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A number sign (#) is used with this entry because autosomal dominant mental retardation-29 (MRD29) is caused by heterozygous mutation in the SETBP1 gene (611060) on chromosome 18q12. Clinical Features Coe et al. (2014) reported 9 patients, including 1 reported by Rauch et al. (2012), with frameshift or nonsense mutations in SETBP1 who had a cognitive phenotype ranging from normal with impaired speech to profound intellectual disability (ID). The majority of patients had speech and motor delays, mild dysmorphic features, and behavioral difficulties. Two of the patients had seizures or EEG abnormalities. In addition, the authors reported 1 patient with a deletion encompassing the SETBP1 gene. Coe et al. (2014) also reported on 1 patient studied by Marseglia et al. (2012) and 2 patients studied by Filges et al. (2011). These patients had mild or moderate ID, speech and motor delays, and facial dysmorphisms. Two of the 3 patients had seizures or EEG abnormalities. In patients positive for mutation in SETBP1, Coe et al. (2014) observed a dysmorphism typified by a long face, characteristic eyebrows, and, in a few patients, low-set ears and cafe-au-lait spots. In 7 of 13 patients for whom brain MRI was available, no abnormalities were found; in 1 additional patient, MRI showed no major anomalies but minimal signal of the peritrigonal white matter. Molecular Genetics Coe et al. (2014) created an expanded copy number variant (CNV) morbidity map from 29,085 children with developmental delay in comparison to 19,584 healthy controls, identifying 70 significant CNVs. They then resequenced 26 candidate genes in 4,716 additional cases with developmental delay or autism and 2,193 controls. An integrated analysis of CNV and single-nucleotide variant (SNV) data pinpointed 10 genes enriched for putative loss of function. Among these was SETBP1, haploinsufficiency of which was associated with intellectual disability and loss of expressive language. Coe et al. (2014) reported 4 nonsense mutations in SETBP1 (e.g., 611060.0007), 2 of which were confirmed to be de novo, as well as 4 frameshift mutations (e.g., 611060.0006), of which 1 was confirmed to be de novo. INHERITANCE \- Autosomal dominant HEAD & NECK Head \- Brachycephaly \- Dolicocephaly Face \- Dysmorphic facies, variable \- Long face \- Pointed chin Ears \- Low-set ears Eyes \- Downslanting palpebral fissures \- Hypertelorism \- Ptosis \- Synophrys Nose \- Full nasal tip Mouth \- High palate \- Narrow palate \- Thin upper lip Teeth \- Crowded teeth NEUROLOGIC Central Nervous System \- Mental retardation, mild to moderate (IQ 30-76) \- Delayed speech \- Absent speech \- Delayed motor development \- Seizures (uncommon) Behavioral Psychiatric Manifestations \- Attention deficit hyperactivity disorder MISCELLANEOUS \- Variable dysmorphic features MOLECULAR BASIS \- Caused by mutation in the SET-binding protein 1 gene (SETBP1, 611060.0006 ) ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	MENTAL RETARDATION, AUTOSOMAL DOMINANT 29	c4015141	3,700	omim	https://www.omim.org/entry/616078	2019-09-22T15:50:00	{"doid": ["0070059"], "omim": ["616078"], "orphanet": ["436151"], "synonyms": ["Intellectual disability-loss of expressive language-facial dysmorphism syndrome"]}
A number sign (#) is used with this entry because of evidence that Warburg Micro syndrome-3 (WARBM3) is caused by homozygous or compound heterozygous mutation in the RAB18 gene (602207) on chromosome 10p12. Description Warburg Micro syndrome is a rare autosomal recessive syndrome characterized by microcephaly, microphthalmia, microcornea, congenital cataracts, optic atrophy, cortical dysplasia, in particular corpus callosum hypoplasia, severe mental retardation, spastic diplegia, and hypogonadism (summary by Morris-Rosendahl et al., 2010). For a discussion of genetic heterogeneity of Warburg Micro syndrome, see 600118. Clinical Features Graham et al. (2004) described a Caucasian sister and brother who had microcephaly, postnatal growth retardation, cataract, microcornea, atonic pupils, optic atrophy, profound mental retardation, hypotonic spastic diplegia, polymicrogyria, hypoplasia of the corpus callosum, and hypogenitalism. A nerve conduction study in the boy was markedly abnormal due to severe loss of neurons, suggesting an axonal peripheral neuropathy. Bem et al. (2011) studied 6 consanguineous families segregating Warburg Micro syndrome, including 4 Pakistani families originally described by Ainsworth et al. (2001), 1 Caucasian family originally reported by Graham et al. (2004), and 1 Turkish family. All of the affected children had microcephaly, brachycephaly, microphthalmia, microcornea, low anterior hairline, large protruding pinnae, and downturned mouth corners. The older children were wheelchair bound and had kyphoscoliosis, severe spastic quadriplegia with contractures, and diminished muscle bulk. The clinical features were indistinguishable from those in patients with WARBM1 (600118) with RAB3GAP1 (602356) mutations and from those in patients with WARBM2 (614225) with RAB3GAP2 (609275) mutations, but mutations in these genes were excluded by linkage and direct sequencing. Handley et al. (2013) studied a 4-year-old Egyptian girl who had postnatal growth retardation and microcephaly, bilateral cataracts, microphthalmia, microcornea, atonic pupils, optic nerve atrophy, profound mental retardation with no words or signs, axial hypotonia, hypotonic upper limbs, hypertonic lower limbs with contractures, myoclonic seizures, and hypoplastic labia minora and clitoral hypoplasia. MRI showed bilateral frontoparietal polymicrogyria extending to the insula and temporal gyri, cortical atrophy, delayed myelinization, hypoplasia of the cerebellar vermis and corpus callosum, and mild ventriculomegaly. Mapping Bem et al. (2011) performed a genomewide linkage scan in 5 large consanguineous families segregating Warburg Micro syndrome and genotyped 11 affected children and 4 unaffected sibs. In all affected children, a 10,113.089-kb region of shared homozygosity was identified on chromosome 10p12.1. The genotyping was consistent with linkage; the parents were heterozygous and the unaffected sibs had a haplotype different from that of their affected sibs. A maximum 2-point lod score of 8.93 (theta = 0 at D10S1749) was calculated on the assembled haplotypes. Molecular Genetics In affected members of 5 large consanguineous kindreds segregating Warburg Micro syndrome, including 4 Pakistani families originally described by Ainsworth et al. (2001) and 1 Turkish family, Bem et al. (2011) identified homozygous loss-of-function mutations in the RAB18 gene (602207.0001 and 602207.0002, respectively). The mutation in the Pakistani families was a founder mutation. Direct sequencing for RAB18 mutations in 58 additional families segregating Warburg Micro syndrome detected compound heterozygous mutations (602207.0003-602207.0004) in the affected sibs previously described by Graham et al. (2004). Bem et al. (2011) performed nucleotide-binding assays and showed that although RAB18 bound GDP and GTP comparably to other RABs (RAB5A, 179512; RAB35, 604199), the RAB18 L24Q (602207.0001) and R93del (602207.0003) mutant proteins did not bind detectable levels of either GDP or GTP and are therefore functionally null. Bem et al. (2011) noted that the pathogenicity of these mutations could be explained by their lack of guanosine nucleotide binding because, as for other RAB proteins, this is a prerequisite for correct subcellular localization and function. In a 4-year-old Egyptian girl with 'classic' Warburg Micro syndrome, Handley et al. (2013) identified homozygosity for a missense mutation in the RAB18 gene (T95R; 602207.0005). INHERITANCE \- Autosomal recessive GROWTH Height \- Postnatal growth retardation HEAD & NECK Head \- Postnatal microcephaly \- Brachycephaly Face \- Short prominent overhanging philtrum \- Micrognathia Ears \- Large ears Eyes \- Cataract, congenital \- Microcornea \- Microphthalmia \- Prominent Schwalbe line \- Shallow anterior chamber \- Atonic pupils \- Optic nerve atrophy \- Nystagmus \- Blepharophimosis, mild Nose \- Short nose \- Prominent root of nose Mouth \- Downturned corners of mouth \- Narrow palate Teeth \- Prominent secondary alveolar ridges CHEST Breasts \- Widely spaced nipples GENITOURINARY External Genitalia (Male) \- Small penis \- Hypoplastic scrotum External Genitalia (Female) \- Fused, hypoplastic labia minora Internal Genitalia (Male) \- Retractile testes \- Small testes \- Soft testes SKELETAL Skull \- Microcephaly, postnatal Spine \- Kyphoscoliosis Limbs \- Distal limb contractures Hands \- Cortical thumbs \- Bilateral fifth finger clinodactyly \- Flexion contractures of fingers Feet \- Externally rotated feet in valgus position SKIN, NAILS, & HAIR Hair \- Low anterior hairline \- Centrally placed hair whorl \- Hypertrichosis of upper back MUSCLE, SOFT TISSUES \- Decreased muscle mass, especially distally NEUROLOGIC Central Nervous System \- Spastic quadriplegia, severe \- Truncal hypotonia \- Profound mental retardation \- Seizures \- Polymicrogyria \- Thickened frontal cortex \- Cortical atrophy \- Enlarged ventricles \- Hypoplastic corpus callosum Peripheral Nervous System \- Increased deep tendon responses of lower extremities \- Ankle clonus MOLECULAR BASIS \- Caused by mutation in the RAS-associated protein RAB18 gene (RAB18, 602207.0001 ) ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	WARBURG MICRO SYNDROME 3	c1838625	3,701	omim	https://www.omim.org/entry/614222	2019-09-22T15:56:00	{"doid": ["0110718"], "mesh": ["C536681"], "omim": ["614222"], "orphanet": ["2510"], "synonyms": ["Alternative titles", "MICRO SYNDROME 3"], "genereviews": ["NBK475670"]}
A rare non-Langerhans cell histiocytosis characterized by infiltration of lymph nodes or extranodal tissues by non-malignant histiocytes displaying emperipolesis, a non-destructive phagocytosis of lymphocytes or erythrocytes. Most typical presentation is as a massive cervical lymphadenopathy in adolescents and young adults. Most frequent sites of extranodal disease are skin, soft tissue, bones, paranasal sinuses, orbit, salivary glands, and central nervous system. Symptoms are related to mass effect in the affected organs. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Rosaï-Dorfman disease	c0019625	3,702	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=158014	2021-01-23T18:44:26	{"gard": ["7588"], "mesh": ["D015618"], "icd-10": ["D76.3"], "synonyms": ["Destombes-Rosaï-Dorfman disease", "Rosaï-Dorfman-Destombes disease", "SHML", "Sinus histiocytosis with massive lymphadenopathy"]}
Blister beetle dermatitis SpecialtyDermatology Blister beetle dermatitis is a cutaneous condition that occurs after contact with any of several types of beetles, including those from the Meloidae and Oedemeridae families.[1]:449 Blister beetles secrete an irritant called cantharidin, a vesicant that can get onto humans if they touch the beetles. The term "blister beetle dermatitis" is also occasionally and inappropriately used as a synonym for Paederus dermatitis, a somewhat different dermatitis caused by contact with pederin, an irritant in the hemolymph of a different group of beetles, the rove beetles.[2] ## Contents * 1 Symptoms * 2 Diagnosis * 3 Treatment * 4 See also * 5 References * 6 External links ## Symptoms[edit] After skin comes in contact with cantharidin, local irritation begins within a few hours.[3] (This is in contrast to Paederus dermatitis, where symptoms first appear 12–36 hours after contact with rove beetles.)[4] Painful blisters appear, but scarring from these epidermal lesions is rare.[5] ## Diagnosis[edit] Typical Vesicles/Blister at site where beetle salivates.[citation needed] ## Treatment[edit] Wash with soap and water. Cold application Topical Steroid and Antihistamines application.[citation needed] ## See also[edit] * List of cutaneous conditions * Skin lesion ## References[edit] 1. ^ James, William D.; Berger, Timothy G.; et al. (2006). Andrews' Diseases of the Skin: clinical Dermatology. Saunders Elsevier. ISBN 978-0-7216-2921-6. 2. ^ [1] 'Paederus dermatitis' by Gurcharan Singh and Syed Yousuf Ali, Indian Journal of Dermatology, Venereology and Leprology, Jan-Feb 2007 3. ^ "7.7 Blister beetles, clinical features". Institute of Tropical Medicine. Archived from the original on 23 August 2011. Retrieved 11 August 2011. "On skin contact with cantharidin-containing blister beetles, local tissue irritation occurs after a few hours. This results from the disruption of tonofilaments in the desmosomes with acantholysis and intra-epidermal blister formation." 4. ^ "Just the facts…Paederus Beetles" (PDF). US Army Public Health Command. Archived from the original (PDF) on 16 March 2012. Retrieved 30 July 2011. 5. ^ Barceloux, Donald (2008). Medical toxicology of natural substances: foods, fungi, medicinal herbs, plants, and venomous animals. John Wiley and Sons. p. 973. ISBN 9780470335574. ## External links[edit] * Research paper describing both blister beetle dermatitis and Paederus dermatitis, with photos of both This cutaneous condition article is a stub. You can help Wikipedia by expanding it. * v * t * e [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Blister beetle dermatitis	c0275108	3,703	wikipedia	https://en.wikipedia.org/wiki/Blister_beetle_dermatitis	2021-01-18T18:53:42	{"umls": ["C0275108"], "wikidata": ["Q4158999"]}
Hereditary sensory neuropathy type I (HSN I) is a slowly progressive neurological disorder characterised by prominent predominantly distal sensory loss, autonomic disturbances, autosomal dominant inheritance, and juvenile or adulthood disease onset. ## Epidemiology The exact prevalence is unknown, but is estimated as very low. ## Clinical description Disease onset varies between the 2nd and 5th decade of life. The main clinical feature of HSN I is a reduction of sensation sense, mainly distributed around the distal parts of the upper and lower limbs. Variable distal muscle weakness and wasting, and chronic skin ulcers are characteristic. Autonomic features (usually sweating disturbances) are invariably observed. Serious and common complications are spontaneous fractures, osteomyelitis and necrosis, as well as neuropathic arthropathy which may even necessitate amputations. Some patients suffer from severe pain attacks. Hypacusis or deafness, or cough and gastrooesophageal reflux have been observed in rare cases. ## Etiology HSN I is a genetically heterogenous condition with three loci and mutations in two genes (SPTLC1 and RAB7) identified so far. ## Diagnostic methods Diagnosis is based on the clinical observation and is supported by a family history. Nerve conduction studies confirm a sensory and motor neuropathy predominantly affecting the lower limbs. Radiological studies, including magnetic resonance imaging, are useful when complications such as bone infections or necrosis are suspected. Definitive diagnosis is based on the detection of mutations by direct sequencing of the SPTLC1 and RAB7 genes. Correct clinical assessment and genetic confirmation of the diagnosis are important for appropriate genetic counselling and prognosis. ## Differential diagnosis Differential diagnosis includes the other hereditary sensory and autonomic neuropathies (HSAN), especially HSAN II, as well as diabetic foot syndrome, alcoholic neuropathy, neuropathies caused by other neurotoxins/drugs, immune mediated neuropathy, amyloidosis, spinal cord diseases, tabes dorsalis, lepra neuropathy, or decaying skin tumours like amelanotic melanoma (see these terms). ## Management and treatment Management of HSN I follows the guidelines given for diabetic foot care (removal of pressure to the ulcer and eradication of infection, followed by the use of specific protective footwear) and starts with early and accurate counselling of patients about risk factors for developing foot ulcerations. ## Prognosis The disorder is slowly progressive and does not influence life expectancy but is often severely disabling after a long duration of the disease. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Hereditary sensory and autonomic neuropathy type 1	c0020071	3,704	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=36386	2021-01-23T17:49:16	{"gard": ["6635"], "mesh": ["D009477"], "omim": ["162400", "613640", "613708", "615632"], "umls": ["C0020071"], "icd-10": ["G60.8"], "synonyms": ["HSAN1", "Hereditary sensory and autonomic neuropathy type I"]}
Infantile systemic hyalinosis Other namesJuvenile systemic hyalinosis Infantile systemic hyalinosis is inherited in an autosomal recessive manner. SpecialtyDermatology, medical genetics Infantile systemic hyalinosis is an allelic autosomal-recessive condition characterized by multiple skin nodules, hyaline deposition, gingival hypertrophy, osteolytic bone lesions and joint contractures.[1]:606 ## Contents * 1 Genetics * 2 Diagnosis * 3 Management * 4 See also * 5 References * 6 External links ## Genetics[edit] This disease is caused by mutations in the CMG2 gene (ANTXR2).[2] ## Diagnosis[edit] This section is empty. You can help by adding to it. (October 2017) ## Management[edit] This section is empty. You can help by adding to it. (October 2017) ## See also[edit] * Skin lesion * List of cutaneous conditions ## References[edit] 1. ^ James, William; Berger, Timothy; Elston, Dirk (2005). Andrews' Diseases of the Skin: Clinical Dermatology. (10th ed.). Saunders. ISBN 0-7216-2921-0. 2. ^ Vahidnezhad H, Ziaee V, Youssefian L, Li Q, Sotoudeh S, Uitto J (2015) Infantile systemic hyalinosis in an Iranian family with a mutation in the CMG2/ANTXR2 gene. Clin Exp Dermatol doi: 10.1111/ced.12616 ## External links[edit] * GeneReview/NIH/UW entry on Hyalinosis, Inherited Systemic Classification D * OMIM: 228600 608041 * MeSH: D057770 External resources * GeneReviews: Hyalinosis, Inherited Systemic This Dermal and subcutaneous growths article is a stub. You can help Wikipedia by expanding it. * v * t * e [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Infantile systemic hyalinosis	c2745948	3,705	wikipedia	https://en.wikipedia.org/wiki/Infantile_systemic_hyalinosis	2021-01-18T18:45:05	{"mesh": ["D057770"], "orphanet": ["2176"], "synonyms": [], "wikidata": ["Q6029067"]}
Nijmegen breakage syndrome is a rare genetic disease presenting at birth with microcephaly, dysmorphic facial features, becoming more noticeable with age, growth delay, and later-onset complications such as malignancies and infections. ## Epidemiology Prevalence and incidence are not known. 150 patients have been reported in the literature but many more are recorded in patient registries. The disease seems to occur worldwide, but has a much higher prevalence among Central and Eastern European Slavic populations due to a founder mutation. ## Clinical description Clinical manifestations are not pathognomonic and may vary in severity. The main signs are microcephaly, present at birth and progressing with age, dysmorphic facial features (prominent midface emphasized by a sloping forehead and receding mandible). Other facial characteristics are more subtle and diverse, e.g. upwardly slanted palpebral fissures, long and beaked nose or short nose with anteverted upturned nostrils. In a few patients, cleft lip/palate or choanal atresia have been described. Mild growth retardation, and, in females, premature ovarian insufficiency are common. Minor skeletal anomalies, such as clinodactyly of the 5th fingers and partial syndactyly of the 2nd and 3rd toes are found (50% of patients). Delayed speech development is common. Café au lait spots and/or vitiligo spots are observed (50-70%). Hair in NBS is usually thin and sparse in infancy but improves with age. Hair greying can appear as early as in the 2nd or 3rd decade. Congenital renal anomalies (hypoplasia/aplasia, horseshoe or double kidney, ectopic/dystopic kidneys) are relatively frequent. Hypospadias, cryptorchidism, urethro-anal fistula are also found. Immune deficiency with recurrent respiratory tract infections that may be life-threatening and a strong predisposition to malignancies (predominantly lymphoid) and radiosensitivity are other integral manifestations. By age 20, over 40% of patients develop a malignant disease. ## Etiology NBS is caused by mutations in the NBN gene (8q21-q24) which lead to partially functional truncated fragments of nibrin, the gene product involved in repairing DNA double strand breaks. ## Diagnostic methods Diagnosis is based on the clinical manifestations, chromosomal instability (spontaneous and induced), increased cellular sensitivity to ionizing radiation in vitro, combined immunodeficiency, mutations in both alleles of the NBN gene, and complete absence of full-length nibrin. Early diagnosis is very important to avoid severe recurrent infections, unnecessary exposure to radiation for diagnostic purposes, and adverse effects of radiotherapy for treatment of tumors. Analysis of the family pedigree can also support diagnosis (malignancies, microcephaly or hydrocephaly, early death of a sibling). Molecular testing confirms diagnosis. ## Differential diagnosis Differential diagnosis includes Fanconi anemia, Bloom syndrome, NBS-like disorder, ataxia-telangectasia-like disorder, LIG4 syndrome, NHEJ1 syndrome and Seckel syndrome (see these terms). ## Antenatal diagnosis Affected families may be offered prenatal diagnosis by molecular analysis if both disease-causing gene mutations are known. ## Genetic counseling Parents of an affected child are obligate carriers of NBN mutations (25% risk for each pregnancy). Parents should be offered monitoring for cancer. NBS follows an autosomal recessive pattern of inheritance. ## Management and treatment There is no specific therapy for NBS. Due to the specific defect underlying immune deficiency and sensitivity to IR radiation, patients require multidisciplinary management and long term follow-up (malignancy, immunodeficiency, growth, hypergonadotropic hypogonadism in females). ## Prognosis Prognosis is poor, with malignancy as the major cause of death. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Nijmegen breakage syndrome	c0398791	3,706	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=647	2021-01-23T18:57:20	{"gard": ["3904"], "mesh": ["C531759", "D049932"], "omim": ["251260"], "umls": ["C0398791", "C2930831"], "icd-10": ["Q87.8"], "synonyms": ["AT V1", "Ataxia-telangiectasia, variant 1", "Berlin breakage syndrome", "Immunodeficiency-microcephaly-chromosomal instability syndrome", "Microcephaly-immunodeficiency-lymphoreticuloma syndrome", "NBS", "Seemanova syndrome type 2"]}
A rare autosomal recessive acromesomelic dysplasia characterized by severe dwarfism (adult height approximately 120 cm) with abnormalities limited to the limbs (affecting the lower limbs more than upper limbs, with middle and distal segments being the most affected), severe shortening, absence or fusion of tubular bones of hands and feet and large joint dislocations. As seen in acromesomelic dysplasia, Grebe type and acromesomelic dysplasia, Maroteaux type, facial features and intelligence are normal. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Acromesomelic dysplasia, Hunter-Thompson type	c2930970	3,707	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=968	2021-01-23T18:43:05	{"gard": ["506"], "mesh": ["C535658"], "omim": ["201250"], "umls": ["C2930970"], "icd-10": ["Q78.8"], "synonyms": ["Acromesomelic dwarfism"]}
A number sign (#) is used with this entry because of evidence that Oguchi disease-1 (CSNBO1) is caused by homozygous or compound heterozygous mutation in the arrestin gene (SAG; 181031) on chromosome 2q37. Description Oguchi disease is a rare autosomal recessive form of congenital stationary night blindness in which all other visual functions, including visual acuity, visual field, and color vision, are usually normal. A typical feature of the disease is a golden or gray-white discoloration of the fundus that disappears in the dark-adapted state and reappears shortly after the onset of light (Mizuo phenomenon, or Mizuo-Nakamura phenomenon). The course of dark adaptation of rod photoreceptors is extremely retarded, whereas that of cones appears to proceed normally (summary by Fuchs et al., 1995). ### Genetic Heterogeneity of Oguchi Disease Oguchi disease-2 (CSNBO2) is caused by mutation in the rhodopsin kinase gene (GRK1; 180381) on chromosome 13q34. Clinical Features Oguchi disease is characterized by congenital static night blindness and diffuse yellow or gray coloration of the fundus. After 2 or 3 hours in total darkness, the normal color of the fundus returns (Oguchi, 1907; Mizuo, 1913; Carr and Ripps, 1967). Maw et al. (1998) reported 2 Indian brothers with night blindness from an early age. The 28-year-old brother demonstrated the distinctive Mizuo-Nakamura phenomenon (light-dependent golden fundus discoloration) and normal photopic and 30-Hz flicker electroretinogram (ERG) responses; under scotopic conditions, a white flash elicited a negative wave, whereas the response to a blue flash was extinguished. The 18-year-old brother had similar findings in his right eye, whereas in his left eye visual acuity was markedly decreased, both scotopic and photopic ERGs were extinguished, and fundus examination showed macular degeneration, mottled retinal pigment epithelium in the posterior pole and midperiphery, vitreous floaters, pale disc, and sheathed, attenuated vessels. Nakamura et al. (2004) studied 2 unrelated Japanese men, aged 23 and 30 years, who both had night blindness from childhood and also exhibited the Mizuo-Nakamura phenomenon, with golden-yellow discoloration throughout the posterior pole out to the equatorial region. Full-field ERGs elicited by Ganzfeld stimuli after 30 minutes of dark adaptation were nonrecordable in both patients, whereas photopic ERG responses and amplitudes of the 30-Hz flicker ERG were within normal limits. The bright-flash mixed rod-cone ERGs demonstrated a 'negative' configuration with reduced a-wave amplitudes and nearly absent b-wave. Oscillatory potentials were present in both patients. Mapping Maw et al. (1995) considered the gene encoding S antigen (SAG; 181031), also known as arrestin, to be a plausible candidate gene for Oguchi disease because the gene appeared to be involved in the recovery phase of light transduction (Palczewski et al., 1989; Palczewski et al., 1992). The SAG gene had previously been mapped to 2q37.1. Maw et al. (1995) found linkage of Oguchi disease to markers that mapped to distal 2q in an inbred Indian kindred. The segregation data suggested that 3 affected sisters were homozygous by descent for a region between D2S172 and D2S345. An intragenic SAG polymorphism was homozygous in all affected persons and a recombination event suggested that SAG maps proximal to D2S345. Collectively, the findings supported the suggestion that a defect in S antigen is responsible for Oguchi disease. Molecular Genetics Fuchs et al. (1995) identified a homozygous 1-bp deletion in the SAG gene (1147delA; 181031.0001) in 5 of 6 unrelated Japanese patients with Oguchi disease. Nakazawa et al. (1998) reported 2 sibs with the SAG 1147delA mutation: one had Oguchi disease and the other had retinitis pigmentosa (RP47; 613758). In an Indian family in which 2 brothers had Oguchi disease, Maw et al. (1998) performed SSCP screening of the arrestin gene, which revealed a bandshift in exon 8 that was homozygous in the 2 patients, heterozygous in the unaffected parents and an unaffected sister, and absent in 80 Indian controls. Sequencing identified a nonsense mutation (R193X; 181031.0002) that segregated with disease in the family. Noting that some Oguchi patients with congenital night blindness subsequently undergo progressive pigmentary retinal degeneration, as seen in the 18-year-old brother, Maw et al. (1998) suggested that similar molecular pathologic events might be responsible for pigment formation in both Oguchi disease and some cases of retinitis pigmentosa. In 2 unrelated Japanese men with Oguchi disease, Nakamura et al. (2004) identified compound heterozygosity and homozygosity, respectively, for mutations in the SAG gene (258100.0001, 258100.0003 and 258100.0004). The authors noted that all of the known arrestin gene mutations associated with Oguchi disease were nonsense mutations or frameshift mutations with premature terminations that are likely null alleles, suggesting that only critical mutations cause the disorder. In a 15-year-old Pakistani girl with typical Oguchi disease, Waheed et al. (2012) identified homozygosity for a nonsense mutation (E306X; 181031.0005) in the SAG gene that was present in heterozygosity in her unaffected mother and 4 other unaffected relatives and was not found in a healthy control panel from the same population. The authors noted that the patient was also diagnosed with dural sinus thrombosis, thrombocytopenia, and systemic lupus erythematosus, which were not likely to be associated with the SAG variant. In addition, the patient, as well as 4 other family members, had hyperhomocysteinemia, which was found to segregate with the known 677C-T polymorphism in the MTHFR gene (607093.0003). INHERITANCE \- Autosomal recessive HEAD & NECK Eyes \- Night blindness, congenital stationary \- Yellow or gray discoloration of retina that disappears after prolonged dark adaptation MISCELLANEOUS \- Other visual functions, including visual acuity, visual field, and color vision, are usually normal in these patients MOLECULAR BASIS \- Caused by mutation in the S-antigen gene (SAG, 181031.0001 ) ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	OGUCHI DISEASE 1	c1306122	3,708	omim	https://www.omim.org/entry/258100	2019-09-22T16:24:08	{"doid": ["0110712"], "mesh": ["C537743"], "omim": ["258100"], "orphanet": ["75382"], "synonyms": ["Alternative titles", "NIGHT BLINDNESS, CONGENITAL STATIONARY, OGUCHI TYPE 1"]}
Italian conjoined twins Lazarus and his brother Joannes Baptista in a contemporary etching. Lazarus Colloredo and Joannes Baptista Colloredo (1617 – after 1646) were Italian conjoined twins who toured freak shows in 17th-century Europe. They were born in Genoa, Italy. The upper body and left leg of Joannes Baptista (named after John the Baptist) stuck out of his mobile brother, Lazarus. He did not speak, kept his eyes closed and mouth open all the time, and was a parasitic twin. According to a later account by Copenhagen anatomist Thomas Bartholinus, if someone pushed the breast of Joannes Baptista, he moved his hands, ears, and lips. To make a living, Lazarus toured around Europe and visited at least Basel, Switzerland and Copenhagen, Denmark before he arrived in Scotland in 1642 and later visited the court of Charles I of England. He also visited Danzig, Turkey, and toured Germany and Italy in 1646.[1] Contemporary accounts described Lazarus as courteous and handsome, but for his brother who just dangled before him. When Lazarus was not exhibiting himself, he covered his brother with his cloak to avoid unnecessary attention. Later accounts claim that Lazarus married and sired several children, none with his condition. His engraved portrait depicts him in a costume of a courtier of the period of the House of Stuart. As reported by Henri Sauval, Lazarus was sentenced to death for killing a man, but averted the execution by pointing out that this would also kill his innocent twin brother. The brothers' exact date of death is unknown. ## References[edit] 1. ^ Bondeson, Jan. (2000) The Two-Headed Boy, and Other Medical Marvels ISBN 978-0-8014-3767-0 ## Further Reading and Listening[edit] * Gould, George M. & Pyle, and Walter L. (1896) Anomalies and Curiosities of Medicine. Retrieved July 5, 2007. * "Lazarus and Johannes Baptista Colloredo." (n.d.). Phreeque.com. Retrieved July 5, 2007. * Baratta Luca (2018), ‘Due idee del mostruoso, due idee di nazione. I gemelli Colloredo a Londra (1637) in due ballate di Robert Milbourne e Martin Parker’, Rivista di Letterature Moderne e Comparate, 70(2), pp. 109-131 [ISSN 0391-2108]. * On November 27, 2020 The Ripple Podcast featured the story of Lazarus and Joannes Baptista Colloredo on Episode 46: A Medical Oddity from Italy: Parasitic Twins https://anchor.fm/ripplepod/episodes/A-Medical-Oddity-from-Italy-Parasitic-Twins-Episode-46-en25le [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Lazarus and Joannes Baptista Colloredo	None	3,709	wikipedia	https://en.wikipedia.org/wiki/Lazarus_and_Joannes_Baptista_Colloredo	2021-01-18T18:47:20	{"wikidata": ["Q1393097"]}
Postpoliomyelitis syndrome (PPS) is a neurologic disorder characterized by the development of new neuromuscular symptoms such as progressive muscular weakness or abnormal muscle fatigability occurring in survivors of the acute paralytic form of poliomyelitis (see this term), 15-40 years after recovery from the disease, and that is unexplained by other medical causes. Other manifestations that can occur gradually include generalized fatigue, muscle atrophy, muscle and joint pain, intolerance to cold, and difficulties sleeping, swallowing or breathing. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Postpoliomyelitis syndrome	c0080040	3,710	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=2942	2021-01-23T17:02:07	{"gard": ["4454"], "mesh": ["D016262"], "umls": ["C0080040"], "icd-10": ["G14"], "synonyms": ["Postpolio sequelae", "Postpolio syndrome", "Postpoliomyelitic syndrome", "Postpoliomyelitis sequelae"]}
An umbrella term covering two types of dementia Lewy body dementias (LBDs, or Lewy body disorders) describe two similar common dementias that are characterized by changes in thinking, movement, behavior, and mood.[1] They are dementia with Lewy bodies (DLB), and Parkinson's disease dementia (PDD).[2][3][4][5] Lewy body dementia is an umbrella term encompassing the two conditions.[1] The two conditions have similar features and may have similar causes, and are believed to belong on a spectrum of Lewy body disease[2] that includes Parkinson's disease.[5] As of 2014, they were more often misdiagnosed than any other common dementia.[6] The exact cause is unknown, but involves widespread deposits of abnormal clumps of protein that form in neurons of the diseased brain. Known as Lewy bodies (discovered in 1912 by Frederic Lewy[7]) and Lewy neurites, these clumps affect both the central nervous system and the autonomic nervous system.[8] ## Contents * 1 Classification * 2 Cause and mechanisms * 3 Diagnosis * 4 Epidemiology * 5 Society and culture * 5.1 Advocacy and awareness * 5.2 Notable individuals * 5.3 In popular culture * 6 Notes * 7 References * 8 External links ## Classification[edit] The synucleinopathies (dementia with Lewy bodies, Parkinson's disease dementia, and Parkinson's disease) are characterized by shared features of parkinsonism motor symptoms, neuropsychiatric symptoms, impaired cognition, sleep disorders, and visual hallucinations.[9][10] The Lewy body dementias – dementia with Lewy bodies (DLB), and Parkinson's disease dementia (PDD) are distinguished by the timing when cognitive and motor symptoms appear.[11] The two Lewy body dementias are often considered to belong on a spectrum of Lewy body disease that includes Parkinson's disease.[2][5] MeSH lists Lewy body disease in several categories: as a nervous system disease in two listings one as a basal ganglia Parkinsonian movement disorder and the other under brain disease as a dementia; as a neurodegenerative disorder listed as a synucleinopathy; and as a neurocognitive disorder listed with dementia.[12] ## Cause and mechanisms[edit] Further information: Dementia with Lewy bodies § Pathophysiology Dementia with Lewy bodies and Parkinson's disease dementia are similar in many ways, suggesting there may be a common pathophysiological mechanism, with PDD and DLB at opposite ends of a Lewy body disease spectrum,[2] and a shared component of protein deposits in Lewy bodies and Lewy neurites.[13] Lewy bodies and neurites have been found to develop from the aggregation of misfolded alpha-synuclein, a protein thought to assist in neurotransmitter release and vesicle turnover; whether these misfolded proteins are responsible for the neurodegenerative effects remains unclear, and no definitive link between Lewy bodies and neurodegenerative effects has been found.[14] Despite differences in the timing of the appearance of symptoms, the two dementias "show remarkably convergent neuropathological changes at autopsy".[2] The relationship between Parkinson's disease dementia and dementia with Lewy bodies is unclear as of 2020, but there is likely to be genetic overlap, and the two conditions may represent different points on a continuum.[15] ## Diagnosis[edit] Further information: Dementia with Lewy bodies § Diagnosis Dementia with Lewy bodies and Parkinson's disease dementia have similar neuropathological features, but these features are highly variable and the conditions cannot be distinguished on pathological features alone.[14] Generally, dementia with Lewy bodies is distinguished from Parkinson's disease dementia by the time frame in which dementia symptoms appear relative to parkinsonian symptoms and is diagnosed when cognitive symptoms begin before or at the same time as parkinsonism. Parkinson's disease dementia is the diagnosis when Parkinson's disease is already well established before the dementia occurs.[10] ## Epidemiology[edit] Between 5% and 25% of diagnosed dementias in older adults are due to Lewy body dementias.[11][a] As of 2014, the Lewy body dementias affect about 1.3 million people in the US and 140,000 in the UK.[6] LBD usually develops after the age of 50.[7] Men are more likely to be diagnosed than women.[7] ## Society and culture[edit] ### Advocacy and awareness[edit] As of 2014, the Lewy body dementias were more often misdiagnosed than any other common dementia.[6] Most people with DLB had not heard of the condition prior to diagnosis; general awareness about LBD lags well behind that of Parkinson's and Alzheimer's diseases, even though LBD is the second most common dementia, after Alzheimer's.[6] It is not only frustrating for families and caregivers to find that few people, including many healthcare professionals, are knowledgeable about LBD; lack of knowledge can have significant health consequences because people with LBD have severe sensitivity to antipsychotics often used to treat the symptoms.[6] The Lewy Body Dementia Association (LBDA) and the UK Lewy Body Society promote awareness and provide support that helps society, by reducing costly use of healthcare, and families with LBD, by reducing stress.[6] These organizations, and others in Argentina, Australia and Japan, help raise knowledge and help families with LBD become advocates to raise awareness about the disease.[6] ### Notable individuals[edit] Further information: List of people diagnosed with Parkinson's disease Robin Williams (shown in 2011): his widow said he was diagnosed on autopsy with Lewy bodies.[18][19] Robin Williams, the American actor and comedian, died on August 11, 2014. Before his suicide, he had been diagnosed with Parkinson's disease,[18] and according to his widow, Susan Schneider Williams, he experienced depression, anxiety, and increasing paranoia.[19] Upon autopsy, his widow said he was found to have diffuse Lewy body disease,[18][19][20] while the autopsy used the term diffuse Lewy body dementia.[21] Dennis Dickson, a spokesperson for the Lewy Body Dementia Association, clarified the distinction by stating that diffuse Lewy body dementia is more commonly called diffuse Lewy body disease and refers to the underlying disease process.[21] According to Dickson, "Lewy bodies are generally limited in distribution", while in dementia with Lewy bodies, "the Lewy bodies are spread widely throughout the brain, as was the case with Robin Williams."[21] Ian G. McKeith, professor and researcher of Lewy body dementias, commented that Williams' symptoms and autopsy findings were explained by dementia with Lewy bodies.[22] The British author and poet Mervyn Peake died in 1968 and was diagnosed posthumously as a probable case of DLB in a 2003 paper published in JAMA Neurology.[23] Sahlas said his death was "variously ascribed to Alzheimer disease, Parkinson disease, or postencephalitic parkinsonism".[23] Based on signs in his work and letters of progressive deterioration, fluctuating cognitive decline, deterioration in visuospatial function, declining attention span, and visual hallucinations and delusions, his may be the earliest known case where DLB was found to have been the likely cause of death.[23] Other entertainers and artists who have or died from LBD include Estelle Getty, an actress known for her role in the television series The Golden Girls,[24] Nicholas King, a US actor and horticulturist,[25] actress Dina Merrill,[26] Donald Featherstone, who created the plastic pink flamingo,[27] American radio and television host Casey Kasem,[28] Canadian singer Pierre Lalonde,[29][30] and graphic artist/film set designer Ron Cobb.[31] Individuals from industry or government who have or died from LBD are Seymour Berry, US Director of the Bureau of Engraving and Printing,[32] Los Angeles Times publisher Otis Chandler,[33] Philip J. Rock, a US Democratic politician of the Illinois Senate,[34] and U.S. media mogul and philanthropist Ted Turner.[35] Arnold R. Hirsch, an American historian who taught at the University of New Orleans,[36] and Jessie Isabelle Price, an American veterinary microbiologist,[37] died from LBD. In the sports realm, Jerry Sloan, American professional basketball player and coach, died from LBD.[38] Major League Baseball players Tom Seaver,[39] Andy Carey,[40] and Bill Buckner died of LBD.[41] Stan Mikita, Canadian ice hockey player, was diagnosed with possible LBD,[42] but a post-mortem brain autopsy found that he had chronic traumatic encephalopathy.[43] ### In popular culture[edit] Robin's Wish, a documentary exploring Williams' Lewy body disease and how it contributed to his death, was released in September 2020.[44][45][46] Sleepwalk with Me is a book, one-man comedy, and film about a young man with relationship problems and RBD, a precursor to synucleinopathy, including LBD.[47] ## Notes[edit] 1. ^ Kosaka (2017) writes: "Dementia with Lewy bodies (DLB) is now well known to be the second most frequent dementia following Alzheimer disease (AD). Of all types of dementia, AD is known to account for about 50%, DLB about 20% and vascular dementia (VD) about 15%. Thus, AD, DLB, and VD are now considered to be the three major dementias."[16] The NINDS (2020) says that Lewy body dementia "is one of the most common causes of dementia, after Alzheimer’s disease and vascular disease."[7] Hershey (2019) says, "DLB is the third most common of all the neurodegenerative diseases behind both Alzheimer's disease and Parkinson's disease".[17] ## References[edit] 1. ^ a b Walker Z, Possin KL, Boeve BF, Aarsland D (October 2015). "Lewy body dementias". Lancet (Review). 386 (10004): 1683–97. doi:10.1016/S0140-6736(15)00462-6. PMC 5792067. PMID 26595642. 2. ^ a b c d e Gomperts SN (April 2016). "Lewy Body Dementias: Dementia With Lewy Bodies and Parkinson Disease Dementia". Continuum (Minneap Minn). 22 (2 Dementia): 435–63. doi:10.1212/CON.0000000000000309. PMC 5390937. PMID 27042903. 3. ^ Pezzoli S, Cagnin A, Bandmann O, Venneri A (July 2017). "Structural and Functional Neuroimaging of Visual Hallucinations in Lewy Body Disease: A Systematic Literature Review". Brain Sci. 7 (12): 84. doi:10.3390/brainsci7070084. PMC 5532597. PMID 28714891. 4. ^ Galasko D (May 2017). "Lewy Body Disorders". Neurol Clin. 35 (2): 325–38. doi:10.1016/j.ncl.2017.01.004. PMC 5912679. PMID 28410662. 5. ^ a b c Kon T, Tomiyama M, Wakabayashi K (February 2020). "Neuropathology of Lewy body disease: Clinicopathological crosstalk between typical and atypical cases". Neuropathology. 40 (1): 30–39. doi:10.1111/neup.12597. PMID 31498507. S2CID 201983865. 6. ^ a b c d e f g Taylor A, Yardley C (2014). "Advocacy, education, and the role of not-for-profit organizations in Lewy body dementias". Alzheimers Res Ther (Review). 6 (5): 59. doi:10.1186/s13195-014-0059-0. PMC 4468791. PMID 26082807. 7. ^ a b c d "Lewy body dementia: Hope through research". National Institute of Neurological Disorders and Stroke. US National Institutes of Health. January 10, 2020. Retrieved March 18, 2020. 8. ^ Lin YW, Truong D (April 2019). "Diffuse Lewy body disease". J. Neurol. Sci. (Review). 399: 144–50. doi:10.1016/j.jns.2019.02.021. PMID 30807982. S2CID 72335064. 9. ^ Velayudhan L, Ffytche D, Ballard C, Aarsland D (September 2017). "New Therapeutic Strategies for Lewy Body Dementias". Curr Neurol Neurosci Rep (Review). 17 (9): 68. doi:10.1007/s11910-017-0778-2. PMID 28741230. S2CID 3739100. 10. ^ a b McKeith IG, Boeve BF, Dickson DW, et al. (July 2017). "Diagnosis and management of dementia with Lewy bodies: Fourth consensus report of the DLB Consortium". Neurology (Review). 89 (1): 88–100. doi:10.1212/WNL.0000000000004058. PMC 5496518. PMID 28592453. 11. ^ a b Connors MH, Quinto L, McKeith IG, et al. (August 2018). "Non-pharmacological interventions for Lewy body dementia: a systematic review". Psychol Med (Review). 48 (11): 1749–58. doi:10.1017/S0033291717003257. PMC 6088773. PMID 29143692. 12. ^ "MeSH Browser". meshb.nlm.nih.gov. Retrieved 17 November 2020. 13. ^ Weil RS, Lashley TL, Bras J, Schrag AE, Schott JM (2017). "Current concepts and controversies in the pathogenesis of Parkinson's disease dementia and Dementia with Lewy Bodies". F1000Res (Review). 6: 1604. doi:10.12688/f1000research.11725.1. PMC 5580419. PMID 28928962. 14. ^ a b Latimer CS, Montine TJ. "Epidemiology, pathology, and pathogenesis of dementia with Lewy bodies". UpToDate, Inc. Retrieved August 2, 2019. 15. ^ Taylor JP, McKeith IG, Burn DJ, et al. (February 2020). "New evidence on the management of Lewy body dementia" (PDF). Lancet Neurol (Review). 19 (2): 157–69. doi:10.1016/S1474-4422(19)30153-X. hdl:10871/36535. PMC 7017451. PMID 31519472. 16. ^ Kosaka K, ed. (2017). Dementia with Lewy bodies: clinical and biological aspects (1st ed.). Springer: Japan. doi:10.1007/978-4-431-55948-1. ISBN 978-4-431-55948-1. 17. ^ Hershey LA, Coleman-Jackson R (April 2019). "Pharmacological management of dementia with Lewy dodies". Drugs Aging (Review). 36 (4): 309–19. doi:10.1007/s40266-018-00636-7. PMC 6435621. PMID 30680679. 18. ^ a b c Gallman S (November 4, 2015). "Robin Williams' widow speaks: Depression didn't kill my husband". CNN. Archived from the original on November 4, 2015. Retrieved April 6, 2018. 19. ^ a b c Williams SS (September 2016). "The terrorist inside my husband's brain". Neurology. 87 (13): 1308–11. doi:10.1212/WNL.0000000000003162. PMID 27672165. 20. ^ Robbins R (September 30, 2016). "How Lewy body dementia gripped Robin Williams". Scientific American. Retrieved April 9, 2018. 21. ^ a b c "LBDA Clarifies Autopsy Report on Comedian, Robin Williams". Lewy Body Dementia Association. November 10, 2014. Archived from the original on August 12, 2020. Retrieved April 19, 2018. 22. ^ McKeith IG. "Robin Williams had dementia with Lewy bodies – so, what is it and why has it been eclipsed by Alzheimer's?". The Conversation. Archived from the original on November 4, 2016. Retrieved April 6, 2018. 23. ^ a b c Sahlas DJ (June 2003). "Dementia with Lewy bodies and the neurobehavioral decline of Mervyn Peake". Arch. Neurol. 60 (6): 889–92. doi:10.1001/archneur.60.6.889. PMID 12810496. 24. ^ Carlson M (July 24, 2008). "Obituary: Estelle Getty". theguardian.com. Archived from the original on September 2, 2013. Retrieved October 13, 2013. 25. ^ McLellan D (April 23, 2012). "Nicholas King dies at 79; actor helped preserve the Watts Towers". The Los Angeles Times. Retrieved April 19, 2018. 26. ^ Dangremond S (May 23, 2017). "Actress and philanthropist Dina Merrill dies at 93". Town and Country Magazine. Retrieved March 22, 2018. 27. ^ Woo E (June 24, 2015). "Don Featherstone dies at 79; creator of the plastic pink flamingo". Los Angeles Times. Retrieved March 22, 2018. 28. ^ Caffrey J (April 18, 2016). "Casey Kasem and a lesson about end-of-life care". CNN. Retrieved March 22, 2018. 29. ^ Papineau P (June 23, 2016). "L'idole d'une génération s'éteint" (in French). Le Devoir. Retrieved April 9, 2018. 30. ^ Belanger C (June 22, 2016). "Pierre Lalonde souffrait aussi de la démence à corps de Lewy" (in French). Le Journal de Montréal. Retrieved March 22, 2018. 31. ^ Bartlett R, Parker R (September 21, 2020). "Ron Cobb, designer of the 'Alien' Ship and the 'Back to the Future' DeLorean, dies at 83". www.hollywoodreporter.com. Retrieved September 26, 2020. 32. ^ "Seymour Berry, 86; Headed U.S. Agency". Washington Post. December 27, 2008. Retrieved April 19, 2018. 33. ^ Shaw D, Landsberg M (February 27, 2006). "L.A. icon Otis Chandler dies at 78". The Los Angeles Times. Archived from the original on April 26, 2007. Retrieved July 23, 2008. 34. ^ "Philip Rock, ex-Senate leader known for mentoring and bipartisanship, dies". Chicago Sun-Times. January 29, 2016. Archived from the original on February 1, 2016. Retrieved April 19, 2018. 35. ^ Deerwester J (September 28, 2018). "Ted Turner has Lewy Body Dementia". USA Today. Retrieved September 30, 2018. 36. ^ O'Donnell M (March 26, 2018). "Arnold R. Hirsch dies; analyzed Chicago segregation in influential book". Chicago Sun Times. Retrieved April 19, 2018. 37. ^ "Jessie Isabelle Price Dies On November 12". The Southampton Press. November 23, 2015. Retrieved April 19, 2018. 38. ^ "Hall of Fame coach Jerry Sloan passes away at 78". National Basketball Association (Press release). NBA Media Ventures, LLC. May 22, 2020. Retrieved June 8, 2020. 39. ^ Canova D (September 2, 2020). "Tom Seaver, Mets' star who won 3 Cy Young awards and 311 games, dead at 75". Fox News. Retrieved September 2, 2020. 40. ^ Weber B (January 7, 2012). "Andy Carey, Third Baseman for 1950s Yankees, Dies at 80". The New York Times. p. A26. Retrieved April 19, 2018. 41. ^ Kelly M (May 27, 2019). "Batting champ, All-Star Buckner dies at 69". MLB.com. Retrieved May 27, 2019. 42. ^ Kuc C (June 15, 2015). "For Stan Mikita, all the Blackhawks memories are gone". Chicago Tribune. Archived from the original on June 16, 2015. Retrieved March 22, 2018. 43. ^ "Study shows hockey Hall of Famer Stan Mikita suffered from CTE". USA Today. Associated Press. September 13, 2019. Retrieved June 8, 2020. 44. ^ Huff L (August 6, 2020). "Robin Williams' final days detailed in touching trailer for new documentary Robin's Wish". Entertainment Weekly. Retrieved August 7, 2020. 45. ^ Boone J. "Robin Williams' Struggles on Final Film Set Detailed by His Director". Entertainment Tonight. Retrieved 2020-08-20. 46. ^ VanHoose B. "Robin Williams' Final Days Revealed in Touching New Documentary Robin's Wish". People.com. Retrieved 2020-08-20. 47. ^ "Sleepwalk with Me: Comedian's sleep disorder experience comes to film". American Academy of Sleep Medicine. January 26, 2012. Retrieved April 22, 2018. ## External links[edit] Classification D * ICD-10: G31.8† F02.8* * MeSH: D020961 * 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]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Lewy body dementias	c1851958	3,711	wikipedia	https://en.wikipedia.org/wiki/Lewy_body_dementias	2021-01-18T18:58:32	{"gard": ["3243"], "mesh": ["D020961", "C565078"], "umls": ["C1851958", "C1851957"], "orphanet": ["1648"], "wikidata": ["Q1331905"]}
A rare subtype of pyoderma gangrenosum characterized by multiple painful, sterile pustules with a surrounding erythematous halo, predominantly occurring on the trunk and extensor surfaces of the limbs, and potentially persisting for months. Histopathology shows a dermal neutrophilic infiltrate and subcorneal neutrophilic micropustules. The condition is commonly associated with inflammatory bowel disease. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Pustular pyoderma gangrenosum	None	3,712	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=538866	2021-01-23T16:53:07	{"icd-10": ["L88"]}
Rare autoinflammatory condition STING-associated vasculopathy with onset in infancy Autosomal dominant pattern is the inheritance manner of this condition SpecialtyMedical genetics CausesMutations in the TMEM173 gene STING-associated vasculopathy with onset in infancy (SAVI[1]) is a rare autoinflammatory vasculopathy associated with the stimulator of interferon genes (STING) protein and characterised by severe skin lesions and interstitial lung disease. ## Contents * 1 Signs and symptoms * 2 Genetics * 3 Pathopysiology * 4 Diagnosis * 5 Treatment * 6 Epidemiology * 7 Research * 8 References ## Signs and symptoms[edit] The onset is in infancy. The skin lesions occur on cheeks, nose, fingers, toes and soles.[2] They may vary in appearance but frequently develop into non-healing ulcers. Interstitial lung disease is also common. Some individuals may not experience any obvious skin issues. All affected children fail to thrive.[citation needed] Other features include myositis and joint stiffness. Some children experience hyper mobility, and joint pain.[citation needed] Imaging: Chest X rays show sign consistent with interstitial lung disease.[citation needed] Bloods: Anemia, leukopenia, thrombocytosis, T cell lymphopenia with normal B cells and hypergammaglobulinemia may occur.[citation needed] Autoantibodies may be present including antinuclear, antiphospholipid, and anticardiolipin antibodies.[citation needed] The erythrocyte sedimentation rate and C reactive protein levels tend to be raised.[citation needed] Biopsies: Skin biopsies show inflammation of the capillaries and microthrombosis. Immunoglobulin M and C3 deposition may be present.[citation needed] Lung biopsies show alveolitis, follicular hyperplasia, B-cell germinal centers and interstitial fibrosis. Some children demonstrate pulmonary alveolar protianosis on Lavage.[citation needed] ## Genetics[edit] This condition is due to mutations in the TMEM173 gene. This gene is located on the long arm of chromosome 5 (5q31.2) and encodes the stimulator of interferon genes (STING) protein. There are 3 disease causing mutations in the dimerization domain of STING that cause SAVI; V155M, N154S, and V147L.[citation needed] ## Pathopysiology[edit] This only partly understood. The wild type protein (STING) is normally found in the cytoplasm of the cell. The mutant forms are located in the Golgi apparatus.[citation needed] ## Diagnosis[edit] The condition may be suspected on clinical grounds. The diagnosis is made by sequencing the TMEM173 gene.[citation needed] ## Treatment[edit] No specific treatment is known. Management is supportive. Research into the efficacy of a subgroup of medications known as JAK inhibitors is underway.[citation needed] ## Epidemiology[edit] This condition is considered rare, with 9 cases reported in the literature up to 2019.[citation needed] ## Research[edit] This condition was first described in 2014.[3] In 2017 a group led by Dr. Jonathan Miner at Washington University in St. Louis created a mouse model of SAVI. Dr. Miner's research team used CRISPR-CAS9 genome editing to introduce a mutation into the mouse STING gene (TMEM173)[4] that was analogous to a human SAVI-associated mutation. These mice, known as STING N153S mice, developed spontaneous lung disease and a severe immunodeficiency to a herpesviruses.[5] ## References[edit] 1. ^ Reference, Genetics Home. "SAVI". Genetics Home Reference. Retrieved 2019-02-21. 2. ^ Jeremiah N, Neven B, Gentili M, Callebaut I, Maschalidi S, Stolzenberg M-C, Goudin N, Fremond, M-L, Nitschke P, Molina TJ, Blanche S, Picard C, Rice GI, Crow YJ, Manel N, Fischer A, Bader-Meunier B, Rieux-Laucat, F (2014) Inherited STING-activating mutation underlies a familial inflammatory syndrome with lupus-like manifestations. J Clin Invest 124: 5516-5520 3. ^ Liu Y, Jesus AA, Marrero B, Yang D, Ramsey SE, Montealegre Sanchez GA, Tenbrock K, Wittkowski H, Jones OY, Kuehn HS, Lee C-C R, DiMattia M A, and 40 others. Activated STING in a vascular and pulmonary syndrome. New Eng J Med 371: 507-518 4. ^ Miner, Jonathan J.; Yan, Nan; Platt, Derek J.; Wu, Jianjun; Gonugunta, Vijay K.; Sakai, Tomomi; Miner, Cathrine A.; Smith, Amber M.; Ai, Teresa L. (2017-11-06). "STING-associated vasculopathy develops independently of IRF3 in mice". Journal of Experimental Medicine. 214 (11): 3279–3292. doi:10.1084/jem.20171351. ISSN 0022-1007. PMC 5679177. PMID 28951494. 5. ^ Miner, Jonathan J.; Baldridge, Megan T.; Smith, Amber M.; Platt, Derek J.; Miner, Cathrine A.; Ai, Teresa L.; Ingle, Harshad; Bennion, Brock G. (2019-02-15). "A Human Gain-of-Function STING Mutation Causes Immunodeficiency and Gammaherpesvirus-Induced Pulmonary Fibrosis in Mice". Journal of Virology. 93 (4): e01806–18. doi:10.1128/JVI.01806-18. ISSN 0022-538X. PMC 6364005. PMID 30463976. Classification D * ICD-10: M35.8 * OMIM: 615934 External resources * Orphanet: ORPHA:425120 [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	STING-associated vasculopathy with onset in infancy	c4014722	3,713	wikipedia	https://en.wikipedia.org/wiki/STING-associated_vasculopathy_with_onset_in_infancy	2021-01-18T18:30:33	{"gard": ["12357"], "umls": ["C4014722"], "orphanet": ["425120"], "wikidata": ["Q55784812"]}
## Description Splenogonadal fusion (SGF) is a rare congenital anomaly of abnormal fusion between the spleen and the gonad or the remnants of the mesonephros. In 'continuous SGF,' there is a cord-like connection between the 2 organs, whereas in 'discontinuous SGF,' there is fusion of accessory splenic tissue and the gonad without a distinct structural connection to the spleen itself. Forty-eight percent of individuals with continuous SGF have additional malformations, compared to 9% of those with discontinuous SGF (McPherson et al., 2003). Clinical Features Putschar and Manion (1956) first proposed that fusion of the spleen and gonad with accompanying ectromelia was a specific entity. Hives and Eggum (1961) reported a ninth case. Seven were stillborn or died in infancy; the eighth died at age 10. Their patient was 15 years old. Pauli and Greenlaw (1982) reported a 10-year-old boy with tetramelic limb deficiencies, splenogonadal fusion, and mild mandibular and oral abnormalities (micrognathia, multiple unerupted teeth, crowding of the upper incisors, and deep, narrow, V-shaped palate without cleft). They reviewed 14 cases in the literature. The extent of the terminal transverse hemimelia was variable. They suggested that the disorder is not 'invariably lethal.' This still may be a genetic lethal; procreation by an affected person has not been reported. Of the 15 cases, only 1 was female. Bonneau et al. (1999) reported 5 new cases of what they called splenogonadal fusion limb defect (SGFLD) syndrome and reviewed the 25 cases reported since 1989. Most cases had a combination of severe limb and oromandibular defects, suggesting that SGFLD may be related to the broader group of Hanhart complex. In addition, several cases had limb malformations and facial anomalies, which suggested that SGFLD overlaps with both femur-fibula-ulna dysostosis (228200) and femoral-facial syndrome (134780). A vascular disruptive event, occurring between the fifth and seventh weeks of gestation, could explain the limb defects, mandibular hypoplasia, and fusion of the spleen to the gonad observed in SGFLD. All reported cases were sporadic. McPherson et al. (2003) reported a 19-week male fetus with SGFLD. Postmortem analysis showed epicanthal folds, depressed nasal bridge, posteriorly angulated ears, and micrognathia. The upper lip and palate were intact. The right lower limb was a single, short, distally pointed leg bone with absence of 1 mesomelic leg bone of the foot and ankle; the right femur was bowed. The left lower limb was a single bent bone, possibly a tibia, with a single metatarsal and rudimentary digit. The upper limbs were unremarkable. Internal examination showed bilobed lungs, tetralogy of Fallot, malrotation of the small bowel, anal atresia, bilateral renal agenesis, absent urinary bladder, and enlarged adrenal glands. There was a cleft of the distal end of the spleen and a fibrous connection to the left testis. External genitalia were absent, but there was a midline 0.2-cm long skin tag resembling a penis. Chromosomal analysis showed a normal 46,XY karyotype. The authors postulated a developmental defect during blastogenesis, with earlier occurrence resulting in more severe manifestations. McPherson et al. (2003) stated that over 30 cases of SGFLD and 145 cases of SGF had been reported. GU \- Fused spleen and gonad Facies \- Micrognathia Inheritance \- Autosomal dominant Misc \- Usually stillborn or die in infancy \- Almost all male Limbs \- Ectromelia \- Tetramelic limb deficiencies \- Terminal transverse hemimelia Mouth \- Deep, narrow, V-shaped palate Teeth \- Multiple unerupted teeth \- Crowded upper incisors ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	SPLENOGONADAL FUSION WITH LIMB DEFECTS AND MICROGNATHIA	c1866745	3,714	omim	https://www.omim.org/entry/183300	2019-09-22T16:34:29	{"mesh": ["C537318"], "omim": ["183300"], "orphanet": ["2063"], "synonyms": ["Alternative titles", "SPLENOGONADAL FUSION LIMB DEFECT SYNDROME", "SGFLD SYNDROME"]}
## Clinical Features Say and Meyer (1981) observed trigonocephaly in 3 males in 3 maternally related sibships, consistent with X-linked recessive inheritance. Autosomal dominant inheritance with low expressivity in women could not be excluded. The oldest of the 3, aged 30, was 162 cm tall and was moderately mentally retarded. The other 2, nephews of this man, had a closed posterior fontanel, very small anterior fontanel, and a marked frontal vertical ridge; narrow forehead; hypotelorism and marked retardation in weight, height, head circumference, and psychomotor development. Normally the major sutures of the cranial vault close between 28 and 32 years of age; the metopic suture closes much earlier, usually during the second or third year of life. Say and Meyer (1981) found no similar reported case and specifically distinguished the disorder from the trigonocephaly with minor anomalies reported in mother and son by Hunter et al. (1976) and from the Opitz trigonocephaly syndrome (211750). Inheritance The transmission pattern of SAMES in the family reported by Say and Meyer (1981) was consistent with X-linked recessive inheritance. Molecular Genetics In 2 brothers, born of unrelated Indian parents, with features suggestive of Say-Meyer syndrome, including X-linked recessive inheritance, trigonocephaly, short stature, dysmorphic facial features, and impaired intellectual development, Muthusamy et al. (2019) identified a hemizygous splice site mutation in the HUWE1 gene (300697.0010). The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family; it was found in the unaffected mother. The molecular findings, as well as clinical features, confirmed that the patients had the Turner-type of X-linked mental retardation syndrome (MRXST; 309590). However, these patients were not part of the original family reported by Say and Meyer (1981). INHERITANCE \- X-linked recessive GROWTH Height \- Short stature Other \- Small for gestational age HEAD & NECK Head \- Premature posterior fontanelle closure \- Small anterior fontanelle \- Trigonocephaly Face \- Narrow forehead Ears \- Low-set ears \- Posteriorly rotated ears Eyes \- Hypotelorism \- Epicanthal folds Nose \- Wide nasal bridge \- Beaked nose Mouth \- Secondary alveolar ridges \- High-arched palate CARDIOVASCULAR Heart \- Ventricular septal defect GENITOURINARY External Genitalia (Male) \- Inguinal hernia SKELETAL Skull \- Craniosynostosis (metopic, sagittal, lambdoid) Hands \- Fifth finger clinodactyly NEUROLOGIC Central Nervous System \- Developmental delay \- Seizures \- Mental retardation ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	TRIGONOCEPHALY WITH SHORT STATURE AND DEVELOPMENTAL DELAY	c1839125	3,715	omim	https://www.omim.org/entry/314320	2019-09-22T16:17:10	{"mesh": ["C536620"], "omim": ["314320"], "orphanet": ["3369"], "synonyms": ["Alternative titles", "SAY-MEYER SYNDROME"]}
Alcoholic polyneuropathy Other namesAlcohol leg An illustration of a neuron's structure. In alcoholic polyneuropathy myelin loss and axonal degeneration occurs. SpecialtyNeurology Alcoholic polyneuropathy is a neurological disorder in which peripheral nerves throughout the body malfunction simultaneously. It is defined by axonal degeneration in neurons of both the sensory and motor systems and initially occurs at the distal ends of the longest axons in the body. This nerve damage causes an individual to experience pain and motor weakness, first in the feet and hands and then progressing centrally. Alcoholic polyneuropathy is caused primarily by chronic alcoholism; however, vitamin deficiencies are also known to contribute to its development. This disease typically occurs in chronic alcoholics who have some sort of nutritional deficiency. Treatment may involve nutritional supplementation, pain management, and abstaining from alcohol. ## Contents * 1 Signs and symptoms * 1.1 Sensory * 1.2 Motor * 2 Causes * 3 Pathophysiology * 4 Diagnosis * 5 Management * 5.1 Nutrition * 5.2 Pain * 6 Prognosis * 7 Epidemiology * 7.1 Acetaldehyde * 8 History * 9 Research directions * 10 References * 11 External links ## Signs and symptoms[edit] Alcoholic polyneuropathy usually has a gradual onset over months or even years although axonal degeneration often begins before an individual experiences any symptoms.[1] An early warning sign (prodrome) of the possibility of developing alcoholic polyneuropathy, especially in a chronic alcoholic, would be weight loss because this usually signifies a nutritional deficiency that can lead to the development of the disease.[2] The disease typically involves sensory and motor loss, as well as painful physical perceptions (paresthesias), though all sensory modalities may be involved.[3] Symptoms that affect the sensory and motor systems seem to develop symmetrically. For example, if the right foot is affected, the left foot is affected simultaneously or soon becomes affected.[2] In most cases, the legs are affected first, followed by the arms. The hands usually become involved when the symptoms reach above the ankle.[3] This is called a stocking-and-glove pattern of sensory disturbances.[4] Polyneuropathy spans a large range of severity. Some cases are seemingly asymptomatic and may only be recognized on careful examination. The most severe cases may cause profound physical disability.[2] ### Sensory[edit] Common manifestations of sensory issues include numbness or painful sensations in the arms and legs, abnormal sensations like “pins and needles,” and heat intolerance.[5] Pain experienced by individuals depends on the severity of the polyneuropathy. It may be dull and constant in some individuals while being sharp and lancinating in others.[4] In many subjects, tenderness is seen upon the palpitation of muscles in the feet and legs.[2] Certain people may also feel cramping sensations in the muscles affected and others say there is a burning sensation in their feet and calves.[4] ### Motor[edit] Sensory symptoms are gradually followed by motor symptoms.[3] Motor symptoms may include muscle cramps and weakness, erectile dysfunction in men, problems urinating, constipation, and diarrhea.[3] Individuals also may experience muscle wasting and decreased or absent deep tendon reflexes.[2] Some people may experience frequent falls and gait unsteadiness due to ataxia. This ataxia may be caused by cerebellar degeneration, sensory ataxia, or distal muscle weakness.[4] Over time, alcoholic polyneuropathy may also cause difficulty swallowing (dysphagia), speech impairment (disarthria), muscle spasms, and muscle atrophy.[5] In addition to alcoholic polyneuropathy, the individual may also show other related disorders such as Wernicke–Korsakoff syndrome and cerebellar degeneration that result from alcoholism-related nutritional disorders.[2] ## Causes[edit] The general cause of this disease is prolonged and heavy consumption of alcohol accompanied by a nutritional deficiency. There is some debate over whether the main cause is the direct toxic effect of alcohol itself or whether the disease is a result of alcoholism-related malnutrition.[2] Frequently alcoholics have disrupted social links in their lives and have an irregular lifestyle. This may cause an alcoholic to change their eating habits including more missed meals and a poor dietary balance.[6] Alcoholism may also result in loss of appetite, alcoholic gastritis, and vomiting, which decrease food intake. Alcohol abuse damages the lining of the gastrointestinal system and reduces absorption of nutrients that are taken in.[7] The combination of all of them may result in a nutritional deficiency that is linked to the development of alcoholic polyneuropathy.[6] There is evidence that providing individuals with adequate vitamins improves symptoms despite continued alcohol intake, indicating that vitamin deficiency may be a major factor in the development and progression of alcoholic polyneuropathy.[1] In model experimental models of alcoholic polyneuropathy utilizing rats and monkeys no convincing evidence was found that proper nutritional intake along with alcohol results in polyneuropathy.[2] In addition, the consumption of alcohol may lead to the buildup of certain toxins in the body. For example, in the process of breaking down alcohol, the body produces acetaldehyde, which can accumulate to toxic levels in alcoholics. This suggests that there is a possibility ethanol (or its metabolites) may cause alcoholic polyneuropathy.[4] There is evidence that polyneuropathy is also prevalent in well nourished alcoholics, supporting the idea that there is a direct toxic effect of alcohol. Many of the studies conducted that observe alcoholic polyneuropathy in patients are often criticized for their criteria used to assess nutritional deficiency in the subjects because they may not have completely ruled out the possibility of a nutritional deficiency in the genesis of the polyneuropathy.[2] Many researchers favor the nutritional origin of this disease, but the possibility of alcohol having a toxic effect on the peripheral nerves has not been completely ruled out.[2] ## Pathophysiology[edit] Thiamine pyrophosphate structure. As a result of nutritional deficiency in those with alcoholic polyneuropathy, low thiamine levels are usually present and have been proposed as a cause of the nerve destruction. The pathophysiology of alcoholic polyneuropathy is an area of current research. Damage to the nervous system takes place before symptoms appear in individuals, beginning with segmental thinning and loss of myelin on the peripheral ends of the longest nerves. Segmental thinning is the demyelination of axons in small sections at a time. This occurrence increases leakage of an action potential current down the axon, so it is weakest at the peripheral end. Decrease in current causes further thinning of myelin.[1] In most cases, individuals with alcoholic polyneuropathy have some degree of nutritional deficiency. Alcohol, a carbohydrate, increases the metabolic demand for thiamine (vitamin B1) because of its role in the metabolism of glucose. Thiamine levels are usually low in alcoholics due to their decreased nutritional intake. In addition, alcohol interferes with intestinal absorption of thiamine, thereby further decreasing thiamine levels in the body.[8] Thiamine is important in three reactions in the metabolism of glucose: the decarboxylation of pyruvic acid, d-ketoglutaric acid, and transketolase. A lack of thiamine in the cells may therefore prevent neurons from maintaining necessary adenosine triphosphate (ATP) levels as a result of impaired glycolosis. Thiamine deficiency alone could explain the impaired nerve conduction in those with alcoholic polyneuropathy, but other factors likely play a part.[1] The metabolic effects of liver damage associated with alcoholism may also contribute to the development of alcoholic polyneuropathy. Normal products of the liver, such as lipoic acid, may be deficient in alcoholics. This deficiency would also disrupt glycolosis and alter metabolism, transport, storage, and activation of essential nutrients.[1] The malnutrition many alcoholics suffer deprives them of important cofactors for the oxidative metabolism of glucose. Neural tissues depend on this process for energy, and disruption of the cycle would impair cell growth and function. Schwann cells produce myelin that wraps around the sensory and motor nerve axons to enhance action potential conduction in the periphery. An energy deficiency in Schwann cells would account for the disappearance of myelin on peripheral nerves, which may result in damage to axons or loss of nerve function altogether. In peripheral nerves, oxidative enzyme activity is most concentrated around the nodes of Ranvier, making these locations most vulnerable to cofactor deprivation. Lacking essential cofactors reduces myelin impedance, increases current leakage, and slows signal transmission. Disruptions in conductance first affect the peripheral ends of the longest and largest peripheral nerve fibers because they suffer most from decreased action potential propagation. Thus, neural deterioration occurs in an accelerating cycle: myelin damage reduces conductance, and reduced conductance contributes to myelin degradation. The slowed conduction of action potentials in axons causes segmental demyelination extending proximally; this is also known as retrograde degeneration.[1] Acetaldehyde is toxic to peripheral nerves. There are increased levels of acetaldehyde produced during ethanol metabolism. If the acetaldehyde is not metabolized quickly the nerves may be affected by the accumulation of acetaldehyde to toxic levels.[4][9] ## Diagnosis[edit] Alcoholic polyneuropathy is very similar to other axonal degenerative polyneuropathies and therefore can be difficult to diagnose. When alcoholics have sensorimotor polyneuropathy as well as a nutritional deficiency, a diagnosis of alcoholic polyneuropathy is often reached.[2][10] To confirm the diagnosis, a physician must rule out other causes of similar clinical syndromes. Other neuropathies can be differentiated on the basis of typical clinical or laboratory features.[10] Differential diagnoses to alcoholic polyneuropathy include amyotrophic lateral sclerosis, beriberi, Charcot-Marie-Tooth disease, diabetic lumbosacral plexopathy, Guillain Barre Syndrome, diabetic neuropathy, mononeuritis multiplex and post-polio syndrome.[3] To clarify the diagnosis, medical workup most commonly involves laboratory tests, though, in some cases, imaging, nerve conduction studies, electromyography, and vibrometer testing may also be used.[3] A number of tests may be used to rule out other causes of peripheral neuropathy. One of the first presenting symptoms of diabetes mellitus may be peripheral neuropathy, and hemoglobin A1C can be used to estimate average blood glucose levels. Elevated blood creatinine levels may indicate chronic kidney disease and may also be a cause of peripheral neuropathy. A heavy metal toxicity screen should also be used to exclude lead toxicity as a cause of neuropathy.[3] Alcoholism is normally associated with nutritional deficiencies, which may contribute to the development of alcoholic polyneuropathy. Thiamine, vitamin B-12, and folic acid are vitamins that play an essential role in the peripheral and central nervous system and should be among the first analyzed in laboratory tests.[3] It has been difficult to assess thiamine status in individuals due to difficulties in developing a method to directly assay thiamine in the blood and urine.[2] A liver function test may also be ordered, as alcoholic consumption may cause an increase in liver enzyme levels.[3] ## Management[edit] Although there is no known cure for alcoholic polyneuropathy, there are a number of treatments that can control symptoms and promote independence. Physical therapy is beneficial for strength training of weakened muscles, as well as for gait and balance training.[3] ### Nutrition[edit] An intravenous home parenteral nutrition formula may be a part of the treatment plan for those with alcoholic polyneuropathy who also suffer from nutritional deficiency. To best manage symptoms, refraining from consuming alcohol is essential. Abstinence from alcohol encourages proper diet and helps prevent progression or recurrence of the neuropathy.[10] Once an individual stops consuming alcohol it is important to make sure they understand that substantial recovery usually isn't seen for a few months. Some subjective improvement may appear right away, but this is usually due to the overall benefits of alcohol detoxification.[8] If alcohol consumption continues, vitamin supplementation alone is not enough to improve the symptoms of most individuals.[4] Nutritional therapy with parenteral multivitamins is beneficial to implement until the person can maintain adequate nutritional intake.[2] Treatments also include vitamin supplementation (especially thiamine). In more severe cases of nutritional deficiency 320 mg/day of benfotiamine for 4 weeks followed by 120 mg/day for 4 more weeks may be prescribed in an effort to return thiamine levels to normal.[4] ### Pain[edit] Painful dysesthesias caused by alcoholic polyneuropathy can be treated by using gabapentin or amitriptyline in combination with over-the-counter pain medications, such as aspirin, ibuprofen, or acetaminophen. Tricyclic antidepressants such as amitriptyline, or carbamazepine may help stabbing pains and have central and peripheral anticholinergic and sedative effects. These agents have central effects on pain transmission and block the active reuptake of norepinephrine and serotonin.[3][5] Anticonvulsant drugs like gabapentin block the active reuptake of norepinephrine and serotonin and have properties that relieve neuropathic pain. However, these medications take a few weeks to become effective and are rarely used in the treatment of acute pain.[3] Topical analgesics like capsaicin may also relieve minor aches and pains of muscles and joints.[3] ## Prognosis[edit] It is difficult to assess the prognosis of a patient because it is hard to convince chronic alcoholics to abstain from drinking alcohol completely. It has been shown that a good prognosis may be given for mild neuropathy if the alcoholic has abstained from drinking for 3–5 years.[9] During the early stages of the disease the damage appears reversible when people take adequate amounts of vitamins, such as thiamine.[1] If the polyneuropathy is mild, the individual normally experiences a significant improvement and symptoms may be completely eliminated within weeks to months after proper nutrition is established.[2] When those people diagnosed with alcohol polyneuropathy experience a recovery, it is presumed to result from regeneration and collateral sprouting of the damaged axons.[4] As the disease progresses, the damage may become permanent. In severe cases of thiamine deficiency, a few of the positive symptoms (including neuropathic pain) may persist indefinitely.[9] Even after the restoration of a balanced nutritional intake, those patients with severe or chronic polyneuropathy may experience lifelong residual symptoms.[2] Alcoholic polyneuropathy is not life-threatening but may significantly affect one's quality of life. Effects of the disease range from mild discomfort to severe disability.[5] ## Epidemiology[edit] Total recorded alcohol consumption per capita of individuals 15 years or older, in liters of pure alcohol. Alcoholism is the main cause of alcoholic polyneuropathy. The rate of incidence of alcoholic polyneuropathy involving sensory and motor polyneuropathy varies from 10% to 50% of alcoholics depending on the subject selection and diagnostic criteria. If electrodiagnostic criteria is used, alcoholic polyneuropathy may be found in up to 90% of individuals being assessed.[4] The distribution and severity of the disease depends on regional dietary habits, individual drinking habits, as well as an individual's genetics.[9] Large studies have been conducted and show that alcoholic polyneuropathy severity and incidence correlates best with the total lifetime consumption of alcohol. Factors such as nutritional intake, age, or other medical conditions are correlate in lesser degrees.[8] For unknown reasons, alcoholic polyneuropathy has a high incidence in women.[4] Certain alcoholic beverages can also contain congeners that may also be bioactive; therefore, the consumption of varying alcoholic beverages may result in different health consequences.[9] An individual's nutritional intake also plays a role in the development of this disease. Depending on the specific dietary habits, they may have a deficiency of one or more of the following: thiamine (vitamin B1), pyridoxine (vitamin B6), pantothenic acid and biotin, vitamin B12, folic acid, niacin (vitamin B3), and vitamin A.[5] ### Acetaldehyde[edit] Conversion of ethanol to acetaldehyde. The toxic buildup of acetaldehyde may result in alcoholic polyneuropathy. Main article: Acetaldehyde It is also thought there is perhaps a genetic predisposition for some alcoholics that results in increased frequency of alcoholic polyneuropathy in certain ethnic groups. During the body's processing of alcohol, ethanol is oxidized to acetaldehyde mainly by alcohol dehydrogenase; acetaldehyde is then oxidized to acetate mainly by aldehyde dehydrogenase (ALDH). ALDH2 is an isozyme of ALDH and ALDH2 has a polymorphism (ALDH22, Glu487Lys) that makes ADLH2 inactive; this allele is more prevalent among Southeast and East Asians and results in a failure to quickly metabolize acetaldehyde. The neurotoxicity resulting from the accumulation of acetaldehyde may play a role in the pathogenesis of alcoholic polyneuropathy.[4][9] ## History[edit] John C. Lettsome noted in 1787 hyperesthesia and paralysis in legs more than arms of patients, a characteristic of alcoholic polyneuropathy. The first description of symptoms associated with alcoholic polyneuropathy were recorded by John C. Lettsome in 1787 when he noted hyperesthesia and paralysis in legs more than arms of patients.[1] Jackson has also been credited with describing polyneuropathy in chronic alcoholics in 1822. The clinical title of alcoholic polyneuropathy was widely recognized by the late nineteenth century. It was thought that the polyneuropathy was a direct result of the toxic effect alcohol had on peripheral nerves when used excessively. In 1928, George C. Shattuck argued that the polyneuropathy resulted from a vitamin B deficiency commonly found in alcoholics and he claimed that alcoholic polyneuropathy should be related to beriberi. This debate continues today over what exactly causes this disease, some argue it is just the alcohol toxicity, others claim the vitamin deficiencies are to blame and still others say it is some combination of the two.[2] ## Research directions[edit] The mechanism of axonal degeneration has not been clarified and is an area of continuing research on alcoholic polyneuropathy.[9] Further research is looking at the effect an alcoholics’ consumption and choice of alcoholic beverage on their development of alcoholic polyneuropathy. Some beverages may include more nutrients than others (such as thiamine), but the effects of this with regards to helping with a nutritional deficiency in alcoholics is yet unknown.[7] There is still controversy about the reasons for the development of alcoholic polyneuropathy. Some argue it is a direct result of alcohol's toxic effect on the nerves, but others say factors such as a nutritional deficiency or chronic liver disease may play a role in the development as well. This debate is ongoing and research is continuing in an effort to discover the real cause of alcoholic polyneuropathy.[8] ## References[edit] 1. ^ a b c d e f g h Mawdsley, C.; Mayer, R. F. (1965). "Nerve Conduction in Alcoholic Polyneuropathy". Brain. 88 (2): 335–356. doi:10.1093/brain/88.2.335. PMID 4284013. 2. ^ a b c d e f g h i j k l m n o p Aminoff, Michael J.; Brown, William A.; Bolton, Charles Francis (2002). Neuromuscular function and disease: basic, clinical and electrodiagnostic aspects. Philadelphia: W. B. Saunders. pp. 1112–1115. ISBN 978-0-7216-8922-7. 3. ^ a b c d e f g h i j k l m Laker, SR; Sullivan, WJ. "Alcoholic Neuropathy". eMedicine. Medscape. Retrieved 18 March 2011. 4. ^ a b c d e f g h i j k l Roongroj Bhidayasiri; Lisak, Robert P.; Daniel Truong; Carroll, William K. (2009). International Neurology. Wiley-Blackwell. pp. 413–414. ISBN 978-1-4051-5738-4. 5. ^ a b c d e MedlinePlus; National Library of Medicine (20 February 2011). "Alcoholic Polyneuropathy". National Institute of Health. 6. ^ a b Preedy, Victor R.; Watson, Ronald R. (2004). Nutrition and alcohol: linking nutrient interactions and dietary intake. Boca Raton: CRC Press. pp. 7–13. ISBN 978-0-8493-1680-7. 7. ^ a b Vittadini G, Buonocore M, Colli G, Terzi M, Fonte R, Biscaldi G (2001). "Alcoholic Polyneuropathy: A Clinical and Epidemiological Study". Alcohol and Alcoholism. 36 (5): 393–400. doi:10.1093/alcalc/36.5.393. PMID 11524304. 8. ^ a b c d Cornblath, David R.; Jerry R. Mendell; Kissel, John T. (2001). Diagnosis and management of peripheral nerve disorders. Oxford [Oxfordshire]: Oxford University Press. pp. 332–334. ISBN 978-0-19-513301-1. 9. ^ a b c d e f g Koike, H; Sobue, G (2006). "Alcoholic Neuropathy". Current Opinion in Neurology. 19 (5): 481–486. doi:10.1097/01.wco.0000245371.89941.eb. ISSN 1350-7540. PMID 16969158. 10. ^ a b c Shields Jr., RW (Mar–Apr 1985). "Alcoholic Polyneuropathy". Muscle & Nerve. 8 (3): 183–187. doi:10.1002/mus.880080302. PMID 4058462. ## External links[edit] Classification D ICD-10: G62.1 * ICD-9-CM: 357.5 * MeSH: D020269 * DiseasesDB: 9850 External resources * MedlinePlus: 000714 * eMedicine: article/315159 * v * t * e Diseases relating to the peripheral nervous system Mononeuropathy Arm median nerve * Carpal tunnel syndrome * Ape hand deformity ulnar nerve * Ulnar nerve entrapment * Froment's sign * Ulnar tunnel syndrome * Ulnar claw radial nerve * Radial neuropathy * Wrist drop * Cheiralgia paresthetica long thoracic nerve * Winged scapula * Backpack palsy Leg lateral cutaneous nerve of thigh * Meralgia paraesthetica tibial nerve * Tarsal tunnel syndrome plantar nerve * Morton's neuroma superior gluteal nerve * Trendelenburg's sign sciatic nerve * Piriformis syndrome Cranial nerves * See Template:Cranial nerve disease Polyneuropathy and Polyradiculoneuropathy HMSN * Charcot–Marie–Tooth disease * Dejerine–Sottas disease * Refsum's disease * Hereditary spastic paraplegia * Hereditary neuropathy with liability to pressure palsy * Familial amyloid neuropathy Autoimmune and demyelinating disease * Guillain–Barré syndrome * Chronic inflammatory demyelinating polyneuropathy Radiculopathy and plexopathy * Brachial plexus injury * Thoracic outlet syndrome * Phantom limb Other * Alcoholic polyneuropathy Other General * Complex regional pain syndrome * Mononeuritis multiplex * Peripheral neuropathy * Neuralgia * Nerve compression syndrome * v * t * e Psychoactive substance-related disorder General * SID * Substance intoxication / Drug overdose * Substance-induced psychosis * Withdrawal: * Craving * Neonatal withdrawal * Post-acute-withdrawal syndrome (PAWS) * SUD * Substance abuse / Substance-related disorders * Physical dependence / Psychological dependence / Substance dependence Combined substance use * SUD * Polysubstance dependence * SID * Combined drug intoxication (CDI) Alcohol SID Cardiovascular diseases * Alcoholic cardiomyopathy * Alcohol flush reaction (AFR) Gastrointestinal diseases * Alcoholic liver disease (ALD): * Alcoholic hepatitis * Auto-brewery syndrome (ABS) Endocrine diseases * Alcoholic ketoacidosis (AKA) Nervous system diseases * Alcohol-related dementia (ARD) * Alcohol intoxication * Hangover Neurological disorders * Alcoholic hallucinosis * Alcoholic polyneuropathy * Alcohol-related brain damage * Alcohol withdrawal syndrome (AWS): * Alcoholic hallucinosis * Delirium tremens (DTs) * Fetal alcohol spectrum disorder (FASD) * Fetal alcohol syndrome (FAS) * Korsakoff syndrome * Positional alcohol nystagmus (PAN) * Wernicke–Korsakoff syndrome (WKS, Korsakoff psychosis) * Wernicke encephalopathy (WE) Respiratory tract diseases * Alcohol-induced respiratory reactions * Alcoholic lung disease SUD * Alcoholism (alcohol use disorder (AUD)) * Binge drinking Caffeine * SID * Caffeine-induced anxiety disorder * Caffeine-induced sleep disorder * Caffeinism * SUD * Caffeine dependence Cannabis * SID * Cannabis arteritis * Cannabinoid hyperemesis syndrome (CHS) * SUD * Amotivational syndrome * Cannabis use disorder (CUD) * Synthetic cannabinoid use disorder Cocaine * SID * Cocaine intoxication * Prenatal cocaine exposure (PCE) * SUD * Cocaine dependence Hallucinogen * SID * Acute intoxication from hallucinogens (bad trip) * Hallucinogen persisting perception disorder (HPPD) Nicotine * SID * Nicotine poisoning * Nicotine withdrawal * SUD * Nicotine dependence Opioids * SID * Opioid overdose * SUD * Opioid use disorder (OUD) Sedative / hypnotic * SID * Kindling (sedative–hypnotic withdrawal) * benzodiazepine: SID * Benzodiazepine overdose * Benzodiazepine withdrawal * SUD * Benzodiazepine use disorder (BUD) * Benzodiazepine dependence * barbiturate: SID * Barbiturate overdose * SUD * Barbiturate dependence Stimulants * SID * Stimulant psychosis * amphetamine: SUD * Amphetamine dependence Volatile solvent * SID * Sudden sniffing death syndrome (SSDS) * Toluene toxicity * SUD * Inhalant abuse [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Alcoholic polyneuropathy	c0085677	3,716	wikipedia	https://en.wikipedia.org/wiki/Alcoholic_polyneuropathy	2021-01-18T18:31:33	{"mesh": ["D020269"], "umls": ["C0085677"], "wikidata": ["Q4062508"]}
A number sign (#) is used with this entry because familial spinal neurofibromatosis is caused by heterozygous mutation in the neurofibromin gene (NF1; 613113) on chromosome 17q11. Description Spinal neurofibromatosis is an autosomal dominant disorder characterized by a high load of spinal tumors. These tumors may be asymptomatic or result in neurologic symptoms, including back pain, difficulty walking, and paresthesias. Spinal NF is considered to be a subtype of neurofibromatosis type I (NF1; 162200), which is an allelic disorder. Patients with spinal NF may or may not have the classic cutaneous cafe-au-lait pigmentary macules or ocular Lisch nodules typically observed in patients with classic NF1. Patients with spinal NF should be followed closely for spinal sequelae (summary by Burkitt Wright et al., 2013). Clinical Features Pulst et al. (1991) reported 2 families with spinal neurofibromatosis. The first family also had cafe-au-lait spots, whereas the second family had no cafe-au-lait spots. Other signs of neurofibromatosis I (NF1; 162200) or neurofibromatosis type II (NF2; 101000), such as cutaneous tumors, Lisch nodules, or acoustic tumors, were absent in both families. Poyhonen et al. (1997) described a family in which 7 members in 3 generations had spinal neurofibromatosis. The affected adults showed, at the ages of 32, 37, 38, and 61 years, respectively, multiple spinal neurofibromas symmetrically affecting all spinal roots. Two patients were operated on for histopathologically proven cervical spinal neurofibromas. All patients had cafe-au-lait spots, 1 had several freckles in the axillary area, and 2 had possible dermal neurofibromas, but iris Lisch nodules were not present. Other signs of neurofibromatosis type I and type II were absent. Several patients had lower extremity weakness. Ars et al. (1998) reported a 3-generation family in which 5 members, all female, had spinal neurofibromatosis. All presented with multiple spinal neurofibromas and cafe-au-lait spots. The oldest affected patient was a 58-year-old woman who had developed progressive paraparesis of her legs and right arm at age 45 years. She had multiple cafe-au-lait spots, but no cutaneous neurofibromas. Her affected daughter was a 34-year-old woman who had surgery at 16 years of age to remove a mediastinal neurofibroma. She had multiple cafe-au-lait spots and 3 cutaneous neurofibromas. At age 23 years, she developed signs of progressive spastic paraparesis. Another 24-year-old daughter had multiple cafe-au-lait spots and a history of surgical resection of a plexiform neurofibroma on the right arm. Multiple intra- and extraspinal neurofibromas were demonstrated. A third woman in the second generation, aged 21 years, had multiple cafe-au-lait spots and Lisch nodules, as well as spinal tumors. An affected member of the third generation, a 12-year-old girl, had multiple cafe-au-lait spots and Lisch nodules. Spinal MRI showed multiple bilateral tumors from C2 to D4 and 2 paravertebral masses. Kaufmann et al. (2001) reported 2 unrelated families with spinal neurofibromatosis but without cafe-au-lait macules. The 32-year-old proposita in the first family had an intrathoracic upper mediastinal tumor detected at age 17 years. Subsequent MRI examinations detected multiple tumors of the psoas muscle and cervical and lumbar spine. Two of the spinal tumors were surgically excised and identified as a schwannoma and neurofibroma. In addition, a subcutaneous neurofibroma and a subcutaneous schwannoma were excised. Tumors in the CNS typical of NF2 were not found. She had no cafe-au-lait macules, intertriginous freckling, or Lisch nodules. There were no signs of mental retardation or scoliosis. The 31-year-old proposita from the second family observed multiple painful intradermal tumors of the extremities and trunk at the age of 17 years, 1 of which was identified as a neurofibroma. Another tumor, identified histologically as a schwannoma, was excised from the thoracic spine at age 29 years. Multiple spinal tumors were identified by MRI scans in all segments of the spine, especially in C5/C6. Other symptoms typical of NF1, such as cafe-au-lait macules, freckles, Lisch nodules, scoliosis, or tumors of the CNS, were not found. The patient's mother had 2 lumbar hyperpigmentations and presented with acute lumbago. MRI scan showed enlarged spinal nerves in all segments of the spine. Burkitt Wright et al. (2013) reported 5 families with spinal neurofibromatosis. Most of the probands presented with neurologic symptoms in adulthood and were found to have spinal tumors on imaging; they usually had no pigmentary features or subcutaneous neurofibromas. Affected family members were subsequently identified when screened by imaging and/or molecular studies. A range of mutations was found in the NF1 gene in these families, with no specific mutation type associated with the presentation. Inheritance The transmission pattern of spinal neurofibromatosis in the families reported by Pulst et al. (1991) was consistent with autosomal dominant inheritance, with at least 1 instance of male-to-male transmission in each family. Mapping Using genetic linkage analysis with DNA markers tightly linked to the NF1 and NF2 loci, Pulst et al. (1991) determined that the likely location for the mutation in a family with spinal neurofibromatosis and cafe-au-lait spots was in the NF1 gene with odds of 97:1, whereas the mutation in a second family, with spinal neurofibromatosis but without cafe-au-lait spots, was excluded from the NF1 locus with odds of more than 100,000:1. However, markers for the NF2 locus were uninformative in the unlinked family. Linkage study of the affected family reported by Poyhonen et al. (1997) suggested close linkage to the NF1 locus and excluded linkage with the NF2 locus. DNA analysis of histopathologically verified spinal neurofibromas in 2 patients showed no evidence of loss of heterozygosity (LOH) at 17q11.2. Poyhonen et al. (1997) suggested that the disorder was a clinically distinct form of neurofibromatosis with extensive spinal involvement and cafe-au-lait macules which may be allelic to classic NF1. Molecular Genetics In affected members of a family with spinal neurofibromatosis, Ars et al. (1998) identified a frameshift mutation in the NF1 gene (613113.0018). In affected members of 2 families with spinal neurofibromas but no cafe-au-lait macules, Kaufmann et al. (2001) identified 2 different mutations in the NF1 gene (613113.0028 and 613113.0029, respectively). Both NF1 mutations caused a reduction in neurofibromin of approximately 50%, with no truncated protein present in the cells. The findings demonstrated that typical NF1 null mutations can result in a phenotype that is distinct from classical NF1, showing only a small spectrum of the NF1 symptoms, such as multiple spinal tumors, but not completely fitting the current clinical criteria for spinal NF. Kaufmann et al. (2001) suggested that the spinal NF phenotype may be caused by a modifying gene that partially compensates for the effects of neurofibromin deficiency. In 4 affected members of the family with spinal NF and cafe-au-lait spots reported by Pulst et al. (1991), Messiaen et al. (2003) identified a mutation in the NF1 gene (613113.0039). In affected members of the family with spinal NF reported by Poyhonen et al. (1997), Messiaen et al. (2003) identified a mutation in the NF1 gene (613113.0038). INHERITANCE \- Autosomal dominant HEAD & NECK Eyes \- Lisch nodules (iris hamartomas) may or may not be present SKIN, NAILS, & HAIR Skin \- Neurofibromas may or may not be present \- Cafe-au-lait spots may or may not be present \- Freckling may or may not be present NEUROLOGIC Central Nervous System \- Spinal nerve root neurofibromas, symmetric, multiple \- Neurofibromas can occur at cervical, thoracic, lumbar, and sacral levels \- Paraparesis \- Lower extremity weakness MISCELLANEOUS \- Spinal tumors are necessary for diagnosis \- Other features of neurofibromatosis type I (NF1, 162200 ) may or may not be present \- Allelic disorder to NF1 MOLECULAR BASIS \- Caused by mutation in the neurofibromin gene (NF1, 162200.0018 ) ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	NEUROFIBROMATOSIS, FAMILIAL SPINAL	c0027831	3,717	omim	https://www.omim.org/entry/162210	2019-09-22T16:37:27	{"doid": ["8712", "0111253"], "mesh": ["D009456"], "omim": ["162210"], "orphanet": ["636"], "synonyms": ["Alternative titles", "FSNF"]}
A number sign (#) is used with this entry because evidence suggests that spinocerebellar ataxia-8 (SCA8) is caused by bidirectional transcription at the SCA8 locus on chromosome 13q21 involving both an expanded CTG trinucleotide repeat in the ATXN8OS gene (603680.0001) and the complementary CAG repeat in the ATXN8 gene (613289.0001). These variations result in expression of a CUG expansion mRNA transcript and a polyglutamine protein, respectively, suggesting a toxic gain of function at both the protein and RNA levels. The molecular defect is often referred to as the 'CTGCAG' repeat expansion, referring to the complementary basepairs of the ATXN8OS and ATXN8 genes, reading 5-prime to 3-prime (review by Ikeda et al., 2008). Normal alleles contain 15 to 50 repeats, whereas pathogenic alleles contain 71 to 1,300 repeats (Todd and Paulson, 2010). For a general discussion of autosomal dominant spinocerebellar ataxia, see SCA1 (164400). Clinical Features Koob et al. (1999) reported a large kindred with autosomal dominant spinocerebellar ataxia. Onset of symptoms ranged from age 18 to 65, with a mean of 39 years. Dysarthria, mild aspiration, and gait instability were commonly the initial symptoms. Clinical findings included spastic and ataxic dysarthria, nystagmus, limb and gait ataxia, limb spasticity, and diminished vibration perception. Progression was generally fairly slow, but severely affected family members were nonambulatory by the fourth to fifth decades. MRI showed cerebellar atrophy. Disease severity appeared to correlate with repeat length and age. Ikeda et al. (2000) reported 6 patients with expanded CTG repeat alleles in the ATXN8OS gene. The expanded alleles from the patients ranged from 89 to 155 repeats, and those from normal elderly subjects (over age 79 years) ranged from 15 to 34 repeats. The mean age at onset in the SCA8 cases was 53.8 years, ranging from 20 to 72 years. One father and daughter from an SCA8 family showed remarkable paternal anticipation: the number increase from father to daughter was +16 CTG repeats, with a 31-year acceleration of onset. In general, the SCA8 patients showed trunk and limb incoordination, ataxic dysarthria, impaired smooth pursuit and horizontal nystagmus, and significant atrophy of the cerebellar vermis and hemispheres on MRI. Ikeda et al. (2000) noted that the SCA8 phenotype corresponded to autosomal dominant cerebellar ataxia type III (ADCA III). Factor et al. (2005) reported a patient with onset of dysarthria and impairment of balance and coordination at age 53 years that rapidly progressed to include gait and postural instability, urinary incontinence, impotence, and depression. MRI showed cerebellar and pontine atrophy. Molecular analysis identified an expansion of 145 CTA/CTG repeats in one allele and 28 repeats in the other allele, which was consistent with SCA8. However, postmortem examination showed findings consistent with multiple system atrophy. Factor et al. (2005) noted that the association between the SCA8 repeat expansion and ataxia is controversial, and suggested that testing sporadic cases with late-onset ataxia may lead to misdiagnosis, as in their case. Ito et al. (2006) reported a Japanese father and son with heterozygous expanded SCA8 CAG repeats of 240 and 221, respectively. The father developed progressive gait unsteadiness at age 41 years. Other features included ataxic dysarthria, limb and trunk ataxia, limited upward gaze, and later onset of bradykinesia, rigidity, and difficulty swallowing. The son presented at age 14 with dysarthria and later developed cerebellar ataxia, facial grimacing, hyperreflexia, rigidity, spasticity, dystonia, and bradykinesia. His verbal IQ was 63. The father died suddenly at age 45 from accidental suffocation by sputum while hiking. Postmortem examination showed cerebellar atrophy, depigmentation of the substantia nigra, and severe atrophy or loss of Purkinje cells. The sites of Purkinje cell loss had been replaced by fibrillary accumulations resembling afferent axons. Some residual Purkinje cells had somatic sprouts and contained clusters of granular material. The inferior olives also showed neuronal loss, but the dentate nucleus was preserved. There was extensive gliosis in the periaqueductal gray matter. Mapping By PCR analysis of a large 7-generation kindred with SCA and expanded repeats of the SCA8 CTG allele, Koob et al. (1999) found linkage to the SCA8 gene on chromosome 13q21 (maximum lod score of 6.8). Molecular Genetics In 8 pedigrees with autosomal dominant spinocerebellar ataxia, Koob et al. (1999) identified a CTG repeat expansion in the ATXN8OS gene (603680.0001), which was found to be transcribed into an mRNA with an expanded CUG repeat in its 3-prime UTR. The corresponding CAG repeat expansion in the 5-prime-to-3-prime orientation of the ATXN8 (613289) template strand was determined not to be translated into a polyglutamine-containing protein. In the largest pedigree, which included affected members spanning at least 4 generations, repeat length ranged from 107 to 127 CTG repeats. However, 20 unaffected individuals also carried expanded repeats. Daughters et al. (2009) presented evidence that the expanded CTG repeat in the ATXN8OS gene is transcribed into an mRNA with an expanded CUG repeat, conferring a toxic gain of function that plays a role in the SCA8 phenotype. Moseley et al. (2006) identified IC2-immunoreactive intranuclear inclusions, detecting polyglutamine expansions, in brain tissue from patients with SCA8, but not in normal controls. The polyglutamine protein was determined to be encoded by an expanded CAG repeat in the ATXN8 gene (613289.0001). This CAG repeat was complementary to the expanded CTG repeat in the ATXN8OS gene on the opposite strand. The findings of Moseley et al. (2006) indicated that bidirectional transcription at the SCA8 locus results in expression of both a polyglutamine protein and a CUG expansion transcript, which may represent a toxic gain of function at both the protein and RNA levels. Pathogenesis Daughters et al. (2009) presented evidence that the expanded CTG repeat in the ATXN8OS gene (603680.0001) is transcribed into an mRNA with an expanded CUG repeat, conferring a toxic gain of function that plays a role in the SCA8 phenotype. In brain tissue from humans and mice with SCA8, ATXN8OS mRNA containing the expanded repeat was found to accumulate as ribonuclear inclusions, or RNA foci, that colocalized with the RNA-binding protein MBNL1 (606516) in selected cerebellar cortical neurons in the brain. In Sca8 mice, genetic loss of Mbnl1 enhanced motor deficits, suggesting that loss of MBNL1 plays a role in SCA8 pathogenesis. In Sca8 mice and SCA8 human brains, sequestration of MBNL1 in RNA foci resulted in the dysregulation of downstream splicing patterns normally regulated by the CUGBP1 (601074)/MBNL1 pathway, including that of mouse GABA transporter-4 (GAT4, or SLC6A11; 607952). These changes in Gat4 were associated with loss of GABAergic inhibition in the granular cell layer. These data indicated that expanded CUG ATXN8OS mRNA transcripts can dysregulate gene pathways in the brain, similar to the mechanism involved in myotonic dystrophy (DM1; 160900), which is caused by a CTG repeat expansion in the 3-prime UTR of the DMPK gene (605377) on chromosome 19q13. Daughters et al. (2009) also suggested that the findings may have relevance for other mainly CAG repeat expansion disorders in which an expanded CTG repeat on the opposite stand may also have toxic effects. INHERITANCE \- Autosomal dominant HEAD & NECK Eyes \- Nystagmus \- Slow saccades \- Dysmetric saccades \- Impaired smooth pursuit NEUROLOGIC Central Nervous System \- Progressive cerebellar ataxia \- Dysarthria \- Incoordination of trunk and limbs \- Spasticity \- Tremor \- Pyramidal signs \- Hypperreflexia \- Dysphagia \- Cerebellar atrophy Peripheral Nervous System \- Sensory neuropathy has been reported MISCELLANEOUS \- Onset between 18 and 65 years \- SCA8 is caused by bidirectional transcription on chromosome 13q21 involving complementary repeat expansion in ATXN8 ( 613289 ) and ATXN8-opposite strand ( 603680 ) \- Normal alleles contain 15 to 50 repeats \- Pathogenic alleles contain 71 to 1,300 repeats MOLECULAR BASIS \- Caused by a trinucleotide repeat expansion (CTG)n in the ataxin 8 opposite strand gene (ATXN8OS, 603680.0001 ) \- Caused by a trinucleotide repeat expansion (CAG)n in the ataxin 8 gene (ATXN8, 613289.0001 ) ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease	SPINOCEREBELLAR ATAXIA 8	c1837454	3,718	omim	https://www.omim.org/entry/608768	2019-09-22T16:07:19	{"doid": ["0050959"], "mesh": ["C537307"], "omim": ["608768"], "orphanet": ["98760"], "genereviews": ["NBK1268"]}
Dastani et al. (2006) investigated 13 multigenerational French Canadian families in which multiple members had plasma levels of high density lipoprotein cholesterol (HDLC) less than the tenth percentile of population studies. Genomewide linkage analysis yielded a parametric 2-point lod score of 4.6 on chromosome 4q31.21 at marker D4S424. Approximately 50% of the families were linked to this region. Multipoint analysis in 1 family yielded a lod score of 3.8, and fine mapping restricted the region to 2.9 cM. In a genomewide scan in 274 healthy adult sibs pairs from the Victorian Family Heart Study to identify genetic factors influencing population variation in plasma levels of HDLC, Harrap et al. (2006) found suggestive evidence for a quantitative trait locus (QTL) on chromosome 4q (peak Z score of 3.5 between markers D4S1597 and D4S1539). Fine mapping of the QTL on chromosome 4q in 233 2-generation adult families yielded a peak Z score of 3.9 at 4q32.3. The candidate region overlapped that reported by Dastani et al. (2006). [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	HIGH DENSITY LIPOPROTEIN CHOLESTEROL LEVEL QUANTITATIVE TRAIT LOCUS 4	c1853253	3,719	omim	https://www.omim.org/entry/610239	2019-09-22T16:04:53	{"omim": ["610239"], "synonyms": ["Alternative titles", "HDLCQ4"]}
## Clinical Features Waters and West (1995) described a lethal congenital nonspherocytic, nonimmune hemolytic anemia associated with abnormalities of the external genitalia, flat occiput, dimpled earlobes, deep plantar creases, and increased space between the first and second toes in 2 brothers. The birth of these children was separated by a spontaneous abortion at 3 months and the delivery of a normal girl. The authors suggested that this was a hitherto undescribed autosomal or X-linked recessive syndrome. The second-born infant had marked ascites and hepatosplenomegaly. Although the parents were not known to be consanguineous, they shared a French Canadian and Native American ethnic origin. INHERITANCE \- ?Autosomal dominant HEAD & NECK Head \- Flat occiput Ears \- Dimpled earlobes ABDOMEN External Features \- Ascites Liver \- Hepatosplenomegaly Spleen \- Hepatosplenomegaly GENITOURINARY External Genitalia (Male) \- Small penis \- Hypospadias SKELETAL Hands \- Deep plantar creases Feet \- Increased space between first and second toes HEMATOLOGY \- Hemolytic anemia, nonspherocytic MISCELLANEOUS \- Onset in utero \- Death shortly after birth \- Based on report of 2 brothers ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	HEMOLYTIC ANEMIA, LETHAL CONGENITAL NONSPHEROCYTIC, WITH GENITAL AND OTHER ABNORMALITIES	c1838120	3,720	omim	https://www.omim.org/entry/600461	2019-09-22T16:16:12	{"mesh": ["C563935"], "omim": ["600461"], "orphanet": ["1046"]}
Lathosterolosis is an extremely rare inborn error of sterol biosynthesis characterized by facial dysmorphism, congenital anomalies (including limb and kidney anomalies), failure to thrive, developmental delay and liver disease. ## Epidemiology Only 4 cases have been reported in the literature to date. ## Clinical description Microcephaly is present at birth along with hypotonia, failure to thrive and facial dysmorphic features such as bitemporal narrowing, ptosis, puffy cheeks, and micrognathia. Limb anomalies that have been reported include postaxial polydactyly of upper or lower limbs (mainly feet), bilateral syndactyly between the 2nd and 3rd or 2nd and 4th toes and bilateral club feet. Developmental delay and learning disability starting in early childhood have been noted in all patients. Additional anomalies have also been reported such as corneal clouding, cataract, conductive hearing loss, gingival hypertrophy, ambiguous genitalia, horseshoe kidney (see this term) and neurological manifestations (i.e. myoclonus). Liver disease seen in patients ranges from hypertransaminasemia to progressive cholestasis and can lead to end stage hepatic disease, occurring in childhood. ## Etiology Lathosterolosis is due to mutations in the SC5D gene (11q23.3). A mutation in this gene leads to a deficiency in 3-beta-hydroxysteroid-delta-5-desaturase, which is necessary in the conversion of lathosterol into 7-dehydrocholesterol. This prevents the synthesis of cholesterol, which among other functions acts as a structural lipid, a precursor for bile acids and steroid hormones, and is necessary for the maturation of hedgehog morphogens during embryonic development. ## Diagnostic methods Diagnosis is based on clinical and biochemical findings. An elevation of lathosterol by gas chromatography/mass spectroscopy (GC/MS) is noted in both skin fibroblasts and plasma. The levels of 7-dehydrocholesterol and cholesterol are normal or low. Molecular genetic testing revealing mutations in the SC5D gene confirms the diagnosis. ## Differential diagnosis The main differential diagnosis is Smith-Lemli-Opitz syndrome (see this term) that shares many clinical features with lathosterolosis but that can be excluded with biochemical and genetic testing. ## Antenatal diagnosis Prenatal diagnosis is feasible if the mutations are known but it has never been performed given the rarity of the disease. ## Genetic counseling Lathosterolosis is inherited in an autosomal recessive manner. The parents of an affected child are obligate heterozygotes and they therefore have a 25% risk of having an affected child at each pregnancy. ## Management and treatment Treatment involves cholesterol supplementation and reduction of 7-hydrocholesterol. Simvastin, a 3-hydroxy-3-methylglutaryl co-enzyme A (HMG-CoA) reductase inhibitor, has been proven to be beneficial in normalizing the lathosterol level in one patient. Liver transplantation was successful in normalizing liver function and cholesterol levels in a patient who had developed end stage liver disease. Moreover, it appeared to improve neurocognitive functions. Regular opthalmological evalutations and ultrasound monitoring of the liver are recommended. ## Prognosis The prognosis is poor but treatment appears to prolong life and arrest progression of neurological damage. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Lathosterolosis	c1846421	3,721	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=46059	2021-01-23T18:14:57	{"gard": ["9711"], "mesh": ["C537880"], "omim": ["607330"], "umls": ["C1846421"], "icd-10": ["Q87.8"], "synonyms": ["Sterol C5-desaturase deficiency"]}
Malignant hyperthermia (MH) is a severe reaction to certain gases used during anesthesia and/or a muscle relaxant used to temporarily paralyze a person during surgery. Signs and symptoms of MH include marked hyperthermia, a rapid heart rate, rapid breathing, acidosis, muscle rigidity, and breakdown of muscle tissue (rhabdomyolysis). Without prompt treatment, MH can be life-threatening. People who are at increased risk for this reaction are said to have MH susceptibility. Susceptibility to MH may be caused by mutations in any of several genes and is inherited in an autosomal dominant manner. People with certain inherited muscle diseases (e.g., central core disease and multiminicore disease) also have MH susceptibility. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Malignant hyperthermia	c0024591	3,722	gard	https://rarediseases.info.nih.gov/diseases/6964/malignant-hyperthermia	2021-01-18T17:59:16	{"mesh": ["D008305"], "orphanet": ["423"], "synonyms": ["MH", "Anesthesia related hyperthermia", "Malignant hyperpyrexia", "Fulminating hyperpyrexia", "Pharmacogenic myopathy", "Hyperpyrexia malignant", "Hyperthermia of anesthesia", "Malignant hyperthermia of anesthesia"]}
Neural tube defect in which the brain is exposed Cranioschisis (Greek: κρανιον kranion, "skull", and σχίσις schisis, "split"), or dysraphism, is a neural tube defect involving the skull. In this defect, the cranium fails to close completely (especially at the occipital region). Thus, the brain is exposed to the amnios and eventually degenerates, causing anencephaly. Craniorachischisis is on the extreme end of the dysraphism spectrum, wherein the entire length of the neural tube fails to close.[1] ## See also[edit] * Rachischisis * Spina bifida ## References[edit] 1. ^ Larsen's Human Embryology (5 ed.). Churchill Livingstone. 2015. pp. 81–107. * v * t * e Congenital malformations and deformations of musculoskeletal system / musculoskeletal abnormality Appendicular limb / dysmelia Arms clavicle / shoulder * Cleidocranial dysostosis * Sprengel's deformity * Wallis–Zieff–Goldblatt syndrome hand deformity * Madelung's deformity * Clinodactyly * Oligodactyly * Polydactyly Leg hip * Hip dislocation / Hip dysplasia * Upington disease * Coxa valga * Coxa vara knee * Genu valgum * Genu varum * Genu recurvatum * Discoid meniscus * Congenital patellar dislocation * Congenital knee dislocation foot deformity * varus * Club foot * Pigeon toe * valgus * Flat feet * Pes cavus * Rocker bottom foot * Hammer toe Either / both fingers and toes * Polydactyly / Syndactyly * Webbed toes * Arachnodactyly * Cenani–Lenz syndactylism * Ectrodactyly * Brachydactyly * Stub thumb reduction deficits / limb * Acheiropodia * Ectromelia * Phocomelia * Amelia * Hemimelia multiple joints * Arthrogryposis * Larsen syndrome * RAPADILINO syndrome Axial Skull and face Craniosynostosis * Scaphocephaly * Oxycephaly * Trigonocephaly Craniofacial dysostosis * Crouzon syndrome * Hypertelorism * Hallermann–Streiff syndrome * Treacher Collins syndrome other * Macrocephaly * Platybasia * Craniodiaphyseal dysplasia * Dolichocephaly * Greig cephalopolysyndactyly syndrome * Plagiocephaly * Saddle nose Vertebral column * Spinal curvature * Scoliosis * Klippel–Feil syndrome * Spondylolisthesis * Spina bifida occulta * Sacralization Thoracic skeleton ribs: * Cervical * Bifid sternum: * Pectus excavatum * Pectus carinatum [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Cranioschisis	c0265541	3,723	wikipedia	https://en.wikipedia.org/wiki/Cranioschisis	2021-01-18T18:57:37	{"mesh": ["D009421"], "umls": ["C0265541"], "wikidata": ["Q5182152"]}
## Inheritance Linder (1949) examined 104 men and 70 women and found the ability to move the ears in 54% and 22%, respectively. The frequency of the trait among sibs of probands was 47% and among parents was 74%. However, in 5 of 24 cases both parents lacked the trait, leading Linder (1949) to suggest that the ability is inherited as a somewhat irregular dominant. In Barcelona, Hernandez (1980) found that 19.9% of men and 9.57% of women could move their ears. In males, there was an association with tongue rolling (189300). Inheritance \- Autosomal dominant Misc \- Association with tongue rolling (189300) in males Ears \- Ability to move ears ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	EARS, ABILITY TO MOVE	c1851889	3,724	omim	https://www.omim.org/entry/129100	2019-09-22T16:42:00	{"omim": ["129100"]}
Parasystole SpecialtyCardiology Parasystole is a kind of arrhythmia caused by the presence and function of a secondary pacemaker in the heart, which works in parallel with the SA node. Parasystolic pacemakers are protected from depolarization by the SA node by some kind of entrance block. This block can be complete or incomplete. Parasystolic pacemakers can exist in both the atrium or the ventricle. Atrial parasystolia are characterized by narrow QRS complexes Two forms of ventricular parasystole have been described in the literature, fixed parasystole and modulated parasystole. Fixed ventricular parasystole occurs when an ectopic pacemaker is protected by entrance block, and thus its activity is completely independent from the sinus pacemaker activity. Hence, the ectopic pacemaker is expected to fire at a fixed rate. Therefore, on ECG, the coupling intervals of the manifest ectopic beats will wander through the basic cycle of the sinus rhythm. Accordingly, the traditional electrocardiographic criteria used to recognize the fixed form of parasystole are: * the presence of variable coupling intervals of the manifest ectopic beats; * inter-ectopic intervals that are simple multiples of a common denominator; * fusion beats. According to the modulated parasystole hypothesis, rigid constancy of a pacemaker might be expected if the entrance block were complete, but if there is an escape route available for the emergence of ectopic activity, then clearly there must be an effective ionic communication, not complete insulation, between the two tissues. If there is an electrical communication between the two, then the depolarization of the surrounding ventricle may influence the ectopic pacemaker. That influence will be electrotonic; depolarization of the surrounding field will induce a partial depolarization of the pacemaker cells. Therefore, appropriate diagnosis of modulated parasystole relies upon the construction of a “phase response curve” as theoretical evidence of modulation of the ectopic pacemaker cycle length by the electrotonic activity generated by the sinus discharges across the area of protection. In this case, the timing of the arrival of the electronic stimulus will serve to delay or advance the subsequent pacemaker activation. In this case, the coupling intervals between the manifest ectopic and sinus discharges will be either fixed or variable, depending on the cycle length relations between the two pacemakers. ## See also[edit] * Extrasystole ## References[edit] ## External links[edit] Classification D * MeSH: D017574 * ventricular parasystole * atrial parasystole * v * t * e Cardiovascular disease (heart) Ischaemic Coronary disease * Coronary artery disease (CAD) * Coronary artery aneurysm * Spontaneous coronary artery dissection (SCAD) * Coronary thrombosis * Coronary vasospasm * Myocardial bridge Active ischemia * Angina pectoris * Prinzmetal's angina * Stable angina * Acute coronary syndrome * Myocardial infarction * Unstable angina Sequelae * hours * Hibernating myocardium * Myocardial stunning * days * Myocardial rupture * weeks * Aneurysm of heart / Ventricular aneurysm * Dressler syndrome Layers Pericardium * Pericarditis * Acute * Chronic / Constrictive * Pericardial effusion * Cardiac tamponade * Hemopericardium Myocardium * Myocarditis * Chagas disease * Cardiomyopathy * Dilated * Alcoholic * Hypertrophic * Tachycardia-induced * Restrictive * Loeffler endocarditis * Cardiac amyloidosis * Endocardial fibroelastosis * Arrhythmogenic right ventricular dysplasia Endocardium / valves Endocarditis * infective endocarditis * Subacute bacterial endocarditis * non-infective endocarditis * Libman–Sacks endocarditis * Nonbacterial thrombotic endocarditis Valves * mitral * regurgitation * prolapse * stenosis * aortic * stenosis * insufficiency * tricuspid * stenosis * insufficiency * pulmonary * stenosis * insufficiency Conduction / arrhythmia Bradycardia * Sinus bradycardia * Sick sinus syndrome * Heart block: Sinoatrial * AV * 1° * 2° * 3° * Intraventricular * Bundle branch block * Right * Left * Left anterior fascicle * Left posterior fascicle * Bifascicular * Trifascicular * Adams–Stokes syndrome Tachycardia (paroxysmal and sinus) Supraventricular * Atrial * Multifocal * Junctional * AV nodal reentrant * Junctional ectopic Ventricular * Accelerated idioventricular rhythm * Catecholaminergic polymorphic * Torsades de pointes Premature contraction * Atrial * Junctional * Ventricular Pre-excitation syndrome * Lown–Ganong–Levine * Wolff–Parkinson–White Flutter / fibrillation * Atrial flutter * Ventricular flutter * Atrial fibrillation * Familial * Ventricular fibrillation Pacemaker * Ectopic pacemaker / Ectopic beat * Multifocal atrial tachycardia * Pacemaker syndrome * Parasystole * Wandering atrial pacemaker Long QT syndrome * Andersen–Tawil * Jervell and Lange-Nielsen * Romano–Ward Cardiac arrest * Sudden cardiac death * Asystole * Pulseless electrical activity * Sinoatrial arrest Other / ungrouped * hexaxial reference system * Right axis deviation * Left axis deviation * QT * Short QT syndrome * T * T wave alternans * ST * Osborn wave * ST elevation * ST depression * Strain pattern Cardiomegaly * Ventricular hypertrophy * Left * Right / Cor pulmonale * Atrial enlargement * Left * Right * Athletic heart syndrome Other * Cardiac fibrosis * Heart failure * Diastolic heart failure * Cardiac asthma * Rheumatic fever This article about a medical condition affecting the circulatory system is a stub. You can help Wikipedia by expanding it. * v * t * e [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Parasystole	c0206068	3,725	wikipedia	https://en.wikipedia.org/wiki/Parasystole	2021-01-18T18:56:26	{"mesh": ["D017574"], "wikidata": ["Q3494080"]}
Familial hypertrophic cardiomyopathy (HCM) is an inherited heart condition characterized by thickening of the heart muscle. The thickening most often occurs in the muscle wall that separates the left and right ventricles from each other (interventricular septum). This may restrict the flow of oxygen-rich blood from the heart, or it may lead to less efficient pumping of blood. Signs and symptoms can vary. While some people have no symptoms, others may have chest pain, shortness of breath, palpitations, lightheadedness, dizziness, and/or fainting. Even in the absence of symptoms, familial HCM can have serious consequences such as life-threatening arrhythmias, heart failure, and an increased risk of sudden death. Familial HCM may be caused by mutations in any of several genes and is typically inherited in an autosomal dominant manner. Treatment may depend on severity of symptoms and may include medications, surgical procedures, and/or an implantable cardioverter-defibrillator (ICD). [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Familial hypertrophic cardiomyopathy	c0949658	3,726	gard	https://rarediseases.info.nih.gov/diseases/7229/familial-hypertrophic-cardiomyopathy	2021-01-18T18:00:35	{"mesh": ["D024741"], "synonyms": ["Cardiomyopathy familial hypertrophic", "Heritable hypertrophic cardiomyopathy", "Familial HCM"]}
A number sign (#) is used with this entry because of evidence that fatal infantile cardioencephalomyopathy due to cytochrome c oxidase (COX) deficiency-4 (CEMCOX4) is caused by homozygous or compound heterozygous mutation in the COA6 gene (614772) on chromosome 1q42. For a general phenotypic description and a discussion of genetic heterogeneity of fatal infantile cardioencephalomyopathy due to cytochrome c oxidase deficiency, see CEMCOX1 (604377). Clinical Features Calvo et al. (2012) and Ghosh et al. (2014) reported a male infant with fatal infantile cardioencephalomyopathy. He was diagnosed with hypertrophic obstructive cardiomyopathy at age 6 months, and showed decreased muscle bulk and tone as well as progressive weakness and lethargy. He died of cardiac failure at 18 months of age (summary by Stroud et al., 2015). Baertling et al. (2015) reported a female infant, born of consanguineous parents of Arabic origin, with fatal cardioencephalomyopathy. She presented at birth with hypotonia, a systolic murmur, and mild dysmorphic features, including abnormal facies with small chin and flat orbital ridges. Soon after birth, she developed severe lactic acidosis, hypothermia, and tachypnea. Echocardiography showed severe hypertrophic cardiomyopathy affecting both ventricles, with some areas of noncompaction in the left ventricle. Mitral, tricuspid, and pulmonic insufficiency were also noted. She died at age 5 weeks. Patient fibroblasts showed isolated complex IV deficiency. Inheritance The transmission pattern of CEMCOX4 in the families reported by Ghosh et al. (2014) and Baertling et al. (2015) was consistent with autosomal recessive inheritance. Molecular Genetics In a male infant with CEMCOX4, Ghosh et al. (2014) identified compound heterozygous mutations in the COA6 gene (614772.0001 and 614772.0002). Studies in yeast homologs showed that the mutations resulted in decreased mitochondrial levels of mutant Coa6 and that the mutant proteins were unable to rescue the mitochondrial respiratory growth defect in Coa6-null yeast, consistent with a loss of function. Morpholino knockdown of the coa6 gene in zebrafish embryos resulted in defective cardiac development and function. The patient was previously reported by Calvo et al. (2012) (patient 31) as having combined oxidative phosphorylation deficiency, with markedly decreased activities of complexes I and IV in heart tissue. In a female infant, born of consanguineous parents of Arabic descent, with CEMCOX4, Baertling et al. (2015) identified a homozygous missense mutation in the COA6 gene (W66R; 614772.0003). The mutation, which was found by whole-exome sequencing, was confirmed by Sanger sequencing. Patient fibroblasts showed absence of the COA6 protein and a reduction of mitochondrial complex IV. Treatment of patient fibroblasts with copper led to a stable increase of complex IV and its subunits, suggesting a possible therapeutic option. INHERITANCE \- Autosomal recessive HEAD & NECK Face \- Abnormal facies \- Small chin \- Flat orbital ridges CARDIOVASCULAR Heart \- Hypertrophic cardiomyopathy \- Left ventricular noncompaction MUSCLE, SOFT TISSUES \- Hypotonia METABOLIC : Lactic acidosis LABORATORY ABNORMALITIES \- Mitochondrial complex IV deficiency in cardiac tissue MISCELLANEOUS \- Onset in utero or at birth \- Lethal in first weeks of life \- Two unrelated patients have been reported (last curated July 2015) MOLECULAR BASIS \- Caused by mutation in the cytochrome c oxidase assembly factor 6 gene (COA6, 614772.0001 ) ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	CARDIOENCEPHALOMYOPATHY, FATAL INFANTILE, DUE TO CYTOCHROME c OXIDASE DEFICIENCY 4	c1858424	3,727	omim	https://www.omim.org/entry/616501	2019-09-22T15:48:40	{"doid": ["0080360"], "mesh": ["C565784"], "omim": ["616501"], "orphanet": ["1561"]}
Chromosome 13q duplication is a chromosome abnormality that occurs when there is an extra (duplicated) copy of genetic material on the long arm (q) of chromosome 13. The severity of the condition and the signs and symptoms depend on the size and location of the duplication and which genes are involved. Features that often occur in people with chromosome 13q duplication include developmental delay, intellectual disability, behavioral problems and distinctive facial features. Chromosome testing of both parents can provide more information on whether or not the duplication was inherited. In most cases, parents do not have any chromosomal anomaly. However, sometimes one parent is found to have a balanced translocation, where a piece of a chromosome has broken off and attached to another one with no gain or loss of genetic material. The balanced translocation normally does not cause any signs or symptoms, but it increases the risk for having an affected child with a chromosomal anomaly like a duplication. Treatment is based on the signs and symptoms present in each person. This page is meant to provide general information about chromosome 13q duplication. You can contact GARD if you have questions about a specific duplication on chromosome 13. To learn more about chromosomal anomalies please visit our GARD webpage on FAQs about Chromosome Disorders. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Chromosome 13q duplication	c0795849	3,728	gard	https://rarediseases.info.nih.gov/diseases/1929/chromosome-13q-duplication	2021-01-18T18:01:25	{"mesh": ["C535485"], "umls": ["C0795849"], "synonyms": ["Duplication 13q", "Trisomy 13q", "13q duplication", "13q trisomy", "Partial trisomy 13q"]}
A number sign (#) is used with this entry because of evidence that neonatal intractable myoclonus (NEIMY) is caused by heterozygous mutation in the KIF5A gene (602821) on chromosome 12q13. Description Neonatal intractable myoclonus is a severe neurologic disorder characterized by the onset of intractable myoclonic seizures soon after birth. Affected infants have intermittent apnea, abnormal eye movements, pallor of the optic nerve, and lack of developmental progress. Brain imaging shows a progressive leukoencephalopathy. Some patients may die in infancy. There is phenotypic and biochemical evidence of mitochondrial dysfunction (summary by Duis et al., 2016). Clinical Features Duis et al. (2016) reported 2 unrelated patients who presented shortly after birth with nearly continuous nonrhythmic large-amplitude myoclonic jerks associated with intermittent apnea. Neither patient had visual fixation, and both had hypotonia. Additional features included abnormal saccades, nystagmus, ptosis, and optic nerve pallor. Both had minimal developmental progress. One patient died at age 3 months, whereas the other was alive at age 5 years with microcephaly, poor feeding requiring gastrostomy tube, recurrent apnea, developmental arrest, myoclonus, and choreiform movements. EEG showed background slowing but no epileptiform discharges during myoclonus, suggesting that the myoclonus may be of spinal cord origin. Brain imaging was initially normal, but showed increased T2-weighted signals in the brainstem and pons in the surviving patient at age 2 years. Muscle biopsy, performed in 1 patient, showed nonspecific myopathic features with increased fiber size variability and atrophy of type 1 fibers. There was borderline mitochondrial complex IV deficiency. Rydzanicz et al. (2017) reported a male infant, born of unrelated Polish parents, with neonatal intractable myoclonus. He had hypotonia, treatment-resistant clonic seizures, no spontaneous eye opening, and evidence of hearing loss. Brain imaging showed Dandy-Walker variant, narrowing of the corpus callosum, progressive leukoencephalopathy, progressive ventricular dilation, and delayed myelination. EMG studies showed muscle fibrillations. There was also evidence of reinnervation potentials corresponding to axonal-demyelinating lesions with neuropathic damage to the muscle. The patient had muscle atrophy and respiratory insufficiency, and he died at age 12 months. Molecular Genetics In 2 unrelated patients with NEIMY, Duis et al. (2016) reported different de novo heterozygous frameshift mutations in the KIF5A gene (c.2854delC, 602821.0011 and c.2934delG, 602821.0012), both of which were predicted to result in a stop-loss with read-through of the normal termination codon to create an elongated protein with 14 additional residues. The predicted abnormal protein was the same in both cases. The c.2854delC mutation was found in case 1 by whole-exome sequencing. The c.2934delG mutation was initially found in case 2 by DaRe et al. (2013) by sequencing of a panel of genes involved in mitochondrial function. Both mutations were confirmed by Sanger sequencing. Functional studies of the variant and studies of patient cells were not performed, but the mutations were predicted to result in a dominant-negative effect on the kinesin complex, thus disrupting organelle transport in neurons. The clinical features were consistent with mitochondrial dysfunction within neurons, likely resulting from abnormal mitochondrial transport due to an abnormal kinesin 'motor.' Duis et al. (2016) noted that the C-terminal region of KIF5A binds GABARAP (605125), which clusters neurotransmitter receptors by mediating interaction with microtubules. These data suggested that the myoclonus in these patients may be caused by increased neuronal excitation due to aberrant GABA signaling. In a male infant with NEIMY, Rydzanicz et al. (2017) identified a de novo heterozygous stop-loss mutation in the KIF5A gene (602821.0013). The mutation was found by whole-exome sequencing and confirmed by Sanger sequencing. Functional studies of the variant and studies of patient cells were not performed. Rydzanicz et al. (2017) speculated that the mutation induced abnormal binding to TRAK2 (607334) or other kinesin adaptor proteins. INHERITANCE \- Autosomal dominant HEAD & NECK Head \- Microcephaly Eyes \- Nystagmus \- Ptosis \- Optic nerve pallor \- Abnormal saccades \- Cortical visual impairment \- Lack of visual fixation RESPIRATORY \- Apnea, intermittent ABDOMEN Gastrointestinal \- Dysphagia \- Poor feeding MUSCLE, SOFT TISSUES \- Hypotonia \- Myopathic features seen on biopsy \- Type 1 fiber atrophy \- Mitochondrial complex IV deficiency, mild \- Neuropathic features with reinnervation potentials seen on EMG NEUROLOGIC Central Nervous System \- Myoclonus, intractable \- Clonic seizures \- Developmental arrest \- Athetoid movements \- Choreiform movements \- T2-weighted signal abnormalities in the brainstem and pons \- Leukoencephalopathy, progressive \- Delayed myelination MISCELLANEOUS \- Onset at birth \- Three unrelated patients have been reported (last curated December 2016) \- Two patients died in infancy MOLECULAR BASIS \- Caused by mutation in the kinesin family member 5A gene (KIF5A, 602821.0011 ) ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	MYOCLONUS, INTRACTABLE, NEONATAL	c4310658	3,729	omim	https://www.omim.org/entry/617235	2019-09-22T15:46:24	{"omim": ["617235"]}
## Summary ### Clinical characteristics. The phenotypic spectrum of X-linked hypophosphatemia (XLH) ranges from isolated hypophosphatemia to severe lower-extremity bowing. XLH frequently manifests in the first two years of life when lower-extremity bowing becomes evident with the onset of weight bearing; however, it sometimes is not manifest until adulthood, as previously unevaluated short stature. In adults, enthesopathy (calcification of the tendons, ligaments, and joint capsules) associated with joint pain and impaired mobility may be the initial presenting complaint. Persons with XLH are prone to spontaneous dental abscesses; sensorineural hearing loss has also been reported. ### Diagnosis/testing. Low serum phosphate concentration and reduced tubular resorption of phosphate corrected for glomerular filtration rate (TmP/GFR) are characteristic. Additionally, the normal physiologic response to hypophosphatemia of an elevation of 1,25 (OH)2 vitamin D is absent. Serum calcium and 25-hydroxy vitamin D are within the normal range; parathyroid hormone is normal to slightly elevated. Alkaline phosphatase is characteristically elevated in children, especially during periods of rapid growth, and usually returns to normal in adulthood with or without treatment. Identification of a hemizygous (in males) or heterozygous (in females) pathogenic variant in PHEX by molecular genetic testing confirms the diagnosis. ### Management. Treatment of manifestations: Pain and lower-extremity bowing improve with frequent oral administration of phosphate and high-dose calcitriol. Children are generally treated from the time of diagnosis until long bone growth is complete. The role of pharmacologic treatment in adults is less clear; such treatment is generally reserved for individuals with symptoms such as skeletal pain, upcoming orthopedic surgery, biochemical evidence of osteomalacia with an elevated alkaline phosphatase, or recurrent pseudofractures or stress fractures. Persistent lower-limb bowing and/or torsion resulting in misalignment of the lower extremity may require surgery. Prevention of primary manifestations: Frequent oral administration of phosphate and high-dose calcitriol to minimize bowing of long bones during growth. Good oral hygiene with flossing, regular dental care, and active strategies to prevent dental abscesses. Surveillance: For individuals on calcitriol and phosphate therapy: * Quarterly monitoring of serum concentrations of phosphate, calcium, creatinine, alkaline phosphatase, intact parathyroid hormone; and urinary calcium, phosphate, and creatinine for evidence of hyperparathyroidism and increased renal phosphate or calcium excretion * Annual lower-extremity x-rays to assess skeletal response to treatment * Periodic renal ultrasound examination to assess for nephrocalcinosis * Dental follow up twice a year Agents/circumstances to avoid: Treatment with phosphate without calcitriol because of the increased risk for hyperparathyroidism. Evaluation of relatives at risk: Molecular genetic testing (if the PHEX pathogenic variant has been identified in the family) or biochemical testing of infants at risk to ensure early treatment for optimal outcome. Pregnancy management: No data are available on the use of phosphate and calcitriol in pregnant women who have XLH. Most women with XLH who are on active therapy at the time of conception are continued on treatment throughout the pregnancy with vigilant monitoring of urinary calcium-to-creatinine ratios to detect hypercalciuria early in order to modify treatment accordingly. ### Genetic counseling. X-linked hypophosphatemia is inherited in an X-linked manner. An affected male passes the pathogenic variant to all his daughters and none of his sons; an affected female passes the pathogenic variant to 50% of her offspring. Offspring who inherit the pathogenic variant will be affected, but because of the great intrafamilial variation, severity cannot be predicted. Prenatal testing for a pregnancy at increased risk is possible if the PHEX pathogenic variant in the family has been identified. ## Diagnosis ### Suggestive Findings X-linked hypophosphatemia (XLH) should be suspected in an individual with the following clinical findings, radiographic findings, and results of biochemical testing. It should be noted that this is a dominant X-linked disorder in which males and females are similarly affected. #### Clinical Findings in children include progressive lower-extremity bowing with a decrease in height velocity after the child starts ambulating and the characteristic clinical signs of rickets: rachitic rosary, craniotabes, Harrison's groove (a horizontal channel at the lower end of the chest caused by the diaphragm pulling the osteomalacic bone inward), and epiphyseal swelling. Findings in adults include musculoskeletal complaints, stress fractures, dental abscesses, and/or the diagnosis of XLH in an offspring. #### Radiographic In children the metaphyses may be widened, frayed, or cupped; sometimes rachitic rosary or beading of the ribs results from poor skeletal mineralization leading to overgrowth of the costochondral joint cartilage. Although involvement of the metaphyses of the lower limbs is typical, any metaphysis can be involved. #### Biochemical The two main laboratory findings characteristic of XLH are low-serum phosphate concentration and reduced tubular resorption of phosphate corrected for glomerular filtration rate. Low serum phosphate concentration. Normal phosphate concentrations vary with age, with higher values observed in infants; therefore, it is important to use the age-related values. One widely used data set is reviewed in Table 1. Several studies have reported the normative data for age-related serum phosphate values [reviewed by Meites 1989]. ### Table 1. Age-Based Normal Serum Phosphate Reference Intervals View in own window Agemg/dLmmol/L 0-5 days4.8-8.21.55-2.65 1-3 yrs3.8-6.51.25-2.10 4-11 yrs3.7-5.61.20-1.80 12-15 yrs2.9-5.40.95-1.75 >15 yrs2.7-4.70.90-1.50 Lockitch et al [1988] Reduced tubular resorption of phosphate corrected for glomerular filtration rate (TmP/GFR). Historically, the calculation of TmP/GFR has relied on the nomogram-based method described by Walton & Bijvoet [1975] (Figure 1). #### Figure 1. Nomogram from Walton & Bijvoet [1975] for calculation of the tubular resorption of phosphate corrected for glomerular filtration rate (TmP/GFR) utilizing the plasma phosphate concentration and the calculated tubular resorption of phosphate: 1- (more...) In order to use the nomogram, the tubular resorption of phosphate (TRP) must first be calculated as follows: * TRP = 1- [(urinephosphate/ plasmaphosphate)/(urinecreatinine/plasmacreatinine)] When the TRP is less than 0.86, the TmP/GFR can be calculated directly as follows: * TmP/GFR = TRP x Plasmaphosphate The age-related reference ranges for the TmP/GFR are shown in Table 2 [Payne 1998]. ### Table 2. Age-Based Normal TmP/GFR Reference Intervals View in own window AgeSexRange (mg/dL)Range (mmol/L) BirthBoth3.6 - 8.61.43 - 3.43 3 mosBoth3.7 - 8.251.48 - 3.30 6 mosBoth2.9 - 6.51.15 - 2.60 2-15 yrsBoth2.9 - 6.51.15 - 2.44 25-35 yrsMale2.5 - 3.41.00 - 1.35 25-35 yrsFemale2.4 - 3.60.96 - 1.44 45-55 yrsMale2.2 - 3.40.90 - 1.35 45-55 yrsFemale2.2 - 3.60.88 - 1.42 65-75 yrsBoth2.0 - 3.40.80 - 1.35 Payne [1998] Note: For the calculation of the TRP the urine should be collected as an untimed urine after an overnight fast. Other suggestive laboratory findings include: * Normal serum calcium and 25-hydroxyvitamin D [25(OH)D]. Note: If the serum 25(OH)D concentration is low, vitamin D levels need to be replete before the diagnosis of XLH can be confirmed by laboratory testing. * Inappropriately normal serum calcitriol concentration in the presence of hypophosphatemia * Normal parathyroid hormone level; however, it may be minimally elevated in some individuals. * Absence of glycosuria, bicarbonaturia, proteinuria, or amino aciduria ### Establishing the Diagnosis The diagnosis of XLH is established in a proband with low serum phosphate concentration (see Table 1), a reduced TmP/GFR based on normative values for age (see Table 2), an inappropriate level of calcitriol for the level of hypophosphatemia, and/or by identification on molecular genetic testing of: * A hemizygous PHEX pathogenic variant in a male proband; or * A heterozygous PHEX pathogenic variant in a female proband. Molecular genetic testing approaches can include single-gene testing, use of a multigene panel, and more comprehensive genomic testing: * Single-gene testing. Sequence analysis of PHEX is performed first and followed by gene-targeted deletion/duplication analysis if no pathogenic variant is found. * A multigene panel that includes PHEX 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) 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 comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing 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 3. Molecular Genetic Testing Used in X-Linked Hypophosphatemia View in own window Gene 1MethodProportion of Probands with a Pathogenic Variant 2 Detectable by Method PHEXSequence analysis 3, 457%-78% 5, 6, 7 Gene-targeted deletion/duplication analysis 822%-43% 5, 7 1\. See Table A. Genes and Databases for chromosome locus and protein. 2\. See Molecular Genetics for information on allelic variants detected in this gene. 3\. Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here. 4\. Lack of amplification by PCR prior to sequence analysis can suggest a putative (multi)exon or whole-gene deletion on the X chromosome in affected males; confirmation requires additional testing by gene-targeted deletion/duplication analysis. 5\. Morey et al [2011] 6\. Holm et al [1997], Dixon et al [1998], Ichikawa et al [2008], Gaucher et al [2009], Ruppe et al [2011]. Some of the reports suggest a lower rate of variant detection in simplex cases (i.e., a single occurrence in a family); however, this has not been clearly documented. 7\. Two studies utilized multiplex ligation-dependent probe amplification (MLPA) to detect deletions and duplications [Clausmeyer et al 2009, Morey et al 2011]. Of note, using both exon sequencing and MLPA analysis, Morey et al [2011] detected pathogenic variants in 100% of their cohort of 36 unrelated families. In contrast, the Clausmeyer study (which also utilized both techniques) failed to find a pathogenic variant in a subset of individuals tested. 8\. Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. ## Clinical Characteristics ### Clinical Description The clinical presentation of X-linked hypophosphatemia (XLH) ranges from isolated hypophosphatemia to severe lower-extremity bowing. The diagnosis is frequently made in the first two years of life when lower-extremity bowing becomes evident with the onset of weight bearing; however, because of the extremely variable presentation, the diagnosis is sometimes not made until adulthood. #### Skeletal Abnormalities Individuals with XLH commonly present with short stature and lower-extremity bowing (valgus or varus deformities). Joint pain and impaired mobility associated with enthesopathy, osteophyte formation or other radiologic findings can occur. Short stature * Adults with XLH have a significantly reduced final height with a standard deviation score (SDS) of -1.9 compared to reference standards. Individuals appear disproportionate, with leg length scores (-2.7) being significantly lower than those for sitting height (-1.1) [Beck-Nielsen et al 2010]. * In a longitudinal study that assessed growth in children prior to and during treatment, Zivičnjak et al [2011] found that untreated children had disproportionate total height (-2.48 SDS) to sitting height (-0.99 SDS); lower leg length was -2.90 SDS. During treatment there was an uncoupling of growth between the trunk and the legs: the difference between SDS sitting and lower leg length became more pronounced as the subjects grew. Lower extremity bowing * Genu varum (outward bowing of the lower leg) or genu valgus (inward bowing) can occur. * Lower extremity torsion and rotation may also be seen. Joint pain and impaired mobility * In adults, calcification of the tendons, ligaments, and joint capsules, known as enthesopathy, can cause joint pain and impair mobility [Polisson et al 1985]. * Enthesopathy of vertebral ligaments has been reported [Beck-Nielsen et al 2010], including a case report of spinal cord compression and paraplegia following calcification of the ligamenta flava [Vera et al 1997]. * Increased osteophyte formation with spinal hyperostosis and arthritis or fusion of the sacroiliac joints can also lead to pain and compromised mobility. * A radiologic survey of 38 untreated adults revealed flaring of the iliac wings, trapezoidal distal femoral condyles, shortening of the talar neck, and flattening of the talar dome [Hardy et al 1989]. Looser's zone or pseudofractures that may be symptomatic or asymptomatic were commonly seen and have been reported to occur at any age. #### Cranial Structures Cranial abnormalities include frontal bossing, craniosynostosis, and Chiari malformations. A detailed cephalometric study revealed increased head length, decreased occipital breadth, and a low mean cephalic index (the ratio of the maximum width of the head multiplied by 100 divided by its maximum length) [Pronicka et al 2004]. The incidence of Chiari malformations, which may cause headache and vertigo, has not been determined. #### Dental Abnormalities Persons with XLH are prone to spontaneous dental abscesses, which have been attributed to changes in the dentin component of teeth: irregular spaces with defective mineralization in the tooth dentin have been described [Boukpessi et al 2006]; panoramic imaging reveals enlarged pulp chambers with prominent pulp horns leading to susceptibility to abscess formation [Baroncelli et al 2006]. #### Hearing Loss Sensorineural hearing loss has been reported; the actual prevalence of hearing loss is not known. Radiographic evaluation of a small number of persons with XLH and hearing loss showed generalized osteosclerosis and thickening of the petrous bone [O'Malley et al 1988], a finding that has not been evaluated in other cohorts. #### Differences in Manifestations in Males and Females The features of X-linked hypophosphatemia are the same in males and females. The severity can differ among members of the same family. The etiology of this variability within the same cohort is not known. ### Genotype-Phenotype Correlations Several studies have evaluated genotype-phenotype correlations in XLH. * The largest study, involving 59 persons, correlated dental and hearing defects with pathogenic variants in exons near the 5' (or beginning) of the gene and increased head length with pathogenic variants in exons near the end of the gene [Popowska et al 2001]. * Two studies suggested a correlation between more severe bone disease (defined by the severity of bowing and a history of osteotomies) and truncating variants [Holm et al 2001] or pathogenic variants in the C-terminal portion of PHEX [Song et al 2007]. * A study by Morey et al [2011] showed that clearly deleterious PHEX pathogenic variants (nonsense variants, insertions or deletions, and splice site variants leading to premature stop codons) had lower tubular resorption of phosphate and lower calcitriol levels than did plausibly deleterious variants (missense changes or in-frame deletions). ### Penetrance Despite a wide degree of clinical variability in XLH, penetrance is often said to be 100% by age one year [Sabbagh et al 2014]. There is no known difference between penetrance in males and females. One instance of discordance for XLH in monozygotic twin girls was reported by Owen et al [2009]: at age 19 months the girls were diagnosed with XLH based on biochemical findings and family history; no PHEX pathogenic variant was identified in either twin. One twin was significantly shorter than the other (length: -1.3 vs -0.4 SD). The shorter twin had marked bilateral genu varum; the other twin had mild genu valgum. The authors proposed that non-penetrance resulted from discordant X-chromosome inactivation with non-random lack of PHEX expression in critical tissues. ### Nomenclature X-linked hypophosphatemia (or its common abbreviation, XLH) is the current and preferable term. Other terms that have been used: * X-linked hypophosphatemic rickets (XLH) * Hypophosphatemic rickets * X-linked dominant hypophosphatemic rickets (XLHR) * X-linked rickets (XLR) * Vitamin D-resistant rickets * X-linked vitamin D-resistant rickets (VDRR) * Hypophosphatemic vitamin D-resistant rickets (HPDR) * Phosphate diabetes * Familial hypophosphatemic rickets ### Prevalence The incidence of XLH is 3.9-5 per 100,000 live births [Davies & Stanbury 1981, Beck-Nielsen et al 2009]. ## Differential Diagnosis The rachitic skeletal changes of nutritional and hereditary forms of rickets are indistinguishable. These types of rickets can be distinguished by biochemical testing: in hypophosphatemic rickets, serum concentrations of 25-hydroxy vitamin D and calcium are normal, whereas in vitamin D-deficient rickets the 25-hydroxy vitamin D serum concentration is low and the calcium concentration may be low or normal. The different forms of hypophosphatemic rickets are distinguished by the presence of hypercalciuria or elevated 1,25(OH)2D. Mode of inheritance and molecular genetic testing help distinguish the different forms of hereditary hypophosphatemic rickets without hypercalciuria (of which XLH is the most common). ### Table 4. Other Genetic and Acquired Disorders of Renal Phosphate Wasting View in own window DiffDx DisorderGene(s)MOIClinical Features of DiffDx DisorderPathogenesis of DiffDx Disorder Overlapping w/XLHDistinguishing from XLH AD hypophosphatemic rickets (ADHR) (OMIM 193100)FGF23ADRenal phosphate wasting w/o hypercalciuriaADHR is much rarer than XLH. Onset of ADHR can be delayed; rarely, phosphate wasting resolves later in life. 1ADHR results in stabilization of the full-length active form of the protein leading to prolonged or enhanced FGF23 action. AR hypophosphatemic rickets (OMIM 241520, 613312)DMP1 2 ENPP1 3ARRenal phosphate wasting w/o hypercalciuriaExtremely rare Tumor-induced osteomalacia (TIO) (oncogenic osteomalacia) 4NA 5NA 5Renal phosphate wasting w/o hypercalciuria; skeletal deformities & growth restriction in children; progressive muscle & bone pain in adultsMost persons w/TIO are adults (although onset can occur at any age); acquired form of hypophosphatemia.Secretion of FGF23 by slow-growing mesenchymal tumors known as "phosphaturic mesenchymal tumors, mixed connective tissue type" McCune-Albright syndromeGNASSee footnote 7.Hypophosphatemic ricketsFibrous dysplasia of the bone; precocious puberty; café au lait lesionsOverproduction of FGF23 by the fibrous dysplastic bone resulting in renal phosphate wasting 6 Cutaneous skeletal hypophosphatemia syndrome 8 (OMIM 163200)HRAS KRAS NRASSee footnote 7.Hypophosphatemia is frequent & biochemically indistinguishable from that seen in XLH.Multiple cutaneous nevi; radiologic evidence of fibrous dysplasiaFGF23 is the cause of the phosphate wasting. 9 Hereditary hypophosphatemic rickets with hypercalciuria (OMIM 241530)SLC34A3ARHypophosphatemia; hypercalciuria↑ 1,25(OH)2 vitamin (not assoc w/the inappropriately normal 1,25(OH)2 vitamin D seen in XLH) Hypophosphatemic nephrolithiasis/osteoporosis (OMIM PS612286)SLC34A1 SLC9A3R1AD Hypophosphatemic rickets, X-linked recessive (OMIM 300554)CLCN5XL Fanconi syndrome (OMIM PS134600)See footnote 10.See footnote 10.Renal phosphate lossPresence of glycosuria, bicarbonaturia, and/or amino aciduriaProximal renal tubule transport of many different substances can be impaired. Nutritional forms of ricketsNot applicableNARachitic skeletal changes of nutritional & hereditary forms of rickets are clinically indistinguishable.In vitamin D-deficient rickets: 25-hydroxy vitamin D serum concentration is ↓; calcium concentration may be ↓ or normal. Raine syndrome 11FAM20CAROsteosclerotic skeletal changes; hypophosphatemiaSevere form is neonatal lethal. Milder form is assoc w/hypophosphatemia.↓ DMP1 activity leads to ↑ FGF23 production. Osteoglophonic dysplasia 12FGFR1ADHypophosphatemia; lower than expected calcitriol levelsHypophosphatemia; lower than expected calcitriol levels↑ FGF23 production from abnormal bone Hypophosphatemia rickets with hyperparathyroidism 13KLARHypophosphatemia; inappropriately normal calcitriol levelHyperparathyroidism↑ alpha-KLOTHO & ↑ FGF23 AD = autosomal dominant; AR = autosomal recessive; DiffDx = differential diagnosis; MOI = mode of inheritance; NA = not applicable; XL = X-linked 1\. Econs & McEnery [1997] 2\. Feng et al [2006], Lorenz-Depiereux et al [2006] 3\. Levy-Litan et al [2010], Lorenz-Depiereux et al [2010] 4\. Folpe et al [2004] 5\. Tumor-induced osteomalacia is a paraneoplastic syndrome. 6\. Riminucci et al [2003] 7\. Caused by postzygotic somatic activating variant in GNAS 8\. Previously referred to as linear sebaceous nevus syndrome or epidermal nevus syndrome 9\. Hoffman et al [2005] 10\. See OMIM Phenotypic Series: Fanconi renotubular syndrome and related OMIM entries to view associated genes (and information about MOI). 11\. Kinoshita et al [2014] 12\. White et al [2005] 13\. Brownstein et al [2008] ## Management ### Evaluations Following Initial Diagnosis To establish the extent of disease and needs of an individual diagnosed with X-linked hypophosphatemia (XLH), the following evaluations are recommended. Children * A lower-extremity x-ray (teleoroentgenogram), and x-ray of the wrists to assess the extent of skeletal disease * Bone age measurement to evaluate growth potential * Craniofacial examination for signs of craniosynostosis * Dental examination * Hearing evaluation Adults * X-ray of skeletal sites with reported pain to assess for possible enthesopathy or stress fractures * Dental examination * Hearing evaluation Individuals of any age * Evaluation of those with headache and vertigo for Chiari malformation * Consultation with a clinical geneticist and/or genetic counselor ### Treatment of Manifestations Pharmacologic treatment focuses on improving pain and correcting bone deformation. In children, treatment generally begins at the time of diagnosis and continues until long bone growth is complete. Treatment for most children consists of oral phosphate administered three to five times daily and high-dose calcitriol, the active form of vitamin D. Two different regimens have been used, but have not been compared: * Low dose. Treatment is generally started at a low dose to avoid the gastrointestinal side effects of diarrhea and gastrointestinal upset. The doses are then titrated to a weight-based dose of calcitriol at 20 to 30 ng/kg/day administered in two to three divided doses and phosphate at 20 to 40 mg/kg/day administered in three to five divided doses [Carpenter et al 2011]. * High dose. Some clinicians favor a high-dose phase of treatment for up to a year. The high-dose phase consists of calcitriol at 50-70 ng/kg/day (up to a maximum dose of 3.0 µg daily) along with the phosphate [Sabbagh et al 2014]. Doses are adjusted based on (1) evidence of therapeutic success including reduction in serum alkaline phosphatase activity, changes in musculoskeletal examination, improvement in radiographic rachitic changes, and (when possible) improved growth velocity; and (2) evidence of therapeutic complications including hyperparathyroidism, hypercalciuria, and nephrocalcinosis (see Prevention of Secondary Complications). Note: Normalization of the serum phosphate concentration is not a therapeutic goal as normal serum phosphate concentration frequently indicates overtreatment and increases the risk for treatment-related complications. Jehan et al [2008] described differences in growth during treatment that are associated with different vitamin D receptor promoter haplotypes, providing a possible explanation for some of the clinical variability observed in XLH. After growth is complete, lower doses of the medications can be used to reach the treatment goals. In adults, the role of treatment has not been well studied; treatment is generally reserved for individuals with symptoms such as skeletal pain, upcoming orthopedic surgery, biochemical evidence of osteomalacia with an elevated alkaline phosphatase, or recurrent pseudofractures or stress fractures [Carpenter et al 2011]. The calcitriol doses that are frequently employed in adults are in the range of 0.50 to 0.75 µg daily; the phosphate is given as 750 to 1000 mg/day in three to four divided doses. As with children, the phosphate dose is slowly titrated to avoid gastrointestinal side effects, starting at 250 mg/day and titrating up by 250 mg/day each week until the final dose is reached. Orthopedic treatment. Despite what appears to be adequate pharmacologic therapy (see following Note), some individuals have persistent lower-limb bowing and torsion, which may lead to misalignment of the lower extremity. In these individuals, surgical treatment is frequently pursued. No control trials of the different surgical techniques have been undertaken; the literature consists of case series. Note: Poor compliance with pharmacologic therapy during childhood and the teen years may be one factor for persistent lower-limb deformities. In prepubertal children who have not yet reached their peak growth velocity (generally before age 10 years), stapling or toggle plate insertion can be considered as a minimally invasive method of reversible hemi-epiphysiodesis [Novais & Stevens 2006]. Note: The risk with this procedure is prematurely stopping growth. In older children and adults, surgical techniques reported include distraction osteogenesis by external fixation, acute correction by external fixation with intramedullary nailing, internal fixation with intramedullary nailing, and acute correction by intramedullary nailing [Song et al 2006, Petje et al 2008]. Additionally, total hip and knee arthroplasty is sometimes required because of degenerative joint disease and enthesopathy. Treatment in adults has not been shown to influence enthesopathy [Connor et al 2015]. Craniofacial treatment. Although hypophosphatemic rickets is a rare condition, a recent review from three neurosurgical centers reported on ten patients treated over twenty years and recommended prompt referral to a craniofacial specialist when head shape abnormalities are seen in patients with this disorder [Vega et al 2016]. Dental treatment. Because individuals with XLH are susceptible to recurrent dental abscesses which may result in premature loss of decidual and permanent teeth, good oral hygiene with flossing and regular dental care and fluoride treatments are the cornerstones of prevention. Pit and fissure sealants have been recommended but have not been well studied. A recent study has suggested that treatment of adults with phosphate and calcitriol can improve the severity of dental disease [Connor et al 2015]. Sensorineural hearing loss has been reported in persons with XLH; individuals with this complication are treated in a standard manner. See Hereditary Hearing Loss and Deafness Overview, Management. ### Prevention of Primary Manifestations See Treatment of Manifestations, Pharmacologic treatment. ### Prevention of Secondary Complications Hyperparathyroidism is associated with treatment for XLH. Rarely, hyperparathyroidism is present at the time of diagnosis; most often it occurs secondary to high phosphate doses and may proceed to tertiary hyperparathyroidism. In order to monitor for these complications, intact parathyroid hormone, serum calcium concentrations, and TmP/GFR should be measured quarterly (see Surveillance). If secondary hyperparathyroidism is identified, either the calcitriol dose may be increased or the phosphate dose decreased. A small clinical trial and several case reports have investigated the use of cinacalcet in adults with XLH who have secondary hyperparathyroidism [Alon et al 2008]. No long-term studies have been conducted. The clinical trial (comprising 8 individuals ages 6-19) involved in-patient monitoring of phosphate, iPTH, and Tmp/GFR after a single dose of cinacalcet; results showed a decrease in iPTH and an increase in phosphate and TmP/GFR. If tertiary hyperparathyroidism is identified, surgical evaluation is warranted. Hypercalcemia and hypercalciuria may also complicate long-term treatment for XLH and is associated with high calcitriol doses. Serum calcium concentrations and urine calcium/creatinine ratio should be monitored quarterly (see Surveillance). If hypercalcemia or hypercalciuria is detected, the calcitriol dose should be decreased. Nephrocalcinosis, reported in persons medically treated for XLH, may occur independent of hypercalcemia and hypercalciuria detected on laboratory evaluation. A baseline renal ultrasound examination should be performed at the start of treatment. The frequency of renal ultrasound examination to monitor for the development of nephrocalcinosis is not established; one- to five-year intervals have been recommended [Carpenter et al 2011, Sabbagh et al 2014]. ### Surveillance Periodic clinical evaluation to assess for disease progression, treatment response, and therapeutic complications is indicated. For individuals on calcitriol and phosphate therapy the following are recommended: * Quarterly monitoring of the following: serum concentrations of phosphate, calcium, and creatinine; alkaline phosphatase level; intact parathyroid hormone level; and urinary calcium, phosphate, and creatinine to identify and thus prevent therapeutic complications * Intermittent monitoring of lower-extremity x-rays (teleoroentgenograms) to assess skeletal response to treatment. The frequency has not been well established; although annual imaging can be considered, the decision for imaging should be based on symptoms and physical examination findings. * Renal ultrasound examination to assess for nephrocalcinosis. The frequency has not been well established. * Dental follow up twice a year (as for children and teenagers at high risk for caries) ### Agents/Circumstances to Avoid It is recommended that treatment with unopposed phosphate (without 1,25(OH)2 vitamin D) be avoided as this is felt to increase the risk for hyperparathyroidism. Although 1,25(OH)2 vitamin D has been used as a single agent, this use is felt to increase the risk for hypercalcemia, hypercalciuria, and nephrocalcinosis. ### Evaluation of Relatives at Risk Testing of at-risk infants and children is warranted to ensure early diagnosis and early treatment for optimal outcome. Evaluation can be accomplished by: * Molecular genetic testing if the PHEX pathogenic variant has been identified in an affected family member; * Biochemical testing consisting of serum phosphorus, creatinine, calcium, alkaline phosphatase, intact parathyroid hormone, 25-hydroxy vitamin D [25(OH)D], and 1,25(OH)2 vitamin D concentrations and urine phosphorus and creatinine concentrations. Infants with initially normal test results require reevaluation every two to three months until at least age one year. No role has been established for screening asymptomatic adult family members. See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes. ### Pregnancy Management No data on the use of phosphate and calcitriol in pregnant women with XLH are available. Most women with XLH who are on active therapy at the time of conception are continued on treatment throughout the pregnancy with vigilant monitoring of urinary calcium-to-creatinine ratios to detect hypercalciuria early in order to modify treatment accordingly. Those individuals who are not on therapy at the time of conception are generally not started on treatment during pregnancy. ### Therapies Under Investigation Currently, a novel therapeutic agent KRN23 is under investigation for XLH. This is a recombinant human monoclonal antibody targeting FGF23 (see Molecular Genetics). A randomized trial of a single dose of KRN23 has shown an increase in the renal tubular threshold for phosphate reabsorption (TmP/GFR) and an increase in serum Pi and 1,25(OH)2D compared with placebo [Carpenter et al 2014]. A second study in adults looking at monthly dosing of KRN23 for 16 months demonstrated increases in serum phosphate, TmP/GFR, and 1,25 (OH)2D3 [Imel et al 2015]. Analysis from quality of life testing during the first four months of the trial showed improvements in physical functioning and stiffness [Ruppe et al 2016]. Phase II studies in adults and children with XLH are ongoing. Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	X-Linked Hypophosphatemia	c0733682	3,730	gene_reviews	https://www.ncbi.nlm.nih.gov/books/NBK83985/	2021-01-18T20:48:25	{"mesh": ["D053098"], "synonyms": ["XLHR", "X-Linked Hypophosphatemic Rickets", "X-Linked Vitamin D-Resistant Rickets"]}
Majeed syndrome is characterized by recurrent episodes of fever and inflammation in the bones and skin. The two main features of this condition are chronic recurrent multifocal osteomyelitis (CRMO) and congenital dyserythropoietic anemia (CDA). CRMO causes recurrent episodes of pain and joint swelling which can lead to complications such as slow growth and the development of joint deformities called contractures. CDA involves a shortage of red blood cells which can lead to fatigue (tiredness), weakness, pale skin, and shortness of breath. Most people with Majeed syndrome also develop inflammatory disorders of the skin, most often a condition known as Sweet syndrome. Majeed syndrome results from mutations in the LPIN2 gene. This condition is inherited in an autosomal recessive pattern. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Majeed syndrome	c1864997	3,731	gard	https://rarediseases.info.nih.gov/diseases/10088/majeed-syndrome	2021-01-18T17:59:16	{"mesh": ["C537839"], "omim": ["609628"], "umls": ["C1864997"], "orphanet": ["77297"], "synonyms": ["Chronic recurrent multifocal osteomyelitis, congenital", "Dyserythropoietic anemia, and neutrophilic dermatosis", "Congenital dyserythropoietic anemia and chronic recurrent multifocal osteomyelitis", "CDA and CRMO"]}
Black pod disease Common namesBlack pod disease of cocoa Causal agentsPhytophthora palmivora Phytophthora megakarya Hostscocoa (Theobroma cacao) EPPO CodePHYTPL Black pod disease is a protozoal disease of Cocoa trees. This pathogen if left untreated can destroy all yields; annually the pathogen can cause a yield loss of up to 1/3 and up to 10% of total trees can be lost completely. With the value of the cocoa industry throughout the world being so large there are much research and control efforts that go into these Phytophthora spp. pathogens. This pathogen can be located anywhere on the cocoa trees but is most noted for the black mummified look it will give to the fruit of the cocoa tree. Staying ahead of the pathogen is the best means of control, the pathogen can be greatly reduced if leaf litter is not allowed to stay on the ground and if the pathogen gets out of hand chemical control can be used. This pathogen is mostly found in tropical areas where the cocoa trees are located and need rainfall in order to spread its spores. ## Contents * 1 Disease cycle, symptoms and signs * 2 Hosts * 2.1 Cocoa trees * 3 Pathogen * 4 Environment * 5 Inoculum dispersal * 5.1 Soil and litter * 5.2 Air and water dispersal from sporulating pods * 5.3 Invertebrate * 6 Disease management * 6.1 Cultural control * 6.2 Chemical control * 6.3 Cultural and chemical control * 6.4 Biological control * 6.5 Resistant variety * 7 Importance * 8 References ## Disease cycle, symptoms and signs[edit] The symptom of black pod disease is the necrotic lesion on the cocoa pod with brown or black color, which eventually enlarged to cover the whole pod. White mycelia growth on lesions that appeared several days after infection is the sign for the causal pathogen of black pod disease, which is Phytophthora spp. Black pod disease starts when the infected pod shows some little yellow spots, which eventually turn brown and enlarge to a dark brown or black lesion within five days. The lesion is fast growing and covers the entire pod after eight days of infection. The infection does not only occur on the pod surface, but also invades inside the pod affecting the beans. The growth of white mycelia on black pod is visible after 11 days and the sporulation is initiated. The dispersal of sporangia or zoospores through water, ants and other insects occurs at this stage and will infect other healthy pods nearby. Direct contact of a black pod with healthy pods also leads to the spread of disease.[1] In addition, the infected flower cushion and mummified pods are the locations for P. palmivora survival during dry season, where the pathogen will grow and continue to infect other developing pods[2] The infection occurs on any stage of pod development, where it causes wilting and dying of young pods and destroyed the beans of mature pods.[3][4] The fully infected pods (the mummified pod), which then become dehydrated, are capable of providing the inoculum of P. palmivora for at least 3 years.[5] P. megakarya causes the same symptom as P. palmivora, but the occurrence is faster and generally produces greater amount of spores. Both P. palmivora and P. megakarya also caused canker on bark, flower cushion and chupóns, and cankers on the base could extend to the main roots. Cankers were identified as one of inoculum sources for black pod disease.[6] Furthermore, the pattern of infection caused by P. megakarya starts from the ground and moves up to the canopy, however there is no distinct pattern of disease infection caused by P. palmivora was reported.[7] This pattern of infection could be due to P. megakarya and P. palmivora that were found to survive in soil[8] and P. megakarya could be surviving in the roots of a few species of shade trees found in cocoa plantation.[9] ## Hosts[edit] Black pod disease while its name indicates that it is found in Theobroma cacao more commonly known as cocoa trees also has different hosts, for example; P. megakarya has been detected in the roots of shade trees of Western Africa[3] while these trees can also be affected by the pathogen it is because of the market value of the cocoa trees that all emphasis and research on the disease is done on cocoa trees. ### Cocoa trees[edit] In the cocoa trees, P. megakarya infects the bark, flower, and trees with cankers. These cankers will often exude a reddish gum reducing the life of the tree, in turn, reducing the yield of the plant. The most devastating place the pathogen attacks is in the flowers as from these flowers is where the cocoa fruit will set. An infected flower will have infected fruit, which will turn black and will be unable to be harvested and processed. ## Pathogen[edit] Seven different pathogens have been named to cause black pod disease all over the world. All of the pathogens are found in the genus Phytophthora (a plant-damaging Oomycetes). The seven species responsible for black pod disease are; P. capsici, P. citrophthora, P. megasperma, P. katsurae, P. palmivora, and P. megakarya. While all of these pathogens can cause black pod disease the two major pathogens are P. palmivora and P. megakarya.[3] The black pod disease pathogens affect all cocoa trees all over the world P. capsici and P. citrophthora are found in Central and South America while others such as P. megakarya is found in Central and Western Africa. All of these pathogens can present themselves in all parts of the cocoa trees but are most devastating in the fruit itself where it will turn the fruit to a black mummified casing. This fruit is then useless and can no longer be used. ## Environment[edit] P. megakarya is found in Central and Western Africa.[3] During the cooler wetter times of the year, there is a spike in the incidents of black pod disease as when compared to the hotter more dry times of the year.[10] The disease has a spike shortly after a rainfall. The humid weather that is associated with this pathogen and all other black pod disease pathogens is needed as the sporangia forms and starts distributing spores through rainfall, splashing water, and running water.[11] With this pathogen spreading behavior needing water is why there is almost always a spike in the prevalence of the disease shortly after the rainy season. ## Inoculum dispersal[edit] ### Soil and litter[edit] The spread of infection to pods above bare soil was shown to be greater relative to pods above litter.[12] The reason for this is due to the splash of rain from bare soil spreads the inoculum to pods. However, litter under the tree prevented water droplets from splashing the soil particles as well as the inoculum beneath the litter to the above pods. Further, it was also reported that pods near the ground showed greater infections compared to higher pods due to greater soil was splashed and stick on the lower pods, therefore causes more infections. ### Air and water dispersal from sporulating pods[edit] The spread of spores through air from infected pods was observed and some assumption regarding this mechanism of dispersion has been made in previous studies,[13] however it is remained uncertain due to unconvincing results from an experiment that collected some spores in the air using the volumetric spore trap, where a small amount of spores were found in the trap. Conversely, the dispersal of inoculum via rain is considered an effective mechanism in spreading the inoculum. It was assumed that under close canopy, less water will reach the sporulating pods to spread the inoculum, however, rain drops from leaves and branches could also splash the inoculum to the surroundings. Infected pods laying on the ground or litter could also spread the inoculum, yet greater infection was observed on pods located under infected pods hanging on the tree compared to pods at the same level of infected pods. It was reported that splash of wind-blown droplets from the infected pods are also able to infect pods on different trees nearby[12] ### Invertebrate[edit] The dispersal of the disease is also associated with the invertebrate vectors. Tent building ants such as Crematogaster striatula and Camponotus acvapimensis were reported as the primary vector in disseminating the spores of P. palmivora from infected pods to healthy pods in Ghana.[14] C. striatula was thought to be the most important vector that is responsible for black pod losses due to its building tent behavior as well as its dominancy within the area under particular condition. In Ghana, C. striatula removes the outer layer of cocoa pod and uses this material to construct the tent. Therefore, this ant effectively spread the disease by transporting the spores from the infected pods on the ground or on trees to healthy pods. Several other ant species namely C. africana, C. clariventris and C. depressa were also responsible for the spread of the disease besides C. striatula[14] In addition, Camponotus acvapimensis, another type of tent-building ant that uses soil as building materials for tent construction was identified as the most important agent to spread the inoculum in Nigeria.[15] Soil was identified as the source of inoculum for P. megakarya[12] and therefore, it was implied that this ant species might use the infected soil to build tents, which infects healthy pods on trees. Other invertebrates that were reported to be associated with spreading the disease are several species of beetle, snail, caterpillar and millipedes.[13] Fecal samples from these organisms were found to contain viable spores of P. palmivora. It was reported that beetle of family Nitidulidae is the most common vector for black pod as it was found 50 to 60% of black pod occurrences. These invertebrates consume the outer layer of the infected pods and incidentally ingest the mycelium and spores of the pathogen, thus spread the pathogen to other healthy pods. ## Disease management[edit] There are several methods available in order to control black pod disease such as cultural, chemical and biological control. In addition, the cultivation of varieties that resistant to black pod is an alternative in order to reduce disease incidence. ### Cultural control[edit] Several cultural practices to manage black pod disease could be implemented in cocoa plantation.[4] A spacing of 3.1 x 3.1m and pruning of trees are recommended for cocoa planting in order to allow more light and air flow around the trees. This will reduce the level of humidity that is causing black pod disease. The removal of pods with black pod symptom should also be done in favor to eliminate the source of inoculum. In another study, the utilization of litter mulch under cocoa plantation has been reported in Papua New Guinea, which has some negative effect on the population of P. palmivora, and therefore could reduce the pod infection especially at the beginning of raining season. Leaf litter showed rapid decline in pathogen recovery of colonized cocoa tissue after 18 weeks, relative to grass ground cover.[16] An explanation for this is due to higher moisture content and microbial activity of other microbes under leaf litter that reduces the survival of Phytophthora cinnamomi as documented by Aryantha et al. (2000).[17] More frequent ripe pod harvest (i.e. twice a week) and removal of infected pod on the ground was demonstrated to significantly reduced disease occurrence and improve pod yield compared to less frequent harvest and removal (i.e. once a month). In addition, scattered healthy pod on the ground should also be removed, as it will be infected and become the source of inoculum later.[18] Sanitation is one cultural method to control for black pod disease. Sanitation practices include weed removal, pruning, thinning and removal of infected and mummified pods every two weeks [7] in order to eliminate the source for inoculum. Phytosanitary pod removal was observed to significantly reduce disease occurrences by 9–11% to 22–31%, where this practice removes the source for secondary inoculum. However, increase in disease incidence after raining season was observed to be most likely due to the spread of inoculum from survival site by the rain. The application of fungicide following sanitation is commonly performed for an effective control of disease, as sanitation practice alone would not completely eliminate the source of inoculum and still causes greater black pod incident compared to sanitation followed by at least one fungicide application [7] ### Chemical control[edit] The application of copper fungicide has been shown to significantly reduce a great number of black pod incidences in Nigeria. Metalaxyl (Ridomil) and cuprous oxide (Perenox) were identified to be successful in increasing the number of harvested healthy pod compared to the application of fosetyl aluminium (Aliete) and control treatment. On top of that, the timing of fungicide application has some positive effect on the final pod yield where this plot produced greater yield than the unsprayed plot. The application was done before August, which is before the main disease epidemic that usually occurs in September and October.[8] The recommended standard for fungicide application to control black pod disease caused by P. megakarya for a season is 6 to 8 times of application in every 3–4 weeks. However, the adoption of recommended application was very low among farmers in Ghana. Therefore, an experiment with a reduced number of fungicide applications demonstrated that there was 25 to 45% reduction in disease incidence.[7] In terms of disease control and yields, sanitation and three applications of Ridomil 72 plus (12% metalaxyl + 60% copper-1-oxide) fungicide showed a better control compared to sanitation alone and sanitation with one or two fungicide applications. However, reduced in fungicide application was shown to be significantly less effective than the recommended standard fungicide application. It was suggested that the understanding regarding the source of inoculum, the amount of infective inoculum production and how the disease is disseminated is important in order to identify the appropriate and economical method in fungicide application as well as for an effective control of the disease. For example, the application of fungicide on the trunk will help farmers to control the spread of the disease up in the canopy, as it is difficult to reach the canopy during fungicide application. This will eventually save more time, labor and cost for disease management.[7] ### Cultural and chemical control[edit] In Ghana, a study that combined the sanitation and fungicide application showed a significant reduction in the percentage of disease incidence, where greater black pod incident were observed from pods on the trunk than the canopy in control treatment (no fungicide application). This suggested that the application of fungicide on the trunk would protect pods from infection, therefore reduce primary and secondary infection rate, both on the trunk and in the canopy. In addition, the application of systemic (potassium phosphonate) with one and double injection (20 ml and 40 ml of fungicide for each injection frequency), and semi-systemic (metalaxyl) fungicide showed better control compared to contact fungicides (copper based fungicide) in both locations that were used in the experiment.[7] ### Biological control[edit] Chris Tonaldo applying chemical fungicide on cocoa Heavy application of chemical fungicide would eventually leads to resistant of pathogen and causing soil and water pollutions. Hence, more sustainable and environmental friendly method should be established and implemented, such as biological control. Several species of fungi from the genera of Trichoderma was identified to be a beneficial endophyte, to control black pod caused by Phytophthora spp. An isolate of Trichoderma asperellum from soil was observed as a potential mycoparasite for P. megakarya where this fungus has the potential to reduce black pod incident under field condition in Cameroon. It was reported that moderate black pod cases (47%) occurred in the T. asperellum treatment to control black pod disease compared to trees with untreated (71%) and chemical fungicide (1.73%).[19] Another species, which is T. virens also has been documented to reduce some black pod incident in Peru.[20] In Brazil, a new species known as Trichoderma martiale Samuels, sp. nov. was identified as an endophyte on cocoa, which has the ability to reduce black pod symptoms caused by P. megakarya.[21] This endophyte species survives on cocoa pods, and has the ability to establish a long endophytic association with the host (about 3.5 months). Nevertheless, the protection against black pod via biological control is not as effective as the control using chemical fungicides[19][21] ### Resistant variety[edit] There is no specific variety of cocoa that shows resistant to Phytophthora infections and the establishment and utilization of resistant variety will be most likely depends on the region. Numerous breeding programs have been established worldwide in order to screen and test for local hybrids for disease resistant of Phytophthora spp. For example, a study in Cameroon assessed the performance of local cocoa cultivars (the southern and northern Cameroon cultivar) compared to the local and international gene bank cultivars. The local genebank cultivar consisted of F1 hybrid of Upper Amazon X Trinidad, and an international cultivar from Papua New Guinea, and Latin America were provided through International Cocoa Genebank, Trinidad. Based on the information provided by farmers and leaf disc test to assess resistant variety, the local cultivars selected from farmers field showed some resistant to P. megakarya compared to other varieties. Thus, it was concluded that there are some potential resistant varieties available in this area.[22] In addition, some molecular work on developing resistant varieties to black pod is being done by CEPLAC (Executive Plan of Cocoa Farming) agency in Brazil [23] and hopefully more breeding program focusing on black pod resistant will be established and produced commercialized resistant varieties. ## Importance[edit] The United States chocolate industry consumes 1.4 billion dollars of cocoa and supplies 68,450 jobs throughout the United States.[24] With this industry being so important not only in the US but also all over the world the black pod disease is of high importance. This pathogen if left untreated can destroy all yields; annually the pathogen causes 20-30% yield loss and kills about 10% of trees completely. ## References[edit] 1. ^ Philip-Mora, Wilbert; Rolando Cerda (2009). "Catalog: Cacao Diseases in Central America" (PDF). Tropical Agricultural Research and Higher Education Center, CATIE. Archived from the original (PDF) on 2013-12-12. Retrieved 20 November 2013. 2. ^ Brasier, C. M.; M.J. Griffin; A.C. Maddison (1981). "Cocoa black pod Phytophthoras". In P.H. Gregory and A.C. Maddison) (ed.). Epidemiology of Phytophthora on cocoa in Nigeria. UK: Commonwealth Mycological Institute, Kew. pp. 18–30. 3. ^ a b c d Guest, D. (2007). "Black Pod: Diverse pathogens with a global impact on cocoa yield". Phytopathology. 97 (12): 1650–1653. doi:10.1094/phyto-97-12-1650. PMID 18943728. 4. ^ a b Luseni, M.M.; S. Kroma (2012). "Black pod disease of cacao" (PDF). www.plantwise.org. 5. ^ Dennis, J.J.C.; J.K. Konam (1994). "Phytophthora palmivora cultural control methods and their relationship to disease epidemiology on cocoa in Papua New Guinea". 11th International Cocoa Research Conference. Cocoa Producers Alliance. 11: 953–957. 6. ^ Gregory, P.H; A.C. Maddison (1981). Epidemiology of Phytophthora on Cocoa in Nigeria. UK: Commonwealth Mycological Institute, Kew. 7. ^ a b c d e f Opoku, I.Y.; A.Y. Akrofi; A.A. Appiah (2007). "Assessment of sanitation and fungicide application directed at cocoa tree trunks for the control of Phytophthora black pod infections in pods growing in the canopy". Eur. J. Plant Pathol. 117 (2): 167–175. doi:10.1007/s10658-006-9082-8. S2CID 6620069. 8. ^ a b Ward, M.R.; A.C. Maddison; A.A. Adebayo (1981). "The epidemic on sprayed cocoa at Gambari". In P. H. Gregory and A. C. Maddison (ed.). Epidemiology of Phytophthora on Cocoa in Nigeria. UK: Commonwealth Mycological Institute, Kew. pp. 145–162. 9. ^ Opoku, I.Y.; A.Y. Akrofi; A.A. Appiah (2002). "Shade trees are alternative hosts of the cocoa pathogen Phytophthora megakarya". Crop Prot. 21 (8): 629–634. doi:10.1016/s0261-2194(02)00013-3. 10. ^ Dakwa, J.T (1973). "The relationship between black pod incidence and the weather in Ghana". Ghana J. Agric. Sci. 6: 93–102. 11. ^ Bowers, J.H.; B.A. Bailey; P.K. Hebbar; S. Sanogo; R.D. Lumsden (2001). "The impact of plant diseases on world chocolate production". Plant Health Progress. Archived from the original on 2013-12-12. Retrieved 2013-11-22. 12. ^ a b c Maddison, A.C.; M.J. Griffin (1981). "Detection and movement of inoculum". In P.H. Gregory and A.C. Maddison (ed.). Epidemiology of Phytophthora on Cocoa in Nigeria, Phytopathological. UK: Commonwealth Mycological Institute, Kew. pp. 31–49. 13. ^ a b Thorold, C.A. (1952). "Airborne dispersal of Phytophthora palmivora, causing black pod disease in Theobroma cacao". Nature. 170 (4330): 718–719. Bibcode:1952Natur.170..718T. doi:10.1038/170718a0. PMID 13002424. S2CID 4264153. 14. ^ a b Evans, H.C. (1971). "Transmission of Phytophthora pod rot of cocoa by invertebrates". Nature. 232 (5309): 346–347. Bibcode:1971Natur.232..346E. doi:10.1038/232346a0. PMID 5094846. S2CID 4181889. 15. ^ Taylor, B.; M.J. Griffin (1981). "The role and relative importance of different ant species in the dissemination of black pod disease of cocoa". In P.H. Gregory and A.C. Maddison (ed.). Epidemiology of Phytophthora on Cocoa in Nigeria. UK: Commonwealth Mycological Institute, Kew. pp. 114–131. 16. ^ Konam, J.K.; D.I. Guest (2002). "Leaf litter mulch reduces the survival of Phytophthora palmivora under cocoa trees in Papua New Guinea". Aust. Plant Pathol. 31 (4): 381–383. doi:10.1071/ap02043. S2CID 40787476. 17. ^ Aryantha, I.P.; R. Cross; D.I. Guest (2000). "Suppression of Phytophthora cinnamomi in potting mixes amended with uncomposted and composted animal manures". Phytopathology. 90 (7): 775–782. doi:10.1094/PHYTO.2000.90.7.775. PMID 18944498. 18. ^ Dennis, J.J.C.; J.K. Konam (1994). "Phytophthora palmivora cultural control methods and their relationship to disease epidemiology on cocoa in Papua New Guinea". 11th International Cocoa Research Conference. Cocoa Producers Alliance. 11 (953–957). 19. ^ a b Deberdt, P.; C.V. Mfegue; P.R. Tondje; M.C. Bon; M. Ducamp; C. Hurard; B.A.D. Begoude; M. Ndoumbe-Nkeng; P.K. Hebbar; C. Cilas (2008). "Impact of environmental factors, chemical fungicide and biological control on cacao pod production dynamics and black pod disease (Phytophthora megakarya) in Cameroon". Biological Control. 44 (2): 149–159. doi:10.1016/j.biocontrol.2007.10.026. 20. ^ Krauss, U.; W. Soberanis (2002). "Effect of fertilization and biocontrol application frequency on cocoa pod diseases". Biological Control. 24: 82–89. doi:10.1016/s1049-9644(02)00007-5. 21. ^ a b Hanada, R.E; T.J. Souza; A.W.V. Pomella; K. P. Hebbar; J. O. Pereira; A. Ismaiel; G.J. Samuels (2008). "Trichoderma martiale sp. nov., a new endophyte from sapwood of Theobroma cacao with a potential for biological control". Mycol. Res. 112 (11): 1335–1343. doi:10.1016/j.mycres.2008.06.022. PMID 18672059. 22. ^ Efombagn, M.I.B.; S. Nyassé; O. Sounigo; M. Kolesnikova-Allen; A.B. Eskes (2007). "Participatory cocoa (Theobroma cacao) selection in Cameroon: Phytophthora pod rot resistant accessions identified in farmers' fields". Crop Prot. 26 (10): 1467–1473. doi:10.1016/j.cropro.2006.12.008. 23. ^ ICCO - International Cocoa Organization. (2013). "Pest and Diseases". 24. ^ U.S. Bureau of Census (2010). "Current Industrial Reports: MA311D - Confectionery". [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Black pod disease	None	3,732	wikipedia	https://en.wikipedia.org/wiki/Black_pod_disease	2021-01-18T18:29:23	{"wikidata": ["Q17115915"]}
## Description Dyschromatosis universalis hereditaria (DUH) is a rare autosomal dominant genodermatosis characterized by irregularly shaped, asymptomatic hyper- and hypopigmented macules that appear in infancy or early childhood and occur in a generalized distribution over the trunk, limbs, and sometimes the face. Involvement of the palms or soles is unusual. Abnormalities of hair and nails have been reported, and DUH may be associated with abnormalities of dermal connective tissue, nerve tissue, or other systemic complications (summary by Zhang et al., 2013). For a discussion of genetic heterogeneity of dyschromatosis universalis hereditaria, see DUH1 (127500). Clinical Features Bukhari et al. (2006) reported a consanguineous Saudi Bedouin family in which 2 boys and 2 girls had dyschromatosis universalis hereditaria (DUH). The sibs presented during infancy or early childhood with multiple asymptomatic 2- to 5-mm maculae that were hypopigmented, depigmented and hyperpigmented, bilaterally symmetric, and scattered all over the body including the back, hands, feet, and face. The palms and soles, mucous membranes, teeth, and nails appeared normal. The hair appeared normal but was light brown, in contrast to unaffected family members who had black hair. Histologic investigation of a skin biopsy from the hyperpigmented lesion of 1 of the affected boys showed basal layer hypermelanosis with pigmentary incontinence in some areas. The paternal grandmother was also reportedly affected. Inheritance The transmission pattern of DUH in the family reported by Bukhari et al. (2006) was consistent with autosomal recessive inheritance. Mapping By genomewide analysis of a Saudi Bedouin family with DUH reported by Bukhari et al. (2006), Stuhrmann et al. (2008) found linkage of the disorder to an 18.9-cM region on chromosome 12q21-q23 between SNPs rs1921045 and rs2373584 (maximum lod score of 3.4). Molecular analysis excluded mutations in the ADAR gene (146920). [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	DYSCHROMATOSIS UNIVERSALIS HEREDITARIA 2	c1306229	3,733	omim	https://www.omim.org/entry/612715	2019-09-22T16:00:43	{"doid": ["0060304"], "omim": ["612715"], "orphanet": ["241"]}
## Clinical Features Fryns et al. (1996) presented the clinical and radiologic findings in a newborn male with severe micromelic dwarfism, short neck, short and narrow upper thorax, and brachydactyly. At the age of 1 year, mental development was slightly retarded. Radiographically, severe vertebral segmentation defects and a generalized metaphyseal skeletal dysplasia were demonstrated. Fryns et al. (1996) suggested that this patient may represent a new type of micromelic spondyloepimetaphyseal dysplasia. INHERITANCE \- ?Autosomal recessive GROWTH Height \- Micromelic dwarfism, severe HEAD & NECK Head \- Short neck CHEST External Features \- Short and narrow upper thorax SKELETAL Spine \- Vertebral segmentation defects, severe Limbs \- Brachydactyly \- Metaphyseal skeletal dysplasia, generalized NEUROLOGIC Central Nervous System \- Mental retardation MISCELLANEOUS \- Based on the report of 1 male child ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	SPONDYLOEPIMETAPHYSEAL DYSPLASIA, MICROMELIC	c1832800	3,734	omim	https://www.omim.org/entry/601096	2019-09-22T16:15:24	{"mesh": ["C537556"], "omim": ["601096"], "synonyms": ["Alternative titles", "SEMD, MICROMELIC", "DWARFISM, MICROMELIC, WITH CONE EPIPHYSES, METAPHYSEAL DYSPLASIA, AND VERTEBRAL SEGMENTATION DEFECTS"]}
A number sign (#) is used with this entry because of evidence that congenital anomalies of the kidney and urinary tract-3 (CAKUT3) is caused by heterozygous mutation in the NRIP1 gene (602490) on chromosome 21q11-q21. One such family has been reported. For a discussion of genetic heterogeneity of CAKUT, see 610805. Clinical Features Vivante et al. (2017) reported a 3-generation Yemenite Jewish family in which 7 individuals had a variety of urinary abnormalities. One patient in the older generation was diagnosed at age 69, but the other patients were diagnosed in the first decade or on prenatal ultrasound. Six patients had renal hypodysplasia, 4 of whom also had vesicoureteral reflux. Other manifestations included dilated ureters, hydronephrosis, multicystic kidneys, and small kidneys. Two patients had renal ectopia. One additional family member had small renal cysts on ultrasound, but he was not considered to be affected because that is a common finding. Two patients underwent nephrectomy for their malformations. None had extrarenal manifestations. Inheritance The transmission pattern of CAKUT3 in the family reported by Vivante et al. (2017) was consistent with autosomal dominant inheritance and possible incomplete penetrance. Molecular Genetics In 7 affected members of a 3-generation Yemenite Jewish family (family H) with CAKUT3, Vivante et al. (2017) identified a heterozygous 1-bp deletion (c.279delG; 602490.0001) in the NRIP1 gene. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family, although there was 1 possible unaffected mutation carrier, suggesting incomplete penetrance. In vitro functional expression studies in HEK293 cells showed that the mutant protein remained localized in the cytoplasm, did not translocate to the nucleus, abrogated the NRIP1-retinoic acid receptor (RAR) interaction, and had no repressor activity for RA-mediated transcription. Coexpression with wildtype NRIP1 showed that the mutation resulted in haploinsufficiency with a loss of function and did not show a dominant-negative effect. Nrip1 was expressed in Xenopus during development, particularly in the pronephric tubules. Morpholino knockdown of the nrip1 gene resulted in distorted pronephric structures, and the mutant mRNA identified in the family could not rescue the defect. Exon sequencing of the NRIP1 gene in 155 additional patients with sporadic disease and 253 familial cases did not identify any additional variants. Animal Model Vivante et al. (2017) found that heterozygous Nrip1-null mouse embryos had urinary tract abnormalities, including dysplastic kidneys with cystic dilations and severe hydroureter with hydronephrosis and ureterocele. INHERITANCE \- Autosomal dominant GENITOURINARY Kidneys \- Renal hypodysplasia \- Renal cysts \- Renal ectopia \- Hydronephrosis Ureters \- Dilated ureters Bladder \- Vesicoureteral reflux MISCELLANEOUS \- Variable age at diagnosis (onset usually in childhood) \- Variable expressivity \- Incomplete penetrance \- One family has been reported (last curated January 2019) MOLECULAR BASIS \- Caused by mutation in the nuclear receptor-interacting protein 1 gene (NRIP1, 602490.0001 ) ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	CONGENITAL ANOMALIES OF KIDNEY AND URINARY TRACT 3	None	3,735	omim	https://www.omim.org/entry/618270	2019-09-22T15:42:45	{"omim": ["618270"]}
## Description The autoimmune thyroid disorders, or AITDs, comprise 2 related disorders, Graves disease (GD; 275000) and Hashimoto thyroiditis (HT; 140300). See 608173. Mapping Sakai et al. (2001) undertook a genomewide analysis of 123 Japanese sib pairs affected with AITD. At 19 regions on 14 chromosomes, the multipoint maximum lod score was greater than 1. Chromosome 5q31-q33 yielded suggestive evidence for linkage to AITD as a whole, with a maximum lod score of 3.14 at marker D5S436, and chromosome 8q23-q24 yielded suggestive evidence for linkage to HT, with a maximum lod score of 3.77 at marker D8S272. Akamizu et al. (2003) performed an association study using 6 microsatellite markers situated at or near the 5q31-q33 locus associated with AITD in a set of 440 unrelated Japanese AITD patients and 218 Japanese controls. They found significant allelic association between AITD and 3 markers located in 5q23-q33. Graves disease demonstrated significant associations with 2 of these markers, while Hashimoto thyroiditis did not show significant associations with any markers. When patients with Graves disease were stratified according to clinical manifestations, the association was significantly different from the other subgroup of each category. Akamizu et al. (2003) concluded that they confirmed the presence of susceptibility genes in or near the 5q31-q33 region identified by linkage analysis (Sakai et al., 2001) to contain a susceptibility locus for AITD by the genomewide screening in Japanese. In 146 sporadic Chinese patients with Graves disease, 142 unrelated controls, and 54 multiplex families with Graves disease, Yang et al. (2005) performed an association study involving polymorphisms in 4 genes in the 5q31 chromosome region and found no difference in genotype or allele frequency distribution between patients and controls, and no evidence for dominant transmission from heterozygous parents to affected offspring. However, comparison of the clinical variables of the Graves patients revealed that the age of onset in patients carrying TT at the 6477T/G locus (rs2070729) in the IRF1 gene (147575) was lower than those with a variant allele (TG or GG, p = 0.005). Jin et al. (2003) conducted a genomewide scan on 322 individuals from 54 Chinese Han multiplex Graves disease pedigrees. Parametric linkage analysis revealed the strongest evidence for linkage at D5S436 on chromosome 5q31, with a maximum 2-point lod score of 2.8 and a maximum multipoint lod score of 2.3. To further assess the significance of this suggestive finding, Jin et al. (2003) typed 4 additional markers around D5S436 in this chromosome region, and obtained a maximum 2-point lod score of 4.31 and a maximum multipoint lod score of 4.12 for marker D5S2090 (with heterogeneity, alpha = 0.38). Nonparametric multipoint analysis also showed significant excess allele sharing, with a P value as low as 0.001, at the same locus. Song et al. (2009) performed an association analysis using SNPs between markers D5S436 and D5S434 in 2,811 Chinese patients with Graves disease and found the strongest associations with GD at 2 SNPS in the promoter of the SCGB3A2 gene (606531): SNP76 (rs1368408, p = 1.43 x 10(-6), odds ratio (OR) = 1.28) and SNP75 (-623AG-T, p = 7.62 x 10(-5), OR = 1.32). Haplotypes composed of SNP76+SNP74 (rs6882292) or SNP76+SNP75 variants were correlated with disease susceptibility (p = 0.007 and p = 0.0192, respectively). These haplotypes were associated with reduced SCGB3A2 gene expression levels in human thyroid tissue, while functional analysis revealed a relatively low efficiency of SCGB3A2 promoters of the SNP76+SNP75 and SNP76+SNP74 haplotypes in driving gene expression. Song et al. (2009) suggested that the SCGB3A2 gene may contribute to GD susceptibility. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	AUTOIMMUNE THYROID DISEASE, SUSCEPTIBILITY TO, 2	c1842445	3,736	omim	https://www.omim.org/entry/608174	2019-09-22T16:08:12	{"omim": ["608174"], "synonyms": ["Alternative titles", "AITD2"]}
Illness featuring muscle tenderness and rhabdomyolysis after consuming quail that have fed on poisonous plants Coturnism Coturnix coturnix SpecialtyToxicology Coturnism is an illness featuring muscle tenderness and rhabdomyolysis[1] (muscle cell breakdown) after consuming quail (usually common quail, Coturnix coturnix,[2] from which the name derives) that have fed on poisonous plants. ## Contents * 1 Causes * 2 Epidemiology * 3 History * 4 References * 5 External links ## Causes[edit] From case histories it is known that the toxin is stable, as four-month-old pickled quail have been poisonous. Humans vary in their susceptibility; only one in four people who consumed quail soup containing the toxin fell ill.[3] The toxin is apparently fat-soluble as potatoes fried in quail fat have proven poisonous themselves.[3] Coniine from hemlock consumed by quail has been suggested as the cause of Coturnism,[4] though quail resist eating hemlock.[3] Hellebore has also been suggested as the source of the toxin.[5] It has also been asserted that this evidence points to the seeds of the annual woundwort (Stachys annua) being the causal agent.[3] It has been suggested that Galeopsis ladanum seeds are not responsible.[6] ## Epidemiology[edit] Migration routes and season may affect quail risk.[7] Quail are never poisonous outside the migration season nor are the vast majority poisonous while migrating.[3] European common quail migrate along three different flyways, each with different poisoning characteristics, at least in 20th century records. The western flyway across Algeria to France is associated with poisonings only on the spring migration and not on the autumn return. The eastern flyway, which funnels down the Nile Valley, is the reverse. Poisonings were only reported in the autumn migration before the quail had crossed the Mediterranean. The central flyway across Italy had no associated poisonings.[3] Migrating quail used to be caught and eaten in prodigious numbers (150,000 quail exported from Capri in 1850)[8] but modern farming and droughts in the Sahel have led to a vast reduction in the size of the migrations. Conservation efforts and the availability of farmed quail have also reduced the consumption of these wild birds. Coturnism may well disappear before it is understood. ## History[edit] The condition was certainly known by the 4th century BC to the ancient Greek (and subsequently Roman) naturalists, physicians, and theologians. The Bible (Numbers 11:31-34) mentions an incident where the Israelites became ill after having consumed large amounts of quail in Sinai.[9] Philo gives a more detailed version of the same Biblical story (The Special Laws: 4: 120-131). Early writers used quail as the standard example of an animal that could eat something poisonous to man without ill effects for themselves. Aristotle (On Plants 820:6-7), Philo (Geoponics: 14: 24), Lucretius (On the Nature of Things: 4: 639-640), Galen (De Temperamentis: 3:4) and Sextus Empiricus (Outlines of Pyrrhonism: 1: 57) all make this point. Central to these ancient accounts is the thesis that quail became toxic to humans after consuming seeds from hellebore or henbane (Hyoscyamus niger). However Sextus Empiricus suggested that quail ate hemlock (Conium maculatum), an idea revived in the 20th century. Confirmation that the ancients understood the problem, comes from a 10th-century text Geoponica, based on ancient sources. This states, "Quails may graze hellebore putting those who afterwards eat them at risk of convulsions and vertigo....".[10] ## References[edit] 1. ^ Korkmaz I, Kukul Güven FM, Eren SH, Dogan Z (October 2008). "Quail Consumption Can Be Harmful". J Emerg Med. 41 (5): 499–502. doi:10.1016/j.jemermed.2008.03.045. PMID 18963719. 2. ^ Tsironi M, Andriopoulos P, Xamodraka E, et al. (August 2004). "The patient with rhabdomyolysis: have you considered quail poisoning?". CMAJ. 171 (4): 325–6. doi:10.1503/cmaj.1031256. PMC 509041. PMID 15313988. 3. ^ a b c d e f Lewis DC, Metallinos-Katzaras E, Grivetti LE (1987). "Coturnism: Human Poisoning by European Migratory Quail". Journal of Cultural Geography. 7 (2): 51–65. doi:10.1080/08873638709478507. 4. ^ Clatworthy, Menna (2010). Nephrology: Clinical Cases Uncovered. John Wiley and Sons. p. 145. ISBN 978-1-4051-8990-3. 5. ^ Dobbs, Michael R. (2009). Clinical neurotoxicology: syndromes, substances, environments. Elsevier Health Sciences. p. 166. ISBN 978-0-323-05260-3. 6. ^ Uriarte-Pueyo I, Goicoechea M, Gil AG, López de Cerain A, López de Munain A, Calvo MI (November 2009). "Negative evidence for stachydrine or Galeopsis ladanum L. seeds as the causal agents of coturnism after quail meat ingestion". J. Agric. Food Chem. 57 (22): 11055–9. doi:10.1021/jf902764n. PMID 19860419. 7. ^ Giannopoulos D, Voulioti S, Skarpelos A, Arvanitis A, Chalkiopoulou C (2006). "Quail poisoning in a child". Rural Remote Health. 6 (2): 564. PMID 16700632. 8. ^ Toschi A (1959). La quaglia: vita, caccia, allevamento. Supplemento alle Ricerche di Zoologia Applicata alla Caccia. 3. Bologna: Università di Bologna. p. 110. OCLC 66552512. 9. ^ Ouzounellis T (16 February 1970). "Some notes on quail poisoning". JAMA. 211 (7): 1186–7. doi:10.1001/jama.1970.03170070056017. PMID 4904256. 10. ^ Andrew Dalby Totnes (2011). Geoponica : farm work: a modern translation of the Roman and Byzantine farming handbook. Prospect. p. 294. ISBN 978-1-903018-69-9. ## External links[edit] Classification D * v * t * e * Poisoning * Toxicity * Overdose History of poison Inorganic Metals Toxic metals * Beryllium * Cadmium * Lead * Mercury * Nickel * Silver * Thallium * Tin Dietary minerals * Chromium * Cobalt * Copper * Iron * Manganese * Zinc Metalloids * Arsenic Nonmetals * Sulfuric acid * Selenium * Chlorine * Fluoride Organic Phosphorus * Pesticides * Aluminium phosphide * Organophosphates Nitrogen * Cyanide * Nicotine * Nitrogen dioxide poisoning CHO * alcohol * Ethanol * Ethylene glycol * Methanol * Carbon monoxide * Oxygen * Toluene Pharmaceutical Drug overdoses Nervous * Anticholinesterase * Aspirin * Barbiturates * Benzodiazepines * Cocaine * Lithium * Opioids * Paracetamol * Tricyclic antidepressants Cardiovascular * Digoxin * Dipyridamole Vitamin poisoning * Vitamin A * Vitamin D * Vitamin E * Megavitamin-B6 syndrome Biological1 Fish / seafood * Ciguatera * Haff disease * Ichthyoallyeinotoxism * Scombroid * Shellfish poisoning * Amnesic * Diarrhetic * Neurotoxic * Paralytic Other vertebrates * amphibian venom * Batrachotoxin * Bombesin * Bufotenin * Physalaemin * birds / quail * Coturnism * snake venom * Alpha-Bungarotoxin * Ancrod * Batroxobin Arthropods * Arthropod bites and stings * bee sting / bee venom * Apamin * Melittin * scorpion venom * Charybdotoxin * spider venom * Latrotoxin / Latrodectism * Loxoscelism * tick paralysis Plants / fungi * Cinchonism * Ergotism * Lathyrism * Locoism * Mushrooms * Strychnine 1 including venoms, toxins, foodborne illnesses. * Category * Commons * WikiProject [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Coturnism	None	3,737	wikipedia	https://en.wikipedia.org/wiki/Coturnism	2021-01-18T18:31:36	{"wikidata": ["Q5175885"]}
Lymphedema-distichiasis syndrome is a condition that affects the normal function of the lymphatic system, which is a part of the circulatory and immune systems. The lymphatic system produces and transports fluids and immune cells throughout the body. People with lymphedema-distichiasis syndrome develop puffiness or swelling (lymphedema) of the limbs, typically the legs and feet. Another characteristic of this syndrome is the growth of extra eyelashes (distichiasis), ranging from a few extra eyelashes to a full extra set on both the upper and lower lids. These eyelashes do not grow along the edge of the eyelid, but out of its inner lining. When the abnormal eyelashes touch the eyeball, they can cause damage to the clear covering of the eye (cornea). Related eye problems can include an irregular curvature of the cornea causing blurred vision (astigmatism) or scarring of the cornea. Other health problems associated with this disorder include swollen and knotted (varicose) veins, droopy eyelids (ptosis), heart abnormalities, and an opening in the roof of the mouth (a cleft palate). All people with lymphedema-distichiasis syndrome have extra eyelashes present at birth. The age of onset of lymphedema varies, but it most often begins during puberty. Males usually develop lymphedema earlier than females, but all affected individuals will develop lymphedema by the time they are in their forties. ## Frequency The prevalence of lymphedema-distichiasis syndrome is unknown. Because the extra eyelashes can be overlooked during a medical examination, researchers believe that some people with this condition may be misdiagnosed as having lymphedema only. ## Causes Lymphedema-distichiasis syndrome is caused by mutations in the FOXC2 gene. The FOXC2 gene provides instructions for making a protein that plays a critical role in the formation of many organs and tissues before birth. The FOXC2 protein is a transcription factor, which means that it attaches (binds) to specific regions of DNA and helps control the activity of many other genes. Researchers believe that the FOXC2 protein has a role in a variety of developmental processes, such as the formation of veins and the development of the lungs, eyes, kidneys and urinary tract, cardiovascular system, and the transport system for immune cells (lymphatic vessels). ### Learn more about the gene associated with Lymphedema-distichiasis syndrome * FOXC2 ## Inheritance Pattern This condition is inherited in an autosomal dominant pattern, which means one copy of the altered gene in each cell is sufficient to cause the disorder. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Lymphedema-distichiasis syndrome	c0265345	3,738	medlineplus	https://medlineplus.gov/genetics/condition/lymphedema-distichiasis-syndrome/	2021-01-27T08:24:49	{"gard": ["333"], "mesh": ["C537710"], "omim": ["153400"], "synonyms": []}
A rare syndrome characterised by mesomelic shortening and bowing of the limbs, camptodactyly, skin dimpling and cleft palate with retrognathia and mandibular hypoplasia. It has been described in a brother and sister born to consanguineous parents. 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 [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Mesomelic dwarfism-cleft palate-camptodactyly syndrome	c2930871	3,739	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=2631	2021-01-23T17:39:44	{"gard": ["3552"], "mesh": ["C535294"], "omim": ["249710"], "umls": ["C2930871"], "icd-10": ["Q78.8"], "synonyms": ["Mesomelic dysplasia, Kozlowski-Reardon type", "Mesomelic dysplasia, Reardon type", "Reardon-Hall-Slaney syndrome"]}
Bark-binding is a disease in trees, cured by slitting the bark, or cutting it along the grain of the tree. ## Further reading[edit] * Trees portal * This article incorporates text from a publication now in the public domain: Chambers, Ephraim, ed. (1728). "Bark-binding". Cyclopædia, or an Universal Dictionary of Arts and Sciences (1st ed.). James and John Knapton, et al. p. 82. * Crabb, George. The Book of Knowledge: Or, An Explanation of Words and Things Connected with All the Arts... Leavitt & Allen. 1858. * Lyon, Patrick (1816). A Treatise on the Physiology and Pathology of Trees: With Observations on the Barrenness and Canker of Fruit Trees. p. 121. This plant disease article is a stub. You can help Wikipedia by expanding it. * v * t * e [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Bark-binding	None	3,740	wikipedia	https://en.wikipedia.org/wiki/Bark-binding	2021-01-18T18:40:41	{"wikidata": ["Q4860854"]}
A rare organic aciduria characterized by increased urinary excretion of 3-methylglutaconic acid, variably associated with neutropenia (sometimes causing recurrent severe infections and potentially resulting in leukemia) and progressive neurologic manifestations, such as global developmental delay, intellectual disability, hypotonia, movement disorder, and seizures. Microcephaly, cataract, facial dysmorphism, growth retardation, endocrine abnormalities, and cardiomyopathy have also been reported. Brain imaging may show cerebral or cerebellar atrophy, or abnormalities of the basal ganglia. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	3-methylglutaconic aciduria type 7	c4225393	3,741	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=445038	2021-01-23T19:09:23	{"omim": ["616271"], "icd-10": ["E71.1"], "synonyms": ["3-methylglutaconic aciduria-cataract-neurologic involvement-neutropenia syndrome", "MGA7"]}
Membranous glomerulonephritis Micrograph of membranous nephropathy showing prominent glomerular basement membrane spikes. Jones' stain. SpecialtyNephrology Membranous glomerulonephritis (MGN) is a slowly progressive disease of the kidney affecting mostly people between ages of 30 and 50 years, usually Caucasian. Play media Video explanation It is the second most common cause of nephrotic syndrome in adults, with focal segmental glomerulosclerosis (FSGS) recently becoming the most common.[1] ## Contents * 1 Signs and symptoms * 2 Causes * 2.1 Primary/idiopathic * 2.2 Secondary * 3 Pathogenesis * 4 Morphology * 5 Treatment * 5.1 Immunosuppressive therapy options * 6 Prognosis * 7 Terminology * 8 References * 9 External links ## Signs and symptoms[edit] Most people will present as nephrotic syndrome, with the triad of albuminuria, edema and low serum albumin (with or without kidney failure). High blood pressure and high cholesterol are often also present. Others may not have symptoms and may be picked up on screening, with urinalysis finding high amounts of protein loss in the urine. A definitive diagnosis of membranous nephropathy requires a kidney biopsy, though given the very high specificity of anti-PLA2R antibody positivity this can sometimes be avoided in patients with nephrotic syndrome and preserved kidney function[2] ## Causes[edit] ### Primary/idiopathic[edit] 85% of MGN cases are classified as primary membranous glomerulonephritis—that is to say, the cause of the disease is idiopathic (of unknown origin or cause). This can also be referred to as idiopathic membranous nephropathy. One study has identified antibodies to an M-type phospholipase A2 receptor in 70% (26 of 37) cases evaluated.[3] Testing for these anti-PLA2R has revolutionised diagnosis and treatment of this disease in antibody positive patients, and tracking titre level over time allows you to predict risk of disease progression and chance of spontaneous remission[4] In 2014, a second autoantigen was discovered, the thrombospondin type 1 domain-containing 7A (THSD7A) system that might account for an additional 5-10% of membranous nephropathy cases, and appears to be associated with malignancies.[5] New studies are identifying novel auto-antigens responsible for membranous nephropathy continue to be published, with antibodies against NELL-1[6] and EXT1/EXT2[7] in 2019. ### Secondary[edit] The remainder is secondary due to: * autoimmune conditions (e.g., systemic lupus erythematosus[8]). * infections (e.g., syphilis, malaria, hepatitis B, hepatitis C, HIV).[9] * drugs (e.g., captopril, NSAIDs, penicillamine, probenecid, Bucillamine, Anti-TNF therapy, Tiopronin).[10] * inorganic salts (e.g. gold, mercury).[11] * tumors, frequently solid tumors of the lung and colon; hematological malignancies such as chronic lymphocytic leukemia are less common.[12] ## Pathogenesis[edit] Immune complexes (black) are deposited in a thickened basement membrane creating a "spike and dome" appearance on electron microscopy. MGN is caused by immune complex formation in the glomerulus. The immune complexes are formed by binding of antibodies to antigens in the glomerular basement membrane. The antigens may be part of the basement membrane, or deposited from elsewhere by the systemic circulation. The immune complex serves as an activator that triggers a response from the C5b - C9 complements, which form a membrane attack complex (MAC) on the glomerular epithelial cells. This, in turn, stimulates release of proteases and oxidants by the mesangial and epithelial cells, damaging the capillary walls and causing them to become "leaky". In addition, the epithelial cells also seem to secrete an unknown mediator that reduces nephrin synthesis and distribution. Within membranous glomerulonephritis, especially in cases caused by viral hepatitis, serum C3 levels are low.[13] Similar to other causes of nephrotic syndrome (e.g., focal segmental glomerulosclerosis or minimal change disease), membranous nephropathy is known to predispose affected individuals to develop blood clots such as pulmonary emboli. Membranous nephropathy in particular is known to increase this risk more than other causes of nephrotic syndrome though the reason for this is not yet clear. ## Morphology[edit] The defining point of MGN is the presence of subepithelial immunoglobulin-containing deposits along the glomerular basement membrane (GBM). * By light microscopy, the basement membrane is observed to be diffusely thickened. Using Jones' stain, the GBM appears to have a "spiked" or "holey" appearance. * On electron microscopy, subepithelial deposits that nestle against the glomerular basement membrane seems to be the cause of the thickening. Also, the podocytes lose their foot processes. As the disease progresses, the deposits will eventually be cleared, leaving cavities in the basement membrane. These cavities will later be filled with basement membrane-like material, and if the disease continues even further, the glomeruli will become sclerosed and finally hyalinized. * Immunofluorescence microscopy will reveal typical granular deposition of immunoglobulins and complement along the basement membrane.[14] Although it usually affects the entire glomerulus, it can affect parts of the glomerulus in some cases.[15] ## Treatment[edit] Treatment of secondary membranous nephropathy is guided by the treatment of the original disease. For treatment of idiopathic membranous nephropathy, the treatment options include immunosuppressive drugs and non-specific anti-proteinuric measures such as ACE inhibitors or angiotensin II receptor blockers. Given spontaneous remission is common, international guidelines recommend a period of watchful waiting before considering immunosuppressive treatment.[16] Likelihood of achieving spontaneous remission is much higher if anti-proteinuric therapy with ace inhibitors or angiotensin II receptor blockers is commenced. Recommended first line immunsosuppressive therapy often includes: cyclophosphamide alternating with a corticosteroid,[17] also known as the Ponticelli regime. ### Immunosuppressive therapy options[edit] 1. Corticosteroids: They have been tried with mixed results, with one study showing prevention of progression to kidney failure without improvement in proteinuria. 2. Chlorambucil 3. Cyclosporine[18] 4. Tacrolimus 5. Cyclophosphamide 6. Mycophenolate mofetil 7. Rituximab Perhaps the most difficult aspect of membranous glomerulonephritis is deciding which people to treat with immunosuppressive therapy as opposed to simple "background" or anti-proteinuric therapies. A large part of this difficulty is due to a lack of ability to predict which people will progress to end-stage kidney disease, or kidney disease severe enough to require dialysis. Because the above medications carry risk, treatment should not be initiated without careful consideration as to risk/benefit profile. Of note, corticosteroids (typically Prednisone) alone are of little benefit. They should be combined with one of the other 5 medications, each of which, along with prednisone, has shown some benefit in slowing down progression of membranous nephropathy. It must be kept in mind, however, that each of the 5 medications also carry their own risks, on top of prednisone. The twin aims of treating membranous nephropathy are first to induce a remission of the nephrotic syndrome and second to prevent the development of end-stage kidney failure. A meta-analysis of four randomized controlled trials comparing treatments of membranous nephropathy showed that regimes comprising chlorambucil or cyclophosphamide, either alone or with steroids, were more effective than symptomatic treatment or treatment with steroids alone in inducing remission of the nephrotic syndrome. ## Prognosis[edit] About a third of untreated patients have spontaneous remission, another third progress to require dialysis and the last third continue to have proteinuria, without progression of kidney failure.[citation needed] ## Terminology[edit] The closely related terms membranous nephropathy (MN)[19] and membranous glomerulopathy[20] both refer to a similar constellation but without the assumption of inflammation. Membranous nephritis (in which inflammation is implied, but the glomerulus not explicitly mentioned) is less common, but the phrase is occasionally encountered.[21] These conditions are usually considered together. By contrast, membranoproliferative glomerulonephritis has a similar name, but is considered a separate condition with a distinctly different causality. Membranoproliferative glomerulonephritis involves the basement membrane and mesangium, while membranous glomerulonephritis involves the basement membrane but not the mesangium. (Membranoproliferative glomerulonephritis has the alternate name "mesangiocapillary glomerulonephritis", to emphasize its mesangial character.) ## References[edit] 1. ^ Membranous Glomerulonephritis at eMedicine 2. ^ Bobart, Shane A.; Vriese, An S. De; Pawar, Aditya S.; Zand, Ladan; Sethi, Sanjeev; Giesen, Callen; Lieske, John C.; Fervenza, Fernando C. (2019-02-01). "Noninvasive diagnosis of primary membranous nephropathy using phospholipase A2 receptor antibodies". Kidney International. 95 (2): 429–438. doi:10.1016/j.kint.2018.10.021. ISSN 0085-2538. PMID 30665573. 3. ^ Beck LH, Bonegio RG, Lambeau G, Beck DM, Powell DW, Cummins TD, Klein JB, Salant DJ (July 2009). "M-type phospholipase A2 receptor as target antigen in idiopathic membranous nephropathy". The New England Journal of Medicine. 361 (1): 11–21. doi:10.1056/NEJMoa0810457. PMC 2762083. PMID 19571279. 4. ^ Logt, Anne-Els van de; Fresquet, Maryline; Wetzels, Jack F.; Brenchley, Paul (2019-12-01). "The anti-PLA2R antibody in membranous nephropathy: what we know and what remains a decade after its discovery". Kidney International. 96 (6): 1292–1302. doi:10.1016/j.kint.2019.07.014. ISSN 0085-2538. PMID 31611068. 5. ^ Tomas NM, Beck LH, Meyer-Schwesinger C, Seitz-Polski B, Ma H, Zahner G, Dolla G, Hoxha E, Helmchen U, Dabert-Gay AS, Debayle D, Merchant M, Klein J, Salant DJ, Stahl RA, Lambeau G (December 2014). "Thrombospondin type-1 domain-containing 7A in idiopathic membranous nephropathy". The New England Journal of Medicine. 371 (24): 2277–2287. doi:10.1056/NEJMoa1409354. PMC 4278759. PMID 25394321. 6. ^ Sethi, Sanjeev; Debiec, Hanna; Madden, Benjamin; Charlesworth, M. Cristine; Morelle, Johann; Gross, LouAnn; Ravindran, Aishwarya; Buob, David; Jadoul, Michel; Fervenza, Fernando C.; Ronco, Pierre (2020-01-01). "Neural epidermal growth factor-like 1 protein (NELL-1) associated membranous nephropathy". Kidney International. 97 (1): 163–174. doi:10.1016/j.kint.2019.09.014. ISSN 0085-2538. PMID 31901340. 7. ^ Sethi, Sanjeev; Madden, Benjamin J.; Debiec, Hanna; Charlesworth, M. Cristine; Gross, LouAnn; Ravindran, Aishwarya; Hummel, Amber M.; Specks, Ulrich; Fervenza, Fernando C.; Ronco, Pierre (2019-06-01). "Exostosin 1/Exostosin 2–Associated Membranous Nephropathy". Journal of the American Society of Nephrology. 30 (6): 1123–1136. doi:10.1681/ASN.2018080852. ISSN 1046-6673. PMC 6551791. PMID 31061139. 8. ^ "Renal Pathology". Retrieved 2008-11-25. 9. ^ "UpToDate". www.uptodate.com. Retrieved 2019-05-11. 10. ^ "UpToDate". www.uptodate.com. Retrieved 2019-05-11. 11. ^ "UpToDate". www.uptodate.com. Retrieved 2019-05-11. 12. ^ Ziakas PD, Giannouli S, Psimenou E, Nakopoulou L, Voulgarelis M (July 2004). "Membranous glomerulonephritis in chronic lymphocytic leukemia". American Journal of Hematology. 76 (3): 271–4. doi:10.1002/ajh.20109. PMID 15224365. S2CID 35937418. 13. ^ Menon S, Valentini RP (August 2010). "Membranous nephropathy in children: clinical presentation and therapeutic approach". Pediatric Nephrology. 25 (8): 1419–28. doi:10.1007/s00467-009-1324-5. PMC 2887508. PMID 19908069. 14. ^ "Renal Pathology". Retrieved 2008-11-25. 15. ^ Obana M, Nakanishi K, Sako M, Yata N, Nozu K, Tanaka R, Iijima K, Yoshikawa N (July 2006). "Segmental membranous glomerulonephritis in children: comparison with global membranous glomerulonephritis". Clinical Journal of the American Society of Nephrology. 1 (4): 723–9. doi:10.2215/CJN.01211005. PMID 17699279. 16. ^ "KDIGO GN guidelines" (PDF). 17. ^ Chen Y, Schieppati A, Chen X, Cai G, Zamora J, Giuliano GA, Braun N, Perna A (October 2014). "Immunosuppressive treatment for idiopathic membranous nephropathy in adults with nephrotic syndrome". The Cochrane Database of Systematic Reviews (10): CD004293. doi:10.1002/14651858.CD004293.pub3. PMC 6669245. PMID 25318831. 18. ^ Goumenos DS, Katopodis KP, Passadakis P, Vardaki E, Liakopoulos V, Dafnis E, Stefanidis I, Vargemezis V, Vlachojannis JG, Siamopoulos KC (2007). "Corticosteroids and ciclosporin A in idiopathic membranous nephropathy: higher remission rates of nephrotic syndrome and less adverse reactions than after traditional treatment with cytotoxic drugs". American Journal of Nephrology. 27 (3): 226–31. doi:10.1159/000101367. PMID 17389782. S2CID 1475371. 19. ^ Passerini P, Ponticelli C (July 2003). "Corticosteroids, cyclophosphamide, and chlorambucil therapy of membranous nephropathy". Seminars in Nephrology. 23 (4): 355–61. doi:10.1016/S0270-9295(03)00052-4. PMID 12923723. 20. ^ Markowitz GS (May 2001). "Membranous glomerulopathy: emphasis on secondary forms and disease variants". Advances in Anatomic Pathology. 8 (3): 119–25. doi:10.1097/00125480-200105000-00001. PMID 11345236. S2CID 39640332. 21. ^ Hallegua D, Wallace DJ, Metzger AL, Rinaldi RZ, Klinenberg JR (2016). "Cyclosporine for lupus membranous nephritis: experience with ten patients and review of the literature". Lupus. 9 (4): 241–51. doi:10.1191/096120300680198935. PMID 10866094. S2CID 20048968. ## External links[edit] Classification D * ICD-10: N03.2 * ICD-9-CM: 583.1 * MeSH: D015433 * DiseasesDB: 7970 External resources * eMedicine: med/885 * v * t * e Lupus nephritis * Class I (Minimal mesangial glomerulonephritis) * Class II (Mesangial proliferative lupus nephritis) * Class III (Focal proliferative nephritis) * Class IV (Diffuse proliferative nephritis) * Class V (Membranous nephritis) * Class VI (Glomerulosclerosis) * v * t * e Disease of the kidney glomerules Primarily nephrotic Non-proliferative * Minimal change * Focal segmental * Membranous Proliferative * Mesangial proliferative * Endocapillary proliferative * Membranoproliferative/mesangiocapillary By condition * Diabetic * Amyloidosis Primarily nephritic, RPG Type I RPG/Type II hypersensitivity * Goodpasture syndrome Type II RPG/Type III hypersensitivity * Post-streptococcal * Lupus * diffuse proliferative * IgA Type III RPG/Pauci-immune * Granulomatosis with polyangiitis * Microscopic polyangiitis * Eosinophilic granulomatosis with polyangiitis General * glomerulonephritis * glomerulonephrosis [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Membranous glomerulonephritis	c0017665	3,742	wikipedia	https://en.wikipedia.org/wiki/Membranous_glomerulonephritis	2021-01-18T18:44:09	{"gard": ["9180"], "mesh": ["D015433"], "umls": ["C0017665"], "icd-9": ["583.1"], "wikidata": ["Q1713037"]}
A rare mitochondrial disease characterized by a distinctive MRI pattern of cavitating leukodystrophy, predominantly in the posterior region of the cerebral hemispheres. The clinical picture varies widely between acute neurometabolic decompensation in infancy with loss of developmental milestones, seizures, and pyramidal signs rapidly evolving into spastic tetraparesis, to subtle neurological symptoms presenting in adolescence. The disease course tends to stabilize over time in most patients, and marked recovery of milestones may be observed. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Non-progressive predominantly posterior cavitating leukoencephalopathy with peripheral neuropathy	None	3,743	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=436271	2021-01-23T17:44:53	{"icd-10": ["G93.4"]}
Barraquer–Simons syndrome Other namesAcquired partial lipodystrophy,[1] Cephalothoracic lipodystrophy,[1] and Progressive lipodystrophy[1] SpecialtyEndocrinology Barraquer–Simons syndrome is a rare form of lipodystrophy, which usually first affects the head, and then spreads to the thorax.[2][3] It is named for Luis Barraquer Roviralta (1855–1928), a Spanish physician, and Arthur Simons (1879–1942), a German physician.[4][5][6] Some evidence links it to LMNB2.[7] ## Contents * 1 Causes * 2 Diagnosis * 2.1 Diagnostic criteria * 3 Treatment * 4 Prognosis * 5 Epidemiology * 6 See also * 7 References * 8 External links ## Causes[edit] The etiology of this condition has not been fully elucidated.[8] Lipodystrophy is often associated with glomerulonephritis, low C3 serum complement levels, and the presence of a C3 nephritic factor. C3 nephritic factor is a serum immunoglobulin G that interacts with the C3bBb alternative pathway convertase to activate C3. C3 nephritic factor induces the lysis of adipocytes that secrete adipsin, a product identical to complement factor D. The distribution of the lipoatrophy is postulated to be dictated by the variable amounts of adipsin secreted by the adipocytes at different locations.[citation needed] Human PTRF mutations may cause secondary deficiency of caveolins, resulting in generalized lipodystrophy in association with in muscular dystrophy. Complement dysfunction may predispose some patients to bacterial infections.[9] ## Diagnosis[edit] The diagnosis of the disease is mainly clinical (see diagnostic criteria). A laboratory workup is needed primarily to investigate for the presence of associated disorders (metabolic, autoimmune, and renal diseases).[9] * Every patient should have a fasting blood glucose and lipid profile, creatinine evaluation, and urinalysis for protein content at the first visit, after which he/she should have these tests on a regular basis. * Although uncommon, lipid abnormalities can occur in the form of raised triglyceride levels and low high-density lipoprotein cholesterol levels. * Patients usually have decreased serum C3 levels, normal levels of C1 and C4, and high levels of C3NeF (autoantibody), which may indicate the presence of renal involvement. * Antinuclear antibodies (ANA) and antidouble-stranded deoxyribonucleic acid (DNA) antibodies have reportedly been observed in some patients with acquired partial lipodystrophy. * A genetic workup should be performed if the familial form of lipodystrophy is suggested. Laboratory work for associated diseases includes:[citation needed] * Metabolic disease - fasting glucose, glucose tolerance test, lipid profile, and fasting insulin to characterize the insulin resistance state; free testosterone (in women) to look for polycystic ovary syndrome. * Autoimmune disease - ANA, antidouble-stranded DNA, rheumatoid factor, thyroid antibodies, C3, and C3NeF. As a confirmatory test, whole-body MRI usually clearly demonstrates the extent of lipodystrophy. MRI is not recommended on a routine basis. ### Diagnostic criteria[edit] A review published in 2004, which was based on 35 patients seen by the respective authors over 8 years and also a literature review of 220 cases of acquired partial lipodystrophy (APL), proposed an essential diagnostic criterion.[10] Based on the review and the authors experience, they proposed that APL presents as a gradual onset of bilaterally symmetrical loss of subcutaneous fat from the face, neck, upper extremities, thorax, and abdomen, in the "cephalocaudal" sequence, sparing the lower extremities. The median age of the onset of lipodystrophy was seven years. Several autoimmune diseases, in particular systemic lupus erythematosus and dermatomyositis, were associated with APL. The prevalence rates of diabetes mellitus and impaired glucose tolerance were 6.7% and 8.9%, respectively. Around 83% of APL patients had low complement 3 (C3) levels and the presence of polyclonal immunoglobulin C3 nephritic factor. About 22% of patients developed membranoproliferative glomerulonephritis (MPGN) after a median of about 8 years following the onset of lipodystrophy. Compared with patients without renal disease, those with MPGN had earlier age of onset of lipodystrophy (12.6 ± 10.3 yr vs 7.7 ± 4.4 yr, respectively; p < 0.001) and a higher prevalence of C3 hypocomplementemia (78% vs 95%, respectively; p = 0.02).[citation needed] The adipose stores of the gluteal regions and lower extremities (including soles) tend to be either preserved or increased, particularly among women.[11] Variable fat loss of the palms, but no loss of intramarrow or retro-orbital fat, has been demonstrated.[citation needed] ## Treatment[edit] In general, treatment for acquired partial lipodystrophy is limited to cosmetic, dietary, or medical options.[9] Currently, no effective treatment exists to halt its progression. Diet therapy has been shown to be of some value in the control of metabolic problems. The use of small, frequent feedings and partial substitution of medium-chain triglycerides for polyunsaturated fats appears to be beneficial.[citation needed] Plastic surgery with implants of monolithic silicon rubber for correction of the deficient soft tissue of the face has been shown to be effective. False teeth may be useful in some cases for cosmetic reasons. Long-term treatment usually involves therapy for kidney and endocrine dysfunction.[citation needed] Data on medications for APL are very limited. Thiazolidinediones have been used in the management of various types of lipodystrophies. They bind to peroxisome proliferator-activator receptor gamma (PPAR-gamma), which stimulates the transcription of genes responsible for growth and differentiation of adipocytes. A single report has suggested a beneficial effect from treatment with rosiglitazone on fat distribution in acquired partial lipodystrophy; however, preferential fat gain was in the lower body.[citation needed] Direct drug therapy is administered according to the associated condition. Membranoproliferative glomerulonephritis and the presence of renal dysfunction largely determine the prognosis of acquired partial lipodystrophy. Standard guidelines for the management of renal disease should be followed. The course of membranoproliferative glomerulonephritis in acquired partial lipodystrophy has not been significantly altered by treatment with corticosteroids or cytotoxic medications. Recurrent bacterial infections, if severe, might be managed with prophylactic antibiotics.[citation needed] ## Prognosis[edit] Estimating the mortality rate based on the available literature is difficult.[9] Several case reports have revealed an association between acquired partial lipodystrophy and other diseases. Nephropathy, in the form of membranoproliferative glomerulonephritis, occurs in about 20% of patients. Usually, patients do not have clinically evident renal disease or abnormalities in renal function until they have had the disease for 8 or more years. Membranoproliferative glomerulonephritis usually presents with asymptomatic proteinuria or hematuria.[citation needed] The disease may gradually progress. About 40-50% of patients develop end-stage renal disease over the course of 10 years. This condition is responsible for most recurrent hospital admissions in patients with acquired partial lipodystrophy. Rapid progression of renal disease in a pregnant patient was reported. Recurrent disease in transplanted kidneys is common, although there have been reports of successful transplantations.[citation needed] Associated autoimmune diseases (e.g., systemic lupus erythematosus, thyroiditis) contribute significantly to increased morbidity in these patients compared with the general population. Although uncommon, insulin resistance increases cardiovascular risk. Susceptibility to bacterial infections probably results from a C3 deficiency (due to complement activation and consumption of C3). Low C3 levels may impair complement-mediated phagocytosis and bacterial killing. ## Epidemiology[edit] Around 250 cases have been reported since the recognition of this syndrome.[9] It is a rare syndrome with no known prevalence, although it is more common than the generalized form of acquired lipodystrophy (Lawrence syndrome).[citation needed] * Race: No clear relationship exists between incidence and race in this syndrome; however, most reported patients have been of European descent. * Age: The median age of onset of lipodystrophy has been reported to be around seven years; however, onset occurring as late as the fourth or fifth decade of life also has been reported. The median age at presentation has been about 25 years, and women have been found to present later than men (age 28 for women, age 18 for men). * Sex: Analysis of the pooled data revealed female patients were affected about four times more often than males. ## See also[edit] * Lipodystrophy * Laminopathy * List of cutaneous conditions ## References[edit] 1. ^ a b c Rapini, Ronald P.; Bolognia, Jean L.; Jorizzo, Joseph L. (2007). Dermatology: 2-Volume Set. St. Louis: Mosby. ISBN 978-1-4160-2999-1. 2. ^ Ferrarini A, Milani D, Bottigelli M, Cagnoli G, Selicorni A (2004). "Two new cases of Barraquer–Simons syndrome". Am. J. Med. Genet. A. 126 (4): 427–429. doi:10.1002/ajmg.a.20623. PMID 15098243. S2CID 6409973. 3. ^ Brniteanu DD, Zbranca E (2000). "Barraquer–Simons syndrome. Report of a case and review of the literature". Revista Medico-chirurgical a Societii de Medici I Naturaliti Din IAI. 104 (2): 155–158. PMID 12089983. 4. ^ synd/1565 at Who Named It? 5. ^ L. Barraquer Roviralta. Histoire clinique d'un cas d'atrophie du tissue cellulo-adipeux. Barcelona, 1906. 6. ^ A. Simons. Eine seltene Trophoneurose ("Lipodystrophia progressiva"). Zeitschrift fr die gesamte Neurologie und Psychiatrie, Berlin, 1911, 5: 29–38. 7. ^ Hegele RA, Cao H, Liu DM, et al. (2006). "Sequencing of the reannotated LMNB2 gene reveals novel mutations in patients with acquired partial lipodystrophy". Am. J. Hum. Genet. 79 (2): 383–389. doi:10.1086/505885. PMC 1559499. PMID 16826530. 8. ^ Schwartz Robert. "eMedicine – Lipodystrophy, Progressive". Retrieved 2013-05-03. 9. ^ a b c d e Griffing, George T. "eMedicine- Acquired Partial Lipodystrophy". Retrieved 2013-05-03. 10. ^ Misra A.; Peethambaram A.; Garg A. (2004). "Clinical features and metabolic and autoimmune derangements in acquired partial lipodystrophy: report of 35 cases and review of the literature". Medicine (Baltimore). 83 (1): 18–34. doi:10.1097/01.md.0000111061.69212.59. PMID 14747765. S2CID 37138509. 11. ^ Hegele RA, Joy TR, Al-Attar SA, Rutt BK (Jul 2007). "Thematic review series: Adipocyte Biology. Lipodystrophies: windows on adipose biology and metabolism". J Lipid Res. 48 (7): 1433–44. doi:10.1194/jlr.R700004-JLR200. PMID 17374881. ## External links[edit] Classification D * ICD-10: 272.6 * OMIM: 608709 * MeSH: C562448 * DiseasesDB: 9697 External resources * Orphanet: 79087 * v * t * e Inborn error of lipid metabolism: dyslipidemia Hyperlipidemia * Hypercholesterolemia/Hypertriglyceridemia * Lipoprotein lipase deficiency/Type Ia * Familial apoprotein CII deficiency/Type Ib * Familial hypercholesterolemia/Type IIa * Combined hyperlipidemia/Type IIb * Familial dysbetalipoproteinemia/Type III * Familial hypertriglyceridemia/Type IV * Xanthoma/Xanthomatosis Hypolipoproteinemia Hypoalphalipoproteinemia/HDL * Lecithin cholesterol acyltransferase deficiency * Tangier disease Hypobetalipoproteinemia/LDL * Abetalipoproteinemia * Apolipoprotein B deficiency * Chylomicron retention disease Lipodystrophy * Barraquer–Simons syndrome Other * Lipomatosis * Adiposis dolorosa * Lipoid proteinosis * APOA1 familial renal amyloidosis * v * 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 * t * e Disorders of subcutaneous fat Panniculitis Lobular * without vasculitis * Cold * Cytophagic histiocytic * Factitial * Gouty * Pancreatic * Traumatic * needle-shaped clefts * Subcutaneous fat necrosis of the newborn * Sclerema neonatorum * Post-steroid panniculitis * Lipodermatosclerosis * Weber–Christian disease * Lupus erythematosus panniculitis * Sclerosing lipogranuloma * with vasculitis: Nodular vasculitis/Erythema induratum Septal * without vasculitis: Alpha-1 antitrypsin deficiency panniculitis * Erythema nodosum * Acute * Chronic * with vasculitis: Superficial thrombophlebitis Lipodystrophy Acquired * generalized: Acquired generalized lipodystrophy * partial: Acquired partial lipodystrophy * Centrifugal abdominal lipodystrophy * HIV-associated lipodystrophy * Lipoatrophia annularis * localized: Localized lipodystrophy Congenital * Congenital generalized lipodystrophy * Familial partial lipodystrophy * Marfanoid–progeroid–lipodystrophy syndrome * Poland syndrome [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Barraquer–Simons syndrome	c0220989	3,744	wikipedia	https://en.wikipedia.org/wiki/Barraquer%E2%80%93Simons_syndrome	2021-01-18T18:37:33	{"gard": ["10509"], "mesh": ["C562448"], "umls": ["C0220989"], "icd-9": ["272.6"], "icd-10": ["E88.1"], "orphanet": ["79087"], "wikidata": ["Q4863247"]}
A number sign (#) is used with this entry because Cenani-Lenz syndactyly syndrome (CLSS) is caused by homozygous or compound heterozygous mutation in the LRP4 gene (604270) on chromosome 11p11. Clinical Features Cenani and Lenz (1967) described 2 brothers with a form of syndactyly resembling that of Apert syndrome (101200). However, additional features were severe shortening of the ulna and radius with fusion, fusion of the metacarpals and 'disorganization' of phalangeal development. The feet were less severely affected. They identified similar cases reported by Liebenam (1938), Borsky (1958), and Yelton (1962). Yelton (1962) observed concordantly affected like-sex twins. Lenz and Cenani later reported another pair of affected sibs; their parents were consanguineous. Drohm et al. (1976) reported an affected 7-year-old girl. Pfeiffer and Meisel-Stosiek (1982) reported affected brothers; one of them had 2 daughters, each by a different woman. Elcioglu et al. (1997) described this disorder in a 4.5-year-old boy from a consanguineous Turkish family. The digital anomalies consisted partly of synostosis and partly of malformations of the phalanges. Although there was no radioulnar synostosis or abnormality of the bones of the feet, the findings were considered comparable to those described in the Cenani-Lenz type syndactyly. Dermatoglyphic features were described and correlated with the bony malformations. Seven et al. (2000) reported a 16-month-old girl who had small spoon-like hands with complete syndactyly of all fingers, nail fusion, absent thumbs, syndactyly of the second through fifth toes on the right and of the second and third on the left, and scoliosis of the thoracic vertebral column. Radiography revealed bilateral radioulnar synostosis, with only 2 carpals on the right hand and 3 on the left, and complete disorganization of metacarpals and phalanges, with metacarpals represented by 4 bony masses on the right and 3 on the left. The right foot had synostosis between the fourth and fifth metatarsals and between the third and fourth proximal phalanges, and the left foot had only 4 metatarsal bones, and the fourth metatarsal was broad and short. There was scoliosis of the thoracic spine, and hemivertebrae at T10, T11, and T12, as well as rib abnormalities including a fork-like fifth rib, a thickened eighth rib, and wide separation between the sixth and seventh ribs. On CT scan, diastometamyelia was noted at T12. The patient also had mixed hearing loss. Dermatoglyphic examination revealed bilateral absence of axial triradius t and transverse alignment of the ridges of the proximal palm. Bacchelli et al. (2001) described Cenani-Lenz syndactyly in the offspring of first-cousin Asian parents. In addition to striking and characteristic limb changes, ultrasound showed bilateral renal hypoplasia. The limb abnormalities in Cenani-Lenz syndactyly closely resemble those found in a recessive mouse mutant, 'limb deformity' (ld). Renal hypoplasia or agenesis is an associated feature of the mouse mutant, which is known to be due to mutations in the formin gene (FMN1; 136535). A downstream target of formin is gremlin (GREM1; 603054), which encodes a secreted BMP (bone morphogenetic protein) antagonist whose expression is lost in ld mice. Formin maps to 15q13-q14; gremlin lies in the same chromosomal region. Since the parents were first cousins, the child was likely to be homozygous by descent for a mutation in the gene underlying Cenani-Lenz syndactyly. Therefore, Bacchelli et al. (2001) carried out haplotype analysis of the patient and her parents using 9 polymorphic markers from a 12-cM interval on 15q13-q14 that contains both the formin and the gremlin genes. The patient proved to be heterozygous for all 9 markers, thereby excluding a recessively-acting inherited-by-descent mutation in either of these 2 genes as the cause of limb and renal abnormalities. Temtamy et al. (2003) reported 2 probands with typical features of Cenani-Lenz syndactyly who also had similar mild facial dysmorphism: a high broad, prominent forehead, hypertelorism, a depressed nasal bridge, downslanting palpebral fissures, a short nose, a short prominent philtrum, and malar hypoplasia. Both sets of parents were consanguineous. In 1 family, the proband had a similarly affected brother and father; however, the father's parents were also consanguineous, suggesting quasidominant inheritance. In the other family, there was a similarly affected sib who also had genital anomalies and cleft palate. Percin and Percin (2003) reported a 29-year-old woman who had Cenani-Lenz syndactyly associated with duplication of the distal phalanges of the first and second toes of the right foot and proximal phalangeal duplication of the first toe of the left foot. In addition, the patient had right congenital cataract and a history of systemic lupus erythematosus. The patient's mother had hypoplastic middle and distal phalanges of the second through fifth toes of both feet; and a 15-year-old niece, who was born of consanguineous parents, had 4 fingers on each hand with synostosis of all the phalanges of the third and fourth fingers, and partial soft tissue syndactyly of the right second and third toes. Jarbhou et al. (2008) described a girl with Cenani-Lenz syndactyly who had facial dysmorphism consisting of prominent forehead, deep-set eyes, low-set ears, retrognathia, high-arched narrow palate, short-beaked nose, and high nasal bridge. Abdominal ultrasound showed that the right kidney was hypoplastic and ectopic. Additional, previously unreported, features in this patient included congenital hypothyroidism, laryngomalacia, and congenital dislocation of the hips. Jarbhou et al. (2008) proposed that Cenani-Lenz syndactyly be reclassified as a syndromic form of syndactyly. Li et al. (2010) examined affected individuals from 14 families with Cenani-Lenz syndactyly syndrome (CLSS), 6 of which had been previously reported (Elcioglu et al., 1997; Seven et al., 2000; Bacchelli et al., 2001; Temtamy et al., 2003; Percin and Percin, 2003; and Jarbhou et al., 2008). There was mild facial dysmorphism in the majority of CLS cases, with prominent forehead, hypertelorism, downslanting palpebral fissures, and micrognathia. Typical limb malformations included total to partial syndactyly of hands and feet, as well as distal bone malformations affecting the radius and ulna in addition to the metacarpal and phalangeal bones. Li et al. (2010) noted that kidney anomalies, including renal agenesis and hypoplasia, were present in more than 50% of families. Mapping Li et al. (2010) performed homozygosity mapping in 6 consanguineous families with Cenani-Lenz syndactyly syndrome, including the families previously reported by Elcioglu et al. (1997), Seven et al. (2000), Bacchelli et al. (2001), Temtamy et al. (2003), and Percin and Percin (2003), and obtained a combined parametric lod score of 7.46 at a 19.7-Mb region between SNPs rs1346671 and rs490192 on chromosome 11p11.2-q13.1. Li et al. (2010) considered the LRP4 gene to be a highly relevant positional and functional candidate gene. Molecular Genetics In 14 unrelated consanguineous families with Cenani-Lenz syndactyly syndrome, Li et al. (2010) sequenced the candidate gene LRP4 and identified homozygous and compound heterozygous missense and splice site mutations (see, e.g., 604270.0001-604270.0008) that segregated with disease in 12 of the families, including the families previously reported by Elcioglu et al. (1997), Seven et al. (2000), Bacchelli et al. (2001), Temtamy et al. (2003), Percin and Percin (2003), and Jarbhou et al. (2008). The fact that LRP4 mutations were not found in 2 CLSS families suggested further locus heterogeneity. For discussion of a possible role of variation in the APC gene in Cenani-Lenz syndrome, see 611731.0052. INHERITANCE \- Autosomal recessive HEAD & NECK Face \- Prominent forehead \- Micrognathia Eyes \- Hypertelorism \- Downslanting palpebral fissures GENITOURINARY Kidneys \- Renal hypoplasia \- Renal aplasia SKELETAL Limbs \- Fused ulna and radius \- Short ulnae \- Short radii Hands \- Syndactyly, total or partial \- Synostosis \- Fused metacarpals \- Malformed phalanges Feet \- Syndactyly, total or partial \- Synostosis \- Fused metacarpals \- Malformed phalanges MOLECULAR BASIS \- Caused by mutation in the low density lipoprotein receptor-related protein 4 gene (LRP4, 604270.0001 ) ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	CENANI-LENZ SYNDACTYLY SYNDROME	c1859309	3,745	omim	https://www.omim.org/entry/212780	2019-09-22T16:30:02	{"doid": ["0090015"], "mesh": ["C538150"], "omim": ["212780"], "orphanet": ["3258"], "synonyms": ["Alternative titles", "CENANI SYNDACTYLISM", "CENANI-LENZ SYNDACTYLY", "SYNDACTYLY, TYPE VII"]}
A number sign (#) is used with this entry because of evidence that multiple mitochondrial dysfunctions syndrome-2 (MMDS2) with hyperglycinemia is caused by homozygous mutation in the BOLA3 gene (613183) on chromosome 2p13. Description Multiple mitochondrial dysfunctions syndrome-2 (MMDS2) with hyperglycinemia is a severe autosomal recessive disorder characterized by developmental regression in infancy. Affected children have an encephalopathic disease course with seizures, spasticity, loss of head control, and abnormal movement. Additional more variable features include optic atrophy, cardiomyopathy, and leukodystrophy. Laboratory studies show increased serum glycine and lactate. Most patients die in childhood. The disorder represents a form of 'variant' nonketotic hyperglycinemia and is distinct from classic nonketotic hyperglycinemia (NKH, or GCE; 605899), which is characterized by significantly increased CSF glycine. Several forms of 'variant' NKH, including MMDS2, appear to result from defects of mitochondrial lipoate biosynthesis (summary by Baker et al., 2014). For a general description and a discussion of genetic heterogeneity of multiple mitochondrial dysfunctions syndrome, see MMDS1 (605711). Clinical Features Seyda et al. (2001) reported a male infant, born of first-cousin East Indian parents, who developed epileptic seizures associated with elevated levels of serum glycine and cerebrospinal fluid (CSF) glycine at age 4 months. At age 6 months, he was developmentally delayed, and subsequently developed dilated cardiomyopathy and epileptic encephalopathy. He had recurrent vomiting, lethargy, respiratory distress, and hepatomegaly. At age 7 months, he became acidotic. His CSF glycine rose to very high levels, and he died at 11 months of age. Studies of skin fibroblasts showed lactate/pyruvate ratios that were 6 times greater than those of controls. Fibroblasts showed decreased activity of the pyruvate dehydrogenase complex, branched-chain alpha-keto acid dehydrogenase (608348), and mitochondrial respiratory chain complexes. In contrast, the activities of fibroblast pyruvate carboxylase (608786), mitochondrial aconitase (100850), and citrate synthase (118950) were normal. Baker et al. (2014) reported 3 unrelated children with a severe metabolic disorder resulting in neurologic dysfunction. The patients were of Caucasian, Indian, and African American descent, respectively. All had normal development in early infancy, but then showed regression in motor skills with loss of head control and severe hypotonia beginning between 6 and 8 months of age. Two had seizures, 2 had optic atrophy with poor vision, and 2 had spasticity with abnormal movements. All developed hypertrophic cardiomyopathy. The patients died at ages 7 months, 22 months, and 11 years. Brain MRI of the 2 patients who died in infancy showed signal abnormalities involving the deep white matter. The 11-year-old child lost the ability to walk, became nonverbal, and had severe malnutrition and contractures. All patients had increased serum and CSF levels of glycine and lactate, leading to a diagnosis of 'variant' nonketotic hyperglycinemia. Biochemical studies showed impaired enzymatic activity of the glycine cleavage system and deficient pyruvate dehydrogenase (PDH) activity, both consistent with a defect in lipoate biosynthesis. Patient fibroblasts showed reduced to absent lipoylation of proteins. Mitochondrial respiratory chain enzymes were normal in fibroblasts isolated from 2 of the patients, with a partial decrease in the liver of the third. Inheritance The transmission pattern of MMDS2 in the families reported by Baker et al. (2014) was consistent with autosomal recessive inheritance. Mapping Complementation studies by Seyda et al. (2001) indicated that the defect in the patient with multiple mitochondrial dysfunctions syndrome-2 maps to chromosome 2p14-p13. Molecular Genetics In the East Indian patient with MMDS2 reported by Seyda et al. (2001), Cameron et al. (2011) identified a homozygous truncating mutation in the BOLA3 gene (613183.0001). Transduction of fibroblast lines with retroviral vectors expressing the mitochondrial, but not the cytosolic, isoform of BOLA3 corrected the defects in respiratory chain and oxoacid dehydrogenase complex function. The results indicated that BOLA3 plays an essential role in the production of iron-sulfur (Fe-S) clusters for the normal maturation of lipoate-containing 2-oxoacid dehydrogenases and for the assembly of the respiratory chain complexes. In 3 unrelated children with MMDS2, Baker et al. (2014) identified a homozygous truncating mutation in the BOLA3 gene (R46X; 613183.0002). The mutation was found by sequencing of candidate genes involved in lipoate synthesis, as 2 of the patients who were studied had reduced lipoylated E2 subunits of the PDH and alpha-ketoglutarate dehydrogenase (alpha-KGDH) complexes. The unaffected parents were heterozygous for the mutation. INHERITANCE \- Autosomal recessive HEAD & NECK Eyes \- Optic atrophy (in some patients) \- Visual impairment (in some patients) CARDIOVASCULAR Heart \- Dilated cardiomyopathy \- Hypertrophic cardiomyopathy RESPIRATORY \- Respiratory failure ABDOMEN Liver \- Hepatomegaly Gastrointestinal \- Vomiting MUSCLE, SOFT TISSUES \- Hypotonia NEUROLOGIC Central Nervous System \- Developmental regression in infancy \- Seizures (in most patients) \- Epileptic encephalopathy \- Lethargy \- Poor head control \- Delayed development \- Spasticity \- Extrapyramidal signs \- Ataxia (in some patients) \- Myoclonus (in some patients) \- Abnormal movements \- Leukodystrophy (in most patients) \- Upper spinal cord lesions METABOLIC FEATURES \- Lactic acidosis LABORATORY ABNORMALITIES \- Increased serum and urinary lactate \- Increased urinary 2-hydroxybutyrate \- Increased serum glycine \- Increased serum leucine, isoleucine, valine \- Decreased activity of pyruvate dehydrogenase complex \- Decreased activity of 2-oxoacid dehydrogenases \- Decreased activity of the glycine cleavage enzyme \- Decreased activity of mitochondrial respiratory complexes (in some patients) MISCELLANEOUS \- Onset in infancy \- Death in early childhood may occur MOLECULAR BASIS \- Caused by mutation in the bolA family member 3 gene (BOLA3, 613183.0001 ) ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	MULTIPLE MITOCHONDRIAL DYSFUNCTIONS SYNDROME 2 WITH HYPERGLYCINEMIA	c3280378	3,746	omim	https://www.omim.org/entry/614299	2019-09-22T15:55:55	{"doid": ["0080134"], "omim": ["614299"], "orphanet": ["401874"], "synonyms": ["BOLA3 deficiency"]}
A number sign (#) is used with this entry because Aarskog-Scott syndrome (AAS) can be caused by mutation in the FGD1 gene (300546) on chromosome Xp11. Aarskog-Scott syndrome with attention deficit-hyperactivity disorder and a form of syndromic X-linked mental retardation (MRXS16) are also caused by mutation in the FGD1 gene. Description Aarskog-Scott syndrome, also known as faciogenital dysplasia, is an X-linked disorder characterized by short stature, hypertelorism, shawl scrotum, and brachydactyly, although there is wide phenotypic variability and other features, such as joint hyperextensibility, short nose, widow's peak, and inguinal hernia, may also occur. Most patients do not have mental retardation, but some may have neurobehavioral features. Carrier females may present with subtle features, such as widow's peak or short stature (summary by Orrico et al., 2010). Clinical Features Aarskog (1970) described an X-linked disorder characterized by embryonic ocular hypertelorism, anteverted nostrils, broad upper lip, and peculiar penoscrotal relations ('saddle-bag scrotum' or 'shawl scrotum'). Affected males can reproduce. Scott (1971) emphasized the occurrence of ligamentous laxity manifest by hyperextensibility of the fingers, genu recurvatum, and flat feet. Furthermore, hypermobility in the cervical spine with anomaly of the odontoid resulted in neurologic deficit. He studied a family with 9 affected males in 5 sibships. Sugarman et al. (1973) described a Mexican-American family in which 2 half brothers and their 2 maternal uncles had Aarskog syndrome. An obligate heterozygote in this kindred was found to have partial expression of the disorder with hand and foot anomalies. Sugarman et al. (1973) favored sex-influenced autosomal dominant inheritance. Teebi et al. (1993) reported the case of an affected mother and 4 sons (including a pair of monozygotic twins) by 2 different husbands. They suggested that the manifestations were as severe in the mother as in the sons and that this suggested autosomal dominant inheritance. Actually, the mother seemed less severely affected, compatible with X-linked inheritance. Escobar and Weaver (1978) reported a patient who had features more suggestive of the Noonan syndrome than of the Aarskog syndrome. The patient, aged 28 years, also had severe macrocytic anemia refractory to iron therapy, hepatomegaly, hemochromatosis, portal cirrhosis, and interstitial pulmonary disease. Berry et al. (1980) suggested that the first report of this syndrome was that of Hanley et al. (1967), who described brothers with multiple osteochondritis dissecans (165800). The features were hypertelorism, cryptorchidism, digital contractures, sternal deformity, and osteochondritis dissecans at multiple sites. Early fusion of the manubrium and corpus sterni occurred. The ears were floppy; 'lop-ear' or cup-ear may be appropriately descriptive. One brother had ptosis. Grier et al. (1981) observed typically affected father and son, a situation suggestive of autosomal dominant inheritance (with sex influence) for at least one form of the disorder; see 100050. The phenotype in both males was classic. The father was not related to the mother. Van den Bergh et al. (1984) described a 17-year-old girl who developed the syndrome of benign intracranial hypertension after minor head trauma. A small area of congenital alopecia was found on the midline vertex and an underlying bony defect was revealed by skull x-rays. Cerebral angiography showed absence of the straight sinus and other abnormalities of cerebral venous drainage. A 9-year-old brother showed full-blown Aarskog syndrome. The proband, her sister, and her mother showed signs interpreted as features of Aarskog syndrome. Friedman (1985) described the distinctive umbilical changes of Aarskog syndrome, Rieger syndrome (180500), and Robinow syndrome (180700). He quoted the famous monograph on the umbilicus by Cullen (1916), which had illustrations by Max Broedel. Two of 5 patients reported by Tsukahara and Fernandez (1994) had a protruding umbilicus and the other 3 had a characteristic umbilicus consisting of a smooth depression with radiating branches of the cicatrix and a flat cushion. Nielsen (1988) reported the first Danish case of Aarskog syndrome in a child who had attended several specialized outpatient clinics before the diagnosis was suggested. In a review, Porteous and Goudie (1991) reported that they knew of at least 12 affected persons in a population of 1.6 million in the West of Scotland, but believed that the true incidence must be higher since the benign nature of the disorder results in underdiagnosis. Mikelsaar and Lurie (1992) described a boy with features typical of Aarskog syndrome who also had leg lymphedema extending to the knees when examined at the age of 10 years. The lymphedema was presumably congenital but the age of onset was not stated. The mother had no features of the Aarskog syndrome, but the maternal grandfather showed hypertelorism, camptodactyly, and lymphedema of the feet. Fryns (1992) commented on the disappearance of manifestations in postpubertal males. Social integration and functioning as adults was usually satisfactory. Fryns (1993) described 2 unrelated males, aged 22 and 20, with episodes of chronic abdominal pain over several months. Investigations showed dolichomegarectosigmoid ('long and large rectum and sigmoid'); in both, sigmoid resection with end-to-end reanastomosis was performed after acute volvulus. For further information concerning the 22-year-old patient, see Casteels et al. (1994). Fernandez et al. (1994) described 10 Japanese patients with Aarskog syndrome from 3 families. One of these patients had pulmonary stenosis, and another had ventricular septal defect. Analysis of the literature showed that congenital heart defects were described in 2 of 169 non-Japanese cases and in 2 of 20 previously reported Japanese cases. Fernandez et al. (1994) suggested that cardiac evaluation is indicated for all children with Aarskog syndrome. Fryns (1992) concluded that the incidence of mental handicap in Aarskog syndrome may be as high as 30%. Logie and Porteous (1998) tested this observation in 21 males under 17 years of age with clinically confirmed Aarskog syndrome and found their IQs to lie within the normal range. They concluded that Aarskog syndrome is not associated with mental handicap. On the other hand, Lebel et al. (2002) found a missense mutation (300546.0005) in the FGD1 gene in 3 brothers with X-linked mental retardation. Although the brothers had short stature and small feet, they lacked distinct craniofacial, skeletal, or genital findings suggestive of Aarskog syndrome. Their mother was a carrier and was of normal intelligence. Orrico et al. (2005) reported a 16-year-old boy who was evaluated for attention deficit-hyperactivity disorder (ADHD; 143465) and low intelligence quotient, in whom they noted dysmorphic features reminiscent of AAS. A missense mutation was found in the FGD1 gene (300546.0007). The authors stated that their findings supported the observation that a spectrum of behavioral disorders may be part of the AAS phenotype. Bottani et al. (2007) reported a boy with classic Aarskog-Scott syndrome with normal neurologic status and good school performance. At age 9 years, he developed generalized seizures and was found to have unilateral focal frontoparietal polymicrogyria (see 610031), which had not previously been described in this syndrome. Genetic analysis identified a hemizygous mutation in the FGD1 gene (300546.0011). Orrico et al. (2010) reported 11 patients with genetically confirmed Aarskog-Scott syndrome. Consistent features included hypertelorism, short nose, short broad hands, short stature, shawl scrotum, and genitourinary abnormalities. Secondary features, which were variable, included widow's peak, ptosis, downward slanting palpebral fissures, broad feet, abnormal auricles, umbilical hernia, and cryptorchidism. Five patients had developmental delay. Obesity was present in 4 (36.3%) patients. Inheritance Aarskog-Scott syndrome usually shows an X-linked recessive pattern of inheritance. Pilozzi-Edmonds et al. (2011) reported 2 fraternal twin brothers with the disorder, each of whom carried the same truncating mutation in the FGD1 gene. However, the mutation was not detected in the mother's lymphocytes, suggesting maternal germline mosaicism. The authors emphasized the implications for genetic counseling. Cytogenetics Tyrkus et al. (1980) described mother and son with Aarskog-Scott syndrome. Expression was complete in the mother. The mother and son had a reciprocal translocation between the X chromosome and chromosome 8. The breakpoint on the X was at Xq12. The mother's parents and sibs were clinically normal and the parents had normal karyotypes. Tyrkus et al. (1980) described parental exposure to ionizing radiation. They found that the Aarskog-Scott locus may be located at Xq12. The normal X chromosome in the mother was consistently inactivated. Thus the full expression in the mother was explained. Bawle et al. (1984) published definitively on the family in which a balanced X-autosome translocation was associated with Aarskog syndrome in mother and son. They placed the X chromosome breakpoint at Xq13. Noteworthy was the full expression in the mother comparable to the full expression of Duchenne muscular dystrophy (310200) in women with balanced X-autosome translocations involving Xp21. The authors postulated that, as in the latter case, the break at Xq13 creating the translocation also caused a presumed de novo point mutation in the 'Aarskog gene' and that the woman had nonrandom (preferential) inactivation of her structurally normal X. By high resolution cytogenetic studies, Rafael et al. (1992) demonstrated that the X chromosome breakpoint in the patient of Bawle et al. (1984) was located in the proximal short arm of the X chromosome rather than at Xq13. The autosomal breakpoint was 8q11 rather than 8p21.1, as previously reported. By study of somatic cell hybrids containing the der(X) chromosome by a combination of fluorescence in situ hybridization and Southern blot analysis with X-chromosome probes, Glover et al. (1993) refined the localization of the breakpoint to Xp11.21. Molecular Genetics By SSCP analysis, Pasteris et al. (1994) identified a mutation (300546.0001) in the FGD1 gene in affected members of a family with Aarskog-Scott syndrome. Orrico et al. (2000) analyzed 13 unrelated patients with the clinical diagnosis of Aarskog-Scott syndrome. One patient carried an arg610-to-gln mutation (300546.0002) located in 1 of the 2 pleckstrin homology (PH) domains of the FGD1 gene. Using SSCP analysis of the FGD1 gene, Schwartz et al. (2000) identified a missense mutation (300546.0003) in a familial case of Aarskog-Scott syndrome and a deletion mutation (300546.0004) in a sporadic case. Orrico et al. (2010) identified mutations in the FGD1 gene in 11 (18.33%) of 60 European patients with a clinically suspected diagnosis of Aarskog-Scott syndrome. Nine mutations were novel, including 3 missense mutations, 4 truncating mutations, an in-frame deletion, and a splice site mutation. One mutation (R656X; 300546.0012) was recurrent, present in 3 unrelated families. There were no apparent genotype/phenotype correlations. INHERITANCE \- X-linked recessive GROWTH Height \- Short stature, mild to moderate Other \- Failure to thrive \- Delayed puberty \- Increased upper to lower segment ratio HEAD & NECK Face \- Round face \- Maxillary hypoplasia \- Wide philtrum \- Curved linear dimple below the lower lip Ears \- Fleshy earlobes Eyes \- Hypertelorism \- Ptosis \- Downslanting palpebral fissures \- Strabismus \- Hyperopia Nose \- Small, short nose \- Anteverted nostrils \- Broad nasal bridge Mouth \- Cleft lip \- Cleft palate Teeth \- Hypodontia Neck \- Short neck with or without webbing CHEST Ribs Sternum Clavicles & Scapulae \- Pectus excavatum ABDOMEN External Features \- Prominent umbilicus \- Inguinal hernia GENITOURINARY External Genitalia (Male) \- Shawl scrotum Internal Genitalia (Male) \- Cryptorchidism SKELETAL Spine \- Cervical spine hypermobility \- Odontoid hypoplasia \- Scoliosis Hands \- Short, broad hands \- Brachydactyly \- Clinodactyly \- Mild syndactyly \- Single transverse palmar crease \- Finger joint hyperextensibility Feet \- Short broad feet SKIN, NAILS, & HAIR Skin \- Single transverse palmar crease Hair \- Widow's peak NEUROLOGIC Central Nervous System \- Mental retardation (one-third) \- Attention deficit disorder \- Hyperactivity MISCELLANEOUS \- Normal fertility MOLECULAR BASIS \- Caused by mutation in the faciogenital dysplasia gene (FGD1, 300546.0001 ) ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	AARSKOG-SCOTT SYNDROME	c0175701	3,747	omim	https://www.omim.org/entry/305400	2019-09-22T16:18:24	{"mesh": ["C535331"], "omim": ["305400"], "icd-10": ["Q87.1"], "orphanet": ["915"], "synonyms": ["Alternative titles", "FACIOGENITAL DYSPLASIA", "FACIODIGITOGENITAL SYNDROME", "AARSKOG SYNDROME, X-LINKED"]}
Van Kuijck et al. (1996) reported the cloning, expression, and functional characterization of a rabbit epithelial basolateral chloride conductance regulator (EBCR), a protein belonging to the superfamily of ATP-binding cassette (ABC) transporters (see 170260). They cloned an approximately 6-kb cDNA from a rabbit ileum mucosal cDNA library. The largest ORF encodes a 1,564-amino acid polypeptide with 12 predicted membrane spanning domains and 2 large predicted cytoplasmic domains, both of which bear a putative ATP binding site. EBCR shows 49% identity with human multidrug resistance-associated protein (158343) and 29% identity with the cystic fibrosis transmembrane conductance regulator (602421). Northern blot analysis revealed high expression in small intestine, kidney, and liver. In kidney, immunohistochemistry showed a conspicuous basolateral localization mainly in the thick ascending limb of Henle loop, distal convoluted tubules, and to a lesser extent connecting tubules. The functional activation by cAMP and its conspicuous localization to the basolateral domain in epithelial cells of nephron segments involved in cAMP-dependent chloride reabsorption suggested to van Kuijck et al. (1996) that EBCR is involved in chloride reabsorption and might be a basolateral counterpart of CFTR. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	EPITHELIAL BASOLATERAL CHLORIDE CONDUCTANCE REGULATOR, RABBIT, HOMOLOG OF	c1832477	3,748	omim	https://www.omim.org/entry/601315	2019-09-22T16:15:07	{"omim": ["601315"], "synonyms": ["Alternative titles", "EBCR"]}
Autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) is an uncommon form of epilepsy that runs in families. This disorder causes seizures that usually occur at night (nocturnally) while an affected person is sleeping. Some people with ADNFLE also have seizures during the day. The seizures characteristic of ADNFLE tend to occur in clusters, with each one lasting from a few seconds to a few minutes. Some people have mild seizures that simply cause them to wake up from sleep. Others have more severe episodes that can include sudden, repetitive movements such as flinging or throwing motions of the arms and bicycling movements of the legs. The person may get out of bed and wander around, which can be mistaken for sleepwalking. The person may also cry out or make moaning, gasping, or grunting sounds. These episodes are sometimes misdiagnosed as nightmares, night terrors, or panic attacks. In some types of epilepsy, including ADNFLE, a pattern of neurological symptoms called an aura often precedes a seizure. The most common symptoms associated with an aura in people with ADNFLE are tingling, shivering, a sense of fear, dizziness (vertigo), and a feeling of falling or being pushed. Some affected people have also reported a feeling of breathlessness, overly fast breathing (hyperventilation), or choking. It is unclear what brings on seizures in people with ADNFLE. Episodes may be triggered by stress or fatigue, but in most cases the seizures do not have any recognized triggers. The seizures associated with ADNFLE can begin anytime from infancy to mid-adulthood, but most begin in childhood. The episodes tend to become milder and less frequent with age. In most affected people, the seizures can be effectively controlled with medication. Most people with ADNFLE are intellectually normal, and there are no problems with their brain function between seizures. However, some people with ADNFLE have experienced psychiatric disorders (such as schizophrenia), behavioral problems, or intellectual disability. It is unclear whether these additional features are directly related to epilepsy in these individuals. ## Frequency ADNFLE appears to be an uncommon form of epilepsy; its prevalence is unknown. This condition has been reported in more than 100 families worldwide. ## Causes Mutations in the CHRNA2, CHRNA4, and CHRNB2 genes can cause ADNFLE. These genes provide instructions for making different parts (subunits) of a larger molecule called a neuronal nicotinic acetylcholine receptor (nAChR). This receptor plays an important role in chemical signaling between nerve cells (neurons) in the brain. Communication between neurons depends on chemicals called neurotransmitters, which are released from one neuron and taken up by neighboring neurons. Researchers believe that mutations in the CHRNA2, CHRNA4, and CHRNB2 genes affect the normal release and uptake of certain neurotransmitters in the brain. The resulting changes in signaling between neurons likely trigger the abnormal brain activity associated with seizures. The seizures associated with ADNFLE begin in areas of the brain called the frontal lobes. These regions of the brain are involved in many critical functions, including reasoning, planning, judgment, and problem-solving. It is unclear why mutations in the CHRNA2, CHRNA4, and CHRNB2 genes cause seizures in the frontal lobes rather than elsewhere in the brain. Researchers are also working to determine why these seizures occur most often during sleep. The genetic cause of ADNFLE has been identified in only a small percentage of affected families. In some cases, a gene other than those that make up the nAChR are involved. In the remaining families, the cause of the condition is unknown. Researchers are searching for other genetic changes, including mutations in other subunits of nAChR, that may underlie the condition. ### Learn more about the genes associated with Autosomal dominant nocturnal frontal lobe epilepsy * CHRNA2 * CHRNA4 * CHRNB2 * KCNT1 ## 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 raise the risk of developing epilepsy. About 70 percent of people who inherit a mutation in the CHRNA2, CHRNA4, or CHRNB2 gene will develop seizures. In most cases, an affected person has one affected parent and other relatives with the condition. Other cases are described as sporadic, which means an affected person has no family history of the disorder. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Autosomal dominant nocturnal frontal lobe epilepsy	c1838049	3,749	medlineplus	https://medlineplus.gov/genetics/condition/autosomal-dominant-nocturnal-frontal-lobe-epilepsy/	2021-01-27T08:24:40	{"gard": ["11918"], "mesh": ["C563930"], "omim": ["600513", "603204", "605375", "610353"], "synonyms": []}
Hyperparathyroidism is an endocrine disorder in which the parathyroid glands in the neck produce too much parathyroid hormone (PTH). Signs and symptoms are often mild and nonspecific, such as a feeling of weakness and fatigue, depression, or aches and pains. With more severe disease, a person may have a loss of appetite, nausea, vomiting, constipation, confusion or impaired thinking and memory, and increased thirst and urination. Patients may have thinning of the bones without symptoms, but with risk of fractures. There are two main types of hyperparathyroidism: primary hyperparathyroidism and secondary hyperparathyroidism. Surgery to remove the parathyroid gland(s) is the main treatment for the disorder. Some patients with mild disease do not require treatment. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Primary hyperparathyroidism	c0221002	3,750	gard	https://rarediseases.info.nih.gov/diseases/8612/primary-hyperparathyroidism	2021-01-18T17:58:11	{"mesh": ["D049950"], "synonyms": ["Hyperparathyroidism, primary"]}
## Summary ### Clinical characteristics. DNMT1-related disorder is a degenerative disorder of the central and peripheral nervous systems comprising a phenotypic spectrum that includes hereditary sensory and autonomic neuropathy type 1E (HSAN1E) and autosomal dominant cerebellar ataxia, deafness, and narcolepsy (ADCA-DN). DNMT1 disorder is often characterized by moderate-to-severe sensorineural hearing loss beginning in the teens or early 20s, sensory impairment, sudomotor dysfunction (loss of sweating), and dementia usually beginning in the mid-40s. In some affected individuals, narcolepsy/cataplexy syndrome and ataxia are predominant findings. ### Diagnosis/testing. The diagnosis of DNMT1 disorder is established by identification of a heterozygous pathogenic variant in DNMT1 by molecular genetic testing. ### Management. Treatment of manifestations: No cure for DNMT1 disorder currently exists. The emphasis of management is to help affected individuals and their caregivers understand the sudomotor defect and injury prevention when sensory impairment is significant. Because hearing loss may be severe, initial use of hearing aids and/or assistive communication methods may be needed. Sedative or antipsychotic drugs help to reduce extreme restlessness, roaming behavior, delusions, and hallucinations associated with dementia. Because behavioral changes and the loss of insight and judgment often present a considerable burden for partners or other caregivers, information about the disorder and psychological support for partners or other caregivers are essential. Surveillance: Examination of feet daily for evidence of skin injury; annual routine clinical testing for dementia and audiogram to monitor hearing loss. Agents/circumstances to avoid: To prevent injury to extremities with decreased sensation, protect the skin with appropriate socks and shoes and avoid exposure of feet to hot water. ### Genetic counseling. DNMT1 disorder is inherited in an autosomal dominant manner. Most affected individuals have an affected parent; the proportion of affected individuals with a de novo DNMT1 pathogenic variant is unknown. Each child of an individual with DNMT1 disorder has a 50% chance of inheriting the pathogenic variant. Once the DNMT1 pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible. ## Diagnosis The phenotype of DNMT1-related disorder is a continuum ranging from hereditary sensory and autonomic neuropathy type 1E (HSAN1E) to autosomal dominant cerebellar ataxia, deafness, and narcolepsy (ADCA-DN). ### Suggestive Findings DNMT1 disorder should be suspected in individuals with the following clinical, electrophysiologic, and neuroimaging findings and family history. Clinical findings * Sensory neuropathy that is predominantly loss of feeling to touch, pain, temperature, and proprioception of the feet and legs, with less severe loss in the hands. Pain tends to be minimal but can be lancinating or burning; some have described parathesias. Tendon reflexes tend to be depressed in the lower limbs. The face and trunk are characteristically spared. Age of onset ranges from early 20s to late 40s. * Autonomic neuropathy, manifest as loss of sweating (sudomotor abnormalities). Significant symptoms of autonomic neuropathy usually do not occur until the late 40s. Laboratory-based tests such as tilt table testing for postural hypotension, quantitative sudomotor axon reflex testing, and thermoregulatory sweat testing can help to identify postganglionic sudomotor abnormalities that spare cardiovagal and adrenergic autonomic functions. Special quantitative sensory testing and histopathologic preparations can assist in studying the sensory fibers implicated in autonomic involvement. The pan sensory neuropathy affects large proprioceptive and vibratory sensing fibers as well as small heat-, pain-, and temperature-sensing fibers. * Cerebellar ataxia manifest as impaired coordination, loss of balance, unsteady gait, difficulty performing fine motor tasks, and changes in speech. Age of onset ranges from the late 30s to late 40s. * Dementia that typically first manifests as progressive decline in cognition and behavior. Wechsler Adult Intelligence and Memory Scales as well as Boston naming test and the Mini Mental State Exam (MMSE) can be used to identify diffuse cortical dementia. Dementia usually starts in the mid-40s. * Moderate to severe progressive sensorineural hearing loss (i.e., 70- to 80-db loss at 4,000 Hz) beginning in the teens or early 20s * Early- or late-onset narcolepsy/cataplexy syndrome. Narcolepsy is a chronic sleep disorder characterized by overwhelming daytime drowsiness and sudden attacks of sleep. Cataplexy refers to a sudden loss of muscle tone. Age of onset ranges from early 20s to late 40s. Electrophysiologic testing shows: * Length-dependent sensory axonal loss including both small fiber loss (drC and Aσ) and large fiber proprioceptive Aβ loss; * Absent or reduced sensory nerve action potentials with normal motor nerve conduction velocities. Brain imaging can help to determine the existence of global atrophy without intraparenchymal signal change. Family history is consistent with autosomal dominant inheritance, including simplex cases (i.e., a single occurrence in a family) caused by a de novo pathogenic variant. ### Establishing the Diagnosis The diagnosis of DNMT1 disorder is established in a proband with suggestive findings and a heterozygous pathogenic variant in DNMT1 identified by molecular genetic testing (see Table 1). Molecular genetic testing approaches can include a combination of gene-targeted testing (single-gene testing or multigene panel) and comprehensive genomic testing (exome sequencing, 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 DNMT1-related disorder 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 progressive sensorineural hearing loss, pure sensory neuropathy, and/or cognitive decline are more likely to be diagnosed using genomic testing (see Option 2). #### Option 1 When the phenotypic and laboratory findings suggest the diagnosis of DNMT1-related disorder, molecular genetic testing approaches can include single-gene testing or use of a multigene panel: * Single-gene testing. Sequence analysis of DNMT1 detects small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, heterozygous exon or whole-gene deletions/duplications are not detected. Perform sequence analysis first. If no pathogenic variant is identified, gene-targeted deletion/duplication analysis can be considered to detect intragenic deletions or duplications; however, to date such variants have not been identified as a cause of DNMT1-related disorder. * A multigene panel that includes DNMT1 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. Of note, given the rarity of DNMT1-related disorder, some panels for hearing loss and/or dementia may not include this gene. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests. For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here. #### Option 2 When the phenotype is indistinguishable from many other inherited disorders characterized by sensory neuropathy, and/or hearing loss, 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. Note: To date such variants have not been identified as a cause of DNMT1-related disorder. 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 DNMT1-Related Disorder View in own window Gene 1MethodProportion of Probands with a Pathogenic Variant 2 Detectable by Method DNMT1Sequence analysis 3100% of variants reported to date 4 Gene-targeted deletion/duplication analysis 5Unknown 6 1\. See Table A. Genes and Databases for chromosome locus and protein. 2\. See Molecular Genetics for information on allelic variants detected in this gene. 3\. Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here. 4\. Klein et al [2011], Winkelmann et al [2012], Baets et al [2015] 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\. No data on detection rate of gene-targeted deletion/duplication analysis are available. ## Clinical Characteristics ### Clinical Description DNMT1-related disorder is a degenerative disorder of the central and peripheral nervous systems characterized by sensory impairment, sudomotor dysfunction (loss of sweating), dementia, and sensorineural hearing loss. In some patients, late-onset narcolepsy/cataplexy syndrome presents as the prominent manifestation along with: ataxia that appears to be cerebellar in nature, deafness, sensory neuropathy, and memory loss [Klein et al 2011, Winkelmann et al 2012]. Affected persons are normal in their youth but begin to manifest progressive findings, such as sensorineural hearing loss, sensory neuropathy, and/or narcolepsy/cataplexy, by their late teens or early 20s. In a cohort of 45 affected individuals, the average age of onset was estimated to be 37.7 years; the most common initial manifestation was hearing loss (36%), followed by sensory loss, ulcerations and/or arthropathy (33%), cognitive decline (7%), and gait imbalance (7%). It is likely that the range of phenotypes will expand as more affected individuals are identified [Baets et al 2015]. Sensory impairment, which can manifest as early as the second decade of life starting with loss of sensation leading to painless extremity injuries, is associated with hyporeflexia. Sensory impairment predominantly affects the distal lower extremities with minimal to no motor involvement. The sensory alterations are associated with gait unsteadiness and mutilating acropathy with ulcers and/or amputations of distal extremities in approximately 50% of affected persons. Autonomic dysfunction is limited to loss of sweating (sudomotor) on the distal aspects of the upper and lower limbs. Dementia manifests as progressive cognitive, executive function, and behavioral decline usually by the fourth decade. Behavior changes including anger and change in personality may precede decline in memory. Memory loss, apathy, indifference, inattention, and somnolence have all been described [Wright & Dyck 1995, Hojo et al 1999]. Irritability, delusions, and delirium are also reported. Moderate-to-severe sensorineural hearing loss (i.e., 70- to 80-db loss at 4,000 Hz) typically begins in the teens or early 20s. Gait ataxia is common and is usually the result of sensory loss in the feet, but rarely may be cerebellar ataxia. Narcolepsy/cataplexy syndrome sometimes presents as the prominent manifestation. Other clinical findings observed on occasion include visual hallucinations, myoclonic seizures, and renal failure. Other findings * PET and SPECT imaging have been used to show medial frontal and thalamic hypometabolism. * Sural nerve biopsy shows marked loss of myelinated fibers without onion bulb change. * Brain neuropathology at autopsy has shown diffuse neuronal loss without distinctive histologic features and no amyloid, tau, or α-synuclein inclusions [Klein et al 2011]. ### Genotype-Phenotype Correlations All pathogenic variants that cause DNMT1-related disorder are located in the targeting sequence (TS) domain of the DNMT1 protein (see Molecular Genetics, Normal gene product). * Variants resulting in the HSAN1E phenotype (a predominantly sensory neuropathy) are in the N-terminus or middle part of the TS domain [Baets et al 2015]. * Variants that cause autosomal dominant cerebellar ataxia, deafness and narcolepsy are located in the C-terminus of the TS domain [Baets et al 2015]. ### Penetrance The penetrance of DNMT1 disorder is 100% in both males and females. However, age of onset and rate of progression vary between individuals. ### Nomenclature This GeneReview, formerly titled "DNMT1-related dementia, deafness, and sensory neuropathy," was renamed "DMNT1-related disorder" to reflect the broader phenotypic spectrum now known to be associated with pathogenic variants in DNMT1. Hereditary sensory and autonomic neuropathy type IE (HSAN1E) is considered a sensory-predominant neuropathy. ### Prevalence To date, a total of 21 families with DNMT1 disorder have been reported. ## Differential Diagnosis Autosomal dominant hereditary sensory and autonomic neuropathies are genetically heterogeneous, but hereditary sensory and autonomic neuropathy type IE (HSAN1E) that includes dementia and hearing loss represents a unique phenotype. The combination of neuropathy with hearing loss can be confused with some forms of Charcot-Marie-Tooth, and the dementia is similar to that found in frontotemporal dementia or, more commonly, global cognitive disorder. However, if it is recognized that the neuropathy, hearing loss, and dementia represent a single syndrome, the diagnosis should be clear when it occurs in persons younger than age 50 years. See Hereditary Sensory and Autonomic Neuropathy: OMIM Phenotypic Series to view genes associated with HSAN in OMIM. ## Management ### Evaluations Following Initial Diagnosis To establish the extent of disease and needs of an individual diagnosed with DNMT1-related disorder, the evaluations summarized in this section (if not performed as part of the evaluation that led to the diagnosis) are recommended: * Neurologic examination to determine the extent of sensory involvement, including sensory testing and observation for skin ulceration * Past medical history to determine extent of autonomic involvement * Evaluation of central nervous system involvement, using tests of cognitive function and brain imaging * Audiologic examination to determine if hearing loss is present and, if present, its type and severity * Consultation with a clinical geneticist and/or genetic counselor ### Treatment of Manifestations No cure for DNMT1 disorder currently exists. The emphasis of management is to help parents and affected individuals understand the sudomotor defect and injury prevention when sensory impairment is significant. To prevent injury to extremities with decreased sensation, protect the skin with appropriate socks and shoes and avoid exposure of feet to hot water. Because hearing loss may be severe, initial use of hearing aids and/or assistive communication methods may be needed. See also Hereditary Hearing Loss and Deafness Overview. Sedative or antipsychotic drugs help to reduce extreme restlessness, roaming behavior, delusions, and hallucinations associated with dementia. Because behavioral changes and the loss of insight and judgment in individuals often present a considerable burden for partners or other caregivers, information about the disease and psychological support for partners or other caregivers are essential. ### Surveillance Sensory impairment. Examine feet on a daily basis to screen for skin injury. Dementia. Perform annual routine clinical testing for dementia: * Observation of behavior * Use of tools such as the Mini Mental State Exam (MMSE) Hearing loss. Perform annual audiogram. ### Agents/Circumstances to Avoid Avoid sharp objects and hot water, which may damage skin. ### 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 information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	DNMT1-Related Disorder	None	3,751	gene_reviews	https://www.ncbi.nlm.nih.gov/books/NBK84112/	2021-01-18T21:31:22	{"synonyms": []}
A rare viral disease caused by arboviruses and are classically characterized by encephalitis and hemorrhage, however, most commonly only aspecific fever is observed. ## Clinical description Arboviruses are a heterogeneous group of viruses transmitted by a hematophagous arthropod vector. The most well known and most severe disease caused by an arbovirus is yellow fever. Arboviruses belong to the following families: togaviridae (equine encephalitis; see this term) Chikungunya virus, flaviviridae (dengue, yellow fever, St Louis encephalitis and West Nile encephalitis; see these terms) and bunyaviridae (California encephalitis and Bunyaviral hemorrhagic fever; see these terms). Ticks, sandflies or mosquitoes are their vectors. Arboviruses predominate in tropical countries. They all show tropism towards small vessels and the central nervous system. The incubation period is 7-10 days, after which onset is sudden, with high fever, cephalalgia, aches, and general malaise that lasts 2 or 3 days. The disease can then either heal spontaneously or progress to a clinical presentation that is specific to each virus. Classical dengue fever and related syndromes are characterized by a macular rash, polyadenopathy, and minor hemorrhage, after which the symptoms resolve spontaneously. Hemorrhagic dengue is complicated by significant hemorrhage and a mortality rate that ranges from 10-20% (South East Asia and the Caribbean). Encephalitis ranges from mild, uncomplicated meningitis to severe cases. Arboviruses that cause encephalitis have been classified into four groups: American equine encephalitis, Japanese encephalitis complex, encephalitis caused by ticks, and California encephalitis. Yellow fever is caused by the amarillic or yellow fever virus and progresses in two phases: a red congestive phase with diffuse erythema and conjunctival hyperemia, followed by the yellow phase with hepatocellular failure. Mortality remains high. ## Management and treatment There are no effective drugs for this virus, however, an antiamarillic vaccine gives protection against the virus for 10 years. This vaccine is essential for the prevention of this severe disease and its use is regulated by international law. Studies are currently under way to adjust a vaccine for West Nile virus because no antiviral has so far been proved effective in vitro. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Arbovirus fever	None	3,752	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=344	2021-01-23T17:23:22	{}
## Summary ### Clinical characteristics. Hermansky-Pudlak syndrome (HPS) is characterized by oculocutaneous albinism, a bleeding diathesis, and, in some individuals, pulmonary fibrosis, granulomatous colitis, or immunodeficiency. Ocular findings include reduced iris pigment with iris transillumination, reduced retinal pigment, foveal hypoplasia with significant reduction in visual acuity (usually in the range of 20/50 to 20/400), nystagmus, and increased crossing of the optic nerve fibers. Hair color ranges from white to brown; skin color ranges from white to olive and is usually a shade lighter than that of other family members. The bleeding diathesis can result in variable bruising, epistaxis, gingival bleeding, postpartum hemorrhage, colonic bleeding, and prolonged bleeding with menses or after tooth extraction, circumcision, and other surgeries. Pulmonary fibrosis, a restrictive lung disease, typically causes symptoms in the early thirties and can progress to death within a decade. Granulomatous colitis is severe in about 15% of affected individuals. Neutropenia and/or immune defects occur primarily in individuals with pathogenic variants in AP3B1 and AP3D1. ### Diagnosis/testing. The diagnosis of HPS is established by clinical findings of hypopigmentation of the skin and hair, characteristic eye findings, and demonstration of absent delta granules (dense bodies) on whole-mount electron microscopy of platelets. Identification of biallelic pathogenic variants in AP3B1, AP3D1, BLOC1S3, BLOC1S6, DTNBP1, HPS1, HPS3, HPS4, HPS5, or HPS6 confirms the diagnosis if clinical features are inconclusive. ### Management. Treatment of manifestations: Correction of refractive errors and use of low vision aids; humidifier to reduce frequency of epistaxis; oral contraceptives can limit the duration of menstrual periods; thrombin-soaked gelfoam for skin wounds with prolonged bleeding; DDAVP (1-desamino-8-D-arginine vasopressin) for wisdom tooth extraction and invasive procedures; platelet or red blood cell transfusions for surgery or protracted bleeding; supplemental oxygen and, ultimately, lung transplantation for severe pulmonary disease; steroids, other anti-inflammatory agents, and/or Remicade® for granulomatous colitis. Immunodeficiency, when present, is granulocyte colony-stimulating factor (G-CSF) responsive. Prevention of secondary complications: Protection of the skin from the sun; wearing a medical alert bracelet that explicitly describes the functional platelet defect; maximizing pulmonary function before development of pulmonary fibrosis by prompt treatment of pulmonary infections, immunizing with influenza and pneumococcal vaccines, and regular moderate exercise. Surveillance: Annual ophthalmologic examination; at least annual examination of the skin for solar keratoses (premalignant lesions), basal cell carcinoma, squamous cell carcinoma; annual pulmonary function testing in those older than age 20 years; routine history for symptoms of colitis (e.g., cramping, increased mucus in the stool, rectal bleeding). Agents/circumstances to avoid: Aspirin-containing products; activities that increase the risk of bleeding; cigarette smoke; direct sun exposure. Evaluation of relatives at risk: In rare families with the milder types (HPS3, HPS5, and HPS6-related HPS), the evaluation of apparently unaffected sibs may yield a positive diagnosis. ### Genetic counseling. HPS is inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Carrier testing for at-risk relatives and prenatal testing for a pregnancy at increased risk are possible for those families in which the pathogenic variants have been identified. ## Diagnosis ### Suggestive Findings Hermansky-Pudlak syndrome (HPS) should be suspected in a proband with the following clinical and laboratory features. Clinical features * Nystagmus, wandering eye movements, lack of visual attention * Skin and hair color lighter than that of other family members * Prolonged bleeding after minor procedures (e.g., circumcision, tooth extraction), bruising, epistaxis, gingival bleeding Laboratory features (coagulation studies) * Platelet aggregation testing showing impaired secondary aggregation response * Prothrombin time, partial thromboplastin time, and platelet counts typically normal * Bleeding time generally prolonged * Absence of platelet delta granules (dense bodies) on whole mount electron microscopy ### Establishing the Diagnosis The diagnosis of Hermansky-Pudlak syndrome (HPS) is established in a proband with the clinical findings of oculocutaneous albinism in combination with the absence of platelet delta granules (dense bodies) on whole-mount electron microscopy (the sine qua non for HPS). Identification of biallelic pathogenic variants in one of the genes listed in Table 1a or Table 1b confirms the diagnosis if clinical features are inconclusive, and allows for family studies. #### Clinical Findings Oculocutaneous albinism is established by finding hypopigmentation of the skin and hair on physical examination associated with the following characteristic ocular findings: * Nystagmus * Reduced iris pigment with iris transillumination * Reduced retinal pigment on fundoscopic examination * Foveal hypoplasia associated with significant reduction in visual acuity * Increased crossing of the optic nerve fibers Absence of platelet delta granules (dense bodies) is identified by electron microscopy (preferably "whole mount" as opposed to transmission) [Witkop et al 1989]. On stimulation of platelets, the dense bodies, which contain ADP, ATP, serotonin, calcium, and phosphate, release their contents to attract other platelets. This process constitutes the secondary aggregation response, which cannot occur in the absence of the dense bodies. There are normally four to eight dense bodies per platelet; there are no dense bodies in the platelets of individuals with HPS. #### Molecular Genetic Testing Approaches can include serial single-gene testing, use of a multigene panel, or more comprehensive genomic testing. Serial single-gene testing. Targeted analysis for the HPS1 pathogenic variant c.1470_1486dup16 can be performed first in individuals of northwestern Puerto Rican ancestry. Targeted analysis for the HPS3 splice site variant c.1163+1G>A can be performed first in individuals of Ashkenazi Jewish ancestry. Targeted analysis for the HPS3 g.339_4260del3904 variant (also referred to as the 3.9-kb deletion) can be performed first in individuals of central Puerto Rican ancestry. For other individuals, the order of testing may be guided by the severity of clinical findings; visual acuity provides a rough measure of severity: * Sequence analysis of HPS1 and HPS4 can be considered first in severely affected individuals (severe oculocutaneous albinism or signs of pulmonary fibrosis). * Sequence analysis of HPS3, HPS5, and HPS6 can be considered first in mildly affected individuals. * If an affected individual had neutropenia or infections as a child, sequence analysis of AP3B1 and AP3D1 should be considered first, followed by gene-targeted deletion/duplication testing if biallelic pathogenic variants are not identified. A multigene panel that includes AP3B1, AP3D1, BLOC1S3, BLOC1S6, DTNBP1, HPS1, HPS3, HPS4, HPS5, HPS6, and other genes of interest (see Differential Diagnosis) can be considered. Note: (1) The genes included and the sensitivity of multigene panels vary by laboratory and are likely to change over time. In some laboratories, panel options may include custom laboratory-designed panels and/or custom phenotype-focused exome analysis. (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 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 particularly because of the large number of genes associated with HPS. 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 1a. Molecular Genetics of Hermansky-Pudlak Syndrome: Most Common Genetic Causes View in own window Gene 1, 2Proportion of HPS Attributed to Pathogenic Variants in GeneProportion of Pathogenic Variants 3 Detectable by Method Non-Puerto Rican 4Puerto Rican 5Sequence analysis 6Gene-targeted deletion/duplication analysis 7 AP3B1~10%~90%~10% 8 HPS1~37%~82% 9~99%2 individuals 10 HPS3~12%~20% 11100%100% of Puerto Ricans 11, 12 HPS4~11.5%100%Unknown 13 HPS5~9%99%1 individual 14 HPS6~16.5% 1598%1 individual 16 1\. HGNC-approved gene symbols, listed alphabetically. Click here (pdf) for gene symbol aliases. 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\. Based on approximately 278 individuals with HPS of non-Puerto Rican ancestry reported as of July 2017 5\. Based on approximately 311 individuals with HPS of Puerto Rican ancestry reported as of July 2017 6\. 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. 7\. 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. 8\. Jung et al [2006], Wenham et al [2010], Jessen et al [2013]; a homozygous chromosome 5 inversion with a breakpoint in AP3B1 has also been reported [Jones et al 2013]. 9\. Homozygosity for the HPS1 c.1470_1486dup16 is found in approximately 80% of all affected individuals of (northwest) Puerto Rican ancestry [Santiago Borrero et al 2006]. 10\. A ~14-kb insertion/deletion [Griffin et al 2005] and an exon 15-18 deletion [Wei et al 2016] 11\. Anikster et al [2001] 12\. Apart from the Puerto Rican 3.9-kb deletion, no other large insertions/deletions have been reported in HPS3. 13\. No data on detection rate of gene-targeted deletion/duplication analysis are available. 14\. A 1.4-kb HPS5 deletion was reported in one individual [Michaud et al 2017]. 15\. This includes 20 individuals of Israeli-Bedouin descent homozygous for the c.1066_1067insG frameshift variant [Schreyer-Shafir et al 2006]. 16\. A heterozygous ~20-kb deletion in HPS6 has been identified in one individual [Huizing et al 2009]. ### Table 1b. Molecular Genetics of Hermansky-Pudlak Syndrome: Less Common Genetic Causes View in own window Gene 1, 2, 3Reference AP3D1Ammann et al [2016] BLOC1S3Morgan et al [2006], Cullinane et al [2012] BLOC1S6Badolato et al [2012], Yousaf et al [2016] DTNBP1Li et al [2003], Lowe et al [2013], Bryan et al [2017] Pathogenic variants of any one of the genes listed in this table are reported in only a few families (i.e., they account for <1% of Hermansky-Pudlak syndrome). 1\. HGNC-approved gene symbols, listed alphabetically. Click here (pdf) for gene symbol aliases. 2\. See Table A. Genes and Databases for chromosome locus and protein. 3\. Click here (pdf) for further information on the genes included in this table. ## Clinical Characteristics ### Clinical Description Hermansky-Pudlak syndrome (HPS) is characterized by oculocutaneous albinism, a bleeding diathesis, and other organ involvement in specific subtypes [Huizing et al 2008]. Signs and symptoms of oculocutaneous albinism in HPS are variable but visual acuity generally remains stable. Eyes. Nearly all children with the albinism of HPS have nystagmus at birth, often noticed by the parents in the delivery room and by the examining physician. Children with HPS may also have periodic alternating nystagmus [Gradstein et al 2005], wandering eye movements, and lack of visual attention. The initial diagnosis of albinism is sometimes made by the ophthalmologist. The nystagmus can be very fast early in life, and generally slows with time, but nearly all individuals with albinism have nystagmus throughout their lives. The development of pigment in the iris or retina does not affect the nystagmus. Nystagmus is most noticeable when an individual is tired or anxious, and less marked when s/he is well rested and relaxed. Individuals with HPS have increased crossing of the optic nerve fibers [King et al 2001]. Photophobia may accompany severe foveal hypoplasia. Iris color may remain blue or change to a green/hazel or brown/tan color. Globe transillumination can be complete or can show peripupillary clumps or streaks of pigment in the iris that appear like spokes of a wagon wheel. Fine granular pigment may develop in the retina. Visual acuity, usually between 20/50 and 20/400, is typically 20/200 and usually remains constant after early childhood [Iwata et al 2000]. Alternating strabismus is found in many individuals with albinism and is generally not associated with the development of amblyopia. Skin/hair. The hair color ranges from white to brown, and can occasionally darken with age. Skin color can be white to olive, but is generally at least a shade lighter than that of other family members. Over many years, exposure to the sun of lightly pigmented skin can result in coarse, rough, thickened skin (pachydermia), solar keratoses (premalignant lesions), and skin cancer. Both basal cell carcinoma and squamous cell carcinoma can develop. Although skin melanocytes are present in individuals with HPS, melanoma is rare. Affected Puerto Ricans typically have solar damage manifesting as actinic keratoses and nevi. Ephelids, lentigines, and basal cell carcinoma also occur with increased frequency among Puerto Ricans with HPS [Toro et al 1999]. Bleeding diathesis. The bleeding diathesis of HPS results from absent or severely deficient dense granules in platelets; the alpha granule contingent is normal [Huizing et al 2007]. Affected individuals experience variable bruising, epistaxis, gingival bleeding, postpartum hemorrhage, colonic bleeding, and prolonged bleeding during menstruation or after tooth extraction, circumcision, or other surgeries. Typically, cuts bleed longer than usual but heal normally. Bruising generally first appears at the time of ambulation. Epistaxis occurs in childhood and diminishes after adolescence. Menstrual cycles may be heavy and irregular. Prolonged bleeding after tooth extraction can lead to the diagnosis of HPS. Affected individuals with colitis may bleed excessively per rectum. Exsanguination as a complication of childbirth, trauma, or surgery is extremely rare. Pulmonary fibrosis. The fibrosis consists of progressive restrictive lung disease with an extremely variable time course [Gahl et al 2002]. Symptoms usually begin in the thirties and are fatal within a decade. Pulmonary fibrosis has been described largely in affected individuals from northwestern Puerto Rico [Brantly et al 2000, Avila et al 2002], but also occurs in other individuals with pathogenic variants in HPS1, HPS4, and AP3B1 [Gochuico et al 2012]. To date, convincing evidence of pulmonary fibrosis has not been reported in affected individuals with pathogenic variants in other HPS-related genes (see Table 1a, Table 1b). Colitis. A bleeding granulomatous colitis resembling Crohn's disease presents on average at age 15 years, with wide variability [Gahl et al 1998]. The colitis is severe in 15% of affected individuals and occasionally requires colectomy; affected individuals may have the inflammatory bowel disease of HPS without the explicit diagnosis of colitis. Objective signs of colitis have been found primarily in persons with pathogenic variants in HPS1 or HPS4 [Hussain et al 2006]. Although the colon is primarily involved in HPS, any part of the alimentary tract, including the gingiva, can be affected. Neutropenia. Neutropenia and/or immune defects have been associated with AP-3-deficient HPS, including individuals with pathogenic variants in AP3B1 [Fontana et al 2006, de Boer et al 2017] or AP3D1 [Ammann et al 2016]. Other. Cardiomyopathy and renal failure have also been reported in individuals with HPS [Witkop et al 1989]. Pathogenesis. The mechanism of pulmonary fibrosis, granulomatous colitis, cardiomyopathy, and renal failure remains unknown. It is likely associated with aberrant biogenesis of lysosome-related organelles in specialized cells [Huizing et al 2008]. Ceroid lipofuscin, a poorly defined, amorphous, granular, electron-dense, autofluorescent lipid-protein material, has been found to accumulate in the lysosomes of HPS cells, including renal tubular cells, alveolar macrophages, and cells of the gastrointestinal tract, bone marrow, liver, spleen, lymph nodes, and heart. The clinical consequences of lipofuscin accumulation in HPS remain greatly unexplored, as does the underlying cellular cause [Gahl et al 1998]. ### Phenotype Correlations by Gene All individuals with HPS exhibit oculocutaneous albinism (due to aberrant melanosome formation) and a bleeding diathesis (due to absent platelet delta granules). Other clinical features occur per subtype and are listed below; individuals with pathogenic variants in the same HPS protein complex of AP-3, BLOC-1, BLOC-2, or BLOC-3 exhibit similar clinical characteristics [Huizing et al 2008]. These complexes are described in Molecular Pathogenesis. #### AP3B1, AP3D1 (AP-3 Deficiency) As of July 2017, 30 individuals with pathogenic variants in AP3B1 or AP3D1 have been reported. These individuals differ from those with other forms of HPS in that they exhibit immunodeficiency. They have an increased susceptibility to infections due to congenital neutropenia and impaired NK-cell cytotoxicity. It has been suggested that the neutropenia is caused by mislocalization of granule proteins in neutrophils [de Boer et al 2017], including elastase [Di Pietro et al 2006, Jung et al 2006]. The one individual reported with AP3D1-related HPS, a boy of consanguineous Turkish parents, also exhibited neurodevelopmental delay, generalized seizures, and impaired hearing, features not commonly seen in individuals with AP3B1-related HPS. The boy died at age 3.5 years of septic pneumonia [Ammann et al 2016]. See Less Common Genetic Causes, AP3D1 (pdf) for variant details. #### BLOC1S3, BLOC1S6, DTNBP1 (BLOC-1 Deficiency) As of July 2017, 12 individuals with pathogenic variants in BLOC1S3, BLOC1S6, or DTNBP1 have been described [Li et al 2003, Morgan et al 2006, Badolato et al 2012, Cullinane et al 2012, Lowe et al 2013, Yousaf et al 2016, Bryan et al 2017]. Data are insufficient to determine whether individuals with BLOC-1 deficiency are prone to complications besides albinism and a bleeding diathesis. It appears that these individuals have a silvery/blond/gold hair color at birth that may turn darker with age [Cullinane et al 2012, Lowe et al 2013]. No pulmonary defects have been reported in these individuals. One Italian individual with BLOC1S6-related HPS presented with immunodeficiency [Badolato et al 2012]; therefore, close follow up of other individuals is required to determine if immunodeficiency is a feature of BLOC-1 deficiency. #### HPS3, HPS5, HPS6 (BLOC-2 Deficiency) As of July 2017, about 190 individuals with pathogenic variants in HPS3, HPS5, or HPS6 have been reported (including ~55 Puerto Rican individuals homozygous for a 3.9-kb deletion in HPS3 and 20 Israeli-Bedouin individuals homozygous for a frameshift variant in HPS6). Individuals with pathogenic variants in HPS3, HPS5, or HPS6 are BLOC-2 deficient and generally have milder symptoms than those with BLOC-3 deficiency (pathogenic variants in HPS1 or HPS4) [Huizing et al 2008]. The albinism in individuals with BLOC-2-related HPS can present with such minimal hypopigmentation that some individuals may be diagnosed with ocular albinism rather than oculocutaneous albinism. Visual acuity often approximates 20/100 or better. Bleeding is also mild and pulmonary involvement has not been observed in individuals with BLOC-2 deficiency. Individuals with BLOC-2 deficiency can go undiagnosed for decades: a new diagnosis of HPS5-related HPS was described in a man age 92 years with light skin and hair, nystagmus, decreasing visual acuity with age, and a bleeding history. He is the oldest reported individual with HPS [Ringeisen et al 2013]. #### HPS1, HPS4 (BLOC-3 Deficiency) As of July 2017, approximately 390 individuals with pathogenic variants in HPS1 or HPS4 have been reported (including ~255 Puerto Rican individuals homozygous for a 16-bp duplication in HPS1). These individuals with BLOC-3 deficiency exhibit a generally severe form of oculocutaneous albinism and bleeding diathesis [Huizing et al 2008]. BLOC-3 deficiency is associated with lethal pulmonary fibrosis. The lung fibrosis is a restrictive lung disease and individuals with BLOC-3-deficiency typically begin to display symptoms in their early thirties and progress to death within a decade, unless lung transplantation is achieved [Gahl et al 2002, Huizing et al 2008]. Significant granulomatous colitis occurs primarily in individuals with HPS1 or HPS4 pathogenic variants [Hussain et al 2006]. ### Genotype-Phenotype Correlations Correlations between specific HPS-causing variants in any one gene and particular clinical presentations are not convincing. ### Nomenclature HPS may have been referred to as non-neuronal ceroid-lipofuscinosis to differentiate it from neuronal ceroid-lipofuscinosis, or Batten disease. In HPS, the nervous system appears to be spared. Individuals with HPS with mild hypopigmentation but a bleeding disorder could be referred to as having "delta storage pool deficiency"; however, individuals with isolated delta storage pool deficiency do not have vision defects. ### Prevalence HPS is a rare disorder with an estimated worldwide prevalence of 1-9 per 1,000,000 individuals (www.orpha.net). The prevalence per subtype can differ due to founder variants. The prevalence of HPS1-related HPS in northwestern Puerto Rico is 1:1800 [Witkop et al 1989]. HPS1-related HPS has also been reported in a small isolate in a Swiss village [Schallreuter et al 1993] and as a genetic isolate in Japan [Ito et al 2005]. HPS3-related HPS occurs as a genetic isolate in central Puerto Rico, where about 1:16,000 individuals are affected [Anikster et al 2001, Santiago Borrero et al 2006]. Newborn screening of 12% of the Puerto Rican population detected two homozygotes and 73 heterozygotes with the common variant g.339_4260del3904 (also referred to as the 3.9-kb deletion) [Torres-Serrant et al 2010]. Individuals with HPS have been identified in many other regions, including China, India, South America, and Western Europe. ## Differential Diagnosis Albinism. The diagnosis of Hermansky-Pudlak syndrome (HPS) should be considered in anyone with oculocutaneous albinism or ocular albinism, as the bleeding diathesis can be mild, unrecognized, or previously disregarded. Some would advocate screening all individuals with albinism for HPS by examining their platelets for absent dense bodies. The following disorders with albinism are included in the differential diagnosis: * Oculocutaneous albinism (OCA) including OCA1 (OMIM 203100, 606952) OCA2 (OMIM 203200), OCA3 (OMIM 203290), OCA4, OCA5 (OMIM 615312), OCA6 (OMIM 113750), and OCA7 (OMIM 615179), consists of a group of autosomal recessive disorders characterized by reduction or complete lack of melanin pigment in the skin, hair, and eyes. Individuals with OCA-related albinism often present with white/blonde/light hair, white or light skin that does not tan and is very susceptible to damage from the sun including skin cancer, and fully translucent irises that do not darken with age. Ocular findings can include nystagmus, reduced iris pigment with iris translucency, reduced retinal pigment, foveal hypoplasia with significantly reduced visual acuity, and misrouting of the optic nerves resulting in alternating strabismus and reduced stereoscopic vision. All individuals with OCA have severe visual changes, but the amount of skin, hair, and iris pigment can vary depending on the gene (or type of OCA) and pathogenic variant involved. The seven types of OCA are caused by pathogenic variants in different genes (TYR, OCA2, TYRP1, SLC45A2, SLC24A5, C10orf11). * X-linked ocular albinism (XLOA) is caused by pathogenic variants in GPR143. Affected males have minor skin manifestations and congenital and persistent visual impairment. XLOA is characterized by congenital nystagmus, reduced visual acuity, hypopigmentation of the iris pigment epithelium and the ocular fundus, and foveal hypoplasia. Significant refractive errors, reduced or absent binocular functions, photoaversion, and strabismus are common. Disorders of platelet-dense bodies. Reviewed in Gunay-Aygun et al [2004], these disorders include the following: * Chediak-Higashi syndrome (CHS), caused by biallelic pathogenic variants in LYST. Affected individuals have a significantly increased frequency of infection in childhood, mild oculocutaneous albinism, and a bleeding diathesis. This entity is characterized by huge, fused, dysfunctional lysosomes and macromelanosomes. Individuals with CHS always have giant intracellular granules in their neutrophils on peripheral blood smear; individuals with HPS never exhibit this finding. Persons with CHS also frequently develop fatal lymphohistiocytosis or the accelerated phase of CHS, a finding that also sporadically occurs in AP3B1-related HPS [Enders et al 2006, de Boer et al 2017]. Without bone marrow transplantation, individuals with classic Chediak-Higashi syndrome die in childhood. * Griscelli syndrome including GS1 (OMIM 214450), GS2 (OMIM 607624), and GS3 (OMIM 609227). Affected individuals have mild hypopigmentation and immunodeficiency and can have the accelerated phase of lymphohistiocytosis. A distinguishing finding is silvery-gray hair. GS1, GS2, and GS3 are inherited in an autosomal recessive manner. Note: Elejalde syndrome (OMIM 256710) is considered a type of Griscelli syndrome in which neurologic involvement (rather than immunodeficiency and lymphohistiocytosis) occurs. ## Management ### Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with Hermansky-Pudlak syndrome (HPS), the following are recommended if they have not already been completed: * Complete ophthalmologic evaluation * Skin examination for severity of hypopigmentation and, after infancy, for evidence of skin damage and skin cancer * History of bleeding problems and symptoms suggesting pulmonary fibrosis and/or colitis. For evaluation for lung fibrosis, pulmonary function tests (PFTs) should be performed in individuals older than age 20 years. * Consultation with a clinical geneticist and/or genetic counselor ### Treatment of Manifestations Eyes * The majority of individuals with albinism have significant hyperopia (far-sightedness) or myopia (near-sightedness), and astigmatism. Correction of these refractive errors can improve visual acuity. * Strabismus surgery is usually not required but can be performed for cosmetic purposes, particularly if the strabismus is marked or fixed. The surgery is not always successful. * Aids such as hand-held magnifying devices or bioptic lenses are helpful adjuncts in the care of visually impaired individuals with HPS. * Preferential seating in school is beneficial, and a vision consultant may be useful. Skin. Treatment of skin cancer does not differ from that in the general population. Bleeding * Humidifiers may reduce the frequency of nosebleeds. * Oral contraceptives can limit the duration of menstrual periods. Menorrhagia has been treated with a levonorgestrel-releasing intrauterine system [Kingman et al 2004] and with recombinant factor VIIa [Lohse et al 2011]. * Treatment of minor cuts includes placing thrombin-soaked Gelfoam® over an open wound that fails to clot spontaneously. * For more invasive trauma, such as wisdom tooth extraction, DDAVP (1-desamino-8-D-arginine vasopressin, 0.2 µg/kg in 50 mL of normal saline) can be given as a 30-minute intravenous infusion just prior to the procedure. The use of DDAVP may or may not improve the bleeding time [Cordova et al 2005]. * For extensive surgeries or protracted bleeding, platelet or red blood cell transfusions may be required. Pulmonary fibrosis * When the pulmonary disease becomes severe, oxygen therapy can be palliative. * Several individuals with HPS1-related pulmonary fibrosis successfully underwent bilateral or single-lung transplantations [Lederer et al 2005]. The authors know of several additional successful lung transplantations. Colitis. The granulomatous colitis of HPS resembles Crohn's colitis and, as such, may respond to steroids and other anti-inflammatory agents [Mora & Wolfsohn 2011]. Remicade® has also been used with benefit [Erzin et al 2006, Felipez et al 2010]. Immunodeficiency. When present, immunodeficiency is typically responsive to granulocyte colony-stimulating factor (G-CSF). ### Prevention of Secondary Complications Skin. Skin care in HPS is dictated by the amount of pigment in the skin and the cutaneous response to sunlight. Protection from the sun should be provided to prevent burning, other skin damage, and skin cancer. In very sensitive individuals, sun exposure as short as five to ten minutes can be significant, while exposure of 30 minutes or more is usually significant in less sensitive individuals. Prolonged periods in the sun require skin protection with clothing (hats with brims, long sleeves and pants, and socks). For extremely sun-sensitive individuals, sunscreen with a high SPF value (total blocks with SPF 45-50+) are appropriate; for less sun-sensitive individuals, sunscreen with SPF values of 15 or above can be used. Bleeding. Individuals with HPS should consider obtaining a medical alert bracelet that explicitly describes the functional platelet defect, as the standard tests for bleeding dysfunction (e.g., platelet count, prothrombin time, partial thromboplastin time) are normal in HPS. Pulmonary fibrosis. Prior to the development of pulmonary fibrosis, attention should be paid to maximizing pulmonary function. This entails avoidance of cigarette smoke, prompt treatment of pulmonary infections, immunization with influenza and pneumococcal vaccines, and regular moderate exercise. ### Surveillance The following are appropriate: * Eyes. Annual ophthalmologic examination, including assessment of refractive error * Skin. Annual skin examination for basal cell carcinoma and squamous cell carcinoma, and more frequent examinations for individuals with concerning lesions or a history of skin cancer * Pulmonary fibrosis. Annual pulmonary function testing in those over age 20 years. A CT examination of the chest with high-resolution images to screen for pulmonary fibrosis is recommended for young adults with pathogenic variants in HPS1, HPS4, and AP3B1. * Colitis. Colonoscopy to confirm the diagnosis when colitis is suspected (i.e., by presence of a history of cramping, increased mucus in the stool, and rectal bleeding) ### Agents/Circumstances to Avoid Bleeding. All aspirin-containing products as well as activities that could involve the risk of a bleeding episode should be avoided. Pulmonary fibrosis. Cigarette smoking decreases pulmonary function and may worsen progression of pulmonary fibrosis. ### Evaluation of Relatives at Risk In individuals with HPS1- and HPS4-related HPS, the diagnosis will be apparent because the hypopigmentation and nystagmus are clinically evident. In rare families with the milder types (HPS3, HPS5, and HPS6-related HPS), the evaluation of apparently unaffected sibs may identify an affected individual and allow identification as early as possible of those who would benefit from prompt initiation of treatment and preventive measures: * If the pathogenic variants in the family are known, molecular genetic testing can be used to clarify the genetic status of at-risk sibs. * If the pathogenic variants in the family are not known, platelet whole-mount electron microscopy studies can be used to clarify the genetic status of at-risk sibs. See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes. ### Pregnancy Management Pregnancies should proceed normally for an affected mother or an affected fetus. Delivery, however, carries risk for bleeding in a woman with HPS; surveillance and a hematology consultation for anticipation of bleeding complications during delivery should be initiated once pregnancy is confirmed. ### Therapies Under Investigation Initial studies suggest a salutary effect on pulmonary function of the investigational drug pirfenidone in affected individuals with pulmonary function greater than 50% of normal [Gahl et al 2002]. A follow-up clinical trial was unable to confirm this finding, but also did not refute it [O'Brien et al 2011]. 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. ### Other In general, opaque contact lenses or darkly tinted lenses do not improve visual function. Dark glasses may be helpful for individuals with albinism, but many prefer to go without dark glasses because they reduce vision. No successful therapy for or prophylaxis against the pulmonary fibrosis of HPS exists. Steroids are often tried but have no apparent beneficial effect. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Hermansky-Pudlak Syndrome	c0079504	3,753	gene_reviews	https://www.ncbi.nlm.nih.gov/books/NBK1287/	2021-01-18T21:19:41	{"mesh": ["D022861"], "synonyms": []}
For a general phenotypic description and a discussion of genetic heterogeneity of neuroblastoma, see NBLST1 (256700). Mapping In a genomewide analysis of 397 patients with high-risk aggressive neuroblastoma derived from the 1,032 patients in a study by Maris et al. (2008) and 2,043 controls, Capasso et al. (2009) found a significant association with 6 SNPs at chromosome 2q35 within the BARD1 locus (601593) (p = 2.35 x 10(-9) to 2.25 x 10(-8)). The associations were confirmed in a second series of 189 high-risk cases and 1,178 controls (p = 7.90 x 10(-7) to 2.77 x 10(-4)). Testing of the 2 most significant SNPs (rs6435862 and rs3768716) in 2 additional independent high-risk neuroblastoma case series yielded a combined allelic odds ratio of 1.68 for each SNP (p = 8.65 x 10(-18) and 2.74 x 10(-16), respectively). These data suggested that common variation in the BARD1 gene may contribute to the etiology of aggressive human neuroblastoma. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	NEUROBLASTOMA, SUSCEPTIBILITY TO, 5	c0027819	3,754	omim	https://www.omim.org/entry/613016	2019-09-22T16:00:08	{"mesh": ["D009447"], "omim": ["613016"], "orphanet": ["635"]}
Zellweger spectrum disorder is a group of conditions that have overlapping signs and symptoms and affect many parts of the body. This group of conditions includes Zellweger syndrome, neonatal adrenoleukodystrophy (NALD), and infantile Refsum disease. These conditions were once thought to be distinct disorders but are now considered to be part of the same condition spectrum. Zellweger syndrome is the most severe form of the Zellweger spectrum disorder, NALD is intermediate in severity, and infantile Refsum disease is the least severe form. Because these three conditions are now considered one disorder, some researchers prefer not to use the separate condition names but to instead refer to cases as severe, intermediate, or mild. Individuals with Zellweger syndrome, at the severe end of the spectrum, develop signs and symptoms of the condition during the newborn period. These infants experience weak muscle tone (hypotonia), feeding problems, hearing and vision loss, and seizures. These problems are caused by the breakdown of myelin, which is the covering that protects nerves and promotes the efficient transmission of nerve impulses. The part of the brain and spinal cord that contains myelin is called white matter. Destruction of myelin (demyelination) leads to loss of white matter (leukodystrophy). Children with Zellweger syndrome also develop life-threatening problems in other organs and tissues, such as the liver, heart, and kidneys. They may have skeletal abnormalities, including a large space between the bones of the skull (fontanelles) and characteristic bone spots known as chondrodysplasia punctata that can be seen on x-ray. Affected individuals have distinctive facial features, including a flattened face, broad nasal bridge, and high forehead. Children with Zellweger syndrome typically do not survive beyond the first year of life. People with NALD or infantile Refsum disease, which are at the less-severe end of the spectrum, have more variable features than those with Zellweger syndrome and usually do not develop signs and symptoms of the disease until late infancy or early childhood. They may have many of the features of Zellweger syndrome; however, their condition typically progresses more slowly. Children with these less-severe conditions often have hypotonia, vision problems, hearing loss, liver dysfunction, developmental delay, and some degree of intellectual disability. Most people with NALD survive into childhood, and those with infantile Refsum disease may reach adulthood. In rare cases, individuals at the mildest end of the condition spectrum have developmental delay in childhood and hearing loss or vision problems beginning in adulthood and do not develop the other features of this disorder. ## Frequency Zellweger spectrum disorder is estimated to occur in 1 in 50,000 individuals. ## Causes Mutations in at least 12 genes have been found to cause Zellweger spectrum disorder. These genes provide instructions for making a group of proteins known as peroxins, which are essential for the formation and normal functioning of cell structures called peroxisomes. Peroxisomes are sac-like compartments that contain enzymes needed to break down many different substances, including fatty acids and certain toxic compounds. They are also important for the production of fats (lipids) used in digestion and in the nervous system. Peroxins assist in the formation (biogenesis) of peroxisomes by producing the membrane that separates the peroxisome from the rest of the cell and by importing enzymes into the peroxisome. Mutations in the genes that cause Zellweger spectrum disorder prevent peroxisomes from forming normally. Diseases that disrupt the formation of peroxisomes, including Zellweger spectrum disorder, are called peroxisome biogenesis disorders. If the production of peroxisomes is altered, these structures cannot perform their usual functions. The signs and symptoms of Zellweger syndrome are due to the absence of functional peroxisomes within cells. NALD and infantile Refsum disease are caused by mutations that allow some peroxisomes to form. Mutations in the PEX1 gene are the most common cause of Zellweger spectrum disorder and are found in nearly 70 percent of affected individuals. The other genes associated with Zellweger spectrum disorder each account for a smaller percentage of cases of this condition. ### Learn more about the gene associated with Zellweger spectrum disorder * PEX1 Additional Information from NCBI Gene: * PEX10 * PEX11B * PEX12 * PEX13 * PEX14 * PEX16 * PEX19 * PEX2 * PEX26 * PEX3 * PEX5 * PEX6 ## Inheritance Pattern This condition is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Zellweger spectrum disorder	c1864171	3,755	medlineplus	https://medlineplus.gov/genetics/condition/zellweger-spectrum-disorder/	2021-01-27T08:24:55	{"gard": ["11890", "7917"], "mesh": ["C566405"], "omim": ["614882", "614883", "614886", "614887", "614920", "214100", "601539", "214110", "202370", "614859", "266510", "614862", "614866", "614870", "614872", "614876"], "synonyms": []}
A rare bone tumor characterized by a benign lesion composed of lobules of spindle shaped or stellate cells and an abundant myxoid or chondroid matrix. The tumor may occur in almost any osseous location but is most common in long bones, in particular the proximal tibia and the distal femur. Pain is the most common presenting symptom. Prognosis is excellent even in cases with local recurrence. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Chondromyxoid fibroma	c0221290	3,756	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=404507	2021-01-23T17:56:26	{"umls": ["C0221290"], "icd-10": ["D16.9"]}
An inherited, subacute encephalopathy characterised by the association of basal ganglia calcification, leukodystrophy and cerebrospinal fluid (CSF) lymphocytosis. ## Epidemiology Just over 120 cases have been reported in the literature so far. ## Clinical description The majority of affected infants are born at full term with normal growth parameters. Onset occurs within the first few days or month of life with severe, subacute encephalopathy (feeding problems, irritability and psychomotor regression or delay) associated with epilepsy (53% of cases), chilblain skin lesions on the extremities (43% of cases) and episodes of aseptic febrile illness (40% of cases). Symptoms progress over several months (with the development of microcephaly and pyramidal signs) before the disease course stabilises. However, less severe forms have been described with onset after 1 year of age and preservation of language skills and cognitive function, and normal head circumference. The phenotype shows inter- and intrafamilial variation. ## Etiology In 2006, causative mutations were identified in four genes: TREX1, encoding a 3'->5' exonuclease, and in RNASEH2A, RNASEH2B and RNASEH2C, genes encoding subunits of the RNase H2 endonuclease complex. TREX1 (25% of cases), RNASEH2C (14% of cases) and RNASEH2A (4% of cases) mutations result in a severe phenotype, whereas RNASEH2B (41% of cases) mutations generally lead to a milder phenotype. No mutations in any of these genes are found in the remaining cases. ## Diagnostic methods Calcification (involving the basal ganglia and white matter), cystic leukodystrophy (predominantly frontotemporal) and cortical-subcortical atrophy are the cardinal features for diagnosis, often associated with atrophy of the corpus callosum, brain stem and cerebellum. Elevated IFN-alpha levels and CSF lymphocytosis are very frequent but not constant findings (90% and 75% of cases, respectively) in the initial stage of the disease but tend to normalise or resolve within a few years. The diagnosis is confirmed by detection of a mutation in one of the four disease-causing genes. ## Differential diagnosis The principle differential diagnoses are TORCH congenital infections (toxoplasma, rubella, CMV, HSV1 and HSV2). ## Antenatal diagnosis Prenatal diagnosis is feasible through molecular analysis of amniotic fluid or trophoblasts. ## Genetic counseling Transmission is autosomal recessive but rare cases of autosomal dominant inheritance have been reported. ## Management and treatment Treatment is symptomatic (management of the feeding problems, psychomotor delay and, if present, epilepsy). ## Prognosis Around 80% of patients presenting with the severe form die within the first 10 years of life but prolonged survival after the first decade of life has been reported in milder forms. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Aicardi-Goutières syndrome	c0393591	3,757	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=51	2021-01-23T18:51:17	{"gard": ["575"], "mesh": ["C535607"], "omim": ["114100", "225750", "610181", "610329", "610333", "612952", "615010", "615846"], "umls": ["C0393591"], "icd-10": ["G31.8"], "synonyms": ["Encephalopathy with basal ganglia calcification", "Encephalopathy with intracranial calcification and chronic lymphocytosis of cerebrospinal fluid"]}
Mental illness characterized by abnormal behavior and misinterpretation of reality For other uses, see Schizophrenia (disambiguation). Schizophrenia Cloth embroidered by a person diagnosed with schizophrenia Pronunciation * /ˌskɪtsəˈfriːniə/, UK also /ˌskɪdzə-/, US also /-ˈfrɛniə/[1] SpecialtyPsychiatry SymptomsHallucinations (usually hearing voices), delusions, confused thinking[2][3] ComplicationsSuicide, heart disease, lifestyle diseases[4] Usual onsetAges 16 to 30[3] DurationChronic[3] CausesEnvironmental and genetic factors[5] Risk factorsFamily history, cannabis use in adolescence, problems during pregnancy, childhood adversity, birth in late winter or early spring, older father, being born or raised in a city[5][6] Diagnostic methodBased on observed behavior, reported experiences, and reports of others familiar with the person[7] Differential diagnosisSubstance abuse, Huntington's disease, mood disorders (bipolar disorder), autism,[8] borderline personality disorder[9] ManagementCounseling, job training[2][5] MedicationAntipsychotics[5] Prognosis20 years shorter life expectancy[4][10] Frequency~0.5%[11] Deaths~17,000 (2015)[12] Schizophrenia is a psychiatric disorder characterized by continuous or relapsing episodes of psychosis.[5] Major symptoms include hallucinations (typically hearing voices), delusions, and disorganized thinking.[7] Other symptoms include social withdrawal, decreased emotional expression, and apathy.[5][13] Symptoms typically come on gradually, begin in young adulthood, and in many cases never resolve.[3][7] There is no objective diagnostic test; diagnosis is based on observed behavior, a history that includes the person's reported experiences, and reports of others familiar with the person.[7] To be diagnosed with schizophrenia, symptoms and functional impairment need to be present for six months (DSM-5) or one month (ICD-11).[7][11] Many people with schizophrenia have other mental disorders that often includes an anxiety disorder such as panic disorder, an obsessive–compulsive disorder, or a substance use disorder.[7] About 0.3% to 0.7% of people are affected by schizophrenia during their lifetime.[14] In 2017, there were an estimated 1.1 million new cases and in 2019 a total of 20 million cases globally.[15][2] Males are more often affected and on average have an earlier onset.[2] The causes of schizophrenia include genetic and environmental factors.[5] Genetic factors include a variety of common and rare genetic variants.[16] Possible environmental factors include being raised in a city, cannabis use during adolescence, infections, the ages of a person's mother or father, and poor nutrition during pregnancy.[5][17] About half of those diagnosed with schizophrenia will have a significant improvement over the long term with no further relapses, and a small proportion of these will recover completely.[7][18] The other half will have a lifelong impairment,[19] and severe cases may be repeatedly admitted to hospital.[18] Social problems such as long-term unemployment, poverty, homelessness, exploitation, and victimization are common consequences of schizophrenia.[20][21] Compared to the general population, people with schizophrenia have a higher suicide rate (about 5% overall) and more physical health problems,[22][23] leading to an average decreased life expectancy of 20 years.[10] In 2015, an estimated 17,000 deaths were caused by schizophrenia.[12] The mainstay of treatment is antipsychotic medication, along with counselling, job training, and social rehabilitation.[5] Up to a third of people do not respond to initial antipsychotics, in which case the antipsychotic clozapine may be used.[24] In situations where there is a risk of harm to self or others, a short involuntary hospitalization may be necessary.[25] Long-term hospitalization may be needed for a small number of people with severe schizophrenia.[26] In countries where supportive services are limited or unavailable, long-term hospital stays are more typical.[27] ## Contents * 1 Signs and symptoms * 1.1 Positive symptoms * 1.2 Negative symptoms * 1.3 Cognitive symptoms * 1.4 Onset * 2 Risk factors * 2.1 Genetic * 2.2 Environment * 2.2.1 Substance use * 3 Mechanisms * 4 Diagnosis * 4.1 Criteria * 4.2 Changes made * 4.3 Comorbidities * 4.4 Differential diagnosis * 5 Prevention * 6 Management * 6.1 Medication * 6.1.1 Side effects * 6.1.2 Treatment resistant schizophrenia * 6.2 Psychosocial interventions * 6.3 Other * 7 Violence * 8 Prognosis * 9 Epidemiology * 10 History * 11 Society and culture * 12 Research directions * 13 References * 14 External links ## Signs and symptoms My Eyes at the Moment of the Apparitions by German artist August Natterer, who had schizophrenia Schizophrenia is a mental disorder characterized by significant alterations in perception, thoughts, mood, and behavior.[28] Symptoms are described in terms of positive, negative, and cognitive symptoms.[3][29] The positive symptoms of schizophrenia are the same for any psychosis and are sometimes referred to as psychotic symptoms. These may be present in any of the different psychoses, and are often transient making early diagnosis of schizophrenia problematic. Psychosis noted for the first time in a person who is later diagnosed with schizophrenia is referred to as a first-episode psychosis (FEP).[30][31] ### Positive symptoms Positive symptoms are those symptoms that are not normally experienced, but are present in people during a psychotic episode in schizophrenia. They include delusions, hallucinations, and disorganized thoughts and speech, typically regarded as manifestations of psychosis.[30] Hallucinations most commonly involve the sense of hearing as hearing voices but can sometimes involve any of the other senses of taste, sight, smell, and touch.[32] They are also typically related to the content of the delusional theme.[33] Delusions are bizarre or persecutory in nature. Distortions of self-experience such as feeling as if one's thoughts or feelings are not really one's own, to believing that thoughts are being inserted into one's mind, sometimes termed passivity phenomena, are also common.[34] Thought disorders can include thought blocking, and disorganized speech – speech that is not understandable is known as word salad.[3][35] Positive symptoms generally respond well to medication,[5] and become reduced over the course of the illness, perhaps related to the age-related decline in dopamine activity.[7] ### Negative symptoms Negative symptoms are deficits of normal emotional responses, or of other thought processes. The five recognised domains of negative symptoms are: blunted affect – showing flat expressions or little emotion; alogia – a poverty of speech; anhedonia – an inability to feel pleasure; asociality – the lack of desire to form relationships, and avolition – a lack of motivation and apathy.[36][37] Avolition and anhedonia are seen as motivational deficits resulting from impaired reward processing.[38][39] Reward is the main driver of motivation and this is mostly mediated by dopamine.[39] It has been suggested that negative symptoms are multidimensional and they have been categorised into two subdomains of apathy or lack of motivation, and diminished expression.[36][40] Apathy includes avolition, anhedonia, and social withdrawal; diminished expression includes blunt effect, and alogia.[41] Sometimes diminished expression is treated as both verbal and non-verbal.[42] Apathy accounts for around 50 per cent of the most often found negative symptoms and affects functional outcome and subsequent quality of life. Apathy is related to disrupted cognitive processing affecting memory and planning including goal-directed behaviour.[43] The two subdomains has suggested a need for separate treatment approaches.[44] A lack of distress – relating to a reduced experience of depression and anxiety is another noted negative symptom.[45] A distinction is often made between those negative symptoms that are inherent to schizophrenia, termed primary; and those that result from positive symptoms, from the side effects of antipsychotics, substance abuse, and social deprivation - termed secondary negative symptoms.[46] Negative symptoms are less responsive to medication and the most difficult to treat.[44] However if properly assessed, secondary negative symptoms are amenable to treatment.[40] Scales for specifically assessing the presence of negative symptoms, and for measuring their severity, and their changes have been introduced since the earlier scales such as the PANNS that deals with all types of symptoms.[44] These scales are the Clinical Assessment Interview for Negative Symptoms (CAINS), and the Brief Negative Symptom Scale (BNSS) also known as second-generation scales.[45][44][47] In 2020, ten years after its introduction a cross-cultural study of the use of BNSS found valid and reliable psychometric evidence for the five-domain structure cross-culturally.[45] The BNSS is designed to assess both the presence and severity and change of negative symptoms of the five recognised domains, and the additional item of reduced normal distress.[45] BNSS can register changes in negative symptoms in relation to psychosocial and pharmacological intervention trials. BNSS has also been used to study a proposed non-D2 treatment called SEP-363856. Findings supported the favouring of five domains over the two-dimensional proposition.[45] ### Cognitive symptoms See also: Visual processing abnormalities in schizophrenia Cognitive deficits are the earliest and most constantly found symptoms in schizophrenia. They are often evident long before the onset of illness in the prodromal stage, and may be present in early adolescence, or childhood.[48][49] They are a core feature but not considered to be core symptoms, as are positive and negative symptoms.[50][51] However, their presence and degree of dysfunction is taken as a better indicator of functionality than the presentation of core symptoms.[48] Cognitive deficits become worse at first episode psychosis but then return to baseline, and remain fairly stable over the course of the illness.[52][53] The deficits in cognition are seen to drive the negative psychosocial outcome in schizophrenia, and are claimed to equate to a possible reduction in IQ from the norm of 100 to 70–85.[54][55] Cognitive deficits may be of neurocognition (nonsocial) or of social cognition.[56] Neurocognition is the ability to receive and remember information, and includes verbal fluency, memory, reasoning, problem solving, speed of processing, and auditory and visual perception.[53] Verbal memory and attention are seen to be the most affected.[57][55] Verbal memory impairment is associated with a decreased level of semantic processing (relating meaning to words).[58] Another memory impairment is that of episodic memory.[59] An impairment in visual perception that is consistently found in schizophrenia is that of visual backward masking.[53] Visual processing impairments include an inability to perceive complex visual illusions.[60] Social cognition is concerned with the mental operations needed to interpret, and understand the self and others in the social world.[56][53] This is also an associated impairment, and facial emotion perception is often found to be difficult.[61][62] Facial perception is critical for ordinary social interaction.[63] Cognitive impairments do not usually respond to antipsychotics, and there are a number of interventions that are used to try to improve them; cognitive remediation therapy has been found to be of particular help.[51] ### Onset Further information: Basic symptoms of schizophrenia See also: Childhood schizophrenia and Adolescence § Changes in the brain Onset typically occurs between the late teens and early 30s, with the peak incidence occurring in males in the early to mid twenties, and in females in the late twenties.[3][7][11] Onset before the age of 17 is known as early-onset,[64] and before the age of 13, as can sometimes occur, is known as childhood schizophrenia or very early-onset.[65][7] A later stage of onset can occur between the ages of 40 and 60, known as late-onset schizophrenia.[56] A later onset over the age of 60, which may be difficult to differentiate as schizophrenia, is known as very-late-onset schizophrenia-like psychosis.[56] Late onset has shown that a higher rate of females are affected; they have less severe symptoms and need lower doses of antipsychotics.[56] The tendency for earlier onset in males is later seen to be balanced by a post-menopausal increase in the development in females. Estrogen produced pre-menopause has a dampening effect on dopamine receptors but its protection can be overridden by a genetic overload.[66] There has been a dramatic increase in the numbers of older adults with schizophrenia.[67] An estimated 70% of those with schizophrenia have cognitive deficits, and these are most pronounced in early onset and late-onset illness.[56][68] Onset may happen suddenly or may occur after the slow and gradual development of a number of signs and symptoms, a period known as the prodromal stage.[7] Up to 75% of those with schizophrenia go through a prodromal stage.[69] The negative and cognitive symptoms in the prodrome stage can precede FEP by many months and up to five years.[70][52] The period from FEP and treatment is known as the duration of untreated psychosis (DUP) which is seen to be a factor in functional outcome. The prodromal stage is the high-risk stage for the development of psychosis.[53] Since the progression to first episode psychosis is not inevitable, an alternative term is often preferred of at risk mental state[53] Cognitive dysfunction at an early age impact a young person's usual cognitive development.[71] Recognition and early intervention at the prodromal stage would minimize the associated disruption to educational and social development and has been the focus of many studies.[70][52] It is suggested that the use of anti-inflammatory compounds such as D-serine may prevent the transition to schizophrenia.[52] Cognitive symptoms are not secondary to positive symptoms or to the side effects of antipsychotics.[53] Cognitive impairments in the prodromal stage become worse after first episode psychosis (after which they return to baseline and then remain fairly stable), making early intervention to prevent such transition of prime importance.[52] Early treatment with cognitive behavioral therapies are the gold standard.[70] Neurological soft signs of clumsiness and loss of fine motor movement are often found in schizophrenia, which may resolve with effective treatment of FEP.[72][11] ## Risk factors Main article: Risk factors of schizophrenia See also: Developmental psychobiology Schizophrenia is described as a neurodevelopmental disorder with no precise boundary, or single cause, and is thought to develop from gene–environment interactions with involved vulnerability factors.[73][74][5] The interactions of these risk factors are complex, as numerous and diverse insults from conception to adulthood can be involved.[74] A genetic predisposition on its own, without interacting environmental factors, will not give rise to the development of schizophrenia.[75][74] ### Genetic Estimates of the heritability of schizophrenia are between 70% and 80%, which implies that 70% to 80% of the individual differences in risk to schizophrenia is associated with genetics.[76][16] These estimates vary because of the difficulty in separating genetic and environmental influences, and their accuracy has been queried.[77][78] The greatest risk factor for developing schizophrenia is having a first-degree relative with the disease (risk is 6.5%); more than 40% of identical twins of those with schizophrenia are also affected.[79] If one parent is affected the risk is about 13% and if both are affected the risk is nearly 50%.[76] However, DSM-5 points out that most people with schizophrenia have no family history of psychosis.[7] Results of candidate gene studies of schizophrenia have generally failed to find consistent associations,[80] and the genetic loci identified by genome-wide association studies explain only a small fraction of the variation in the disease.[81] Many genes are known to be involved in schizophrenia, each with small effect and unknown transmission and expression.[16][82] The summation of these effect sizes into a polygenic risk score can explain at least 7% of the variability in liability for schizophrenia.[83] Around 5% of cases of schizophrenia are understood to be at least partially attributable to rare copy-number variations (CNVs); these structural variations are associated with known genomic disorders involving deletions at 22q11.2 (DiGeorge syndrome), duplications at 16p11.2 16p11.2 duplication (most frequently found) and deletions at 15q11.2 (Burnside-Butler syndrome).[84] Some of these CNVs increase the risk of developing schizophrenia by as much as 20-fold, and are frequently comorbid with autism and intellectual disabilities.[84] The genes CRHR1 and CRHBP have been shown to be associated with a severity of suicidal behavior. These genes code for stress response proteins needed in the control of the HPA axis, and their interaction can affect this axis. Response to stress can cause lasting changes in the function of the HPA axis possibly disrupting the negative feedback mechanism, homeostasis, and the regulation of emotion leading to altered behaviors.[75] The question of how schizophrenia could be primarily genetically influenced, given that people with schizophrenia have lower fertility rates, is a paradox. It is expected that genetic variants that increase the risk of schizophrenia would be selected against due to their negative effects on reproductive fitness. A number of potential explanations have been proposed, including that alleles associated with schizophrenia risk confers a fitness advantage in unaffected individuals.[85][86] While some evidence has not supported this idea,[78] others propose that a large number of alleles each contributing a small amount can persist.[87] ### Environment Further information: Prenatal nutrition, Prenatal stress, and Neuroplastic effects of pollution Environmental factors, each associated with a slight risk of developing schizophrenia in later life include oxygen deprivation, infection, prenatal maternal stress, and malnutrition in the mother during prenatal development.[88] A risk is also associated with maternal obesity, in increasing oxidative stress, and dysregulating the dopamine and serotonin pathways.[89] Both maternal stress and infection have been demonstrated to alter fetal neurodevelopment through an increase of pro-inflammatory cytokines.[90] There is a slighter risk associated with being born in the winter or spring possibly due to vitamin D deficiency[91] or a prenatal viral infection.[79] Other infections during pregnancy or around the time of birth that have been linked to an increased risk include infections by Toxoplasma gondii and Chlamydia.[92] The increased risk is about five to eight percent.[93] Viral infections of the brain during childhood are also linked to a risk of schizophrenia during adulthood.[94] Adverse childhood experiences (ACEs), severe forms of which are classed as childhood trauma, range from being bullied or abused, to the death of a parent.[95] Many adverse childhood experiences can cause toxic stress and increase the risk of psychosis.[96][97][95] Chronic trauma can promote lasting inflammatory dysregulation throughout the nervous system.[98] It is suggested that early stress may contribute to the developmenmt of schizophrenia through these alterations in the immune system.[98] Schizophrenia was the last diagnosis to benefit from the link made between ACEs and adult mental health outcomes.[99] Living in an urban environment during childhood or as an adult has consistently been found to increase the risk of schizophrenia by a factor of two,[22][100] even after taking into account drug use, ethnic group, and size of social group.[101] A possible link between the urban environment and pollution has been suggested to be the cause of the elevated risk of schizophrenia.[102] Other risk factors of importance include social isolation, immigration related to social adversity and racial discrimination, family dysfunction, unemployment, and poor housing conditions.[79][103] Having a father older than 40 years, or parents younger than 20 years are also associated with schizophrenia.[5][104] It has been suggested that apart from gene-environment interactions, environment-environment interactions also be taken into account as each environmental risk factor on its own is not enough.[88] #### Substance use About half of those with schizophrenia use recreational drugs, including cannabis, nicotine, and alcohol excessively.[105][106] Use of stimulants such as amphetamine and cocaine can lead to a temporary stimulant psychosis, which presents very similarly to schizophrenia. Rarely, alcohol use can also result in a similar alcohol-related psychosis.[79][107] Drugs may also be used as coping mechanisms by people who have schizophrenia, to deal with depression, anxiety, boredom, and loneliness.[105][108] The use of cannabis and tobacco are not associated with the development of cognitive deficits, and sometimes a reverse relationship is found where their use improves these symptoms.[51] However, substance abuse is associated with an increased risk of suicide, and a poor response to treatment.[109] Cannabis-use may be a contributory factor in the development of schizophrenia, potentially increasing the risk of the disease in those who are already at risk.[17] The increased risk may require the presence of certain genes within an individual.[17] Its use is associated with doubling the rate.[110] The use of more potent strains of cannabis having a high level of its active ingredient tetrahydrocannabinol (THC), increases the risk further. One of these strains is well known as skunk.[111][112] ## Mechanisms Main article: Mechanisms of schizophrenia See also: Aberrant salience The mechanisms of schizophrenia are unknown, and a number of models have been put forward to explain the link between altered brain function and schizophrenia.[22] The prevailing model of schizophrenia is that of a neurodevelopmental disorder, and the underlying changes that occur before symptoms become evident are seen as arising from the interaction between genes and the environment.[113] Extensive studies support this model.[69] Maternal infections, malnutrition and complications during pregnancy and childbirth are known risk factors for the development of schizophrenia, which usually emerges between the ages of 18-25 a period that overlaps with certain stages of neurodevelopment.[114] Gene-environment interactions lead to deficits in the neural circuitry that affect sensory and cognitive functions.[69] The common dopamine and glutamate models proposed are not mutually exclusive; each is seen to have a role in the neurobiology of schizophrenia.[115] The most common model put forward was the dopamine hypothesis of schizophrenia, which attributes psychosis to the mind's faulty interpretation of the misfiring of dopaminergic neurons.[116] This has been directly related to the symptoms of delusions and hallucinations.[117][118][119] Abnormal dopamine signaling has been implicated in schizophrenia based on the usefulness of medications that affect the dopamine receptor and the observation that dopamine levels are increased during acute psychosis.[120][121] A decrease in D1 receptors in the dorsolateral prefrontal cortex may also be responsible for deficits in working memory.[122][123] The glutamate hypothesis of schizophrenia links alterations between glutamatergic neurotransmission and the neural oscillations that affect connections between the thalamus and the cortex.[124] Studies have shown that a reduced expression of a glutamate receptor – NMDA receptor, and glutamate blocking drugs such as phencyclidine and ketamine can mimic the symptoms and cognitive problems associated with schizophrenia.[125][126][124] Post-mortem studies consistently find that a subset of these neurons fail to express GAD67 (GAD1),[127] in addition to abnormalities in brain morphometry. The subsets of interneurons that are abnormal in schizophrenia are responsible for the synchronizing of neural ensembles needed during working memory tasks. These give the neural oscillations produced as gamma waves that have a frequency of between 30 and 80 hertz. Both working memory tasks and gamma waves are impaired in schizophrenia, which may reflect abnormal interneuron functionality.[127][128][129][130] Deficits in executive functions, such as planning, inhibition, and working memory, are pervasive in schizophrenia. Although these functions are separable, their dysfunction in schizophrenia may reflect an underlying deficit in the ability to represent goal related information in working memory, and to utilize this to direct cognition and behavior.[131][132] These impairments have been linked to a number of neuroimaging and neuropathological abnormalities. For example, functional neuroimaging studies report evidence of reduced neural processing efficiency, whereby the dorsolateral prefrontal cortex is activated to a greater degree to achieve a certain level of performance relative to controls on working memory tasks. These abnormalities may be linked to the consistent post-mortem finding of reduced neuropil, evidenced by increased pyramidal cell density and reduced dendritic spine density. These cellular and functional abnormalities may also be reflected in structural neuroimaging studies that find reduced grey matter volume in association with deficits in working memory tasks.[133] Positive symptoms have been linked to cortical thinning in the superior temporal gyrus.[134] Severity of negative symptoms has been linked to reduced thickness in the left medial orbitofrontal cortex.[135] Anhedonia, traditionally defined as a reduced capacity to experience pleasure, is frequently reported in schizophrenia. However, a large body of evidence suggests that hedonic responses are intact in schizophrenia,[136] and that what is reported to be anhedonia is a reflection of dysfunction in other processes related to reward.[137] Overall, a failure of reward prediction is thought to lead to impairment in the generation of cognition and behavior required to obtain rewards, despite normal hedonic responses.[138] It has been hypothesized that in some people, development of schizophrenia is related to intestinal tract dysfunction such as seen with non-celiac gluten sensitivity or abnormalities in the gut microbiota.[139] A subgroup of persons with schizophrenia present an immune response to gluten differently from that found in people with celiac, with elevated levels of certain serum biomarkers of gluten sensitivity such as anti-gliadin IgG or anti-gliadin IgA antibodies.[140] Another theory links abnormal brain lateralization to the development of being left-handed which is significantly more common in those with schizophrenia.[141] This abnormal development of hemispheric asymmetry is noted in schizophrenia.[142] Studies have concluded that the link is a true and verifiable effect that may reflect a genetic link between lateralization and schizophrenia.[141][143] An important process that may be disrupted in neurodevelopment is astrogenesis – the formation of astrocytes. Astrocytes are crucial in contributing to the formation and maintenance of neural circuits and it is believed that disruption in this role can result in a number of neurodevelopmental disorders including schizophrenia.[144] Bayesian models of brain functioning have been utilized to link abnormalities in cellular functioning to symptoms.[145][146] Both hallucinations and delusions have been suggested to reflect improper encoding of prior expectations, thereby causing expectation to excessively influence sensory perception and the formation of beliefs. In approved models of circuits that mediate predictive coding, reduced NMDA receptor activation, could in theory result in the positive symptoms of delusions and hallucinations.[147][148][149] ## Diagnosis Main article: Diagnosis of schizophrenia There is no objective test or biomarker to confirm diagnosis. Psychoses can occur in several conditions and are often transient making early diagnosis of schizophrenia difficult. Psychosis noted for the first time in a person that is later diagnosed with schizophrenia is referred to as a first-episode psychosis (FEP). ### Criteria Schizophrenia is diagnosed based on criteria in either the Diagnostic and Statistical Manual of Mental Disorders (DSM) published by the American Psychiatric Association or the International Statistical Classification of Diseases and Related Health Problems (ICD) published by the World Health Organization. These criteria use the self-reported experiences of the person and reported abnormalities in behavior, followed by a psychiatric assessment. The mental status examination is an important part of the assessment.[150] An established tool for assessing the severity of positive and negative symptoms is the Positive and Negative Syndrome Scale (PANSS).[151] This has been seen to have shortcomings relating to negative symptoms, and other scales – the Clinical Assessment Interview for Negative Symptoms (CAINS), and the Brief Negative Symptoms Scale (BNSS) have been introduced.[44] The DSM-5, published in 2013, gives a Scale to Assess the Severity of Symptom Dimensions outlining eight dimensions of symptoms.[50] DSM-5 states that to be diagnosed with schizophrenia, two diagnostic criteria have to be met over the period of one month, with a significant impact on social or occupational functioning for at least six months. One of the symptoms needs to be either delusions, hallucinations, or disorganized speech. A second symptom could be one of the negative symptoms, or severely disorganized or catatonic behaviour.[7] A different diagnosis of schizophreniform disorder can be made before the six months needed for the diagnosis of schizophrenia.[7] In Australia the guideline for diagnosis is for six months or more with symptoms severe enough to affect ordinary functioning.[152] In the UK diagnosis is based on having the symptoms for most of the time for one month, with symptoms that significantly affect the ability to work, study, or to carry on ordinary daily living, and with other similar conditions ruled out.[153] The ICD criteria are typically used in European countries; the DSM criteria are used predominantly in the United States and Canada, and are prevailing in research studies. In practice, agreement between the two systems is high.[154] The current proposal for the ICD-11 criteria for schizophrenia recommends adding self-disorder as a symptom.[34] A major unresolved difference between the two diagnostic systems is that of the requirement in DSM of an impaired functional outcome. WHO for ICD argues that not all people with schizophrenia have functional deficits and so these are not specific for the diagnosis.[50] ### Changes made Both manuals have adopted the chapter heading of Schizophrenia spectrum and other psychotic disorders; ICD modifying this as Schizophrenia spectrum and other primary psychotic disorders.[50] The definition of schizophrenia remains essentially the same as that specified by the 2000 text revised DSM-IV (DSM-IV-TR). However, with the publication of DSM-5, the APA removed all sub-classifications of schizophrenia.[50] ICD-11 has also removed subtypes. The removed subtype from both, of catatonic has been relisted in ICD-11 as a psychomotor disturbance that may be present in schizophrenia.[50] Another major change was to remove the importance previously given to Schneider's first-rank symptoms.[155] DSM-5 still uses the listing of schizophreniform disorder but ICD-11 no longer includes it.[50] DSM-5 also recommends that a better distinction be made between a current condition of schizophrenia and its historical progress, to achieve a clearer overall characterization.[155] A dimensional assessment has been included in DSM-5 covering eight dimensions of symptoms to be rated (using the Scale to Assess the Severity of Symptom Dimensions) – these include the five diagnostic criteria plus cognitive impairments, mania, and depression.[50] This can add relevant information for the individual in regard to treatment, prognosis, and functional outcome; it also enables the response to treatment to be more accurately described.[50][156] Two of the negative symptoms – avolition and diminished emotional expression, have been given more prominence in both manuals.[50] ### Comorbidities Many people with schizophrenia may have one or more other mental disorders, such as panic disorder, obsessive-compulsive disorder, or substance use disorder. These are separate disorders that require treatment.[7] When comorbid with schizophrenia, substance use disorder and antisocial personality disorder both increase the risk for violence.[157] Comorbid substance abuse also increases risk for suicide.[109] Sleep disorders often co-occur with schizophrenia, and may be an early sign of relapse.[158] Sleep disorders are linked with positive symptoms such as disorganized thinking and can adversely affect cortical plasticity and cognition.[158] The consolidation of memories is disrupted in sleep disorders.[159] They are associated with severity of illness, a poor prognosis, and poor quality of life.[160][161] Sleep onset and maintenance insomnia is a common symptom, regardless of whether treatment has been received or not.[160] Genetic variations have been found associated with these conditions involving the circadian rhythm, dopamine and histamine metabolism, and signal transduction.[162] Limited positive evidence has been found for the use of acupuncture as an add-on.[163] ### Differential diagnosis See also: Dual diagnosis and Comparison of bipolar disorder and schizophrenia To make a diagnosis of schizophrenia other possible causes of psychosis need to be excluded.[164] Psychotic symptoms lasting less than a month may be diagnosed as brief psychotic disorder, or as schizophreniform disorder. Psychosis is noted in Other specified schizophrenia spectrum and other psychotic disorders as a DSM-5 category. Schizoaffective disorder is diagnosed if symptoms of mood disorder are substantially present alongside psychotic symptoms. Psychosis that results from a general medical condition or substance is termed secondary psychosis.[7] Psychotic symptoms may be present in several other conditions, including bipolar disorder,[8] borderline personality disorder,[9] substance intoxication, substance-induced psychosis, and a number of drug withdrawal syndromes. Non-bizarre delusions are also present in delusional disorder, and social withdrawal in social anxiety disorder, avoidant personality disorder and schizotypal personality disorder. Schizotypal personality disorder has symptoms that are similar but less severe than those of schizophrenia.[7] Schizophrenia occurs along with obsessive-compulsive disorder (OCD) considerably more often than could be explained by chance, although it can be difficult to distinguish obsessions that occur in OCD from the delusions of schizophrenia.[165] There can be considerable overlap with the symptoms of post-traumatic stress disorder.[166] A more general medical and neurological examination may be needed to rule out medical illnesses which may rarely produce psychotic schizophrenia-like symptoms, such as metabolic disturbance, systemic infection, syphilis, HIV-associated neurocognitive disorder, epilepsy, limbic encephalitis, and brain lesions. Stroke, multiple sclerosis, hyperthyroidism, hypothyroidism, and dementias such as Alzheimer's disease, Huntington's disease, frontotemporal dementia, and the Lewy body dementias may also be associated with schizophrenia-like psychotic symptoms.[167] It may be necessary to rule out a delirium, which can be distinguished by visual hallucinations, acute onset and fluctuating level of consciousness, and indicates an underlying medical illness. Investigations are not generally repeated for relapse unless there is a specific medical indication or possible adverse effects from antipsychotic medication. In children hallucinations must be separated from typical childhood fantasies.[7] It is difficult to distinguish childhood schizophrenia from autism.[65] ## Prevention Prevention of schizophrenia is difficult as there are no reliable markers for the later development of the disorder.[168] There is tentative though inconclusive evidence for the effectiveness of early intervention to prevent schizophrenia in the prodrome phase.[169] There is some evidence that early intervention in those with first-episode psychosis may improve short-term outcomes, but there is little benefit from these measures after five years.[22] Cognitive behavioral therapy may reduce the risk of psychosis in those at high risk after a year[170] and is recommended in this group, by the National Institute for Health and Care Excellence (NICE).[28] Another preventive measure is to avoid drugs that have been associated with development of the disorder, including cannabis, cocaine, and amphetamines.[79] Antipsychotics are prescribed following a first-episode psychosis, and following remission a preventive maintenance use is continued to avoid relapse. However, it is recognised that some people do recover following a single episode and that long-term use of antipsychotics will not be needed but there is no way of identifying this group.[171] ## Management Main article: Management of schizophrenia The primary treatment of schizophrenia is the use of antipsychotic medications, often in combination with psychosocial interventions and social supports.[22][172] Community support services including drop-in centers, visits by members of a community mental health team, supported employment,[173] and support groups are common. The time between the onset of psychotic symptoms to being given treatment – the duration of untreated psychosis (DUP) is associated with a poorer outcome in both the short term and the long term.[174] Voluntary or involuntary admittance to hospital may be needed to treat a severe episode, however, hospital stays are as short as possible. In the UK large mental hospitals termed asylums began to be closed down in the 1950s with the advent of antipsychotics, and with an awareness of the negative impact of long-term hospital stays on recovery.[20] This process was known as deinstitutionalization, and community and supportive services were developed in order to support this change. Many other countries followed suit with the US starting in the 60s.[175] There will still remain a few people who do not improve enough to be discharged.[20][26] In those countries that lack the necessary supportive and social services long-term hospital stays are more usual.[27] ### Medication Risperidone (trade name Risperdal) is a common atypical antipsychotic medication. The first-line treatment for schizophrenia is an antipsychotic. The first-generation antipsychotics, now called typical antipsychotics, are dopamine antagonists that block D2 receptors, and affect the neurotransmission of dopamine. Those brought out later, the second-generation antipsychotics known as atypical antipsychotics, can also have effect on another neurotransmitter, serotonin. Antipsychotics can reduce the symptoms of anxiety within hours of their use but for other symptoms they may take several days or weeks to reach their full effect.[30][176] They have little effect on negative and cognitive symptoms, which may be helped by additional psychotherapies and medications.[177] There is no single antipsychotic suitable for first-line treatment for everyone, as responses and tolerances vary between people.[178] Stopping medication may be considered after a single psychotic episode where there has been a full recovery with no symptoms for twelve months. Repeated relapses worsen the long-term outlook and the risk of relapse following a second episode is high, and long-term treatment is usually recommended.[179][180] Tobacco smoking increases the metabolism of some antipsychotics, by strongly activitating CYP1A2, the enzyme that breaks them down, and a significant difference is found in these levels between smokers and non-smokers.[181][182][183] It is recommended that the dosage for those smokers on clozapine be increased by 50%, and for those on olanzapine by 30%.[182] The result of stopping smoking can lead to an increased concentration of the antipsychotic that may result in toxicity, so that monitoring of effects would need to take place with a view to decreasing the dosage; many symptoms may be noticeably worsened, and extreme fatigue, and seizures are also possible with a risk of relapse. Likewise those who resume smoking may need their dosages adjusted accordingly.[184][181] The altering effects are due to compounds in tobacco smoke and not to nicotine; the use of nicotine replacement therapy therefore has the equivalent effect of stopping smoking and monitoring would still be needed.[181] About 30 to 50 percent of people with schizophrenia fail to accept that they have an illness or comply with their recommended treatment.[185] For those who are unwilling or unable to take medication regularly, long-acting injections of antipsychotics may be used,[186] which reduce the risk of relapse to a greater degree than oral medications.[187] When used in combination with psychosocial interventions, they may improve long-term adherence to treatment.[188] Research findings suggested that other neurotransmission systems, including serotonin, glutamate, GABA, and acetycholine, were implicated in the development of schizophrenia, and that a more inclusive medication was needed.[183] A new first-in-class antipsychotic that targets multiple neurotransmitter systems called lumateperone (ITI-007), was trialed and approved by the FDA in December 2019 for the treatment of schizophrenia in adults.[189][190][183] Lumateperone is a small molecule agent that shows improved safety, and tolerance. It interacts with dopamine, serotonin, and glutamate in a complex, uniquely selective manner, and is seen to improve negative and positive symptoms, and social functioning.[191] Lumateperone was also found to reduce potential metabolic dysfunction, have lower rates of movement disorders, and have lower cardiovascular side effects such as a fast heart rate.[183] #### Side effects Typical antipsychotics are associated with a higher rate of movement disorders including akathisia. Some atypicals are associated with considerable weight gain, diabetes and the risk of metabolic syndrome.[192] Risperidone (atypical) has a similar rate of extrapyramidal symptoms to haloperidol (typical).[192] A rare but potentially lethal condition of neuroleptic malignant syndrome (NMS) has been associated with the use of antipsychotics. Through its early recognition, and timely intervention rates have declined. However, an awareness of the syndrome is advised to enable intervention.[193] Another less rare condition of tardive dyskinesia can occur due to long-term use of antipsychotics, developing after many months or years of use. It is more often reported with use of typical antipsychotics.[194] Clozapine is associated with side effects that include weight gain, tiredness, and hypersalivation. More serious adverse effects include seizures, NMS, neutropenia, and agranulocytosis (lowered white blood cell count) and its use needs careful monitoring.[195][196] Studies have found that antipsychotic treatment following NMS and neutropenia may sometimes be successfully rechallenged (restarted) with clozapine.[197][198] Clozapine is also associated with thromboembolism (including pulmonary embolism), myocarditis, and cardiomyopathy.[199][200] A systematic review of clozapine-associated pulmonary embolism indicates that this adverse effect can often be fatal, and that it has an early onset, and is dose-dependent. The findings advised the consideration of using a prevention therapy for venous thromboembolism after starting treatment with clozapine, and continuing this for six months.[200] Constipation is three times more likely to occur with the use of clozapine, and severe cases can lead to ileus and bowel ischemia resulting in many fatalities.[195] However, the risk of serious adverse effects from clozapine is low, and there are the beneficial effects to be gained of a reduced risk of suicide, and aggression.[201][202] Typical antipsychotics and atypical risperidone can have a side effect of sexual dysfunction.[79] Clozapine, olanzapine, and quetiapine are associated with beneficial effects on sexual functioning helped by various psychotherapies.[203] Unwanted side effects cause people to stop treatment, resulting in relapses.[204] #### Treatment resistant schizophrenia About half of those with schizophrenia will respond favourably to antipsychotics, and have a good return of functioning.[205] However, positive symptoms persist in up to a third of people. Following two trials of different antipsychotics over six weeks, that also prove ineffective, they will be classed as having treatment resistant schizophrenia (TRS), and clozapine will be offered.[206][24] Clozapine is of benefit to around half of this group although it has the potentially serious side effect of agranulocytosis (lowered white blood cell count) in less than 4% of people.[22][79][207] Between 12 and 20 per cent will not respond to clozapine and this group is said to have ultra treatment resistant schizophrenia.[206][208] ECT may be offered to treat TRS as an add-on therapy, and is shown to sometimes be of benefit.[208] A review concluded that this use only has an effect on medium-term TRS and that there is not enough evidence to support its use other than for this group.[209] TRS is often accompanied by a low quality of life, and greater social dysfunction.[210] TRS may be the result of inadequate rather than inefficient treatment; it also may be a false label due to medication not being taken regularly, or at all.[202] About 16 per cent of people who had initially been responsive to treatment later develop resistance. This could relate to the length of time on APs, with treatment becoming less responsive.[211] This finding also supports the involvement of dopamine in the development of schizophrenia.[202] Studies suggest that TRS may be a more heritable form.[212] TRS may be evident from first episode psychosis, or from a relapse. It can vary in its intensity and response to other therapies.[210] This variation is seen to possibly indicate an underlying neurobiology such as dopamine supersensitivity (DSS), glutamate or serotonin dysfunction, inflammation and oxidative stress.[206] Studies have found that dopamine supersensitivity is found in up to 70% of those with TRS.[213] The variation has led to the suggestion that treatment responsive and treatment resistant schizophrenia be considered as two different subtypes.[206][212] It is further suggested that if the subtypes could be distinguished at an early stage significant implications could follow for treatment considerations, and for research.[208] Neuroimaging studies have found a significant decrease in the volume of grey matter in those with TRS with no such change seen in those who are treatment responsive.[208] In those with ultra treatment resistance the decrease in grey matter volume was larger.[206][208] A link has been made between the gut microbiota and the development of TRS. The most prevalent cause put forward for TRS is that of mutation in the genes responsible for drug effectiveness. These include liver enzyme genes that control the availability of a drug to brain targets, and genes responsible for the structure and function of these targets. In the colon the bacteria encode a hundred times more genes than exist in the human genome. Only a fraction of ingested drugs reach the colon, having been already exposed to small intestinal bacteria, and absorbed in the portal circulation. This small fraction is then subject to the metabolic action of many communities of bacteria. Activation of the drug depends on the composition and enzymes of the bacteria and of the specifics of the drug, and therefore a great deal of individual variation can affect both the usefulness of the drug and its tolerability. It is suggested that parenteral administration of antipsychotics would bypass the gut and be more successful in overcoming TRS. The composition of gut microbiota is variable between individuals, but they are seen to remain stable. However, phyla can change in response to many factors including ageing, diet, substance-use, and medications – especially antibiotics, laxatives, and antipsychotics. In FEP, schizophrenia has been linked to significant changes in the gut microbiota that can predict response to treatment.[214] ### Psychosocial interventions Further information: Management of schizophrenia § Psychosocial A number of psychosocial interventions that include several types of psychotherapy may be useful in the treatment of schizophrenia such as: family therapy,[215] group therapy, cognitive remediation therapy,[216] cognitive behavioral therapy, and metacognitive training.[217] Skills training, and help with substance use, and weight management– often needed as a side effect of an antipsychotic, are also offered.[218] In the US, interventions for first episode psychosis have been brought together in an overall approach known as coordinated speciality care (CSC) and also includes support for education.[30] In the UK care across all phases is a similar approach that covers many of the treatment guidelines recommended.[28] The aim is to reduce the number of relapses and stays in hospital.[215] Other support services for education, employment, and housing are usually offered. For people suffering from severe schizophrenia, and discharged from a stay in hospital, these services are often brought together in an integrated approach to offer support in the community away from the hospital setting. In addition to medicine management, housing, and finances, assistance is given for more routine matters such as help with shopping and using public transport. This approach is known as assertive community treatment (ACT) and has been shown to achieve positive results in symptoms, social functioning and quality of life.[219][220] Another more intense approach is known as intensive care management (ICM). ICM is a stage further than ACT and emphasises support of high intensity in smaller caseloads, (less than twenty). This approach is to provide long-term care in the community. Studies show that ICM improves many of the relevant outcomes including social functioning.[221] Some studies have shown little evidence for the effectiveness of cognitive behavioral therapy (CBT) in either reducing symptoms or preventing relapse.[222][223] However, other studies have found that CBT does improve overall psychotic symptoms (when in use with medication) and has been recommended in Canada, but it has been seen here to have no effect on social function, relapse, or quality of life.[224] In the UK it is recommended as an add-on therapy in the treatment of schizophrenia, but is not supported for use in treatment resistant schizophrenia.[223][225] Arts therapies are seen to improve negative symptoms in some people, and are recommended by NICE in the UK.[176][226] This approach however, is criticised as having not been well-researched, and arts therapies are not recommended in Australian guidelines for example.[226][227][228] Peer support, in which people with personal experience of schizophrenia, provide help to each other, is of unclear benefit.[229] ### Other Exercise including aerobic exercise has been shown to improve positive and negative symptoms, cognition, working memory, and improve quality of life.[230][231] Exercise has also been shown to increase the volume of the hippocampus in those with schizophrenia. A decrease in hippocampal volume is one of the factors linked to the development of the disease.[230] However, there still remains the problem of increasing motivation for, and maintaining participation in physical activity.[232] Supervised sessions are recommended.[231] In the UK healthy eating advice is offered alongside exercise programs.[233] An inadequate diet is often found in schizophrenia, and associated vitamin deficiencies including those of folate, and vitamin D are linked to the risk factors for the development of schizophrenia and for early death including heart disease.[234][235] Those with schizophrenia possibly have the worst diet of all the mental disorders. Lower levels of folate and vitamin D have been noted as significantly lower in first episode psychosis.[234] The use of supplemental folate is recommended.[236] A zinc deficiency has also been noted.[237] Vitamin B12 is also often deficient and this is linked to worse symptoms. Supplementation with B vitamins has been shown to significantly improve symptoms, and to put in reverse some of the cognitive deficits.[234] It is also suggested that the noted dysfunction in gut microbiota might benefit from the use of probiotics.[237] ## Violence Most people with schizophrenia are not aggressive, and are more likely to be victims of violence rather than perpetrators.[7] However, though the risk of violence in schizophrenia is small the association is consistent, and there are minor subgroups where the risk is high.[157] This risk is usually associated with a comorbid disorder such as a substance use disorder - in particular alcohol, or with antisocial personality disorder.[157] Substance abuse is strongly linked, and other risk factors are linked to deficits in cognition and social cognition including facial perception and insight that are in part included in theory of mind impairments.[238][239] Poor cognitive functioning, decision-making, and facial perception may contribute to making a wrong judgement of a situation that could result in an inappropriate response such as violence.[240] These associated risk factors are also present in antisocial personality disorder which when present as a comorbid disorder greatly increases the risk of violence.[241][242] A review in 2012 showed that schizophrenia was responsible for 6 per cent of homicides in Western countries.[241] Another wider review put the homicide figure at between 5 and 20 per cent.[243] There was found to be a greater risk of homicide during first episode psychosis that accounted for 38.5 per cent of homicides.[243] The association between schizophrenia and violence is complex. Homicide is linked with young age, male sex, a history of violence, and a stressful event in the preceding year. Clinical risk factors are severe untreated psychotic symptoms - untreated due to either not taking medication or to the condition being treatment resistant.[241] A comorbid substance use disorder or an antisocial personality disorder increases the risk for homicidal behaviour by 8-fold, in contrast to the 2-fold risk in those without the comorbid disorders.[157] Rates of homicide linked to psychosis are similar to those linked to substance misuse, and parallel the overall rate in a region.[244] What role schizophrenia has on violence independent of substance misuse is controversial, but certain aspects of individual histories or mental states may be factors.[245] Hostility is anger felt and directed at a person or group and has related dimensions of impulsiveness and aggression. When this impulsive-aggression is evident in schizophrenia neuroimaging has suggested the malfunctioning of a neural circuit that modulates hostile thoughts and behaviours that are linked with negative emotions in social interactions. This circuit includes the amygdala, striatum, prefrontal cortex, anterior cingulate cortex, insula, and hippocampus. Hostility has been reported during acute psychosis, and following hospital discharge.[246] There is a known association between low cholesterol levels, and impulsivity, and violence. A review finds that people with schizophrenia, and lower cholesterol levels are four times more likely to instigate violent acts. This association is also linked to the increased number of suicides in schizophrenia. It is suggested that cholesterol levels could serve as a biomarker for violent and suicidal tendencies.[247] A review found that just under 10 per cent of those with schizophrenia showed violent behaviour compared to 1.6 per cent of the general population. An excessive risk of violence is associated with drugs or alcohol and increases the risk by as much as 4-fold. Violence often leads to imprisonment. Clozapine is an effective medication that can be used in penal settings such as prisons. However, a condition of benign ethnic neutropenia in many African-Americans excludes them from the use of clozapine the most effective medication. Cognitive deficits are recognised as playing an important part in the origin and maintenance of aggression, and cognitive remediation therapy may therefore help to prevent the risk of violence in schizophrenia.[240] ## Prognosis Main article: Prognosis of schizophrenia See also: Physical health in schizophrenia Disability-adjusted life years lost due to schizophrenia per 100,000 inhabitants in 2004. no data ≤ 185 185–197 197–207 207–218 218–229 229–240 240–251 251–262 262–273 273–284 284–295 ≥ 295 Schizophrenia has great human and economic costs.[5] It results in a decreased life expectancy of 20 years.[10][4] This is primarily because of its association with obesity, poor diet, a sedentary lifestyle, and smoking, with an increased rate of suicide playing a lesser role.[10][248] Side effects of antipsychotics may also increase the risk.[10] These differences in life expectancy increased between the 1970s and 1990s.[249] An Australian study puts the rate of early death at 25 years, and views the main cause to be related to heart disease.[199] Several studies indicate that almost 40% of those with schizophrenia die from complications of cardiovascular disease including heart attacks, and sudden cardiac death which is seen to be increasingly associated.[235] An underlying factor of sudden cardiac death may be Brugada syndrome (BrS) – BrS mutations that overlap with those linked with schizophrenia are the calcium channel mutations.[235] BrS may also be drug-induced from certain antipsychotics and antidepressants.[235] Primary polydipsia, or excessive fluid intake, is relatively common in people with chronic schizophrenia.[250][251] This may lead to hyponatremia which can be life-threatening. Antipsychotics can lead to a dry mouth, but there are several other factors that may contribute to the disorder. It is suggested to lead to a reduction in life expectancy by 13 per cent.[251] A study has suggested that real barriers to improving the mortality rate in schizophrenia are poverty, overlooking the symptoms of other illnesses, stress, stigma, and medication side effects, and that these need to be changed.[252] Schizophrenia is a major cause of disability. In 2016 it was classed as the 12th most disabling condition.[253] Approximately 75% of people with schizophrenia have ongoing disability with relapses[254] and 16.7 million people globally are deemed to have moderate or severe disability from the condition.[255] Some people do recover completely and others function well in society.[256] Most people with schizophrenia live independently with community support.[22] About 85% are unemployed.[5] In people with a first episode of psychosis in scizophrenia a good long-term outcome occurs in 31%, an intermediate outcome in 42% and a poor outcome in 31%.[257] Males are affected more often than females, and have a worse outcome.[258] Outcomes for schizophrenia appear better in the developing than the developed world.[259] These conclusions have been questioned.[260] Social problems, such as long-term unemployment, poverty, homelessness, exploitation, stigmatization and victimization are common consequences, and lead to social exclusion.[20][21] There is a higher than average suicide rate associated with schizophrenia estimated at around 5% to 6%, most often occurring in the period following onset or first hospital admission.[23][11] Several times more (20 to 40%) attempt suicide at least once.[7][261] There are a variety of risk factors, including male gender, depression, a high IQ,[261] heavy smoking,[262] and substance abuse.[109] Repeated relapse is linked to an increased risk of suicidal behavior.[171] The use of clozapine can reduce the risk of suicide and aggression.[202] A strong association between schizophrenia and tobacco smoking has been shown in worldwide studies.[263][264] Smoking is especially high in those diagnosed with schizophrenia, with estimates ranging from 80 to 90% being regular smokers, as compared to 20% of the general population.[264] Those who smoke tend to smoke heavily, and additionally smoke cigarettes with high nicotine content.[33] Some propose that this is in an effort to improve symptoms.[265] Among people with schizophrenia use of cannabis is also common.[109] ## Epidemiology Main article: Epidemiology of schizophrenia Deaths per million persons due to schizophrenia in 2012. 0–0 1–1 2–2 3–3 4–6 7–20 In 2017, the Global Burden of Disease Study estimated there were 1.1 million new cases, and in 2019 WHO reported a total of 20 million cases globally.[15][2] Schizophrenia affects around 0.3–0.7% of people at some point in their life.[14] It occurs 1.4 times more frequently in males than females and typically appears earlier in men[79] – the peak ages of onset are 25 years for males and 27 years for females.[266] Onset in childhood, before the age of 13 can sometimes occur.[7][65] A later onset can occur between the ages of 40 and 60, known as late onset, and also after 60 known as very late onset.[56] Worldwide, schizophrenia is the most common psychotic disorder.[68] The frequency of schizophrenia varies across the world,[7][267] within countries,[268] and at the local and neighborhood level.[269] This variation has been estimated to be fivefold.[5] It causes approximately one percent of worldwide disability adjusted life years[79] and resulted in 17,000 deaths in 2015.[12] In 2000, the World Health Organization found the percentage of people affected and the number of new cases that develop each year is roughly similar around the world, with age-standardized prevalence per 100,000 ranging from 343 in Africa to 544 in Japan and Oceania for men, and from 378 in Africa to 527 in Southeastern Europe for women.[270] About 1.1% of adults have schizophrenia in the United States.[271] However, in areas of conflict this figure can rise to between 4.0 and 6.5%.[272] ## History Main article: History of schizophrenia Further information: Dementia praecox The term "schizophrenia" was coined by Eugen Bleuler. Accounts of a schizophrenia-like syndrome are rare in records before the 19th century. The earliest cases detailed were reported in 1797, and 1809.[273] Dementia praecox, meaning premature dementia was used by German psychiatrist Heinrich Schüle in 1886, and then in 1891 by Arnold Pick in a case report of hebephrenia. In 1893 Emil Kraepelin used the term in making a distinction, known as the Kraepelinian dichotomy, between the two psychoses – dementia praecox, and manic depression (now called bipolar disorder).[10] Kraepelin believed that dementia praecox was probably caused by a systemic disease that affected many organs and nerves, affecting the brain after puberty in a final decisive cascade.[274] It was thought to be an early form of dementia, a degenerative disease.[10] When it became evident that the disorder was not degenerative it was renamed schizophrenia by Eugen Bleuler in 1908.[275] The word schizophrenia translates roughly as "splitting of the mind" and is Modern Latin from the Greek roots schizein (σχίζειν, "to split") and phrēn, (φρεν, "mind")[276] Its use was intended to describe the separation of function between personality, thinking, memory, and perception.[275] The term schizophrenia used to be associated with split personality by the general population but that usage went into decline when split personality became known as a separate disorder, first as multiple identity disorder , and later as dissociative identity disorder.[277] In 2002 in Japan the name was changed to integration disorder, and in 2012 in South Korea, the name was changed to attunement disorder to reduce the stigma, both with good results.[22][278][279] A molecule of chlorpromazine, the first antipsychotic developed in the 1950s. In the early 20th century, the psychiatrist Kurt Schneider listed the psychotic symptoms of schizophrenia into two groups of hallucinations, and delusions. The hallucinations were listed as specific to auditory, and the delusional included thought disorders. These were seen as the symptoms of first-rank importance and were termed first-rank symptoms. Whilst these were also sometimes seen to be relevant to the psychosis in manic-depression, they were highly suggestive of schizophrenia and typically referred to as first-rank symptoms of schizophrenia. The most common first-rank symptom was found to belong to thought disorders.[280][281] In 2013 the first-rank symptoms were excluded from the DSM-5 criteria.[155] First-rank symptoms are seen to be of limited use in detecting schizophrenia but may be of help in differential diagnosis.[282] The earliest attempts to treat schizophrenia were psychosurgical, involving either the removal of brain tissue from different regions or the severing of pathways.[283] These were notably frontal lobotomies and cingulotomies which were carried out from the 1930s.[283][284] In the 1930s a number of shock therapies were introduced which induced seizures (convulsions) or comas.[285] Insulin shock therapy involved the injecting of large doses of insulin in order to induce comas, which in turn produced hypoglycemia and convulsions.[285][284] The use of electricity to induce seizures was developed, and in use as electroconvulsive therapy (ECT) by 1938.[286] Stereotactic surgeries were developed in the 1940s.[286] Treatment was revolutionized in the mid-1950s with the development and introduction of the first typical antipsychotic, chlorpromazine.[287] In the 1970s the first atypical antipsychotic clozapine, was introduced followed by the introduction of others.[288] In the early 1970s in the US, the diagnostic model used for schizophrenia was broad and clinically-based using DSM II. It had been noted that schizophrenia was diagnosed far more in the US than in Europe which had been using the ICD-9 criteria. The US model was criticised for failing to demarcate clearly those people with a mental illness, and those without. In 1980 DSM III was published and showed a shift in focus from the clinically-based biopsychosocial model to a reason-based medical model.[289] DSM IV showed an increased focus to an evidence-based medical model.[290] Subtypes of schizophrenia classified as paranoid, disorganized, catatonic, undifferentiated, and residual type were difficult to distinguish between and are no longer recognized as separate conditions by DSM-5 (2013)[291] or ICD-11.[292][293][294] ## Society and culture See also: Social construction of schizophrenia, List of people with schizophrenia, and Religion and schizophrenia John Nash, an American mathematician and joint recipient of the 1994 Nobel Memorial Prize in Economic Sciences, who had schizophrenia. His life was the subject of the 1998 book, A Beautiful Mind by Sylvia Nasar. In 2002, the term for schizophrenia in Japan was changed from seishin-bunretsu-byō (精神分裂病, lit. "mind-split disease") to tōgō-shitchō-shō (統合失調症, lit. "integration-dysregulation syndrome") to reduce stigma.[295] The new name also interpreted as "integration disorder" was inspired by the biopsychosocial model; it increased the percentage of people who were informed of the diagnosis from 37 to 70% over three years.[278] A similar change was made in South Korea in 2012 to attunement disorder.[279] A professor of psychiatry, Jim van Os, has proposed changing the English term to psychosis spectrum syndrome.[296] In 2013 with the reviewed DSM-5, the DSM-5 committee was in favor of giving a new name to schizophrenia but they referred this to WHO.[297] In the United States, the cost of schizophrenia – including direct costs (outpatient, inpatient, drugs, and long-term care) and non-health care costs (law enforcement, reduced workplace productivity, and unemployment) – was estimated to be $62.7 billion in 2002.[298] In the UK the cost in 2016 was put at £11.8 billion per year with a third of that figure directly attributable to the cost of hospital and social care, and treatment.[5] The book A Beautiful Mind chronicled the life of John Forbes Nash who had been diagnosed with schizophrenia but who went on to win the Nobel Memorial Prize in Economic Sciences. This was later made into the film with the same name. An earlier documentary was made with the title A Brilliant Madness. In 1964 a lengthy case study of three males diagnosed with schizophrenia who each had the delusional belief that they were Jesus Christ was published as a book. This has the title of The Three Christs of Ypsilanti, and a film with the title Three Christs was released in 2020. Such religious delusions are a fairly common feature in psychoses including schizophrenia.[299][300] Media coverage relating to violent acts by people with schizophrenia reinforces public perception of an association between schizophrenia and violence.[301] Such sensationalist reporting stigmatizes schizophrenia more than any other mental illness.[302] In the UK guidelines are given for the reporting of different conditions. Its campaigns have shown a reduction in negative reporting.[302][303] ## Research directions See also: Animal models of schizophrenia Research into schizophrenia has made use of a number of animal models in particular rats, that have shown to be useful in evaluating the different aspects of its development and pathology. [304] Effects of early intervention is an active area of research, importantly focusing on the early detection of at-risk individuals and the development of risk calculators.[169][305] Methods for large-scale population screening are also included.[306] Various agents have been explored for possible effectiveness in treating negative symptoms, for which antipsychotics have been of little benefit.[307] There have been trials on medications with anti-inflammatory activity, based on the premise that inflammation might play a role in the pathology of schizophrenia.[308] Various brain stimulation techniques are being studied to treat the positive symptoms of schizophrenia, in particular auditory verbal hallucinations (AVHs).[309][310] A 2015 Cochrane review found unclear evidence of benefit.[311] Most studies focus on transcranial direct-current stimulation (tDCM), and repetitive transcranial magnetic stimulation (rTMS).[310] Techniques based on focused ultrasound for deep brain stimulation could provide insight for the treatment of AVHs.[310] Another active area of research is the study of a variety of potential biomarkers that would be of invaluable help not only in the diagnosis but also in the treatment and prognosis of schizophrenia. Possible biomarkers include markers of inflammation, neuroimaging, BDNF, genetics, and speech analysis. Some inflammatory markers such as C-reactive protein are useful in detecting levels of inflammation implicated in some psychiatric disorders but they are not disorder-specific. However, other inflammatory cytokines are found to be elevated in first episode psychosis and acute relapse that are normalized after treatment with antipsychotics, and these may be considered as state markers.[312] Deficits in sleep spindles in schizophrenia may serve as a marker of an impaired thalamocortical circuit, and a mechanism for memory impairment.[159] MicroRNAs are highly influential in early neuronal development, and their disruption is implicated in several CNS disorders; circulating microRNAs (cimiRNAs) are found in body fluids such as blood and cerebrospinal fluid, and changes in their levels are seen to relate to changes in microRNA levels in specific regions of brain tissue. These studies suggest that cimiRNAs have the potential to be early and accurate biomarkers in a number of disorders including schizophrenia.[313][314] The use of choline as a supplement during pregnancy may have effect in the prevention of the later development of schizophrenia, and is an area of research.[315] In 2020 over 3,000 clinical trials into drugs, symptom assessment tools, and treatments related to schizophrenia were listed with some recruiting, and some newly completed.[316] ## References 1. ^ Jones D (2003) [1917]. Roach P, Hartmann J, Setter J (eds.). English Pronouncing Dictionary. Cambridge: Cambridge University Press. ISBN 978-3-12-539683-8. 2. ^ a b c d e "Schizophrenia Fact sheet". www.who.int. 4 October 2019. Retrieved 22 January 2020. 3. ^ a b c d e f g "NIMH » Schizophrenia". www.nimh.nih.gov. May 2020. Retrieved 27 December 2020. 4. ^ a b c "Medicinal treatment of psychosis/schizophrenia". 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PMID 26120259. 316. ^ "Search of: schizophrenia - List Results - ClinicalTrials.gov". www.clinicaltrials.gov. ## External links Schizophreniaat Wikipedia's sister projects * Definitions from Wiktionary * Media from Wikimedia Commons * News from Wikinews * Quotations from Wikiquote * Data from Wikidata Wikipedia's health care articles can be viewed offline with the Medical Wikipedia app. Listen to this article (17.3 megabytes) This audio file was created from a revision of this article dated 14 October 2014 (2014-10-14), and does not reflect subsequent edits. (Audio help · More spoken articles) * Schizophrenia at Curlie Classification D * ICD-10: F20 * ICD-9-CM: 295 * OMIM: 181500 * MeSH: D012559 * DiseasesDB: 11890 External resources * MedlinePlus: 000928 * eMedicine: med/2072 emerg/520 * Patient UK: Schizophrenia * Scholia: Q41112 * 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 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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 Disability Main topics * Disability * Disability studies * Medical model * Social model * Society for Disability Studies Approaches * Freak show * IEP * Inclusion * Learning disability * Mainstreaming * Physical therapy * driver rehabilitation * Special needs * school * education Rights, law, support Rights * Ableism/disablism * Disability rights * Pejorative terms Law * AODA * ADA * Convention on the Rights of Persons with Disabilities * Declaration on the Rights of Disabled Persons * International Classification of Functioning, Disability and Health Services * Services for mental disorders * Services for the disabled Support * DLA * ODSP * Rail * SSDI * SSI * Students * CNIB Activist groups * CCD * DPI * MINDS * Reach Canada * Visitability Structural and assistive * Activities of daily living * Assistive technology * Independent living * Mobility aid * Orthotics and braces * Personal Care Assistant * Physical accessibility * Prosthetics * Universal design * Web accessibility Social issues * Augmentative and alternative communication * Emotional or behavioral disability * Invisible disability * Disability and religion * Disability and poverty * Disability and sexuality Arts, media, culture, sport * Disability culture * Disability art * Disability in the arts * Disability in the media * Disabled sports * Deaflympics * Paralympics * Special Olympics * Category * Lists * Psychiatry portal * Psychology portal Authority control * GND: 4052527-2 * LCCN: sh85118162 * NDL: 00570393 * NSK: 000227242 [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Schizophrenia	c0036341	3,758	wikipedia	https://en.wikipedia.org/wiki/Schizophrenia	2021-01-18T18:41:36	{"mesh": ["D012559"], "umls": ["C0036341"], "icd-9": ["295295"], "icd-10": ["F20"], "wikidata": ["Q41112"]}
Simple cryoglobulinemia occurs when the body makes an abnormal immune system protein called a cryoglobulin. At temperatures less than 98.6 degrees Fahrenheit (normal body temperature), cryoglobulins become solid or gel-like and can block blood vessels. This causes a variety of health problems. Many people with cryoglobulins will not experience any symptoms. If symptoms occur, they may include skin ulcers, purple skin spots (purpura), numbness in the fingers and toes (Raynaud's phenomenon), joint pain, and kidney problems. The underlying cause is unknown. Simple cryoglobulinemia is typically associated with immune system cancers, such as multiple myeloma or non-Hodgkin lymphoma. It is diagnosed based on the results of a clinical exam and the presence of cryoglobulins in the blood. Treatment varies based on the severity of symptoms and any underlying conditions. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Simple cryoglobulinemia	c0010403	3,759	gard	https://rarediseases.info.nih.gov/diseases/6217/simple-cryoglobulinemia	2021-01-18T17:57:42	{"mesh": ["D003449"], "umls": ["C0010403"], "orphanet": ["91139"], "synonyms": ["Cryoglobulinemia type 1"]}
Nezelof syndrome Other namesThymic dysplasia with normal immunoglobulins[1]:85 Autosomal recessive is the manner in which this condition is inherited SpecialtyImmunology SymptomsHepatosplenomegaly[2] CausesCurrently unknown[3] Diagnostic methodBlood test[3][4] TreatmentAntimicrobial therapy, IV immunoglobulin[5] Nezelof syndrome is an autosomal recessive[6] congenital immunodeficiency condition due to underdevelopment of the thymus. The defect is a type of purine nucleoside phosphorylase deficiency with inactive phosphorylase, this results in an accumulation of deoxy-GTP which inhibits ribonucleotide reductase. Ribonucleotide reductase catalyzes the formation of deoxyribonucleotides from ribonucleotides, thus, DNA replication is inhibited.[medical citation needed] ## Contents * 1 Symptoms and signs * 2 Cause * 3 Mechanism * 4 Diagnosis * 4.1 Differential diagnosis * 5 Treatment * 6 See also * 7 References * 8 Further reading * 9 External links ## Symptoms and signs[edit] This condition causes severe infections. it is characterized by elevated immunoglobulins that function poorly.[7][8] Other symptoms are:[2] * Bronchiectasis * Hepatosplenomegaly * Pyoderma * Emphysema * Diarrhea ## Cause[edit] Genetically speaking, Nezelof syndrome is autosomal recessive. the condition is thought to be a variation of severe combined immunodeficiency(SCID)[8] However, the precise cause of Nezelof syndrome remains uncertain[3] ## Mechanism[edit] In the mechanism of this condition, one first finds that the normal function of the thymus has it being important in T-cell development and release into the body's blood circulation[9] Hassal's corpuscles[10] absence in thymus(atrophy) has an effect on T-cells.[3] ## Diagnosis[edit] Human Thymus The diagnosis of Nezelof syndrome will indicate a deficiency of T-cells,[11] additionally in ascertaining the condition the following is done:[3][4] * Blood test(B-cell will be normal) * X-ray of thymus(atrophy present) ### Differential diagnosis[edit] The differential diagnosis for this condition consists of acquired immune deficiency syndrome and severe combined immunodeficiency syndrome[3][8] ## Treatment[edit] Bone marrow for transplant In terms of treatment for individuals with Nezelof syndrome, which was first characterized in 1964,[12] includes the following(how effective bone marrow transplant is uncertain[4]) : * Antimicrobial therapy[5] * IV immunoglobulin[5] * Bone marrow transplantation[5] * Thymus transplantation[5] * Thymus factors[5] ## See also[edit] * List of radiographic findings associated with cutaneous conditions ## References[edit] 1. ^ James, William D.; Berger, Timothy G.; et al. (2006). Andrews' Diseases of the Skin: clinical Dermatology. Saunders Elsevier. ISBN 978-0-7216-2921-6. 2. ^ a b "Immune defect due to absence of thymus \| Genetic and Rare Diseases Information Center (GARD) – an NCATS Program". rarediseases.info.nih.gov. Retrieved 2017-06-02. 3. ^ a b c d e f Lavini, Corrado; Moran, Cesar A.; Uliano, Morandi; Schoenhuber, Rudolf (2009). Thymus Gland Pathology: Clinical, Diagnostic and Therapeutic Features. Springer Science & Business Media. p. 35 & 22\. ISBN 9788847008281. Retrieved 7 June 2017. 4. ^ a b c Mosby (2016-04-28). Mosby's Dictionary of Medicine, Nursing & Health Professions - eBook. Elsevier Health Sciences. p. 1226. ISBN 9780323414197. 5. ^ a b c d e f Smeltzer, Suzanne C. O'Connell; Bare, Brenda G.; Hinkle, Janice L.; Cheever, Kerry H. (2010). Brunner & Suddarth's Textbook of Medical-surgical Nursing (12 ed.). Lippincott Williams & Wilkins. p. 1563. ISBN 9780781785891. Retrieved 6 June 2017. 6. ^ Online Mendelian Inheritance in Man (OMIM): 242700 7. ^ Cantani, Arnaldo (2008-01-23). Pediatric Allergy, Asthma and Immunology. Springer Science & Business Media. p. 1298. ISBN 9783540333951. 8. ^ a b c Disorders, National Organization for Rare (2003). NORD Guide to Rare Disorders. Lippincott Williams & Wilkins. p. 408. ISBN 9780781730631. 9. ^ Pearse, Gail (2006-08-01). "Normal Structure, Function and Histology of the Thymus". Toxicologic Pathology. 34 (5): 504–514. doi:10.1080/01926230600865549. ISSN 0192-6233. PMID 17067941. 10. ^ Kierszenbaum, Abraham L.; Tres, Laura (2015-05-04). Histology and Cell Biology: An Introduction to Pathology E-Book. Elsevier Health Sciences. p. 339. ISBN 9780323313353. 11. ^ Wallach, Jacques Burton (2007). Interpretation of Diagnostic Tests. Lippincott Williams & Wilkins. p. 504. ISBN 9780781730556. "Nezelof syndrome diagnosis." 12. ^ Nezelof, C.; Jammet, M. L.; Lortholary, P.; Labrune, B.; Lamy, M. (October 1964). "Hereditary Thymic Hypoplasia: ITS Place and Responsibility in a Case of Lymphocytic, Normoplasmocytic and Normoglobulinemic Aplasia in an Infant". Archives Françaises de Pédiatrie. 21: 897–920. ISSN 0003-9764. PMID 14195287. ## Further reading[edit] * Lavini, Corrado; Moran, Cesar A.; Uliano, Morandi; Schoenhuber, Rudolf (2009-05-08). Thymus Gland Pathology: Clinical, Diagnostic and Therapeutic Features. Springer Science & Business Media. ISBN 9788847008281. ## External links[edit] * PubMed Classification D * ICD-10: D81.4 * ICD-9-CM: 279.13 * OMIM: 242700 * MeSH: C536288 * DiseasesDB: 29571 External resources * Orphanet: 83471 Scholia has a topic profile for Nezelof syndrome. * v * t * e Lymphoid and complement disorders causing immunodeficiency Primary Antibody/humoral (B) Hypogammaglobulinemia * X-linked agammaglobulinemia * Transient hypogammaglobulinemia of infancy Dysgammaglobulinemia * IgA deficiency * IgG deficiency * IgM deficiency * Hyper IgM syndrome (1 * 2 * 3 * 4 * 5) * Wiskott–Aldrich syndrome * Hyper-IgE syndrome Other * Common variable immunodeficiency * ICF syndrome T cell deficiency (T) * thymic hypoplasia: hypoparathyroid (Di George's syndrome) * euparathyroid (Nezelof syndrome * Ataxia–telangiectasia) peripheral: Purine nucleoside phosphorylase deficiency * Hyper IgM syndrome (1) Severe combined (B+T) * x-linked: X-SCID autosomal: Adenosine deaminase deficiency * Omenn syndrome * ZAP70 deficiency * Bare lymphocyte syndrome Acquired * HIV/AIDS Leukopenia: Lymphocytopenia * Idiopathic CD4+ lymphocytopenia Complement deficiency * C1-inhibitor (Angioedema/Hereditary angioedema) * Complement 2 deficiency/Complement 4 deficiency * MBL deficiency * Properdin deficiency * Complement 3 deficiency * Terminal complement pathway deficiency * Paroxysmal nocturnal hemoglobinuria * Complement receptor deficiency * v * t * e Medicine Specialties and subspecialties Surgery * Cardiac surgery * Cardiothoracic surgery * Colorectal surgery * Eye surgery * General surgery * Neurosurgery * Oral and maxillofacial surgery * Orthopedic surgery * Hand surgery * Otolaryngology * ENT * Pediatric surgery * Plastic surgery * Reproductive surgery * Surgical oncology * Transplant surgery * Trauma surgery * Urology * Andrology * Vascular surgery Internal medicine * Allergy / Immunology * Angiology * Cardiology * Endocrinology * Gastroenterology * Hepatology * Geriatrics * Hematology * Hospital medicine * Infectious disease * Nephrology * Oncology * Pulmonology * Rheumatology Obstetrics and gynaecology * Gynaecology * Gynecologic oncology * Maternal–fetal medicine * Obstetrics * Reproductive endocrinology and infertility * Urogynecology Diagnostic * Radiology * Interventional radiology * Nuclear medicine * Pathology * Anatomical * Clinical pathology * Clinical chemistry * Cytopathology * Medical microbiology * Transfusion medicine Other * Addiction medicine * Adolescent medicine * Anesthesiology * Dermatology * Disaster medicine * Diving medicine * Emergency medicine * Mass gathering medicine * Family medicine * General practice * Hospital medicine * Intensive care medicine * Medical genetics * Narcology * Neurology * Clinical neurophysiology * Occupational medicine * Ophthalmology * Oral medicine * Pain management * Palliative care * Pediatrics * Neonatology * Physical medicine and rehabilitation * PM&R * Preventive medicine * Psychiatry * Addiction psychiatry * Radiation oncology * Reproductive medicine * Sexual medicine * Sleep medicine * Sports medicine * Transplantation medicine * Tropical medicine * Travel medicine * Venereology Medical education * Medical school * Bachelor of Medicine, Bachelor of Surgery * Bachelor of Medical Sciences * Master of Medicine * Master of Surgery * Doctor of Medicine * Doctor of Osteopathic Medicine * MD–PhD Related topics * Alternative medicine * Allied health * Dentistry * Podiatry * Pharmacy * Physiotherapy * Molecular oncology * Nanomedicine * Personalized medicine * Public health * Rural health * Therapy * Traditional medicine * Veterinary medicine * Physician * Chief physician * History of medicine * Book * Category * Commons * Wikiproject * Portal * Outline [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Nezelof syndrome	c0152094	3,760	wikipedia	https://en.wikipedia.org/wiki/Nezelof_syndrome	2021-01-18T18:36:33	{"mesh": ["C536288"], "umls": ["C0152094", "C0685894"], "orphanet": ["83471"], "wikidata": ["Q3508681"]}
A fibroinflammatory disorder of the thyroid gland, occuring more frequently in females, characterized a large, hard thyroid mass, and presenting with pressure symptoms (breathing difficul¼ties and dysphagia) or voice hoarseness and aphonia (impingement of recurrent laryngeal nerve). It can often be associated with extracervical fibroinflammatory disorders such as retroperitoneal fibrosis, primary scleroisng cholangitis and autoimmune diseases such as Hashimoto struma, Addison disease, and Biermer disease. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	IgG4-related thyroid disease	c0154162	3,761	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=64744	2021-01-23T18:09:34	{"umls": ["C0154162"], "icd-10": ["E06.5"], "synonyms": ["Riedel disease", "Riedel thyroiditis"]}
A number sign (#) is used with this entry because of evidence that hypochondroplasia can be caused by mutation in the gene for fibroblast growth factor receptor-3 (FGFR3; 134934), located on 4p, which is consistently mutated in achondroplasia (ACH; 100800). Not all patients with presumed hypochondroplasia have demonstrable mutations in the FGFR3 gene, suggesting genetic heterogeneity. Description Hypochondroplasia is a autosomal dominant disorder characterized by short-limbed dwarfism, lumbar lordosis, short and broad bones, and caudad narrowing of the interpediculate distance of the lumbar spine. It shows some resemblance to achondroplasia, but is much milder and can be distinguished on clinical and radiographic grounds (Walker et al., 1971). Nomenclature Lamy and Maroteaux (1961) suggested the term hypochondroplasia. Clinical Features Beals (1969) reported 5 kindreds segregating hypochondroplasia. He found that the limbs in this disorder are usually short, without rhizomelia, mesomelia, or acromelia, but may have mild metaphyseal flaring. Brachydactyly and mild limitation in elbow extension can be evident. Spinal manifestations may include anteroposterior shortening of lumbar pedicles. The spinal canal may be narrowed or unchanged caudally. Lumbar lordosis may be evident. Specht and Daentl (1975) reported 6 new cases of hypochondroplasia with moderate rhizomelic shortness of stature and normal craniofacial appearance and hand configuration. Glasgow et al. (1978) described 3 patients with hypochondroplasia. Clues to the diagnosis were abnormality of body proportions with short limbs and lumbar lordosis, but without the extreme short stature or facial features of achondroplasia, and short, stubby hands and feet. Radiologic features included long bones that were shorter than the normal range for age, as well as broader and slightly bowed with mildly flared metaphyses. Vertebral changes consisted of mild tapering of the spinal canal and low articulation of the sacrum on the iliac bones. The pelvis was small with normal flaring of the iliac wings. Two of the patients had a large head with delayed closure of the fontanels. In a review of 39 cases of hypochondroplasia, Hall and Spranger (1979) found that macrocephaly was noted in approximately half of cases. Evidence that hypochondroplasia and achondroplasia are allelic disorders came from the observation of the presumed genetic compound in an offspring of an achondroplastic father and a hypochondroplastic mother (McKusick et al., 1973). Sommer et al. (1987) gave a follow-up on this child at age 14 years. The patient had severe neurologic impairment and increased deep tendon reflexes and clonus. She had very little speech and could not walk. Her mental scale was placed at about 1 year when tested at age 10. Inheritance Beals (1969) described 5 kindreds with clear evidence of autosomal dominant inheritance. Both father-to-daughter and mother-to-daughter transmission have been reported. Diagnosis The diagnosis of hypochondroplasia on clinical and radiologic grounds is often uncertain. Appan et al. (1990) studied growth and growth hormone therapy in 84 patients with hypochondroplasia, which they suggested could be diagnosed on the basis of 'short stature with near-normal craniofacies and the invariable radiographic finding of a failure of increase in the interpedicular distance in the lumbar spine from L1 to L5 in the absence of any other gross measurable radiological abnormality.' If one defines hypochondroplasia as an achondroplasia-like disorder with mutation in the FGFR3 gene, i.e., a mild allelic form of achondroplasia, it is likely that use of the above criteria would lead to many false-positive diagnoses when checked against a complete mutation search of the FGFR3 gene. Molecular Genetics Bellus et al. (1995) demonstrated that a recurrent mutation in the tyrosine kinase domain of FGFR3 was present in 8 of 14 unrelated patients with hypochondroplasia. The mutation caused a C-to-A transversion at nucleotide 1620, resulting in an asn540-to-lys substitution in the proximal tyrosine kinase domain (134934.0010). Thus, hypochondroplasia and achondroplasia are indeed allelic as are also thanatophoric dysplasia type I (e.g., 134934.0004) and type II (e.g., 134934.0005). Since 6 of the 14 patients with hypochondroplasia did not carry the asn540-to-lys mutation, hypochondroplasia may be caused by mutation in some other gene or perhaps by other undetected mutations in FGFR3. Review of the medical records of the hypochondroplasia patients revealed no obvious phenotypic differences between individuals who did or did not have the asn540-to-lys mutation of FGFR3. Rousseau et al. (1996) examined 13 patients with sporadic hypochondroplasia and 16 probands from familial cases. In all sporadic cases and in 8 of 16 familial cases, the N540K mutation of the FGFR3 gene, located on 4p16.3, was found. In 6 familial cases, linkage to 4p16 was excluded; 2 families were uninformative. Clinical comparison showed that patients unlinked to 4p16 generally had a milder phenotype. Prinster et al. (1998) selected 18 patients with a phenotype compatible with hypochondroplasia based on the most common radiologic criteria. The presence of the N540K mutation was verified by restriction enzyme digestions in 9 of the 18 patients. Although similar in phenotype to patients without the mutation, these 9 had the additional feature of relative macrocephaly. Furthermore, the association of the unchanged or narrow interpedicular distance with the fibula longer than the tibia was more common in patients with the N540K mutation. Ramaswami et al. (1998) screened 65 children with hypochondroplasia diagnosed by clinical and radiologic criteria for 2 previously described mutations, 1620C-A (134934.0010) and 1620C-G (134934.0012), in FGFR3; 28 (43%) of the 65 patients were heterozygous for the 1620C-A transversion, resulting in a lys540-to-asn substitution in the tyrosine kinase domain of FGFR3. Children with the common 1620C-A mutation met all the criteria for the diagnosis of HCH with a severe phenotype resembling that of achondroplasia, and disproportionate stature in early childhood. Patients without the 1620C-A mutation were proportionately short and presented at an older age with the same radiologic characteristics as in HCH and the same failure of the puberty growth spurt. The latter group did not come to attention until a mean age of 10.45 years, whereas the group with the 1620C-A mutation had a mean age at diagnosis of 5.8 years. Huggins et al. (1999) reported an 8-month-old girl with achondroplasia/hypochondroplasia whose father had the G380R achondroplasia mutation (134934.0001) in the FGFR3 gene and whose mother had the N450K hypochondroplasia mutation (134934.0010). Chitayat et al. (1999) simultaneously reported an infant boy with achondroplasia/hypochondroplasia whose mother had the G380R mutation and whose father had the N450K mutation. Molecular analysis confirmed the compound heterozygosity of both children, who displayed an intermediate phenotype that was more severe than either condition in the heterozygous state but less severe than homozygous ACH. Mortier et al. (2000) reported a father and daughter with clinical and radiographic features of hypochondroplasia who were heterozygous for an A-to-G transition resulting in the replacement of an asparagine residue at position 540 by a serine residue (134934.0023). They noted the important role of the asn540 site in the tyrosine kinase I domain in the pathogenesis of hypochondroplasia and recommended that, in patients with hypochondroplasia who do not have the common N540K mutation, sequence analysis of the tyrosine kinase I domain of FGFR3 should be performed to exclude other changes in that region. Heuertz et al. (2006) screened 18 exons of the FGFR3 gene in 25 patients with hypochondroplasia and 1 with achondroplasia in whom the common mutations G380R and N540K had been excluded. The authors identified 7 novel missense mutations, 1 in the patient with achondroplasia (S279C; 134934.0030) and 6 in patients with hypochondroplasia (see, e.g., Y278C, 134934.0031 and S84L, 134934.0032); no mutations were detected in the remaining 19 patients who were diagnosed clinically with hypochondroplasia. Heuertz et al. (2006) noted that 4 of the 6 extracellular mutations created additional cysteine residues and were associated with severe phenotypes. Leroy et al. (2007) identified a missense mutation in the FGFR3 gene (134934.0022) in a girl with a mild form of hypochondroplasia who was also diagnosed with acanthosis nigricans at 8 years of age. By using microarray-based next-generation sequencing to study a Chinese woman with hypochondroplasia, Wang et al. (2013) identified a G342C mutation (134934.0036) in the extracellular IgIII loop of FGFR3. The mutation was also found in the woman's fetus when ultrasound scan detected a short femur and dwarfism. Wang et al. (2013) concluded that the sequencing procedure enabled a correct diagnosis, distinguishing HCH from other skeletal dysplasias. Heterogeneity Mullis et al. (1991) reported findings suggesting that some cases of hypochondroplasia are caused by a defect in insulin-like growth factor I (IGF1; 147440). They studied 20 children with short stature attributed to hypochondroplasia by radiologic and clinical criteria who were undergoing treatment with recombinant human growth hormone. The frequency of a particular heterozygous pattern of restriction fragments was significantly higher in children with hypochondroplasia than in the control groups. The hypochondroplastic children whose response to r-hGH treatment was characterized by a proportionate increase in both spinal and subischial leg length were all heterozygous for 2 coinherited IGF1 RFLP alleles. Those children whose response was characterized by accentuation of the body disproportion by r-hGH treatment were all homozygous for these alleles. Studies of 5 families containing heterozygous children demonstrated strong linkage (lod score = 3.311 at 0 recombination) of the IGF1 locus to this subgroup of hypochondroplasia. An allele at each of 2 RFLP loci were in strong linkage disequilibrium with this trait. Stoilov et al. (1995) found the G380R mutation in the FGFR3 gene (134934.0001) in 21 of 23 achondroplasia patients but in none of 8 hypochondroplasia patients studied. Furthermore, linkage studies in a 3-generation family with hypochondroplasia showed discordant segregation with markers in the 4p16.3 region where the achondroplasia locus is situated, suggesting that at least some cases of hypochondroplasia are caused by mutations in a gene other than FGFR3. Genetic heterogeneity of hypochondroplasia seemed to be evident in the patients reported by Flynn and Pauli (2003), who were thought to be double heterozygotes for mutations at the FGFR3 locus and another unidentified locus. The female probands were dichorionic, diamniotic twins born to a mother with achondroplasia and a father with hypochondroplasia. Mutation of the FGFR3 gene was not identified in the father by either molecular testing for the common hypochondroplasia mutation or by sequencing of the FGFR3 gene. INHERITANCE \- Autosomal dominant GROWTH Height \- Short-limb dwarfism identifiable during childhood \- Final height, 125 to 160 cm HEAD & NECK Head \- Macrocephaly \- Mild frontal bossing Face \- Normal/mild midface hypoplasia SKELETAL Spine \- Variable lumbar lordosis \- Progressive narrowing of interpediculate distance in the lumbar vertebrate Pelvis \- Short, squared ilia Limbs \- Shortened limbs \- Short tubular bones with mild metaphyseal flare \- Limited extension at elbows \- Genu varum \- Bowleg Hands \- Lack of trident hand helps distinguish it from achondroplasia \- Brachydactyly SKIN, NAILS, & HAIR Skin \- Acanthosis nigricans (rare) NEUROLOGIC Central Nervous System \- Occasional mental retardation MISCELLANEOUS \- Genetic heterogeneity, some patients not linked to FGFR3 MOLECULAR BASIS \- Caused by mutation in the fibroblast growth factor receptor-3 gene (FGFR3, 134934.0010 ) ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	HYPOCHONDROPLASIA	c0410529	3,762	omim	https://www.omim.org/entry/146000	2019-09-22T16:39:47	{"doid": ["0080041"], "mesh": ["C562937"], "omim": ["146000"], "icd-10": ["Q77.4"], "orphanet": ["429"], "genereviews": ["NBK1477"]}
Pfeiffer-Palm-Teller syndrome is a very rare dysmorphic syndrome described in two sibs and characterized by a short stature, unique facies, enamel hypoplasia, progressive joint stiffness, high-pitched voice, cup-shaped ears, and narrow palpebral fissures with epicanthal folds, and intellectual deficit. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Pfeiffer-Palm-Teller syndrome	c1849929	3,763	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=2871	2021-01-23T17:11:37	{"gard": ["4305"], "mesh": ["C537889"], "omim": ["261560"], "umls": ["C1849929"], "icd-10": ["Q87.1"]}
A number sign (#) is used with this entry because of evidence that autosomal recessive spinocerebellar ataxia-21 (SCAR21), also known as low gammaglutamyltransferase (GGT) cholestasis, acute liver failure, and neurodegeneration (CALFAN) syndrome, is caused by homozygous mutation in the SCYL1 gene (607982) on chromosome 11q13. Description Autosomal recessive spinocerebellar ataxia-21 is a neurologic disorder characterized by onset of cerebellar ataxia associated with cerebellar atrophy in early childhood. Affected individuals also have recurrent episodes of liver failure in the first decade, resulting in chronic liver fibrosis, as well as later onset of a peripheral neuropathy. Mild learning disabilities may also occur (summary by Schmidt et al., 2015). The phenotype is highly variable: all patients appear to have episodic and severe liver dysfunction in early childhood that tends to resolve with age. Affected individuals also show mild developmental or language delay and/or later onset of variable neurologic features, such as motor dysfunction (summary by Lenz et al., 2018). Clinical Features Schmidt et al. (2015) reported 2 young adult sibs, born of unrelated parents of European origin, with an early-onset ataxia syndrome. At about 9 months of age, both patients developed recurrent episodes of liver failure, which were mainly associated with fever. The episodes ended later in childhood, but both had chronic fibrotic liver disease and marked hepatosplenomegaly. Both sibs also had delayed early motor milestones and presented in early childhood with an ataxic gait, balance difficulties, and intention tremor, consistent with cerebellar dysfunction. Additional features included muscle atrophy of the upper and lower limbs, weakness of the lower legs associated with foot drop, distal sensory impairment, and hyporeflexia, indicating a hereditary sensorimotor neuropathy. Neurogenic stuttering was also noted. Brain imaging showed selective nonprogressive atrophy of the cerebellar vermis. Brain imaging also suggested subclinical optic atrophy, although visual acuity was preserved. One sib had normal cognition; the other had mildly impaired intellectual development. An unrelated 17-year-old girl of Cuban descent had a similar phenotype with early childhood onset of recurrent episodes of liver failure, progressive gait ataxia, and neurogenic stuttering. At age 10, she was barely able to run. In her teenage years, she developed a predominantly motor neuropathy with distal muscle weakness and atrophy and pes equinus. Nerve conduction studies showed a mixed sensorimotor peripheral neuropathy, and brain imaging showed atrophy of the cerebellar vermis. She also had mild spasticity and hyperreflexia, suggesting pyramidal tract involvement, as well as mild learning disability. Lenz et al. (2018) reported 7 children from 5 unrelated families with a syndromic form of liver failure with variable neurologic features. The patients, who were all under 12 years of age at the time of the report, were ascertained from a cohort of pediatric patients with unexplained cholestasis or acute liver failure. The patients presented in infancy with episodic acute liver dysfunction, almost always associated with a febrile illness. Three had prior neonatal jaundice. Acute features during infection included jaundice, cholestasis, elevated liver enzymes with lesser elevation of GGT, and hepatomegaly, sometimes with splenomegaly. The laboratory abnormalities tended to resolve within weeks, but all patients developed liver fibrosis. One patient had a liver transplant at 23 months of age. Liver biopsies showed microvesicular steatosis, bridging fibrosis, hepatocyte degeneration, ductal reactions, cholestasis, and disorganized Golgi apparatus. Six patients had mild microcephaly, 6 had mild language delay, 3 had borderline to mildly impaired intellectual impairment, and 1 had severely impaired intellectual development. Motor dysfunction was observed in 5 patients, with highly variable manifestations, including proximal muscle weakness, tremor, and abnormal gait, although none had frank ataxia. One patient had seizures. Five patients had variable skeletal abnormalities, including short stature, hip dysplasia, rib anomalies, scoliosis, and lordosis. Brain imaging was unremarkable in most patients, but 2 sibs had mild cerebral and cerebellar atrophy. The study highlighted the phenotypic variability associated with recessive SCYL1 mutations, prompting the authors to suggest the name 'CALFAN,' for low GGT cholestasis, acute liver failure, and neurodegeneration. Spagnoli et al. (2019) reported a 7-year-old girl, born of unrelated Italian parents, with SCAR21. Around 2 years of age, she presented with episodic tremor, initially induced by fever, and thereafter showed mild axial hypotonia, broad-based gait, dysmetria, and diffuse tremor. At age 5.5, she developed an ocular motility disorder with upward gaze palsy and oculomotor apraxia. She also had weakness with fatigability and a distal choreic movement disorder affecting the upper limbs. These neurologic symptoms worsened during febrile illness. She also had impaired intellectual development with language involvement. Brain imaging showed mild mild cerebellar atrophy. At age 7, she had hepatosplenomegaly and an axonal motor polyneuropathy; further details on liver involvement were not provided. The authors noted that the patient had recurrent respiratory infections with respiratory insufficiency since infancy. Inheritance The transmission pattern of SCAR21 with hepatopathy in the families reported by Schmidt et al. (2015) was consistent with autosomal recessive inheritance. Molecular Genetics In 3 patients from 2 unrelated families with SCAR21, Schmidt et al. (2015) identified compound heterozygous truncating mutations in the SCYL1 gene (607982.0001-607982.0004). The mutations, which were found by whole-exome sequencing, segregated with the disorder in the families. Patient fibroblasts showed absence of the SCYL1 protein and massively enlarged Golgi apparatus. In 7 patients from 5 unrelated families with a phenotype overlapping SCAR21, termed CALFAN, Lenz et al. (2018) identified homozygous mutations in the SCYL1 gene (see, e.g., 607982.0005-607982.0008). There were 3 nonsense and 2 missense mutations, consistent with a loss of function. The patients, who were all under 12 years of age at the time of the report, were ascertained from a cohort of pediatric patients with unexplained cholestasis or acute liver failure who underwent whole-exome sequencing; the mutations were filtered against public databases. Immunostaining of patient liver tissue showed depletion of SCYL1. Western blot analysis of available patients' fibroblasts showed decreased SCYL1, and functional studies showed impaired retrograde transport from the Golgi, suggesting a defect in intracellular trafficking. However, there was no evidence of ER stress. In a 7-year-old girl with SCA21, Spagnoli et al. (2019) identified a homozygous frameshift mutation in the SCYL1 gene (607982.0009). The mutation, which was found by exome sequencing, segregated with the disorder in the family and was not found in the gnomAD database. It was predicted to result in a loss of protein function. Studies of patient cells were not performed. Animal Model Schmidt et al. (2007) found that the autosomal recessive mouse neurodegenerative disorder 'muscle deficient' (mdf) is caused by a homozygous 1-bp insertion (c.1169_1170insT) in exon 8 of the Scyl1 gene, resulting in a loss of function. Mdf mice show progressive neuromuscular atrophy, hindlimb paralysis, and phenotypes consistent with cerebellar involvement, such as gait ataxia, abnormal hindlimb posture, and tremor. Neuropathologic examination of mdf mice showed cerebellar atrophy, Purkinje cell loss, and optic nerve atrophy. Pelletier et al. (2012) demonstrated that deletion of Scyl1 in mice caused an early-onset progressive motor neuron disease with features characteristic of amyotrophic lateral sclerosis (ALS; 105400). Mutant mice had growth retardation, waddling and abnormal gait, muscle wasting, and progressive motor dysfunction resulting in paralysis of the hind paws. Skeletal muscles of mutant mice showed neurogenic atrophy, fiber type switching, and disuse atrophy, and peripheral nerves showed axonal degeneration and segmental demyelination. There was also a reduction in the number of spinal ventral horn motor neurons, with swollen mitochondria in the remaining neurons and evidence of inflammation. However, there were no major cerebellar changes. Spinal cord ventral neurons from mutant mice showed redistribution of TDP43 (TARDBP; 605078) from the nucleus to cytoplasmic aggregates and the presence of ubiquilin-2 (UBQLN2; 300264) inclusions, as observed in ALS. Neuron-specific depletion, but not muscle-specific depletion, recapitulated the phenotypic changes observed in Slcy1-null mice, suggesting that Scyl1 acts in a neuron-autonomous manner to play a critical role in the survival of large motor neurons. INHERITANCE \- Autosomal recessive HEAD & NECK Eyes \- Cerebellar oculomotor disturbance \- Saccadic pursuit \- Subclinical optic atrophy (1 family) \- Preserved vision ABDOMEN Liver \- Liver failure, episodic, during first decade \- Hepatomegaly \- Hepatic fibrosis Spleen \- Splenomegaly SKELETAL Feet \- Pes equinovarus (1 patient) MUSCLE, SOFT TISSUES \- Muscle atrophy, upper and lower limbs \- Muscle weakness, distal, lower limbs, due to peripheral neuropathy NEUROLOGIC Central Nervous System \- Delayed motor development \- Cerebellar ataxia \- Ataxic gait \- Frequent falls \- Balance difficulties \- Tremor \- Neurogenic stutter \- Intellectual disability, mild (in some patients) \- Spasticity (1 patient) \- Hyperreflexia (1 patient) \- Cerebellar atrophy Peripheral Nervous System \- Sensorimotor neuropathy \- Distal sensory impairment \- Hyporeflexia MISCELLANEOUS \- Onset of episodic liver failure in first 2 years of life \- Liver failure episodes associated with fever \- Liver failure episodes cease in later childhood \- Onset of ataxia in early childhood \- Three patients from 2 unrelated families have been reported (last curated December 2015) MOLECULAR BASIS \- Caused by mutation in the SCY1-like 1 gene (SCYL1, 607982.0001 ) ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	SPINOCEREBELLAR ATAXIA, AUTOSOMAL RECESSIVE 21	c4225236	3,764	omim	https://www.omim.org/entry/616719	2019-09-22T15:48:07	{"doid": ["0111155"], "omim": ["616719"], "orphanet": ["466794"], "synonyms": ["SCAR21", "SPINOCEREBELLAR ATAXIA, AUTOSOMAL RECESSIVE 21, WITH HEPATOPATHY", "Alternative titles", "CHOLESTASIS, LOW GGT, ACUTE LIVER FAILURE, AND NEURODEGENERATION SYNDROME", "Autosomal recessive spinocerebellar ataxia type 21"]}
Jeune syndrome, also called asphyxiating thoracic dystrophy, is a short-rib dysplasia characterized by a narrow thorax, short limbs and radiological skeletal abnormalities including 'trident' aspect of the acetabula and metaphyseal changes. ## Epidemiology Annual incidence at birth is unknown but is estimated to be 1-5/500,000. ## Clinical description The syndrome is recognizable during the antenatal period or at birth. In rare cases, postaxial polydactyly may also be present. The narrow thorax may cause neonatal respiratory failure, and may be associated with persistent respiratory manifestations. Some cases are severe while others have a benign course. The growth rate is variable but may be almost normal. Hepatic and renal failure has been reported in rare cases (liver fibrosis or nephronophthisis) occurring at any age. Retinal pigmentary degeneration could also be observed. Intellectual development is normal. ## Etiology The molecular basis of the syndrome has been partially elucidated indicating involvement of the IFT80 (3q25.33), DYNC2H1 (11q22.3), WDR19 (4p14) and TTC21B (2q24.3) genes, each encoding an intraflagellar transport protein, which confirms that Jeune syndrome belongs to the ciliopathies group. Mutations in other genes may also be implicated in the disease and remain to be identified. ## Diagnostic methods The diagnosis is based on radiologic findings: ribs are short and the pelvis has an abnormal morphology, with a horizontal acetabular roof and a trident aspect formed by a median protrusion and two lateral spurs. Hands are normal or short with possible cone-shaped epiphyses in the phalanges. ## Differential diagnosis Differential diagnosis should include thoracolaryngopelvic dysplasia, Ellis-van Creveld syndrome, Sensenbrenner syndrome and paternal uniparental disomy of chromosome 14 (see these terms). ## Antenatal diagnosis Molecular diagnosis must be confirmed in the proband before proposing prenatal molecular testing. In other cases, only a careful antenatal ultrasound examination can detect the disease. ## Genetic counseling The syndrome is transmitted as an autosomal recessive trait. The recurrence risk is 25% for every pregnancy after the birth of an affected child. ## Management and treatment Treatment consists of management of respiratory infections, which may lead to severe complications. Renal and hepatic function should be monitored regularly, and retinal examination performed. ## Prognosis Prognosis is highly variable depending of the visceral associated diseases, and the risk of severe respiratory complications decreases after 2 years of age. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Jeune syndrome	c0265275	3,765	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=474	2021-01-23T18:34:11	{"gard": ["3049"], "mesh": ["C537571"], "omim": ["208500", "611263", "613091", "613819", "614376", "615630", "615633", "616300", "617088"], "umls": ["C0265275"], "icd-10": ["Q77.2"], "synonyms": ["Asphyxiating thoracic dystrophy of the newborn", "JATD", "Jeune asphyxiating thoracic dystrophy"]}
A number sign (#) is used with this entry because of evidence that autosomal recessive mental retardation-57 (MRT57) is caused by homozygous mutation in the MBOAT7 gene (606048) on chromosome 19q13. Clinical Features Johansen et al. (2016) reported 16 patients from 6 unrelated consanguineous families of Middle Eastern descent with moderate to severe intellectual disability. The patients had delayed psychomotor development with poor or absent speech. Thirteen started to walk between 2 and 7 years, whereas 3 never achieved walking. Ten patients developed seizures, including 6 with infantile-onset focal, multifocal, or myoclonic epilepsy, 2 with onset of seizures at 1.5 or 2 years of age, and 2 with febrile seizures. The seizures were generally well-controlled and even remitted later in childhood in most patients. Additional features included truncal hypotonia and appendicular hypertonia. Three patients had a small head circumference, and brain imaging in 2 patients showed cortical atrophy and mild polymicrogyria, but brain imaging was normal in at least 4 other patients. Seven patients had autism spectrum disorder. Inheritance The transmission pattern of MRT57 in the family reported by Johansen et al. (2016) was consistent with autosomal recessive inheritance. Molecular Genetics In 16 patients from 6 different consanguineous families of Middle Eastern descent with MRT57, Johansen et al. (2016) identified 5 different homozygous mutations in the MBOAT7 gene (606048.0001-606048.0005). The mutations resulted in truncated proteins, abnormal splicing, or intragenic deletions affecting critical domains. The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the families. Functional studies of the variants and studies of patient cells were not performed. Animal Model Lee et al. (2012) found that Mboat7-null mice were significantly smaller than controls and showed reduced postnatal survival. Histologic analysis of embryonic mutant mouse brains showed a smaller cerebral cortex and hippocampus, abnormal cortical lamination, delayed neuronal migration, gyral abnormalities, and increased number of apoptotic cells in the cortex. INHERITANCE \- Autosomal recessive HEAD & NECK Head \- Small head circumference (in some patients) MUSCLE, SOFT TISSUES \- Hypotonia NEUROLOGIC Central Nervous System \- Delayed psychomotor development \- Intellectual disability, moderate to severe \- Delayed walking \- Inability to walk \- Poor or absent speech \- Truncal hypotonia \- Appendicular hypertonia \- Hyperreflexia (in some patients) \- Seizures (in some patients) \- Focal seizures \- Generalized seizures \- Myoclonic seizures \- Febrile seizures \- Brain imaging shows cortical atrophy (2 patients) \- Polymicrogyria, mild (2 patients) Behavioral Psychiatric Manifestations \- Autism spectrum disorder (in some patients) MISCELLANEOUS \- Onset at birth \- Seizures are well-controlled \- Seizures may remit later in childhood MOLECULAR BASIS \- Caused by mutation in the membrane-bound O-acetyltransferase domain-containing protein 7 gene (MBOAT7, 606048.0001 ) ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	MENTAL RETARDATION, AUTOSOMAL RECESSIVE 57	c4310673	3,766	omim	https://www.omim.org/entry/617188	2019-09-22T15:46:30	{"omim": ["617188"], "orphanet": ["88616"], "synonyms": ["AR-NSID", "NS-ARID"]}
Wikipedia list article For the disease involved in the COVID-19 pandemic, see Coronavirus disease 2019. Coronavirus Types * Alphacoronavirus * Betacoronavirus * Gammacoronavirus * Deltacoronavirus Diseases * Common cold * SARS * MERS * COVID-19 Vaccines * COVID-19 vaccine Outbreaks, epidemics, and pandemics * SARS outbreak (2002-2004) * 2012 MERS outbreak * 2015 MERS outbreak in South Korea * 2018 MERS outbreak * COVID-19 pandemic (2019-2021) See also * Coronavirus recession * History of coronavirus * Impact of the COVID-19 pandemic * v * t * e Coronavirus diseases are caused by viruses in the coronavirus subfamily. Coronaviruses are a group of related RNA viruses that cause diseases in mammals and birds. In humans and birds, the group of viruses cause respiratory tract infections that can range from mild to lethal. Mild illnesses in humans include some cases of the common cold (which is also caused by other viruses, predominantly rhinoviruses),[1] while more lethal varieties can cause SARS, MERS, and COVID-19.[2] As of 2020, 45 species are registered as coronaviruses,[3] whilst 11 diseases have been identified, as listed below. Coronaviruses are known for their shape resembling a stellar corona, such as that of the Sun visible during a total solar eclipse; corona is derived from the Latin word corōna, meaning 'garland, wreath, crown'.[4] It was coined by June Almeida and David Tyrrell, the founding fathers of coronavirus studies,[5] and was first used in a Nature article in 1968,[6] with approval by the International Committee for the Nomenclature of Viruses three years later.[7] The first coronavirus disease was discovered in the late 1920s, however the most recent common ancestor of coronaviruses is estimated to have existed as recently as 8000 BCE.[8] Human coronaviruses was discovered in the 1960s, through a variety of experiments in the United States and United Kingdom.[9] A common origin in human coronaviruses are bats.[10] ## List Further information: Coronavirus § Infection in humans Structural view of a coronavirus Listed diseases primarily affect humans unless otherwise noted. Coronavirus diseases Disease Cause First identified Details Avian infectious bronchitis avian coronavirus (IBV) 1920s[11] (isolated in 1938)[12] Originated from North America.[11] Transmissible gastroenteritis Transmissible gastroenteritis virus (TGEV) 1965 (recognized in 1946)[13] Infects pigs,[13] cats,[14] and dogs.[15] Common cold, pneumonia, bronchiolitis, etc. Human coronavirus 229E (HCoV-229E) 1930s (isolated in 1965)[16] Likely originated from bats.[17] Murine encephalitis JHM (named after John Howard Mueller), a murine coronavirus[18] 1949[19] Acute infectious diarrhea Porcine epidemic diarrhea virus (PEDV) 1971[20] Caused outbreaks in 1972[21] and 1978,[22] 2010, 2013, 2014, and 2015.[23] Infects pigs and sows. Severe acute respiratory syndrome (SARS) Severe acute respiratory syndrome coronavirus (SARS-CoV), a strain of SARSr-CoV 2002 Caused the 2002–2004 SARS outbreak. Likely originated from horseshoe bats.[24] Common cold Human coronavirus HKU1 (HCoV-HKU1) 2004 Originated from Hong Kong.[25] Respiratory infection Human coronavirus NL63 (HCoV-NL63) 2004 Originated from Amsterdam, Netherlands.[26] Likely originated from tricolored bats.[27] Middle East respiratory syndrome (MERS) Middle East respiratory syndrome–related coronavirus (MERS-CoV) 2012 Has caused outbreaks in 2012, 2015, and 2018. Likely originated in the Middle East, particularly Jeddah.[28] Porcine diarrhea HKU15 2014 Discovered in Hong Kong.[29] Coronavirus disease 2019 (COVID-19) severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a strain of SARSr-CoV 2019 Cause of ongoing COVID-19 pandemic. Originated in Wuhan, China;[30] possibly from horseshoe bats, pangolins, or both.[31] ## See also * Biology portal * Viruses portal * Medicine portal * Coronaviridae * Alphacoronavirus * Betacoronavirus * Gammacoronavirus * Deltacoronavirus ## References 1. ^ Palmenberg AC, Spiro D, Kuzmickas R, Wang S, Djikeng A, Rathe JA, Fraser-Liggett CM, Liggett SB (2009). "Sequencing and Analyses of All Known Human Rhinovirus Genomes Reveals Structure and Evolution". Science. American Association for the Advancement of Science. 324 (5923): 55–59. Bibcode:2009Sci...324...55P. doi:10.1126/science.1165557. PMC 3923423. PMID 19213880. 2. ^ "Common Human Coronaviruses". Centers for Disease Control and Prevention. 27 May 2020. Archived from the original on 11 April 2020. Retrieved 29 October 2020. 3. ^ "Taxonomy". International Committee on Taxonomy of Viruses. International Union of Microbiological Societies. Archived from the original on 20 March 2020. Retrieved 21 December 2020. 4. ^ "Definition of corona". Dictionary.com. Section Behind the Word. Retrieved 29 October 2020. 5. ^ Tyrrell DA, Fielder M (2002). Cold Wars: The Fight Against the Common Cold. Oxford University Press. p. 96. ISBN 978-0-19-263285-2. Archived from the original on 21 December 2020. Retrieved 21 December 2020. "We looked more closely at the appearance of the new viruses and noticed that they had a kind of halo surrounding them. Recourse to a dictionary produced the Latin equivalent, corona, and so the name coronavirus was born." 6. ^ Almeida JD, Berry DM, Cunningham CH, Hamre D, Hofstad MS, Mallucci L, McIntosh K, Tyrrell DA (November 1968). "Virology: Coronaviruses". Nature. 220 (5168): 650. Bibcode:1968Natur.220..650.. doi:10.1038/220650b0. "[T]here is also a characteristic "fringe" of projections 200 A long, which are rounded or petal shaped ... This appearance, recalling the solar corona, is shared by mouse hepatitis virus and several viruses recently recovered from man, namely strain B814, 229E and several others." 7. ^ Lalchhandama K (2020). "The chronicles of coronaviruses: the bronchitis, the hepatitis and the common cold". Science Vision. 20 (1): 43–53. doi:10.33493/scivis.20.01.04. 8. ^ Wertheim JO, Chu DK, Peiris JS, Kosakovsky Pond SL, Poon LL (June 2013). "A case for the ancient origin of coronaviruses". Journal of Virology. 87 (12): 7039–45. doi:10.1128/JVI.03273-12. PMC 3676139. PMID 23596293. 9. ^ Monto AS (1984). "Coronaviruses". In Evans AS (ed.). Viral Infections of Humans. Viral Infections of Humans: Epidemiology and Control. Springer US. pp. 151–165. doi:10.1007/978-1-4684-4727-9_7. ISBN 978-1-4684-4727-9. 10. ^ Forni D, Cagliani R, Clerici M, Sironi M (January 2017). "Molecular Evolution of Human Coronavirus Genomes". Trends in Microbiology. 25 (1): 35–48. doi:10.1016/j.tim.2016.09.001. PMC 7111218. PMID 27743750. "Specifically, all HCoVs are thought to have a bat origin, with the exception of lineage A beta-CoVs, which may have reservoirs in rodents [2]." 11. ^ a b Estola, T. (1970). "Coronaviruses, a New Group of Animal RNA Viruses". Avian Diseases. 14 (2): 330–336. doi:10.2307/1588476. ISSN 0005-2086. 12. ^ Bushnell, L. D.; Brandly, C. A. (1 January 1933). "Laryngotracheitis in Chicks". Poultry Science. 12 (1): 55–60. doi:10.3382/ps.0120055. ISSN 0032-5791. 13. ^ a b Doyle, L. P.; Hutchings, L. M. (1946). "A transmissible gastroenteritis in pigs". Journal of the American Veterinary Medical Association. 108: 257–259. ISSN 0003-1488. PMID 21020443. Archived from the original on 21 December 2020. Retrieved 8 November 2020. 14. ^ Wolfe, L. G.; Griesemer, R. A. (1966). "Feline infectious peritonitis". Pathologia Veterinaria. 3 (3): 255–270. doi:10.1177/030098586600300309. ISSN 0031-2975. PMID 5958991. 15. ^ Binn, L. N.; Lazar, E. C.; Keenan, K. P.; Huxsoll, D. L.; Marchwicki, R. H.; Strano, A. J. (1974). "Recovery and characterization of a coronavirus from military dogs with diarrhea". Proceedings, Annual Meeting of the United States Animal Health Association (78): 359–366. ISSN 0082-8750. PMID 4377955. Archived from the original on 21 December 2020. Retrieved 8 November 2020. 16. ^ "COVID-19/SARS-CoV-2 Pandemic". FPM. 6 April 2020. Retrieved 29 October 2020. 17. ^ Tao, Ying; Shi, Mang; Chommanard, Christina; Queen, Krista; Zhang, Jing; Markotter, Wanda; Kuzmin, Ivan V.; Holmes, Edward C.; Tong, Suxiang (1 March 2017). "Surveillance of Bat Coronaviruses in Kenya Identifies Relatives of Human Coronaviruses NL63 and 229E and Their Recombination History". Journal of Virology. 91 (5). doi:10.1128/JVI.01953-16. ISSN 1098-5514. PMC 5309958. PMID 28077633. 18. ^ Pappenheimer, Alwin M. (1 May 1958). "Pathology of Infection with the JHM Virus". JNCI: Journal of the National Cancer Institute. 20 (5): 879–891. doi:10.1093/jnci/20.5.879. ISSN 0027-8874. Archived from the original on 21 December 2020. Retrieved 8 November 2020. 19. ^ Cheever, F. Sargent; Daniels, Joan B.; Pappenheimer, Alwin M.; Bailey, Orville T. (31 August 1949). "A MURINE VIRUS (JHM) CAUSING DISSEMINATED ENCEPHALOMYELITIS WITH EXTENSIVE DESTRUCTION OF MYELIN". The Journal of Experimental Medicine. 90 (3): 181–194. ISSN 0022-1007. PMC 2135905. PMID 18137294. 20. ^ Oldham, J (1972). "Letter to the editor". Pig Farming. 72 (October Suppl): 72–73. 21. ^ Pensaert, Maurice B.; Martelli, Paolo (2 December 2016). "Porcine epidemic diarrhea: A retrospect from Europe and matters of debate". Virus Research. 226: 1–6. doi:10.1016/j.virusres.2016.05.030. ISSN 0168-1702. PMC 7132433. PMID 27317168. Archived from the original on 21 December 2020. Retrieved 8 November 2020. 22. ^ Wood, E. N. (19 March 1977). "An apparently new syndrome of porcine epidemic diarrhoea". Veterinary Record. 100 (12): 243–244. doi:10.1136/vr.100.12.243. ISSN 0042-4900. PMID 888300. Archived from the original on 21 December 2020. Retrieved 8 November 2020. 23. ^ Antas, Marta; Woźniakowski, Grzegorz (24 October 2019). "Current Status of Porcine Epidemic Diarrhoea (PED) in European Pigs". Journal of Veterinary Research. 63 (4): 465–470. doi:10.2478/jvetres-2019-0064. ISSN 2450-7393. PMC 6950429. PMID 31934654. Archived from the original on 21 December 2020. Retrieved 8 November 2020. 24. ^ editor, Robin McKie Science (10 December 2017). "Scientists trace 2002 Sars virus to colony of cave-dwelling bats in China". The Observer. ISSN 0029-7712. Archived from the original on 10 December 2017. Retrieved 29 October 2020.CS1 maint: extra text: authors list (link) 25. ^ Woo, Patrick C. Y.; Lau, Susanna K. P.; Chu, Chung-ming; Chan, Kwok-hung; Tsoi, Hoi-wah; Huang, Yi; Wong, Beatrice H. L.; Poon, Rosana W. S.; Cai, James J.; Luk, Wei-kwang; Poon, Leo L. M. (2005). "Characterization and Complete Genome Sequence of a Novel Coronavirus, Coronavirus HKU1, from Patients with Pneumonia". Journal of Virology. 79 (2): 884–895. doi:10.1128/JVI.79.2.884-895.2005. ISSN 0022-538X. PMID 15613317. Archived from the original on 21 July 2020. Retrieved 8 November 2020. 26. ^ Abdul-Rasool, Sahar; Fielding, Burtram C (25 May 2010). "Understanding Human Coronavirus HCoV-NL63". The Open Virology Journal. 4: 76–84. doi:10.2174/1874357901004010076. ISSN 1874-3579. PMC 2918871. PMID 20700397. Archived from the original on 21 December 2020. Retrieved 8 November 2020. 27. ^ Huynh, Jeremy; Li, Shimena; Yount, Boyd; Smith, Alexander; Sturges, Leslie; Olsen, John C.; Nagel, Juliet; Johnson, Joshua B.; Agnihothram, Sudhakar; Gates, J. Edward; Frieman, Matthew B. (2012). "Evidence supporting a zoonotic origin of human coronavirus strain NL63". Journal of Virology. 86 (23): 12816–12825. doi:10.1128/JVI.00906-12. ISSN 1098-5514. PMC 3497669. 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Retrieved 29 October 2020. 31. ^ Lau, Susanna K.P.; Luk, Hayes K.H.; Wong, Antonio C.P.; Li, Kenneth S.M.; Zhu, Longchao; He, Zirong; Fung, Joshua; Chan, Tony T.Y.; Fung, Kitty S.C.; Woo, Patrick C.Y. (2020). "Possible Bat Origin of Severe Acute Respiratory Syndrome Coronavirus 2". Emerging Infectious Diseases. 26 (7): 1542–1547. doi:10.3201/eid2607.200092. ISSN 1080-6040. PMC 7323513. PMID 32315281. 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Bipolar affective disorder is a genetically heterogeneous complex trait. One susceptibility locus for bipolar disorder, MAFD1, has been mapped to chromosome 18p. Other mapped loci include MAFD2 (309200) on chromosome Xq28, MAFD3 (609633) on chromosome 21q22, MAFD4 (611247) on chromosome 16p12, MAFD7 (612371) on chromosome 22q12, MAFD8 (612357) on chromosome 10q21, and MAFD9 (612372) on chromosome 12p13. Epistatic interaction has been postulated for loci designated MAFD5 (611535) on chromosome 2q22-q24 and MAFD6 (611536) on chromosome 6q23-q24. Clinical Features Depressive disorders represent a prevalent (1 to 2%) and major illness characterized by episodes of dysphoria that are associated with somatic symptoms. It may have a manic-depressive (bipolar) or purely depressive (unipolar) course. The most characteristic features of bipolar affective disorder (BPAD) are episodes of mania (bipolar I, BP I) or hypomania (bipolar II, BP II) interspersed with periods of depression (Goodwin and Jamison, 1990). If untreated, manic-depressive illness is associated with a suicide rate of approximately 20%. Biochemical Features Wright et al. (1984) studied binding of radioiodine-labeled hydroxybenzylpindolol to beta-adrenoceptors in lymphoblastoid cell lines from members of 5 families affected by manic-depressive disorder. Binding was reduced to less than half of control values in cell lines from 4 of 6 patients with manic-depressive disorder and only 1 of 18 unaffected relatives or controls. All the cell lines with reduced binding came from 3 families; members of 2 remaining families showed normal binding. The findings were interpreted as indicating genetic heterogeneity in manic-depressive disorder and a role played by a beta-adrenoceptor defect in genetic susceptibility to the disorder in some cases. O'Reilly et al. (1994) presented a 2-generation family in which 8 members met DSM-III-R criteria for major depression. Four of the affected individuals failed to respond to standard therapeutic doses of tricyclic and new generation antidepressants but subsequently responded to the monoamine oxidase inhibitor tranylcypromine. O'Reilly et al. (1994) suggested that families demonstrating preferential response to a particular psychotropic drug may be a more homogeneous group in which to perform linkage analysis. Grof et al. (1994) also suggested that a helpful criterion for selecting more homogeneous groups of patients for linkage analysis would be the presence of a response to specific treatment. To that end, they studied 121 probands with primary affective disorders and 903 first-degree relatives and spouses. Seventy-one probands responded to lithium treatment and 50 were nonresponders. Study of the first-degree relatives of lithium responders revealed that 3.8% had bipolar disorder, whereas none of the relatives of the nonresponders were so affected. Schizophrenia was more common in the families of nonresponders (2.4% vs 0.3%). In studies of the effect of lithium on Xenopus morphogenesis, Klein and Melton (1996) determined that lithium acts through inhibition of glycogen synthase kinase 3-beta (GSK3B; 605004) and not through inhibition of inositol monophosphatase (602064). They suggested that their observations may provide insights into the pathogenesis and treatment of bipolar disorder. Using positron emission tomographic (PET) images of cerebral blood flow and rate of glucose metabolism to measure brain activity, Drevets et al. (1997) localized an area of abnormally decreased activity in the prefrontal cortex ventral to the genu of the corpus callosum in both familial bipolar depression patients and familial unipolar depression patients. The decrement in activity was at least partly explained by a corresponding reduction in cortical volume, as demonstrated by magnetic resonance imaging (MRI). This region had previously been implicated in the mediation of emotional and autonomic responses to socially significant or provocative stimuli, and in the modulation of the neurotransmitter systems targeted by antidepressant drugs. Williams et al. (2002) demonstrated that lithium, carbamazepine, and valproic acid, all drugs used to treat bipolar affective disorder, inhibit the collapse of sensory neuron growth cones and increase growth cone area. These effects do not depend on glycogen synthase kinase-3 (see 606784) or histone deacetylase (see 601241) inhibition. Inositol, however, reverses the effects of the drugs on growth cones, thus implicating inositol depletion in their action. Moreover, the development of Dictyostelium is sensitive to lithium and to valproic acid, but resistance to both is conferred by deletion of the gene that codes for prolyl oligopeptidase (600400), which also regulates inositol metabolism. Inhibitors of prolyl oligopeptidase reversed the effects of all 3 drugs on sensory neuron growth cone area and collapse. Williams et al. (2002) concluded that their results suggest a molecular basis for both bipolar affective disorder and its treatment. Inheritance The role of genetic factors in bipolar disorder is indicated by concordance in monozygotic and dizygotic twins, respectively, of 57% and 14%, and the correlation between adopted persons and their biologic relatives (Cadoret, 1978). Brent and Mann (2005, 2006) noted that in studies of adopted children and twins, familial concordance for suicidal behavior is explained by both genetic and environmental factors. Suicidal behavior that begins before 25 years of age is highly familial, and having a greater number of affected family members is associated with an earlier age. Craddock and Sklar (2013) noted that strong evidence exists for a polygenic contribution to risk of bipolar disorder (i.e., many risk alleles of small effect). They stated that most cases of bipolar disorder involve the interplay of several genes or more complex genetic mechanisms, together with the effects of nongenetic (environmental) risk factors and stochastic factors. ### Anticipation In 34 families unilineal for bipolar affective disorder, McInnis et al. (1993) compared age of onset and disease severity between 2 generations. They found that the second generation experienced onset 8.9 to 13.5 years earlier and illness 1.8 to 3.4 times more severe than did the first generation. They concluded that genetic anticipation was demonstrated and they suggested that genes with expanding trinucleotide repeats might be involved in the genetic etiology of the disorder. Gelernter (1995) reviewed the genetics of BPAD and other behavioral disorders and discussed specifically the difficulties associated with possible anticipation in bipolar affective disorder as discussed by McInnis et al. (1993). McInnis (1996) traced the history of anticipation. He suggested that it has its roots in the social chaos of the French Revolution, as well as in the medical observations of the French 'alienist' (an early term for psychiatrist) (Morel, 1857) and in the theories of atavism advocated by the Italian psychiatrist of the late 19th century (Lombroso, 1911). As to the validity of anticipation in bipolar disorder and schizophrenia, McInnis (1996) quoted Hodge and Wickramaratne (1995) as concluding that 'in psychiatric disorders, bias of ascertainment is pervasive and that there is no simple way to circumvent it.' ### Parent-of-Origin Effect McMahon et al. (1995) tested for parent-of-origin effect on the transmission of bipolar affective disorder, which might reflect either imprinting or mitochondrial inheritance. They examined the frequency and risk of BPAD among relatives in a sample of 31 families ascertained through treated probands with BPAD and selected for the presence of affected phenotypes in only 1 parental lineage. They observed a higher than expected frequency of affected mothers (p less than 0.04), a 2.3- to 2.8-fold increased risk of illness for maternal relatives (P less than 0.006), and a 1.3- to 2.5-fold increased risk of illness for the offspring of affected mothers (p less than 0.017). In 7 large pedigrees, fathers repeatedly failed to transmit the affected phenotype to daughters or sons. Taken together, these findings were interpreted as indicating a maternal effect in the transmission in BPAD susceptibility and suggested that molecular studies of mtDNA and imprinted DNA are warranted in patients with BPAD. A number of family studies had reported increased morbid risk to the mothers, relative to the fathers, of probands with bipolar affective disorder. An excess of mother-offspring pairs had also been reported. These observations suggested that bipolar affective disorder may be caused by mitochondrial DNA mutations. Kirk et al. (1999) sequenced the mitochondrial genome in 25 bipolar patients with family histories of psychiatric disorder that suggested matrilineal inheritance. No polymorphism identified more than once in this sequencing showed any significant association with bipolar affective disorder in association studies using 94 cases and 94 controls. To determine whether their sample of patients showed evidence of selection against the maternal lineage, Kirk et al. (1999) determined genetic distances between all possible pairwise comparisons within the bipolar and control groups, based on multilocus mitochondrial polymorphism haplotypes. These analyses revealed fewer closely related haplotypes in the bipolar group than in the matched control group, suggesting selection against maternal lineages in this disease. Such selection was considered compatible with recurrent mitochondrial mutations, which are associated with slightly decreased fitness. Mapping ### Linkage to Chromosome 18 (MAFD1) In the course of a systematic genomic survey, Berrettini et al. (1994) examined 22 manic-depressive (bipolar) families for linkage to 11 chromosome 18 pericentromeric marker loci, under dominant and recessive models. Overall lod score analysis for the pedigrees was not significant under either model, but several families yielded scores consistent with linkage under dominant or recessive models. Affected sib pair analysis of these data yielded evidence for linkage (p less than 0.001) with D18S21. Affected pedigree member analysis also suggested linkage. The results were interpreted as suggesting a susceptibility gene in the pericentromeric region of chromosome 18, with a complex mode of inheritance. Pursuant to the report by Berrettini et al. (1994) of a BPAD susceptibility locus on chromosome 18 and the report of a parent-of-origin effect by McMahon et al. (1995), Stine et al. (1995) undertook a linkage study in 28 nuclear families selected for apparent unilineal transmission of the BPAD phenotype. They used 31 polymorphic markers spanning chromosome 18. The study was distinguished by relatively small, densely affected families with apparent unilineal transmission and direct clinical evaluation of family members by psychiatrists. Evidence for linkage was tested with affected-sib-pair and lod score methods under 2 definitions of the affected phenotype. The affected-sib-pair analyses indicated excess allele sharing for markers on 18p within the region reported previously. The greatest sharing was at D18S37. In addition, excess sharing of the paternally, but not maternally, transmitted alleles was observed at 3 markers on 18q. The evidence for linkage to loci on both 18p and 18q was strongest in the 11 paternal pedigrees, i.e., those in which the father or one of the father's sibs was affected. The results were interpreted by Stine et al. (1995) as providing further support for linkage of BPAD to chromosome 18. Prompted by the report by Berrettini et al. (1994) of a bipolar susceptibility locus in the region of the centromere of chromosome 18, Pauls et al. (1995) studied markers from this region in Old Order Amish families. Although linkage findings were replicated in 1 previously studied Amish pedigree containing 4 affected individuals, linkage to this region was excluded in the larger sample. Pauls et al. (1995) concluded that if a susceptibility locus for bipolar disorder is located in this region of chromosome 18, it is of minor significance among the Amish. In a genetically isolated population of the central valley of Costa Rica (CVCR), Freimer et al. (1996) undertook a linkage study of severe bipolar disorder in 2 pedigrees. The 2.6 million residents of the CVCR are descended mainly from a small group of Spanish and Amerindian founders who lived in the 16th and 17th centuries; by the beginning of the 18th century, the CVCR had a single population that then grew rapidly, without subsequent immigration, for almost 200 years (Escamilla et al., 1996). Freimer et al. (1996) found strongest evidence for a specific locus on chromosome 18q22-q23 where 7 of 16 markers yielded peak lod scores over 1.0. This localization was supported by marker haplotypes shared by 23 of 26 affected individuals studied. As a continuation of that study, McInnes et al. (1996) performed a complete genome screen for genes predisposing to severe bipolar disorder. They considered as affected only individuals with bipolar mood disorder and screened the genome for linkage with 473 microsatellite markers. They used a model for linkage analysis that incorporated a high phenocopy rate and a conservative estimate of penetrance. They suggested on the basis of their results that 18q, 18p, and 11p deserve further study; in these regions suggestive lod scores were observed for 2 or more contiguous markers. Isolated lod scores that exceeded the threshold in 1 or both families studied also occurred on 10 other chromosomes. Additional linkage studies on 2 extended BP I pedigrees from the CVCR implicated a candidate region on 18p11.3 (Escamilla et al., 1999). Knowles et al. (1998) could find no evidence for significant linkage between bipolar affective disorder and chromosome 18 pericentromeric markers in a large series of multiplex extended pedigrees. This was one of the largest samples reported to date: 1,013 genotyped individuals in 53 unilineal multiplex pedigrees. Ten highly polymorphic markers and a range of parametric and nonparametric analyses were used. Not only was there no evidence for linkage, but there was also no evidence for significant parent-of-origin effect. McInnes et al. (2001) further investigated the 18p11.3 region by creating a physical map and developing 4 new microsatellite and 26 single-nucleotide polymorphism (SNP) markers for typing in the Costa Rican pedigree and population samples. The results of fine-scale association analyses in the population sample, as well as evaluation of haplotypes in 1 of the large pedigrees, suggested a candidate region containing 6 genes but also highlighted the complexities of linkage disequilibrium mapping of common disorders. To clarify the issue of genetic linkage between bipolar affective disorder and 18q, McMahon et al. (2001) analyzed the relationship between clinical features and allele sharing. Relatives ascertained through a proband who had BP I disorder were interviewed by a psychiatrist, assigned an all-sources diagnosis, and genotyped with 32 markers on 18q21-q23. The authors found that paternal allele sharing on 18q21 was significantly associated with a diagnostic subtype, and was greatest in pairs where both sibs had BP II. Paternal allele sharing across 18q21-q23 was also significantly greater in families with at least 1 sib pair in which both had BP II. In these families, multipoint affected sib-pair linkage analysis produced a peak paternal lod score of 4.67 versus 1.53 in all families. Thus, affected sib pairs with BP II discriminated between families who showed evidence of linkage to 18q and families who did not. Families with a BP II sib pair produced an increased lod score and improved linkage resolution. These findings strengthened the evidence of genetic linkage between BPAD and 18q, and provided preliminary support for BP II as a genetically valid subtype of BPAD. Bipolar type II disorder is characterized by hypomania that is so brief or so slight as to cause no significant problems in functioning. BP I, on the other hand, is the diagnosis attached to anyone with a significantly problematic manic state (extreme symptoms of grandiosity, poor social judgment or functional impairment due to distractibility at work, etc.). ### Linkage to Chromosome 2q22-q24 See MAFD5 (611534) for a discussion of linkage of susceptibility to bipolar disorder to chromosome 2q22-q24. ### Linkage to Chromosome 3p Etain et al. (2006) conducted a genomewide search with 384 microsatellite markers using nonparametric linkage (NPL) analysis in 87 sib pairs ascertained as part of the European Collaborative Study of Early Onset Bipolar Affective Disorder. Early-onset patients (age at onset of 21 years or below) were studied because age of onset may help to define homogeneous bipolar affective disorder subtypes. The 3p14 region showed the most significant linkage in the first phase of analysis with an NPL score of 3.51. Additional linkage analysis with increased marker density revealed an NPL score of 3.83 at chromosome 3p14. ### Linkage to Chromosome 4 Blackwood et al. (1996) carried out a linkage study in Scotland in 12 bipolar families. In a single family, a genome search using 193 markers indicated linkage on 4p where D4S394 generated a 2-point lod score of 4.1 under a dominant model of inheritance. With 3-point analyses using neighboring markers, they obtained a maximum lod score of 4.8. (Eleven other bipolar families were typed using D4S394 and in all families combined there was evidence of linkage with heterogeneity with a maximum 2-point lod score of 4.1 (theta = 0.0; alpha = 0.35).) Ginns et al. (1998) reported a different approach to linkage study of BPAD in the Old Order Amish. To determine whether there could be protective alleles that prevent or reduce the risk of developing BPAD, similar to what is observed in other genetic disorders, they used 'mental health wellness' (absence of any psychiatric disorder) as the phenotype in their genomewide linkage scan of several large multigeneration Old Order Amish pedigrees exhibiting a high incidence of BPAD. They found strong evidence for linkage of mental health wellness to a locus on 4p, designated MHW1 (603663), at D4S2949; maximum nonparametric linkage score = 4.05, p = 5.22 x 10(-4). They also found suggestive evidence for a locus on 4q, designated MHW2 (603664), at D4S397; maximum nonparametric linkage score = 3.29, p = 2.57 x 10(-3). Findings were consistent with the hypothesis that certain alleles can prevent or modify the clinical manifestations of BPAD and perhaps other related affective disorders. Ekholm et al. (2003) performed a genomewide scan for susceptibility loci in bipolar disorder in 41 Finnish families with at least 2 affected sibs. They identified a distinct locus on 16p12 (see MAFD4, 611247) and observed 3 additional loci with a 2-point lod score greater than 2.0, at markers on 4q32, 12q23, and Xq25. After fine mapping these chromosomal regions and genotyping additional family members, 4q32 provided significant evidence of linkage for the 3-point analyses (maximum lod = 3.6 between D4S3049 and D4S1629). ### Linkage to Chromosome 5 Garner et al. (2001) used an algorithm that permitted nonparametric linkage analysis of large, complex pedigrees with multiple inbreeding loops to reanalyze the genome-screen data from the Costa Rican kindred segregating severe bipolar disorder (Freimer et al., 1996; McInnes et al., 1996). The results were consistent with previous linkage findings on chromosome 18 and also suggested a novel locus on chromosome 5 that was not identified using traditional linkage analysis. Hong et al. (2004) performed linkage analysis using 74 individuals from the Costa Rican pedigree and found evidence for a 3.2-Mb region between markers D5S1480 and D5S2090 on chromosome 5q31-q33. The authors suggested that conflicting haplotype data reflected incomplete penetrance, phenocopies, or locus/allelic heterogeneity. The authors noted that Freimer et al. (1996) described a conserved haplotype on 18q22-q23 in the same kindred. Hong et al. (2004) found that 12 of 20 affected individuals shared both haplotypes, suggesting that both loci are important in conferring disease risk. Coon et al. (1993) carried out an extensive linkage analysis in 8 moderate-sized families with manic-depression. When autosomal dominant inheritance was assumed, 273 DNA markers gave lod scores less than -2.0 at theta = 0.0, 174 DNA loci produced lod scores less than -2.0 at theta = 0.05, and 4 DNA marker loci yielded lod scores greater than 1. Of the markers giving lod scores greater than 1, only D5S62 continued to show evidence for linkage when the affected-pedigree-member method was used. D5S62 maps to distal 5q, a region containing neurotransmitter receptor genes for dopamine (e.g., 126449), gamma-aminobutyric acid (e.g., 137160, 137164), glutamate (e.g., 138248), and norepinephrine (e.g., 109690, 104219, 104220). ### Linkage to Chromosome 6p Smeraldi et al. (1978) first suggested linkage between HLA on chromosome 6p21.3 and affective disorders on the basis of the finding that pairs of affected sibs shared HLA haplotypes more often than would be predicted by chance. Weitkamp et al. (1981) likewise found evidence of a susceptibility gene or genes linked to HLA. Neither group subdivided the depressive disorders into bipolar and unipolar subtypes. Stronger evidence of linkage might be found in 1 subtype, or it may turn out that both are linked to HLA, suggesting that they are different forms of the same illness. One of Weitkamp's study families was that reported earlier by Pardue (1975)--in fact, Pardue's own kindred (Wingerson, 1982). Weitkamp et al. (1981) found that HLA haplotype identity in pairs of affected sibs and in pairs of unaffected older sibs deviated markedly from expected (p less than 0.005). Perhaps surprisingly, no increase in HLA haplotype identity was found in sibships with more than 2 affected members. When parents had a difference in load of genes for susceptibility (as estimated by the occurrence of affective illness in themselves and their relatives), HLA haplotypes were randomly transmitted to unaffected or affected children from the affected, 'high-load' parent, but not randomly from the unaffected, 'low-load' parent (p less than 0.001), suggesting a recessive effect, i.e., greater chance of illness in homozygotes. Stancer et al. (1988) published data apparently confirming the relationship between HLA and manic depression. When combined with their previous data, the total number of families analyzed was 117. As in the previous study, the increase in HLA haplotype sharing over random expectation was greater if 'high-load' sibships, i.e., sibships with 3 or more affected sibs, were omitted from the analysis. Weitkamp (1981, 1983) suggested that the extent of HLA haplotype sharing among affected sib pairs should decrease as the number of parental HLA haplotypes containing susceptibility genes increases from 1 to 4. Thus, he reasoned that there may actually be less HLA haplotype sharing among sibs when the parents have maximum genetic susceptibility ('high load') compared with families in which the genetic susceptibility that could be contributed by either parent is limited to the genes in 1 of the 2 HLA haplotypes in that parent. If an increased number or variety of affective disorder susceptibility genes in a person results in a greater probability of illness, then nuclear families with a higher proportion of affected family members are likely to have a greater number or variety of affective disorder susceptibility genes than families with a low proportion of affected members. Weitkamp and Stancer (1989) suggested that the HLA effect may be greater in unipolar than in bipolar disorders and more apparent in families with few affected members than in 'high-load' families. Schulze et al. (2004) extended the study of Dick et al. (2003) to test for robustness of the linkage to differing analysis methods, genotyping error, and gender-specific maps; for parent-of-origin effects; and for interaction with markers within the schizophrenia linkage region on chromosome 6p (see SCZD3; 600511). Members of 245 families ascertained through a sib pair affected with bipolar I or schizoaffective-bipolar disorder were genotyped with 18 markers spanning chromosome 6, and nonparametric linkage analysis was performed. Linkage to 6q was robust to analysis methods, gender-specific map differences, and genotyping error. The locus conferred a 1.4-fold increased risk. Affected sibs shared the maternal more often than paternal chromosome (p = 0.006), which could reflect a maternal parent-of-origin effect. There was a positive correlation between family-specific linkage scores on 6q and those on 6p22.2 (p less than 0.0001). Linkage analysis for each locus conditioned on evidence of linkage to the other increased the evidence for linkage at both loci (p less than 0.0005). Lod scores increased from 2.26 to 5.42 on 6q and from 0.35 to 2.26 on 6p22.2. The results supported linkage of bipolar disorder to 6q, revealed a maternal parent-of-origin effect, and demonstrated an interaction of this locus with a locus on chromosome 6p22.2 linked to schizophrenia. ### Linkage to Chromosome 6q22 Middleton et al. (2004) performed a linkage analysis on 25 extended multiplex Portuguese families, including 12 families previously reported by Pato et al. (2004), segregating for bipolar disorder using a high-density SNP genotyping assay with a 0.21-Mb intermarker spacing. The analysis revealed genomewide significance with a maximum NPL of 4.20 and a maximum lod score of 3.56 at 6q22 (125.8 Mb). ### Linkage to Chromosome 8 Ophoff et al. (2002) performed a genomewide association study of severe bipolar disorder in the patients from the central valley of Costa Rica. They observed LD with severe bipolar disorder on several chromosomes; the most striking results were in proximal 8p, a region that had previously shown linkage to schizophrenia. Ophoff et al. (2002) suggested that this region could be important for severe psychiatric disorders rather than for a specific phenotype. Cichon et al. (2001) conducted a complete genome screen with 382 markers in a sample of 75 BPAD families of German, Israeli, and Italian origin. Parametric and nonparametric linkage analysis was performed. The highest 2-point lod score was obtained on 8q24 (D8S514; lod score = 3.62), and the authors confirmed a putative locus on 10q25-q26 (D10S217; lod score = 2.86). By analyzing the autosomal genotype data, putative paternally imprinted loci were identified in chromosomal regions 2p24-p21 and 2q31-q32; maternally imprinted susceptibility genes may be located on 14q32 and 16q21-q23. Park et al. (2004) genotyped 373 individuals from 40 extended pedigrees with high density bipolar disorder and found evidence for significant linkage for psychotic bipolar disorder (genomewide p less than 0.05) to chromosomes 9q31 (lod = 3.55) and 8p21 (lod = 3.46). Nine other sites obtained lod scores supportive of linkage. The highest lod scores occurred in the subgroup of families with the largest concentration of psychotic individuals. Seven of the loci identified in this study had previously been implicated in schizophrenia, suggesting that psychosis is a potentially useful phenotype in bipolar disorder for genetic studies. ### Linkage to Chromosome 9 Sherrington et al. (1994) performed linkage analysis on 5 multigenerational families with bipolar and unipolar affective disorder, using highly polymorphic microsatellite markers from the ABO-AK1-ORM region at 9q34. The dopamine beta-hydroxylase locus (223360) is also at 9q34 and was considered to be a candidate gene. Their analyses provided strong evidence against a major susceptibility allele in this region, in contradistinction to the findings of Hill et al. (1988), Tanna et al. (1989), and Wilson et al. (1989, 1991). Venken et al. (2005) conducted a genomewide scan to identify susceptibility loci for affective spectrum disorder (bipolar disorder and recurrent unipolar depression) in 9 families from an isolated population in Vasterbotten in northern Sweden. A region on chromosome 9q showed the highest 2-point and multipoint lod scores. A common ancestral haplotype was inherited by 18 of 21 patients from 3 families linked to 9q, which reduced the candidate region to 1.6 Mb on 9q31-q33. Further analysis identified the shared haplotype in 4.2% of 182 unrelated patients with bipolar disorder from the Vasterbotten isolate, but not in 182 control individuals. Venken et al. (2005) concluded that a susceptibility locus for affective disorder is located on chromosome 9q31-q33. Park et al. (2004) genotyped 373 individuals from 40 extended pedigrees with high density bipolar disorder and found evidence for significant linkage for psychotic bipolar disorder (genomewide p less than 0.05) to chromosomes 9q31 (lod = 3.55) and 8p21 (lod = 3.46). Nine other sites obtained lod scores supportive of linkage. The highest lod scores occurred in the subgroup of families with the largest concentration of psychotic individuals. Seven of the loci identified in this study had previously been implicated in schizophrenia, suggesting that psychosis is a potentially useful phenotype in bipolar disorder for genetic studies. ### Linkage to Chromosome 10q21 Ferreira et al. (2008) tested 1.8 million variants in 4,387 cases of bipolar disorder and 6,209 controls from 3 independent samples and identified a region of strong association with SNP rs10994336 in the ankyrin G gene (ANK3; 600465) on chromosome 10q21, with a p value of 9.1 x 10(-9). See MAFD8 (612357). ### Linkage to Chromosome 11 A form of manic-depressive disorder in the Old Order Amish of Lancaster County, Pennsylvania, was thought by Egeland et al. (1987) to be tightly linked to INS (176730) and HRAS1 (190020). In linkage studies using RFLPs related to these genes on the tip of 11p, the maximum lod score was 4.5 at theta = 0.0. Of interest is the description by Joffe et al. (1986) of cosegregation of thalassemia and affective disorder in a non-Amish pedigree. Egeland et al. (1987) suggested that the tyrosine hydroxylase (TH; 191290) gene, which maps to 11p, should be considered as a candidate gene because this enzyme catalyzes an important step in the dopamine synthesis pathway. Gill et al. (1988) ruled out tight linkage between manic-depressive psychosis and the 11p markers HRAS1 and INS, however. Two other groups failed to find linkage of 11p markers to manic-depressive illness (Neiswanger et al., 1990). From another extension of the study of the original Amish pedigree, Pauls et al. (1991) likewise excluded linkage to 11p markers. Pakstis et al. (1991) found no evidence of linkage after screening 185 marker loci in the Old Order Amish. They estimated that roughly 23% of the autosomal genome had been excluded. Law et al. (1992) determined the INS and HRAS1 genotypes of 81 persons in this pedigree and excluded that region of chromosome 11 as the site of the gene, which they symbolized BAD (for bipolar affective disorder). In 5 Icelandic pedigrees, Holmes et al. (1991) could find no evidence of linkage of manic depression to the dopamine D2 receptor (DRD2; 126450) or other markers in its vicinity on 11q. ### Linkage to Chromosome 12p13 Ferreira et al. (2008) tested 1.8 million variants in 4,387 cases of bipolar disorder and 6,209 controls from 3 independent samples and identified association with SNP rs1006737 in the CACNA1C gene (114205) on chromosome 12p13, with a p value of 7.0 x 10(-8). See MAFD9 (612372). ### Linkage to Chromosome 12q By linkage analysis in 2 Danish families with bipolar affective disorder, Ewald et al. (1998) found that the microsatellite marker D12S1639 gave a significant lod score of 3.37. Earlier, Craddock et al. (1994) had suggested linkage between affective disorder and Darier disease (124200), which maps to 12q23-q24.1. Linkage results from independent studies in Canadian families (Morissette et al., 1999) supported the existence of a susceptibility locus on 12q23-q24. To take advantage of isolated populations for genetic mapping and disease gene identification, Degn et al. (2001) investigated a possible chromosomal segment shared among distantly related patients with bipolar affective disorder in the Faroe Islands, using 17 microsatellite markers covering 24 cM in the 12q24 region. The region of most interest contained the primary region suggested by the previously reported haplotypes in the 2 Danish families studied by Ewald et al. (1998). Ewald et al. (2002) reported a genomewide scan for risk genes involved in bipolar disorder in 2 Danish Caucasian families with affected members in several generations. Ewald et al. (2002) used 613 microsatellite markers in a 2-stage approach. Linkage was obtained at 12q24.3 (D12S1639) with a 2-point parametric lod score of 3.42 (empirical P-value 0.00004, genomewide P-value 0.0417) in both families tested. The multipoint parametric lod score at D12S1639 was 3.63 (genomewide P-value 0.0265). At 1p22-p21 (D1S216), a parametric, affecteds-only 2-point lod score of 2.75 (empirical P-value 0.0002, genomewide P-value 0.1622) was found. A 3-point lod score of 2.98 (genomewide p value = 0.1022) was found at D1S216, and a multipoint nonparametric analysis yielded a maximum nonparametric linkage (NPL)-all score of 17.60 (p value = 0.00079) at D1S216. In 2 cohorts of patients with bipolar affective disorder from Germany and Russia totaling 883 patients and 1,300 controls, Cichon et al. (2008) observed an association between disease and the minor alleles of 3 SNPs in haplotype 1 of the TPH2 gene on chromosome 12q21, (rs11178997, rs11178998, and rs7954758; odds ratio of 1.6, p value of 0.00073). Haplotype 1 covers part of the 5-prime regulatory region and exons 1 and 2 of the TPH2 gene. Cichon et al. (2008) also observed an association between bipolar disorder and a nonsynonymous SNP in the TPH2 gene (P206S; 607478.0003). ### Linkage to Chromosome 16 See MAFD4 (611247) for a discussion of linkage of susceptibility to bipolar disorder to chromosome 16p12. ### Linkage to Chromosome 17 Dick et al. (2003) performed genomewide linkage analyses on 1,152 individuals from a new sample of 250 families segregating for bipolar disorder and related affective illnesses, ascertained at 10 sites in the United States through a proband with BP I affective disorder and a sib with BP I or schizoaffective disorder, bipolar type. Suggestive evidence for linkage was found on chromosome 17q (peak maximum lod score = 2.4) at marker D17S928, and on 6q (peak maximum lod score = 2.2) near marker D6S1021. Suggestive evidence of linkage was observed in 3 other regions, on chromosomes 2p, 3q, and 8q. This study, based on a linkage sample for bipolar disorder larger than any previously analyzed, indicated that several genes contribute to bipolar disorder. ### Linkage to Chromosome 20 In 9 Australian pedigrees, Le et al. (1994) excluded close linkage of bipolar disorder to the gene encoding the alpha subunit of the stimulatory form of G protein (139320), previously mapped to chromosomal region 20q13.2. Radhakrishna et al. (2001) studied a large Turkish pedigree segregating apparently autosomal dominant BPAD, which contained 13 affected individuals. The age of onset ranged from 15 to 40 years with a mean age of 25 years. The phenotypes consisted of recurrent manic and major depressive episodes, including suicide attempts. There was usually full remission with lithium treatment. A genotyping of 230 highly informative polymorphic markers throughout the genome and subsequent linkage analysis using a dominant mode of inheritance showed strong evidence for a BPAD susceptibility locus on chromosome 20p11.2-q11.2. The highest 2-point lod score of 4.34 (theta = 0.0) was obtained with markers D20S604, D20S470, D20S836, and D20S838 (100% penetrance). Haplotype analysis using informative recombinants enabled the mapping of the BPAD locus in this family between markers D20S186 and D20S109 in a region of approximately 42 cM. The authors noted that the chromosome 20 BPAD susceptibility locus had not been identified in previous studies of common 'polygenic' small pedigrees, which could be explained by an absence of common deleterious mutations of the chromosome 20 BPAD locus in those pedigrees and/or by the presence of a severe mutation in the Turkish pedigree that by itself confers susceptibility to BPAD. ### Linkage to Chromosome 21q22 In a preliminary genome screen of 47 bipolar disorder families, Straub et al. (1994) detected one in which a lod score of 3.41 was demonstrated for linkage with the PFKL (171860) locus on 21q22.3. Largely positive lod scores were obtained also with 14 other markers in 21q22.3 in this family. In a linkage analysis with an 'affecteds-only' method, Aita et al. (1999) found linkage to the 21q22 region, corroborating the findings of the earlier study by the same group (Straub et al., 1994). Following up on the work of Straub et al. (1994) suggesting a susceptibility locus for bipolar affective disorder on the long arm of chromosome 21, Smyth et al. (1997) studied 23 multiply affected pedigrees collected from Iceland and the U.K., using the markers PFKL, D21S171, and D21S49. Positive lod scores were obtained with 3 Icelandic families. Affected sib pair analysis demonstrated increased allele sharing. The same set of pedigrees had previously been typed for a tyrosine hydroxylase gene (TH; 191290) polymorphism at 11p15 and had shown some evidence for linkage. When information from TH and the 21q markers was combined in a 2-locus admixture analysis, an overall admixture lod of 3.87 was obtained using the bipolar affection model. Thus the data of Smyth et al. (1997) were compatible with the hypothesis that a locus at or near TH influences susceptibility of some pedigrees, while a locus near D21S171 is active in others. Age at onset (AAO) is a potential clinical marker of genetic heterogeneity in BP (Bellivier et al., 2001). Rates of comorbidity and clinical indicators of severity (e.g., suicide attempt) vary across different AAO subgroups, and AAO subgroups aggregate in families such that affected relatives typically have similar AAOs. Therefore, Lin et al. (2005) sought to incorporate AAO as a covariate in linkage analysis of BP using 2 different methods in genomewide scans of 150 multiplex pedigrees with 874 individuals. The LODPAL analysis identified 2 loci: one on 21q22.13 (MAFD3; 609633) and the other on 18p11.2 (MAFD1) for early onset (AAO = 21 years or younger) and later onset (AAO = older than 21 years), respectively. The finding on 21q22.13 was significant at the chromosome-wide level, even after correction for multiple testing. Moreover, a similar finding was observed in an independent sample of 65 pedigrees (lod = 2.88). The finding on 18p11.2 was only nominally significant and was not observed in the independent sample. However, 18p11.2 emerged as one of the strongest regions in the ordered-subset analysis (OSA) with a lod of 2.92, in which it was the only finding to meet chromosomewide levels of significance after correction for multiple testing. These results suggested that 21q22.13 and 18p11.2 may harbor genes that increase the risks for early-onset and later-onset forms of BP, respectively. Lin et al. (2005) suggested that previous inconsistent linkage findings may have been due to differences in the AAO characteristics of the samples examined. ### Linkage to Chromosome 22q12 For information on linkage of susceptibility to bipolar disorder to chromosome 22q12, see MAFD7 (612371) and Kelsoe et al., 2001. ### Other Genomewide Linkage Studies In an 'Old Order Amish revisited' study, Ginns et al. (1996) performed a genomewide linkage analysis in the Lancaster County group. In addition to the so-called pedigree 110, which was used for reporting the original genetic linkage data by Egeland et al. (1987), 2 pedigrees closely related to pedigree 110 and 2 other pedigrees, 210 and 310, were studied; all 5 pedigrees traced back to a founder couple who immigrated to the U.S. around 1750. The diagnoses were broken down into BP I (bipolar disorder with mania) and BP II (bipolar disorder with hypomania). Ginns et al. (1996) found evidence that regions on chromosomes 6, 13, and 15 harbor susceptibility loci for bipolar affective disorder, suggesting to them that bipolar affective disorder in the Old Order Amish is inherited as a complex trait. LaBuda et al. (1996) reported progress of a full genome screen for loci predisposing to affective disorder in the Old Order Amish. To the previously reported lod score results published by Gerhard et al. (1994), they added lod score results for an additional 367 markers distributed throughout the genome, along with allele- and haplotype-sharing analyses on those chromosomes sufficiently saturated with markers. No statistically significant lod scores resulted. Some degree of allele sharing was found at 74 loci, and 3.8% of all markers analyzed passed more stringent significance criteria suggestive of linkage. Although genomic areas were highlighted for further exploration, the studies of LaBuda et al. (1996) identified no region clearly involved in the etiology of affective disorder in this population. Risch and Botstein (1996) reviewed 19 linkage studies in manic-depressive illness; the studies purported to identify loci on 10 different autosomes, including both the short arm and the long arm of chromosome 18; linkage in 3 different regions of distal Xq had been proposed. Segurado et al. (2003) applied the rank-based genome scan metaanalysis (GSMA) method (Levinson et al., 2003) to 18 bipolar disorder genome scan datasets in an effort to identify regions with significant support for linkage in the combined data. No region achieved genomewide statistical significance by several simulation-based criteria. The most significant p values (less than 0.01) were observed on chromosomes 9p22.3-p21.1, 10q11.21-q22.1, and 14q24.1-q32.12. Nominally significant p values were observed in several other chromosomal regions. In a study of Ashkenazi Jewish families, Fallin et al. (2004) identified 4 regions suggestive of linkage to bipolar disorder on chromosomes 1, 3, 11, and 18. Pato et al. (2004) conducted a genomewide scan of 16 extended families from a Portuguese genetic isolate with bipolar disorder and identified 3 regions on chromosomes 2, 11, and 19 with genomewide suggestive linkage and several other regions, including chromosome 6q, that approached suggestive levels of significance. This research replicated the finding of an elevated lod score near marker D6S1021 on chromosome 6q (peak NPL at D6S1021 = 2.02; p = 0.025). Higher density mapping provided additional support for this locus (NPL = 2.59; p = 0.0068) and another marker, D6S1639 (NPL = 3.06; p = 0.0019). On chromosome 11, linkage was found to D11S1883 (NPL = 3.15; p = 0.0014). Middleton et al. (2004) performed a linkage analysis on 25 extended multiplex Portuguese families, including 12 families previously reported by Pato et al. (2004), segregating for bipolar disorder using a high-density SNP genotyping assay with a 0.21-Mb intermarker spacing. The analysis revealed genomewide significance with a maximum NPL of 4.20 and a maximum lod score of 3.56 at 6q22 (125.8 Mb). Several other areas had suggestive linkage: 2 regions on chromosome 2 (57 Mb, NPL = 2.98; 145 Mb, NPL = 3.09), chromosome 4 (91 Mb, NPL = 2.97), chromosome 11 (45-68 Mb, NPL = 2.51), chromosome 16 (20 Mb, NPL = 2.89), and chromosome 20 (60 Mb, NPL = 2.99). McQueen et al. (2005) hypothesized that combining original genotype data on linkage of bipolar disorder would provide benefits of increased power and control over sources of heterogeneity that outweigh the difficulty and potential pitfalls of the implementation. Thus, they conducted a combined analysis using the original genotype data from 11 bipolar disorder genomewide linkage scans comprising 5,179 individuals from 1,067 families. Heterogeneity among studies was minimized in the analyses by using uniform methods of analysis and a common, standardized marker map. They demonstrated that combining original genome-scan data is a powerful approach for the elucidation of linkage regions underlying complex disease. Their results established genomewide significant linkage to BP on chromosomes 6q and 8q, and provided solid information to guide future gene-finding efforts that rely on fine mapping and association approaches. McQueen et al. (2005) observed the most significant result for 'narrow' BP (BP type I-only phenotype) on chromosome 6q. When the analysis was expanded to include BP II, the linkage signal on 6q was attenuated, despite the increase in the number of affected relative pairs (ARPs). In contrast, removal of the individuals with BP II from the analysis reduced the evidence of linkage on 8q. Maziade et al. (2005) performed a dense genome scan to identify susceptibility loci shared by schizophrenia and bipolar disorder. They used the same ascertainment, statistical, and molecular methods for 480 members from 21 multigenerational families from Eastern Quebec affected by schizophrenia, bipolar affective disorder, or both. Five genomewide significant linkages with maximized lod scores over 4.0 were observed: 3 for bipolar disorder (15q11.1, 16p12.3, 18q12-q21) and 2 for the shared 'common locus' phenotype (15q26, 18q12-q21). Nine maximized lod scores exceeded the suggestive threshold of 2.6: 3 for bipolar disorder (3q21, 10p13, 12q23), 3 for schizophrenia (6p22, 13q13, 18q21), and 3 for the combined locus phenotype (2q12.3, 13q14, 16p13). Maziade et al. (2005) noted that all of the linkage signals overlapped formerly reported susceptibility regions except the signal at 15q26. Cheng et al. (2006) conducted a 9-cM genomewide scan in a large bipolar pedigree sample from the National Institute of Mental Health Genetics Initiative (1,060 individuals from 154 multiplex families). Parametric and nonparametric analyses using both standard diagnostic models and comorbid conditions thought to identify phenotypic subtypes were conducted. Genomewide significant linkage was observed on chromosomes 10q25, 10p12, 16q24, 16p13, and 16p12 using standard diagnostic models, and on 6q25 (suicidal behavior), 7q21 (panic disorder), and 16p12 (psychosis) using phenotypic subtypes. Several other regions were suggestive of linkage including 1p13 (psychosis), 1p21 (psychosis), 1q44, 2q24 (suicidal behavior), 2p25 (psychosis), 4p16 (psychosis, suicidal behavior), 5p15, 6p25 (psychosis), 8p22 (psychosis), 8q24, 10q21, 10q25 (suicidal behavior), 10p11 (psychosis), 13q32 and 19p13 (psychosis). Kimmel et al. (2005) reported a large family in which bipolar disorder 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; 174000) and 16 (MCDK2; 603860) had previously been linked to bipolar disorder and schizophrenia. ### Exclusion Studies Although corticotropin-releasing hormone (CRH; 122560) and its function in the hypothalamic-pituitary-adrenal axis had been implicated in depression (Stratakis and Chrousos, 1995), Stratakis et al. (1997) could demonstrate no linkage between the CRH gene and bipolar affective disorder. Clinical Management ### Genetic Variation in Lithium Response Lithium has been a first-line choice for maintenance treatment of bipolar disorders to prevent relapse of mania and depression, but many patients do not have a response to lithium treatment. To discover genetic variation influencing response to lithium treatment, Chen et al. (2014) performed a discovery genomewide association study and 2 sets of replication in patients with bipolar I disorder from the Taiwan Bipolar Consortium who were receiving lithium treatment. Two SNPs in high linkage disequilibrium, and , located in the introns of GADL1 (615601) showed the strongest associations in the genomewide association study (p = 5.50 x 10(-37) and p = 2.52 x 10 (-37), respectively) and in the replication sample of 100 patients (p = 9.19 x 10(-15) for each SNP). These 2 SNPs had a sensitivity of 93% for predicting a response to lithium and differentiated between patients with a good response and those with a poor response in the follow-up cohort. Resequencing of GADL1 revealed a novel variant in GADL1 intron 8, IVS8+48delG, that is in complete linkage disequilibrium with rs17026688 and is predicted to affect splicing. These variants are rare in persons of European and African ancestry. In a comment on the report of Chen et al. (2014), Birnbaum et al. (2014) stated that they found a very low level of GADL1 expression in the brain, and suggested that there was higher expression in the kidney; therefore, they concluded that the role of GADL1 is more likely related to taurine biosynthesis and kidney function than to brain function. Birnbaum et al. (2014) encouraged a retrospective review of kidney function and lithium levels in bipolar patients. Lee and Cheng (2014) responded to Birnbaum et al. (2014) that taurine may cross the blood-brain barrier to interact directly with the glutamate NMDA receptor, suggesting that the role of GADL1 in kidney function may be related to bipolar disorder. Commenting on the report of Chen et al. (2014), Vlachadis et al. (2014) speculated that, given the magnitude of the association between the presence of the T allele and the response to lithium therapy, there might be a significant difference in the minimum efficacious serum lithium level between carriers and noncarriers of the 'response' allele. Lee and Cheng (2014) replied that they were unable to examine this issue in their retrospective study. Lee and Cheng (2014) also thanked Vlachadis et al. (2014) for identifying an error in Table 2 of their article. The odds ratio for the association between the presence of the T allele and a response to lithium therapy in the combined cohorts should be 88.5 (95% confidence interval, 41.4-198.0). Ikeda et al. (2014) assessed 154 Japanese patients with bipolar disorder and did not observe an association for any criterion, even in a stringent phenotype analysis, as reported by Chen et al. (2014) for the rs17026688 allele. The Consortium on Lithium Genetics (2014) undertook a replication study in 218 samples that they collected from patients. Because the alleles reported by Chen et al. (2014) are common in Asians but rare in whites, the Consortium on Lithium Genetics (2014) studied only the Asian samples that they had obtained. In samples obtained from patients of Han Chinese or Japanese ancestry, the authors found no association between the variants and a response to lithium therapy at any threshold on the Alda scale. Lee and Cheng (2014) replied to Ikeda et al. (2014) and the Consortium on Lithium Genetics (2014) that the methods were not duplicated precisely, and offered to provide help with independent replication studies. Anghelescu and Dettling (2014) questioned the finding of Chen et al. (2014) of better response to lithium therapy among patients with rapid cycling. Lee and Cheng (2014) replied that the relationship between rapid cycling and the effect of lithium is controversial. Anghelescu and Dettling (2014) also recommended that, based on the assumption that lack of efficacy leads to premature termination of therapy, genetic analysis be extended to include patients who terminated therapy. Lee and Cheng (2014) stated that because adherence to lithium maintenance treatment involves such factors as illness behavior and cognitive function, rapport with psychiatrists, serious adverse effects of treatment, and familial and financial support, the effect of lithium in patients with premature termination cannot be assessed. Molecular Genetics ### Association with the SLC6A3 Gene on Chromosome 5p15 Greenwood et al. (2001) reported evidence for an association between the DAT1 gene (SLC6A3; 126455) and bipolar disorder in a sample of 50 parent-proband trios. Using the transmission disequilibrium test (TDT), they showed an association between a haplotype comprised of 5 SNPs in the 3-prime region of the DAT1 gene, exon 9 through exon 15, and bipolar disorder (allele-wise TDT empirical P = 0.001; genotype-wise TDT empirical P = 0.0004). Greenwood et al. (2006) analyzed a total of 22 SNPs in the 50 previously studied parent-proband trios and an independent set of 70 parent-proband trios. Using TDT analysis, an intron 8 SNP and an intron 13 SNP were found to be moderately associated with bipolar disorder, each in 1 of the 2 independent samples. Analysis of haplotypes of all 22 SNPs in sliding windows of 5 adjacent SNPs revealed an association to the region near intron 7 and 8 in both samples (empirical P values of 0.002 and 0.001, respectively, for the same window). ### Association with the HTR4 Gene on Chromosome 5q32 Ohtsuki et al. (2002) performed mutation and association analyses of the HTR4 gene (602164) on 5q32, which encodes the serotonin 5-HT4 receptor, in 96 Japanese patients, 48 with mood disorders and 48 with schizophrenia. Eight polymorphisms and 4 rare variants were identified. Four polymorphisms at or in close proximity to exon d showed significant association with bipolar disorder with odds ratios of 1.5 to 2; these included g.83097C/T (HTR4-SVR (splice variant region) SNP1), g.83159G/A (HTR4-SVRSNP2), g.83164(T)9-10 (HTR4-SVRSNP3), and g.83198A/G (HTR4-SVRSNP4). These polymorphisms were in linkage disequilibrium, and only 3 common haplotypes were observed. One haplotype (SVRSNP1, SVRSNP4 C-A) was significantly associated with bipolar disorder (p = 0.002). The genotypic and haplotypic associations with bipolar disorder were confirmed by the transmission disequilibrium test in the NIMH Genetics Initiative bipolar pedigrees with ratios of transmitted to not transmitted alleles of 1.5 to 2.0 (p = 0.01). The same haplotype that showed association with bipolar disorder was suggested to be associated with schizophrenia in the case-control analysis (p = 0.003) but was not confirmed when Japanese schizophrenia families were tested. The polymorphisms associated with mood disorder were located within the region that encodes the divergent C-terminal tails of the 5-HT4 receptor. ### Association with the ABCA13 Gene on Chromosome 7p12.3 Knight et al. (2009) reported evidence that ABCA13 (607807) is a susceptibility factor for both schizophrenia and bipolar disorder. After the initial discovery of its disruption by a chromosome abnormality in a person with schizophrenia, Knight et al. (2009) resequenced ABCA13 exons in 100 cases with schizophrenia and 100 controls. Multiple rare coding variants were identified including 1 nonsense and 9 missense mutations and compound heterozygosity/homozygosity in 6 cases. Variants were genotyped in more than 1,600 additional schizophrenia, bipolar, and depression cases and in more than 950 control cohorts, and the frequency of all rare variants combined was greater than controls in schizophrenia (odds ratio = 1.93, P = 0.0057) and bipolar disorder (odds ratio = 2.71, P = 0.00007). The population-attributable risk of these mutations was 2.2% for schizophrenia and 4.0% for bipolar disorder. In a study of 21 families of mutation carriers, Knight et al. (2009) genotyped affected and unaffected relatives and found significant linkage (lod = 4.3) of rare variants with a phenotype including schizophrenia, bipolar disorder, and major depression. Knight et al. (2009) concluded that their data identified a candidate gene (ABCA13), highlighted the genetic overlap between schizophrenia, bipolar disorder, and depression, and suggested that rare coding variants may contribute significantly to risk of these disorders. ### Association with the DRD4 Gene on Chromosome 11p15 Lopez Leon et al. (2005) conducted a metaanalysis to reevaluate the role of the 48-bp repeat polymorphism of the dopamine D4 receptor gene (DRD4; 126452) on chromosome 11p15 in mood disorders by studying 917 patients with unipolar or bipolar affective disorder and 1,164 control subjects from 12 samples using the Cockrane Review Manager. An association was found between all mood disorder groups and the DRD4 2-repeat 48-bp (2R) polymorphism. After correcting for multiple testing, the association between this repeat and bipolar affective disorder dropped to insignificance; however, the evidence for an association between the 2R allele and unipolar depression (p less than 0.001) and the combined group (p less than 0.001) remained. ### Association with the BDNF Gene on Chromosome 11p13 Geller et al. (2004) noted that Sklar et al. (2002) and Neves-Pereira et al. (2002), using family-based methods, had found that the BDNF val66 allele (113505.0002) was preferentially transmitted to predominantly Caucasian adult probands with bipolar disorder. Geller et al. (2004) reported that the val66 allele was also preferentially transmitted in children with bipolar disorder. Lohoff et al. (2005) studied the BDNF val66 allele in 621 European patients with bipolar I disorder and positive family histories of affective disorder and 998 European controls. The frequency of the val66 allele was significantly increased in the bipolar I patients when compared to controls (P = 0.028; OR of 1.22). Rybakowski et al. (2006) studied 111 patients with bipolar disorder, 129 schizophrenia patients, and 92 healthy controls utilizing the Wisconsin Card Sorting Test in the context of the BDNF V66M polymorphism. They found that bipolar patients with the val/val genotype made significantly fewer perseverative errors, had more correctly completed categories and conceptual level responses compared to bipolar patients with the val/met or met/met genotypes. No differences were observed in schizophrenia patients and controls. ### Association with the CUX2 Gene on Chromosome 12q Glaser et al. (2005) performed linkage disequilibrium mapping with 17 microsatellite markers across a 1.6-Mb segment forming the central part of the chromosome 12q23-q24 region implicated in several linkage studies for bipolar affective disorder. In a U.K. Caucasian case-control sample of 347 cases and 374 controls, a significant signal was identified (p = 0.0016) for the microsatellite marker M19 at 12q24. Genes, including regulatory elements, around this marker were screened for mutations and the linkage disequilibrium structure of the region determined by genotyping 22 SNPs and insertion/deletion polymorphisms in 94 individuals. Eleven haplotypes and SNPs were genotyped and 3, an insertion/deletion and a SNP within FLJ32356 (rs3840795 and rs933399) and a SNP within CUX2 (rs3847953), showed significant or nearly significant association with bipolar disorder after Bonferroni-correction (p values from 0.002-0.005). ### Association with the SLC6A4 Gene on Chromosome 17q11 Lasky-Su et al. (2005) conducted a metaanalysis on case-control studies of the association between 2 polymorphisms of the SLC6A4 gene (a 17-bp VNTR in intron 2, and a 44-bp insertion/deletion in the promoter region; see 182138.0001) and affective disorders (bipolar disorder and unipolar depression) resulting in 4 metaanalyses. For each polymorphism, the authors assessed the evidence for allelic association, heterogeneity among studies, the influence of individual studies, and the potential for publication bias. The short alleles of the 44-bp insertion/deletion polymorphism showed a significant association with bipolar disorder (OR = 1.13, p = 0.001) but not unipolar disorder. The VNTR had no association with either disorder. Cho et al. (2005) performed 2 metaanalyses of published studies involving the SLC4A4 gene as a candidate for bipolar disorder. The studies were population-based and family-based studies investigating the association with the promoter polymorphism (5-HTTLPR) and the intron 2 VNTR. Seventeen population-based studies comprising 1,712 cases and 2,583 controls and 6 family-based studies comprising 587 trios were included in the 5-HTTLPR metaanalysis. Sixteen population-based studies comprising 1,764 cases and 2,703 controls as well as for family-based studies comprising 382 trios were included in the intron 2 VNTR metaanalysis. Meta-regression showed that neither study type nor ethnic sample significantly contributed to heterogeneity of the metaanalyses. Overall, odds ratios suggested a very small but detectable effect of the serotonin transporter in susceptibility to bipolar disorder. ### Association with the BCR Gene on Chromosome 22q11 Hashimoto et al. (2005) studied 171 patients with bipolar disorder, 329 with major depressive disorder, and 351 controls, all of whom were Japanese, for genetic association using 11 single nucleotide polymorphisms, including a missense polymorphism (N796S; rs140504) in the region of the breakpoint cluster region gene (BCR; 151410) on chromosome 22q11. Significant allelic associations with bipolar disorder were observed for 3 single nucleotide polymorphisms and associations with bipolar II disorder were observed for 10 polymorphisms including N796S (bipolar disorder, p = 0.0054; bipolar II disorder, p = 0.0014). There was a significant association with major depression for 6 polymorphisms. S796 allele carriers were in excess in bipolar II patients (p = 0.0046; OR = 3.1, 95% CI, 1.53-8.76). ### Association with the COMT Gene on Chromosome 22q11 Comorbid panic disorder may define a subtype of bipolar disorder and may influence the strength of association between bipolar disorder and candidate genes involved in monoamine neurotransmission. Rotondo et al. (2002) studied the frequency of the V158M polymorphism of catechol-O-methyltransferase (COMT; 116790.0001), the 5-HTTLPR polymorphism of the serotonin transporter SLC6A4 (182138.0001), and a splice site polymorphism (IVS7+218C-A) of tryptophan hydroxylase (TPH; 191060) in a case-control association study of bipolar disorder patients with or without lifetime panic disorder. They compared results from DNA extracted from blood leukocytes of 111 unrelated subjects of Italian descent meeting DSM-III-R criteria for bipolar disorder, including 49 with and 62 without comorbid lifetime panic disorder, with those of 127 healthy subjects. Relative to the comparison subjects, subjects with bipolar disorder without panic disorder, but not those with comorbid bipolar disorder and panic disorder, showed significantly higher frequencies of the COMT met158 and the short 5-HTTLPR alleles. No statistical significance was found between the bipolar disorder groups and the TPH polymorphism. Rotondo et al. (2002) concluded that bipolar disorder without panic disorder may represent a more homogeneous form of illness and that variants of the COMT and SLC6A4 genes may influence clinical features of bipolar disorder. ### Association with the XBP1 Gene on Chromosome 22q12 See 194355 for discussion of an association between susceptibility to bipolar disorder and a polymorphism in the XBP1 gene. ### Association with the TRPM2 Gene on Chromosome 21q22 McQuillin et al. (2006) fine mapped chromosome 21q22.3 using 30 genetic markers in 600 bipolar subjects and 450 ancestrally matched supernormal controls. Allelic association with D21S171 (p = 0.016), rs1556314 (p = 0.008), and rs1785467 (p = 0.025) was observed. A test of association with a 3-locus haplotype across a susceptibility region was significant with a permutation test (p = 0.011), and a 2-SNP haplotype was also significantly associated with bipolar disorder (p = 0.01). The 2 brain-expressed genes present in the associated region, TRPM2 (603749) and C21ORF29 (612920), were sequenced from subjects who had inherited the associated marker alleles. The rs1556314 polymorphism in exon 11 of TRPM2, which causes an asp543-to-glu (D543E) change, showed the strongest association with bipolar disorder (p = 0.008). McQuillin et al. (2006) noted that deletion of exon 11 is known to cause dysregulation of cellular calcium homeostasis in response to oxidative stress. ### Association with Repeat Expansions Del-Favero et al. (2002) studied the CTG repeat in the third intron of the SEF2-1B gene (602272) located at 18q21.1 and the CAG repeat at the ERDA1 locus (603279) located at 17q21.3 in a large combined European case-control sample of bipolar affective disorder. The sample consisted of 403 patients and 486 controls matched for age, gender, and ethnicity. The patients were consecutively recruited from 5 participating centers in Belgium, Croatia, Denmark, Scotland, and Sweden. Dichotomous analysis of the combined sample did not show a significant difference in expansion frequency between cases and controls at either of the 2 loci. Secondary analysis after stratification for family history of affective disorder in first-degree relatives and disease severity revealed a borderline significant difference (p = 0.03) with a relative risk of 2.43 of developing bipolar disorder in familial cases homozygous for the expanded SEF2-1B allele. This finding rendered further support to the hypothesis that SEF2-1B cannot be excluded as a susceptibility gene for bipolar disorder or that SEF2-1B is in linkage disequilibrium with a causal gene for bipolar disorder. Tsutsumi et al. (2004) used a repeat expansion detection assay to examine genomic DNA from 100 unrelated probands with schizophrenia and 68 unrelated probands with bipolar affective disorder for the presence of CAG/CTG repeat expansions. They found that 28% of probands with schizophrenia and 38% of probands with bipolar disorder had a CAG/CTG repeat in the expanded range. Each expansion could be explained by 1 of 3 nonpathogenic repeat expansions known to exist in the general population. Thus, a novel CAG/CTG repeat expansion was not a common genetic risk factor for bipolar disorder or schizophrenia in this study. ### Association with the Mitochondrial MTND1 Gene Munakata et al. (2004) reported an association between bipolar disorder and a polymorphism in the mitochondrial MTND1 gene (516000). ### Gene Interaction and Locus Heterogeneity Jamra et al. (2007) presented the first genomewide interaction and locus heterogeneity linkage scan in bipolar affective disorder, using a large linkage dataset (52 families of European descent; 448 participants and 259 affected individuals). The results provided the strongest evidence of interaction between BPAD genes on chromosome 2q22-q24 and 6q23-q24, which was observed symmetrically in both directions; nonparametric lod (NPL) scores of 7.55 on 2q and 7.63 on 6q; P less than 0.0001 and P = 0.0001, respectively, after a genomewide permutation procedure. The second-best BPAD interaction evidence was observed between 2q22-q24 and 15q26. Here, Jamra et al. (2007) also observed a symmetric interaction. Heterogeneity analysis revealed locus heterogeneity at 2q, 6p, 11p, 13q, and 22q, which was supported by adjacent markers within each region and by previously reported BPAD linkage findings. ### Epigenetic Theory of Major Psychosis As a test of the hypothesis that epigenetic misregulation is consistent with various nonmendelian features of schizophrenia (181500) and bipolar disorder, Mill et al. (2008) used CpG island microarrays to identify DNA methylation changes in the frontal cortex and germline associated with schizophrenia and bipolar disorder. In the frontal cortex they found evidence for psychosis-associated DNA methylation differences in numerous loci, including several involved in glutamatergic and GABAergic neurotransmission, brain development, and other processes functionally linked to disease etiology. DNA methylation changes in a significant proportion of these loci corresponded to reported changes of steady-state mRNA levels associated with psychosis. Gene ontology analysis highlighted epigenetic disruption to loci involved in mitochondrial function, brain development, and stress response. Changes in both the brain and the germline of affected individuals suggested that systemic epigenetic dysfunction may be associated with major psychosis. Mill et al. (2008) observed that frontal cortex DNA methylation in the BDNF gene (113505) is correlated with genotype at a nearby nonsynonymous SNP (V66M) that had been associated with major psychosis. ### Reviews See Kato (2007) for a review of molecular genetic findings on bipolar disorder and major depression from 2004 to 2007. Also see the reviews on the genetics of bipolar disorder by Craddock and Sklar (2009, 2013). ### Associations Pending Confirmation For a discussion of a possible association between variation in the KCNH7 gene and susceptibility to bipolar spectrum disorder, see 608169.0001. Animal Model Maeng et al. (2008) found that transgenic mice with selective neuron-specific overexpression of Bag1 (601497) in the hippocampus did not have obvious motor, sensory, or learning impairments, but showed less anxious behavior and had higher spontaneous recovery rates from helplessness behavior compared to wildtype mice. These transgenic mice also recovered faster from tests designed to trigger hyperlocomotion or addictive behaviors. In contrast, heterozygous Bag1 +/- mice showed enhanced extreme behavioral responses and less recovery in similar tests. The data suggested that BAG1 may play a role in affective resilience, and perhaps regulates recovery from behavioral impairments observed in patients with bipolar affective disorder. Maeng et al. (2008) postulated that the effects are mediated by BAG1 regulation of glucocorticoid receptor function. INHERITANCE \- Autosomal dominant NEUROLOGIC Behavioral Psychiatric Manifestations \- Depression with mania (bipolar 1) \- Depression with hypomania (bipolar 2) ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	MAJOR AFFECTIVE DISORDER 1	c1852197	3,768	omim	https://www.omim.org/entry/125480	2019-09-22T16:42:27	{"doid": ["0080220"], "mesh": ["C565111"], "omim": ["125480"], "icd-10": ["F31"], "synonyms": ["Alternative titles", "MANIC-DEPRESSIVE PSYCHOSIS", "BIPOLAR AFFECTIVE DISORDER", "MANIC-DEPRESSIVE PSYCHOSIS, AUTOSOMAL"]}
Jacobsen syndrome Other namesDel(11)(qter), distal deletion 11q, distal monosomy 11q, monosomy 11qter Girl with Jacobsen syndrome SpecialtyMedical genetics Jacobsen syndrome is a rare chromosomal disorder resulting from deletion of genes from chromosome 11 that includes band 11q24.1. It is a congenital disorder. Since the deletion takes place on the q arm of chromosome 11, it is also called 11q terminal deletion disorder.[1] The deletion may range from 5 million to 16 million deleted DNA base pairs.[2] The severity of symptoms depends on the number of deletions; the more deletions there are, the more severe the symptoms are likely to be. People with Jacobsen syndrome have serious intellectual disabilities, dysmorphic features, delayed development and a variety of physical problems including heart defects. Research shows that almost 88.5% of people with Jacobsen syndrome have a bleeding disorder called Paris-Trousseau syndrome.[3] Jacobsen syndrome is catastrophic in 1 out of every 5 cases, with children usually dying within the first 2 years of life due to heart complications.[4] ## Contents * 1 Signs and symptoms * 2 Cause * 3 Genetics * 4 Diagnosis * 5 Treatment * 6 Prevalence * 7 History * 8 References * 9 Sources * 10 External links ## Signs and symptoms[edit] Almost all children with Jacobsen syndrome have intellectual disabilities, which range from mild to moderate depending upon the number of the deletions of genes from the chromosome. Children with intellectual disability take more time than normal to learn new things and acquire new skills. They have problems with assembling new information or adapting to novel situations and associating two events or things together.[5] Most children with the syndrome have delayed development, including delayed speech, motor disabilities and lack of coordination, which makes simple activities like sitting, standing and walking difficult. Most children eventually start speaking, but in cases with severe intellectual disability language use is highly restricted.[6] They have distinctive facial features like: * Small head (microcephaly) * Pointed forehead (trigonocephaly) * Small ears which are low-set * Widely-spaced eyes (hypertelorism) * Droopy eyelids (ptosis) * Broad nasal bridge * Abnormally thin upper lips * Downturned corners of the mouth * Excess skin covering in the inner corner of eyes (epicanthal folds)[7] Some children also suffer from behavioural problems like distractibility, hyperactivity, impaired communication and social skills, which qualifies them for a diagnosis of ASD and ADHD.[8] Heart defects are very common in children with Jacobsen syndrome. 88.5% of people with the disorder have Paris-Trousseau syndrome, which is a bleeding disorder and causes a lifelong risk of abnormal bleeding and bruising due to dysfunction in the platelets.[9] Other symptoms may include eye problems, ear and sinus infections, hearing problems, bone deformities, growth hormone deficiency, gastrointestinal problems, kidney malfunctions, etc.[10] ## Cause[edit] Jacobsen syndrome is caused by deletion of genetic material from the long arm of chromosome 11. The size of deletion may vary across patients, but the deletion always occurs at the end terminal of the q arm of chromosome 11.[11] There are three ways in which the deletion could occur: de novo deletion- this is a random event that occurred during the formation of the sperm or the egg or during the cell division in the embryonic stage, where genes from chromosome 11 get deleted.[12] Imbalanced translocation- in this case, a parent with balanced translocation or other types of chromosomal rearrangement can pass on these genes to their children which further results in an imbalanced translocation. The affected children have deletions on chromosome 11 as well as some extra genetic material from another chromosome.[13] Ring chromosome 11- in this case genetic material from both long and short arm of the chromosome get deleted, and the remaining part joins together and forms a ring like structure. Here the affected person would have symptoms associated with both 11q and 11p deletion.[14] ## Genetics[edit] If de novo deletion occurs then both the parents have normal chromosomes, and chances that another child will have the deletion decline. Very few cases have been found in which the deletion has been present in mosaic form (where some of the cells have deletion on chromosome 11 and some do not, and the symptoms are less severe) in one of the parents, which increases the risk of having another child with Jacobsen syndrome. When the child's chromosomal abnormality occurs due to one of the parents' balanced translocation, the chances of another child having the abnormality is high. [15] ## Diagnosis[edit] Diagnosing Jacobsen syndrome can be difficult in some cases because it is a rare chromosomal disorder.[16] There are a variety of tests that can be carried out, like karyotypes, cardiac echocardiograms, a renal sonogram, a platelet count, blood counts, a brain imaging study. [17]Genetic testing can be carried out for diagnosis. Here chromosomes are stained to give a barcode like appearance and studied under the microscope, which reveals the broken and deleted genes. The condition can also be diagnosed early in the prenatal stage if there are any abnormalities seen in the ultrasound. [18] A simple assessment of the symptoms can be done to diagnose the syndrome. A thorough physical examination could be carried out to assess the symptoms.[19] ## Treatment[edit] There has been no treatment discovered for Jacobsen syndrome to date, but the symptoms can be treated. 56% of children with Jacobsen syndrome have congenital heart problems; to keep them in check, a baseline evaluation can be made by a paediatric cardiologist by carrying out an electrocardiogram or echocardiogram. Any problems that are found can be treated then.[citation needed] Almost all affected children are born with a bleeding disorder; monthly CBT may help ease the problem. Consecutively. platelet transfusion and ddAVP can be carried out. Medication that interferes with platelet count should be avoided, and oral contraceptive therapy may be considered for women with heavy bleeding during menses.[citation needed] Children affected with Jacobsen syndrome have severe to moderate intellectual disabilities and cognitive impairment. An evaluation by a neuropsychologist or a behaviour specialist like a psychiatrist or psychologist can be performed, including brain imaging like MRI or ERP. Later, as deemed appropriate, intervention programs can be carried through. Music therapy is very beneficial for language development. According to the age, vision and hearing tests can aid in fixing problems related cognition.[20] For problems related to behaviour like ADHD, medication or therapy would be required but a combination of both is more effective.[21] An ophthalmologist should be consulted to treat the eye defects. Play and interactive games encourage the child to speak. Habilitiation in children should begin at an early age. A habilitation team includes professionals with special expertise in how disability affects everyday life, health and development. The entire family is supported to help the affected children and their families adjust better.[22] ## Prevalence[edit] The estimated prevalence of Jacobsen syndrome is believed to be approximately 1 out of every 100,000 births. For reasons unknown, females are twice as likely to have Jacobsen syndrome than males. No preference for any race or ethnicity has been reported so far.[23] ## History[edit] The syndrome was first identified by Danish geneticist Petrea Jacobsen in 1973 and was named after her. She discovered Jacobsen syndrome in a family where multiple people had the disorder. She discovered that the affected children had unbalanced translocation between chromosome 11 and 21 which they had inherited from one of their parents who had balanced translocation. Since then, only 200 cases have been reported of Jacobsen syndrome in medical literature.[24] ## References[edit] 1. ^ Reference, Genetics Home. "Jacobsensyndrome". Genetics Home Reference. 2. ^ "Jacobsen Syndrome". prezi.com. 3. ^ Favier, Remi; Akshoomoff, Natacha; Mattson, Sarah; Grossfeld, Paul (1 September 2015). "Jacobsen syndrome: Advances in our knowledge of phenotype and genotype". American Journal of Medical Genetics Part C: Seminars in Medical Genetics. 169 (3): 239–250. doi:10.1002/ajmg.c.31448. PMID 26285164. 4. ^ "Jacobsen Syndrome". DoveMed. 5. ^ "11q deletion syndrome". www.socialstyrelsen.se (in Swedish). 6. ^ "Jacobsen Syndrome". DoveMed. 7. ^ Reference, Genetics Home. "Jacobsen syndrome". Genetics Home Reference. 8. ^ "11q deletion syndrome". www.socialstyrelsen.se (in Swedish). 9. ^ Favier, Remi; Akshoomoff, Natacha; Mattson, Sarah; Grossfeld, Paul (1 September 2015). "Jacobsen syndrome: Advances in our knowledge of phenotype and genotype". American Journal of Medical Genetics Part C: Seminars in Medical Genetics. 169 (3): 239–250. doi:10.1002/ajmg.c.31448. PMID 26285164. 10. ^ "Jacobsen Syndrome". DoveMed. 11. ^ "11q deletion syndrome". www.socialstyrelsen.se (in Swedish). 12. ^ "Jacobsen syndrome \| Genetic and Rare Diseases Information Center (GARD) – an NCATS Program". rarediseases.info.nih.gov. 13. ^ "Jacobsen syndrome \| Genetic and Rare Diseases Information Center (GARD) – an NCATS Program". rarediseases.info.nih.gov. 14. ^ "11q deletion syndrome". www.socialstyrelsen.se (in Swedish). 15. ^ "11q deletion syndrome". www.socialstyrelsen.se (in Swedish). 16. ^ "Jacobsen Syndrome". Healthline. 2016-11-28. 17. ^ "Jacobsen Syndrome". prezi.com. 18. ^ "Jacobsen Syndrome". Healthline. 2016-11-28. 19. ^ "Jacobsen Syndrome". prezi.com. 20. ^ Reference, Genetics Home. "Jacobsen syndrome". Genetics Home Reference. 21. ^ "Treatment". nhs.uk. June 2018. 22. ^ "11q deletion syndrome". www.socialstyrelsen.se (in Swedish). 23. ^ "Jacobsen Syndrome". DoveMed. 24. ^ Favier, Remi; Akshoomoff, Natacha; Mattson, Sarah; Grossfeld, Paul (1 September 2015). "Jacobsen syndrome: Advances in our knowledge of phenotype and genotype". American Journal of Medical Genetics Part C: Seminars in Medical Genetics. 169 (3): 239–250. doi:10.1002/ajmg.c.31448. PMID 26285164. ## Sources[edit] * European Chromosome 11 Network \- Support group for patients with chromosome 11 disorders, their families and relatives * 11Q Research & Resource \- U.S.-based support group for patients with chromosome 11 disorders, their families and relatives ## External links[edit] Classification D * ICD-10: Q93.5 * ICD-9-CM: 758.3 * OMIM: 147791 * MeSH: D054868 * DiseasesDB: 31957 * v * t * e Congenital malformations and deformations of integument / skin disease Genodermatosis Congenital ichthyosis/ erythrokeratodermia AD * Ichthyosis vulgaris AR * Congenital ichthyosiform erythroderma: Epidermolytic hyperkeratosis * Lamellar ichthyosis * Harlequin-type ichthyosis * Netherton syndrome * Zunich–Kaye syndrome * Sjögren–Larsson syndrome XR * X-linked ichthyosis Ungrouped * Ichthyosis bullosa of Siemens * Ichthyosis follicularis * Ichthyosis prematurity syndrome * Ichthyosis–sclerosing cholangitis syndrome * Nonbullous congenital ichthyosiform erythroderma * Ichthyosis linearis circumflexa * Ichthyosis hystrix EB and related * EBS * EBS-K * EBS-WC * EBS-DM * EBS-OG * EBS-MD * EBS-MP * JEB * JEB-H * Mitis * Generalized atrophic * JEB-PA * DEB * DDEB * RDEB * related: Costello syndrome * Kindler syndrome * Laryngoonychocutaneous syndrome * Skin fragility syndrome Ectodermal dysplasia * Naegeli syndrome/Dermatopathia pigmentosa reticularis * Hay–Wells syndrome * Hypohidrotic ectodermal dysplasia * Focal dermal hypoplasia * Ellis–van Creveld syndrome * Rapp–Hodgkin syndrome/Hay–Wells syndrome Elastic/Connective * Ehlers–Danlos syndromes * Cutis laxa (Gerodermia osteodysplastica) * Popliteal pterygium syndrome * Pseudoxanthoma elasticum * Van der Woude syndrome Hyperkeratosis/ keratinopathy PPK * diffuse: Diffuse epidermolytic palmoplantar keratoderma * Diffuse nonepidermolytic palmoplantar keratoderma * Palmoplantar keratoderma of Sybert * Meleda disease * syndromic * connexin * Bart–Pumphrey syndrome * Clouston's hidrotic ectodermal dysplasia * Vohwinkel syndrome * Corneodermatoosseous syndrome * plakoglobin * Naxos syndrome * Scleroatrophic syndrome of Huriez * Olmsted syndrome * Cathepsin C * Papillon–Lefèvre syndrome * Haim–Munk syndrome * Camisa disease * focal: Focal palmoplantar keratoderma with oral mucosal hyperkeratosis * Focal palmoplantar and gingival keratosis * Howel–Evans syndrome * Pachyonychia congenita * Pachyonychia congenita type I * Pachyonychia congenita type II * Striate palmoplantar keratoderma * Tyrosinemia type II * punctate: Acrokeratoelastoidosis of Costa * Focal acral hyperkeratosis * Keratosis punctata palmaris et plantaris * Keratosis punctata of the palmar creases * Schöpf–Schulz–Passarge syndrome * Porokeratosis plantaris discreta * Spiny keratoderma * ungrouped: Palmoplantar keratoderma and spastic paraplegia * desmoplakin * Carvajal syndrome * connexin * Erythrokeratodermia variabilis * HID/KID Other * Meleda disease * Keratosis pilaris * ATP2A2 * Darier's disease * Dyskeratosis congenita * Lelis syndrome * Dyskeratosis congenita * Keratolytic winter erythema * Keratosis follicularis spinulosa decalvans * Keratosis linearis with ichthyosis congenita and sclerosing keratoderma syndrome * Keratosis pilaris atrophicans faciei * Keratosis pilaris Other * cadherin * EEM syndrome * immune system * Hereditary lymphedema * Mastocytosis/Urticaria pigmentosa * Hailey–Hailey see also Template:Congenital malformations and deformations of skin appendages, Template:Phakomatoses, Template:Pigmentation disorders, Template:DNA replication and repair-deficiency disorder Developmental anomalies Midline * Dermoid cyst * Encephalocele * Nasal glioma * PHACE association * Sinus pericranii Nevus * Capillary hemangioma * Port-wine stain * Nevus flammeus nuchae Other/ungrouped * Aplasia cutis congenita * Amniotic band syndrome * Branchial cyst * Cavernous venous malformation * Accessory nail of the fifth toe * Bronchogenic cyst * Congenital cartilaginous rest of the neck * Congenital hypertrophy of the lateral fold of the hallux * Congenital lip pit * Congenital malformations of the dermatoglyphs * Congenital preauricular fistula * Congenital smooth muscle hamartoma * Cystic lymphatic malformation * Median raphe cyst * Melanotic neuroectodermal tumor of infancy * Mongolian spot * Nasolacrimal duct cyst * Omphalomesenteric duct cyst * Poland anomaly * Rapidly involuting congenital hemangioma * Rosenthal–Kloepfer syndrome * Skin dimple * Superficial lymphatic malformation * Thyroglossal duct cyst * Verrucous vascular malformation * Birthmark * v * t * e Chromosome abnormalities Autosomal Trisomies/Tetrasomies * Down syndrome * 21 * Edwards syndrome * 18 * Patau syndrome * 13 * Trisomy 9 * Tetrasomy 9p * Warkany syndrome 2 * 8 * Cat eye syndrome/Trisomy 22 * 22 * Trisomy 16 Monosomies/deletions * (1q21.1 copy number variations/1q21.1 deletion syndrome/1q21.1 duplication syndrome/TAR syndrome/1p36 deletion syndrome) * 1 * Wolf–Hirschhorn syndrome * 4 * Cri du chat syndrome/Chromosome 5q deletion syndrome * 5 * Williams syndrome * 7 * Jacobsen syndrome * 11 * Miller–Dieker syndrome/Smith–Magenis syndrome * 17 * DiGeorge syndrome * 22 * 22q11.2 distal deletion syndrome * 22 * 22q13 deletion syndrome * 22 * genomic imprinting * Angelman syndrome/Prader–Willi syndrome (15) * Distal 18q-/Proximal 18q- X/Y linked Monosomy * Turner syndrome (45,X) Trisomy/tetrasomy, other karyotypes/mosaics * Klinefelter syndrome (47,XXY) * XXYY syndrome (48,XXYY) * XXXY syndrome (48,XXXY) * 49,XXXYY * 49,XXXXY * Triple X syndrome (47,XXX) * Tetrasomy X (48,XXXX) * 49,XXXXX * Jacobs syndrome (47,XYY) * 48,XYYY * 49,XYYYY * 45,X/46,XY * 46,XX/46,XY Translocations Leukemia/lymphoma Lymphoid * Burkitt's lymphoma t(8 MYC;14 IGH) * Follicular lymphoma t(14 IGH;18 BCL2) * Mantle cell lymphoma/Multiple myeloma t(11 CCND1:14 IGH) * Anaplastic large-cell lymphoma t(2 ALK;5 NPM1) * Acute lymphoblastic leukemia Myeloid * Philadelphia chromosome t(9 ABL; 22 BCR) * Acute myeloblastic leukemia with maturation t(8 RUNX1T1;21 RUNX1) * Acute promyelocytic leukemia t(15 PML,17 RARA) * Acute megakaryoblastic leukemia t(1 RBM15;22 MKL1) Other * Ewing's sarcoma t(11 FLI1; 22 EWS) * Synovial sarcoma t(x SYT;18 SSX) * Dermatofibrosarcoma protuberans t(17 COL1A1;22 PDGFB) * Myxoid liposarcoma t(12 DDIT3; 16 FUS) * Desmoplastic small-round-cell tumor t(11 WT1; 22 EWS) * Alveolar rhabdomyosarcoma t(2 PAX3; 13 FOXO1) t (1 PAX7; 13 FOXO1) Other * Fragile X syndrome * Uniparental disomy * XX male syndrome/46,XX testicular disorders of sex development * Marker chromosome * Ring chromosome * 6; 9; 14; 15; 18; 20; 21, 22 [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Jacobsen syndrome	c0795841	3,769	wikipedia	https://en.wikipedia.org/wiki/Jacobsen_syndrome	2021-01-18T18:50:47	{"gard": ["307"], "mesh": ["D054868"], "umls": ["C0795841"], "icd-9": ["758.3"], "icd-10": ["Q93.5"], "orphanet": ["2308"], "wikidata": ["Q1677755"]}
Main article: Agnosia 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: "Apperceptive agnosia" – news · newspapers · books · scholar · JSTOR (September 2019) (Learn how and when to remove this template message) Apperceptive agnosia is a failure in recognition that is due to a failure of perception. In contrast, associative agnosia is a type of agnosia where perception occurs but recognition still does not occur.[1] When referring to apperceptive agnosia, visual and object agnosia are most commonly discussed; this occurs because apperceptive agnosia is most likely to present visual impairments.[2] However, in addition to visual apperceptive agnosia there are also cases of apperceptive agnosia in other sensory areas.[3] ## Contents * 1 Auditory apperceptive agnosia * 2 Tactile apperceptive agnosia * 3 Olfactory Agnosia * 4 Visual apperceptive agnosia * 4.1 Origin * 4.2 Effects * 5 Location of brain damage * 6 Theories of causation * 7 Case studies * 7.1 JB * 7.2 ELM * 7.3 HJA * 8 Populations affected * 8.1 Alzheimer's disease * 9 See also * 10 References * 11 Further reading ## Auditory apperceptive agnosia[edit] Auditory apperceptive agnosia are impairments in audition that take place despite intact audiogram.[4] In some cases the deficit is in the ability to recognize spoken words, and in other cases, may be a deficit in recognizing environmental sounds.[4] In all cases individuals are able to read, write, name objects, and converse intelligently. Similar to visual impairments, the deficit arise because of damage in the primary sensory cortex.[4] In the case of auditory agnosia, lesions are present in the superior temporal gyrus bilaterally or in the posterior temporal lobe of the language-dominant (typically left) hemisphere.[4] In addition to verbal and nonverbal auditory agnosia, there are cases of auditory apperceptive agnosia where patients are unable to recognize music in the absence of sensory, intellectual, and verbal impairments.[5] In these cases there may be a melodic or a memory basis established in the brain and damage to those areas lead to music agnosia.[citation needed] Agnosia occurs because of failure to re-encode melodic information properly. This tends to be associated with right-sided lesions interrupting the melodic route in the brain.[5] ## Tactile apperceptive agnosia[edit] Tactile apperceptive agnosia results in the inability to shape representations specific to tactile modality.[citation needed] The impairment is restricted to the hands even though sensation is not impaired. This is similar to visual apperceptive agnosia in that it is a basic level of processing that is impaired.[6] Some individuals are unable to recognize objects by touch because of a small cerebral infarction.[6] Tactile Apperceptive Agnosia can also affect blind people. A seventy-three year old woman, who was blind since she was born, had been 17 days post coronary bypass grafting, when she started to present some concerns related to her ability to read Braille properly, after being able to read it proficiently since she was seven years old. Before the surgery, she could read 4x the amount of chapters than after having the surgery per day (10 chapters before compared to 2 after). She was diagnosed with Braille alexia, a rare form of Tactile Apperceptive Agnosia, three months after her surgery, which effects the ability to join to gather tactile stimuli and the processing of that information. Braille reading speed can be affected by this condition, being slowed down due to the reduced pace of processing tactile information.[7] ## Olfactory Agnosia[edit] Olfactory agnosia is when a patient can smell something, but they can’t identify what they smell is. Like other forms of agnosia, this neural olfactory loss can be due to brain damage, or various diseases like Alzheimer's and Parkinson's disease.[8] ## Visual apperceptive agnosia[edit] Visual apperceptive agnosia is a visual impairment that results in a patient's inability to name objects.[9] While agnosics suffer from severe deficits, patients' visual acuity and other visual abilities such as perceiving parts and colours remain intact.[6] Deficits seem to occur because of damage to early-level perceptual processing.[9] While patients are able to effectively allocate attention to locate the object and perceive the parts, they are unable to group together the parts they see and name the object accurately.[10] This is demonstrated by the fact that patients are more effective at naming two attributes from a single object than they are able to name one attribute on each of the two superimposed objects. In addition they are still able to describe objects in detail and recognize objects by touch.[2] ### Origin[edit] Following Hermann Munk's identification of a condition he called "Seelenblindheit" (mind-blindness) Heinrich Lissauer published an exhaustive diagnostic evaluation of a patient who could not, or only with great difficulty, visually identify common objects.[11] Because primary visual processing was intact, Lissauer considered the possible diagnostic distinction between deficits in perception (apperceptive agnosia) and in recognition (associative agnosia). The topic became prominent when Kurt Goldstein and Adhėmar Gelb published performance details of a patient Schn. with shrapnel fragments in the brain, the result of being wounded in World War I. .[12] He was followed over many years and created a great deal of controversy when subsequent tests were found to be at variance with the original findings.[13] ### Effects[edit] Apperceptive visual agnosia results in profound difficulties on a patient's ability to recognize visually presented information.[14] Apperceptive agnosia affects the perceptual processing of individuals. Impairments of elements such as color and motion makes it difficult to interpret shape or the spatial arrangements of objects.[15] Deficits in apperceptive agnosics have not been linked to deficits in acuity. Additionally, patients have an intact ability to attend to cued stimuli.[10] They have the ability to maintain fixation, reach for moving targets, and write as well. Those with apperceptive agnosia, however, have difficulty copying geometric shapes and letters. In some cases individuals are able to trace letters and shapes with their finger but they are unable to use the technique as a strategy to name objects.[14] Deficits in apperceptive agnosics seem to be differential based on categories.[citation needed] Apperceptive agnosia has been noted to affect both broad and specific deficits[citation needed]. Specific deficits include impairments in the recognition of body parts, buildings, manipulated objects, animals, and places.[9] Picture naming is impaired in visual apperceptive agnosia but recognition of objects can be achieved through accessing other modalities. For example, an object can be recognized through touch.[6] Also when it is spoken about, individuals with apperceptive agnosia are able to define the object.[16] The continuing of the ability of patients to recognize the object through use of different sensory modalities shows that deficits arise because of a breakdown in the interaction between visual systems and semantic memory.[16] ## Location of brain damage[edit] Each patient that suffers from apperceptive agnosia does not have brain damage in exactly the same area. However, brain damage in proximity to the occipital lobe is largely correlated with the patterns of deficit seen in apperceptive agnosics.[2] For example, patient JB suffered extensive damage to the parietal-occipital areas to the left cerebral hemisphere leading to his deficit in the ability to name distinguish between structurally similar object.[16] Visually presented object recognition is largely mediated by a hierarchical occipitotemporal pathway.[17] This pathway facilitates the distinction between regions allowing the processing of the visual features of objects. In addition the occipitoparietal pathway is sometimes damaged in apperceptive agnosia patients.[citation needed] Damage to this region leads to impairments in localization of visual stimuli.[17] ## Theories of causation[edit] No two apperceptive agnosic patients are the same, but case studies have been used to make theories on what causes the object recognition deficits.[citation needed] While it is established that semantics plays a large role in apperceptive agnosia deficits, it is not agreed upon how semantics alter recognition processes.[citation needed]One theory proposes that semantic memories are divided into differential semantic categories. Brain damage leads to apperceptive agnosia because there is damage to a particular semantic category.[citation needed] Another theory, referred to as functional specialization, states that individual parts of the brain specialize in different tasks. According to this theory, if an area of the brain is damaged, the function that the area is responsible for may decline as well. Yet another theory suggests that the pattern of deficit arise from independent impairments to a particular input modality and a single non perceptual semantic system that is organized by category.[citation needed] Deficits are largely due to semantics, however many categories are related perceptually as well.[18] Objects that are biologically similar are likely to have physical resemblance to each other as well.[citation needed] Evidence for this arises in the finding that perceptual confusion arises because of structural similarity contributes or accounts for some modality specific deficit.[14] Object processing is said to occur by two processes.[citation needed] There is first a stage of object perception.[citation needed] In this step there is mapping of visual description from the stimulus to a set of stored structural descriptions onto a set of structural descriptions of familiar objects.[14] In the second stage, there is object identification.[citation needed] In this step the structural description is mapped onto the semantic representations giving rise to a full specification of the object.[18] Researchers differ in their belief[citation needed] of how perceptual knowledge has an effect. Some believe that the loss of perceptual attributes should always accompany structural similarity. Others observe that perceptual and structural information often accompany each other but they believe that the information can occur independently from each other. Based on patient information it seems that objects belonging to a category with many structurally similar neighbours would be vulnerable to this semantic access impairment.[16] ## Case studies[edit] No two apperceptive agnosics are the same so it is beneficial to look at individuals who suffer from apperceptive agnosia to see the range of impairments that can occur and the range of functioning that can remain. ### JB[edit] Patient JB was able to match spoken words to target pictures almost perfectly when the target was presented with three other dissimilar distractors from the same semantic category. However, when the distractors were similar to each other and from the same semantic category his functioning decreased significantly. His abilities show evidence that the problem may lie in an interaction between processes involved in specification of the object’s visual structural description and access to semantic systems.[16] ### ELM[edit] Patient ELM was sixty-one years old when this case study was under review. In 1982, he was first admitted to a hospital for Atrial Fibrillation, and presented symptoms of left/ right confusion, nominal dysphasia, agraphia (minus the Alexia), and dysgraphia. After further examination, it was discovered that ELM had a Cortical Lesion in his left hemisphere in the temporal lobe.[19] ELM has deficits in the ability to name drawings of living things even though her ability to name man-made things remain intact. The early visual processing of shapes appear to be intact as well. In addition, unlike many patients, the ability to identify overlapping drawings of man-made objects remained intact. ELM was able to match both living and non-living things viewed from different perspectives. ELM’s deficit lied in the fact that she was not able to distinguish between drawings that were real and plausibly unreal objects that were living; however, she was able to make the distinction when the objects were man made. Her impairments resulted due to damage to structural description of living things. There were problems with integrating features of structurally similar shapes of objects belonging to the same semantic category. This inability might be because of the distance between associated objects. The ones that are semantically close to each other are harder to differentiate.[16] ### HJA[edit] HJA had deficits in differentiating between living things. She also made errors while naming line drawings. Instead of naming the pictures HJA frequently gave feature-by-feature description of the object (e.g. instead of saying circle, she would say many little dots). In addition, she would separate parts of drawn object instead of saying the name of the whole (e.g. handle and hairs when referring to paintbrush). HJA has problems segmenting global shapes when elements are closely grouped together. However, unlike the other patients, HJA has no problem copying and identifying overlapping drawings. In addition, HJA was able to draw objects accurately from the memory.[16] ## Populations affected[edit] There are subsets of groups in which apperceptive agnosia is more widespread.[citation needed] ### Alzheimer's disease[edit] Visual agnosia (both apperceptive and associative) is prevalent in Alzheimer's disease (AD) patients. Visual agnosia may be present in early stages of AD and can often act as an indicator of AD.[20] Apperceptive agnosia results from diffuse cortical pathology of AD. There is early involvement in the hippocampus and the entorhinal cortex followed by a spread to adjacent areas with neurofibrillary tangles (NFT). Gradual extension of NFT throughout the occipital, parietal, and temporal regions devoted to vision occur resulting in visual agnosia.[15] ## See also[edit] * Agnosia * Associative visual agnosia * Aphasia * Visual agnosia * Visual space * Patient DF ## References[edit] 1. ^ David Andrewes (13 May 2013). Neuropsychology: From Theory to Practice. Psychology Press. p. 50. ISBN 978-1-134-95046-1. 2. ^ a b c Shelton, P.A.; Bowers, D.; Duara, R. (1994). "Apperceptive Visual Agnosia: A Case Study". Brain and Cognition. 25 (1): 1–23. doi:10.1006/brcg.1994.1019. PMID 8043261. S2CID 30261660. 3. ^ De Renzi, E. (2000). "Disorder of Visual Recognition". Seminars in Neurology. 20 (4): 479–485. doi:10.1055/s-2000-13181. PMID 11149704. 4. ^ a b c d Buchtel, H.A.; Stewart, J.D. (1989). "Auditory Agnosia: Apperceptive or Associative Disorder?". Brain and Language. 37 (1): 12–25. doi:10.1016/0093-934X(89)90098-9. PMID 2752270. S2CID 7549010. 5. ^ a b Ayotte, J.; Peretz, I.; Rousseau, I.; Bard, C.; Bojanowski, M. (2000). "Patterns of Music Agnosia Associated with Middle Cerebral Artery Infarcts". Brain. 123 (9): 1926–1938. doi:10.1093/brain/123.9.1926. PMID 10960056. 6. ^ a b c d Reed, C.L.; Caselli, R.J.; Farah, M.J. (1996). "Tactile Agnosia - Underlying Impairment and Implications for Normal Tactile Object Recognition". Brain. 119 (3): 875–888. doi:10.1093/brain/119.3.875. PMID 8673499. Retrieved 10 March 2012. 7. ^ Larner, Andrew J (August 2007). "Braille alexia: an apperceptive tactile agnosia?". Journal of Neurology, Neurosurgery, and Psychiatry. 78 (8): 907–908. doi:10.1136/jnnp.2006.106922. ISSN 0022-3050. PMC 2117751. PMID 17635985. 8. ^ Lalwani, Anil K. (2012), Lalwani, Anil K. (ed.), "Chapter 10. Olfactory Dysfunction", CURRENT Diagnosis & Treatment in Otolaryngology—Head & Neck Surgery (3 ed.), New York, NY: The McGraw-Hill Companies, retrieved 2020-07-01 9. ^ a b c Vecera, S.; Gilds, K. (1998). "What Processing Is Impaired in Apperceptive Agnosia? Evidence from Normal Subjects". Journal of Cognitive Neuroscience. 10 (5): 568–80. doi:10.1162/089892998562979. PMID 9802990. S2CID 21568462. 10. ^ a b Abrams, R.A.; Law, M.B (2002). "Random Visual Noise Impairs Object-based Attention" (PDF). Exp Brain Res. 142 (3): 349–353. doi:10.1007/s00221-001-0899-2. PMID 11819043. S2CID 10236264. Retrieved 10 March 2012.[permanent dead link] 11. ^ Lissauer H (1890). "Ein Fall von Seelenblindheit". Archiv für Psychiatrie und Nervenkrankheiten. 21 (2): 222–270. doi:10.1007/bf02226765. S2CID 29786214. 12. ^ Gelb, A, Goldstein, K (1920) Zur Psychologie des optischen Wahrnehmungs und Erkennungsvorgangs.pp 1- 142 In Psychologische Analysen hirnpatholosicher Fälle. Leipzig: J.A. Barth 13. ^ Jung R (1949). "Uber eine Nachuntersuchung des Falles Schn. von Goldstein und Gelb". Psychiatrie Neurologie und Medizinische Psychologie. 1: 353–362. 14. ^ a b c d Grossman, M.; Galetta, S.; D'esposito, M. (1997). "Object Recognition Difficulty in Visual Apperceptive Agnosia". Brain and Cognition. 33 (3): 306–342. doi:10.1006/brcg.1997.0876. PMID 9126398. S2CID 11582998. 15. ^ a b Duffy CJ (January 1999). "Visual loss in Alzheimer's disease: out of sight, out of mind". Neurology. 52 (1): 10–1. doi:10.1212/wnl.52.1.10. PMID 9921840. S2CID 45432450. 16. ^ a b c d e f g Funnell, E. (2000). "Apperceptive Agnosia and the Visual Recognition of Object Categories in Dementia of the Alzheimer Type". Neurocase. 6 (6): 451–463. doi:10.1080/13554790008402716. S2CID 144011405. 17. ^ a b Ferreira, C.T.; Ceccaldi, M; Giusiano, B.; Poncet, M. (1998). "Separate Visual Pathways for Perception of Actions and Objects: Evidence from A Case Apperceptive Agnosia". J Neurol Neurosurg Psychiatryiatry. 65 (3): 382–385. doi:10.1136/jnnp.65.3.382. PMC 2170224. PMID 9728957. Retrieved 9 March 2012. 18. ^ a b De Renzi E (2000). "Disorder of Visual Recognition". Seminars in Neurology. 20 (4): 479–485. doi:10.1055/s-2000-13181. PMID 11149704. 19. ^ Forde, Emer; Humphreys, Glyn (2005-07-22). Category Specificity in Brain and Mind. Psychology Press. ISBN 978-1-135-42625-5. 20. ^ Giannakopoulos, P.; Gold, G.; Duc, M.; Michel, J.-P.; Hof, P.R; Bouras, C. (1999). "Neuroanatomic Correlates of Visual Agnosia in Alzheimer's Disease: A Clinicopathologic". Neurology. 52 (1): 71–77. doi:10.1212/wnl.52.1.71. PMID 9921851. S2CID 25961742. Retrieved 10 March 2012. ## Further reading[edit] * Fundamentals of Sensation and Perception, Michael Levine. Oxford University Press (3rd Edition). London, 2000. * Visual Perception, Tom Cornsweet. Harcourt Publishing, London, 1970. * v * t * e * Diseases of the human eye Adnexa Eyelid Inflammation * Stye * Chalazion * Blepharitis * Entropion * Ectropion * Lagophthalmos * Blepharochalasis * Ptosis * Blepharophimosis * Xanthelasma * Ankyloblepharon Eyelash * Trichiasis * Madarosis Lacrimal apparatus * Dacryoadenitis * Epiphora * Dacryocystitis * Xerophthalmia Orbit * Exophthalmos * Enophthalmos * Orbital cellulitis * Orbital lymphoma * Periorbital cellulitis Conjunctiva * Conjunctivitis * allergic * Pterygium * Pseudopterygium * Pinguecula * Subconjunctival hemorrhage Globe Fibrous tunic Sclera * Scleritis * Episcleritis Cornea * Keratitis * herpetic * acanthamoebic * fungal * Exposure * Photokeratitis * Corneal ulcer * Thygeson's superficial punctate keratopathy * Corneal dystrophy * Fuchs' * Meesmann * Corneal ectasia * Keratoconus * Pellucid marginal degeneration * Keratoglobus * Terrien's marginal degeneration * Post-LASIK ectasia * Keratoconjunctivitis * sicca * Corneal opacity * Corneal neovascularization * Kayser–Fleischer ring * Haab's striae * Arcus senilis * Band keratopathy Vascular tunic * Iris * Ciliary body * Uveitis * Intermediate uveitis * Hyphema * Rubeosis iridis * Persistent pupillary membrane * Iridodialysis * Synechia Choroid * Choroideremia * Choroiditis * Chorioretinitis Lens * Cataract * Congenital cataract * Childhood cataract * Aphakia * Ectopia lentis Retina * Retinitis * Chorioretinitis * Cytomegalovirus retinitis * Retinal detachment * Retinoschisis * Ocular ischemic syndrome / Central retinal vein occlusion * Central retinal artery occlusion * Branch retinal artery occlusion * Retinopathy * diabetic * hypertensive * Purtscher's * of prematurity * Bietti's crystalline dystrophy * Coats' disease * Sickle cell * Macular degeneration * Retinitis pigmentosa * Retinal haemorrhage * Central serous retinopathy * Macular edema * Epiretinal membrane (Macular pucker) * Vitelliform macular dystrophy * Leber's congenital amaurosis * Birdshot chorioretinopathy Other * Glaucoma / Ocular hypertension / Primary juvenile glaucoma * Floater * Leber's hereditary optic neuropathy * Red eye * Globe rupture * Keratomycosis * Phthisis bulbi * Persistent fetal vasculature / Persistent hyperplastic primary vitreous * Persistent tunica vasculosa lentis * Familial exudative vitreoretinopathy Pathways Optic nerve Optic disc * Optic neuritis * optic papillitis * Papilledema * Foster Kennedy syndrome * Optic atrophy * Optic disc drusen Optic neuropathy * Ischemic * anterior (AION) * posterior (PION) * Kjer's * Leber's hereditary * Toxic and nutritional Strabismus Extraocular muscles Binocular vision Accommodation Paralytic strabismus * Ophthalmoparesis * Chronic progressive external ophthalmoplegia * Kearns–Sayre syndrome palsies * Oculomotor (III) * Fourth-nerve (IV) * Sixth-nerve (VI) Other strabismus * Esotropia / Exotropia * Hypertropia * Heterophoria * Esophoria * Exophoria * Cyclotropia * Brown's syndrome * Duane syndrome Other binocular * Conjugate gaze palsy * Convergence insufficiency * Internuclear ophthalmoplegia * One and a half syndrome Refraction * Refractive error * Hyperopia * Myopia * Astigmatism * Anisometropia / Aniseikonia * Presbyopia Vision disorders Blindness * Amblyopia * Leber's congenital amaurosis * Diplopia * Scotoma * Color blindness * Achromatopsia * Dichromacy * Monochromacy * Nyctalopia * Oguchi disease * Blindness / Vision loss / Visual impairment Anopsia * Hemianopsia * binasal * bitemporal * homonymous * Quadrantanopia subjective * Asthenopia * Hemeralopia * Photophobia * Scintillating scotoma Pupil * Anisocoria * Argyll Robertson pupil * Marcus Gunn pupil * Adie syndrome * Miosis * Mydriasis * Cycloplegia * Parinaud's syndrome Other * Nystagmus * Childhood blindness Infections * Trachoma * Onchocerciasis [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Apperceptive agnosia	None	3,770	wikipedia	https://en.wikipedia.org/wiki/Apperceptive_agnosia	2021-01-18T18:47:21	{"wikidata": ["Q1859754"]}
In monilethrix the hairs show regularly spaced fusiform, spindle-shaped or elliptical swellings. The nodes are the normal diameter of the shaft and the internodes represent atrophic parts. In pseudomonilethrix the nodes are irregularly spaced and the internodes represent the normal hair-shaft caliber. The latter condition was first described by Bentley-Phillips et al. (1974). It is manifested by alopecia, as in true monilethrix. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	PSEUDOMONILETHRIX	c0432346	3,771	omim	https://www.omim.org/entry/177750	2019-09-22T16:35:36	{"mesh": ["C562988"], "omim": ["177750"]}
## Description Linear and whorled hypermelanosis (LWNH) is a benign skin condition characterized by onset in infancy of hyperpigmented regions composed of small light brown spots that coalesce with age and follow the lines of Blaschko on the trunk and limbs. The soles, palms, face, and mucous membranes are spared. The lesions are asymptomatic and progress with age; affected individuals have no accompanying extradermal features. There is no previous history of inflammation on affected areas (summary by Kalter et al., 1988). Clinical Features Iijima et al. (1987) reported 2 unrelated Japanese children with early-onset reticulate hyperpigmentation distributed in a zosteriform pattern along the lines of Blaschko on the trunk and limbs, but sparing the face, palms, and soles. The first girl presented at age 4 months with a history of the pigmentation beginning at age 1.5 months. She had no other abnormalities except for mild crowding of some baby teeth. The areas of hyperpigmentation were formed by a coalescence of light brown 1- to 2-mm irregular spots with clearly defined borders and no variation in color. Skin biopsy showed increased melanin in the basal layer, but no increase in melanocytes and no melanophages. Her mother and brother had nevus spilus. The second child was a 5-year-old girl with small asymptomatic pigmented spots that appeared on the insides of both lower legs at age 2, which then gradually expanded to involve the thighs, upper limbs, and trunk in a zosteriform pattern. The affected regions consisted of irregular brown 2- to 3-mm spots with clearly defined borders and partially fused to produce a reticulate pattern. Light microscopy showed an increase in melanin in the basal layer, but no melanophages. Both patients had mildly increased peripheral eosinophils. Neither child had any other abnormalities or family history of a similar disorder, and the features could be distinguished from other known pigmentary disorders, particularly incontinentia pigmenti (IP; 308300). Iijima et al. (1987) noted that the entity was most similar to progressive cribriform and zosteriform hyperpigmentation (PCZH; see below) described by Rower et al. (1978), except that it was more extensive and showed earlier onset compared to the latter cases. Kalter et al. (1988) reported 2 unrelated individuals with what they termed congenital linear and whorled nevoid hypermelanosis (LWNH). A 12-month-old Caucasian girl developed brown streaks on her ankles soon after birth, which gradually spread to involve most of her body asymmetrically, but along the lines of Blaschko. Follow-up until age 6 years showed that the lesions grew in size with her and darkened with sun exposure. All other aspects of development were normal. The hyperpigmentation consisted of 1- to 5-mm light brown macules and streaks especially obvious on the flanks and sparing the palms, soles, and mucous membranes. Skin biopsy showed increased basal layer pigmentation with normal basal melanocytes that were somewhat increased in number. Electron microscopy showed an increase in the number of melanosomes in the hyperpigmented skin. There was no family history of a similar disorder. A 6-month-old Indian boy had a similar condition beginning at 2 to 3 weeks of age. The first patient had mildly increased peripheral eosinophil counts on 1 occasion. Chromosome analysis of cultured lymphocytes from both patients showed no evidence of mixoploidy or chimerism, and cytogenetic analysis of cultured fibroblasts showed no detectable chromosomal changes. Kalter et al. (1988) distinguished the disorder from hypomelanosis of Ito (HMI; 300337), but suggested that LWNH may reflect mosaicism of neuroectodermal cells. Bjorngren and Holst (1991) reported a 15-year-old Caucasian girl with reticulate hyperpigmentation similar to that reported by Iijima et al. (1987). She presented for acne evaluation and was found to have hyperpigmentation of several body regions, including the trunk, arms, and legs. The changes were light brown 2- to 3-cm spots, irregular in shape with clearly defined borders. They had coalesced to form streaks and whorls symmetrically. Microscopic analysis showed increased granular pigment in the cytoplasm at the base of the rete ridges, but no increase of melanocytes. History revealed a 7 x 10-mm nevus spilus in infancy and a 2- to 3-mm woolly hair nevus on the scalp at age 3. Di Lernia et al. (1992) suggested that the patient reported by Bjorngren and Holst (1991) more likely had progressive cribriform and zosteriform hyperpigmentation, as described by Rower et al. (1978), due to the later onset. Di Lernia et al. (1992) emphasized that PCZH and LWNH are likely part of the same disorder. Di Lernia (2007) reported a retrospective review of 16 unrelated children referred for segmental, linear, or swirled hyperpigmentation distributed along the lines of Blaschko. Six patients had classic LWNH with onset in infancy of progressive widespread hyperpigmentation. Ten patients had later onset of unilateral hyperpigmentation, which Di Lernia (2007) considered to be consistent with PCZH. The hyperpigmentation was not preceded by inflammation in any case. Histologic studies showed a mild increase of melanin in the basal layer of the epidermis and mild elongation of the rete ridges. Other abnormalities were found in 2 patients: 1 had severe developmental delay with autism, and the other had onset in adolescence of atrophic gastritis and anorexia nervosa. Additional anomalies were not found in any other patient. Di Lernia (2007) noted the overlap of LWNH and PCZH with hypomelanosis of Ito, which is characterized by hypopigmentation in a linear and whorled pattern following the lines of Blaschko and believed to result from somatic mosaicism, and suggested that all 3 conditions represent 1 entity, that of 'pigmentary mosaicism.' ### Progressive Cribriform and Zosteriform Hyperpigmentation Rower et al. (1978) reported 5 unrelated patients with progressive cribriform and zosteriform hyperpigmentation (PCZH). Age at onset ranged between 10 and 18 years. The lesions were composed of light brown spots with increased basal layer pigmentation on microscopy. The lesions were located on the lower thighs or torso, were confined to 1 side of the body, and showed gradual extension with time. None of the patients had other abnormalities and the condition was benign. Inheritance Most cases of LWNH occur sporadically. However, Akiyama et al. (1994) reported a Japanese mother and daughter with the condition. Asymptomatic hyperpigmented macules in a streaky configuration appeared on the trunk and extremities in both patients several weeks after birth and then gradually spread. Light microscopy showed a slight increase in the number of melanocytes in the epidermis and irregular basal melanosis. Ultrastructural studies showed an increase in the number of normal-appearing melanosomes in keratinocytes. Chromosome analysis of peripheral blood cells and dermal fibroblasts showed no evidence of chimerism. Metta et al. (2011) reported an Indian family in which a 12-year-old girl, her 45-year-old mother, and the 65-year-old maternal grandmother all had asymptomatic LWNH with onset in infancy and gradual progression. The mother and grandmother had a history of the lesions fading over time. None of the patients had accompanying features. Genetic studies showed trisomy 20 in the mother's blood, but this was not found in the child. INHERITANCE \- Autosomal dominant \- Isolated cases SKIN, NAILS, & HAIR Skin \- Hyperpigmented streaks following lines of Blaschko \- Hyperpigmented whorls \- Reticulate hyperpigmentation composed of 1- to 5-mm light brown spots with clearly defined borders that may coalesce \- Lesions appear on the trunk and limbs but the face, palms, soles, and mucosa are spared Skin Histology \- Normal or mildly increased numbers of basal melanocytes \- Increased melanin in the basal layer \- Mild elongation of the rete ridges \- No melanophages \- No incontinence of pigment Electron Microscopy \- Increased numbers of melanosomes in keratinocytes LABORATORY ABNORMALITIES \- Mild eosinophilia may occur MISCELLANEOUS \- Onset in infancy \- No preceding skin inflammatory stage \- Lesions grow and spread with age \- May fade with age \- Onset in second decade or unilateral involvement indicates a diagnosis of 'progressive cribriform and zosteriform hyperpigmentation' (PCZH) \- Benign condition ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	NEVOID HYPERMELANOSIS, LINEAR AND WHORLED	c1304501	3,772	omim	https://www.omim.org/entry/614323	2019-09-22T15:55:42	{"omim": ["614323"], "orphanet": ["79150"]}
## Summary ### Clinical characteristics. Urofacial syndrome (UFS) is characterized by prenatal or infantile onset of urinary bladder voiding dysfunction, abnormal facial movement with expression (resulting from abnormal co-contraction of the corners of the mouth and eyes), and often bowel dysfunction (constipation and/or encopresis). Bladder voiding dysfunction increases the risk for urinary incontinence, megacystis, vesicoureteric reflux, hydroureteronephrosis, urosepsis, and progressive renal impairment. In rare instances, an individual who has (a) a molecularly confirmed diagnosis and/or (b) an affected relative meeting clinical diagnostic criteria manifests only the characteristic facial features or only the urinary bladder voiding dysfunction (not both). Nocturnal lagophthalmos (incomplete closing of the eyes during sleep) appears to be a common and significant finding. ### Diagnosis/testing. The diagnosis of UFS is based on investigations of the urinary tract that reveal characteristic urinary tract abnormalities and physical examination that reveals characteristic facial movement with expression. UFS is a heterogeneous condition resulting from biallelic pathogenic variants in either HPSE2 or LRIG2. In some instances no pathogenic change has been identified. Note that the majority of individuals with UFS reported to date have not had molecular confirmation of their diagnosis. ### Management. Treatment of manifestations: Rapid and complete treatment of urinary tract infections and routine treatment of urosepsis. For urinary incontinence and bladder dysfunction: use of anticholinergic and α1-adrenergic blockers; intermittent catheterization or vesicostomy; surgical management of hydroureteronephrosis and bladder augmentation should be considered. Management of chronic kidney disease and end-stage renal disease relies on the standard optimal options. Surveillance: Monitor for evidence of urinary tract features including vesicoureteric reflux and hydroureteronephrosis. Renal function should be monitored at intervals determined by urinary tract features at presentation and their subsequent progression. Agents/circumstances to avoid: Nephrotoxic substances. Evaluation of relatives at risk: It is appropriate to examine sibs of an affected individual as soon as possible after birth to determine if facial and/or urinary tract manifestations of UFS are present to allow prompt evaluation of the urinary tract and renal function and prompt initiation of necessary treatment. Pregnancy management: Although no guidelines for prenatal management of UFS exist, it seems appropriate to perform ultrasound examination of pregnancies at risk to determine if urinary tract involvement of UFS is present, as this may influence the timing and/or location of delivery (e.g., in a tertiary medical center that could manage renal/urinary complications immediately after birth). ### Genetic counseling. UFS is inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. If the pathogenic variants in the family are known, carrier testing for at-risk relatives and prenatal and preimplantation genetic testing are possible. ## Diagnosis No formal diagnostic criteria for urofacial syndrome (UFS) have been published. ### Suggestive Findings Urofacial syndrome (UFS) should be suspected in individuals with the following clinical findings. Classic clinical findings * Urinary bladder dysfunction (also termed non-neurogenic neurogenic voiding dysfunction, occult or subclinical neuropathic bladder) with detrusor overactivity and detrusor sphincter dyssynergia [Feldman & Bauer 2006]. Affected individuals are at risk for urinary incontinence, urosepsis, and progressive renal impairment [Ochoa 2004, Aydogdu et al 2010, Stuart et al 2013]. Urinary tract features have been present in nearly all reported individuals [Aydogdu et al 2010, Stuart et al 2013]. Characteristic urinary tract abnormalities: * Postnatal imaging of the bladder typically shows muscular thickening and trabeculation, but may also be normal [Ochoa 1992, Ochoa 2004, Derbent et al 2009, Aydogdu et al 2010]. * Hydroureteronephrosis is common [Ochoa 1992, Ochoa 2004]. * Micturating cystourethrogram may reveal vesicoureteric reflux [Ochoa 2004]; intra-urethral anatomic lesions are not observed. Cystoscopy, if performed, reveals no urethral lesions. * A characteristic abnormality of facial movement with expression, resulting from abnormal co-contraction of the corners of the mouth and eyes, which is most obvious during smiling or laughing and often described as a "grimace" [Ochoa 2004, Aydogdu et al 2010, Ganesan & Thomas 2011]. Typical facial expressions have been present in all but one individual (who was diagnosed due to classic features in a relative) [Aydogdu et al 2010]. Other clinical findings * Bowel dysfunction, including constipation, reported in about 66% and encopresis in 33% of affected individuals [Ochoa 2004] * Nocturnal lagophthalmos (incomplete closing of the eyelids during sleep) ### Establishing the Diagnosis The diagnosis of UFS is established in a proband by either of the following: * The presence of the two main clinical features involving the urinary bladder and face described in Suggestive Findings [Ochoa 2004] * Identification of biallelic pathogenic variants in either HPSE2 or LRIG2 (Table 1) Note that the majority of individuals with UFS reported to date have not had molecular confirmation of their diagnosis. Molecular genetic testing approaches can include gene-targeted testing (serial single-gene testing) and comprehensive genomic testing (exome or genome sequencing). Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive findings described in Suggestive Findings are likely to be diagnosed using gene-targeted testing (see Option 1), whereas those in whom the diagnosis of UFS has not been considered due to the overlap of the urinary tract features of UFS with other disorders of the lower urinary tract and lack of recognition of the characteristic facial expression are more likely to be diagnosed using genomic testing (see Option 2). #### Option 1 When the phenotypic findings suggest the diagnosis of UFS, serial single-gene testing is typically used. Single-gene testing. Sequence analysis detects small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. Perform sequence analysis of HPSE2 first; if only one or no pathogenic variants are identified perform gene-targeted deletion/duplication analysis to detect intragenic deletions or duplications. If testing of HPSE2 is nondiagnostic, perform sequence analysis of LRIG2. #### Option 2 When the diagnosis of UFS has not been considered, comprehensive genomic testing (which does not require the clinician to determine which gene[s] are likely involved) is the best option [Vivante et al 2017]. Exome sequencing is most commonly used; genome sequencing is also possible. Exome array (when clinically available) may be considered if exome sequencing is nondiagnostic. 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 Urofacial Syndrome View in own window Gene 1, 2Proportion of UFS Attributed to Pathogenic Variants in Gene 3Proportion of Pathogenic Variants 4 Detectable by Method Sequence analysis 5Gene-targeted deletion/duplication analysis 6 HPSE217/2516/17 71 family 8 LRIG24/254/4 9None reported Unknown4/25NA 1\. Genes are listed in alphabetic order. 2\. See Table A. Genes and Databases for chromosome locus and protein. 3\. Stuart et al [2013], Stuart et al [2015] 4\. See Molecular Genetics for information on allelic variants detected in this gene. 5\. Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here. 6\. Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. 7\. Daly et al [2010], Pang et al [2010], Al Badr et al [2011], Mahmood et al [2012], Stuart et al [2015] 8\. Daly et al [2010] 9\. Note: A large Alu insertion resulting in exon skipping has been reported [Stuart et al 2013]. ## Clinical Characteristics ### Clinical Description The main features of urofacial syndrome (UFS) are congenital urinary bladder voiding dysfunction and an abnormality of facial movement with expression that can be observed from birth. Bowel dysfunction is common. In rare instances, an individual who has: (a) a molecularly confirmed diagnosis; and/or (b) an affected relative meeting clinical diagnostic criteria manifests only the characteristic facial features or only the urinary bladder voiding dysfunction (not both). Significant inter- and intrafamilial phenotypic variability has been observed [Ochoa 1992, Aydogdu et al 2010, Stuart et al 2013, Stuart et al 2015]. Urinary tract features are the main reason for presenting to medical attention and the main cause of associated morbidity and mortality. UFS is not associated with growth or developmental abnormality other than that attributable to chronic renal disease. Intellect is normal. Urinary tract. Urinary tract features have been present in all but two of more than 150 clinically defined individuals [Aydogdu et al 2010, Stuart et al 2013, Stuart et al 2015]. Antenatal ultrasound examination (if performed) is frequently described as abnormal and is associated with megacystis, hydroureteronephrosis, and renal pelvis dilatation [Skálová et al 2006, Bacchetta & Cochat 2010, Daly et al 2010, Stuart et al 2013]. Severe neonatal and infant presentations with urinary tract complications including urinary bladder rupture and sepsis have been reported [Ochoa 1992, Skálová et al 2006]. More typical presentations of urinary tract features include recurrent urinary sepsis and failure to achieve urinary continence [Ochoa 1992, Ochoa 2004]. In the Ochoa cohort hydroureteronephrosis was found in 29/50 (58%) of affected individuals [Ochoa 1992, Ochoa 2004], a finding consistent with the range of urinary tract abnormalities in other case reports [Chauve et al 2000, Garcia-Minaur et al 2001, Al-Qahtani 2003, Nicanor et al 2005, Skálová et al 2006, Derbent et al 2009, Aydogdu et al 2010, Daly et al 2010, Stamatiou & Karakos 2010, Sutay et al 2010, Al Badr et al 2011, Akl & Al Momany 2012, Mahmood et al 2012, Stuart et al 2013, Stuart et al 2015]. Ochoa [2004] identified vesicoureteric reflux in 32/50 (64%); reflux was bilateral in 18 (36%). The associated renal parenchymal damage with early impairment of renal function and progression to end-stage renal disease causes substantial morbidity and mortality [Ochoa 2004, Skálová et al 2006, Sutay et al 2010, Mahmood et al 2012]. The proportion of individuals who develop renal impairment is unknown but likely to be significant [Ochoa & Gorlin 1987, Ochoa 1992, Ochoa 2004, Aydogdu et al 2010]. Facial expression. The most prominent facial feature, abnormal co-contraction of the corners of the mouth and eyes, is most obvious during smiling or laughing [Ochoa 2004, Aydogdu et al 2010, Ganesan & Thomas 2011] and can be socially debilitating. Symmetric partial facial paresis in the distribution of the facial nerve has been noted; however, the proportion of individuals in whom weakness is a significant feature is unknown [Garcia-Minaur et al 2001; Author, personal observation]. Abnormal facial movement with crying has been observed as early as the neonatal period [Ochoa 1992, Skálová et al 2006]. Nocturnal lagophthalmos (incomplete closing of the eyes during sleep) appears to be a common and significant finding that may lead to keratitis, corneal abrasion, infection, vascularization, and in extreme cases, ocular perforation, endophthalmitis, and loss of the eye [Mermerkaya et al 2014]. Typical facial expressions have been present in all but one affected individual (who was diagnosed due to classic features in a relative) [Aydogdu et al 2010]. Rarely, affected individuals may have a facial phenotype with no urinary bladder dysfunction or symptoms [Stuart et al 2013; Author, personal communication]. Gastrointestinal tract. Constipation is reported in about 66% of affected individuals; encopresis is present in 33% [Ochoa 2004]. Fecal retention in the neonatal period has been noted once [Nicanor et al 2005]. Rectal prolapse has also been reported once in association with severe constipation [Al Badr et al 2011]. MRI of the central nervous system (CNS) – performed because the urinary tract features mimic those associated with CNS dysfunction – is typically normal [Nicanor et al 2005, Derbent et al 2009, Aydogdu et al 2010, Al Badr et al 2011, Akl & Al Momany 2012]. UFS most likely results from an abnormality of peripheral rather than central nervous system development [Roberts et al 2014], although affected individuals do not typically show any other features of neurologic dysfunction. Note: Although early descriptions of UFS reported individuals with central nervous system abnormalities including spina bifida occulta, occipital meningocele, and hydrocephalus due to stenosis of the aqueduct of Sylvius, the subsequent failure to identify these findings indicates that they were most likely chance associations [Elejalde 1979, Teebi & Hassoon 1991]. ### Genotype-Phenotype Correlations No genotype-phenotype correlations have been reported. ### Prevalence UFS is rare. Its prevalence is currently unknown but is likely to be higher in certain populations – for example, in Colombia as the result of a founder variant and associated consanguinity [Ochoa 2004, Pang et al 2010]. ## Differential Diagnosis The urinary tract features of urofacial syndrome (UFS) overlap with those seen in association with multiple other conditions [Woolf et al 2014a]. Antenatal or congenital megacystis and/or hydronephrosis * Urethral obstruction due to posterior urethral valves or atresia * Chromosome abnormalities (e.g., megacystis in association with trisomy 21 and 13) * Prune belly sequence (e.g., caused by biallelic pathogenic variants in CHRM3 [Weber et al 2011]) * Megacystis microcolon intestinal hypoperistalsis syndrome, a heterogeneous condition resulting from smooth muscle dysfunction caused by heterozygous variants in: * ACTA2 (encoding α-smooth muscle actin) [Richer et al 2012] * ACTG2 (encoding γ2-smooth muscle actin) (see ACTG2-Related Disorders) OR biallelic variants in: * LMOD1 (encoding leiomodin1) [Halim et al 2017b] * MYH11 (encoding myosin light chain kinase) [Gauthier et al 2015] * MYLK (encoding myosin light chain kinase) [Halim et al 2017a] * MYL9 (encoding myosin light chain 9) [Moreno et al 2018] Urinary bladder voiding dysfunction * Neuropathic bladder (e.g., due to a neurologic lesion such as spina bifida) * Voiding dysfunction of unclear etiology, variably termed occult neuropathic bladder, subclinical neuropathic bladder, non-neurogenic neurogenic bladder, and Hinman-Allen syndrome Vesicoureteric reflux * Common in the general population * May be familial and is genetically heterogeneous ## Management ### Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with urofacial syndrome (UFS), the evaluations summarized in this section (if not performed as part of the evaluation that led to the diagnosis) are recommended: * Urinalysis and urine culture for occult or chronic infection * Assessment of renal function: serum creatinine concentration and/or estimated glomerular filtration rate * Urinary tract ultrasound examination * Micturating cystourethrogram * Uroflowmetry or urodynamic testing * Blood pressure measurement * Assessment of renal parenchymal damage: as indicated by the individual's presentation, dimercaptosuccinic acid (DMSA) isotope scan to visualize functional kidney parenchyma [Ochoa 2004, Aydogdu et al 2010, Stuart et al 2013] * Assessment of bowel emptying * Ophthalmologic examination for evidence of nocturnal lagophthalmos * Consultation with a clinical geneticist and/or genetic counselor ### Treatment of Manifestations Urinary tract. No evidence-based guidelines exist for treatment of the urinary tract abnormalities of UFS. Urinary tract infections warrant rapid and complete treatment. Urosepsis should be treated as per the general population with antibiotic use directed by culture; antibiotic prophylaxis may also be considered. Anticholinergic and α1-adrenergic blockers have been used in the medical management of urinary incontinence and bladder dysfunction [Aydogdu et al 2010, Stuart et al 2013]. Intermittent catheterization or vesicostomy to reduce residual urine volumes and achieve continence with a reduced risk of infections have been used. Surgical management of hydroureteronephrosis and bladder augmentation to slow progression of renal impairment have been used; their efficacy is not known [Ochoa 2004, Stuart et al 2013]. Early recognition of renal impairment should prompt initiation of intensive management to prevent or slow progression. Renal impairment and hypertension are managed as per clinical status. Successful renal transplantation has been reported [Ochoa 2004]. Bowel. Constipation is managed as for the general population. Nocturnal lagophthalmos requires lubricant drops during the day and ointments at night to protect the cornea from exposure keratopathy (typically under the care of an ophthalmologist) [Mermerkaya et al 2014]. ### Surveillance Monitor: * For evidence of urinary tract features including vesicoureteric reflux and hydroureteronephrosis; * Renal function at intervals determined by urinary tract features at presentation and their subsequent progression; * For evidence of significant corneal involvement in individuals with nocturnal lagophthalmos. ### Agents/Circumstances to Avoid Nephrotoxic substances contraindicated in individuals with renal impairment should be avoided if possible. ### Evaluation of Relatives at Risk It is appropriate to clarify the genetic/clinical status of sibs of an affected individual as soon as possible after birth in order to identify those who would benefit from prompt evaluation of the urinary tract and renal function and early initiation of necessary treatment. Evaluations can include: * Molecular genetic testing if the pathogenic variants in the family are known; * Examination to determine whether facial and/or urinary tract manifestations of UFS are present if the pathogenic variants in the family are not known. See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes. ### Pregnancy Management Although no guidelines for prenatal management of UFS exist, it seems appropriate to perform ultrasound examination of pregnancies at risk to determine if urinary tract involvement of UFS is present, as it may influence the timing and/or location of delivery (e.g., in a tertiary medical center that could manage renal/urinary complications immediately after birth). ### Therapies Under Investigation Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Urofacial Syndrome	c0403555	3,773	gene_reviews	https://www.ncbi.nlm.nih.gov/books/NBK154138/	2021-01-18T20:51:08	{"mesh": ["C536480"], "synonyms": ["Ochoa Syndrome"]}
This syndrome is characterised by severe microcephaly, agyria, agenesis of the corpus callosum, cerebellar hypoplasia, facial dysmorphology and epiphyseal stippling of the metacarpal bones. It has been described in two brothers. The syndrome is transmitted as an autosomal recessive trait and may be an allelic variant of Neu-Laxova syndrome and Lissencephaly type III with cystic dilations of the cerebellum and foetal akinesia sequence (see these terms). [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Lissencephaly type 3-metacarpal bone dysplasia syndrome	c1832678	3,774	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=86822	2021-01-23T17:36:51	{"mesh": ["C563383"], "omim": ["601160"], "icd-10": ["Q04.3"]}
Brusing injury to the face This article is about the injury. For other uses, see Black eye (disambiguation). Not to be confused with Eye black. 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: "Black eye" – news · newspapers · books · scholar · JSTOR (May 2012) (Learn how and when to remove this template message) Black eye Other namesPeriorbital hematoma SpecialtyEmergency medicine A periorbital hematoma, commonly called a black eye, is bruising around the eye commonly due to an injury to the face rather than to the eye. The name refers to the color of bruising. The so-called black eye is the result of accumulation of blood and fluid in the loose areolar tissue following a blow to the head. This blood tracks freely under the scalp producing a generalised swelling over the dome of the skull but cannot pass into either occiptial or the temple regions because of the bony attachments of the Occipitofrontalis muscle. But this fluid can, however track forward into the eyelid because of the Occipitofrontalis muscle has no bony attachment anteriorly. This leads to formation of Hematoma a few hours after the head injury or cranial operation.[1] If a more extensive injury, potentially even a skull fracture, an apparent black eye can sometimes worsen and may require professional medical treatment before it will resolve. This is more likely if the area around both eyes has been injured (raccoon eyes) or if there is a history of prior head injury or fracture around the eye. Though disfiguring, the vast majority of black eyes are not serious, require little or no treatment, and will resolve spontaneously within a week or two. Bleeding within the eye, a condition called a hyphema, is more serious: it can permanently reduce vision and can result in damage the cornea. In some cases, abnormally high pressure inside the eyeball (ocular hypertension) can also result. ## Contents * 1 Signs and symptoms * 2 Treatment * 3 Associated conditions * 4 References * 5 External links ## Signs and symptoms[edit] Progression of periorbital hematoma over ten days: the blood is gradually absorbed, but the iron-laden pigments in the blood remain in the tissue leaving a discoloration that persists for longer. Despite the name, the eye itself is not affected. Blunt force or trauma to the eye socket results in burst capillaries and subsequent haemorrhaging (hematoma).[2] The fatty tissue along with the lack of muscle around the eye socket allows a potential space for blood accumulation. As this blood decomposes and is resorbed, various pigments are released lending itself to the extreme outward appearance.[2] The appearance (discoloration in purple and blue along with swelling) does not usually indicate a serious injury, and most black eyes resolve within a week. The tissues around the eye are soft and thus bruise easily when compressed against margins of bone which surround and protect the eye socket. The treatment is the same as that for bruises in other parts of the body – cold compresses during the first twenty-four hours. During the process of healing, and so long as there no breaks in the skin, a black eye can be made less conspicuous by using cosmetics designed to obscure discolorations of the skin. In a severe contusion, blowout of the floor of the orbit may occur, leading to double vision. Such an injury requires surgical correction. ## Treatment[edit] Unless there is actual trauma to the eye itself (see below), extensive medical attention is generally not needed.[2] Applying an ice pack will keep down swelling and reduce internal bleeding by constricting the capillaries. Analgesic drugs (painkillers) can be administered to relieve pain.[2] An anecdotal remedy for a black eye consists of applying raw meat to the eye area. Research has yet to find any evidence of this treatment being effective. Likely the raw meat was used when ice packs were not yet commercially available and meat was stored in iceboxes instead of in a protective gas, while cold but not but freezing meat is more gentle to the skin than ice, and will not damage the surface of the skin as the skin temperature cannot go below freezing even in extreme cases. Meat is also soft and comes easier into contact with the skin than blocks of ice that were available.[citation needed] ## Associated conditions[edit] Eye injury and head trauma may also coincide with a black eye. Some common signs of a more serious injury may include: * Double vision * Loss of sight and/or fuzzy vision could occur * Loss of consciousness * Inability to move the eye or large swelling around the eye * Blood or clear fluid from the nose or the ears * Blood on the surface of the eye itself or cuts on the eye itself * Persistent headache or migraine ## References[edit] 1. ^ Singh, Vishram (2014). Textbook of Anatomy - Head & Neck & Brain - Volume III - 2e. New Delhi: Reed Elsevier India Private limited. p. 48. ISBN 9788131237274. 2. ^ a b c d "Black Eye". NHS Choices. NHS. 18 March 2011. Retrieved 27 October 2012. ## External links[edit] Classification D * ICD-10: S00.1 * ICD-9-CM: 921.0 Wikimedia Commons has media related to Black eyes. * v * t * e Nonmusculoskeletal injuries of head (head injury) and neck Intracranial * see neurotrauma Extracranial/ facial trauma eye: * Black eye * Eye injury * Corneal abrasion ear: * Perforated eardrum Either/both * Penetrating head injury * v * t * e General wounds and injuries Abrasions * Abrasion * Avulsion Blisters * Blood blister * Coma blister * Delayed blister * Edema blister * Fracture blister * Friction blister * Sucking blister Bruises * Hematoma/Ecchymosis * Battle's sign * Raccoon eyes * Black eye * Subungual hematoma * Cullen's sign * Grey Turner's sign * Retroperitoneal hemorrhage Animal bites * Insect bite * Spider bite * Snakebite Other: * Ballistic trauma * Stab wound * Blunt trauma/superficial/closed * Penetrating trauma/open * Aerosol burn * Burn/Corrosion/Chemical burn * Frostbite * Occupational injuries * Traumatic amputation By region * Hand injury * Head injury * Chest trauma * Abdominal trauma [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Black eye	c0520723	3,775	wikipedia	https://en.wikipedia.org/wiki/Black_eye	2021-01-18T18:56:10	{"umls": ["C0520723"], "icd-9": ["921.0"], "icd-10": ["S00.1"], "wikidata": ["Q882770"]}
Meesmann corneal dystrophy (MECD) is a rare form of superficial corneal dystrophy characterized by distinct tiny bubble-like, round-to-oval punctate bilateral opacities in the central corneal epithelium, and to a lesser extent in the peripheral cornea, with little impact on vision. ## Epidemiology Prevalence of this form of corneal dystrophy is not known as a registry of affected cases does not exist. Numerous cases have been reported from Denmark, Germany, Japan, USA, Saudi Arabia and Poland. ## Clinical description Lesions develop during infancy. MECD often remains asymptomatic until middle age, when intermittent, mild ocular irritation, photophobia, transient blurred vision, and irregular astigmatism develop. The condition persists throughout life. In severe cases, subepithelial scarring produces a slight grayish central corneal opacification. Corneal sensitivity is normal. ## Etiology Meesmann corneal dystrophy is caused by a mutation in one of a pair of genes, KRT3 (12q13.13) or KRT12 (17q11-q1) that encode the two units of cytokeratin in the corneal epithelium. Stocker-Holt corneal dystrophy is a variant of MECD caused by a p. Arg19Leu amino acid change in cytokeratin 12. ## Diagnostic methods Light microscopy reveals intraepithelial cysts and the epithelium may be thickened and disorganized. Histopathologically, MECD is characterized by intraepithelial cysts at different levels in the corneal epithelium, which is irregular in thickness. ## Differential diagnosis Suspected cases of MECD should be differentiated from other disorders of the corneal epithelium, such as vapor spray keratitis, mild epithelial edema and the bleb pattern of epithelial basement membrane dystrophy. MECD and Lisch epithelial corneal dystrophy (LECD, see this term) have clinical similarities but are easily distinguished from one another by the different modes of inheritance, i.e. autosomal dominant versus X-linked recessive. ## Genetic counseling MECD has an autosomal dominant pattern of inheritance. ## Management and treatment Removal of the abnormal corneal epithelium has been used to treat MECD, but this approach is not curative as the dystrophy recurs in the regenerated epithelium. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Meesmann corneal dystrophy	c0339277	3,776	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=98954	2021-01-23T18:22:55	{"gard": ["9688"], "mesh": ["D053559"], "omim": ["122100", "618767"], "umls": ["C0339277"], "icd-10": ["H18.5"], "synonyms": ["Juvenile hereditary epithelial dystrophy of Meesmann", "MECD"]}
Down syndrome is a chromosomal condition that is associated with intellectual disability, a characteristic facial appearance, and weak muscle tone (hypotonia) in infancy. All affected individuals experience cognitive delays, but the intellectual disability is usually mild to moderate. People with Down syndrome often have a characteristic facial appearance that includes a flattened appearance to the face, outside corners of the eyes that point upward (upslanting palpebral fissures), small ears, a short neck, and a tongue that tends to stick out of the mouth. Affected individuals may have a variety of birth defects. Many people with Down syndrome have small hands and feet and a single crease across the palms of the hands. About half of all affected children are born with a heart defect. Digestive abnormalities, such as a blockage of the intestine, are less common. Individuals with Down syndrome have an increased risk of developing several medical conditions. These include gastroesophageal reflux, which is a backflow of acidic stomach contents into the esophagus, and celiac disease, which is an intolerance of a wheat protein called gluten. About 15 percent of people with Down syndrome have an underactive thyroid gland (hypothyroidism). The thyroid gland is a butterfly-shaped organ in the lower neck that produces hormones. Individuals with Down syndrome also have an increased risk of hearing and vision problems. Additionally, a small percentage of children with Down syndrome develop cancer of blood-forming cells (leukemia). Delayed development and behavioral problems are often reported in children with Down syndrome. Affected individuals can have growth problems and their speech and language develop later and more slowly than in children without Down syndrome. Additionally, speech may be difficult to understand in individuals with Down syndrome. Behavioral issues can include attention problems, obsessive/compulsive behavior, and stubbornness or tantrums. A small percentage of people with Down syndrome are also diagnosed with developmental conditions called autism spectrum disorders, which affect communication and social interaction. People with Down syndrome often experience a gradual decline in thinking ability (cognition) as they age, usually starting around age 50. Down syndrome is also associated with an increased risk of developing Alzheimer disease, a brain disorder that results in a gradual loss of memory, judgment, and ability to function. Approximately half of adults with Down syndrome develop Alzheimer disease. Although Alzheimer disease is usually a disorder that occurs in older adults, people with Down syndrome commonly develop this condition earlier, in their fifties or sixties. ## Frequency Down syndrome occurs in about 1 in 700 newborns. About 5,300 babies with Down syndrome are born in the United States each year, and approximately 200,000 people in this country have the condition. Although women of any age can have a child with Down syndrome, the chance of having a child with this condition increases as a woman gets older. ## Causes Most cases of Down syndrome result from trisomy 21, which means each cell in the body has three copies of chromosome 21 instead of the usual two copies. Less commonly, Down syndrome occurs when part of chromosome 21 becomes attached (translocated) to another chromosome during the formation of reproductive cells (eggs and sperm) in a parent or very early in fetal development. Affected people have two normal copies of chromosome 21 plus extra material from chromosome 21 attached to another chromosome, resulting in three copies of genetic material from chromosome 21. Affected individuals with this genetic change are said to have translocation Down syndrome. A very small percentage of people with Down syndrome have an extra copy of chromosome 21 in only some of the body's cells. In these people, the condition is called mosaic Down syndrome. Researchers believe that having extra copies of genes on chromosome 21 disrupts the course of normal development, causing the characteristic features of Down syndrome and the increased risk of health problems associated with this condition. ### Learn more about the chromosome associated with Down syndrome * chromosome 21 ## Inheritance Pattern Most cases of Down syndrome are not inherited. When the condition is caused by trisomy 21, the chromosomal abnormality occurs as a random event during the formation of reproductive cells in a parent. The abnormality usually occurs in egg cells, but it occasionally occurs in sperm cells. An error in cell division called nondisjunction results in a reproductive cell with an abnormal number of chromosomes. For example, an egg or sperm cell may gain an extra copy of chromosome 21. If one of these atypical reproductive cells contributes to the genetic makeup of a child, the child will have an extra chromosome 21 in each of the body's cells. People with translocation Down syndrome can inherit the condition from an unaffected parent. The parent carries a rearrangement of genetic material between chromosome 21 and another chromosome. This rearrangement is called a balanced translocation. No genetic material is gained or lost in a balanced translocation, so these chromosomal changes usually do not cause any health problems. However, as this translocation is passed to the next generation, it can become unbalanced. People who inherit an unbalanced translocation involving chromosome 21 may have extra genetic material from chromosome 21, which causes Down syndrome. Like trisomy 21, mosaic Down syndrome is not inherited. It occurs as a random event during cell division early in fetal development. As a result, some of the body's cells have the usual two copies of chromosome 21, and other cells have three copies of this chromosome. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Down syndrome	c0013080	3,777	medlineplus	https://medlineplus.gov/genetics/condition/down-syndrome/	2021-01-27T08:25:13	{"gard": ["10247"], "mesh": ["D004314"], "omim": ["190685"], "synonyms": []}
## Clinical Features Failure to thrive, nutritional edema, and hypoproteinemia with normal sweat electrolytes were features of 2 affected male infants reported by Townes (1965) and Townes et al. (1967). The infants had deficiency of trypsinogen (276000). A male sib of the first patient reported by Townes (1965) had died, apparently of the same condition. Townes (1972) noted that the clinical picture in enterokinase deficiency (226200) is closely similar; however, the defect is not in the synthesis of trypsinogen but in the synthesis of the enterokinase (606635), which activates proteolytic enzymes produced by the pancreas. Clinical Management Oral pancreatin represents a therapeutically successful form of enzyme replacement (Townes, 1972). INHERITANCE \- Autosomal recessive GROWTH Other \- Failure to thrive ABDOMEN Gastrointestinal \- Imperforate anus (in some patients) MUSCLE, SOFT TISSUES \- Nutritional edema LABORATORY ABNORMALITIES \- Trypsinogen deficiency \- Hypoproteinemia \- Normal sweat electrolytes ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	TRYPSINOGEN DEFICIENCY	c0268417	3,778	omim	https://www.omim.org/entry/614044	2019-09-22T15:56:43	{"omim": ["614044"]}
## Clinical Features Barbagallo Sangiorgi et al. (1965) described 2 families. In 1 family, 2 of 4 brothers had splenomegaly, compensated cirrhosis, and mild diabetes. Splenic venograph showed splenocaval shunt, and one had chronic hyperammoniacal encephalopathy. In the second family, a brother and 2 sisters had splenomegaly, ascites, and anomalous splenoportal venous system. The father and another brother were symptom-free but had splenomegaly. The vascular anomaly may have been secondary to hepatic fibrosis, and the disorder may be identical to one discussed elsewhere (see 263200) or nongenetic. Radiology \- Splenic venograph shows splenocaval shunt Neuro \- Chronic hepatic encephalopathy Metabolic \- Mild diabetes mellitus Inheritance \- ? Autosomal recessive \- ? secondary to hepatic fibrosis or same as polycystic kidney, type I Abdomen \- Splenomegaly \- Ascites \- Anomalous splenoportal venous system Lab \- Hyperammonemia GI \- Compensated cirrhosis \- Hepatic fibrosis ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	SPLENOPORTAL VASCULAR ANOMALIES	c0340826	3,779	omim	https://www.omim.org/entry/271500	2019-09-22T16:22:06	{"mesh": ["C562761"], "omim": ["271500"]}
Primary immune deficiency disorder Hyper IgM syndrome type 2 Immunoglobulin M TypesHyper-IgM syndrome type 1,2,3,4 and 5[1][2][3][4][5] Diagnostic methodMRI, Chest radiography and genetic testing[6] TreatmentAllogeneic hematopoietic cell transplantation[7] Hyper IgM Syndrome Type 2 is a rare disease. Unlike other hyper-IgM syndromes, Type 2 patients identified thus far did not present with a history of opportunistic infections. One would expect opportunistic infections in any immunodeficiency syndrome. The responsible genetic lesion is in the AICDA gene found at 12p13.[8] ## Contents * 1 Hyper IgM syndromes * 2 Signs and symptoms * 3 Cause * 4 Pathophysiology * 5 Diagnosis * 6 Treatment * 7 References ## Hyper IgM syndromes[edit] Hyper IgM syndromes is a group of primary immune deficiency disorders characterized by defective CD40 signaling; via B cells affecting class switch recombination (CSR) and somatic hypermutation. Immunoglobulin (Ig) class switch recombination deficiencies are characterized by elevated serum IgM levels and a considerable deficiency in Immunoglobulins G (IgG), A (IgA) and E (IgE). As a consequence, people with HIGM have an increased susceptibility to infections.[9][7][10] ## Signs and symptoms[edit] Hyper IgM syndrome can have the following syndromes:[6][11] * Infection/Pneumocystis pneumonia (PCP), which is common in infants with hyper IgM syndrome, is a serious illness.[9] PCP is one of the most frequent and severe opportunistic infections in people with weakened immune systems. * Hepatitis (Hepatitis C) * Chronic diarrhea * Hypothyroidism * Neutropenia * Arthritis * Encephalopathy (degenerative) ## Cause[edit] Class switch recombination Different genetic defects cause HIgM syndrome, the vast majority are inherited as an X-linked recessive genetic trait and most sufferers are male.[7][1][2] [3][12][4] IgM is the form of antibody that all B cells produce initially before they undergo class switching. Healthy B cells efficiently switch to other types of antibodies as needed to attack invading bacteria, viruses, and other pathogens. In people with hyper IgM syndromes, the B cells keep making IgM antibodies because can not switch to a different antibody. This results in an overproduction of IgM antibodies and an underproduction of IgA, IgG, and IgE.[13][7] ## Pathophysiology[edit] CD40 is a costimulatory receptor on B cells that, when bound to CD40 ligand (CD40L), sends a signal to the B-cell receptor.[14] When there is a defect in CD40, this leads to defective T-cell interaction with B cells. Consequently, humoral immune response is affected. Patients are more susceptible to infection.[6] ## Diagnosis[edit] The diagnosis of hyper IgM syndrome can be done via the following methods and tests:[6] * MRI * Chest radiography * Pulmonary function test * Lymph node test * Laboratory test (to measure CD40) ## Treatment[edit] In terms of treatment for hyper IgM syndrome, there is the use of allogeneic hematopoietic cell transplantation. Additionally, anti-microbial therapy, use of granulocyte colony-stimulating factor, immunosuppressants, as well as other treatments, may be needed.[7] ## References[edit] 1. ^ a b "OMIM Entry - # 308230 - IMMUNODEFICIENCY WITH HYPER-IgM, TYPE 1; HIGM1". www.omim.org. Retrieved 16 November 2016. 2. ^ a b "OMIM Entry - # 605258 - IMMUNODEFICIENCY WITH HYPER-IgM, TYPE 2; HIGM2". omim.org. Retrieved 16 November 2016. 3. ^ a b "OMIM Entry - # 606843 - IMMUNODEFICIENCY WITH HYPER-IgM, TYPE 3; HIGM3". www.omim.org. Retrieved 16 November 2016. 4. ^ a b "OMIM Entry - # 608106 - IMMUNODEFICIENCY WITH HYPER-IgM, TYPE 5; HIGM5". omim.org. Retrieved 16 November 2016. 5. ^ "OMIM Entry - 608184 - IMMUNODEFICIENCY WITH HYPER-IgM, TYPE 4; HIGM4". www.omim.org. Retrieved 2 January 2018. 6. ^ a b c d "X-linked Immunodeficiency With Hyper IgM Clinical Presentation: History, Physical, Causes". emedicine.medscape.com. Retrieved 27 November 2016. 7. ^ a b c d e Johnson, Judith; Filipovich, Alexandra H.; Zhang, Kejian (1 January 1993). "X-Linked Hyper IgM Syndrome". GeneReviews. Retrieved 12 November 2016.update 2013 8. ^ Revy P, Muto T, Levy Y, et al. (September 2000). "Activation-induced cytidine deaminase (AID) deficiency causes the autosomal recessive form of the Hyper-IgM syndrome (HIGM2)". Cell. 102 (5): 565–75. doi:10.1016/S0092-8674(00)00079-9. hdl:11655/14257. PMID 11007475. 9. ^ a b Etzioni, Amos; Ochs, Hans D. (1 October 2004). "The Hyper IgM Syndrome—An Evolving Story". Pediatric Research. 56 (4): 519–525. doi:10.1203/01.PDR.0000139318.65842.4A. ISSN 0031-3998. PMID 15319456. 10. ^ "Hyper-Immunoglobulin M (Hyper-IgM) Syndromes \| NIH: National Institute of Allergy and Infectious Diseases". www.niaid.nih.gov. Retrieved 27 November 2016. 11. ^ Davies, E Graham; Thrasher, Adrian J (27 November 2016). "Update on the hyper immunoglobulin M syndromes". British Journal of Haematology. 149 (2): 167–180. doi:10.1111/j.1365-2141.2010.08077.x. ISSN 0007-1048. PMC 2855828. PMID 20180797. 12. ^ Lougaris V, Badolato R, Ferrari S, Plebani A (2005). "Hyper immunoglobulin M syndrome due to CD40 deficiency: clinical, molecular, and immunological features". Immunol. Rev. 203: 48–66. doi:10.1111/j.0105-2896.2005.00229.x. PMID 15661021.subscription needed 13. ^ Reference, Genetics Home. "X-linked hyper IgM syndrome". Genetics Home Reference. Retrieved 27 November 2016. 14. ^ Reference, Genetics Home. "CD40 gene". Genetics Home Reference. Retrieved 27 November 2016. Classification D * ICD-10: D80.5 * OMIM: 608106 External resources * Orphanet: 101092 * v * t * e Lymphoid and complement disorders causing immunodeficiency Primary Antibody/humoral (B) Hypogammaglobulinemia * X-linked agammaglobulinemia * Transient hypogammaglobulinemia of infancy Dysgammaglobulinemia * IgA deficiency * IgG deficiency * IgM deficiency * Hyper IgM syndrome (1 * 2 * 3 * 4 * 5) * Wiskott–Aldrich syndrome * Hyper-IgE syndrome Other * Common variable immunodeficiency * ICF syndrome T cell deficiency (T) * thymic hypoplasia: hypoparathyroid (Di George's syndrome) * euparathyroid (Nezelof syndrome * Ataxia–telangiectasia) peripheral: Purine nucleoside phosphorylase deficiency * Hyper IgM syndrome (1) Severe combined (B+T) * x-linked: X-SCID autosomal: Adenosine deaminase deficiency * Omenn syndrome * ZAP70 deficiency * Bare lymphocyte syndrome Acquired * HIV/AIDS Leukopenia: Lymphocytopenia * Idiopathic CD4+ lymphocytopenia Complement deficiency * C1-inhibitor (Angioedema/Hereditary angioedema) * Complement 2 deficiency/Complement 4 deficiency * MBL deficiency * Properdin deficiency * Complement 3 deficiency * Terminal complement pathway deficiency * Paroxysmal nocturnal hemoglobinuria * Complement receptor deficiency [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Hyper-IgM syndrome type 2	c1720956	3,780	wikipedia	https://en.wikipedia.org/wiki/Hyper-IgM_syndrome_type_2	2021-01-18T18:48:49	{"gard": ["10578"], "mesh": ["D053306"], "umls": ["C1720956"], "orphanet": ["183666", "101089"], "wikidata": ["Q5957516"]}
This article is an orphan, as no other articles link to it. Please introduce links to this page from related articles; try the Find link tool for suggestions. (May 2016) Hypotrichosis with juvenile macular dystrophy Other namesHypotrichosis with juvenile macular degeneration[1] Hypotrichosis (sparse hair growth) in a 5-year-old boy with HJMD Hypotrichosis with juvenile macular dystrophy (HJMD or CDH3) is an extremely rare congenital disease characterized by sparse hair growth (hypotrichosis) from birth and progressive macular corneal dystrophy. ## Contents * 1 Signs and symptoms * 2 Cause * 3 Diagnosis * 3.1 Examination method * 3.2 Differential diagnosis * 4 Treatment * 4.1 Life planning * 5 Epidemiology * 6 History * 7 References * 8 Sources * 9 External links ## Signs and symptoms[edit] Hair growth on the head is noticeably less full than normal, and the hairs are very weak; the rest of the body shows normal hair. The macular degeneration comes on slowly with deterioration of central vision, leading to a loss of reading ability. Those affected may otherwise develop in a completely healthy manner; life expectancy is normal.[citation needed] ## Cause[edit] Hypotrichosis with juvenile macular dystrophy is an autosomal recessive hereditary disease.[2] It is caused by a combination of mutations (compound heterozygosity) in the CDH3 gene, which codes for Cadherin-3 (also known as P-Cadherin), a calcium-binding protein that is responsible for cellular adhesion in various tissues.[citation needed] ## Diagnosis[edit] The markedly anomalous hair growth should lead to a retinal examination by school entry at the latest, since weak vision will not necessarily be detected in the course of normal medical check-ups. Confirmation of a diagnosis, which is necessary for any future therapeutic options, is only possible by means of a molecular genetic diagnosis in the context of genetic counseling.[citation needed] ### Examination method[edit] The extent of retinal damage is assessed by fluorescent angiography, retinal scanning and optical coherence tomography; electrophysiological examinations such as electroretinography (ERG) or multifocal electroretinography (mfERG) may also be used.[citation needed] * Fluorescent angiogram of a 5-year-old boy with HJMD * Optical coherence tomography of a 5-year-old boy with HJMD * Fundoscopy, left eye of a 5-year-old boy with HJMD * Fundoscopy, right eye of a 5-year-old boy with HJMD ### Differential diagnosis[edit] Anomalies of the hair shaft caused by ectodermal dysplasia should be ruled out. Mutations in the CDH3 gene can also appear in EEM syndrome. ## Treatment[edit] There is no treatment for the disorder. A number of studies are looking at gene therapy, exon skipping and CRISPR interference to offer hope for the future. Accurate determination through confirmed diagnosis of the genetic mutation that has occurred also offers potential approaches beyond gene replacement for a specific group, namely in the case of diagnosis of a so-called nonsense mutation, a mutation where a stop codon is produced by the changing of a single base in the DNA sequence. This results in premature termination of protein biosynthesis, resulting in a shortened and either functionless or function-impaired protein. In what is sometimes called "read-through therapy", translational skipping of the stop codon, resulting in a functional protein, can be induced by the introduction of specific substances. However, this approach is only conceivable in the case of narrowly circumscribed mutations, which cause differing diseases.[citation needed] ### Life planning[edit] A disease that threatens the eyesight and additionally produces a hair anomaly that is apparent to strangers causes harm beyond the physical. It is therefore not surprising that learning the diagnosis is a shock to the patient. This is as true of the affected children as of their parents and relatives. They are confronted with a statement that there are at present no treatment options. They probably have never felt so alone and abandoned in their lives. The question comes to mind, "Why me/my child?" However, there is always hope and especially for affected children, the first priority should be a happy childhood. Too many examinations and doctor appointments take up time and cannot practically solve the problem of a genetic mutation within a few months. It is therefore advisable for parents to treat their child with empathy, but to raise him or her to be independent and self-confident by the teenage years. Openness about the disease and talking with those affected about their experiences, even though its rarity makes it unlikely that others will be personally affected by it, will together assist in managing life. ## Epidemiology[edit] It is estimated to affect less than one in a million people.[2] Only 50 to 100 cases have so far been described.[2] ## History[edit] The disease was first described in 1935 by Hans Wagner, a German physician.[3] ## References[edit] 1. ^ RESERVED, INSERM US14-- ALL RIGHTS. "Orphanet: Hypotrichosis with juvenile macular degeneration". www.orpha.net. Retrieved 24 June 2019. 2. ^ a b c "Hypotrichose - juvenile Makuladegeneration: ORPHA1573". Orphanet (in German). Retrieved 2016-08-11. 3. ^ Wagner, H. (1935). "Maculaaffektion, vergesellschaftet mit Haarabnormitat von Lanugotypus, beide vielleicht angeboren bei zwei Geschwistern". Graefes Archiv Klinischer und Experimenteller Ophthalalmologie (in German). 134: 74–81. doi:10.1007/BF01854763. S2CID 21073109. ## Sources[edit] * "A Rare Syndrome: Hypotrichosis with Juvenile Macular Dystrophy (HJMD)". Investigative Ophthalmology & Visual Science. 55 (13): 6424. April 2014. * Online Mendelian Inheritance in Man (OMIM): CADHERIN 3 - 114021 * Samuelov, L; Sprecher, E; Tsuruta, D; Bíró, T; Kloepper, J. E.; Paus, R (2012). "P-cadherin regulates human hair growth and cycling via canonical Wnt signaling and transforming growth factor-β2". Journal of Investigative Dermatology. 132 (10): 2332–41. doi:10.1038/jid.2012.171. PMID 22696062. * Nagel-Wolfrum, K; Möller, F; Penner, I; Wolfrum, U (2014). "Translational read-through as an alternative approach for ocular gene therapy of retinal dystrophies caused by in-frame nonsense mutations". Visual Neuroscience. 31 (4–5): 309–16. doi:10.1017/S0952523814000194. PMID 24912600. (Review). * Gregory-Evans, C. Y.; Wang, X; Wasan, K. M.; Zhao, J; Metcalfe, A. L.; Gregory-Evans, K (2014). "Postnatal manipulation of Pax6 dosage reverses congenital tissue malformation defects". Journal of Clinical Investigation. 124 (1): 111–116. doi:10.1172/JCI70462. PMC 3871240. PMID 24355924. * Schwarz, N.; Carr, A.-J.; Lane, A.; Moeller, F.; Chen, L. L.; Aguila, M.; Nommiste, B.; Muthiah, M. N.; Kanuga, N.; Wolfrum, U.; Nagel-Wolfrum, K.; Da Cruz, L.; Coffey, P. J.; Cheetham, M. E.; Hardcastle, A. J. (2014). "Translational read-through of the RP2 Arg120stop mutation in patient iPSC-derived retinal pigment epithelium cells". Human Molecular Genetics. 24 (4): 972–86. doi:10.1093/hmg/ddu509. PMC 4986549. PMID 25292197. ## External links[edit] Classification D * ICD-10: Q84.0 * ICD-9-CM: xxx * MeSH: C537698 External resources * Orphanet: 1573 [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Hypotrichosis with juvenile macular dystrophy	c1832162	3,781	wikipedia	https://en.wikipedia.org/wiki/Hypotrichosis_with_juvenile_macular_dystrophy	2021-01-18T18:28:38	{"gard": ["3066"], "mesh": ["C537698"], "umls": ["C1832162"], "orphanet": ["1573"], "wikidata": ["Q22132220"]}
Dementia that involves impairments in cognitive function caused by problems in blood vessels that feed the brain Vascular dementia Other namesArteriosclerotic dementia (in the ICD-9) Multi-infarct dementia (in the ICD-10) Vascular cognitive impairment SpecialtyPsychiatry, neurology Vascular dementia (VaD) is dementia caused by problems in the supply of blood to the brain, typically a series of minor strokes, leading to worsening cognitive decline that occurs step by step.[1] The term refers to a syndrome consisting of a complex interaction of cerebrovascular disease and risk factors that lead to changes in the brain structures due to strokes and lesions, and resulting changes in cognition. The temporal relationship between a stroke and cognitive deficits is needed to make the diagnosis.[2] ## Contents * 1 Signs and symptoms * 2 Causes * 3 Diagnosis * 3.1 Pathology * 4 Prevention * 5 Treatment * 6 Prognosis * 7 Epidemiology * 8 See also * 9 References * 10 External links ## Signs and symptoms[edit] Differentiating dementia syndromes can be challenging, due to the frequently overlapping clinical features and related underlying pathology. In particular, Alzheimer's dementia often co-occurs with vascular dementia.[3] People with vascular dementia present with progressive cognitive impairment, acutely or subacutely as in mild cognitive impairment, frequently step-wise, after multiple cerebrovascular events (strokes). Some people may appear to improve between events and decline after further silent strokes. A rapidly deteriorating condition may lead to death from a stroke, heart disease, or infection.[4] Signs and symptoms are cognitive, motor, behavioral, and for a significant proportion of patients also affective. These changes typically occur over a period of 5–10 years. Signs are typically the same as in other dementias, but mainly include cognitive decline and memory impairment of sufficient severity as to interfere with activities of daily living, sometimes with presence of focal neurologic signs, and evidence of features consistent with cerebrovascular disease on brain imaging (CT or MRI).[5] The neurologic signs localizing to certain areas of the brain that can be observed are hemiparesis, bradykinesia, hyperreflexia, extensor plantar reflexes, ataxia, pseudobulbar palsy, as well as gait problems and swallowing difficulties. People have patchy deficits in terms of cognitive testing. They tend to have better free recall and fewer recall intrusions when compared with patients with Alzheimer's disease. In the more severely affected patients, or patients affected by infarcts in Wernicke's or Broca's areas, specific problems with speaking called dysarthrias and aphasias may be present.[citation needed] In small vessel disease, the frontal lobes are often affected. Consequently, patients with vascular dementia tend to perform worse than their Alzheimer's disease counterparts in frontal lobe tasks, such as verbal fluency, and may present with frontal lobe problems: apathy, abulia (lack of will or initiative), problems with attention, orientation, and urinary incontinence. They tend to exhibit more perseverative behavior. VaD patients may also present with general slowing of processing ability, difficulty shifting sets, and impairment in abstract thinking. Apathy early in the disease is more suggestive of vascular dementia.[citation needed] Rare genetic disorders that cause vascular lesions in the brain have other presentation patterns. As a rule, they tend to occur earlier in life and have a more aggressive course. In addition, infectious disorders, such as syphilis, can cause arterial damage, strokes, and bacterial inflammation of the brain.[citation needed] ## Causes[edit] Vascular dementia can be caused by ischemic or hemorrhagic infarcts affecting multiple brain areas, including the anterior cerebral artery territory, the parietal lobes, or the cingulate gyrus. On rare occasion, infarcts in the hippocampus or thalamus are the cause of dementia.[6] A history of stroke increases the risk of developing dementia by around 70%, and recent stroke increases the risk by around 120%.[7] Brain vascular lesions can also be the result of diffuse cerebrovascular disease, such as small vessel disease.[citation needed] Risk factors for vascular dementia include age, hypertension, smoking, hypercholesterolemia, diabetes mellitus, cardiovascular disease, and cerebrovascular disease. Other risk factors include geographic origin, genetic predisposition, and prior strokes.[8] Vascular dementia can sometimes be triggered by cerebral amyloid angiopathy, which involves accumulation of beta amyloid plaques in the walls of the cerebral arteries, leading to breakdown and rupture of the vessels. Since amyloid plaques are a characteristic feature of Alzheimer's disease, vascular dementia may occur as a consequence. Cerebral amyloid angiopathy can, however, appear in people with no prior dementia condition. Amyloid beta accumulation is often present in cognitively normal elderly people.[9][10] Two reviews of 2018 and 2019 found potentially an association between celiac disease and vascular dementia.[11][12] ## Diagnosis[edit] Several specific diagnostic criteria can be used to diagnose vascular dementia,[13] including the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) criteria, the International Classification of Diseases, Tenth Edition (ICD-10) criteria, the National Institute of Neurological Disorders and Stroke criteria, Association Internationale pour la Recherche et l'Enseignement en Neurosciences (NINDS-AIREN) criteria,[14] the Alzheimer's Disease Diagnostic and Treatment Center criteria, and the Hachinski Ischemic Score (after Vladimir Hachinski).[15] The recommended investigations for cognitive impairment include: blood tests (for anemia, vitamin deficiency, thyrotoxicosis, infection, etc.), chest X-Ray, ECG, and neuroimaging, preferably a scan with a functional or metabolic sensitivity beyond a simple CT or MRI. When available as a diagnostic tool, single photon emission computed tomography (SPECT) and positron emission tomography (PET) neuroimaging may be used to confirm a diagnosis of multi-infarct dementia in conjunction with evaluations involving mental status examination.[16] In a person already having dementia, SPECT appears to be superior in differentiating multi-infarct dementia from Alzheimer's disease, compared to the usual mental testing and medical history analysis.[17] Advances have led to the proposal of new diagnostic criteria.[18][19] The screening blood tests typically include full blood count, liver function tests, thyroid function tests, lipid profile, erythrocyte sedimentation rate, C reactive protein, syphilis serology, calcium serum level, fasting glucose, urea, electrolytes, vitamin B-12, and folate. In selected patients, HIV serology and certain autoantibody testing may be done.[citation needed] Mixed dementia is diagnosed when people have evidence of Alzheimer's disease and cerebrovascular disease, either clinically or based on neuro-imaging evidence of ischemic lesions.[citation needed] ### Pathology[edit] Gross examination of the brain may reveal noticeable lesions and damage to blood vessels. Accumulation of various substances such as lipid deposits and clotted blood appear on microscopic views. The white matter is most affected, with noticeable atrophy (tissue loss), in addition to calcification of the arteries. Microinfarcts may also be present in the gray matter (cerebral cortex), sometimes in large numbers. Although atheroma of the major cerebral arteries is typical in vascular dementia, smaller vessels and arterioles are mainly affected.[citation needed] ## Prevention[edit] Early detection and accurate diagnosis are important,[20] as vascular dementia is at least partially preventable. Ischemic changes in the brain are irreversible, but the patient with vascular dementia can demonstrate periods of stability or even mild improvement.[21] Since stroke is an essential part of vascular dementia,[7] the goal is to prevent new strokes. This is attempted through reduction of stroke risk factors, such as high blood pressure, high blood lipid levels, atrial fibrillation, or diabetes mellitus. Meta-analyses have found that medications for high blood pressure are effective at prevention of pre-stroke dementia, which means that high blood pressure treatment should be started early.[22] These medications include angiotensin converting enzyme inhibitors, diuretics, calcium channel blockers, sympathetic nerve inhibitors, angiotensin II receptor antagonists or adrenergic antagonists. Elevated lipid levels, including HDL, were found to increase risk of vascular dementia. However, six large recent reviews showed that therapy with statin drugs was ineffective in treatment or prevention of this dementia.[22][23] Aspirin is a medication that is commonly prescribed for prevention of strokes and heart attacks; it is also frequently given to patients with dementia. However, its efficacy in slowing progression of dementia or improving cognition has not been supported by studies.[22][24] Smoking cessation and Mediterranean diet have not been found to help patients with cognitive impairment; physical activity was consistently the most effective method of preventing cognitive decline.[22] ## Treatment[edit] Currently, there are no medications that have been approved specifically for prevention or treatment of vascular dementia. The use of medications for treatment of Alzheimer's dementia, such as cholinesterase inhibitors and memantine, has shown small[quantify] improvement of cognition in vascular dementia. This is most likely due to the drugs' actions on co-existing AD-related pathology. Multiple studies found a small[quantify] benefit in VaD treatment with: memantine, a non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist; cholinesterase inhibitors galantamine, donepezil, rivastigmine;[25] and ginkgo biloba extract.[22] In those with celiac disease or non-celiac gluten sensitivity, a strict gluten-free diet may relieve symptoms of mild cognitive impairment.[12][11] It should be started as soon as possible. There is no evidence that a gluten free diet is useful against advanced dementia. People with no digestive symptoms are less likely to receive early diagnosis and treatment.[12] General management of dementia includes referral to community services, aid with judgment and decision-making regarding legal and ethical issues (e.g., driving, capacity, advance directives), and consideration of caregiver stress. Behavioral and affective symptoms deserve special consideration in this patient group. These problems tend to resist conventional psychopharmacological treatment, and often lead to hospital admission and placement in permanent care.[citation needed] ## Prognosis[edit] Many studies have been conducted to determine average survival of patients with dementia. The studies were frequently small and limited, which caused contradictory results in the connection of mortality to the type of dementia and the patient's gender. A very large study conducted in Netherlands in 2015 found that the one-year mortality was three to four times higher in patients after their first referral to a day clinic for dementia, when compared to the general population.[26] If the patient was hospitalized for dementia, the mortality was even higher than in patients hospitalized for cardiovascular disease.[26] Vascular dementia was found to have either comparable or worse survival rates when compared to Alzheimer's Disease;[27][28][29] another very large 2014 Swedish study found that the prognosis for VaD patients was worse for male and older patients.[30] Unlike Alzheimer's disease, which weakens the patient, causing them to succumb to bacterial infections like pneumonia, vascular dementia can be a direct cause of death due to the possibility of a fatal interruption in the brain's blood supply.[citation needed] ## Epidemiology[edit] Vascular dementia is the second-most-common form of dementia after Alzheimer's disease (AD) in older adults.[31][32] The prevalence of the illness is 1.5% in Western countries and approximately 2.2% in Japan. It accounts for 50% of all dementias in Japan, 20% to 40% in Europe and 15% in Latin America. 25% of stroke patients develop new-onset dementia within one year of their stroke. One study found that in the United States, the prevalence of vascular dementia in all people over the age of 71 is 2.43%, and another found that the prevalence of the dementias doubles with every 5.1 years of age.[33][34] The incidence peaks between the fourth and the seventh decades of life and 80% of patients have a history of hypertension.[citation needed] A recent meta-analysis identified 36 studies of prevalent stroke (1.9 million participants) and 12 studies of incident stroke (1.3 million participants).[7] For prevalent stroke, the pooled hazard ratio for all-cause dementia was 1.69 (95% confidence interval: 1.49–1.92; P < .00001; I2 = 87%). For incident stroke, the pooled risk ratio was 2.18 (95% confidence interval: 1.90–2.50; P < .00001; I2 = 88%). Study characteristics did not modify these associations, with the exception of sex, which explained 50.2% of between-study heterogeneity for prevalent stroke. These results confirm that stroke is a strong, independent, and potentially modifiable risk factor for all-cause dementia.[citation needed] ## See also[edit] * Binswanger's disease * Cerebrovascular accident ## References[edit] 1. ^ MedlinePlus Encyclopedia: Multi-infarct dementia 2. ^ Cunningham EL, McGuinness B, Herron B, Passmore AP (May 2015). "Dementia". The Ulster Medical Journal. 84 (2): 79–87. PMC 4488926. PMID 26170481. 3. ^ Karantzoulis S, Galvin JE (November 2011). "Distinguishing Alzheimer's disease from other major forms of dementia". Expert Review of Neurotherapeutics. 11 (11): 1579–91. doi:10.1586/ern.11.155. PMC 3225285. PMID 22014137. 4. ^ Office of Communications and Public Liaison. "NINDS Multi-Infarct Dementia Information Page". www.ninds.nih.gov. Retrieved 19 September 2017. 5. ^ Encyclopedia of the Human Brain - Dementia Associated with Depression. Oxford: Elsevier Science and Technology. 2002. Retrieved 20 September 2012. 6. ^ Love S (December 2005). "Neuropathological investigation of dementia: a guide for neurologists". Journal of Neurology, Neurosurgery, and Psychiatry. 76 Suppl 5 (supplement 5): v8-14. doi:10.1136/jnnp.2005.080754. PMC 1765714. PMID 16291923. 7. ^ a b c Kuźma E, Lourida I, Moore SF, Levine DA, Ukoumunne OC, Llewellyn DJ (November 2018). "Stroke and dementia risk: A systematic review and meta-analysis". Alzheimer's & Dementia. 14 (11): 1416–1426. doi:10.1016/j.jalz.2018.06.3061. PMC 6231970. PMID 30177276. 8. ^ Arvanitakis Z. "Dementia And Vascular Disease". Archived from the original on 2012-01-20. 9. ^ Vlassenko AG, Mintun MA, Xiong C, Sheline YI, Goate AM, Benzinger TL, Morris JC (November 2011). "Amyloid-beta plaque growth in cognitively normal adults: longitudinal [11C]Pittsburgh compound B data". Annals of Neurology. 70 (5): 857–61. doi:10.1002/ana.22608. PMC 3243969. PMID 22162065. 10. ^ Sojkova J, Zhou Y, An Y, Kraut MA, Ferrucci L, Wong DF, Resnick SM (May 2011). "Longitudinal patterns of β-amyloid deposition in nondemented older adults". Archives of Neurology. 68 (5): 644–9. doi:10.1001/archneurol.2011.77. PMC 3136195. PMID 21555640. 11. ^ a b Makhlouf S, Messelmani M, Zaouali J, Mrissa R (2018). "Cognitive impairment in celiac disease and non-celiac gluten sensitivity: review of literature on the main cognitive impairments, the imaging and the effect of gluten free diet". Acta Neurol Belg (Review). 118 (1): 21–27. doi:10.1007/s13760-017-0870-z. PMID 29247390. 12. ^ a b c Zis P, Hadjivassiliou M (26 February 2019). "Treatment of Neurological Manifestations of Gluten Sensitivity and Coeliac Disease". Curr Treat Options Neurol (Review). 21 (3): 10. doi:10.1007/s11940-019-0552-7. PMID 30806821. 13. ^ Wetterling T, Kanitz RD, Borgis KJ (January 1996). "Comparison of different diagnostic criteria for vascular dementia (ADDTC, DSM-IV, ICD-10, NINDS-AIREN)". Stroke. 27 (1): 30–6. doi:10.1161/01.str.27.1.30. PMID 8553399. 14. ^ Tang WK, Chan SS, Chiu HF, Ungvari GS, Wong KS, Kwok TC, Mok V, Wong KT, Richards PS, Ahuja AT (2004). "Impact of applying NINDS-AIREN criteria of probable vascular dementia to clinical and radiological characteristics of a stroke cohort with dementia". Cerebrovascular Diseases. 18 (2): 98–103. doi:10.1159/000079256. PMID 15218273. 15. ^ Pantoni L, Inzitari D (October 1993). "Hachinski's ischemic score and the diagnosis of vascular dementia: a review". Italian Journal of Neurological Sciences. 14 (7): 539–46. doi:10.1007/BF02339212. PMID 8282525. 16. ^ Bonte FJ, Harris TS, Hynan LS, Bigio EH, White CL. Tc-99m HMPAO SPECT in the Differential Diagnosis of the Dementias with Histopathologic Confirmation. Clinical Nuclear Medicine. July 2006;31(7):376–378. doi:10.1097/01.rlu.0000222736.81365.63. PMID 16785801. 17. ^ Dougall NJ, Bruggink S, Ebmeier KP. Systematic Review of the Diagnostic Accuracy of 99mTc-HMPAO-SPECT in Dementia. American Journal of Geriatric Psychiatry. 2004;12(6):554–570. doi:10.1176/appi.ajgp.12.6.554. PMID 15545324. 18. ^ Waldemar G.. Recommendations for the Diagnosis and Management of Alzheimer's Disease and Other Disorders Associated with Dementia: EFNS guideline. European Journal of Neurology. January 2007;14(1):e1–26. doi:10.1111/j.1468-1331.2006.01605.x. PMID 17222085. 19. ^ From NINCDS-ADRDA Alzheimer's Criteria: Dubois B, Feldman HH, Jacova C, Dekosky ST, Barberger-Gateau P, Cummings J, Delacourte A, Galasko D, Gauthier S, Jicha G, Meguro K, O'brien J, Pasquier F, Robert P, Rossor M, Salloway S, Stern Y, Visser PJ, Scheltens P (August 2007). "Research criteria for the diagnosis of Alzheimer's disease: revising the NINCDS-ADRDA criteria". The Lancet. Neurology. 6 (8): 734–46. doi:10.1016/S1474-4422(07)70178-3. PMID 17616482. 20. ^ McVeigh, Catherine; Passmore, Peter (Sep 2006). "Vascular dementia: prevention and treatment". Clinical Interventions in Aging. 1 (3): 229–235. doi:10.2147/ciia.2006.1.3.229. ISSN 1176-9092. PMC 2695177. PMID 18046875. 21. ^ Erkinjuntti, Timo (Feb 2012). Gelder, Michael; Andreasen, Nancy; Lopez-Ibor, Juan; Geddes, John (eds.). New Oxford Textbook of Psychiatry (2 ed.). Oxford: Oxford University Press. doi:10.1093/med/9780199696758.001.0001. ISBN 9780199696758. Retrieved 7 November 2015. 22. ^ a b c d e Baskys A, Cheng JX (November 2012). "Pharmacological prevention and treatment of vascular dementia: approaches and perspectives". Experimental Gerontology. 47 (11): 887–91. doi:10.1016/j.exger.2012.07.002. PMID 22796225. 23. ^ Mijajlović MD, Pavlović A, Brainin M, Heiss WD, Quinn TJ, Ihle-Hansen HB, et al. (January 2017). "Post-stroke dementia - a comprehensive review". BMC Medicine. 15 (1): 11. doi:10.1186/s12916-017-0779-7. PMC 5241961. PMID 28095900. 24. ^ Rands, Gianetta; Orrell, Martin (23 October 2000). "Aspirin for vascular dementia" (PDF). Cochrane Database of Systematic Reviews. doi:10.1002/14651858.cd001296. 25. ^ J, Birks; B, McGuinness; D, Craig (2013-05-31). "Rivastigmine for Vascular Cognitive Impairment". The Cochrane Database of Systematic Reviews. PMID 23728651. Retrieved 2020-05-29. 26. ^ a b van de Vorst IE, Vaartjes I, Geerlings MI, Bots ML, Koek HL (October 2015). "Prognosis of patients with dementia: results from a prospective nationwide registry linkage study in the Netherlands". BMJ Open. 5 (10): e008897. doi:10.1136/bmjopen-2015-008897. PMC 4636675. PMID 26510729. 27. ^ Guehne U, Riedel-Heller S, Angermeyer MC (2005). "Mortality in dementia". Neuroepidemiology. 25 (3): 153–62. doi:10.1159/000086680. PMID 15990446. 28. ^ Bruandet A, Richard F, Bombois S, Maurage CA, Deramecourt V, Lebert F, Amouyel P, Pasquier F (February 2009). "Alzheimer disease with cerebrovascular disease and vascular dementia: clinical features and course compared with Alzheimer disease". Journal of Neurology, Neurosurgery, and Psychiatry. 80 (2): 133–9. doi:10.1136/jnnp.2007.137851. PMID 18977819. 29. ^ Villarejo A, Benito-León J, Trincado R, Posada IJ, Puertas-Martín V, Boix R, Medrano MR, Bermejo-Pareja F (2011). "Dementia-associated mortality at thirteen years in the NEDICES Cohort Study". Journal of Alzheimer's Disease. 26 (3): 543–51. doi:10.3233/JAD-2011-110443. PMID 21694455. 30. ^ Garcia-Ptacek S, Farahmand B, Kåreholt I, Religa D, Cuadrado ML, Eriksdotter M (2014). "Mortality risk after dementia diagnosis by dementia type and underlying factors: a cohort of 15,209 patients based on the Swedish Dementia Registry". Journal of Alzheimer's Disease. 41 (2): 467–77. doi:10.3233/JAD-131856. PMID 24625796. 31. ^ Battistin L, Cagnin A (December 2010). "Vascular cognitive disorder. A biological and clinical overview". Neurochemical Research. 35 (12): 1933–8. doi:10.1007/s11064-010-0346-5. PMID 21127967. 32. ^ "Vascular Dementia: A Resource List". 33. ^ Plassman BL, Langa KM, Fisher GG, Heeringa SG, Weir DR, Ofstedal MB, Burke JR, Hurd MD, Potter GG, Rodgers WL, Steffens DC, Willis RJ, Wallace RB (2007). "Prevalence of dementia in the United States: the aging, demographics, and memory study". Neuroepidemiology. 29 (1–2): 125–32. doi:10.1159/000109998. PMC 2705925. PMID 17975326. 34. ^ Jorm AF, Korten AE, Henderson AS (November 1987). "The prevalence of dementia: a quantitative integration of the literature". Acta Psychiatrica Scandinavica. 76 (5): 465–79. doi:10.1111/j.1600-0447.1987.tb02906.x. PMID 3324647. ## External links[edit] * Multi-Infarct Dementia Fact Sheet at ninds.nih.gov * American Academy of Neurology (December 21, 2007). "Walking and Moderate Exercise Help Prevent Dementia". ScienceDaily. Retrieved December 21, 2007, from https://www.sciencedaily.com/releases/2007/12/071219202948.htm Classification D * ICD-10: F01.1 * ICD-9-CM: 290.4 * MeSH: D015161 * DiseasesDB: 8393 External resources * MedlinePlus: 000746 * eMedicine: med/3150 neuro/227 * 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 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]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Vascular dementia	c0011269	3,782	wikipedia	https://en.wikipedia.org/wiki/Vascular_dementia	2021-01-18T18:32:05	{"mesh": ["D015140"], "umls": ["C0011269", "C0011263"], "wikidata": ["Q583908"]}
A rare genetic, muscle channelopathy characterized by recurrent episodic attacks of generalized muscle weakness associated with a decrease in blood potassium levels. ## Epidemiology Prevalence is estimated at around 1/100,000 in Europe. ## Clinical description Attacks of muscle weakness generally begin during childhood/adolescence (second decade). They vary in frequency, duration (hours to days) and severity (focal paresis to total paralysis). They generally involve the limbs muscles and spare the facial and respiratory musculature. Episodes are triggered by rest after strenuous exercise, meals rich in carbohydrates and prolonged immobility. Other factors may include stress, infection, glucocorticoids, anesthesia and pregnancy. In an undefined number of cases, hypokalemic periodic paralysis (hypoPP) may be associated with a vacuolar myopathy resulting in a permanent and progressive muscle weakness predominantly in proximal lower limb muscles. The myopathy may occur independent of paralytic symptoms. ## Etiology Around 70% of cases are associated with mutations in the muscle calcium channel gene CACNA1S (1q32.1) and 10% of cases are linked to mutations in the muscle sodium channel gene SCN4A (17q23.3). ## Diagnostic methods Diagnosis is based on clinical history, electromyographic and genetic tests. Hypokalemia during attacks can be very low. Serum creatinine kinase (CK) levels can be softly elevated. EMG reveals muscle excitability anomalies after a prolonged exercise test (decrement > 30% of the compound muscle action potential). Muscle biopsy may show non-specific results (muscle fibers atrophy with vacuoles). Molecular diagnosis is feasible through analysis of the causative genes identified so far. ## Differential diagnosis Differential diagnoses should include hyper/normokalemic periodic paralysis, Andersen-Tawil syndrome and secondary hypoPP caused by renal or endocrine diseases such as thyrotoxicosis (thyrotoxic periodic paralysis). ## Antenatal diagnosis Once the pathogenic variant has been identified in an affected family member, prenatal testing and preimplantation genetic testing are possible but rarely performed because of the non life-threatening prognosis. ## Genetic counseling HypoPP is transmitted as an autosomal dominant disease with a possible incomplete penetrance, especially in females. Genetic counseling should be offered to affected families. Sporadic cases and de novo mutations have been reported. Offspring of a proband are at a 50% risk of inheriting the pathogenic variant. ## Management and treatment Management of patients consists in medical therapy and avoidance of triggering factors. Gentle physical activity, and ingestion of oral potassium salts at the onset of attacks may abort them. Severe attacks require more intensive medical management with intravenous potassium infusion. Daily potassium supplementation or intake of carbonic anhydrase inhibitors (acetazolamide, dichlorphenamide) or potassium-sparing diuretics help in preventing attacks. Dietary advice includes a diet low in carbohydrates and rich in potassium. There is no known curative treatment for hypoPP-related myopathy; physiotherapy may help to maintain strength and motor skills. ## Prognosis With age, the frequency of the episodes decline but some patients may develop a chronic myopathy of variable severity that may cause a permanent muscle 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 [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Hypokalemic periodic paralysis	c0238357	3,783	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=681	2021-01-23T17:14:47	{"gard": ["6729"], "mesh": ["D020513", "D020514"], "omim": ["170400", "613345"], "umls": ["C0238357", "C0238358"], "icd-10": ["G72.3"], "synonyms": ["Westphall disease"]}
Primary congenital hypothyroidism without thyroid developmental anomaly is a type of primary congenital hypothyroidism (see this term) in which the thyroid gland is anatomically normal. ## Epidemiology Thyroid dyshormonogenesis accounts for 10-15% of permanent congenital hypothyroidism (see this term) while TSH receptor mutations cause less than 5%. ## Etiology It may be caused by either resistance to thyroid stimulating hormone (TSH) as a result of TSH receptor mutations or by inborn errors of thyroid hormone synthesis, also known as thyroid dyshormonogenesis (see these terms), and it results in permanent thyroid hormone deficiency that is present from birth. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Primary congenital hypothyroidism without thyroid developmental anomaly	None	3,784	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=95714	2021-01-23T16:59:23	{"icd-10": ["E03.0", "E03.1"]}
This article needs more medical references for verification or relies too heavily on primary sources. Please review the contents of the article and add the appropriate references if you can. Unsourced or poorly sourced material may be challenged and removed. Find sources: "Hammer toe" – news · newspapers · books · scholar · JSTOR (February 2019) Hammer toe Other namesContracted toe Human feet with hammer toes SpecialtyPodiatry A hammer toe or contracted toe is a deformity of the muscles and ligaments of the proximal interphalangeal joint of the second, third, fourth, or fifth toe causing it to be bent, resembling a hammer. In the early stage a flexible hammertoe is movable at the joints; a rigid hammertoe joint cannot be moved and usually requires surgery.[1] Mallet toe is a similar condition affecting the distal interphalangeal joint.[2] Claw toe is another similar condition, with dorsiflexion of the proximal phalanx on the lesser metatarsophalangeal joint, combined with flexion of both the proximal and distal interphalangeal joints. Claw toe can affect the second, third, fourth, or fifth toes. ## Contents * 1 Risk factors * 2 Causes * 3 Treatment * 4 References * 5 External links ## Risk factors[edit] Older people are more likely to develop hammer toes.[3] Women are at higher risk, due to the construction of women's shoes.[1] Injuries to the toes, and being born with a longer second toe, increase risk.[3] Arthritis and diabetes may also increase the risk of foot deformities.[3] ## Causes[edit] A mallet toe is evident on the 3rd digit. Hammertoes and clawtoes have multiple causes.[4][5] Hammer toe most frequently results from wearing poorly fitting shoes that can force the toe into a bent position, such as high heels or shoes that are too short or narrow for the foot. Having the toes bent for long periods of time can cause the muscles in them to shorten, resulting in the hammer toe deformity. This is often found in conjunction with bunions or other foot problems (e.g., a bunion can force the big toe to turn inward and push the other toes).[3] The toe muscles work in pairs; if the muscles pulling in one direction are much weaker than those pulling in the other direction, the imbalance can bend the toe. If the bend persists, then as the tendons and ligaments tighten (as they do if not stretched[medical citation needed]), the bend may become permanent.[3] Ill-fitting shoes are especially likely to push the toes out of balance.[1] Toe deformities can also be caused by muscle, nerve, or joint damage, resulting from conditions such as osteoarthritis, rheumatoid arthritis, stroke, Charcot–Marie–Tooth disease, complex regional pain syndrome or diabetes.[3] Hammer toe can also be found in Friedreich's ataxia (GAA trinucleotide repeat). Corrective surgery for hammer toe ## Treatment[edit] In many cases, conservative treatment consisting of physical therapy and new shoes with soft, spacious toe boxes is enough to resolve the condition, while in more severe or longstanding cases hammertoe surgery[6] may be necessary to correct the deformity. The patient's doctor may also prescribe some toe exercises that can be done at home to stretch and strengthen the muscles. For example, the individual can gently stretch the toes manually, or use the toes to pick things up off the floor. ## References[edit] 1. ^ a b c Sabrina Felson. "Understanding Hammertoes -- the Basics". WebMD. Reviewed March 31, 2019 2. ^ Mayo Clinic, "Hammertoe and mallet toe" 3. ^ a b c d e f "Hammer toe and mallet toe – causes". Mayo Clinic. Retrieved 2009-01-30. 4. ^ Chadwick, C; Saxby, TS (December 2011). "Hammertoes/Clawtoes: metatarsophalangeal joint correction". Foot and Ankle Clinics. 16 (4): 559–71. doi:10.1016/j.fcl.2011.08.006. PMID 22118229. 5. ^ Ellington, JK (December 2011). "Hammertoes and clawtoes: proximal interphalangeal joint correction". Foot and Ankle Clinics. 16 (4): 547–58. doi:10.1016/j.fcl.2011.08.010. PMID 22118228. 6. ^ Benefits and Risks of Hammertoe Surgery ## External links[edit] * Hammer Toe – American Academy of Orthopedic Surgeons * Hammer Toes – American Podiatric Medical Association * Aetna Clinical Policy Bulletin: Hammertoe Repair Guidelines for surgical repair Classification D * ICD-10: M20.4, Q66.8 * ICD-9-CM: 735.4, 755.66 * MeSH: D037801 External resources * MedlinePlus: 001235 * 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 * t * e Congenital malformations and deformations of musculoskeletal system / musculoskeletal abnormality Appendicular limb / dysmelia Arms clavicle / shoulder * Cleidocranial dysostosis * Sprengel's deformity * Wallis–Zieff–Goldblatt syndrome hand deformity * Madelung's deformity * Clinodactyly * Oligodactyly * Polydactyly Leg hip * Hip dislocation / Hip dysplasia * Upington disease * Coxa valga * Coxa vara knee * Genu valgum * Genu varum * Genu recurvatum * Discoid meniscus * Congenital patellar dislocation * Congenital knee dislocation foot deformity * varus * Club foot * Pigeon toe * valgus * Flat feet * Pes cavus * Rocker bottom foot * Hammer toe Either / both fingers and toes * Polydactyly / Syndactyly * Webbed toes * Arachnodactyly * Cenani–Lenz syndactylism * Ectrodactyly * Brachydactyly * Stub thumb reduction deficits / limb * Acheiropodia * Ectromelia * Phocomelia * Amelia * Hemimelia multiple joints * Arthrogryposis * Larsen syndrome * RAPADILINO syndrome Axial Skull and face Craniosynostosis * Scaphocephaly * Oxycephaly * Trigonocephaly Craniofacial dysostosis * Crouzon syndrome * Hypertelorism * Hallermann–Streiff syndrome * Treacher Collins syndrome other * Macrocephaly * Platybasia * Craniodiaphyseal dysplasia * Dolichocephaly * Greig cephalopolysyndactyly syndrome * Plagiocephaly * Saddle nose Vertebral column * Spinal curvature * Scoliosis * Klippel–Feil syndrome * Spondylolisthesis * Spina bifida occulta * Sacralization Thoracic skeleton ribs: * Cervical * Bifid sternum: * Pectus excavatum * Pectus carinatum [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Hammer toe	c1136179	3,785	wikipedia	https://en.wikipedia.org/wiki/Hammer_toe	2021-01-18T18:38:42	{"mesh": ["D037801"], "umls": ["C1136179"], "icd-9": ["735.4", "755.66"], "icd-10": ["M20.4", "Q66.8"], "wikidata": ["Q602477"]}
A number sign (#) is used with this entry because of evidence that Liddle syndrome-2 (LIDLS2) is caused by heterozygous mutation in the SCNN1G gene (600761), encoding the gamma subunit of the renal epithelial sodium channel (ENaC), on chromosome 16p12. Description Liddle syndrome is an autosomal dominant form of hypertension characterized by early onset of hypertension associated with hypokalemia, suppressed plasma renin activity, and suppressed secretion of the mineralocorticoid hormone aldosterone (summary by Hansson et al., 1995). For a general phenotypic description and a discussion of genetic heterogeneity of Liddle syndrome, see 177200. Clinical Features Hansson et al. (1995) reported a Japanese family (K204) with clinically typical Liddle syndrome and showed that the disorder was caused by mutation in the gamma subunit of the epithelial sodium channel. The family was ascertained through a 17-year-old female who presented with lower limb numbness and was found to have hypokalemia and severe hypertension. Suppressed plasma renal activity and plasma aldosterone concentration was demonstrated, other steroids were normal, and there was no sign of virilization. Blood pressure and hypokalemia were not improved by the mineralocorticoid antagonists spironolactone or the glucocorticoid dexamethasone, but improved markedly in response to dietary salt restriction plus the epithelial sodium channel antagonist triamterene. Hiltunen et al. (2002) reported a Finnish man who developed hypertension associated with low serum aldosterone, suppressed renin activity, and persistent hypokalemia at 25 years of age. His mother had been hypertensive since age 40 years and had a low-normal serum potassium with low plasma renin activity. The proband's blood pressure was initially resistant to treatment but responded to triamterene and later amiloride; similarly, his mother became normotensive when her treatment included amiloride. Wang et al. (2007) studied a Japanese man who was first diagnosed with hypertension at 13 years of age. He had hypokalemic metabolic alkalosis and low plasma renin activity; serum aldosterone was in the low-normal range. Initial treatments for hypertension were ineffective, but after the diagnosis of Liddle syndrome was made, his blood pressure was controlled on triamterene and a low-sodium diet. Inheritance The findings in the pedigree with Liddle syndrome reported by Hansson et al. (1995) were consistent with autosomal dominant inheritance, although there was no male-to-male transmission. Molecular Genetics In affected members of a Japanese family (K204) segregating Liddle syndrome who did not have mutation in the SCNN1B gene (600760), Hansson et al. (1995) identified a truncating mutation in the C terminus of the gamma subunit of the renal epithelial sodium channel (W574X; 600761.0001). Snyder et al. (1995) investigated the mechanism by which truncation of the C terminus of the beta and gamma subunits alter the function of the renal epithelial sodium channel. They identified a conserved motif in the C terminus of all 3 subunits of the sodium channel that, when mutated, reproduced the effect of Liddle truncations. Further, both truncation of the C terminus and mutation of the conserved C-terminal motif increased surface expression of chimeric proteins containing the C terminus of the beta subunit. Thus, by deleting a conserved motif, mutations in the Liddle syndrome increased the number of sodium channels in the apical membrane, which increases renal sodium absorption and creates a predisposition to hypertension. In 3 affected members of a Chinese family with Liddle syndrome, Shi et al. (2010) identified a heterozygous nonsense mutation (Q567X; 600761.0002) in the SCNN1G gene. In a Finnish man with hypertension, hypokalemia, low serum aldosterone, and suppressed renin activity, Hiltunen et al. (2002) screened the SCNN1B and SCNN1G genes and identified heterozygosity for a missense mutation in SCNN1G (N530S; 600761.0008). The mutation was also present in his affected mother, but was not found in his unaffected brother or maternal aunt. However, the N530S variant was detected in 1 of 291 healthy Finnish blood donors as well as in 1 of 175 control Finnish men, aged 50 to 69 years, who had low-normal blood pressure; neither individual was available for further evaluation. Functional analysis demonstrated a 2-fold increase in channel activity with the mutant compared to wildtype SCNN1G. In a Japanese man with Liddle syndrome, Wang et al. (2007) screened the C terminus of the SCCN1B and SCNN1G genes and identified heterozygosity for a de novo 5-bp deletion in SCNN1G (600761.0009) that was not found in his unaffected parents, 50 randomly selected hypertensive patients, or 50 normotensive controls. The authors stated that this was the first reported sporadic patient with a mutation in the SCNN1G gene, and noted that Liddle syndrome should be considered in patients without a family history of hypertension. INHERITANCE \- Autosomal dominant CARDIOVASCULAR Vascular \- Hypertension METABOLIC FEATURES \- Metabolic alkalosis \- Hypokalemia ENDOCRINE FEATURES \- Low plasma renin activity \- Low plasma aldosterone level MISCELLANEOUS \- Phenotype ameliorated by low-salt diet and antagonists of the epithelial channel of the distal nephron \- No improvement with antagonists of the mineralocorticoid receptor MOLECULAR BASIS \- Caused by mutation in the sodium channel, nonvoltage-gated 1, gamma gene (SCNN1G, 600761.0001 ) ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	LIDDLE SYNDROME 2	c0221043	3,786	omim	https://www.omim.org/entry/618114	2019-09-22T15:43:55	{"mesh": ["D056929"], "omim": ["618114"], "orphanet": ["526"]}
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: "Gliomatosis cerebri" – news · newspapers · books · scholar · JSTOR (January 2010) (Learn how and when to remove this template message) Gliomatosis cerebri Other namesInfiltrative diffuse astrocytosis Axial fluid-attenuated inversion recovery MRI image demonstrating tumor-related infiltration involving both temporal lobes (Short arrow), and the substantia nigra (Long arrow). SpecialtyNeurosurgery Gliomatosis cerebri is a rare primary brain tumor. It is commonly characterized by diffuse infiltration of the brain with neoplastic glial cells that affect various areas of the cerebral lobes.[1] These malignancies consist of infiltrative threads that spread quickly and deeply into the surrounding brain tissue, or into multiple parts of the brain simultaneously, making them very difficult to remove with surgery or treat with radiation. Gliomatosis cerebri behaves like a malignant tumor that is very similar to Glioblastoma. While gliomatosis cerebri can occur at any age, it is generally found in the third and fourth decades of life. ## Contents * 1 Signs and symptoms * 2 Diagnosis * 3 Registry * 4 Notes * 5 External links ## Signs and symptoms[edit] It may affect any part of the brain or even the spinal cord, optic nerve and compact white matter. Clinical manifestations are indefinite, and include headache, seizures, visual disturbances, corticospinal tract deficits, lethargy, and dementia. A case of gliomatosis cerebri presenting as rapidly progressive dementia and Parkinson's disease like symptoms has been described in an 82-year-old woman.[2] ## Diagnosis[edit] Before the advent of MRI, diagnosis was generally not established until autopsy. Even with MRI, however, diagnosis is difficult.[3] Typically, gliomatosis cerebri appears as a diffuse, poorly circumscribed, infiltrating non-enhancing lesion that is hyperintense on T2-weighted images and expands the cerebral white matter. It is difficult to distinguish from highly infiltrative anaplastic astrocytoma or GBM.[citation needed] ## Registry[edit] In 2014, Weill Cornell Brain and Spine Center launched an international registry for gliomatosis cerebri, where tissue samples can be stored for genomic study.[4] ## Notes[edit] 1. ^ "Gliomatosis Cerebri, MedPix : 923 - Medical Image Database and Atlas". Archived from the original on 2004-12-16. Retrieved 2007-01-23. 2. ^ "Journal of Medical Case Reports". 3. ^ Bendszus M, Warmuth-Metz M, Klein R, et al. (2000). "MR spectroscopy in gliomatosis cerebri". AJNR Am J Neuroradiol. 21 (2): 375–80. PMID 10696026. 4. ^ GC International Registry ## External links[edit] Classification D * ICD-9-CM: 191.0 * ICD-O: M9381/3 * MeSH: D018302 * SNOMED CT: 26138003 External resources * Orphanet: 251582 * v * t * e Tumours of the nervous system Endocrine Sellar: * Craniopharyngioma * Pituicytoma Other: * Pinealoma CNS Neuroepithelial (brain tumors, spinal tumors) Glioma Astrocyte * Astrocytoma * Pilocytic astrocytoma * Pleomorphic xanthoastrocytoma * Subependymal giant cell astrocytoma * Fibrillary astrocytoma * Anaplastic astrocytoma * Glioblastoma multiforme Oligodendrocyte * Oligodendroglioma * Anaplastic oligodendroglioma Ependyma * Ependymoma * Subependymoma Choroid plexus * Choroid plexus tumor * Choroid plexus papilloma * Choroid plexus carcinoma Multiple/unknown * Oligoastrocytoma * Gliomatosis cerebri * Gliosarcoma Mature neuron * Ganglioneuroma: Ganglioglioma * Retinoblastoma * Neurocytoma * Dysembryoplastic neuroepithelial tumour * Lhermitte–Duclos disease PNET * Neuroblastoma * Esthesioneuroblastoma * Ganglioneuroblastoma * Medulloblastoma * Atypical teratoid rhabdoid tumor Primitive * Medulloepithelioma Meninges * Meningioma * Hemangiopericytoma Hematopoietic * Primary central nervous system lymphoma PNS: * Nerve sheath tumor * Cranial and paraspinal nerves * Neurofibroma * Neurofibromatosis * Neurilemmoma/Schwannoma * Acoustic neuroma * Malignant peripheral nerve sheath tumor Other * WHO classification of the tumors of the central nervous system Note: Not all brain tumors are of nervous tissue, and not all nervous tissue tumors are in the brain (see brain metastasis). [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Gliomatosis cerebri	c0334576	3,787	wikipedia	https://en.wikipedia.org/wiki/Gliomatosis_cerebri	2021-01-18T18:56:35	{"gard": ["6514"], "mesh": ["D018302"], "umls": ["C0334576"], "icd-9": ["191.0"], "orphanet": ["251582"], "wikidata": ["Q1531482"]}
A number sign (#) is used with this entry because Carney complex variant associated with distal arthrogryposis is caused by mutation in the MYH8 gene (160741). For a phenotypic description of Carney complex, see (160980). Veugelers et al. (2004) described a Caucasian Belgian family, originally reported by (Chaudron et al., 1992), with Carney complex variant and trismus-pseudocamptodactyly syndrome (158300). In 18 affected members of the family, they identified an arg674-to-gln substitution in the MYH8 gene (R674Q; 160741.0001). Penetrance of the disorder was complete, although expressivity was highly variable. Three affected family members had had cardiac myxomas, and all affected family members who were available for a complete examination had spotty skin pigmentation alone or in combination with cutaneous lesions. Most of the family members had distal arthrogryposis, including pseudocamptodactyly of the hands and feet, trismus, or both, which improved symptomatically with aging. Two family members had required palliative hand surgery, and 1 had had foot surgery. Stratakis et al. (2004) argued that the syndrome described by Veugelers et al. (2004) was not in fact a variant of Carney complex. They stated that among more than 500 patients with the Carney complex in their database, there was none with trismus-pseudocamptodactyly syndrome. In an analysis of patients reported to have trismus-pseudocamptodactyly syndrome, they identified several with freckling. These patients appeared to have a familial disorder distinct from a simple Carney complex variant. Patients with trismus-pseudocamptodactyly syndrome had none of the lesions or endocrine syndromes typical of Carney complex. Trismus-pseudocamptodactyly syndrome with freckling may or may not be associated with familial myxomas and may or may not be caused by a single mutation of the MYH8 gene, but their own data led Stratakis et al. (2004) to conclude that this disorder is distinct from the Carney complex. Toydemir et al. (2006) studied 4 trismus-pseudocamptodactyly pedigrees and identified the R674Q mutation in the MYH8 gene in 19 affected members, none of whom had multiple hyperpigmented macules or cardiac myxomas. The R674Q mutation was not found in 49 unrelated cases of Carney complex who were negative for mutation in the PRKAR1A gene (188830); Toydemir et al. (2006) concluded that R674Q rarely, if ever, causes Carney complex. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	CARNEY COMPLEX VARIANT	c1837245	3,788	omim	https://www.omim.org/entry/608837	2019-09-22T16:07:06	{"doid": ["0050471"], "mesh": ["C563845"], "omim": ["608837"], "orphanet": ["319340"]}
A rare, genetic, autosomal dominant hereditary axonal motor and sensory neuropathy disorder characterized by childhood-onset palmoplantar keratoderma associated with motor and sensory polyneuropathy manifestating with late-onset, predominantly distal, lower limb muscle weakness and atrophy (later associating mild proximal weakness and upper limb involvement), moderate sensory impairment (hypoesthesia with stocking-glove distribution), and normal or near‐normal nerve conduction velocities. Additional variable manifestations include impaired vibratory sensation, reduced tendon reflexes, paresthesia, pain, talipes equinovarus, pes cavus, and nail dystrophy. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Palmoplantar keratoderma-hereditary motor and sensory neuropathy syndrome	c1835671	3,789	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=538574	2021-01-23T18:04:26	{"mesh": ["C536153"], "omim": ["148360"], "icd-10": ["G60.0"], "synonyms": ["Palmoplantar keratoderma-Charcot-Marie-Tooth syndrome"]}
Clouding of the lens inside the eye, which leads to low vision For other uses, see Cataract (disambiguation). Cataract Magnified view of a cataract seen on examination with a slit lamp SpecialtyOphthalmology SymptomsFaded colors, blurry vision, halos around light, trouble with bright lights, trouble seeing at night[1] ComplicationsFalling, depression, blindness[2][3] Usual onsetGradual[1] CausesAging, trauma, radiation exposure, following eye surgery, genetic[1][4][5] Risk factorsDiabetes, smoking tobacco, prolonged exposure to sunlight, alcohol[1] Diagnostic methodEye examination[1] PreventionSunglasses, proper diet, not smoking[1] TreatmentGlasses, cataract surgery[1] Frequency60 million (2015)[6] A cataract is the clouding of the lens of the eye which leads to a decrease in vision.[1] Cataracts often develop slowly and can affect one or both eyes.[1] Symptoms may include faded colors, blurry or double vision, halos around light, trouble with bright lights, and trouble seeing at night.[1] This may result in trouble driving, reading, or recognizing faces.[7] Poor vision caused by cataracts may also result in an increased risk of falling and depression.[2] Cataracts cause half of all cases of blindness and 33% of visual impairment worldwide.[3][8] Cataracts are most commonly due to aging but may also occur due to trauma or radiation exposure, be present from birth, or occur following eye surgery for other problems.[1][4] Risk factors include diabetes, longstanding use of corticosteroid medication, smoking tobacco, prolonged exposure to sunlight, and alcohol.[1] The underlying mechanism involves accumulation of clumps of protein or yellow-brown pigment in the lens that reduces transmission of light to the retina at the back of the eye.[1] Diagnosis is by an eye examination.[1] Prevention includes wearing sunglasses, a wide brimmed hat, eating leafy vegetables and fruits, and avoiding smoking.[1][9] Early on the symptoms may be improved with glasses.[1] If this does not help, surgery to remove the cloudy lens and replace it with an artificial lens is the only effective treatment.[1] Cataract surgery is not readily available in many countries, and surgery is needed only if the cataracts are causing problems and generally results in an improved quality of life.[1][10][4][11] About 20 million people are blind due to cataracts.[4] It is the cause of approximately 5% of blindness in the United States and nearly 60% of blindness in parts of Africa and South America.[11] Blindness from cataracts occurs in about 10 to 40 per 100,000 children in the developing world, and 1 to 4 per 100,000 children in the developed world.[12] Cataracts become more common with age.[1] In the United States, cataracts occur in 68% of those over the age of 80 years.[13] Additionally they are more common in women, and less common in Hispanic and Black people.[13] ## Contents * 1 Signs and symptoms * 2 Causes * 2.1 Age * 2.2 Trauma * 2.3 Radiation * 2.4 Genetics * 2.5 Skin diseases * 2.6 Smoking and alcohol * 2.7 Inadequate vitamin C * 2.8 Medications * 2.9 Post-operative * 2.10 Other diseases * 3 Diagnosis * 3.1 Classification * 4 Prevention * 5 Treatment * 5.1 Surgical * 6 Prognosis * 6.1 Postoperative care * 6.2 Complications * 7 Epidemiology * 8 History * 8.1 Etymology * 9 Research * 10 See also * 11 References * 12 External links ## Signs and symptoms[edit] An example of normal vision on the left versus vision with cataracts on the right Bilateral cataracts in an infant due to congenital rubella syndrome Signs and symptoms vary depending on the type of cataract, though considerable overlap occurs. People with nuclear sclerotic or brunescent cataracts often notice a reduction of vision. Nuclear cataracts typically cause greater impairment of distance vision than of near vision. Those with posterior subcapsular cataracts usually complain of glare as their major symptom.[14] The severity of cataract formation, assuming no other eye disease is present, is judged primarily by a visual acuity test. Other symptoms include frequent changes of glasses and colored halos due to hydration of lens. Congenital cataracts can result in amblyopia if not treated in a timely manner.[15] ## Causes[edit] ### Age[edit] Age is the most common cause.[1][4] Lens proteins denature and degrade over time, and this process is accelerated by diseases such as diabetes mellitus and hypertension. Environmental factors, including toxins and radiation, including ultraviolet light, have cumulative effects, which are worsened by the loss of protective and restorative mechanisms due to alterations in gene expression and chemical processes within the eye.[16] ### Trauma[edit] Post traumatic rosette cataract of a 60-year-old male Blunt trauma causes swelling, thickening, and whitening of the lens fibers. While the swelling normally resolves with time, the white color may remain. In severe blunt trauma, or in injuries that penetrate the eye, the capsule in which the lens sits can be damaged. This damage allows fluid from other parts of the eye to rapidly enter the lens leading to swelling and then whitening, obstructing light from reaching the retina at the back of the eye. Cataracts may develop in 0.7 to 8.0% of cases following electrical injuries.[17] Blunt trauma can also result in star- (stellate) or petal-shaped cataracts.[18] ### Radiation[edit] Cataracts can arise as an effect of exposure to various types of radiation. X-rays, one form of ionizing radiation, may damage the DNA of lens cells.[19] Ultraviolet light, specifically UVB, has also been shown to cause cataracts, and some evidence indicates sunglasses worn at an early age can slow its development in later life.[20] Microwaves, a type of nonionizing radiation, may cause harm by denaturing protective enzymes (e.g., glutathione peroxidase), by oxidizing protein thiol groups (causing protein aggregation), or by damaging lens cells via thermoelastic expansion.[19] The protein coagulation caused by electric and heat injuries whitens the lens.[16] This same process is what makes the clear albumen of an egg become white and opaque during cooking. ### Genetics[edit] Christmas tree cataract (Diffuse illumination) The genetic component is strong in the development of cataracts,[21] most commonly through mechanisms that protect and maintain the lens. The presence of cataracts in childhood or early life can occasionally be due to a particular syndrome. Examples of chromosome abnormalities associated with cataracts include 1q21.1 deletion syndrome, cri-du-chat syndrome, Down syndrome, Patau's syndrome, trisomy 18 (Edward's syndrome), and Turner's syndrome, and in the case of neurofibromatosis type 2, juvenile cataract on one or both sides may be noted. Examples of single-gene disorder include Alport's syndrome, Conradi's syndrome, cerebrotendineous xanthomatosis, myotonic dystrophy, and oculocerebrorenal syndrome or Lowe syndrome. ### Skin diseases[edit] The skin and the lens have the same embryological origin and so can be affected by similar diseases.[22] Those with atopic dermatitis and eczema occasionally develop shield ulcer cataracts. Ichthyosis is an autosomal recessive disorder associated with cuneiform cataracts and nuclear sclerosis. Basal-cell nevus and pemphigus have similar associations. ### Smoking and alcohol[edit] Cigarette smoking has been shown to double the rate of nuclear sclerotic cataracts and triple the rate of posterior subcapsular cataracts.[23] Evidence is conflicting over the effect of alcohol. Some surveys have shown a link, but others which followed people over longer terms have not.[24] ### Inadequate vitamin C[edit] Low vitamin C intake and serum levels have been associated with greater cataract rates.[25] However, use of supplements of vitamin C has not demonstrated benefit.[26] ### Medications[edit] Some medications, such as systemic, topical, or inhaled corticosteroids, may increase the risk of cataract development.[27][28] Corticosteroids most commonly cause posterior subcapsular cataracts.[28] People with schizophrenia often have risk factors for lens opacities (such as diabetes, hypertension, and poor nutrition) but antipsychotic medications are unlikely to contribute to cataract formation.[29] Miotics[30] and triparanol may increase the risk.[31] ### Post-operative[edit] Nearly every person who undergoes a vitrectomy—without ever having had cataract surgery—will experience progression of nuclear sclerosis after the operation.[32] This may be because the native vitreous humor is different from the solutions used to replace the vitreous (vitreous substitutes), such as BSS Plus.[33] This may also be because the native vitreous humour contains ascorbic acid which helps neutralize oxidative damage to the lens and because conventional vitreous substitutes do not contain ascorbic acid.[34][35] Accordingly, for phakic patients requiring a vitrectomy it is becoming increasingly common for ophthalmologists to offer the vitrectomy combined with prophylactic cataract surgery to prevent cataract formation.[36] ### Other diseases[edit] * Metabolic and nutritional diseases * Aminoaciduria or Lowe's syndrome * Cerebrotendineous xanthomatosis * Diabetes mellitus * Fabry's disease * Galactosemia / galactosemic cataract * Homocystinuria * Hyperparathyroidism * Hypoparathyroidism * Hypervitaminosis D * Hypothyroidism * Hypocalcaemia * Mucopolysaccharidoses * Wilson's disease * Congenital * Congenital syphilis * Cytomegalic inclusion disease * Rubella * Cockayne syndrome * Genetic syndromes * Down syndrome * Patau syndrome * Edwards syndrome * Infections: * Cysticercosis * Leprosy * Onchocerciasis * Toxoplasmosis * Varicella * Secondary to other eye diseases: * Retinopathy of prematurity * Aniridia * Uveitis * Retinal detachment * Retinitis pigmentosa Sunflower cataract of a forty-year-old male with Wilson's disease and decompensated chronic liver disease ## Diagnosis[edit] ### Classification[edit] Cross-sectional view, showing the position of the human lens Play media Ultrasound scan of a unilateral cataract seen in a fetus at twenty weeks of pregnancy Cataracts may be partial or complete, stationary or progressive, or hard or soft. The main types of age-related cataracts are nuclear sclerosis, cortical, and posterior subcapsular. Nuclear sclerosis is the most common type of cataract, and involves the central or 'nuclear' part of the lens. This eventually becomes hard, or 'sclerotic', due to condensation on the lens nucleus and the deposition of brown pigment within the lens. In its advanced stages it is called a brunescent cataract. In early stages, an increase in sclerosis may cause an increase in refractive index of the lens.[37] This causes a myopic shift (lenticular shift) that decreases hyperopia and enables presbyopic patients to see at near without reading glasses. This is only tempororary and is called second sight. Cortical cataracts are due to the lens cortex (outer layer) becoming opaque. They occur when changes in the fluid contained in the periphery of the lens causes fissuring. When these cataracts are viewed through an ophthalmoscope, or other magnification system, the appearance is similar to white spokes of a wheel. Symptoms often include problems with glare and light scatter at night.[37] Posterior subcapsular cataracts are cloudy at the back of the lens adjacent to the capsule (or bag) in which the lens sits. Because light becomes more focused toward the back of the lens, they can cause disproportionate symptoms for their size. An immature cataract has some transparent protein, but with a mature cataract, all the lens protein is opaque. In a hypermature or Morgagnian cataract, the lens proteins have become liquid. Congenital cataract, which may be detected in adulthood, has a different classification and includes lamellar, polar, and sutural cataracts.[38][39] Cataracts can be classified by using the lens opacities classification system LOCS III. In this system, cataracts are classified based on type as nuclear, cortical, or posterior. The cataracts are further classified based on severity on a scale from 1 to 5. The LOCS III system is highly reproducible.[40] Different types of cataracts * Posterior polar cataract of an 8 year old boy in left eye * Nuclear sclerosis cataract of a 70 year old male * Cortical cataract of a 60 year old male * Retroillumination of cortical cataract * Posterior subcapsular cataract of a 16 year old girl with IDDM * Intumescent cataract of a 55 year old male * Anterior subcapsular cataract having back shadow * Posterior subcapsular cataract by retroillumination * Nuclear sclerosis and posterior polar cataract of a 60 year old female * Dense white mature cataract of a 60 year old male * Cortical cataract of a melanoderm male ## Prevention[edit] Risk factors such as UVB exposure and smoking can be addressed. Although no means of preventing cataracts has been scientifically proven, wearing sunglasses that counteract ultraviolet light may slow their development.[41][42] While adequate intake of antioxidants (such as vitamins A, C, and E) has been thought to protect against the risk of cataracts, clinical trials have shown no benefit from supplements;[26] though evidence is mixed, but weakly positive, for a potential protective effect of the nutrients lutein and zeaxanthin.[43][44][45] Statin use is somewhat associated with a lower risk of nuclear sclerotic cataracts.[46] ## Treatment[edit] ### Surgical[edit] Main article: Cataract surgery Cataract surgery, using a temporal-approach phacoemulsification probe (in right hand) and "chopper" (in left hand) being done under operating microscope at a navy medical center Slit lamp photo of posterior capsular opacification visible a few months after implantation of intraocular lens, seen on retroillumination The appropriateness of surgery depends on a person's particular functional and visual needs and other risk factors.[47] Cataract removal can be performed at any stage and no longer requires ripening of the lens. Surgery is usually "outpatient" and usually performed using local anesthesia. About 9 of 10 patients can achieve a corrected vision of 20/40 or better after surgery.[37] Several recent evaluations found that cataract surgery can meet expectations only when significant functional impairment due to cataracts exists before surgery. Visual function estimates such as VF-14 have been found to give more realistic estimates than visual acuity testing alone.[37][48] In some developed countries, a trend to overuse cataract surgery has been noted, which may lead to disappointing results.[49] Phacoemulsification is the most widely used cataract surgery in the developed world.[50][51] This procedure uses ultrasonic energy to emulsify the cataract lens. Phacoemulsification typically comprises six steps: * Anaesthetic – The eye is numbed with either a subtenon injection around the eye (see: retrobulbar block) or topical anesthetic eye drops. The former also provides paralysis of the eye muscles. * Corneal incision – Two cuts are made at the margin of the clear cornea to allow insertion of instruments into the eye. * Capsulorhexis – A needle or small pair of forceps is used to create a circular hole in the capsule in which the lens sits. * Phacoemulsification – A handheld ultrasonic probe is used to break up and emulsify the lens into liquid using the energy of ultrasound waves. The resulting 'emulsion' is sucked away. * Irrigation and aspiration – The cortex, which is the soft outer layer of the cataract, is aspirated or sucked away. Fluid removed is continually replaced with a saline solution to prevent collapse of the structure of the anterior chamber (the front part of the eye). * Lens insertion – A plastic, foldable lens is inserted into the capsular bag that formerly contained the natural lens. Some surgeons also inject an antibiotic into the eye to reduce the risk of infection. The final step is to inject salt water into the corneal wounds to cause the area to swell and seal the incision. A Cochrane review found little to no difference in visual acuity as a function of the size of incisions made for phacoemulsification in the range from ≤ 1.5 mm to 3.0 mm.[52] Extracapsular cataract extraction (ECCE) consists of removing the lens manually, but leaving the majority of the capsule intact.[53] The lens is expressed through a 10- to 12-mm incision which is closed with sutures at the end of surgery. ECCE is less frequently performed than phacoemulsification, but can be useful when dealing with very hard cataracts or other situations where emulsification is problematic. Manual small incision cataract surgery (MSICS) has evolved from ECCE. In MSICS, the lens is removed through a self-sealing scleral tunnel wound in the sclera which, ideally, is watertight and does not require suturing. Although "small", the incision is still markedly larger than the portal in phacoemulsion. This surgery is increasingly popular in the developing world where access to phacoemulsification is still limited. Intracapsular cataract extraction (ICCE) is rarely performed.[54] The lens and surrounding capsule are removed in one piece through a large incision while pressure is applied to the vitreous membrane. The surgery has a high rate of complications. ## Prognosis[edit] ### Postoperative care[edit] Slit lamp photo of anterior capsular opacification visible a few months after implantation of intraocular lens, magnified view A South African woman experiences newfound eyesight after a patch was removed after surgery to remove an eye cataract. The postoperative recovery period (after removing the cataract) is usually short. The patient is usually ambulatory on the day of surgery, but is advised to move cautiously and avoid straining or heavy lifting for about a month. The eye is usually patched on the day of surgery and use of an eye shield at night is often suggested for several days after surgery.[47] In all types of surgery, the cataractous lens is removed and replaced with an artificial lens, known as an intraocular lens, which stays in the eye permanently. Intraocular lenses are usually monofocal, correcting for either distance or near vision. Multifocal lenses may be implanted to improve near and distance vision simultaneously, but these lenses may increase the chance of unsatisfactory vision.[16] ### Complications[edit] Serious complications of cataract surgery include retinal detachment and endophthalmitis.[55] In both cases, patients notice a sudden decrease in vision. In endophthalmitis, patients often describe pain. Retinal detachment frequently presents with unilateral visual field defects, blurring of vision, flashes of light, or floating spots. The risk of retinal detachment was estimated as about 0.4% within 5.5 years, corresponding to a 2.3-fold risk increase compared to naturally expected incidence, with older studies reporting a substantially higher risk. The incidence is increasing over time in a somewhat linear manner, and the risk increase lasts for at least 20 years after the procedure. Particular risk factors are younger age, male sex, longer axial length, and complications during surgery. In the highest risk group of patients, the incidence of pseudophakic retinal detachment may be as high as 20%.[56][57] The risk of endophthalmitis occurring after surgery is less than one in 1000.[58] Corneal edema and cystoid macular edema are less serious but more common, and occur because of persistent swelling at the front of the eye in corneal edema or back of the eye in cystoid macular edema.[59] They are normally the result of excessive inflammation following surgery, and in both cases, patients may notice blurred, foggy vision. They normally improve with time and with application of anti-inflammatory drops. The risk of either occurring is around one in 100. It is unclear whether NSAIDs or corticosteroids are superior at reducing postoperative inflammation.[60] Posterior capsular opacification, also known as after-cataract, is a condition in which months or years after successful cataract surgery, vision deteriorates or problems with glare and light scattering recur, usually due to thickening of the back or posterior capsule surrounding the implanted lens, so-called 'posterior lens capsule opacification'. Growth of natural lens cells remaining after the natural lens was removed may be the cause, and the younger the patient, the greater the chance of this occurring. Management involves cutting a small, circular area in the posterior capsule with targeted beams of energy from a laser, called Nd:YAG laser capsulotomy, after the type of laser used. The laser can be aimed very accurately, and the small part of the capsule which is cut falls harmlessly to the bottom of the inside of the eye. This procedure leaves sufficient capsule to hold the lens in place, but removes enough to allow light to pass directly through to the retina. Serious side effects are rare.[61] Posterior capsular opacification is common and occurs following up to one in four operations, but these rates are decreasing following the introduction of modern intraocular lenses together with a better understanding of the causes. Vitreous touch syndrome is a possible complication of intracapsular cataract extraction.[62] ## Epidemiology[edit] Disability-adjusted life years for cataracts per 100,000 inhabitants in 2004:[63] no data <90 90–180 180–270 270–360 360–450 450–540 540–630 630–720 720–810 810–900 900–990 >990 Age-related cataracts are responsible for 51% of world blindness, about 20 million people.[64] Globally, cataracts cause moderate to severe disability in 53.8 million (2004), 52.2 million of whom are in low and middle income countries.[65] In many countries, surgical services are inadequate, and cataracts remain the leading cause of blindness.[64] Even where surgical services are available, low vision associated with cataracts may still be prevalent as a result of long waits for, and barriers to, surgery, such as cost, lack of information and transportation problems. In the United States, age-related lens changes have been reported in 42% between the ages of 52 and 64,[66] 60% between the ages 65 and 74,[67] and 91% between the ages of 75 and 85.[66] Cataracts affect nearly 22 million Americans age 40 and older. By age 80, more than half of all Americans have cataracts. Direct medical costs for cataract treatment are estimated at $6.8 billion annually.[68] In the eastern Mediterranean region, cataracts are responsible for over 51% of blindness. Access to eye care in many countries in this region is limited.[69] Childhood-related cataracts are responsible for 5–20% of world childhood blindness.[70] ## History[edit] See also: Cataract surgery § History Cataract surgery was first described by the Indian physician, Suśruta (about 5th century BCE) in his manuscript Sushruta Samhita in ancient India. Most of the methods mentioned focus on hygiene. Follow-up treatments include bandaging of the eye and covering the eye with warm butter.[71] References to cataracts and their treatment in Ancient Rome are also found in 29 AD in De Medicinae, the work of the Latin encyclopedist Aulus Cornelius Celsus.[72] Archaeological evidence of eye surgery in the Roman era also exists.[73] Galen of Pergamon (ca. 2nd century CE), a prominent Greek physician, surgeon and philosopher, performed an operation similar to modern cataract surgery. Using a needle-shaped instrument, Galen attempted to remove the cataract-affected lens of the eye.[74] Muslim ophthalmologist Ammar Al-Mawsili, in his Choice of Eye Diseases, written circa 1000, wrote of his invention of a syringe and the technique of cataract extraction while experimenting with it on a patient.[75] ### Etymology[edit] "Cataract" is derived from the Latin cataracta, meaning "waterfall", and from the Ancient Greek καταρράκτης (katarrhaktēs), "down-rushing",[76] from καταράσσω (katarassō) meaning "to dash down"[77] (from kata-, "down"; arassein, "to strike, dash").[78][79] As rapidly running water turns white, so the term may have been used metaphorically to describe the similar appearance of mature ocular opacities. In Latin, cataracta had the alternative meaning "portcullis"[80] and the name possibly passed through French to form the English meaning "eye disease" (early 15th century), on the notion of "obstruction".[81] Early Persian physicians called the term nazul-i-ah, or "descent of the water"—vulgarised into waterfall disease or cataract—believing such blindness to be caused by an outpouring of corrupt humour into the eye.[82] ## Research[edit] N-Acetylcarnosine drops have been investigated as a medical treatment for cataracts. The drops are believed to work by reducing oxidation and glycation damage in the lens, particularly reducing crystallin crosslinking.[83][84] Some benefit has been shown in small manufacturer-sponsored randomized controlled trials but further independent corroboration is still required.[85] Femtosecond laser mode-locking, used during cataract surgery, was originally used to cut accurate and predictable flaps in LASIK surgery, and has been introduced to cataract surgery. The incision at the junction of the sclera and cornea and the hole in capsule during capsulorhexis, traditionally made with a handheld blade, needle, and forceps, are dependent on skill and experience of the surgeon. Sophisticated three-dimensional images of the eyes can be used to guide lasers to make these incisions. Nd:YAG laser can also then break up the cataract as in phacoemulsification.[86] Stem cells have been used in a clinical trial for lens regeneration in twelve children under the age of two with cataracts present at birth.[87] The children were followed for six months, so it is unknown what the long-term results will be, and it is unknown if this procedure would work in adults.[87] ## See also[edit] * Medicine portal * Galactosemic cataract * Intraocular lens ## References[edit] 1. ^ a b c d e f g h i j k l m n o p q r s t "Facts About Cataract". September 2009. Archived from the original on 24 May 2015. Retrieved 24 May 2015. 2. ^ a b Gimbel, HV; Dardzhikova, AA (January 2011). "Consequences of waiting for cataract surgery". Current Opinion in Ophthalmology. 22 (1): 28–30. doi:10.1097/icu.0b013e328341425d. PMID 21076306. S2CID 205670956. 3. ^ a b "Visual impairment and blindness Fact Sheet N°282". August 2014. Archived from the original on 12 May 2015. 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"Dietary supplementation: effects on visual performance and occurrence of AMD and cataracts". Curr. Med. Res. Opin. 26 (8): 2011–23. doi:10.1185/03007995.2010.494549. PMID 20590393. S2CID 206965363. 44. ^ Ma, L.; Hao, Z.; Liu, R.; Yu, R.; Shi, Q.; Pan, J. (2013). "A dose–response meta-analysis of dietary lutein and zeaxanthin intake in relation to risk of age-related cataract". Graefe's Archive for Clinical and Experimental Ophthalmology. 252 (1): 63–70. doi:10.1007/s00417-013-2492-3. PMID 24150707. S2CID 13634941. 45. ^ Hayashi, R. (2014-11-01). "The Effects of Lutein in Preventing Cataract Progression". In Babizhayev, M. A.; Li, D. W.-C.; Kasus-Jacobi, A.; Žorić, L.; Alió, J. L. (eds.). Studies on the Cornea and Lens. Oxidative Stress in Applied Basic Research and Clinical Practice. pp. 317–326. doi:10.1007/978-1-4939-1935-2_17. ISBN 9781493919345. 46. ^ Klein BE, Klein R, Lee KE, Grady LM (2006). "Statin Use and Incident Nuclear Cataract". Journal of the American Medical Association. 295 (23): 2752–8. doi:10.1001/jama.295.23.2752. PMID 16788130. 47. ^ a b Emmett T. Cunningham; Paul Riordan-Eva (2011-05-17). Vaughan & Asbury's general ophthalmology (18th ed.). McGraw-Hill Medical. ISBN 978-0071634205.[page needed] 48. ^ Davis JC, McNeill H, Wasdell M, Chunick S, Bryan S (2012). "Focussing both eyes on health outcomes: Revisiting cataract surgery". BMC Geriatrics. 12: 50. doi:10.1186/1471-2318-12-50. PMC 3497611. PMID 22943071. 49. ^ Black N, Browne J, van der Meulen J, Jamieson L, Copley L, Lewsey J (2008). "Is there overutilisation of cataract surgery in England?" (PDF). British Journal of Ophthalmology. 93 (1): 13–17. doi:10.1136/bjo.2007.136150. PMID 19098042. S2CID 37414146. 50. ^ Eunbi Kim; Sam Young Yoon; Young Joo Shin (2014), Studies on the Cornea and Lens, Springer, p. 4, ISBN 9781493919352 51. ^ Hasler, Pascal (2013), Essential Principles of Phacoemulsification, JP Medical Ltd, ISBN 9789962678618[page needed] 52. ^ Jin C, Chen X, Law A, Kang Y, Wang X, Xu W, Yao K (2017). "Different-sized incisions for phacoemulsification in age-related cataract". Cochrane Database Syst Rev. 9: CD010510. doi:10.1002/14651858.CD010510.pub2. PMC 5665700. PMID 28931202.CS1 maint: multiple names: authors list (link) 53. ^ Henderson, Bonnie (2007), "Extracapsular Cataract Extraction", Essentials of Cataract Surgery, SLACK, p. 187, ISBN 9781556428029 54. ^ Goes, Frank (2013), The Eye in History, JP Medical, p. 367, ISBN 9789350902745 55. ^ Naumann; Holbach; Kruse, eds. (2008), "Complications After Cataract Surgery", Applied Pathology for Ophthalmic Microsurgeons, Springer Science & Business, p. 247, ISBN 9783540683667 56. ^ Olsen T, Jeppesen P (2012). "The Incidence of Retinal Detachment After Cataract Surgery". The Open Ophthalmology Journal. 6: 79–82. doi:10.2174/1874364101206010079. PMC 3447164. PMID 23002414. 57. ^ Herrmann W, Helbig H, Heimann H (2011). "Pseudophakie-Ablatio". Klinische Monatsblätter für Augenheilkunde. 228 (3): 195–200. doi:10.1055/s-0029-1246116. PMID 21374539. 58. ^ Behndig A, Montan P, Stenevi U, Kugelberg M, Lundström M (August 2011). "One million cataract surgeries: Swedish National Cataract Register 1992–2009". J. Cataract Refract. Surg. 37 (8): 1539–45. doi:10.1016/j.jcrs.2011.05.021. PMID 21782099. 59. ^ Gault, Janice; Vander, James (2015), Ophthalmology Secrets in Color, Elsevier Health Sciences, p. 221, ISBN 9780323378024 60. ^ Juthani VV, Clearfield E, Chuck RS (2017). "Non-steroidal anti-inflammatory drugs versus corticosteroids for controlling inflammation after uncomplicated cataract surgery". Cochrane Database Syst Rev. 7: CD010516. doi:10.1002/14651858.CD010516.pub2. PMC 5580934. PMID 28670710.CS1 maint: uses authors parameter (link) 61. ^ "Posterior capsule opacification – why laser treatment is sometimes needed following cataract surgery". rnib.org.uk. 2014-02-19. Archived from the original on 2009-09-17. 62. ^ Dr. Kushal Banerjee (2006). "A review and clinical evaluation of per-operative and post-operative complications in case of manual small incision cataract surgery and extracapsular cataract extraction with posterior chamber intra-ocular lens implantation" (PDF). Archived from the original (PDF) on 5 June 2014. Retrieved 1 June 2014. 63. ^ "Death and DALY estimates for 2004 by cause for WHO Member States" (xls). World Health Organization. who.int. 2004. 64. ^ a b "Priority eye diseases: Cataract". Prevention of Blindness and Visual Impairment. World Health Organization. Archived from the original on 2015-05-24. 65. ^ The global burden of disease : 2004 update. Geneva, Switzerland: World Health Organization. 2008. p. 35. ISBN 9789241563710. 66. ^ a b Sperduto RD, Seigel D (Jul 1980). "Senile lens and senile macular changes in a population-based sample". Am. J. Ophthalmol. 90 (1): 86–91. doi:10.1016/s0002-9394(14)75081-0. PMID 7395962. 67. ^ Kahn HA, Leibowitz HM, Ganley JP, Kini MM, Colton T, Nickerson RS, Dawber TR (Jul 1977). "The Framingham Eye Study. I. Outline and major prevalence findings". Am. J. Epidemiol. 106 (1): 17–32. doi:10.1093/oxfordjournals.aje.a112428. PMID 879158. 68. ^ "Eye Health Statistics at a Glance" (PDF). Archived from the original (PDF) on March 17, 2015. 69. ^ "Health Topics: Cataract". World Health Organization – Eastern Mediterranean Regional Office. Archived from the original on 2013-09-27. 70. ^ Liu, Yu-Chi; Wilkins, Mark; Kim, Terry; Malyugin, Boris; Mehta, Jodhbir S (2017). "Cataracts". The Lancet. 390 (10094): 600–612. doi:10.1016/S0140-6736(17)30544-5. PMID 28242111. S2CID 208790600. 71. ^ Goes, Frank Joseph (2013). The Eye in History. JP Medical Ltd. p. 371. ISBN 9789350902745. 72. ^ Aulus Cornelius Celsus, G. F. Collier (transl.) (1831). De Medicinae. OL 5225311W. 73. ^ Elliott, Jane (February 9, 2008). "The Romans carried out cataract ops". BBC News. Archived from the original on February 18, 2008. 74. ^ Keele, K. D. (1963). "Galen: On Anatomical Procedures: the Later Books". Med Hist. 7 (1): 85–87. doi:10.1017/s002572730002799x. PMC 1034789. 75. ^ Finger, Stanley (1994). Origins of Neuroscience: A History of Explorations Into Brain Function. Oxford University Press. p. 70. ISBN 978-0-19-514694-3. 76. ^ καταρράκτης Archived 2012-04-05 at the Wayback Machine, Henry George Liddell, Robert Scott, A Greek-English Lexicon, on Perseus 77. ^ καταράσσω Archived 2012-04-04 at the Wayback Machine, Henry George Liddell, Robert Scott,A Greek-English Lexicon, on Perseus 78. ^ "cataract". Dictionary.com. Dictionary.com, LLC. Retrieved 1 April 2020. 79. ^ "cataract". Oxford Dictionaries. Oxford University Press. Archived from the original on 8 October 2012. Retrieved 1 April 2020. 80. ^ cataracta Archived 2012-04-04 at the Wayback Machine, Charlton T. Lewis, Charles Short, A Latin Dictionary, on Perseus 81. ^ Online Etymology Dictionary Archived 2007-10-14 at the Wayback Machine, etymonline.com 82. ^ Mistaken Science — Topic Powered by eve community Archived 2008-06-22 at the Wayback Machine, Wordcraft Forums, wordcraft.infopop.cc 83. ^ Williams DL, Munday P (2006). "The effect of a topical antioxidant formulation including N-acetyl carnosine on canine cataract: a preliminary study". Vet Ophthalmol. 9 (5): 311–6. doi:10.1111/j.1463-5224.2006.00492.x. PMID 16939459. 84. ^ Guo Y, Yan H (2006). "Preventive effect of carnosine on cataract development". Yan Ke Xue Bao. 22 (2): 85–8. PMID 17162883. 85. ^ Toh T, Morton J, Coxon J, Elder MJ (2007). "Medical treatment of cataract". Clin. Experiment. Ophthalmol. 35 (7): 664–71. doi:10.1111/j.1442-9071.2007.01559.x. PMID 17894689. S2CID 43125880. 86. ^ Friedman NJ, Palanker DV, Schuele G, Andersen D, Marcellino G, Seibel BS, Batlle J, Feliz R, Talamo JH, Blumenkranz MS, Culbertson WW (July 2011). "Femtosecond laser capsulotomy". J. Cataract Refract. Surg. 37 (7): 1189–98. doi:10.1016/j.jcrs.2011.04.022. PMID 21700099. S2CID 3860204. as PDF Archived 2012-09-14 at the Wayback Machine The authors declare a financial interest in a company producing femtosecond laser equipment. 87. ^ a b "Stem cells used to repair children's eyes after cataracts". NHS. March 10, 2016. Archived from the original on 11 March 2016. Retrieved 11 March 2016. ## External links[edit] Classification D * ICD-10: H25-H26, H28, Q12.0 * ICD-9-CM: 366 * MeSH: D002386 * DiseasesDB: 2179 * SNOMED CT: 128306009 External resources * MedlinePlus: 001001 * Cataract at Curlie * Pictures of different types of cataracts * v * t * e * Diseases of the human eye Adnexa Eyelid Inflammation * Stye * Chalazion * Blepharitis * Entropion * Ectropion * Lagophthalmos * Blepharochalasis * Ptosis * Blepharophimosis * Xanthelasma * Ankyloblepharon Eyelash * Trichiasis * Madarosis Lacrimal apparatus * Dacryoadenitis * Epiphora * Dacryocystitis * Xerophthalmia Orbit * Exophthalmos * Enophthalmos * Orbital cellulitis * Orbital lymphoma * Periorbital cellulitis Conjunctiva * Conjunctivitis * allergic * Pterygium * Pseudopterygium * Pinguecula * Subconjunctival hemorrhage Globe Fibrous tunic Sclera * Scleritis * Episcleritis Cornea * Keratitis * herpetic * acanthamoebic * fungal * Exposure * Photokeratitis * Corneal ulcer * Thygeson's superficial punctate keratopathy * Corneal dystrophy * Fuchs' * Meesmann * Corneal ectasia * Keratoconus * Pellucid marginal degeneration * Keratoglobus * Terrien's marginal degeneration * Post-LASIK ectasia * Keratoconjunctivitis * sicca * Corneal opacity * Corneal neovascularization * Kayser–Fleischer ring * Haab's striae * Arcus senilis * Band keratopathy Vascular tunic * Iris * Ciliary body * Uveitis * Intermediate uveitis * Hyphema * Rubeosis iridis * Persistent pupillary membrane * Iridodialysis * Synechia Choroid * Choroideremia * Choroiditis * Chorioretinitis Lens * Cataract * Congenital cataract * Childhood cataract * Aphakia * Ectopia lentis Retina * Retinitis * Chorioretinitis * Cytomegalovirus retinitis * Retinal detachment * Retinoschisis * Ocular ischemic syndrome / Central retinal vein occlusion * Central retinal artery occlusion * Branch retinal artery occlusion * Retinopathy * diabetic * hypertensive * Purtscher's * of prematurity * Bietti's crystalline dystrophy * Coats' disease * Sickle cell * Macular degeneration * Retinitis pigmentosa * Retinal haemorrhage * Central serous retinopathy * Macular edema * Epiretinal membrane (Macular pucker) * Vitelliform macular dystrophy * Leber's congenital amaurosis * Birdshot chorioretinopathy Other * Glaucoma / Ocular hypertension / Primary juvenile glaucoma * Floater * Leber's hereditary optic neuropathy * Red eye * Globe rupture * Keratomycosis * Phthisis bulbi * Persistent fetal vasculature / Persistent hyperplastic primary vitreous * Persistent tunica vasculosa lentis * Familial exudative vitreoretinopathy Pathways Optic nerve Optic disc * Optic neuritis * optic papillitis * Papilledema * Foster Kennedy syndrome * Optic atrophy * Optic disc drusen Optic neuropathy * Ischemic * anterior (AION) * posterior (PION) * Kjer's * Leber's hereditary * Toxic and nutritional Strabismus Extraocular muscles Binocular vision Accommodation Paralytic strabismus * Ophthalmoparesis * Chronic progressive external ophthalmoplegia * Kearns–Sayre syndrome palsies * Oculomotor (III) * Fourth-nerve (IV) * Sixth-nerve (VI) Other strabismus * Esotropia / Exotropia * Hypertropia * Heterophoria * Esophoria * Exophoria * Cyclotropia * Brown's syndrome * Duane syndrome Other binocular * Conjugate gaze palsy * Convergence insufficiency * Internuclear ophthalmoplegia * One and a half syndrome Refraction * Refractive error * Hyperopia * Myopia * Astigmatism * Anisometropia / Aniseikonia * Presbyopia Vision disorders Blindness * Amblyopia * Leber's congenital amaurosis * Diplopia * Scotoma * Color blindness * Achromatopsia * Dichromacy * Monochromacy * Nyctalopia * Oguchi disease * Blindness / Vision loss / Visual impairment Anopsia * Hemianopsia * binasal * bitemporal * homonymous * Quadrantanopia subjective * Asthenopia * Hemeralopia * Photophobia * Scintillating scotoma Pupil * Anisocoria * Argyll Robertson pupil * Marcus Gunn pupil * Adie syndrome * Miosis * Mydriasis * Cycloplegia * Parinaud's syndrome Other * Nystagmus * Childhood blindness Infections * Trachoma * Onchocerciasis Authority control * BNE: XX526157 * BNF: cb11953097t (data) * GND: 4158095-3 * LCCN: sh85020947 * NDL: 00562858 [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Cataract	c0086543	3,790	wikipedia	https://en.wikipedia.org/wiki/Cataract	2021-01-18T18:53:43	{"mesh": ["D002386"], "umls": ["C1510497", "C0029531", "C0086543"], "orphanet": ["98640"], "wikidata": ["Q127724"]}
## Clinical Features Hunter et al. (1977) identified 6 members of family with characteristic facial features, including microcephaly, almond-shaped palpebral fissures, and downturned or small mouth, mental retardation, mild skeletal anomalies, short stature, and craniosynostosis. Van Maldergem et al. (1990) and Ades et al. (1993) reported 3 additional patients with similar features. Thomas et al. (1996) reported a patient and suggested the designation Hunter-McAlpine syndrome for this disorder. There is phenotypic overlap with Ruvalcaba syndrome (180870). Cytogenetics Thomas et al. (1996) described a sporadic case who also had an interstitial deletion of 17q23.1-q24.2, suggesting the possibility that Hunter-McAlpine syndrome maps to that region. In affected individuals of the family described by Hunter et al. (1977) and in the patient described by Ades et al. (1993), Hunter et al. (2005) identified cryptic translocations resulting in duplication of 5q35-qter. Subtelomeric FISH analysis in the family reported by Hunter et al. (1977) revealed the presence of 5qter material on the short arm of chromosome 13; all obligate carriers had the balanced translocation t(5;13). The patient reported by Ades et al. (1993) had an extra 5q signal present on 1q, indicating a duplication of 5qter and monosomy of 1qter. Hunter et al. (2005) noted similarities in clinical features between these cases and other reported cases with duplication of this chromosome segment. Inheritance The pedigree pattern in the family reported by Hunter et al. (1977) supported autosomal dominant inheritance. Skel \- Mild acral-skeletal anomalies Head \- Craniosynostosis Growth \- Short stature Neuro \- Mental deficiency Inheritance \- Autosomal dominant Mouth \- Downturned or small mouth Eyes \- Almond-shaped palpebral fissures Lab \- 17q23.1-q24.2 deletion in a sporadic case ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	HUNTER-MCALPINE CRANIOSYNOSTOSIS SYNDROME	c1832408	3,791	omim	https://www.omim.org/entry/601379	2019-09-22T16:14:54	{"mesh": ["C536072"], "omim": ["601379"], "orphanet": ["97340"]}
For a phenotypic description and a discussion of genetic heterogeneity of colorectal cancer, see 114500. Mapping Tenesa et al. (2008) performed a genomewide association study to identify loci associated with colorectal cancer risk. They genotyped 555,510 SNPs in 1,012 early-onset Scottish CRC cases and 1,012 controls for phase 1. In phase 2 the authors genotyped 15,008 highest-ranked SNPs in 2,057 Scottish cases and 2,111 controls. The authors then genotyped the 5 highest-ranked SNPs from the joint phase 1 and 2 analysis in 14,500 cases and 13,294 controls from 7 populations, and identified a previously unreported association rs3802842 on 11q23 (odds ratio = 1.1; p = 5.8 x 10(-10)). Risk was greater for rectal than for colon cancer for rs3802842 (P less than 0.008) and rs4939827 (see 612229) (P less than 0.009). The Japanese population did not show the increased risk of colonic cancer associated with rs3802842 that was observed in European populations, but did show a similar risk of rectal cancer at that locus. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	COLORECTAL CANCER, SUSCEPTIBILITY TO, 7	c2677120	3,792	omim	https://www.omim.org/entry/612232	2019-09-22T16:02:05	{"omim": ["612232"], "synonyms": ["Alternative titles", "COLORECTAL CANCER, SUSCEPTIBILITY TO, ON CHROMOSOME 11"]}
Geriatric trauma An elderly woman who was exposed to blast trauma after a rocket exploded nearby SpecialtyEmergency medicine Geriatric trauma refers to a traumatic injury that occurs to an elderly person. The three prevailing causes of traumatic death in the elderly are falls (which account for 40% of traumatic death in this age group), traffic collisions and burns.[1][2] ## Contents * 1 Biomechanics of injury * 2 Physiologic differences in the elderly * 3 Epidemiology * 4 See also * 5 References ## Biomechanics of injury[edit] A progressive decline in central nervous system function leads to a loss of proprioception, balance and overall motor coordination, as well as a reduction in eye–hand coordination, reaction time and an unsteady gait.[2] These degenerative changes are often accompanied by osteoarthritis (degenerative joint disease), which leads to a reduction in the range of motion of the head, neck and extremities. Furthermore, elderly people frequently take multiple medications for control of various diseases and conditions. The side effects of some of these medications may either predispose to injury, or may cause a minor trauma to result in a much more severe condition. For example, a person taking warfarin (Coumadin) and/or clopidogrel (Plavix) may experience a life-threatening intracranial hemorrhage after sustaining a relatively minor closed head injury, as a result of the defect in the hemostatic mechanism caused by such medications. The combined effects of these changes greatly predisposes elderly people to traumatic injury. Both the incidence of falls and the severity of associated complications increase with advancing age.[2] ## Physiologic differences in the elderly[edit] Virtually all organ systems experience a progressive decline in function as a result of the aging process.[1][3] One example is a decline in circulatory system function caused in part by thickening of the cardiac muscle. This can lead to congestive heart failure or pulmonary edema.[4][5] Atrophy of the brain begins to accelerate at around seventy years of age,[5] which leads to a significant reduction in brain mass. Since the skull does not decrease in size with the brain, there is significant space between the two when this occurs which puts the elderly at a higher risk of a subdural hematoma after sustaining a closed head injury.[3] The reduction of brain size can lead to issues with eyesight, cognition and hearing.[5] ## Epidemiology[edit] Elderly people are the most rapidly growing demographic in developed nations. Although they sustain traumatic injury less commonly than children and young adults, the mortality rate for trauma in the elderly is higher than in younger people.[2] In the United States, this population accounts for 14% of all traumatic injuries, of which a majority are secondary to falls.[6] ## See also[edit] * Senescence * Gerontology * Elder abuse ## References[edit] 1. ^ a b Grande, Christopher M.; Søreide, Eldar (2001). Prehospital trauma care. New York, N.Y: Marcel Dekker. pp. 441–50. ISBN 0-8247-0537-8. 2. ^ a b c d Committee on Trauma, American College of Surgeons (2008). "Chapter 10: Extremes of Age". ATLS: Advanced Trauma Life Support Program for Doctors (8th ed.). Chicago: American College of Surgeons. pp. 243–74. ISBN 978-1-880696-31-6. 3. ^ a b Campbell, John Creighton (2008). ITLS. Upper Saddle River, N.J: Pearson/Prentice Hall. pp. 279–87. ISBN 0-13-237982-1. 4. ^ Campbell, John Creighton (2000). Basic trauma life support for paramedics and other advanced providers. Upper Saddle River, New Jersey: Brady/Prentice Hall Health. pp. 231–8. ISBN 0-13-084584-1. 5. ^ a b c Peitzman AB, Rhodes M, Schwab CW, Yealy DM, Fabian TC, eds. (2008). "Chapter 48: Geriatric Trauma". The Trauma Manual (3rd ed.). Philadelphia: Lippincott Williams & Wilkins. pp. 524–32. ISBN 0-7817-6275-8. 6. ^ Marx, John; Hockberger, Robert; Walls, Ron (August 29, 2013). Rosen's Emergency Medicine - Concepts and Clinical Practice (8th ed.). Saunders. pp. 324–9. ISBN 9781455706051. * v * t * e Trauma Principles * Polytrauma * Major trauma * Traumatology * Triage * Resuscitation * Trauma triad of death Assessment Clinical prediction rules * Revised Trauma Score * Injury Severity Score * Abbreviated Injury Scale * NACA score Investigations * Diagnostic peritoneal lavage * Focused assessment with sonography for trauma Management Principles * Advanced trauma life support * Trauma surgery * Trauma center * Trauma team * Damage control surgery * Early appropriate care Procedures * Resuscitative thoracotomy Pathophysiology Injury * MSK * Bone fracture * Joint dislocation * Degloving * Soft tissue injury * Resp * Flail chest * Pneumothorax * Hemothorax * Diaphragmatic rupture * Pulmonary contusion * Cardio * Internal bleeding * Thoracic aorta injury * Cardiac tamponade * GI * Blunt kidney trauma * Ruptured spleen * Neuro * Penetrating head injury * Traumatic brain injury * Intracranial hemorrhage Mechanism * Blast injury * Blunt trauma * Burn * Penetrating trauma * Crush injury * Stab wound * Ballistic trauma * Electrocution Region * Abdominal trauma * Chest trauma * Facial trauma * Head injury * Spinal cord injury Demographic * Geriatric trauma * Pediatric trauma Complications * Posttraumatic stress disorder * Wound healing * Acute lung injury * Crush syndrome * Rhabdomyolysis * Compartment syndrome * Contracture * Volkmann's contracture * Embolism * air * fat * Chronic traumatic encephalopathy * Subcutaneous emphysema [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Geriatric trauma	None	3,793	wikipedia	https://en.wikipedia.org/wiki/Geriatric_trauma	2021-01-18T18:34:27	{"wikidata": ["Q5550848"]}
Inflammation of the cornea due to fungal infection Keratomycosis SpecialtyOphthalmology A fungal keratitis is an inflammation of the cornea that results from infection by a fungal organism. Keratomycosis is the fungal infection of the cornea, the anterior part of the eye which covers the pupil. Those experiencing these symptoms are typically advised to immediately visit the appropriate eyecare professional. ## Contents * 1 Presentation * 2 Causes * 3 Pathophysiology * 4 Diagnosis * 4.1 Classification * 5 Prevention * 6 Treatment * 7 Prognosis * 8 Epidemiology * 9 Social impact * 10 Notable cases * 11 See also * 12 References * 13 External links ## Presentation[edit] The symptoms of fungal keratitis are blurred vision, a red and painful eye that does not improve when contact lenses are removed, or on antibiotic treatment, increased sensitivity to light (photophobia), and excessive tearing or discharge. The symptoms are markedly less as compared to a similar bacterial ulcer. Signs: The eyelids and adnexa involved shows edema and redness, conjunctiva is chemosed. Ulcer may be present. It is a dry looking corneal ulcer with satellite lesions in the surrounding cornea. Usually associated with fungal ulcer is hypopyon, which is mostly white fluffy in appearance. Rarely, it may extend to the posterior segment to cause endophthalmitis in later stages, leading to the destruction of the eye. (Note: Fungal endophthalmitis is extremely rare) ## Causes[edit] Filamentous fungi * Aspergillus flavus * Aspergillus fumigatus * Fusarium spp. * Alternaria spp. * Curvularia * Acremonium Yeasts * Candida Fusarium spp. is most common then Aspergillus spp. and thirdly Dematitious fungi causing fungal keratitis in India. ## Pathophysiology[edit] The precipitating event for fungal keratitis is trauma with a vegetable / organic matter. A thorn injury, or in agriculture workers, trauma with a wheat plant while cutting the harvest is typical. This implants the fungus directly in the cornea. The fungus grows slowly in the cornea and proliferates to involve the anterior and posterior stromal layers. The fungus can break through the descemet's membrane and pass into the anterior chamber. The patient presents a few days or weeks later with fungal keratitis. ## Diagnosis[edit] The diagnosis is made by an ophthalmologist/optometrist correlating typical history, symptoms and signs. Many times it may be missed and misdiagnosed as bacterial ulcer. A definitive diagnosis is established only after a positive culture report (lactophenol cotton blue, calcoflour medium), typically taking a week, from the corneal scraping. Recent advances have been made in PCR ref 3./immunologic tests which can give a much quicker result. ### Classification[edit] Infectious keratitis can be bacterial, fungal, viral, or protozoal. Remarkable differences in presentation of the patient allows presumptive diagnosis by the eye care professional, helping in institution of appropriate anti-infective therapy. ## Prevention[edit] Prevention of trauma with vegetable / organic matter, particularly in agricultural workers while harvesting can reduce the incidence of fungal keratitis. Wearing of broad protective glasses with side shields is recommended for people at risk for such injuries. ## Treatment[edit] A presumptive diagnosis of fungal keratitis requires immediate empirical therapy. Natamycin ophthalmic suspension is the drug of choice for filamentous fungal infection. Fluconazole ophthalmic solution is recommended for Candida infection of the cornea. Amphotericin B eye drops may be required for non-responding cases, but can be quite toxic and requires expert pharmacist for preparation. Other medications have also been tried with moderate success. An updated Cochrane Review published in 2015 looking at the best treatment for fungal keratitis could not draw any conclusions as the studies included used different medications. [1] The review did find that "people receiving natamycin were less likely to develop a hole in their cornea and need a transplant." Consult your eye care professional in any case as they will have the best treatment. ## Prognosis[edit] The infection typically takes a long time to heal, since the fungus itself is slow growing. Corneal perforation can occur in patients with untreated or partially treated infectious keratitis and requires surgical intervention in the form of corneal transplantation. ## Epidemiology[edit] This disease is quite common in the tropics and with large agrarian population. India has a high number of cases with fungal keratitis, but poor reporting system prevents accurate data collection. Florida in US regularly reports cases of fungal keratitis, with Aspergillus and Fusarium spp. as the most common causes. ## Social impact[edit] The loss of vision with fungal keratitis can be quite disabling in terms of economic impact and social consequences. Many people come with fungal keratitis in the only eye and thus become blind due to the disease. The lack of education and proper eye protection in such cases is evidently responsible for their plight. ## Notable cases[edit] Recently, one particular product, ReNu with MoistureLoc brand of soft contact lens solutions made headlines regarding a report from the United States Centers for Disease Control and Prevention suggesting an increased incidence of a specific type of fungal keratitis (Fusarium keratitis) in people using Bausch & Lomb products.[2] Bausch & Lomb subsequently suspended, then recalled, shipments of one particular product, ReNu with MoistureLoc.[3] ## See also[edit] * Tinea ## References[edit] 1. ^ FlorCruz, Nilo Vincent; Evans, Jennifer R (2015-04-09). Cochrane Eyes and Vision Group (ed.). "Medical interventions for fungal keratitis". Cochrane Database of Systematic Reviews (4): CD004241. doi:10.1002/14651858.CD004241.pub4. PMID 25855311. 2. ^ "Fusarium Keratitis --- Multiple States, 2006." Centers for Disease Control and Prevention: Morbidity and Mortality Weekly Report. April 10, 2006 / 55(Dispatch);1-2. 3. ^ "Bausch & Lomb News". Archived 2006-04-12 at the Wayback Machine Bausch & Lomb. Retrieved. June 2, 2006. 3\. Use of PCR targeting of internal transcribed spacer regions and single-stranded conformation polymorphism analysis of sequence variation in different regions of rRNA genes in fungi for rapid diagnosis of mycotic keratitis. Manish Kumar and PK Shukla (2005). J. Clin. Microbiol. 43 (2), 662-668 ## External links[edit] Classification D * ICD-10: B49, H19.2 External resources * eMedicine: oph/99 * v * t * e * Diseases of the human eye Adnexa Eyelid Inflammation * Stye * Chalazion * Blepharitis * Entropion * Ectropion * Lagophthalmos * Blepharochalasis * Ptosis * Blepharophimosis * Xanthelasma * Ankyloblepharon Eyelash * Trichiasis * Madarosis Lacrimal apparatus * Dacryoadenitis * Epiphora * Dacryocystitis * Xerophthalmia Orbit * Exophthalmos * Enophthalmos * Orbital cellulitis * Orbital lymphoma * Periorbital cellulitis Conjunctiva * Conjunctivitis * allergic * Pterygium * Pseudopterygium * Pinguecula * Subconjunctival hemorrhage Globe Fibrous tunic Sclera * Scleritis * Episcleritis Cornea * Keratitis * herpetic * acanthamoebic * fungal * Exposure * Photokeratitis * Corneal ulcer * Thygeson's superficial punctate keratopathy * Corneal dystrophy * Fuchs' * Meesmann * Corneal ectasia * Keratoconus * Pellucid marginal degeneration * Keratoglobus * Terrien's marginal degeneration * Post-LASIK ectasia * Keratoconjunctivitis * sicca * Corneal opacity * Corneal neovascularization * Kayser–Fleischer ring * Haab's striae * Arcus senilis * Band keratopathy Vascular tunic * Iris * Ciliary body * Uveitis * Intermediate uveitis * Hyphema * Rubeosis iridis * Persistent pupillary membrane * Iridodialysis * Synechia Choroid * Choroideremia * Choroiditis * Chorioretinitis Lens * Cataract * Congenital cataract * Childhood cataract * Aphakia * Ectopia lentis Retina * Retinitis * Chorioretinitis * Cytomegalovirus retinitis * Retinal detachment * Retinoschisis * Ocular ischemic syndrome / Central retinal vein occlusion * Central retinal artery occlusion * Branch retinal artery occlusion * Retinopathy * diabetic * hypertensive * Purtscher's * of prematurity * Bietti's crystalline dystrophy * Coats' disease * Sickle cell * Macular degeneration * Retinitis pigmentosa * Retinal haemorrhage * Central serous retinopathy * Macular edema * Epiretinal membrane (Macular pucker) * Vitelliform macular dystrophy * Leber's congenital amaurosis * Birdshot chorioretinopathy Other * Glaucoma / Ocular hypertension / Primary juvenile glaucoma * Floater * Leber's hereditary optic neuropathy * Red eye * Globe rupture * Keratomycosis * Phthisis bulbi * Persistent fetal vasculature / Persistent hyperplastic primary vitreous * Persistent tunica vasculosa lentis * Familial exudative vitreoretinopathy Pathways Optic nerve Optic disc * Optic neuritis * optic papillitis * Papilledema * Foster Kennedy syndrome * Optic atrophy * Optic disc drusen Optic neuropathy * Ischemic * anterior (AION) * posterior (PION) * Kjer's * Leber's hereditary * Toxic and nutritional Strabismus Extraocular muscles Binocular vision Accommodation Paralytic strabismus * Ophthalmoparesis * Chronic progressive external ophthalmoplegia * Kearns–Sayre syndrome palsies * Oculomotor (III) * Fourth-nerve (IV) * Sixth-nerve (VI) Other strabismus * Esotropia / Exotropia * Hypertropia * Heterophoria * Esophoria * Exophoria * Cyclotropia * Brown's syndrome * Duane syndrome Other binocular * Conjugate gaze palsy * Convergence insufficiency * Internuclear ophthalmoplegia * One and a half syndrome Refraction * Refractive error * Hyperopia * Myopia * Astigmatism * Anisometropia / Aniseikonia * Presbyopia Vision disorders Blindness * Amblyopia * Leber's congenital amaurosis * Diplopia * Scotoma * Color blindness * Achromatopsia * Dichromacy * Monochromacy * Nyctalopia * Oguchi disease * Blindness / Vision loss / Visual impairment Anopsia * Hemianopsia * binasal * bitemporal * homonymous * Quadrantanopia subjective * Asthenopia * Hemeralopia * Photophobia * Scintillating scotoma Pupil * Anisocoria * Argyll Robertson pupil * Marcus Gunn pupil * Adie syndrome * Miosis * Mydriasis * Cycloplegia * Parinaud's syndrome Other * Nystagmus * Childhood blindness Infections * Trachoma * Onchocerciasis [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Fungal keratitis	c1262117	3,794	wikipedia	https://en.wikipedia.org/wiki/Fungal_keratitis	2021-01-18T18:52:45	{"icd-10": ["H19.2", "B49"], "wikidata": ["Q5509171"]}
A number sign (#) is used with this entry because the phenotype of hypoparathyroidism, sensorineural deafness, and renal disease (HDR), also known as Barakat syndrome, is caused by haploinsufficiency of the GATA3 gene (131320) on chromosome 10p14. Clinical Features Barakat et al. (1977) reported steroid-resistant nephrosis with progressive renal failure and death at ages 5 and 8 years in 2 brothers who also had nerve deafness and hypoparathyroidism. At autopsy, the parathyroid glands were absent in 1 child and hypoplastic in the other. Barakat et al. (1977) also described male twins from another family with similar findings and death at age 3 years. At autopsy, their parathyroid glands were fibrotic and glomerular basement membranes were thickened. The same syndrome may have been present in the families reported by Yumita et al. (1986) and Shaw et al. (1991). Bilous et al. (1992) described 2 brothers and 2 daughters of 1 of the brothers with hypoparathyroidism, sensorineural deafness, and renal dysplasia. The deafness consisted of a bilateral, symmetric, sensorineural deficit affecting all frequencies but slightly more marked at the higher end of the frequency range. A similarity of the deficit in the adults and children studied suggested that it was not progressive, and the patients did not believe that their hearing loss had changed with age. Intravenous urography showed changes consistent with the presence of bilateral renal dysplasia; they had small, irregular kidneys and abnormally compressed collection systems. Four other members of the most recent generation were either partially affected or possibly affected. Possibly similar reported families were reviewed. Autosomal dominant hypoparathyroidism (146200) and X-linked hypoparathyroidism (307700) have been described. Hypoparathyroidism also occurs in the autosomal dominant DiGeorge syndrome (188400) and occurs in association with candidosis and ectodermal dysplasia in the autosomal recessive syndrome of autoimmune polyendocrinopathy (240300). Phenotypically, the disorder with presumed autosomal recessive inheritance described by Barakat et al. (1977) is very similar to the disorder described by Bilous et al. (1992). Barakat (1997) rightly suggested that the mode of inheritance may not be a fundamental difference; the disorder in the 2 families may be due to different mutations in the same gene. Hasegawa et al. (1997) and Hasegawa (1998) suggested that the inheritance in the family of Barakat et al. (1977) might be autosomal dominant with reduced penetrance since the paternal grandmother and her 3 sibs had hearing loss. Watanabe et al. (1998) ascertained a 3-generation family through a male infant admitted to hospital for seizures that began at 10 days of age. Despite serum and urinary biochemical findings typical of hypoparathyroidism, there were no clinical features of CATCH22 and the karyotype was normal without microdeletion of 22q11.2 by an in situ hybridization method. Five family members were found to have hypoparathyroidism with sensorineural deafness. Normal DNA sequence was found for the PTH gene (168450) and for the calcium-sensing receptor (CASR; 601199). This family was distinguished by the lack of renal dysplasia. Renal tubular function and renal imaging were normal. Ferraris et al. (2009) studied a 14-year-old boy who had symptomatic hypoparathyroidism, bilateral sensorineural deafness, unilateral renal dysplasia, bilateral palpebral ptosis, and horizontal nystagmus. Funduscopy revealed symmetric pseudopapilledema, and brain CT scan showed basal ganglia calcifications. Moldovan et al. (2011) reported a 29-year-old Portuguese woman with severe hypoparathyroidism, bilateral mild neurosensory deafness that was diagnosed in childhood, and agenesis of the vagina and uterus. She had normal renal and abdominal ultrasound and normal renal function. Pelvic ultrasound showed absence of the uterus and vagina, normal uterine adnexae, and a left ovarian cyst. The authors stated that this was the third case of female genital tract malformation associated with HDR, including the mother and daughter reported by Hernandez et al. (2007). Cytogenetics Hasegawa et al. (1997) found this syndrome, which they referred to as HDR syndrome (for hypoparathyroidism, deafness, and renal dysplasia), in a Japanese girl with a de novo deletion of 10p13. The experience led them to suggest that the gene responsible for HDR syndrome is located in the 10pter-p13 region. Hasegawa et al. (1997) found reports of 14 patients with deletion of 10p13: 5 had hypoparathyroidism or hypocalcemia, 6 had urinary tract abnormalities (such as renal dysplasia, agenesis of unilateral kidney, or vesicoureteral reflux), and 2 had deafness. Partial DiGeorge syndrome (188400) was diagnosed in 4 of 5 patients with hypoparathyroidism. None of the patients had all components of the triad of HDR syndrome, however. Van Esch et al. (1999) described 2 patients with a partial DiGeorge syndrome (facial dysmorphism, hypoparathyroidism, renal agenesis, mental retardation) and a rearrangement of chromosome 10p. Fujimoto et al. (1999) reported a Japanese boy with HDR syndrome and recurrent cerebral infarctions in the basal ganglia. Chromosome analysis demonstrated a de novo deletion of 10p15.1-p14, suggesting that the putative gene responsible for HDR syndrome is located at 10p15.1-p14. Lichtner et al. (2000) reported clinical and molecular deletion analysis of a patient described by Hasegawa et al. (1997) and a new case, both with the HDR phenotype: hypoparathyroidism, deafness, and renal dysplasia. They were found to have partial monosomy for 10p due to terminal deletions with breakpoints between D10S585 and D10S1720. By comparison with data previously published on patients with DiGeorge/velocardiofacial syndrome associated with 10p monosomy (see 601362), Lichtner et al. (2000) concluded that HDR is a contiguous gene syndrome. Hemizygosity for a proximal region can cause cardiac defects and T cell deficiency; hemizygosity for a more distal region can cause hypoparathyroidism, sensorineural deafness, and renal dysplasia. Bernardini et al. (2009) reported a 14-month-old girl with the HDR triad associated with psychomotor delay, facial dysmorphism, bilateral cleft lip/palate, tetralogy of Fallot, and tapering fingers and malpositioned toes with cutaneous syndactyly of toes 2 and 3. Array comparative genomic hybridization (CGH) analysis identified a 6.5-Mb deletion of chromosome 10p15.3-p15.1, as well as a 1.9-Mb duplication of chromosome 10p15.1-p14. Both imbalances were de novo. The duplicated sequence included the GATA3 gene and 1.5 Mb upstream and 0.3 Mb downstream of GATA3; real-time PCR confirmed a 2-fold increase in GATA3 copy number compared to controls, and direct DNA sequencing did not show any alteration in GATA3 sequence. Bernardini et al. (2009) suggested that both GATA3 deletion and duplication could lead to a similar phenotype. Molecular Genetics Van Esch et al. (2000) performed deletion-mapping studies in 2 HDR patients (see 131320.0001 and 131320.0002) and defined a critical 200-kb region that contains the GATA3 gene (131320). This gene belongs to a family of zinc finger transcription factors that are involved in vertebrate embryonic development. Search for GATA3 mutations in 3 other HDR probands identified 1 nonsense mutation (131320.0005) and 2 intragenic deletions (131320.0003, 131320.0004) that predicted a loss of function, as confirmed by absence of DNA binding by the mutant GATA3 protein. These results demonstrated that GATA3 is essential in the embryonic development of the parathyroids, auditory system, and kidneys, and showed that GATA3 haploinsufficiency causes human HDR syndrome. Muroya et al. (2001) reported analysis of the GATA3 gene in 9 Japanese families with HDR syndrome. Sequence analysis showed heterozygous novel mutations in 3 families, including missense (131320.0006), insertion (131320.0007), and nonsense (131320.0008) mutations. Deletions of GATA3 were found in 4 families; the chromosome with the deletion was of paternal origin in 3 of these. No mutations were identified in 2 families. The phenotype was variably expressed between and within families. One individual had repeated cerebral infarction which the authors suggested might be related to GATA3 haploinsufficiency since GATA3 is expressed in the central nervous system. Of the 2 families in which no GATA3 abnormalities were detected, typical features of HDR were present in one, but atypical features, including retinitis pigmentosa (268000) and severe growth failure in addition to the HDR triad, were found in the other. Hernandez et al. (2007) reported a mother and daughter with HDR and female genital tract malformations in whom they identified a deletion in the GATA3 gene (131320.0009). The mother had a nonfunctional right kidney and a septate uterus, whereas her daughter had right renal agenesis and uterus didelphys with septate vagina. An unaffected sister and maternal aunt, who did not carry the mutation, had no uterine anomalies. In a 14-year-old boy with neurologic symptoms in addition to the HDR syndrome triad of hypoparathyroidism, sensorineural deafness, and renal dysplasia, who did not have any microdeletion in the 22q11.2 or 10p14 regions by FISH analysis, Ferraris et al. (2009) identified heterozygosity for a de novo 2-bp deletion (131320.0013) in exon 2 of the GATA3 gene, predicted to cause premature termination of the protein. Ferraris et al. (2009) concluded that haploinsufficiency of GATA3 may be responsible for a complex neurologic picture in addition to the known triad of HDR syndrome. Ferraris et al. (2009) stated that 46 HDR cases had been reported, 44 of which had undergone molecular analysis, with another 31 cases known in probands' parents or relatives; they tabulated the clinical and molecular findings of reported patients to date. Sun et al. (2009) reported a Han Chinese brother and sister with hypoparathyroidism and sensorineural hearing impairment, in whom they identified heterozygosity for a GATA3 nonsense mutation (R367X; 131320.0008), previously identified in a Japanese man with HDR syndrome (Muroya et al., 2001). The Chinese sibs did not have any apparent renal disease. The mutation was not found in either of their unaffected parents; Sun et al. (2009) concluded that 1 of the parents likely had germinal mosaicism of the mutant GATA3 gene. In a 29-year-old Portuguese woman who had severe hypoparathyroidism, bilateral mild neurosensory deafness, and agenesis of the vagina and uterus but no kidney abnormalities, Moldovan et al. (2011) analyzed the GATA3 gene and identified a heterozygous missense mutation (C342Y; 131320.0014). The authors noted that this case, along with the mother and daughter studied by Hernandez et al. (2007) who also had HDR and female genital tract malformations, seemed to confirm the role of GATA3 in regulating developmental mechanisms of the uterus and vagina. INHERITANCE \- Autosomal dominant HEAD & NECK Ears \- Deafness, sensorineural GENITOURINARY Internal Genitalia (Female) \- Septate uterus (rare) \- Uterus didelphys (rare) \- Uterine agenesis (rare) \- Septate vagina (rare) \- Vaginal agenesis (rare) Kidneys \- Renal dysplasia \- Renal agenesis, unilateral (in some patients) \- Nephrosis \- Progressive renal failure ENDOCRINE FEATURES \- Hypoparathyroidism MOLECULAR BASIS \- Caused by mutation in the GATA-binding protein-3 gene (GATA3, 131320.0001 ) ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	HYPOPARATHYROIDISM, SENSORINEURAL DEAFNESS, AND RENAL DISEASE	c1840333	3,795	omim	https://www.omim.org/entry/146255	2019-09-22T16:39:41	{"doid": ["0060878"], "mesh": ["C537907"], "omim": ["146255"], "orphanet": ["2237"], "synonyms": ["Alternative titles", "HYPOPARATHYROIDISM, SENSORINEURAL DEAFNESS, AND RENAL DYSPLASIA SYNDROME", "BARAKAT SYNDROME", "NEPHROSIS, NERVE DEAFNESS, AND HYPOPARATHYROIDISM"]}
Localized swellings that feel different from the surrounding tissue Breast mass Other namesBreast lump, breast tumor A breast lump associated with an inverted nipple and skin dimpling. Underlying cause was breast cancer. SpecialtyGynecology SymptomsAn area of the breast that feel different than the surrounding tissue[1] CausesFibrocystic change, fibroadenomas, breast infection, galactoceles, breast cancer[1] Diagnostic methodExamination, medical imaging, tissue biopsy[2] TreatmentDepends on the underlying cause[1] FrequencyCommon[2] A breast mass, also known as a breast lump, is a localized swelling that feel different from the surrounding tissue.[1] Breast pain, nipple discharge, or skin changes may be present.[1] Concerning findings include masses that are hard, do not move easily, are of an irregular shape, or are firmly attached to surrounding tissue.[2] Causes include fibrocystic change, fibroadenomas, breast infection, galactoceles, and breast cancer.[1] Breast cancer makes up about 10% of breast masses.[1] Diagnosis is typically by examination, medical imaging, and tissue biopsy.[2] Tissue biopsy is often by fine needle aspiration biopsy.[3] Repeated examination may be required.[2] Treatment depends on the underlying cause.[1] It may vary from simple pain medication to surgical removal.[1] Some causes may resolve without treatment.[4] Breast masses are relatively common.[2] It is the most common breast complaint with the women's concern generally being that of cancer.[5][6] ## Contents * 1 Types * 1.1 Cysts and abscesses * 1.2 Growths * 1.3 Fatty lumps * 1.4 Other * 2 Diagnosis * 3 Treatment * 3.1 Fibroadenoma treatment * 4 References * 5 External links ## Types[edit] Women seeking evaluation of a breast lump[7] Finding Percentage Fibrocystic breast changes 40% No disease 30% Fibroadenoma 7% Other benign mammary dysplasias and neoplasms 13% Breast cancer 10% ### Cysts and abscesses[edit] A breast cyst is a non-cancerous, fluid-filled sac in the breast. They generally feel smooth or rubbery under the skin and can be quite painful or cause no pain at all. Cysts are caused by the hormones that control the menstrual cycle and are rare in women older than 50.[8] A sebaceous cyst is a non-cancerous, closed sac or cyst below the skin that is caused by plugged ducts at the site of a hair follicle. Hormone stimulation or injury may cause them to enlarge but if no symptoms are present, medical treatment is not required.[8] Breast abscesses are non-cancerous pockets of infection within the breast. They can be quite painful and cause the skin over the breast to turn red or feel hot or solid. Abscesses of the breast are most common in women who are breast-feeding.[8] ### Growths[edit] Adenomas are non-cancerous abnormal growths of the glandular tissue in the breast. The most common form of these growths, fibroadenomas, occur most frequently in women between the ages of 15 and 30 and in women of African descent. They usually feel round and firm and have smooth borders. Adenomas are not related to breast cancer.[8] Intraductal papillomas are wart-like growths in the ducts of the breast. These lumps are usually felt just under the nipple and can cause a bloody discharge from the nipple. Women close to menopause may have only one growth, while younger women are more likely to have multiple growths in one or both breasts.[8] Breast cancer usually feels like a hard or firm lump that is generally irregular in shape and may feel like it is attached to skin or tissue deep inside the breast. Breast cancer is rarely painful and can occur anywhere in the breast or nipple.[8] ### Fatty lumps[edit] Fat necrosis is a condition in which the normal fat cells of the breast become round lumps. Symptoms can include pain, firmness, redness, and/or bruising. Fat necrosis usually goes away without treatment but can form permanent scar tissue that may show up as an abnormality on a mammogram.[8] A lipoma is a non-cancerous lump of fatty tissue that is soft to the touch, usually movable, and is generally painless.[8] ### Other[edit] Breast hematomas and seromas may be visible as a local swelling of the breast. Seromas are a common complication of breast surgery. Hematomas can also occur after breast surgery or breast injury or, more rarely, they can occur spontaneously in patients with coagulopathy. ## Diagnosis[edit] A fine needle biopsy Breast lumps are often discovered during a breast self-examination or during a routine check-up. Upon noticing an unusual lump in the breast the best course of action is to schedule an examination with a physician who can best diagnose the type of breast lump and strategy for treatment. People should make sure that the medical records of any breast-related illnesses are retained,[citation needed] as this facilitates diagnosis in case of recurrence or follow-up. ## Treatment[edit] Treatments for breast lumps vary depending on the type of lump. Standard breast cysts and abscesses require drainage for treatment, while sebaceous cysts and fatty lumps are best treated by surgical removal.[8] ### Fibroadenoma treatment[edit] Several treatment options currently exist for fibroadenomas: "wait and watch," open surgery and minimally-invasive surgical alternatives. * "Waiting and watching" is common for very small fibroadenomas and involves routine check-ups with a physician every 6–12 months. * Open surgery has historically been the most common method for removing large fibroadenomas, but has several disadvantages. Surgery often requires general anesthesia and a day in the hospital, and can leave significant scarring at the site of the incision. * Minimally-invasive surgical alternatives include biopsy-removal techniques and cryoablation. Biopsy-removal involves using a vacuum-assisted biopsy device to remove the fibroadenoma bit by bit. This procedure can be effective but often does not remove all of the fibroadenoma, resulting in a possible re-growth. In cryoablation, an ultrasound-guided probe is inserted into the fibroadenoma through a small incision in the breast. Extremely cold temperatures are then used to freeze the lesion, which eventually dies and is reabsorbed into the body. ## References[edit] 1. ^ a b c d e f g h i "Breast Masses (Breast Lumps)". Merck Manuals Professional Edition. Retrieved 29 October 2018. 2. ^ a b c d e f Klein, S (1 May 2005). "Evaluation of palpable breast masses". American Family Physician. 71 (9): 1731–8. PMID 15887452. 3. ^ Yu, YH; Wei, W; Liu, JL (25 January 2012). "Diagnostic value of fine-needle aspiration biopsy for breast mass: a systematic review and meta-analysis". BMC Cancer. 12: 41. doi:10.1186/1471-2407-12-41. PMC 3283452. PMID 22277164. 4. ^ "Breast lumps". NHS. 2017-10-20. Retrieved 29 October 2018. 5. ^ Hindle, William H. (2012). Breast Care: A Clinical Guidebook for Women's Primary Health Care Providers. Springer Science & Business Media. p. 12. ISBN 9781461221449. 6. ^ Salzman, B; Fleegle, S; Tully, AS (15 August 2012). "Common breast problems". American Family Physician. 86 (4): 343–9. PMID 22963023. 7. ^ Mitchell, Richard Sheppard; Kumar, Vinay; Abbas, Abul K.; Fausto, Nelson (2007). Robbins Basic Pathology (8th ed.). Philadelphia: Saunders. p. 739. ISBN 978-1-4160-2973-1. 8. ^ a b c d e f g h i WebMD: Breast Lump Overview ## External links[edit] Classification D * ICD-10: N63 * ICD-9-CM: 611.72 * DiseasesDB: 15880 External resources * MedlinePlus: 003155 * eMedicine: article/781116 * WebMD - Breast Lump Overview * v * t * e Breast disease Inflammation * Mastitis * Nonpuerperal mastitis * Subareolar abscess * Granulomatous mastitis Physiological changes and conditions * Benign mammary dysplasia * Duct ectasia of breast * Chronic cystic mastitis * Mammoplasia * Gynecomastia * Adipomastia (lipomastia, pseudogynecomastia) * Breast hypertrophy * Breast atrophy * Micromastia * Amastia * Anisomastia * Breast engorgement Nipple * Nipple discharge * Galactorrhea * Inverted nipple * Cracked nipples * Nipple pigmentation Masses * Galactocele * Breast cyst * Breast hematoma * Breast lump * Pseudoangiomatous stromal hyperplasia Other * Pain * Tension * Ptosis * Fat necrosis * Amazia [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Breast mass	c0024103	3,796	wikipedia	https://en.wikipedia.org/wiki/Breast_mass	2021-01-18T18:28:22	{"icd-9": ["611.72"], "icd-10": ["N63"], "wikidata": ["Q953865"]}
Anophthalmia plus syndrome (APS) is a very rare syndrome that involves malformations in multiple organs of the body. The most common findings in affected individuals are anophthalmia (absence of one or both eyes) or severe microphthalmia (abnormally small eyes), and cleft lip and/or cleft palate. Other findings may include wide-set eyes (hypertelorism); low-set ears; narrowed or blocked nasal passages (choanal stenosis or atresia); sacral neural tube defect, midline abdominal wall defects, clinodactyly, eye colobomas and congenital glaucoma. It has been suggested that APS is inherited in an autosomal recessive manner, although the genetic cause has not yet been identified. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Anophthalmia plus syndrome	c1833339	3,797	gard	https://rarediseases.info.nih.gov/diseases/719/anophthalmia-plus-syndrome	2021-01-18T18:02:05	{"mesh": ["C537767"], "omim": ["600776"], "umls": ["C1833339"], "orphanet": ["1104"], "synonyms": ["Fryns microphthalmia syndrome", "Fryns anophthalmia syndrome", "Microphthalmia with facial clefting", "Anophthalmia, cleft lip/palate, facial anomalies, and CNS anomalies and hypothalamic disorder", "Leichtman Wood Rohn syndrome"]}
A number sign (#) is used with this entry because of evidence that microcephaly-micromelia syndrome (MIMIS) is caused by homozygous mutation in the DONSON gene (611428) on chromosome 21q22. Biallelic mutation in the DONSON gene can also cause microcephaly, short stature, and limb abnormalities (MISSLA; 617604), a less severe disorder. Description Microcephaly-micromelia syndrome (MIMIS) is a severe autosomal recessive disorder that usually results in death in utero or in the perinatal period. Affected individuals have severe growth retardation with microcephaly and variable malformations of the limbs, particularly the upper limbs. Defects include radial ray anomalies, malformed digits, and clubfeet (summary by Evrony et al., 2017). Clinical Features Ives and Houston (1980) reported 14 infants with similar congenital malformations resulting in perinatal death who were born in a highly inbred, predominantly Cree Indian community in northern Saskatchewan, Canada. Features included intrauterine growth retardation (IUGR), marked microcephaly, craniosynostosis, and severe malformation of the limbs, especially the arms. Elbows were fused, forearms were greatly shortened and usually contained only a single bone, and the hands were abnormal with only 2 to 4 malformed digits. Evrony et al. (2017) provided follow-up of the family reported by Ives and Houston (1980) and identified multiple additional cases from related families from the same population. The affected individuals had marked IUGR, with low birth weight (average -6.5 SD), length (average -7.4 SD), and head circumference (average -7.4 SD). They had characteristic facial appearance with a broad and beaked nose, short palpebral fissures, microstomia, micrognathia, low-set ears, and short neck. Upper limb abnormalities included underdevelopment or even absence of the radius and/or ulna, humeroradial synostosis, oligodactyly with absent thumbs, and absent or poorly developed fifth fingers. Lower limb abnormalities included limb shortening with underdeveloped fibulae, clubfeet, and toe abnormalities, such as short great toes, abnormally placed great toes, and abnormal metatarsal bones. Additional skeletal anomalies included craniosynostosis or absence of 1 or 2 rib pairs. Brain imaging showed profound microcephaly with only primary sulci and gyri, diminished white matter, and hypoplastic or absent corpus callosum. Microscopic analysis of the cerebral cortex showed decreased cells in the subventricular zone and a disorganized distribution of cells. Some patients had cleft palate and cardiac, gastrointestinal, or genitourinary defects. The lungs were severely hypoplastic with anomalous lobation, and most patients were either stillborn or died within the first week of life due to respiratory failure. Two died at ages 3 months and 2 years. Reynolds et al. (2017) reported 2 sibs, born of consanguineous Saudi Arabian parents (family P21), with a phenotype similar to that reported by Evrony et al. (2017). The patients died in utero. They had severe microcephaly (-7.8 and -8.5 SD), narrow chest, absent ulna and radius, hypoplastic femur and tibia, and severe talipes. Other features included oligohydramnios, cystic hygroma, low-set ears, micrognathia, and microphthalmia. Inheritance Recessive inheritance of the microcephaly-micromelia syndrome was indicated by parental consanguinity, sex ratio close to 1, and a 25% segregation ratio (Ives and Houston, 1980). The transmission pattern of MIMIS in the family reported by Reynolds et al. (2017) was consistent with autosomal recessive inheritance. Molecular Genetics In tissue samples derived from at least 12 patients of Cree descent with MIMIS, Evrony et al. (2017) identified a homozygous splice site mutation in the DONSON gene (c.1047-9A-G; 611428.0001). Most patients belonged to a large consanguineous pedigree of First Nations origin in Saskatchewan, whereas the others belonged to the same population and were known to be descendants of the founders of this pedigree, although the exact relationships were unknown. The variant, which was found by transcriptome sequencing and confirmed by Sanger sequencing, segregated with the disorder in all families. Patient and carrier cells showed decreased transcript levels of DONSON compared to controls, consistent with nonsense-mediated decay. However, a small fraction of transcripts were correctly spliced, suggesting that it is a hypomorphic allele. Evrony et al. (2017) noted that the mutation was not identified by comprehensive exome or genome sequencing initially, which prompted the use of RNA sequencing to identify this noncoding variant. Using public proteomic and gene expression databases, Evrony et al. (2017) found that DONSON is associated with multiple components of the DNA replication and replication fork machinery. Knockdown of DONSON in HeLa cells resulted in disturbance of components of the cell cycle, arrest of the cell cycle, and impaired cellular proliferation. Reynolds et al. (2017) identified homozygosity for the c.1047-9A-G mutation in the DONSON gene in 2 sibs from a consanguineous Saudi Arabian family with MIMIS. INHERITANCE \- Autosomal recessive GROWTH Other \- Intrauterine growth retardation HEAD & NECK Head \- Microcephaly, severe (up to -10 SD) Face \- Micrognathia Ears \- Low-set ears Eyes \- Microphthalmia \- Short palpebral fissures Nose \- Broad nose \- Beaked nose Mouth \- Microstomia \- Cleft palate Neck \- Short neck RESPIRATORY Lung \- Hypoplastic lungs CHEST External Features \- Narrow chest Ribs Sternum Clavicles & Scapulae \- Rib abnormalities SKELETAL Skull \- Craniosynostosis Limbs \- Limb malformations (particularly of the arms) \- Micromelia \- Hypoplastic or absent radius \- Hypoplastic or absent ulna \- Hypoplastic fibulae \- Hypoplastic femurs \- Hypoplastic tibia \- Humeroradial synostosis Hands \- Thumb abnormalities \- Absence of the thumb \- Oligodactyly \- Poorly developed fifth fingers \- Bifid metacarpal bones Feet \- Club feet \- Toe abnormalities NEUROLOGIC Central Nervous System \- Decreased sulci and gyri \- Simplified gyral pattern \- Diminished white matter \- Hypoplastic or absent corpus callosum \- Interhemispheric cysts PRENATAL MANIFESTATIONS Amniotic Fluid \- Oligohydramnios \- Cystic hygroma MISCELLANEOUS \- Increased frequency among Cree Indians from Saskatchewan \- Death in utero or in the perinatal period due to respiratory failure MOLECULAR BASIS \- Caused by mutation in the downstream neighbor of son gene (DONSON, 611428.0001 ) ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	MICROCEPHALY-MICROMELIA SYNDROME	c1855079	3,798	omim	https://www.omim.org/entry/251230	2019-09-22T16:25:13	{"mesh": ["C565382"], "omim": ["251230"]}
A number sign (#) is used with this entry because autosomal dominant endosteal hyperostosis is caused by heterozygous mutation in the LRP5 gene (603506) on chromosome 11q13. A number of other disorders characterized by increased bone density, e.g., osteoporosis-pseudoglioma syndrome (OPPG; 259770), are caused by mutation in this gene. Clinical Features Maroteaux et al. (1971) reported a benign and usually asymptomatic form of osteosclerosis associated with torus palatinus. Worth and Wollin (1966) first described the condition. Gorlin and Glass (1977) proposed the designation for this disorder which is distinguished from van Buchem disease (hyperostosis corticalis generalisata; 239100) by the dominant inheritance pattern and absence of exophthalmos, hypertelorism, increased head circumference, nasal obstruction, cranial nerve involvement, and elevated alkaline phosphatase. A main clinical feature is widened and deepened mandible with increased gonial angle. Radiographically, the disorder shows endosteal sclerosis of the calvaria with loss of the diploe, osteosclerosis and hyperostosis of the mandible with absence of the normal antegonial notches, endosteal sclerosis of the diaphyses of long bones (including metacarpals and metatarsals), and osteosclerosis of the pelvis. The vertebral bodies, ribs, and clavicles are involved to a minor degree. Unlike dominant osteopetrosis (see 166600), osteomyelitis and 'bone-within-bone' x-ray appearance may not occur in this form. Torus palatinus is such a generally common finding--in about 25% of females (Gorlin, 1977)--that it may not be a significant feature. Reports include those of Russell et al. (1968), Dyson (1972), and Owen (1976). Perez-Vicente et al. (1987) pointed out that the autosomal dominant variety of endosteal hyperostosis may not always be benign. He described a Spanish family in which individuals in 4 generations appear to have been affected. A father and daughter who were studied showed severe involvement. The father showed neurologic damage with sensorineural hearing loss, chronic intracranial hypertension, and mild corticospinal tract abnormalities. There was radiologic evidence of progressive bone disease at follow-up. In addition to mild hydrocephalus, CT scan of the head documented a reduction in size with the posterior fossa and encroachment on the foramen magnum. Ades et al. (1994) observed this disorder in a mother and her 2 children. Chronic intracranial hypertension and cranial nerve palsies were found in the mother. CT scans and MRI views of the head demonstrated symmetrical sclerosis of the cranial vault, narrow internal auditory meatus and canals, inferior herniation of the cerebellar tonsils into the foramen magnum, and encroachment of occipital bone into the foramen magnum posteriorly. Molecular Genetics Van Wesenbeeck et al. (2003) described mutations in the LRP5 gene in several conditions with increased bone density, including heterozygous mutations in affected members of 3 families with endosteal hyperostosis (603506.0015-603506.0016). INHERITANCE \- Autosomal dominant GROWTH Height \- Normal height HEAD & NECK Face \- Flattened forehead (adolescence) Ears \- Hearing loss, sensorineural Mouth \- Torus palatinus Teeth \- Malocclusion \- Tooth loss CHEST Ribs Sternum Clavicles & Scapulae \- Mild rib sclerosis \- Mild clavicular sclerosis SKELETAL \- Resistance of bone to fractures Skull \- Elongated mandible \- Increased calvarial density \- Increased mandibular bone density \- Endosteal sclerosis of cranium \- Loss of diploe \- Increased gonial angle (AD osteosclerosis) \- Decreased gonial angle (endosteal hyperostosis) Spine \- Mild vertebral body sclerosis Pelvis \- Mild sclerosis Limbs \- Thickened cortex of long bones Hands \- Metacarpal diaphyseal endosteal sclerosis Feet \- Metatarsal diaphyseal endosteal sclerosis MISCELLANEOUS \- Onset of disease in late childhood \- Allelic to type I osteopetrosis ( 607634 ), osteoporosis-pseudoglioma ( 259770 ), type II van Buchem disease ( 607636 ), and high bone mass ( 601884 ) MOLECULAR BASIS \- Caused by mutation in the low density lipoprotein receptor-related protein 5 gene (LRP5, 603506.0015 ) ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	ENDOSTEAL HYPEROSTOSIS, AUTOSOMAL DOMINANT	c0432273	3,799	omim	https://www.omim.org/entry/144750	2019-09-22T16:39:54	{"mesh": ["C536748"], "omim": ["144750"], "orphanet": ["2790"], "synonyms": ["Alternative titles", "HYPEROSTOSIS CORTICALIS GENERALISATA, BENIGN FORM OF WORTH, WITH TORUS PALATINUS", "OSTEOSCLEROSIS, AUTOSOMAL DOMINANT"]}

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