infinite penetration and perforation, in which the target is not perforated but the projectile, as it nears the back face of the target, meets reduced resistance and is capable of penetrating a greater distance than it would in a semi-infinite target. This effect is variously named the back or rear surface, plate, or face effect and is also present when perforation occurs. A penetrating projectile may cause the target to break into multiple pieces, spewing from both the front and back of the target, themselves at high velocity. These pieces are collectively referred to as spall. Spall can be generated even if a perforation is not achieved (the projectile fails to pass through the target), generated instead by the shock wave generated by the impact of the projectile. Bombs designed for great penetration into the earth or for perforation of hardened targets are known as bunker busters. ## Overpenetration[edit] Overpenetration of a projectile through a synthetic ordnance gelatin. Excessive penetration or overpenetration occurs when a projectile completely passes through (perforates) its intended target and out of the other side, with enough residual kinetic energy to continue flying as a stray projectile, and risk causing unintended collateral damages to objects or persons beyond. According to the energy transfer hypothesis, this happens because the projectile has not released all its energy within the target. This article related to weaponry 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	Penetration (weaponry)	None	1,781	wikipedia	https://en.wikipedia.org/wiki/Penetration_(weaponry)	2021-01-18T18:44:29	{"wikidata": ["Q4096960"]}
Myhre syndrome is a rare, connective tissue disorder that affects many parts of the body. Signs and symptoms include fibrosis (thickening and scarring of connective tissue), intellectual disability, distinctive facial features, skeletal abnormalities, and/or various birth defects. The syndrome may affect the structure or function of the heart, the respiratory system, the gastrointestinal system, and the skin. Myhre syndrome is caused by a mutation in the SMAD4 gene. The mutation typically occurs for the first time in an affected person. To date, no reported cases have been inherited from a parent. Inheritance is autosomal dominant, but there are no reported cases of a person with Myhre syndrome having children. Treatment addresses each symptom present and may include limiting the risk of trauma to tissues, surgery for birth defects or complications, and routine management of learning delays or behavioral problems. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-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	Myhre syndrome	c0796081	1,782	gard	https://rarediseases.info.nih.gov/diseases/2572/myhre-syndrome	2021-01-18T17:58:51	{"mesh": ["C537620"], "omim": ["139210"], "umls": ["C0796081"], "orphanet": ["2588"], "synonyms": ["Facial dysmorphism - intellectual deficit - short stature - hearing loss", "Laryngotracheal stenosis, arthropathy, prognathism, and short stature", "LAPS syndrome", "Growth mental deficiency syndrome of Myhre"]}
## Description Split-hand/split-foot malformation is a limb malformation involving the central rays of the autopod and presenting with syndactyly, median clefts of the hands and feet, and aplasia and/or hypoplasia of the phalanges, metacarpals, and metatarsals (Elliott and Evans, 2006). For additional phenotypic information and a discussion of genetic heterogeneity of split-hand/split-foot malformation, see SHFM1 (183600). Clinical Features Ahmad et al. (1987) described a Pakistani kindred in which 36 members in 7 generations had split-hand and split-foot anomaly. The full expression of the trait, monodactylous or split hand and split foot, mainly of the lobster-claw type, was present in 33 males and 3 females. Other females showed a distinctly milder expression of the trait, usually in the form of partial syndactyly, metacarpal and phalangeal hypoplasia, and malformation of the bones of the hand. The distribution of affected members in the pedigree was considered to be compatible with X-linked inheritance. Hemizygous males and presumably homozygous females exhibit the typical split-hand/split-foot anomaly, whereas only part of the obligatory heterozygous females show the milder expression. The pedigree contained one example of father and son affected, but it seemed in this case that the mother was heterozygous because there was mild expression of the trait and 2 daughters were apparent homozygotes. The authors referred to the article by Bujdoso and Lenz (1980) proposing 3 distinct types. Mapping Faiyaz ul Haque et al. (1992) performed linkage studies in the Pakistani kindred reported by Ahmad et al. (1987). No recombination was found between the disease locus and the loci DXS294 and HPRT (308000); maximum lod = 5.13 and 4.43, respectively. Thus, linkage analysis suggested that the gene for X-linked split hand/split foot anomaly is located at Xq26. Faiyaz-Ul-Haque et al. (2005) performed additional linkage studies in the Pakistani kindred reported by Ahmad et al. (1987) and narrowed the SHFM2 locus to a 5.1-Mb region on Xq26.3 between markers DXS1114 and DXS1192. Molecular Genetics ### Exclusion Studies In the Pakistani kindred with SHFM2, Faiyaz-Ul-Haque et al. (2005) screened the exons and exon/intron boundaries of 19 candidate genes in the Xq26.3 region and did not identify any mutations. Nomenclature Palmer et al. (1994) suggested that since split-hand/split-foot is a malformation, not a deformity, the gene symbol should be SHSF. The HUGO nomenclature committee determined in 1994 that split hand/foot malformation should be symbolized SHFM. Limbs \- Split-hand \- Split-foot \- Monodactylous lobster-claw anomaly \- Partial syndactyly \- Metacarpal hypoplasia \- Phalangeal hypoplasia Misc \- Heterozygous females show milder expression Inheritance \- X-linked (Xq26) ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors	SPLIT-HAND/FOOT MALFORMATION 2	c0265554	1,783	omim	https://www.omim.org/entry/313350	2019-09-22T16:17:16	{"doid": ["0090027"], "mesh": ["C574275"], "omim": ["313350"], "orphanet": ["2440"], "synonyms": ["Alternative titles", "SPLIT-HAND/SPLIT-FOOT ANOMALY, X-LINKED", "SPLIT-HAND/FOOT DEFORMITY 2", "SHSF2"]}
Neonatal hemochromatosis (NH) is an iron storage disorder present at birth. It is a distinct entity that differs from adult hemochromatosis with respect to its molecular origin. ## Clinical description Clinical signs occur as early as 48 hours after birth and are characterized by the association of severe hepatocellular failure with hyperbilirubinemia, signs of hemorrhage, edema, ascites, hypoglycemia, and lactic acidosis with little to no elevation of transaminases. ## Etiology The underlying cause of this iron storage disorder is unknown but it may be associated with an anomaly in placental iron transfer. ## Diagnostic methods Although the diagnosis may be suspected following measurement of transaminase activity, it can only be confirmed by demonstrating the generalized iron overload affecting the salivary glands, liver and pancreas, among other organs. ## Management and treatment The disease is fatal and the limited efficiency of antioxydant treatment does not allow liver transplantation to be delayed, despite the fact that this operation is of high risk in neonates. A recent study described a treatment with high-dose intravenous immunoglobulin (IVIG) administered during gestation to women whose most recent pregnancy ended in documented NH. This therapy appears to be effective in preventing or changing the severity of neonatal hemochromatosis and supports the hypothesis of an alloimmune mechanism 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	Neonatal hemochromatosis	c0268059	1,784	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=446	2021-01-23T18:18:35	{"gard": ["7172"], "mesh": ["C536394"], "omim": ["231100"], "umls": ["C0268059"], "icd-10": ["E83.1"]}
## Clinical Features In an inbred kindred of south India, Mathew et al. (1970) observed 9 persons with static ophthalmoparesis beginning in childhood. Oropharyngeal weakness was not associated, but limb weakness was noted in 2. There was no response to neostigmine or echophonium, and the response to tetanic stimulation of the ulnar nerve was normal. For these reasons, the authors regarded the condition as an ocular myopathy and not a form of myasthenia gravis, despite the fact that all of those affected were as sensitive to tubocurarine as patients with myasthenia gravis. Two asymptomatic presumed heterozygotes showed sensitivity to tubocurarine. Inheritance The transmission pattern of ocular myopathy with curare sensitivity in the family reported by Mathew et al. (1970) was consistent with autosomal recessive inheritance. HEENT \- Ocular myopathy \- Static ophthalmoparesis \- No oropharyngeal weakness Muscle \- Limb weakness Misc \- Childhood onset Lab \- No response to neostigmine or edrophonium \- Normal tetanic stimulation of ulnar nerve \- Curare sensitivity 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	OCULAR MYOPATHY WITH CURARE SENSITIVITY	c1850341	1,785	omim	https://www.omim.org/entry/257600	2019-09-22T16:24:10	{"mesh": ["C564937"], "omim": ["257600"]}
Woolf et al. (1955) suggested that some families have scattered polyps as a dominant trait distinct from multiple polyposis of the colon. The kindred of Lindberg and Kock (1975) had these features. However, studies of polyposis I families (175100) show such wide variability in the number of polyps that it is difficult to accept the idea that a separate mutation exists. The evidence is, to say the least, inconclusive. GI \- Discrete intestinal polyps Inheritance \- Autosomal dominant \- ? same as FAP (175100) ▲ 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	POLYPOSIS, INTESTINAL, SCATTERED AND DISCRETE	c1868006	1,786	omim	https://www.omim.org/entry/175400	2019-09-22T16:35:58	{"omim": ["175400"], "synonyms": ["Alternative titles", "POLYPS, SCATTERED, DISCRETE INTESTINAL"]}
For a discussion of genetic heterogeneity of isolated microphthalmia with coloboma, see MCOPCB1 (300345). Isolated microphthalmia associated with colobomatous cyst results from a defect in the closure of the embryonic fissure at the 7- to 20-mm stage of development. Microphthalmia can be associated with either a small, clinically undetectable cyst, or a large, typically inferior cyst that deforms the eye and its surroundings. It is usually unilateral, although bilateral cases have been described. Porges et al. (1992) described 5 cases of microphthalmia with colobomatous cyst in 3 separate sibships of a highly inbred kindred. Orbital computed tomography was useful in defining the size of the globe and characterizing the cystic lesions. None of the 5 patients had light perception in either eye and there was no recordable electroretinogram or visual evoked potentials. Most of the globes were deeply set and undetectable clinically (clinical anophthalmos). Hornby et al. (2000) correlated visual function with clinical features and biometric findings in the eyes of children with coloboma. Of the 196 eyes with colobomatous malformations, 11 had microphthalmos with cyst, and 185 eyes had coloboma (associated with microcornea in 155 eyes and with normal corneal diameter in 30 eyes). The visual prognosis depended on the phenotype of the more normal eye. Microphthalmos with cyst had the worst prognosis (all worse than 20/400). Microcornea with microphthalmos had a worse prognosis than microcornea without microphthalmos. For microcornea with microphthalmos, 67% saw worse than 20/400. Of the children with microcornea without microphthalmos, 76% saw better than 20/400. Simple coloboma (without microcornea or microphthalmos) had the best visual prognosis: only 7% saw 20/400 or worse. A corneal diameter of less than 6 mm had a poor visual prognosis, whereas a corneal diameter of more than 10 mm had a good prognosis. Eyes \- Microphthalmia \- Colobomatous cyst 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	MICROPHTHALMIA, ISOLATED, WITH COLOBOMA 4	c2931501	1,787	omim	https://www.omim.org/entry/251505	2019-09-22T16:25:08	{"mesh": ["C537463"], "omim": ["251505"], "orphanet": ["98938"], "synonyms": ["Alternative titles", "MICROPHTHALMIA WITH COLOBOMATOUS CYST"]}
Acute fatty liver of pregnancy SpecialtyObstetrics, Perinatology, Hepatology ComplicationsDeath, Disseminated intravascular coagulation Usual onsetThird trimester of pregnancy CausesLong-chain 3-hydroxyacyl-coenzyme A dehydrogenase deficiency Diagnostic methodClinical history and physical examination Liver biopsy (rarely needed) TreatmentPrompt delivery of the infant, Intensive supportive care Liver transplantation Frequency1 in 7,000 to 1 in 15,000 pregnancies Deaths18%[1] Acute fatty liver of pregnancy is a rare life-threatening complication of pregnancy that occurs in the third trimester or the immediate period after delivery.[1] It is thought to be caused by a disordered metabolism of fatty acids by mitochondria in the mother, caused by long-chain 3-hydroxyacyl-coenzyme A dehydrogenase deficiency.[2] The condition was previously thought to be universally fatal,[3] but aggressive treatment by stabilizing the mother with intravenous fluids and blood products in anticipation of early delivery has improved prognosis.[4] ## Contents * 1 Signs and symptoms * 2 Pathophysiology * 3 Diagnosis * 3.1 Pathology * 4 Treatment * 5 Epidemiology * 6 History * 7 See also * 8 References * 9 External links ## Signs and symptoms[edit] Acute fatty liver of pregnancy (or hepatic lipidosis of pregnancy) usually manifests in the third trimester of pregnancy, but may occur any time in the second half of pregnancy, or in the puerperium, the period immediately after delivery.[1] On average, the disease presents during the 35th or 36th week of pregnancy.[5] The usual symptoms in the mother are non-specific including nausea, vomiting, anorexia (or lack of desire to eat) and abdominal pain; excessive thirst may be the earliest symptom without overlap with otherwise considered normal pregnancy symptoms;[5] however, jaundice and fever may occur in as many as 70% of patients.[1][6] In patients with more severe disease, pre-eclampsia may occur, which involves elevation of blood pressure and accumulation of fluid (termed oedema).[5] This may progress to involvement of additional systems, including acute kidney failure,[7] hepatic encephalopathy,[8] and pancreatitis.[9] There have also been reports of diabetes insipidus complicating this condition.[10] Many laboratory abnormalities are seen in acute fatty liver of pregnancy. Liver enzymes are elevated, with the AST and ALT enzymes ranging from minimal elevation to 1000 IU/L, but usually staying in the 300-500 range.[1] Bilirubin is almost universally elevated. Alkaline phosphatase is often elevated in pregnancy due to production from the placenta, but may be additionally elevated.[4] Other abnormalities may include an elevated white blood cell count, hypoglycemia, elevated coagulation parameters, including the international normalized ratio, and decreased fibrinogen.[1][4][5] Frank disseminated intravascular coagulation, or DIC, may occur in as many as 70% of people.[1] Abdominal ultrasound may show fat deposition in the liver, but, as the hallmark of this condition is microvesicular steatosis (see pathology below), this is not seen on ultrasound.[11] Rarely, the condition can be complicated by rupture or necrosis of the liver, which may be identified by ultrasound. ## Pathophysiology[edit] Schematic demonstrating mitochondrial fatty acid beta-oxidation and effects of LCHAD deficiency, a hallmark of acute fatty liver of pregnancy The understanding of the causes of acute fatty liver of pregnancy has been improved by advances in mitochondrial biochemistry. Deficiency of LCHAD (3-hydroxyacyl-CoA dehydrogenase) leads to an accumulation of medium and long chain fatty acids. When this occurs in the foetus, the unmetabolized fatty acids will re-enter the maternal circulation through the placenta, and overwhelm the beta-oxidation enzymes of the mother.[12] The gene responsible for LCHAD has been isolated, and the most common mutation found in acute fatty liver of pregnancy is the E474Q missense mutation.[13] LCHAD deficiency is autosomal recessive in inheritance and mothers are often found to be heterozygous for the affected mutation.[14] ## Diagnosis[edit] The diagnosis of acute fatty liver of pregnancy is usually made on clinical grounds by the treating physician, but differentiation from other conditions affecting the liver may be difficult.[1] The diagnosis of acute fatty liver of pregnancy is suggested by jaundice with a lesser elevation of liver enzymes, elevated white blood cell count, disseminated intravascular coagulation, and a clinically unwell patient.[4] A liver biopsy can provide a definitive diagnosis,[15] but is not always done, due to the increased chance of bleeding in acute fatty liver of pregnancy.[16] Often testing will be done to exclude more common conditions that present in a similar fashion, including viral hepatitis,[17] pre-eclampsia,[5] HELLP syndrome,[4] intrahepatic cholestasis of pregnancy,[1] and autoimmune hepatitis.[3] ### Pathology[edit] If a liver biopsy is needed for diagnosis of the condition, the mother should be appropriately stabilized and treated to reduce bleeding related complications. The diagnosis can be made by a frozen-section (as opposed to a specimen in formalin) that is stained with the Oil red O stain, that shows microvesicular steatosis (or small collections of fat within the liver cells). The microvesicular steatosis usually spares zone one of the liver, which is the area closest to the hepatic artery. On the regular trichrome stain, the liver cell cytoplasm shows a foamy appearance due to the prominence of fat. Necrosis is rarely seen. The diagnosis can be enhanced by electron microscopy which can be used to confirm the presence of microvesicular steatosis, and specifically the presence of megamitochondria and paracrystalline inclusions.[18][19] Liver diseases with similar appearances include Reye's syndrome, drug-induced hepatitis from agents with mitochondrial toxicity, including nucleoside reverse transcriptase inhibitors used to treat HIV,[20] and a rare condition known as Jamaican vomiting sickness which is caused by the eating of the unripened Ackee fruit.[21] ## Treatment[edit] Acute fatty liver of pregnancy is best treated in a centre with expertise in hepatology, high-risk obstetrics, maternal-fetal medicine and neonatology. The physicians who treat this condition will often consult with experts in liver transplantation in severe cases. Admission to the intensive care unit is recommended.[1] Initial treatment involves supportive management with intravenous fluids, intravenous glucose and blood products, including fresh frozen plasma and cryoprecipitate to correct DIC. The foetus should be monitored with cardiotocography. After the mother is stabilized, arrangements are usually made for delivery. This may occur vaginally, but, in cases of severe bleeding or compromise of the mother's status, a caesarian section may be needed.[1] Often AFLP is not diagnosed until the mother and baby are in trouble, so it is most likely that an emergency C-section is needed.[citation needed] The complications of acute fatty liver of pregnancy may require treatment after delivery, especially if pancreatitis occurs.[9] Liver transplantation is rarely required for treatment of the condition, but may be needed for mothers with severe DIC, those with rupture of the liver, or those with severe encephalopathy.[22] ## Epidemiology[edit] Acute fatty liver of pregnancy is a rare condition and occurs in approximately one in 7,000 to one in 15,000 pregnancies.[3][19] The mortality from acute fatty liver of pregnancy has been reduced significantly to 18%, and is now related primarily to complications, particularly DIC (Disseminated Intravascular Coagulation) and infections.[1][3] After delivery, most mothers do well, as the stimulus for fatty acid overload is removed. The disease can recur in future pregnancies, with a calculated genetic chance of 25%; the actual rate is lower, however.[12] Mortality of the foetus has also diminished significantly, but still remains 23%,[23] and may be related to the need for premature delivery.[1] ## History[edit] The disease was first described in 1940 by H. L. Sheehan as an "acute yellow atrophy" of the liver, then thought to be related to delayed chloroform poisoning.[1][24] ## See also[edit] * Fatty liver ## References[edit] 1. ^ a b c d e f g h i j k l m n Ko H, Yoshida EM (2006). "Acute fatty liver of pregnancy". Canadian Journal of Gastroenterology. 20 (1): 25–30. doi:10.1155/2006/638131. PMC 2538964. PMID 16432556. 2. ^ Bellig LL (2004). "Maternal acute fatty liver of pregnancy and the associated risk for long-chain 3-hydroxyacyl-coenzyme a dehydrogenase (LCHAD) deficiency in infants". Advances in Neonatal Care. 4 (1): 26–32. doi:10.1016/j.adnc.2003.12.001. PMID 14988877. 3. ^ a b c d Mjahed K, Charra B, Hamoudi D, Noun M, Barrou L (2006). "Acute fatty liver of pregnancy". Archives of Gynecology and Obstetrics. 274 (6): 349–353. doi:10.1007/s00404-006-0203-6. PMID 16868757. 4. ^ a b c d e Riely CA (1999). "Liver disease in the pregnant patient. American College of Gastroenterology". The American Journal of Gastroenterology. 94 (7): 1728–1732. PMID 10406228. 5. ^ a b c d e Riely CA (1987). "Acute fatty liver of pregnancy". Seminars in Liver Disease. 7 (1): 47–54. doi:10.1055/s-2008-1040563. PMID 3296215. 6. ^ Riely CA, Latham PS, Romero R, Duffy TP (1987). "Acute fatty liver of pregnancy. A reassessment based on observations in nine patients". Annals of Internal Medicine. 106 (5): 703–6. doi:10.7326/0003-4819-106-5-703. PMID 3565968. 7. ^ Koroshi A, Babameto A (2002). "Acute renal failure during acute fatty liver of pregnancy". Nephrology Dialysis Transplantation. 17 (6): 1110–1112. doi:10.1093/ndt/17.6.1110. PMID 12032205. 8. ^ Aggarwal R (2003). "Hepatic encephalopathy in pregnancy". Indian Journal of Gastroenterology. 22 Suppl 2: S78–80. PMID 15025263. 9. ^ a b Moldenhauer JS, O'brien JM, Barton JR, Sibai B (2004). "Acute fatty liver of pregnancy associated with pancreatitis: a life-threatening complication". American Journal of Obstetrics and Gynecology. 190 (2): 502–505. doi:10.1016/j.ajog.2003.09.022. PMID 14981397. 10. ^ Kennedy S, Hall PM, Seymour AE, Hague WM (1994). "Transient diabetes insipidus and acute fatty liver of pregnancy". BJOG: An International Journal of Obstetrics and Gynaecology. 101 (5): 387–91. doi:10.1111/j.1471-0528.1994.tb11909.x. PMID 8018608. 11. ^ Castro MA, Ouzounian JG, Colletti PM, Shaw KJ, Stein SM, Goodwin TM (1996). "Radiologic studies in acute fatty liver of pregnancy. A review of the literature and 19 new cases". The Journal of Reproductive Medicine. 41 (11): 839–43. PMID 8951135. 12. ^ a b Tein I (2000). "Metabolic disease in the foetus predisposes to maternal hepatic complications of pregnancy". Pediatric Research. 47 (1): 6–8. doi:10.1203/00006450-200001000-00005. PMID 10625076. 13. ^ IJlst L, Oostheim W, Ruiter JP, Wanders RJ (1997). "Molecular basis of long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency: identification of two new mutations" (PDF). Journal of Inherited Metabolic Disease. 20 (3): 420–422. doi:10.1023/A:1005310903004. PMID 9266371. 14. ^ Wanders RJ, Vreken P, den Boer ME, Wijburg FA, van Gennip AH, IJlst L (1999). "Disorders of mitochondrial fatty acyl-CoA beta-oxidation" (PDF). Journal of Inherited Metabolic Disease. 22 (4): 442–487. doi:10.1023/A:1005504223140. PMID 10407780. 15. ^ Brunt EM (2000). "Liver biopsy interpretation for the gastroenterologist". Current Gastroenterology Reports. 2 (1): 27–32. doi:10.1007/s11894-000-0048-2. PMID 10981000. 16. ^ Castro MA, Goodwin TM, Shaw KJ, Ouzounian JG, McGehee WG (1996). "Disseminated intravascular coagulation and antithrombin III depression in acute fatty liver of pregnancy". American Journal of Obstetrics and Gynecology. 174 (1 Pt 1): 211–216. doi:10.1016/S0002-9378(96)70396-4. PMID 8572009. 17. ^ Pang WW, Lei CH, Chang DP, Yang TF, Chung YT, Huang MH (1999). "Acute jaundice in pregnancy: acute fatty liver or acute viral hepatitis?". Acta Anaesthesiologica Sinica. 37 (3): 167–70. PMID 10609353. 18. ^ Bacq Y (1998). "Acute fatty liver of pregnancy". Seminars in Perinatology. 22 (2): 134–140. doi:10.1016/S0146-0005(98)80045-1. PMID 9638907. 19. ^ a b Reyes H, Sandoval L, Wainstein A, et al. (1994). "Acute fatty liver of pregnancy: a clinical study of 12 episodes in 11 patients". Gut. 35 (1): 101–106. doi:10.1136/gut.35.1.101. PMC 1374642. PMID 8307428. 20. ^ Montessori V, Harris M, Montaner JS (2003). "Hepatotoxicity of nucleoside reverse transcriptase inhibitors". Seminars in Liver Disease. 23 (2): 167–172. doi:10.1055/s-2003-39947. PMID 12800069. 21. ^ Hautekeete ML, Degott C, Benhamou JP (1990). "Microvesicular steatosis of the liver". Acta Clinica Belgica. 45 (5): 311–26. doi:10.1080/17843286.1990.11718105. PMID 2177300. 22. ^ Pereira SP, O'Donohue J, Wendon J, Williams R (1997). "Maternal and perinatal outcome in severe pregnancy-related liver disease". Hepatology. 26 (5): 1258–1262. doi:10.1002/hep.510260525. PMID 9362370. 23. ^ Fesenmeier MF, Coppage KH, Lambers DS, Barton JR, Sibai BM (2005). "Acute fatty liver of pregnancy in 3 tertiary care centers". American Journal of Obstetrics and Gynecology. 192 (5): 1416–1419. doi:10.1016/j.ajog.2004.12.035. PMID 15902124. 24. ^ Sheehan HL (1940). "The pathology of acute yellow atrophy and delayed chloroform poisoning". Journal of Obstetrics and Gynaecology of the British Empire. 47: 49–62. doi:10.1111/j.1471-0528.1940.tb14731.x. ## External links[edit] Classification D * ICD-10: O26.6 * ICD-9-CM: 646.7 * OMIM: 609016 * MeSH: C537957 * DiseasesDB: 32879 * v * t * e Diseases of the digestive system Upper GI tract Esophagus * Esophagitis * Candidal * Eosinophilic * Herpetiform * Rupture * Boerhaave syndrome * Mallory–Weiss syndrome * UES * Zenker's diverticulum * LES * Barrett's esophagus * Esophageal motility disorder * Nutcracker esophagus * Achalasia * Diffuse esophageal spasm * Gastroesophageal reflux disease (GERD) * Laryngopharyngeal reflux (LPR) * Esophageal stricture * Megaesophagus * Esophageal intramural pseudodiverticulosis Stomach * Gastritis * Atrophic * Ménétrier's disease * Gastroenteritis * Peptic (gastric) ulcer * Cushing ulcer * Dieulafoy's lesion * Dyspepsia * Pyloric stenosis * Achlorhydria * Gastroparesis * Gastroptosis * Portal hypertensive gastropathy * Gastric antral vascular ectasia * Gastric dumping syndrome * Gastric volvulus * Buried bumper syndrome * Gastrinoma * Zollinger–Ellison syndrome Lower GI tract Enteropathy Small intestine (Duodenum/Jejunum/Ileum) * Enteritis * Duodenitis * Jejunitis * Ileitis * Peptic (duodenal) ulcer * Curling's ulcer * Malabsorption: Coeliac * Tropical sprue * Blind loop syndrome * Small bowel bacterial overgrowth syndrome * Whipple's * Short bowel syndrome * Steatorrhea * Milroy disease * Bile acid malabsorption Large intestine (Appendix/Colon) * Appendicitis * Colitis * Pseudomembranous * Ulcerative * Ischemic * Microscopic * Collagenous * Lymphocytic * Functional colonic disease * IBS * Intestinal pseudoobstruction / Ogilvie syndrome * Megacolon / Toxic megacolon * Diverticulitis/Diverticulosis/SCAD Large and/or small * Enterocolitis * Necrotizing * Gastroenterocolitis * IBD * Crohn's disease * Vascular: Abdominal angina * Mesenteric ischemia * Angiodysplasia * Bowel obstruction: Ileus * Intussusception * Volvulus * Fecal impaction * Constipation * Diarrhea * Infectious * Intestinal adhesions Rectum * Proctitis * Radiation proctitis * Proctalgia fugax * Rectal prolapse * Anismus Anal canal * Anal fissure/Anal fistula * Anal abscess * Hemorrhoid * Anal dysplasia * Pruritus ani GI bleeding * Blood in stool * Upper * Hematemesis * Melena * Lower * Hematochezia Accessory Liver * Hepatitis * Viral hepatitis * Autoimmune hepatitis * Alcoholic hepatitis * Cirrhosis * PBC * Fatty liver * NASH * Vascular * Budd–Chiari syndrome * Hepatic veno-occlusive disease * Portal hypertension * Nutmeg liver * Alcoholic liver disease * Liver failure * Hepatic encephalopathy * Acute liver failure * Liver abscess * Pyogenic * Amoebic * Hepatorenal syndrome * Peliosis hepatis * Metabolic disorders * Wilson's disease * Hemochromatosis Gallbladder * Cholecystitis * Gallstone / Cholelithiasis * Cholesterolosis * Adenomyomatosis * Postcholecystectomy syndrome * Porcelain gallbladder Bile duct/ Other biliary tree * Cholangitis * Primary sclerosing cholangitis * Secondary sclerosing cholangitis * Ascending * Cholestasis/Mirizzi's syndrome * Biliary fistula * Haemobilia * Common bile duct * Choledocholithiasis * Biliary dyskinesia * Sphincter of Oddi dysfunction Pancreatic * Pancreatitis * Acute * Chronic * Hereditary * Pancreatic abscess * Pancreatic pseudocyst * Exocrine pancreatic insufficiency * Pancreatic fistula Other Hernia * Diaphragmatic * Congenital * Hiatus * Inguinal * Indirect * Direct * Umbilical * Femoral * Obturator * Spigelian * Lumbar * Petit's * Grynfeltt-Lesshaft * Undefined location * Incisional * Internal hernia * Richter's Peritoneal * Peritonitis * Spontaneous bacterial peritonitis * Hemoperitoneum * Pneumoperitoneum * v * t * e Pathology of pregnancy, childbirth and the puerperium Pregnancy Pregnancy with abortive outcome * Abortion * Ectopic pregnancy * Abdominal * Cervical * Interstitial * Ovarian * Heterotopic * Embryo loss * Fetal resorption * Molar pregnancy * Miscarriage * Stillbirth Oedema, proteinuria and hypertensive disorders * Gestational hypertension * Pre-eclampsia * HELLP syndrome * Eclampsia Other, predominantly related to pregnancy Digestive system * Acute fatty liver of pregnancy * Gestational diabetes * Hepatitis E * Hyperemesis gravidarum * Intrahepatic cholestasis of pregnancy Integumentary system / dermatoses of pregnancy * Gestational pemphigoid * Impetigo herpetiformis * Intrahepatic cholestasis of pregnancy * Linea nigra * Prurigo gestationis * Pruritic folliculitis of pregnancy * Pruritic urticarial papules and plaques of pregnancy (PUPPP) * Striae gravidarum Nervous system * Chorea gravidarum Blood * Gestational thrombocytopenia * Pregnancy-induced hypercoagulability Maternal care related to the fetus and amniotic cavity * amniotic fluid * Oligohydramnios * Polyhydramnios * Braxton Hicks contractions * chorion / amnion * Amniotic band syndrome * Chorioamnionitis * Chorionic hematoma * Monoamniotic twins * Premature rupture of membranes * Obstetrical bleeding * Antepartum * placenta * Circumvallate placenta * Monochorionic twins * Placenta accreta * Placenta praevia * Placental abruption * Twin-to-twin transfusion syndrome Labor * Amniotic fluid embolism * Cephalopelvic disproportion * Dystocia * Shoulder dystocia * Fetal distress * Locked twins * Nuchal cord * Obstetrical bleeding * Postpartum * Pain management during childbirth * placenta * Placenta accreta * Preterm birth * Postmature birth * Umbilical cord prolapse * Uterine inversion * Uterine rupture * Vasa praevia Puerperal * Breastfeeding difficulties * Low milk supply * Cracked nipples * Breast engorgement * Childbirth-related posttraumatic stress disorder * Diastasis symphysis pubis * Postpartum bleeding * Peripartum cardiomyopathy * Postpartum depression * Postpartum psychosis * Postpartum thyroiditis * Puerperal fever * Puerperal mastitis Other * Concomitant conditions * Diabetes mellitus * Systemic lupus erythematosus * Thyroid disorders * Maternal death * Sexual activity during pregnancy * Category * 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]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-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	Acute fatty liver of pregnancy	c1455728	1,788	wikipedia	https://en.wikipedia.org/wiki/Acute_fatty_liver_of_pregnancy	2021-01-18T18:56:16	{"gard": ["9578"], "mesh": ["C537957"], "umls": ["C1455728"], "icd-9": ["646.7"], "icd-10": ["O26.6"], "orphanet": ["243367"], "wikidata": ["Q4677929"]}
A number sign (#) is used with this entry because hereditary paragangliomas-2 (PGL2) is caused by mutation in the SDHAF2 gene (613019), which encodes a protein necessary for flavination of SDHA (600857). For a phenotypic description and a discussion of genetic heterogeneity of familial paragangliomas, see PGL1 (168000). Clinical Features Van Baars (1980) and van Baars et al. (1981, 1981, 1982) reported a large Dutch family in which 26 persons had nonchromaffin paragangliomas of the head and neck. The disorder was inherited in an autosomal pattern spanning 6 generations, with increased penetrance with age. There was a fairly equal distribution of different locations in the head and neck, with the most common location at the carotid body, and a tendency toward tumor multiplicity. Mapping By linkage analysis and haplotyping of the large Dutch family reported by van Baars et al. (1981), Mariman et al. (1993) found linkage to a region on chromosome 11q14-q21 proximal to the tyrosinase locus (TYR; 606933) (maximum lod score of 5.4 at theta = 0.0 between FGF3 164950 on 11q13.3 and D11S527 on 11q13.5). The pattern of inheritance was consistent with maternal genomic imprinting. In the same family, Mariman et al. (1995) refined the putative disease locus to a 5-cM region on 11q13.1 between D11S956 and PYGM (608455). A maximum lod score of 7.62 at theta = 0.0 was obtained for D11S480. The interval did not overlap with the PGL1 locus for glomus tumors at 11q22.3-q23.3. Molecular Genetics In the large Dutch family with hereditary paragangliomas described by van Baars et al. (1982), Hao et al. (2009) found a missense mutation in the SDH5 gene on chromosome 11q13.1 encoding a change of a glycine at position 78 to an arginine (G78R; 613019.0001). This mutation was not detected in 400 unaffected control individuals. Within the family, the mutation was found to cosegregate with the disease haplotype in all 45 individuals who inherited this haplotype, and was not detected in 44 unaffected members without this haplotype. Thirty-three individuals with the mutation had developed the disease, but not 7 individuals (median age 74 years) who inherited the mutation from their mothers. This suggested an SDHD (602690)-like parent of origin-specific inheritance pattern. Only 5 individuals with a paternal mutation (median age 42 years) had not developed overt paragangliomas. Because penetrance of this disease increases with age, Hao et al. (2009) suggested that these individuals may develop tumors, or that tumors were already present but undetected. Population Genetics Hensen et al. (2012) determined the mutation frequency of 4 succinate dehydrogenase genes in a total of 1,045 patients from 340 Dutch families with paraganglioma and pheochromocytoma. Mutations were identified in 690 cases from 239 families. The most commonly affected gene in mutation carriers was SDHD (87.1%), followed by SDHAF2 (6.7%), SDHB (185470) (5.9%), and SDHC (602413) (0.3%). Almost 70% of all carriers had the founder mutation D92Y (602690.0004) in SDHD; approximately 89% of all SDH mutation carriers had 1 of 6 Dutch founder mutations. The founder G78R mutation in SDHAF2 (613019.0001) was identified in 46 cases from 4 families. The dominance of SDHD mutations was unique to the Netherlands, contrasting with the higher prevalence of SDHB mutations found elsewhere. INHERITANCE \- Autosomal dominant HEAD & NECK Ears \- Pulsatile tinnitus (tympanic paraganglioma) RESPIRATORY Larynx \- Vocal cord paralysis (caused by tumor impingement) NEUROLOGIC Central Nervous System \- Cranial nerve palsies can arise with head and neck paragangliomas VOICE \- Hoarse voice (caused by tumor impingement) \- Loss of voice NEOPLASIA \- Paragangliomas \- Multiple tumors \- Paragangliomas, head and neck \- Chemodectomas \- Carotid body tumors (most common) \- Glomus jugular tumors \- Vagal nerve tumors (glomus vagale) \- Tympanic nerve tumors (glomus tympanicum) MISCELLANEOUS \- Cells of origin are part of the diffuse neuroendocrine system (DNES) \- Adult onset (wide range of age) \- Usually asymptomatic \- See also PGL1 ( 168000 ) MOLECULAR BASIS \- Caused by mutation in the succinate dehydrogenase complex assembly factor-2 gene (SDHAF2, 613019.0001 ) ▲ 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	PARAGANGLIOMAS 2	c1866552	1,789	omim	https://www.omim.org/entry/601650	2019-09-22T16:14:28	{"doid": ["0050773"], "mesh": ["C566646"], "omim": ["601650"], "orphanet": ["29072"], "synonyms": ["GLOMUS TUMORS, FAMILIAL, 2", "Alternative titles", "Familial pheochromocytoma-paraganglioma"], "genereviews": ["NBK1548"]}
Fibrous ankylosis is a fibrous connective tissue process which results in decreased range of motion.[1] Symptoms present as bony ankylosis, in which osseous tissue fuses two bones together reducing mobility, which is why fibrous ankylosis is also known as false ankylosis. Pathology may be the result of trauma, disease, chronic inflammation, or surgery. Some research suggests fibrous ankylosis may precede the development of bony ankylosis.[2] ## Notes[edit] 1. ^ Chabner, Davi-Ellen. (2007). The Language of Medicine (8th ed.). Saunders Elsevier, St. Louis, MO, USA. 2. ^ Ikeno, Hidenori; Matsumura, Hirofumi; Murakami, Gen; Sato, Toshio J.; Ohta, Makoto (March 2006). "Which morphology of dry bone articular surfaces suggests so-called fibrous ankylosis in the elderly human sacroiliac joint?". Anatomical Science International. 81 (1): 39–46. doi:10.1111/j.1447-073X.2006.00126.x. PMID 16526595. This article about a disease, disorder, or medical condition 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	Fibrous ankylosis	c0332791	1,790	wikipedia	https://en.wikipedia.org/wiki/Fibrous_ankylosis	2021-01-18T18:56:17	{"umls": ["C0332791"], "icd-9": ["718.5"], "wikidata": ["Q5446480"]}
Congenital partial agenesis of pericardium is a rare, mostly asymptomatic, congenital heart malformation mainly characterized by the partial absence of the left pericardium. It is occasionally associated with chest pain or dyspnea and is usually incidentally diagnosed during surgery or at autopsy. Herniation and strangulation of a portion of the heart through the pericardial foramen may occur, resulting in myocardial acute ischemia and possible sudden death. Right side pericardium involvement is rare. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors	Congenital partial agenesis of pericardium	None	1,791	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=99130	2021-01-23T17:01:39	{"icd-10": ["Q24.8"]}
Kamijo et al. (1997) concluded that deficiency of mitochondrial medium chain 3-ketoacyl-coenzyme A thiolase was responsible for the disorder of mitochondrial fatty acid beta-oxidation in a Japanese male neonate who died at 13 days of age. The patient presented at 2 days of age with vomiting, dehydration, metabolic acidosis, liver dysfunction, and terminal rhabdomyolysis with myoglobinuria. A systematic study of the catalytic activities of 9 enzymes of the beta-oxidation cycle using the respective optimal substrates revealed deficiency of a single enzyme not previously associated with a metabolic disorder. Immunoprecipitation with antibodies raised against medium chain 3-ketoacyl-CoA thiolase revealed a 60% decrease compared with controls. Inheritance \- Autosomal recessive Metabolic \- Dehydration \- Metabolic acidosis Misc \- Neonatal death Lab \- Mitochondrial medium chain 3-ketoacyl-coenzyme A thiolase deficiency \- Myoglobinuria Muscle \- Rhabdomyolysis GI \- Vomiting \- Liver dysfunction ▲ 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	MEDIUM CHAIN 3-KETOACYL-CoA THIOLASE DEFICIENCY	c1865781	1,792	omim	https://www.omim.org/entry/602199	2019-09-22T16:13:53	{"mesh": ["C566566"], "omim": ["602199"], "synonyms": ["Alternative titles", "MCKAT DEFICIENCY"]}
A number sign (#) is used with this entry because of evidence that long QT syndrome-14 (LQT14) is caused by heterozygous mutation in the CALM1 gene (114180) on chromosome 14q32. For a general phenotypic description and discussion of genetic heterogeneity of long QT syndrome, see LQT1 (192500). Clinical Features Crotti et al. (2013) reported an Italian girl who underwent cardiac arrest due to ventricular fibrillation (VF) at age 6 months. Electrocardiogram (ECG) after defibrillation showed a markedly prolonged QTc interval (630 ms), frequent episodes of T-wave alternans, and intermittent 2:1 atrioventricular block. Echocardiogram showed normal cardiac anatomy and contractile function. An internal cardioverter-defibrillator (ICD) was placed, and multiple episodes of VF were terminated by the ICD in the following months. Despite treatment with various medications as well as left-cardiac sympathetic denervation at age 1 year, the patient had 16 episodes of VF during the first 2 years of life: these were mostly induced by adrenergic stimulation, and either began abruptly or were preceded by a brief episode of torsade de pointes that was not pause-dependent. Her parents were asymptomatic with normal ECGs, and there was no history of sudden death in the family. Marsman et al. (2014) studied a Moroccan family with 5 sibs in which the proband experienced cardiac arrest at age 16 years while romping with a classmate at school; an initial recorded rhythm of VF was converted to a sinus rhythm after 2 defibrillatory shocks. Evaluation revealed no structural or functional cardiac abnormalities, ECG showed a normal QTc interval at rest, and flecainide provocation did not uncover a Brugada ECG pattern. On exercise testing, however, mild prolongation of the QTc interval was revealed (459 ms), which was maximal during early recovery (464 ms). An ICD was placed, and in 12 years of follow-up, the proband did not report any syncopal episodes, nor did the ICD record any events involving ventricular tachycardia. Just 7 months following the index event of the proband, his younger sister died suddenly at age 10 years. The family history also included a sister who had died suddenly at age 9 years. Another sister collapsed on the playground at age 10 years and was successfully resuscitated from VF; during the 8-year period following ICD implantation, she experienced 3 episodes of VF that were terminated by ICD shocks. Exercise testing revealed prolongation of the QTc interval in both early and late recovery (474 and 464 ms, respectively). The youngest sister in the family was asymptomatic but also demonstrated prolonged QTc interval on exercise testing. She underwent implantation of an ICD at 7 years of age, and the device did not discharge in 3 years of follow-up. Both parents were asymptomatic with normal ECGs at rest; however, the mother had prolonged QTc intervals (476 ms) at high heart rates. Marsman et al. (2014) stated that although none of the family members met the diagnostic criteria for long QT syndrome, ECG recordings were not available for a large number of mutation carriers in the family, and it was thus 'difficult to rule out LQTS with certainty.' Molecular Genetics In an Italian girl with markedly prolonged QTc intervals and multiple episodes of ventricular fibrillation, who was negative for mutation in the 5 genes most frequently associated with long QT syndrome, Crotti et al. (2013) performed exome sequencing and identified a heterozygous de novo missense mutation in the CALM1 gene (D130G; 114180.0003). Analysis of CALM1 in 82 additional patients with LQTS who had no mutations in known LQTS genes revealed a 3-year-old Greek boy who also carried the D130G mutation, as well as a 14-year-old Italian boy with a phe142-to-leu mutation in CALM1 (F142L; 114180.0004). Neither mutation was found in 1,800 white European controls or in public databases, and functional analysis demonstrated a several-fold reduction in calcium-binding affinity for both variants compared to wildtype calmodulin. In a Moroccan family with mild prolongation of the QTc interval in the recovery phase after exercise as well as onset of ventricular fibrillation within the first 2 decades of life, Marsman et al. (2014) performed whole-exome sequencing and identified a heterozygous mutation in the CALM1 gene (F90L; 114180.0005) that segregated with disease in the family. The mutation was not found in 500 Moroccan controls, and the proband was negative for mutation in 14 genes known to be involved in primary arrhythmia syndromes and arrhythmogenic cardiomyopathy. INHERITANCE \- Autosomal dominant CARDIOVASCULAR Heart \- Recurrent episodes of ventricular fibrillation \- Ventricular tachycardia, nonsustained (in some patients) \- Syncopal episodes (in some patients) \- Cardiac arrest (in some patients) \- Sudden death (in some patients) \- Prolonged QTc interval on electrocardiogram (ECG) \- T-wave alternans on ECG (in some patients) \- Atrioventricular block, 2:1, on ECG (in some patients) \- Torsade de pointes on ECG (in some patients) MISCELLANEOUS \- Some patients have onset at birth or in early infancy, whereas other have onset in late childhood or adolescence \- Some patients experience neurologic sequelae (seizures or developmental delay) after multiple episodes of cardiac arrest \- In some patients, QTc interval is prolonged only during exercise testing MOLECULAR BASIS \- Caused by mutation in the calmodulin-1 gene (CALM1, 114180.0003 ) ▲ 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	LONG QT SYNDROME 14	c1141890	1,793	omim	https://www.omim.org/entry/616247	2019-09-22T15:49:29	{"doid": ["0110655"], "omim": ["616247"], "orphanet": ["768", "101016"], "genereviews": ["NBK1129"]}
This article is about genetic disorders associated with the SMN1 gene. For a list of conditions with similar names, see Spinal muscular atrophies. Rare congenital neuromuscular disorder Spinal muscular atrophy Other namesAutosomal recessive proximal spinal muscular atrophy, 5q spinal muscular atrophy Location of neurons affected by spinal muscular atrophy in the spinal cord SpecialtyNeurology SymptomsProgressive muscle weakness[1] ComplicationsScoliosis, joint contractures, pneumonia[2] TypesType 0 to type 4[2] CausesMutation in SMN1[2] Diagnostic methodGenetic testing[1] Differential diagnosisCongenital muscular dystrophy, Duchenne muscular dystrophy, Prader-Willi syndrome[2] TreatmentSupportive care, medications[1] MedicationNusinersen, onasemnogene abeparvovec, Risdiplam PrognosisVaries by type[2] Frequency1 in 10,000 people[2] Spinal muscular atrophy (SMA) is a rare neuromuscular disorder that results in the loss of motor neurons and progressive muscle wasting.[3][4][5] It is usually diagnosed in infancy or early childhood and if left untreated it is the most common genetic cause of infant death.[6] It may also appear later in life and then have a milder course of the disease. The common feature is progressive weakness of voluntary muscles, with arm, leg and respiratory muscles being affected first.[7][8] Associated problems may include poor head control, difficulties swallowing, scoliosis, and joint contractures.[9][8] The age of onset and the severity of symptoms form the basis of the traditional classification of spinal muscular atrophy into a number of types.[4] Spinal muscular atrophy is due to an abnormality (mutation) in the SMN1 gene[10][9] which encodes SMN, a protein necessary for survival of motor neurons.[8] Loss of these neurons in the spinal cord prevents signalling between the brain and skeletal muscles.[8] Another gene, SMN2, is considered a disease modifying gene, since usually the more the SMN2 copies, the milder is the disease course. The diagnosis of SMA is based on symptoms and confirmed by genetic testing.[11][1] Usually, the mutation in the SMN1 gene is inherited from both parents in an autosomal recessive manner, although in around 2% of cases it occurs during early development (de novo).[10][12] The incidence of spinal muscular atrophy worldwide varies from about 1 in 4,000 births to around 1 in 16,000 births,[13] with 1 in 7,000 and 1 in 10,000 commonly quoted for Europe and the US respectively.[2] Outcomes in the natural course of the disease vary from a few months in most severe cases to normal life expectancy in milder SMA forms.[8] The introduction of causative treatments in 2016 has significantly improved the outcomes. Medications that target the genetic cause of the disease include nusinersen, risdiplam, and gene therapy medication onasemnogene abeparvovec. Supportive care includes physical therapy, occupational therapy, respiratory support, nutritional support, orthopaedic interventions, and mobility support.[10] ## Contents * 1 Classification * 2 Signs and symptoms * 3 Causes * 4 Diagnosis * 4.1 Preimplantation testing * 4.2 Prenatal testing * 4.3 Carrier testing * 4.4 Newborn screening * 5 Management * 5.1 Medication * 5.2 Breathing * 5.3 Nutrition * 5.4 Orthopaedics * 5.5 Other * 6 Prognosis * 7 Research directions * 7.1 SMN1 gene replacement * 7.2 SMN2 alternative splicing modulation * 7.3 SMN2 gene activation * 7.4 SMN stabilisation * 7.5 Neuroprotection * 7.6 Muscle restoration * 7.7 Stem cells * 7.8 Registries * 8 See also * 9 References * 10 Further reading * 11 External links ## Classification[edit] SMA manifests over a wide range of severity, affecting infants through adults. The disease spectrum has been divided into 3–5 types in accordance with the highest attained milestone in motor development. The traditional, most commonly used classification is as follows: Type Eponym Usual age of onset Characteristics OMIM SMA 0 Prenatal A very rare form whose symptoms become apparent before birth (reduced foetal movement). Affected children typically have only 1 copy of the SMN2 gene and usually survive only a few weeks even with intensive respiratory support. SMA 1 (Infantile) Werdnig–Hoffmann disease 0–6 months The severe form manifests in the first months of life, usually with a quick and unexpected onset ("floppy baby syndrome"). Children never learn to sit unsupported. Rapid motor neuron death causes inefficiency of the major bodily organs – especially of the respiratory system. Pneumonia-induced respiratory failure is the most frequent cause of death. Untreated and without respiratory support, babies diagnosed with SMA type 1 do not generally survive past two years of age. With proper respiratory support, those with milder SMA type 1 phenotypes, which account for around 10% of SMA 1 cases, are known to survive into adolescence and adulthood. 253300 SMA 2 (Intermediate) Dubowitz disease 6–18 months The intermediate form affects people who were able to maintain a sitting position at least some time in their life but never learned to walk unsupported. The onset of weakness is usually noticed some time between 6 and 18 months of life. The progress is known to vary greatly, some people gradually grow weaker over time while others through careful maintenance remain relatively stable. Body muscles are weakened, and the respiratory system is a major concern. Life expectancy is reduced but most people with SMA 2 live well into adulthood. 253550 SMA 3 (Juvenile) Kugelberg–Welander disease >12 months The juvenile form usually manifests after 12 months of age and describes people who have been able to walk without support at least for some time in their lives, even if they later lost this ability. Respiratory involvement is less frequent, and life expectancy is normal or near normal. Most people with SMA 3 require mobility support. 253400 SMA 4 (Adult onset) Adulthood The adult-onset form (sometimes classified as a late-onset SMA type 3) usually manifests after the third decade of life with gradual weakening of leg muscles, frequently requiring the person to use walking aids. Other complications are rare and life expectancy is unaffected. 271150 Newer classifications classify patients into "non-sitters", "sitters" and "walkers" based on their actual functional status. Motor development and disease progression in people with SMA is usually assessed using validated functional scales – CHOP-INTEND (The Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders) or HINE (Hammersmith Infant Neurological Examination) in infants; and either the MFM (Motor Function Measure) or one of a few variants of the HFMS (Hammersmith Functional Motor Scale)[14][15][16][17] in older patients. The eponymous label Werdnig–Hoffmann disease (sometimes misspelled with a single n) refers to the earliest clinical descriptions of childhood SMA by Johann Hoffmann and Guido Werdnig. The eponymous term Kugelberg–Welander disease is after Erik Klas Hendrik Kugelberg (1913–1983) and Lisa Welander (1909–2001), who distinguished SMA from muscular dystrophy.[18] Rarely used Dubowitz disease (not to be confused with Dubowitz syndrome) is named after Victor Dubowitz, an English neurologist who authored several studies on the intermediate SMA phenotype.[citation needed] ## Signs and symptoms[edit] X-ray showing bell-shaped torso due to atrophy of intercostal muscles and using abdominal muscles to breathe. Bell-shaped torso is not specific to individuals with SMA The symptoms vary depending on the SMA type, the stage of the disease as well as individual factors. Signs and symptoms below are most common in the severe SMA type 0/I:[19][medical citation needed] * Areflexia, particularly in extremities * Overall muscle weakness, poor muscle tone, limpness or a tendency to flop * Difficulty achieving developmental milestones, difficulty sitting/standing/walking * In small children: adopting of a frog-leg position when sitting (hips abducted and knees flexed) * Loss of strength of the respiratory muscles: weak cough, weak cry (infants), accumulation of secretions in the lungs or throat, respiratory distress * Bell-shaped torso (caused by using only abdominal muscles for respiration) in severe SMA type * Fasciculations (twitching) of the tongue * Difficulty sucking or swallowing, poor feeding ## Causes[edit] Spinal muscular atrophy has an autosomal recessive pattern of inheritance. Spinal muscular atrophy is linked to a genetic mutation in the SMN1 gene.[20] Human chromosome 5 contains two nearly identical genes at location 5q13: a telomeric copy SMN1 and a centromeric copy SMN2. In healthy individuals, the SMN1 gene codes the survival of motor neuron protein (SMN) which, as its name says, plays a crucial role in survival of motor neurons. The SMN2 gene, on the other hand – due to a variation in a single nucleotide (840.C→T) – undergoes alternative splicing at the junction of intron 6 to exon 8, with only 10–20% of SMN2 transcripts coding a fully functional survival of motor neuron protein (SMN-fl) and 80–90% of transcripts resulting in a truncated protein compound (SMNΔ7) which is rapidly degraded in the cell.[21] In individuals affected by SMA, the SMN1 gene is mutated in such a way that it is unable to correctly code the SMN protein – due to either a deletion[22] occurring at exon 7[23] or to other point mutations (frequently resulting in the functional conversion of the SMN1 sequence into SMN2). Almost all people, however, have at least one functional copy of the SMN2 gene (with most having 2–4 of them) which still codes small amounts of SMN protein – around 10–20% of the normal level – allowing some neurons to survive. In the long run, however, reduced availability of the SMN protein results in gradual death of motor neuron cells in the anterior horn of spinal cord and the brain. Muscles that depend on these motor neurons for neural input now have decreased innervation (also called denervation), and therefore have decreased input from the central nervous system (CNS). Decreased impulse transmission through the motor neurons leads to decreased contractile activity of the denervated muscle. Consequently, denervated muscles undergo progressive atrophy (waste away).[citation needed] Muscles of lower extremities are usually affected first, followed by muscles of upper extremities, spine and neck and, in more severe cases, pulmonary and mastication muscles. Proximal muscles are always affected earlier and to a greater degree than distal.[24][citation needed] The severity of SMA symptoms is broadly related to how well the remaining SMN2 genes can make up for the loss of function of SMN1. This is partly related to the number of SMN2 gene copies present on the chromosome. Whilst healthy individuals carry two SMN2 gene copies, people with SMA can have anything between 1 and 4 (or more) of them, with the greater the number of SMN2 copies, the milder the disease severity. Thus, most SMA type I babies have one or two SMN2 copies; people with SMA II and III usually have at least three SMN2 copies; and people with SMA IV normally have at least four of them. However, the correlation between symptom severity and SMN2 copy number is not absolute, and there seem to exist other factors affecting the disease phenotype.[25] Spinal muscular atrophy is inherited in an autosomal recessive pattern, which means that the defective gene is located on an autosome. Two copies of the defective gene – one from each parent – are required to inherit the disorder: the parents may be carriers and not personally affected. SMA seems to appear de novo (i.e., without any hereditary causes) in around 2–4% of cases. Spinal muscular atrophy affects individuals of all ethnic groups, unlike other well known autosomal recessive disorders, such as sickle cell disease and cystic fibrosis, which have significant differences in occurrence rate among ethnic groups. The overall prevalence of SMA, of all types and across all ethnic groups, is in the range of 1 per 10,000 individuals; the gene frequency is around 1:100, therefore, approximately one in 50 persons are carriers.[26][27] There are no known health consequences of being a carrier. A person may learn carrier status only if one's child is affected by SMA or by having the SMN1 gene sequenced. Affected siblings usually have a very similar form of SMA. However, occurrences of different SMA types among siblings do exist – while rare, these cases might be due to additional de novo deletions of the SMN gene, not involving the NAIP gene, or the differences in SMN2 copy numbers.[citation needed] ## Diagnosis[edit] The most severe manifestation on the SMA spectrum can be noticeable to mothers late in their pregnancy by reduced or absent fetal movements. Symptoms are critical (including respiratory distress and poor feeding) which usually result in death within weeks, in contrast to the mildest phenotype of SMA (adult-onset), where muscle weakness may present after decades and progress to the use of a wheelchair but life expectancy is unchanged.[28] The more common clinical manifestations of the SMA spectrum that prompt diagnostic genetic testing: * Progressive bilateral muscle weakness (Usually upper arms & legs more so than hands and feet) preceded by an asymptomatic period (all but most severe type 0)[28] * Flattening of the chest wall when taking a breath and belly protrusion when taking a breath in. * hypotonia associated with absent reflexes. While the above symptoms point towards SMA, the diagnosis can only be confirmed with absolute certainty through genetic testing for bi-allelic deletion of exon 7 of the SMN1 gene which is the cause in over 95% of cases.[19] Genetic testing is usually carried out using a blood sample, and MLPA is one of more frequently used genetic testing techniques, as it also allows establishing the number of SMN2 gene copies.[19] ### Preimplantation testing[edit] Preimplantation genetic diagnosis can be used to screen for SMA-affected embryos during in-vitro fertilisation. ### Prenatal testing[edit] Prenatal testing for SMA is possible through chorionic villus sampling, cell-free fetal DNA analysis and other methods. ### Carrier testing[edit] Those at risk of being carriers of SMN1 deletion, and thus at risk of having offspring affected by SMA, can undergo carrier analysis using a blood or saliva sample. The American College of Obstetricians and Gynecologists recommends all people thinking of becoming pregnant be tested to see if they are a carrier.[29] The carrier frequency of SMA is comparable to other disorders like thalassemia and in a north Indian cohort has been found to be 1 in 38. [30] However, genetic testing will not be able to identify all individuals at risk since about 2% of cases are caused by de novo mutations and 5% of the normal populations have two copies of SMN1 on the same chromosome, which makes it possible to be a carrier by having one chromosome with two copies and a second chromosome with zero copies. This situation will lead to a false negative result, as the carrier status will not be correctly detected by a traditional genetic test.[31] [32] ### Newborn screening[edit] Given the availability of treatments that appear most effective in early stages of the disease, a number of experts have recommended to routinely test all newborn children for SMA.[33][34][35] In 2018, newborn screening for SMA was added to the US list of recommended newborn screening tests[36][37][38] and as of May 2020 it has been adopted in 33 US states.[39] Since 2020, SMA newborn screening is mandated in the Netherlands.[40] Additionally, pilot projects in newborn screening for SMA have been conducted in Australia,[41] Belgium,[42] China,[43] Germany,[44] Italy, Japan,[45] Taiwan,[46] and the US.[47] ## Management[edit] The management of SMA varies based upon the severity and type. In the most severe forms (types 0/1), individuals have the greatest muscle weakness requiring prompt intervention. Whereas the least severe form (type 4/adult onset), individuals may not seek the certain aspects of care until later (decades) in life. While types of SMA and individuals among each type may differ, therefore specific aspects of an individual's care can differ.[medical citation needed] ### Medication[edit] Nusinersen (Spinraza) is used to treat spinal muscular atrophy.[48] It is an antisense nucleotide that modifies the alternative splicing of the SMN2 gene.[48] It is given directly to the central nervous system using an intrathecal injection.[48][49] Nusinersen prolongs survival and improves motor function in infants with SMA.[50] [51] It was approved for use in the US in 2016, and for use in the EU in 2017.[52][53][54] Onasemnogene abeparvovec (Zolgensma) is a gene therapy treatment which uses self-complementary adeno-associated virus type 9 (scAAV-9) as a vector to deliver the SMN1 transgene.[55][56] The therapy was approved in the US in 2019, as an intravenous formulation for children below 24 months of age.[57][58] Approval in Europe and Japan was granted the following year.[59][60] Risdiplam (Evrysdi) is a medication taken by mouth in liquid form.[61][62] It is a pyridazine derivative that works by increasing the amount of functional survivor motor neuron protein produced by the SMN2 gene through modifying its splicing pattern.[63][64] Risdiplam was approved for medical use in the United States in August 2020.[61] ### Breathing[edit] The respiratory system is the most common system to be affected and the complications are the leading cause of death in SMA types 0/1 and 2. SMA type 3 can have similar respiratory problems, but it is more rare.[24] The complications that arise due to weakened intercostal muscles because of the lack of stimulation from the nerve. The diaphragm is less affected than the intercostal muscles.[24] Once weakened, the muscles never fully recover the same functional capacity to help in breathing and coughing as well as other functions. Therefore, breathing is more difficult and pose a risk of not getting enough oxygen/shallow breathing and insufficient clearance of airway secretions. These issues more commonly occurs while asleep, when muscles are more relaxed. Swallowing muscles in the pharynx can be affected, leading to aspiration coupled with a poor coughing mechanism increases the likelihood of infection/pneumonia.[65] Mobilizing and clearing secretions involve manual or mechanical chest physiotherapy with postural drainage, and manual or mechanical cough assistance device. To assist in breathing, Non-invasive ventilation (BiPAP) is frequently used and tracheostomy may be sometimes performed in more severe cases;[66] both methods of ventilation prolong survival to a comparable degree, although tracheostomy prevents speech development.[67] ### Nutrition[edit] The more severe the type of SMA, the more likely to have nutrition related health issues. Health issues can include difficulty in feeding, jaw opening, chewing and swallowing. Individuals with such difficulties can be at increase risk of over or undernutrition, failure to thrive and aspiration. Other nutritional issues, especially in individuals that are non-ambulatory (more severe types of SMA), include food not passing through the stomach quickly enough, gastric reflux, constipation, vomiting and bloating.[68][medical citation needed] Therein, it could be necessary in SMA type I and people with more severe type II to have a feeding tube or gastrostomy.[68][69][70] Additionally, metabolic abnormalities resulting from SMA impair β-oxidation of fatty acids in muscles and can lead to organic acidemia and consequent muscle damage, especially when fasting.[71][72] It is suggested that people with SMA, especially those with more severe forms of the disease, reduce intake of fat and avoid prolonged fasting (i.e., eat more frequently than healthy people)[73] as well as choosing softer foods to avoid aspiration.[65] During an acute illness, especially in children, nutritional problems may first present or can exacerbate an existing problem (example: aspiration) as well as cause other health issues such as electrolyte and blood sugar disturbances.[74][medical citation needed] ### Orthopaedics[edit] Skeletal problems associated with weak muscles in SMA include tight joints with limited range of movement, hip dislocations, spinal deformity, osteopenia, an increase risk of fractures and pain.[24] Weak muscles that normally stabilize joints such as the vertebral column lead to development of kyphosis and/or scoliosis and joint contracture.[24] Spine fusion is sometimes performed in people with SMA I/II once they reach the age of 8–10 to relieve the pressure of a deformed spine on the lungs. Furthermore, immobile individuals, posture and position on mobility devices as well as range of motion exercises, and bone strengthening can be important to prevent complications.[74] People with SMA might also benefit greatly from various forms of physiotherapy, occupational therapy and physical therapy. Orthotic devices can be used to support the body and to aid walking. For example, orthotics such as AFOs (ankle foot orthoses) are used to stabilise the foot and to aid gait, TLSOs (thoracic lumbar sacral orthoses) are used to stabilise the torso. Assistive technologies may help in managing movement and daily activity and greatly increase the quality of life. ### Other[edit] Although the heart is not a matter of routine concern, a link between SMA and certain heart conditions has been suggested.[75][76][77][78] Children with SMA do not differ from the general population in their behaviour; their cognitive development can be slightly faster, and certain aspects of their intelligence are above the average.[79][80][81] Despite their disability, SMA-affected people report high degree of satisfaction from life.[82] Palliative care in SMA has been standardised in the Consensus Statement for Standard of Care in Spinal Muscular Atrophy[24] which has been recommended for standard adoption worldwide. ## Prognosis[edit] In lack of pharmacological treatment, people with SMA tend to deteriorate over time. Recently, survival has increased in severe SMA patients with aggressive and proactive supportive respiratory and nutritional support.[83] If left untreated, the majority of children diagnosed with SMA type 0 and I do not reach the age of 4, recurrent respiratory problems being the primary cause of death.[84] With proper care, milder SMA type I cases (which account for approx. 10% of all SMA1 cases) live into adulthood.[85] Long-term survival in SMA type I is not sufficiently evidenced; however, recent advances in respiratory support seem to have brought down mortality.[86] In untreated SMA type II, the course of the disease is slower to progress and life expectancy is less than the healthy population. Death before the age of 20 is frequent, although many people with SMA live to become parents and grandparents. SMA type III has normal or near-normal life expectancy if standards of care are followed. Type IV, adult-onset SMA usually means only mobility impairment and does not affect life expectancy. ## Research directions[edit] Since the underlying genetic cause of SMA was identified in 1995,[22] several therapeutic approaches have been proposed and investigated that primarily focus on increasing the availability of SMN protein in motor neurons.[87] The main research directions are as follows: ### SMN1 gene replacement[edit] Gene therapy in SMA aims at restoring the SMN1 gene function through inserting specially crafted nucleotide sequence (a SMN1 transgene) into the cell nucleus using a viral vector; scAAV-9 and scAAV-10 are the primary viral vectors under investigation. In 2019 an AAV9 therapy was approved: Onasemnogene abeparvovec.[88] Only one programme has reached the clinical stage. Work on developing gene therapy for SMA is also conducted at the Institut de Myologie in Paris[89] and at the University of Oxford. In 2018, also Biogen announced working on a gene therapy product to treat SMA.[90] ### SMN2 alternative splicing modulation[edit] This approach aims at modifying the alternative splicing of the SMN2 gene to force it to code for higher percentage of full-length SMN protein. Sometimes it is also called gene conversion, because it attempts to convert the SMN2 gene functionally into SMN1 gene. It is the therapeutic mechanism of the approved medications nusinersen and risdiplam. An additional splicing modulator has reached the clinical stage of development, namely branaplam (LMI070, NVS-SM1), a proprietary small-molecule experimental drug administered orally and being developed by Novartis. As of October 2017[update] the compound remains in phase-II clinical trial in infants with SMA type 1 while trials in other patient categories are under development.[91] Of discontinued clinical-stage molecules, RG3039, also known as Quinazoline495, was a proprietary quinazoline derivative developed by Repligen and licensed to Pfizer in March 2014 which was discontinued shortly after, having only completed phase I trials. PTK-SMA1 was a proprietary small-molecule splicing modulator of the tetracyclines group developed by Paratek Pharmaceuticals and about to enter clinical development in 2010 which however never happened. RG7800 is a molecule akin to RG7916, developed by Hoffmann-La Roche, which has undergone phase I testing.[92] Basic research has also identified other compounds which modified SMN2 splicing in vitro, like sodium orthovanadate[93] and aclarubicin.[94] Morpholino-type antisense oligonucleotides, with the same cellular target as nusinersen, remain a subject of intense research, including at the University College London[95] and at the University of Oxford.[96] ### SMN2 gene activation[edit] This approach aims at increasing expression (activity) of the SMN2 gene, thus increasing the amount of full-length SMN protein available. * Oral salbutamol (albuterol), a popular asthma medicine, showed therapeutic potential in SMA both in vitro[97] and in three small-scale clinical trials involving patients with SMA types 2 and 3,[98][99][100] besides offering respiratory benefits. A few compounds initially showed promise but failed to demonstrate efficacy in clinical trials: * Butyrates (sodium butyrate and sodium phenylbutyrate) held some promise in in vitro studies[101][102][103] but a clinical trial in symptomatic people did not confirm their efficacy.[104] Another clinical trial in pre-symptomatic types 1–2 infants was completed in 2015 but no results have been published.[105] * Valproic acid (VPA) was used in SMA on an experimental basis in the 1990s and 2000s because in vitro research suggested its moderate effectiveness.[106][107] However, it demonstrated no efficacy in achievable concentrations when subjected to a large clinical trial.[108][109][110] It has also been proposed that it may be effective in a subset of people with SMA but its action may be suppressed by fatty acid translocase in others.[111] Others argue it may actually aggravate SMA symptoms.[112] It is currently not used due to the risk of severe side effects related to long-term use. A 2019 meta-analysis suggested that VPA may offer benefits, even without improving functional score.[113] * Hydroxycarbamide (hydroxyurea) was shown effective in mouse models[114] and subsequently commercially researched by Novo Nordisk, Denmark, but demonstrated no effect on people with SMA in subsequent clinical trials.[115] Compounds which increased SMN2 activity in vitro but did not make it to the clinical stage include growth hormone, various histone deacetylase inhibitors,[116] benzamide M344,[117] hydroxamic acids (CBHA, SBHA, entinostat, panobinostat,[118] trichostatin A,[119][120] vorinostat[121]), prolactin[122] as well as natural polyphenol compounds like resveratrol and curcumin.[123][124] Celecoxib, a p38 pathway activator, is sometimes used off-label by people with SMA based on a single animal study[125] but such use is not backed by clinical-stage research. ### SMN stabilisation[edit] SMN stabilisation aims at stabilising the SMNΔ7 protein, the short-lived defective protein coded by the SMN2 gene, so that it is able to sustain neuronal cells.[126] No compounds have been taken forward to the clinical stage. Aminoglycosides showed capability to increase SMN protein availability in two studies.[127][128] Indoprofen offered some promise in vitro.[129] ### Neuroprotection[edit] Neuroprotective drugs aim at enabling the survival of motor neurons even with low levels of SMN protein. * Olesoxime is a proprietary neuroprotective compound developed by the French company Trophos, later acquired by Hoffmann-La Roche, which showed stabilising effect in a phase-II clinical trial involving people with SMA types 2 and 3. Its development was discontinued in 2018 in view of competition with Spinraza and worse than expected data coming from an open-label extension trial.[130] Of clinically studied compounds which did not show efficacy, thyrotropin-releasing hormone (TRH) held some promise in an open-label uncontrolled clinical trial[131][132][133] but did not prove effective in a subsequent double-blind placebo-controlled trial.[134] Riluzole, a drug that has mild clinical benefit in amyotrophic lateral sclerosis, was proposed to be similarly tested in SMA,[135][136] however a 2008–2010 trial in SMA types 2 and 3[137] was stopped early due to lack of satisfactory results.[138] Compounds that had some neuroprotective effect in in vitro research but never moved to in vivo studies include β-lactam antibiotics (e.g., ceftriaxone)[139][140] and follistatin.[141] ### Muscle restoration[edit] This approach aims to counter the effect of SMA by targeting the muscle tissue instead of neurons. * CK-2127107 (CK-107) is a skeletal troponin activator developed by Cytokinetics in cooperation with Astellas. The drug aims at increasing muscle reactivity despite lowered neural signalling. As of October 2016[update], the molecule is in a phase II clinical trial in adolescent and adults with SMA types 2, 3, and 4.[142] ### Stem cells[edit] In 2013–2014, a small number of SMA1 children in Italy received court-mandated stem cell injections following the Stamina scam, but the treatment was reported having no effect.[143][144] Whilst stem cells never form a part of any recognised therapy for SMA, a number of private companies, usually located in countries with lax regulatory oversight, take advantage of media hype and market stem cell injections as a "cure" for a vast range of disorders, including SMA. The medical consensus is that such procedures offer no clinical benefit whilst carrying significant risk, therefore people with SMA are advised against them.[145][146] ### Registries[edit] People with SMA in the European Union can participate in clinical research by entering their details into registries managed by TREAT-NMD.[147] ## See also[edit] * Motor neuron disease ## References[edit] 1. ^ a b c d "Spinal muscular atrophy". Genetic and Rare Diseases Information Center (GARD) – an NCATS Program. Retrieved 27 May 2019. 2. ^ a b c d e f g "Spinal Muscular Atrophy". NORD (National Organization for Rare Disorders). Retrieved 27 May 2019. 3. ^ "Spinal muscular atrophy". nhs.uk. 23 October 2017. Retrieved 24 October 2020. 4. ^ a b "Spinal muscular atrophy: MedlinePlus Genetics". medlineplus.gov. Retrieved 24 October 2020. 5. ^ "Spinal Muscular Atrophy (SMA) \| Boston Children's Hospital". www.childrenshospital.org. 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AFM Téléthon. 22 September 2010. 139. ^ Nizzardo M, Nardini M, Ronchi D, Salani S, Donadoni C, Fortunato F, Colciago G, Falcone M, Simone C, Riboldi G, Govoni A, Bresolin N, Comi GP, Corti S (June 2011). "Beta-lactam antibiotic offers neuroprotection in a spinal muscular atrophy model by multiple mechanisms" (PDF). Experimental Neurology. 229 (2): 214–25. doi:10.1016/j.expneurol.2011.01.017. hdl:2434/425410. PMID 21295027. S2CID 47567316. 140. ^ Hedlund E (September 2011). "The protective effects of β-lactam antibiotics in motor neuron disorders". Experimental Neurology. 231 (1): 14–8. doi:10.1016/j.expneurol.2011.06.002. PMID 21693120. S2CID 26353910. 141. ^ Rose FF, Mattis VB, Rindt H, Lorson CL (March 2009). "Delivery of recombinant follistatin lessens disease severity in a mouse model of spinal muscular atrophy". Human Molecular Genetics. 18 (6): 997–1005. doi:10.1093/hmg/ddn426. PMC 2649020. PMID 19074460. 142. ^ "CK-2127107". 143. ^ Carrozzi M, Amaddeo A, Biondi A, Zanus C, Monti F, Alessandro V (November 2012). "Stem cells in severe infantile spinal muscular atrophy (SMA1)". Neuromuscular Disorders. 22 (11): 1032–4. doi:10.1016/j.nmd.2012.09.005. PMID 23046997. S2CID 42093152. 144. ^ Mercuri E, Bertini E (December 2012). "Stem cells in severe infantile spinal muscular atrophy". Neuromuscular Disorders. 22 (12): 1105. doi:10.1016/j.nmd.2012.11.001. PMID 23206850. S2CID 43858783. 145. ^ Committee for Advanced Therapies and CAT Scientific Secretariat (August 2010). "Use of unregulated stem-cell based medicinal products". Lancet. 376 (9740): 514. doi:10.1016/S0140-6736(10)61249-4. PMID 20709228. S2CID 6906599. 146. ^ European Medicines Agency (16 April 2010). "Concerns over unregulated medicinal products containing stem cells" (PDF). European Medicines Agency. 147. ^ "National registries for DMD, SMA and DM". Archived from the original on 22 January 2011. ## Further reading[edit] * Parano E, Pavone L, Falsaperla R, Trifiletti R, Wang C (August 1996). "Molecular basis of phenotypic heterogeneity in siblings with spinal muscular atrophy". Annals of Neurology. 40 (2): 247–51. doi:10.1002/ana.410400219. PMID 8773609. * Wang CH, Finkel RS, Bertini ES, Schroth M, Simonds A, Wong B, Aloysius A, Morrison L, Main M, Crawford TO, Trela A (August 2007). "Consensus statement for standard of care in spinal muscular atrophy". Journal of Child Neurology. 22 (8): 1027–49. doi:10.1177/0883073807305788. PMID 17761659. S2CID 6478040. ## External links[edit] Classification D * ICD-10: G12.0-G12.1 * ICD-9-CM: 335.0-335.1 * OMIM: 253300 253550 253400 271150 * MeSH: D014897 * DiseasesDB: 14093 External resources * MedlinePlus: 000996 * Patient UK: Spinal muscular atrophy * GeneReviews: Spinal Muscular Atrophy * Spinal muscular atrophy at Curlie * SMA at NINDS * v * t * e Diseases of the nervous system, primarily CNS Inflammation Brain * Encephalitis * Viral encephalitis * Herpesviral encephalitis * Limbic encephalitis * Encephalitis lethargica * Cavernous sinus thrombosis * Brain abscess * Amoebic Brain and spinal cord * Encephalomyelitis * Acute disseminated * Meningitis * Meningoencephalitis Brain/ encephalopathy Degenerative Extrapyramidal and movement disorders * Basal ganglia disease * Parkinsonism * PD * Postencephalitic * NMS * PKAN * Tauopathy * PSP * Striatonigral degeneration * Hemiballismus * HD * OA * Dyskinesia * Dystonia * Status dystonicus * Spasmodic torticollis * Meige's * Blepharospasm * Athetosis * Chorea * Choreoathetosis * Myoclonus * Myoclonic epilepsy * Akathisia * Tremor * Essential tremor * Intention tremor * Restless legs * Stiff-person Dementia * Tauopathy * Alzheimer's * Early-onset * Primary progressive aphasia * Frontotemporal dementia/Frontotemporal lobar degeneration * Pick's * Dementia with Lewy bodies * Posterior cortical atrophy * Vascular dementia Mitochondrial disease * Leigh syndrome Demyelinating * Autoimmune * Inflammatory * Multiple sclerosis * For more detailed coverage, see Template:Demyelinating diseases of CNS Episodic/ paroxysmal Seizures and epilepsy * Focal * Generalised * Status epilepticus * For more detailed coverage, see Template:Epilepsy Headache * Migraine * Cluster * Tension * For more detailed coverage, see Template:Headache Cerebrovascular * TIA * Stroke * For more detailed coverage, see Template:Cerebrovascular diseases Other * Sleep disorders * For more detailed coverage, see Template:Sleep CSF * Intracranial hypertension * Hydrocephalus * Normal pressure hydrocephalus * Choroid plexus papilloma * Idiopathic intracranial hypertension * Cerebral edema * Intracranial hypotension Other * Brain herniation * Reye syndrome * Hepatic encephalopathy * Toxic encephalopathy * Hashimoto's encephalopathy Both/either Degenerative SA * Friedreich's ataxia * Ataxia–telangiectasia MND * UMN only: * Primary lateral sclerosis * Pseudobulbar palsy * Hereditary spastic paraplegia * LMN only: * Distal hereditary motor neuronopathies * Spinal muscular atrophies * SMA * SMAX1 * SMAX2 * DSMA1 * Congenital DSMA * Spinal muscular atrophy with lower extremity predominance (SMALED) * SMALED1 * SMALED2A * SMALED2B * SMA-PCH * SMA-PME * Progressive muscular atrophy * Progressive bulbar palsy * Fazio–Londe * Infantile progressive bulbar palsy * both: * Amyotrophic lateral sclerosis * v * t * e Nucleus diseases Telomere * Revesz syndrome Nucleolus * Treacher Collins syndrome * Spinocerebellar ataxia 7 * Cajal body: Spinal muscular atrophy Centromere * CENPJ * Seckel syndrome 4 Other * AAAS * Triple-A syndrome * Laminopathy * SMC1A/SMC3 * Cornelia de Lange Syndrome * SETBP1 * Schinzel–Giedion syndrome see also nucleus [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-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	Spinal muscular atrophy	c0026847	1,794	wikipedia	https://en.wikipedia.org/wiki/Spinal_muscular_atrophy	2021-01-18T19:05:31	{"gard": ["7674"], "mesh": ["D009134"], "umls": ["C0026847"], "wikidata": ["Q580290"]}
Nodulosis–arthropathy–osteolysis syndrome SpecialtyDermatology Nodulosis–arthropathy–osteolysis syndrome is a cutaneous condition that shares features with juvenile hyaline fibromatosis.[1] ## See also[edit] * Winchester syndrome * List of cutaneous conditions ## References[edit] 1. ^ Rapini, Ronald P.; Bolognia, Jean L.; Jorizzo, Joseph L. (2007). Dermatology: 2-Volume Set. St. Louis: Mosby. ISBN 978-1-4160-2999-1. This dermatology article is a stub. You can help Wikipedia by expanding it. * v * t * e [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors	Nodulosis–arthropathy–osteolysis syndrome	c1850155	1,795	wikipedia	https://en.wikipedia.org/wiki/Nodulosis%E2%80%93arthropathy%E2%80%93osteolysis_syndrome	2021-01-18T19:04:20	{"mesh": ["C536051"], "umls": ["C1850155"], "orphanet": ["85196"], "wikidata": ["Q4420136"]}
A number sign (#) is used with this entry because of evidence that occult macular dystrophy (OCMD) is caused by heterozygous mutation in the RP1L1 gene (608581) on chromosome 8p23. Description Occult macular dystrophy is characterized by progressive decline of visual acuity in both eyes, associated with a normal fundus and normal fluorescein angiography. Patients have normal full-field electroretinograms (ERGs) but severely reduced focal macular ERGs, as recorded by conventional techniques using small stimuli under background illumination. OCMD patients are believed to have localized retinal dysfunction distal to the ganglion cells in the central retina (summary by Piao et al., 2000). Clinical Features Miyake et al. (1989) reported a family in which a sister and brother and their father displayed an unusual form of macular dystrophy. Both sibs reported noticing reduced visual acuity around 13 years of age, with acuity measurements of 20/20 to 20/25 at that time; their visual acuity progressively worsened to 20/100 by 29 years and 19 years of age, respectively. Both sibs also had mild disturbances of color vision, with both red-green and yellow-blue defects. Their 55-year-old father had no severe visual complaints, but had noticed some progressive visual disturbance over the past 20 years. His best-corrected visual acuity was 20/20, and he had a mild red-green color vision defect bilaterally. Despite the patients' poor visual acuity and the advanced age of the father, their maculas appeared normal by ophthalmoscopy, with good ring and foveal reflexes, and fluorescein angiography was also normal. Results of full-field electroretinograms were normal in both cone and rod components, but the focal macular ERG results were severely affected: the central fovea was most impaired and the parafovea and perifovea were relatively spared in the sibs, whereas the reverse was true in their father, findings that were consistent with the sibs' poor visual acuity and their father's good visual acuity. Examination of the mother and an unaffected brother revealed normal visual acuity, color vision, fundi, full-field ERGs, and focal macular ERGs. Miyake et al. (1996) examined 13 patients with occult macular dystrophy from 8 families, including 3 patients from the family previously studied by Miyake et al. (1989). The fundi of 12 of the patients showed normal findings on ophthalmoscopy and fluorescein angiography, but the oldest patient (aged 65 years) had bull's eye maculopathy bilaterally. Electroretinograms in all 12 patients showed cone sensitivity loss only in the macular area; in addition, 6 older patients showed borderline or abnormal rod sensitivity in the macular area, whereas 6 relatively young patients had normal rod sensitivity. Miyake et al. (1996) suggested that the most suitable name for the disorder might be central cone dystrophy. Piao et al. (2000) examined 8 patients with OCMD, 5 of whom were previously studied by Miyake et al. (1996). Three patients were considered to represent autosomal dominant inheritance, and the other 5 patients were classified as sporadic. The diagnosis of OCMD was made based on bilateral involvement, normal ophthalmoscopic findings, normal fluorescein angiography, decreased visual acuity, normal full-field ERGs for both rod and cone components, and decreased focal macular cone ERGs. Corrected visual acuities ranged from 20/200 (0.1) to 20/50 (0.4), and light-adapted perimetry showed abnormally elevated cone thresholds within the central 10 degrees in all patients. Multifocal ERGs were performed in the 8 patients and 20 age-matched controls with normal visual acuity and color vision and normal full-field ERGs. OCMD patients had severely depressed responses from the central retina, with all patients having reduced amplitudes within 7 degrees of the fovea, although a large variation in amplitude was observed among the patients. Responses were relatively well-preserved peripherally, with differences in ERG amplitude between patients and controls becoming smaller towards the peripheral retina. In addition, most OCMD patients had slight but significantly delayed implicit times across the whole testing field, and the differences between patients and controls did not change with retinal eccentricity. Piao et al. (2000) stated that their results supported the concept of localized retinal dysfunction distal to the ganglion cells in the central retina in OCMD, and that the delayed implicit times across the whole test field suggested that the retinal dysfunction is more widespread than expected by ERG amplitudes and psychophysical perimetric results. Wildberger et al. (2003) studied an Italian family segregating autosomal dominant OCMD, in which affected individuals reported reduced visual acuity beginning in early childhood. The fundus in the 3 examined patients appeared normal, with no signs of maculopathy even in the oldest, at age 53 years. Multifocal ERGs demonstrated a marked depression of signal amplitudes in the macular region, whereas the retinal near-periphery was less disturbed. Wildberger et al. (2003) noted that amplitude values in these patients were depressed to an extent similar to that of patients reported previously by Piao et al. (2000); implicit times, however, were less prolonged than in the previous report, perhaps due to the higher mean age of patients in the earlier study. Brockhurst and Sandberg (2007) used optical coherence tomography (OCT) to evaluate foveal structure in 8 patients with OCMD who had corrected visual acuities ranging from 20/25 to count fingers. All reported slowly progressive vision loss, and all had normal pupillary responses, full peripheral fields, normal slit-lamp and ophthalmoscopic examinations, and normal full-field ERGs. Fluorescein angiography, performed in 3 of the patients, was also normal. OCT in 7 of the patients showed reduced foveal thickness associated with thinning of the outer nuclear layer, and the degree of visual impairment could be predicted from the OCT because visual acuity was proportional to central foveal thickness (p = 0.005). The eighth patient, whose visual acuity was reduced to counting fingers, had normal tomograms but reduced foveal ERGs, indicating that foveal malfunction rather than photoreceptor loss resulted in her visual acuity impairment. Park et al. (2010) used spectral-domain (SD)-OCT to investigate photoreceptor status in 8 sporadic OCMD patients and 1 patient with autosomal dominant OCMD. The decline in visual acuity was bilateral and symmetric in 4 patients, whereas 5 had unilateral deterioration of vision. Conventional time-domain OCT showed reduced foveal thickness in these patients, but revealed no other retinal layer abnormality. However, in 15 eyes of 8 patients, SD-OCT demonstrated a well-defined disruption of the inner segment-outer segment (IS-OS) junction of the photoreceptors and of the Verhoeff membrane (cone outer segment tips). Degrees of abnormality in the photoreceptor layer varied and correlated with the severity of vision deterioration and duration of symptoms. Park et al. (2010) noted that there was no correlation between multifocal ERG amplitudes and the severity of photoreceptor disruption, which they suggested might be due to technical difficulties in performing multifocal ERGs. No morphologic abnormality could be demonstrated in the photoreceptors of 1 patient. The other retinal layers, including the outer nuclear layer and the retinal pigment epithelium, were normal in all patients. SD-OCT also showed that 3 of 5 patients with presumed unilateral OCMD had bilateral OCMD after initial or follow-up examinations. Kim et al. (2011) studied 5 patients with OCMD. Color vision testing in 4 of the patients showed total dyschromatopsia in 3 and strong red-green color defect in 1. Visual field testing demonstrated central scotomata in all 5 patients, and all had decreased amplitude in the first ring on multifocal ERGs. SD-OCT showed decreased bowing of the IS-OS boundary of the photoreceptors in all patients, with disruption of the IS-OS boundary in 5 of 9 eyes and interruption of the external limiting membrane in 3 of 9 eyes. Tsunoda et al. (2012) examined 14 mutation-positive members of a large 5-generation Japanese family with RP1L1 (608581)-associated OCMD, previously studied by Akahori et al. (2010). All of the affected individuals had a similar phenotype, consisting of bilateral slowly progressive visual disturbances with a normal-appearing fundus, normal fluorescein angiography and full-field ERGs over the entire course of the disease, selective dysfunction of the macula detected by focal macular and multifactorial ERGs, selective abnormality of the photoreceptor layer in the macular on OCT, and a final best-corrected visual acuity (BCVA) not poorer than 20/200 (0.1). However, age at onset of OCMD was very variable among family members and ranged from 6 years to 50 years. Tsunoda et al. (2012) stated that their findings in this family confirmed that there are patients with OCMD who have normal visual acuity and no subjective visual disturbances until the disease has progressed to a more advanced stage; in addition, once the BCVA is reduced to 20/100 (0.2) to 20/200, the disease becomes stationary and both subjective and objective visual functions do not deteriorate thereafter. One family member, a 60-year-old woman, carried the mutation but had no subjective or objective signs of macular dysfunction. Because OCT examination of 2 OCMD patients who were negative for mutation in the RP1L1 gene showed dissimilar findings, Tsunoda et al. (2012) suggested that OCMD may represent different disease entities with similar retinal dysfunction. Kabuto et al. (2012) reported a 52-year-old Japanese patient with sporadic occult macular dystrophy. After 2 to 3 years of slow, painless visual loss, her best corrected visual acuity was mildly to moderately reduced (20/50-20/63); fundus examination, fluorescein angiography, and full-field ERG were normal. SD-OCT showed obvious blurring of the photoreceptor IS/OS boundary and focal macular ERG revealed an absent a-wave with a depolarizing pattern. Multifocal ERG of the macular region was severely reduced as well. Mapping Akahori et al. (2010) performed linkage analysis in a large 5-generation Japanese pedigree with occult macular dystrophy and mapped the disease locus to an approximately 10-Mb region of chromosome 8p23-p22 with a maximum lod score of 3.77. A common haplotype between SNPs rs365309 and rs263841 was shared by all affected family members. With additional linkage study of a second family with OCMD, the cumulative parametric multipoint lod score was greater than 4. Molecular Genetics In a large 5-generation Japanese pedigree with occult macular dystrophy mapping to chromosome 8p23-p22, Akahori et al. (2010) identified a heterozygous missense mutation in the candidate gene RP1L1 (R45W; 608581.0001) that segregated with the disease. The authors analyzed RP1L1 in 3 additional Japanese families with OCMD and detected R45W in affected members of 2 of the families and a different heterozygous mutation (W960R; 608581.0002) in the third family. Neither mutation was found in 876 Japanese controls. There were 3 apparently unaffected individuals from 2 families who carried the R45W mutation, suggesting either reduced penetrance of the mutation or possibly a later onset of disease for these individuals, who were 55, 58, and 60 years old. Akahori et al. (2010) noted that 4 of the 8 OCMD patients described by Brockhurst and Sandberg (2007) had onset of disease at over 65 years of age, and that an elderly patient in the 5-generation Japanese pedigree had no symptoms in one of her eyes even at 81 years of age. Davidson et al. (2013) sequenced the coding region and intron-exon boundaries of the RP1L1 gene in 28 probands with clinical and electrophysiologic findings of OCMD similar to those previously reported by Akahori et al. (2010). Heterozygosity for the R45W variant was identified in 5 probands, but 8 unaffected family members, including an asymptomatic 90-year-old woman, were also found to carry R45W, for a penetrance of only 38%. Four of the asymptomatic carriers, including 3 who were over 55 years of age, underwent detailed phenotypic assessment and no signs of OCMD were detected. Davidson et al. (2013) concluded that the R45W variant represents a risk factor for OCMD rather than a causative mutation. They also identified heterozygosity for a different RP1L1 missense mutation, P110L, in 1 OCMD proband. By direct sequencing of the RP1L1 gene in a 52-year-old Japanese patient with sporadic OCMD, Kabuto et al. (2012) identified a heterozygous missense mutation (S1199C; 608581.0004). Family history revealed no other members with any eye diseases, including her parents who were deceased. Only 1 of the patient's 4 sibs were studied, and she did not carry the mutation. The authors thought the mutation was likely pathogenic but noted the need to examine more family members and a larger number of controls. INHERITANCE \- Autosomal dominant HEAD & NECK Eyes \- Decreased visual acuity, slowly progressive \- Normal fundus on ophthalmoscopy \- Normal full-field electroretinogram \- Severely reduced focal macular electroretinogram MISCELLANEOUS \- Variable age of onset, from 6 to 50 years of age \- Progression of disease stops at a best-corrected visual acuity of 0.2 (20/100) to 0.1 (20/200) MOLECULAR BASIS \- Caused by mutation in the RP1-like protein 1 gene (RP1L1, 608581.0001 ) ▲ 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	OCCULT MACULAR DYSTROPHY	c3150833	1,796	omim	https://www.omim.org/entry/613587	2019-09-22T15:58:15	{"doid": ["0050578"], "omim": ["613587"], "orphanet": ["247834"], "synonyms": ["OCMD", "OMD", "Alternative titles"]}
A rare genetic disease characterized by childhood onset of multiple endocrine manifestations in combination with central and peripheral nervous system abnormalities. Reported signs and symptoms include postnatal growth retardation, moderate intellectual disability, hypogonadotropic hypogonadism, insulin-dependent diabetes mellitus, central hypothyroidism, demyelinating sensorimotor polyneuropathy, and cerebellar and pyramidal signs. Progressive hearing loss and a hypoplastic pituitary gland have also been described. Brain imaging shows moderate white matter abnormalities. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-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	Polyendocrine-polyneuropathy syndrome	c4015261	1,797	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=453533	2021-01-23T17:04:27	{"omim": ["616113"]}
A number sign (#) is used with this entry because autosomal recessive deafness-9 (DFNB9) and auditory neuropathy-1 (AUNB1) are caused by homozygous or compound heterozygous mutation in the gene encoding otoferlin (OTOF; 603681) on chromosome 2p23. Clinical Features Chaib et al. (1996) reported a consanguineous Lebanese family with autosomal recessive sensorineural nonsyndromic hearing loss. For affected children, deafness was noted by their parents at birth or before the age of 2 years. None of the children had balance problems, and there was no evidence for an acquired risk factor predisposing to hearing loss. Audiometry showed no response at 100 dB for frequencies superior to 1,000 Hz in all affected subjects. In affected children, no auditory brainstem response was observed up to 100 dB. In the parents, who were obligate carrier heterozygotes, audiometric tests were normal. ### Nonsyndromic Recessive Auditory Neuropathy Varga et al. (2003) defined a specific type of deafness, termed 'nonsyndromic recessive auditory neuropathy' (NSRAN). Affected patients have hearing loss based on pure-tone audiometry and auditory brainstem response test results, which measure the overall auditory pathway, but have a normal otoacoustic emissions (OAE) test, which detects responses of the outer hair cells to environmental sound. Subjects with NSRAN can have varying degrees of hearing loss with poor speech reception out of proportion to the degree of hearing loss. Most subjects with NSRAN are not helped by hearing aids, but may be helped by cochlear implants. Varga et al. (2003) reported 9 affected children from 4 families with NSRAN. Tekin et al. (2005) reported 3 Turkish sibs, born of consanguineous parents, with NSRAN confirmed by genetic analysis (603681.0010). All 3 children had severe to profound prelingual sensorineural hearing loss. Acoustic middle ear reflexes were absent in the 2 older children, and all 3 children had absent auditory brainstem responses. All 3 sibs showed U- or bowl-shaped audiometric configurations at ages 8, 7, and 6 years, respectively, with the most severe hearing loss in the 500-2,000 Hz frequency range. Otoacoustic emissions were present in 2 children, consistent with auditory neuropathy. OAE were absent in 1 child, although emissions may have disappeared through damage caused by several years of hearing aid use. Tekin et al. (2005) suggested that auditory neuropathy is the only phenotypic manifestation of mutations in the OTOF gene. Varga et al. (2006) summarized findings in auditory neuropathy. The term 'auditory neuropathy' was first coined by Starr et al. (1996). Auditory neuropathy/auditory dys-synchrony (AN/AD) is a unique type of hearing loss diagnosed when tympanographs are normal and acoustic reflexes (AR) and auditory brainstem response (ABR) are absent or severely abnormal, but outer hair cell (OHC) function is normal as indicated by the presence of otoacoustic emissions (OAE) and/or cochlear microphonics (CM). These test results indicate that the auditory pathway up to and including the OHC is functioning but the auditory signal is not transmitted to the brainstem, suggesting that the lesion lies at the level of the inner hair cells (IHC), the IHC synapse to the afferent nerve fibers, or the auditory nerve itself. Individuals with this disorder can have various degrees of hearing loss as measured by pure tone audiometry. They generally have disproportionately poor speech understanding. In contrast to individuals with non-AN/AD hearing loss, hearing aids may provide little help in speech understanding in most individuals with AN/AD. Cochlear implantation has been shown to help the speech understanding in some cases of AN/AD, but others have not had favorable results. ### Nonsyndromic Recessive Auditory Neuropathy, Temperature-Sensitive Varga et al. (2006) reported 2 sibs with a temperature-sensitive auditory neuropathy phenotype. Audiogram of the proband when afebrile showed mild low frequency hearing loss, and speech comprehension was below the 10th percentile for both quiet and noise. Tympanometry was normal and AR were absent. ABR was abnormal, but CM were present. On 2 occasions testing was performed during febrile illness. At a temperature of 38.1 degrees C, her pure tone thresholds decreased to profound deafness in the low frequencies, rising to severe hearing loss in the high frequencies. Speech awareness threshold was 80 dB hearing level (HL), but she was unable to repeat any of the test spondee words. Tympanometry and OAE were normal, but AR and ABR were absent. With a temperature of 37.8 degrees C she was tested again and showed a mild to moderate hearing loss and zero speech comprehension. The following day her auditory functions returned to baseline after the fever abated. The proband had reported to her parents that her hearing becomes affected suddenly when she is febrile. Her brother was similarly affected. Varga et al. (2006) found that these sibs carried an ile515-to-thr mutation in otoferlin (603681.0001). The mutation was heterozygous in the unaffected father; the mutation in the mother and on the maternal allele of the sibs was unknown at the time of the report. Clinical features of the family had been reported by Starr et al. (1998). Matsunaga et al. (2012) reported a 26-year-old Japanese man, born of consanguineous parents, with temperature-sensitive auditory neuropathy associated with a homozygous mutation in the OTOF gene (G541S; 603681.0013) that only affected the long isoform. The patient complained of difficulty in understanding conversation and reported that his hearing deteriorated when he became febrile or was exposed to loud noise. Pure-tone audiometry when he was afebrile revealed mild hearing loss with a flat configuration. Mapping In a consanguineous family living in an isolated region of Lebanon, Chaib et al. (1996) demonstrated linkage of an autosomal form of neurosensory deafness to markers on 2p23-p22. A maximum lod score of 8.03 was detected with a new polymorphic marker, D2S2144. Observed recombinants and homozygosity mapping defined a maximum interval of 2 cM for this gene which lies between D2S2303 and D2S174. Leal et al. (1998) found linkage to the same region of 2p23-p22 in a highly consanguineous kindred from eastern Turkey. Affected members had prelingual profound hearing loss involving all the frequencies. The genetic map generated by the authors suggested that the region for DFNB9 is less than 1.08 cM (95% CI = 0-2.59 cM). In 4 families with NSRAN, Varga et al. (2003) found linkage to the OTOF gene on chromosome 2p23. Molecular Genetics In all members affected with DFNB9 in 4 unrelated Lebanese kindreds, Yasunaga et al. (1999) identified a missense mutation in the OTOF gene (603681.0001). In 1 Cuban family, 2 Spanish families, and 8 sporadic Spanish patients with nonsyndromic sensorineural hearing loss, Migliosi et al. (2002) identified a gln829-to-ter mutation in exon 22 of the OTOF gene (Q829X; 603681.0004). Migliosi et al. (2002) determined that the Q829X mutation was responsible for 4.4% of recessive familial or sporadic cases of deafness in the Spanish population, and presented evidence for a founder effect. In 3 of 4 families with NSRAN, Varga et al. (2003) identified 4 mutations in the OTOF gene (603681.0006-603681.0009). Two of the families had heterozygous mutations. Varga et al. (2003) noted that previous publications on patients with DFNB9 did not report testing for outer hair cell functioning; thus, it is unclear whether there is a consistent phenotype for hearing loss caused by mutation in the OTOF gene. Varga et al. (2006) described an allele of the OTOF gene that appeared to be associated with temperature-sensitive auditory neuropathy (603681.0011). Romanos et al. (2009) identified 10 different mutations in the OTOF gene, including 6 novel mutations, in affected individuals from 8 Brazilian families with hearing loss or auditory neuropathy. The common Spanish Q829X mutation was not identified in a larger sample of 342 deaf individuals, indicating that it is not a common cause of deafness in Brazil. Population Genetics Choi et al. (2009) screened a cohort of 557 large Pakistani families segregating recessive severe to profound prelingual-onset deafness and identified 13 families with linkage to markers for DFNB9; analysis of the OTOF gene revealed probable pathogenic sequence variants in affected individuals from all 13 families. OTOF mutations thus accounted for deafness in 13 (2.3%) of 557 Pakistani families, which Choi et al. (2009) stated was not significantly different from the prevalence found in other populations. Matsunaga et al. (2012) identified an R1939Q (603681.0012) mutation in the OTOF gene, in 13 (56.5%) of 23 Japanese patients with early-onset auditory neuropathy. Seven patients were homozygous for the mutation, 4 were compound heterozygous for R1939Q and a truncating or splice site mutation in OTOF, 1 was compound heterozygous for R1939Q and a nontruncating mutation in OTOF, and 1 was heterozygous for the R1939Q mutation. Haplotype analysis indicated a founder effect for the R1939Q mutation. Those who were homozygous for R1939Q or compound heterozygous for R1939Q and a truncating mutation had a consistent and severe phenotype, whereas the patient who was compound heterozygous for R1939Q and a nontruncating mutation had a less severe phenotype, with moderate hearing loss at age 29 years and sloping audiograms. The findings suggested that the R1939Q variant likely causes a severe impairment of protein function, and that, in general, truncating mutations cause a more severe phenotype than nontruncating mutations. Animal Model Roux et al. (2006) found that Otof -/- mice were profoundly deaf. Exocytosis in Otof -/- auditory inner hair cells was almost completely abolished, despite normal ribbon synapse morphogenesis and Ca(2+) current. Roux et al. (2006) concluded that OTOF is essential for a late step of synaptic vesicle exocytosis and may act as the major Ca(2+) sensor triggering membrane fusion at the auditory inner hair cell ribbon synapse. Nomenclature Chaib et al. (1996) referred to the deafness locus that they located on 2p23-p22 as DFNB6; however, this designation had been preempted for the locus defined by Fukushima et al. (1995) (see 600971). Therefore, the 2p23-p22 locus is referred to here as DFNB9. INHERITANCE \- Autosomal recessive HEAD & NECK Ears \- Deafness, sensorineural (severe to profound) \- No auditory brainstem response (ABR) \- Absence of acoustic middle ear muscle reflexes \- U- or bowl-shaped audiogram \- Normal otoacoustic emissions (OAE), indicating intact outer ear hair cell function \- OAE responses may decrease with age or use of hearing aids NEUROLOGIC Central Nervous System \- Deafness, sensorineural MISCELLANEOUS \- Congenital onset or onset before 2 years (prelingual) \- Nonsyndromic disorder MOLECULAR BASIS \- Caused by mutations in the otoferlin gene (OTOF, 603681.0001 ) ▲ 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	DEAFNESS, AUTOSOMAL RECESSIVE 9	c1832828	1,798	omim	https://www.omim.org/entry/601071	2019-09-22T16:15:28	{"doid": ["0110535"], "mesh": ["C563396"], "omim": ["601071"], "orphanet": ["90636"], "synonyms": ["Autosomal recessive non-syndromic neurosensory deafness type DFNB", "NEUROSENSORY NONSYNDROMIC RECESSIVE DEAFNESS 9", "Alternative titles", "Autosomal recessive isolated sensorineural deafness type DFNB", "Autosomal recessive isolated neurosensory deafness type DFNB"], "genereviews": ["NBK1434", "NBK1251"]}
Bicipital tenosynovitis is tendinitis or inflammation of the tendon and sheath lining of the biceps muscle. It is often the result of many years of small tears or other degenerative changes in the tendon first manifesting in middle age, but can be due to a sudden injury. Calcification of the tendon, and osteophytes ("bone spurs") in the intertubercular groove can be apparent on x-rays.[1][2] The condition (which can also occur in dogs) [3] is commonly treated with physical therapy and cortisone[4] ## References[edit] 1. ^ Tendinitis and Tenosynovitis at Merck Manuals 2. ^ bicipital tenosynovitis at The Free Dictionary 3. ^ "Archived copy" (PDF). Archived from the original (PDF) on 2011-07-17. Retrieved 2011-01-02.CS1 maint: archived copy as title (link) 4. ^ Bicipital tenosynovitis in Adult Orthopaedic Nursing, by Delores Christina Schoen [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-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	Bicipital tenosynovitis	c0158304	1,799	wikipedia	https://en.wikipedia.org/wiki/Bicipital_tenosynovitis	2021-01-18T18:34:05	{"umls": ["C0158304"], "wikidata": ["Q4903638"]}

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