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A number sign (#) is used with this entry because of evidence that distal arthrogryposis type 1B (DA1B) is caused by heterozygous mutation in the MYBPC1 gene (160794) on chromosome 12q23. For a general phenotypic description and a discussion of genetic heterogeneity of distal arthrogryposis, see DA1A (108120). Clinical Features Gurnett et al. (2010) described a 5-generation family in which 12 members had distal arthrogryposis type 1. Nine of the 12 had congenital talipes equinovarus (clubfoot) and the 3 others had congenital vertical talus. The lower limb contractures were bilateral in all cases except 1 female with left-sided clubfoot and 1 female with right-sided clubfoot. Five of the 12 had hand contractures manifesting as either camptodactyly and ulnar deviation of the fingers (3 individuals) or extension contracture of the fourth digit (2 individuals). The other 7 had no evidence of hand involvement. Mapping Gurnett et al. (2010) described a 5-generation family with DA1 segregating as an autosomal dominant disorder with complete penetrance. Genomewide linkage data from 12 affected members revealed a multipoint maximum lod of 3.27 on chromosome 12q23.2. Recombinants delineated the critical region to an interval of 9 cM between SNPs rs3869308 and rs1196761. Molecular Genetics Gurnett et al. (2010) sequenced the MYBPC1 gene, which encodes the slow-twitch skeletal muscle myosin binding protein C1, in affected members of 2 families segregating autosomal dominant distal arthrogryposis and identified a different heterozygous missense mutation in each family (160794.0001-160794.0002) that segregated with disease. Neither mutation was found in chromosomes of 400 control individuals. Skeletal muscle biopsies from affected patients showed that type I (slow-twitch) fibers were smaller than type II fibers. Expression of a green fluorescent protein (GFP)-tagged MYBPC1 construct containing wildtype and DA1 mutations in mouse skeletal muscle revealed robust sarcomeric localization. In contrast, a more diffuse localization was seen when nonfused GFP and MYBPC1 proteins containing corresponding MYBPC3 (600958) amino acid substitutions (R326Q, E334K) that caused hypertrophic cardiomyopathy were expressed. These findings revealed that the MYBPC1 is a novel gene responsible for DA1B, although the mechanism of disease may differ from how some cardiac MYBPC3 mutations cause hypertrophic cardiomyopathy. INHERITANCE \- Autosomal dominant SKELETAL Hands \- Camptodactyly \- Ulnar deviation of fingers Feet \- Talipes equinovarus \- Vertical talus MUSCLE, SOFT TISSUES \- Reduced extensor strength (in some patients) \- Type 1 fibers smaller than type II fibers MISCELLANEOUS \- Phenotypic variability \- Some patients show only distal extremity involvement MOLECULAR BASIS \- Caused by mutation in the slow-type myosin-binding protein C gene (MYBPC1, 160794.0001 ) ▲ 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	ARTHROGRYPOSIS, DISTAL, TYPE 1B	c1852085	3,400	omim	https://www.omim.org/entry/614335	2019-09-22T15:55:39	{"doid": ["0050646"], "mesh": ["C565097"], "omim": ["614335"], "orphanet": ["1146"]}
Iridocorneal endothelial syndrome SpecialtyOphthalmology Iridocorneal Endothelial (ICE) syndromes are a spectrum of diseases characterized by slowly progressive abnormalities of the corneal endothelium and features including corneal edema, iris distortion, and secondary angle-closure glaucoma. [1,2,4] ICE syndromes are predominantly unilateral and nonhereditary [1,2,4]. The condition occurs in predominantly middle-aged women [1,3,4]. ## Contents * 1 Signs and Symptoms * 2 Mechanism * 2.1 Variations * 3 Diagnosis * 4 Treatment * 5 Prognosis * 6 References * 7 External links ## Signs and Symptoms[edit] Many cases are asymptomatic, however patients many have decreased vision, glare, monocular diplopia or polyopia, and noticeable iris changes [2,6]. On exam patients have normal to decreased visual acuity, and a “beaten metal appearance” of the corneal endothelium, corneal edema, increased intraocular pressure, peripheral anterior synechiae, and iris changes [1,2,6]. ## Mechanism[edit] The exact mechanism is unknown, however there appears to be a component of abnormal corneal endothelium that proliferates onto the iris forming a membrane that then obstructs the trabecular meshwork, leading to iris distortion [1,2]. Nodule formation can also occur when the abnormal corneal endothelium causes contractions around the iris stroma [1]. Herpesvirus DNA has been identified in some patients following keratoplasty, suggesting the possibility that herpes simplex virus may induce the abnormal endotheliazation in the anterior chamber angle and on the surface of the iris [2,3,5]. ### Variations[edit] The Chandler variant of ICE is characterized by pathology on the inner surface of the cornea leading to abnormal endothelial pump function [2,6]. Other features include possible mild iris changes, corneal edema, and normal to slight elevations in intraocular pressure [1,6]. Cogan-Reese variant is characterized by multiple pigmented iris nodules [2,6]. This variant is most commonly unilateral and seen in middle-aged females [2]. ## Diagnosis[edit] This section is empty. You can help by adding to it. (September 2017) ## Treatment[edit] Penetrating karatoplasty and endothelial keratoplasty can be used as treatments for severe cases of ICE [2,8]. Because glaucoma and elevated intraocular pressure are often present in ICE patients, long term follow up may be needed to ensure adequate intraocular pressures are maintained [2,7] ## Prognosis[edit] The disease is chronic and often progresses slowly. Prognosis is generally poor when associated with glaucoma [1,2]. ## References[edit] [1] Friedman NJ, Kaiser PK, Pineda R. (2009). The Massachusetts Eye and Ear Infirmary Illustrated Manual of Ophthalmology. Chapter 7: Iris and Pupils (pp. 285–287). Philadelphia PA:W.B. Saunders Company. [2] Weisenthal RW. 2012-2013 Basic and Clinical Science Course, Section 8, Chapter 12: External Disease and Cornea (pp 344–345). San Francisco CA: American Academy of Ophthalmology The Eye M.D. Association. [3] Alvardo JA, Underwood JL, Green WR, et al. (1994) Detection of herpes simplex viral DNA in the iridocorneal endothelial syndrome. Archives of Ophthalmology, 112(12), 1601-1609 [4] Carpel EF. (2005). Iridocorneal endothelial syndrome. In: Krachmer JH, Mannis MJ, Holland EJ. Cornea. 2nd ed. Vol 1. Chapter 79 (pp 975–985). Philadelphia: Elsever/Mosby [5] Groh MJ, Seitz B, Schumacher S, Naumann GO. Detection of herpes simplex virus in aqueous humor in iridocorneal endothelial (ICE) syndrome. Cornea. 1999;18(3):359-360. [6] Herde J. Iridocorneal endothelial syndrome (ICE-S): classification, clinical picture, diagnosis. Klin Monatsbl Augenheilkd. 2005;222(10):797-801 [7] Price MO, Price FW Jr. Descemet stripping with endothelial keratoplasty for treatment of iridocorneal endothelial syndrome. Cornea. 2007;26(4):493-497. ## External links[edit] Classification D * ICD-10: H21.1 * MeSH: D057129 * DiseasesDB: 32706 External resources * Orphanet: 64734 * Facts About the Cornea and Corneal Disease The National Eye Institute (NEI). * 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	Iridocorneal endothelial syndrome	c0339285	3,401	wikipedia	https://en.wikipedia.org/wiki/Iridocorneal_endothelial_syndrome	2021-01-18T19:07:31	{"gard": ["60"], "mesh": ["D057129"], "orphanet": ["64734"], "wikidata": ["Q17121503"]}
A number sign (#) is used with this entry because of evidence that photosensitive trichothiodystrophy-3 (TTD3) is caused by homozygous or compound heterozygous mutation in the TFB5 gene (GTF2H5; 608780), which encodes a subunit of the transcription/repair factor TFIIH, on chromosome 6q25. Description Trichothiodystrophy is a rare autosomal recessive disorder in which patients have brittle, sulfur-deficient hair that displays a diagnostic alternating light and dark banding pattern, called 'tiger tail banding,' under polarizing microscopy. TTD patients display a wide variety of clinical features, including cutaneous, neurologic, and growth abnormalities. Common additional clinical features are ichthyosis, intellectual/developmental disabilities, decreased fertility, abnormal characteristics at birth, ocular abnormalities, short stature, and infections. There are both photosensitive and nonphotosensitive forms of the disorder. Patients with TTD have not been reported to have a predisposition to cancer (summary by Faghri et al., 2008). For a discussion of genetic heterogeneity of TTD, see 601675. Clinical Features Jorizzo et al. (1982) described a patient with typical symptoms of TTD: characteristic hair-shaft abnormalities with reduced sulfur content, collodion baby, short stature, ichthyosis, bilateral congenital cataracts, and asthmatic attacks. Stefanini et al. (1993) examined this patient at age 20 years and found that he had had recurrent infective exacerbations of his asthma and that he remained severely growth retarded (height and weight below the 3rd centile) and of limited intelligence (IQ 70-80). His ichthyosiform erythroderma continued. He had developed joint contractures of the hands due to the severe ichthyosiform involvement of the palms, but sensitivity to sunlight had been present from early childhood. There was, however, no significant freckling or other pigmentary changes, no telangiectases or actinic keratoses, and no skin tumors. Biochemical Features Stefanini et al. (1993) demonstrated that cells from the patient (TTD1BR) originally described by Jorizzo et al. (1982) were able to complement the excision-repair defect in all xeroderma pigmentosum (XP) complementation groups. They also showed that complementation was not intragenic. Thus, the cell strain represented a new excision-repair complementation group. Lehmann et al. (1994) recommended that this second complementation group be referred to as TTDA and its gene as TTDA. Vermeulen et al. (2000) found that patients with the TTDA complementation form of trichothiodystrophy had a severely reduced steady-state level of the entire TFIIH complex. The reduction of TFIIH affected mainly its repair function and hardly influenced transcription. Petrini (2000) interpreted the findings as indicating that the normal TTDA protein modulates the proteasome-mediated degradation of TFIIH. Microinjected TFIIH is less stable in TTDA cells; the absence of TFIIH in TTDA cells would thus decrease its half-life and therefore its abundance. It is conceivable that a threshold level of TFIIH is required to switch between the transcriptional mode and the nucleotide excision repair (NER) mode. Below that threshold, the essential need for transcription functions would override the signal to switch to NER mode, and DNA repair would therefore be differentially affected. Giglia-Mari et al. (2004) found that polynucleated fibroblasts from individuals with TTDA microinjected with GTF2H5 cDNA showed greater unscheduled DNA synthesis than uninjected neighboring cells. GTF2H5 cDNA corrected the repair defect of cells from individuals with TTDA to a level comparable to that observed in wildtype cells assayed in parallel, suggesting that the GTF2H5 gene is mutated in TTDA. Molecular Genetics In 3 unrelated individuals with TTDA, Giglia-Mari et al. (2004) identified different inactivating mutations in the GTF2H5 gene in homozygous or compound heterozygous state (see, e.g., R56X, 608780.0001 and L21P, 608780.0002). The severe effect of GTF2H5 mutations on NER function suggests that NER requires higher concentrations of TFIIH than does transcription. Live cell studies showed that TFIIH participates substantially longer in NER than in transcription (Hoogstraten et al., 2002), providing a possible explanation for the increased need for sufficient amounts of TFIIH in NER. Additionally, an altered structure of TFIIH caused by a mutant GTF2H5 may primarily affect NER function. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: 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	TRICHOTHIODYSTROPHY 3, PHOTOSENSITIVE	c1955934	3,402	omim	https://www.omim.org/entry/616395	2019-09-22T15:49:00	{"mesh": ["D054463"], "omim": ["616395"], "orphanet": ["33364"], "synonyms": ["Alternative titles", "TRICHOTHIODYSTROPHY, COMPLEMENTATION GROUP A"]}
A number sign (#) is used with this entry because primary ciliary dyskinesia-7 (CILD7) is caused by homozygous or compound heterozygous mutation in the DNAH11 gene (603339) on chromosome 7p15. For a phenotypic description and a discussion of genetic heterogeneity of primary ciliary dyskinesia and the Kartagener syndrome, see CILD1 (244400). Description Primary ciliary dyskinesia is an autosomal recessive disorder resulting from loss of normal ciliary function. Kartagener (pronounced KART-agayner) syndrome is characterized by the combination of primary ciliary dyskinesia and situs inversus, and occurs in approximately half of patients with ciliary dyskinesia. Since normal nodal ciliary movement in the embryo is required for normal visceral asymmetry, absence of normal ciliary movement results in a lack of definitive patterning; thus, random chance alone appears to determine whether the viscera take up the normal or reversed left-right position during embryogenesis. This explains why approximately 50% of patients, even within the same family, have situs inversus (Afzelius, 1976; El Zein et al., 2003). Clinical Features Schwabe et al. (2008) reported a German family in which 6 sibs had primary ciliary dyskinesia, 1 of whom also had situs inversus totalis, consistent with Kartagener syndrome. Clinical features included chronic respiratory infections, chronic sinusitis, recurrent bronchitis, and pneumonia beginning in infancy or early childhood. Three patients had recurrent otitis media. Pulmonary examination showed normal lung function with restrictive or obstructive changes during exacerbation. Three individuals had bronchiectasis, and 5 had chronic mucosal inflammatory changes with purulent hypersecretions and the presence of bacteria. One affected male fathered a child without use of medical assistance, suggesting normal fertility. Analysis of respiratory cilia from 5 patients showed severely altered beating patterns, with nonflexible and hyperkinetic beating of axonemes only detectable in slow-motion analysis of video microscopy. Electron microscopy showed normal axonemal ultrastructure. Lucas et al. (2012) reported 2 unrelated patients with CILD7. Both had neonatal respiratory symptoms, chronic cough, rhinitis, and otitis. Electron microscopy showed normal ciliary ultrastructure in both patients. However, functional studies showed that 1 patient had rapid, erratic, dyskinetic ciliary beating, whereas the other had static cilia with slow activity. Cytogenetics Pan et al. (1998) reported an infant boy with primary ciliary dyskinesia, complete situs inversus, and cystic fibrosis (CF; 219700). He developed respiratory distress at 10 days of age and later showed growth retardation. Genetic analysis showed paternal isodisomy for 21 loci on chromosome 7 as well as homozygosity for a common mutation in the CFTR gene (602421.0001) on chromosome 7q31, which was absent in the mother. Bronchial cilia showed no normal ciliary motion but were structurally normal on electron microscopy. Other known genetic causes for the situs abnormalities were excluded. Pan et al. (1998) suggested that the most likely explanation for the uniparental disomy was monosomy duplication associated with a nullisomic maternal gamete, or a paternal meiosis II nondisjunction resulting in a trisomic conceptus, with subsequent reduction to disomy through loss of the maternal chromosome 7, so-called trisomic rescue. The authors suggested that the child inherited 2 recessive disorders linked to chromosome 7 from his father: CF and immotile cilia associated with complete situs inversus, although it could not be excluded that the 2 disorders were unrelated. Pan et al. (1998) noted that Koiffmann et al. (1993) reported complete situs inversus in a boy with a complex karyotype involving chromosome 7q22 (ins(7;8)(q22;q12q24)), suggesting that this locus was important in the pathogenesis of the disorder. Molecular Genetics In a patient with primary ciliary dyskinesia and situs inversus totalis originally reported by Pan et al. (1998), Bartoloni et al. (2002) identified a homozygous mutation in the DNAH11 gene (603339.0001). In affected members of a German family with primary ciliary dyskinesia, Schwabe et al. (2008) identified compound heterozygosity for 2 mutations in the DNAH11 gene (603339.0002; 603339.0003). One of the patients had Kartagener syndrome. In a patient with CILD7, Lucas et al. (2012) identified compound heterozygous mutations in the DNAH11 gene (603339.0004 and 603339.0005). An unrelated patient had a heterozygous truncating mutation in the CILD7 gene (603339.0006), but a second pathogenic mutation was not identified. INHERITANCE \- Autosomal recessive RESPIRATORY \- Recurrent respiratory infections due to impaired ciliary motility Lung \- Bronchiectasis ABDOMEN \- Situs inversus (in some patients) GENITOURINARY Internal Genitalia (Male) \- Male fertility remains intact LABORATORY ABNORMALITIES \- Cilia show nonflexible and hyperkinetic beating of axonemes \- Cilia may also be static, with slow activity \- Axonemes show normal structure MOLECULAR BASIS \- Caused by mutation in the dynein axonemal heavy chain 11 gene (DNAH11, 603339.0001 ) ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	CILIARY DYSKINESIA, PRIMARY, 7	c2678473	3,403	omim	https://www.omim.org/entry/611884	2019-09-22T16:02:40	{"doid": ["0110605"], "mesh": ["C567504"], "omim": ["611884", "244400"], "orphanet": ["244"], "synonyms": ["Alternative titles", "CILIARY DYSKINESIA, PRIMARY, 7, WITH OR WITHOUT SITUS INVERSUS", "PCD"], "genereviews": ["NBK1122"]}
Goldstein's toe sign Differential diagnosisDown syndrome or cretinism "Goldstein's Toe Sign" is a feature identified by Dr. Hyman Isaac Goldstein (1887–1954), an American physician and medical historian. A greater distance separates the largest two toes of some people exhibiting Down syndrome or cretinism."[1] ## References[edit] 1. ^ "Who Named It Website Wide distance between the great toe and the adjoining toe; associated with cretinism and trisomy 21. This medical sign article is a stub. You can help Wikipedia by expanding it. * v * t * e [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Goldstein's toe sign	c3279012	3,404	wikipedia	https://en.wikipedia.org/wiki/Goldstein%27s_toe_sign	2021-01-18T18:49:13	{"umls": ["C3279012", "C1840069"], "wikidata": ["Q5580342"]}
A rare central nervous system malformation characterized by congenital absence of the spinal cord, usually associated with segmental bony spinal anomalies. Neurologic deficits depend on the affected segments and the functioning of the residual spinal cord. Typically, the spinal cord appears normal above the defect and bulky, thickened, and low-lying caudally. Clinical presentation includes varying degrees of motor weakness (associated with deformities of the lower limbs) and neurogenic bladder dysfunction. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Isolated amyelia	None	3,405	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=268868	2021-01-23T17:27:51	{"icd-10": ["Q06.0"]}
Chromosome instability syndromes are a group of inherited conditions associated with chromosomal instability and breakage. They often lead to an increased tendency to develop certain types of malignancies.[1] The following chromosome instability syndromes are known: * Ataxia telangiectasia * Ataxia telangiectasia-like disorder * Bloom syndrome * Fanconi anaemia * Nijmegen breakage syndrome ## Neurodegenerative diseases[edit] Chromosome instability syndromes include several inherited neurodegenerative diseases that are due to mutations in genes that encode enzymes necessary for DNA repair. Epigenetic alterations often occur in association with the DNA repair defect, and such alterations likely have a role in the etiology of the disease. Chromosome instability syndromes due to impaired DNA repair and with features of neurodegeneration and epigenetic alteration were summarized by Bernstein and Bernstein.[citation needed] These syndromes include Aicardi-Goutieres syndrome, amyotrophic lateral sclerosis, ataxia-telangiectasia, Cockayne syndrome, fragile X syndrome, Friedrich's ataxia, Huntington's disease, spinocerebellar ataxia type 1, trichothiodystrophy and xeroderma pigmentosum. ## Hypogonadism[edit] Genes MCM8 and MCM9 encode proteins that form a complex. This complex functions in homologous recombination and repair of DNA double-strand breaks. Inherited mutations in MCM8 and MCM9 can cause a chromosomal instability syndrome characterized by ovarian failure.[2][3] The germline MCM8-MCM9 protein complex is most likely required for the resolution of double-strand breaks that occur during homologous recombination in the pachytene stage of meiosis I.[2] ## References[edit] 1. ^ Taylor AM (2001). "Chromosome instability syndromes". Best Pract Res Clin Haematol. 14 (3): 631–44. doi:10.1053/beha.2001.0158. PMID 11640873. 2. ^ a b Wood-Trageser MA, Gurbuz F, Yatsenko SA, Jeffries EP, Kotan LD, Surti U, Ketterer DM, Matic J, Chipkin J, Jiang H, Trakselis MA, Topaloglu AK, Rajkovic A (December 2014). "MCM9 mutations are associated with ovarian failure, short stature, and chromosomal instability". Am. J. Hum. Genet. 95 (6): 754–62. doi:10.1016/j.ajhg.2014.11.002. PMC 4259971. PMID 25480036. 3. ^ Desai S, Wood-Trageser M, Matic J, Chipkin J, Jiang H, Bachelot A, Dulon J, Sala C, Barbieri C, Cocca M, Toniolo D, Touraine P, Witchel S, Rajkovic A (February 2017). "MCM8 and MCM9 Nucleotide Variants in Women With Primary Ovarian Insufficiency". J. Clin. Endocrinol. Metab. 102 (2): 576–582. doi:10.1210/jc.2016-2565. PMC 5413161. PMID 27802094. * v * t * e Metabolic disease: DNA replication and DNA repair-deficiency disorder DNA replication * Separation/initiation: RNASEH2A * Aicardi–Goutières syndrome 4 * Termination/telomerase: DKC1 * Dyskeratosis congenita DNA repair Nucleotide excision repair * Cockayne syndrome/DeSanctis–Cacchione syndrome * Thymine dimer * Xeroderma pigmentosum * IBIDS syndrome MSI/DNA mismatch repair * Hereditary nonpolyposis colorectal cancer * Muir–Torre syndrome * Mismatch repair cancer syndrome MRN complex * Ataxia telangiectasia * Nijmegen breakage syndrome Other * RecQ helicase * Bloom syndrome * Werner syndrome * Rothmund–Thomson syndrome/Rapadilino syndrome * Fanconi anemia * Li-Fraumeni syndrome * Severe combined immunodeficiency [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: 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 instability syndrome	c1563697	3,406	wikipedia	https://en.wikipedia.org/wiki/Chromosome_instability_syndrome	2021-01-18T18:58:06	{"mesh": ["D049914"], "wikidata": ["Q1087749"]}
See also: Neonatal cephalic pustulosis Benign cephalic histiocytosis Other namesHistiocytosis with intracytoplasmic worm-like bodies[1] SpecialtyHematology Benign cephalic histiocytosis not to be confused with "Neonatal cephalic pustulosis" is a rare skin condition affecting boys and girls equally, characterized by skin lesions[vague] that initially present on the head in all cases, often the cheeks, eyelids, forehead, and ears.[2]:717 ## See also[edit] * Childhood granulomatous periorificial dermatitis * Non-X histiocytosis * List of cutaneous conditions ## References[edit] 1. ^ Rapini, Ronald P.; Bolognia, Jean L.; Jorizzo, Joseph L. (2007). Dermatology: 2-Volume Set. St. Louis: Mosby. ISBN 978-1-4160-2999-1. 2. ^ James, William D.; Berger, Timothy G.; et al. (2006). Andrews' Diseases of the Skin: clinical Dermatology. Saunders Elsevier. ISBN 978-0-7216-2921-6. ## External links[edit] Classification D * ICD-10: D76.3 (ILDS D76.320) External resources * Orphanet: 157997 * v * t * e Histiocytosis WHO-I/Langerhans cell histiocytosis/ X-type histiocytosis * Letterer–Siwe disease * Hand–Schüller–Christian disease * Eosinophilic granuloma * Congenital self-healing reticulohistiocytosis WHO-II/non-Langerhans cell histiocytosis/ Non-X histiocytosis * Juvenile xanthogranuloma * Hemophagocytic lymphohistiocytosis * Erdheim-Chester disease * Niemann–Pick disease * Sea-blue histiocyte * Benign cephalic histiocytosis * Generalized eruptive histiocytoma * Xanthoma disseminatum * Progressive nodular histiocytosis * Papular xanthoma * Hereditary progressive mucinous histiocytosis * Reticulohistiocytosis (Multicentric reticulohistiocytosis, Reticulohistiocytoma) * Indeterminate cell histiocytosis WHO-III/malignant histiocytosis * Histiocytic sarcoma * Langerhans cell sarcoma * Interdigitating dendritic cell sarcoma * Follicular dendritic cell sarcoma Ungrouped * Rosai–Dorfman disease This cutaneous condition article is a stub. You can help Wikipedia by expanding it. * v * t * e [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [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	Benign cephalic histiocytosis	c0347403	3,407	wikipedia	https://en.wikipedia.org/wiki/Benign_cephalic_histiocytosis	2021-01-18T18:39:45	{"umls": ["C0347403"], "icd-10": ["D76.3"], "orphanet": ["157997"], "wikidata": ["Q3136516"]}
Neuroendocrine cell hyperplasia of infancy (NCHI) is a non-lethal pediatric form of interstitial lung disease (ILD, see this term) characterized by tachypnea without respiratory failure. ## Epidemiology Prevalence of this disease is not known. It appears to affect young infants (mean age 3.8 months found in a large series) but cases have been reported in older children. ## Clinical description Clinical presentation is typically persistent tachypnea. ## Etiology High-resolution computed tomography (HRCT) shows patchy central ground-glass opacifications and air trapping. Lung biopsy shows hyperplasia of neuroendocrine cells within bronchioles documented by bombesin immunohistochemistry. ## Management and treatment Follow-up reveals in some cases the persistence of tachypnea and oxygen requirement for several months. ## Prognosis The prognosis is usually good. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: 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	Neuroendocrine cell hyperplasia of infancy	c3161105	3,408	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=217560	2021-01-23T18:23:44	{"umls": ["C3161105"], "synonyms": ["NCHI", "NEHI"]}
Agenesis of the dorsal pancreas describes a congenital malformation of the pancreas in which either the entire dorsal pancreas or part of the dorsal pancreas fails to develop (complete agenesis or partial agenesis, respectively). Some individuals experience no symptoms, while others may develop hyperglycemia, diabetes mellitus, bile duct obstruction, abdominal pain, pancreatitis, or other conditions. Hyperglycemia has been shown to be present in approximately 50% of affected individuals. The cause of agenesis of the dorsal pancreas is currently not well understood. It may occur in individuals with no history of the condition in the family (sporadically) and in some cases, autosomal dominant or X-linked dominant inheritance has been suggested. It has also been reported to occur with very rare conditions including polysplenia and polysplenia/heterotaxy 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	Agenesis of the dorsal pancreas	c1868659	3,409	gard	https://rarediseases.info.nih.gov/diseases/4203/agenesis-of-the-dorsal-pancreas	2021-01-18T18:02:14	{"mesh": ["C538109"], "omim": ["167755"], "umls": ["C1868659"], "orphanet": ["2805"], "synonyms": ["Pancreas, dorsal, agenesis of", "Pancreas agenesis, dorsal", "Complete agenesis of the dorsal pancreas", "Partial agenesis of the dorsal pancreas", "Congenital short pancreas", "Congenital pancreatic agenesis", "Partial pancreatic agenesis"]}
Ornithine translocase deficiency is an inherited disorder that causes ammonia and other substances to build up (accumulate) in the blood. Ammonia, which is formed when proteins are broken down in the body, is toxic if the levels become too high. The nervous system is especially sensitive to the effects of excess ammonia. Ornithine translocase deficiency varies widely in its severity and age of onset. Affected infants show signs and symptoms of ornithine translocase deficiency within days after birth. In most affected individuals, however, signs and symptoms of ornithine translocase deficiency do not appear until later in life, with health problems first appearing anytime from childhood to adulthood. Later-onset forms of ornithine translocase deficiency are usually less severe than the infantile form. Infants with ornithine translocase deficiency may lack energy (be lethargic), refuse to eat, vomit frequently, or have poorly controlled breathing or body temperature. Seizures or unusual body movements are common in these individuals. Some people with this condition have intellectual disability or developmental delay, but others have normal intelligence. Severe cases may result in coma. Some people with later-onset ornithine translocase deficiency have episodes of vomiting, lethargy, problems with coordination (ataxia), vision problems, episodes of brain dysfunction (encephalopathy), developmental delay, learning disabilities, or stiffness caused by abnormal tensing of the muscles (spasticity). Affected individuals may have chronic liver problems and mild abnormal bleeding. Individuals with ornithine translocase deficiency often cannot tolerate high-protein foods, such as meat. Occasionally, high-protein meals or stress caused by illness or periods without food (fasting) may cause ammonia to accumulate more quickly in the blood. This rapid increase of ammonia likely leads to the signs and symptoms of ornithine translocase deficiency. While the signs and symptoms of ornithine translocase deficiency can vary greatly among affected individuals, proper treatment can prevent some complications from occurring and may improve quality of life. ## Frequency Ornithine translocase deficiency is a very rare disorder. More than 100 affected individuals have been described in the scientific literature. ## Causes Mutations in the SLC25A15 gene cause ornithine translocase deficiency. The SLC25A15 gene provides instructions for making a protein called mitochondrial ornithine transporter 1. This protein participates in the urea cycle, which is a sequence of biochemical reactions that occurs in liver cells. The urea cycle breaks down excess nitrogen, made when protein is broken down by the body, to make a compound called urea that is excreted by the kidneys in urine. Mitochondrial ornithine transporter 1 is located within the mitochondria (the energy-producing centers in cells), where the protein transports a molecule called ornithine so it can participate in the urea cycle. Mutations in the SLC25A15 gene cause the production of a mitochondrial ornithine transporter 1 with reduced or absent function. As a result, ornithine transport is impaired and the urea cycle cannot proceed normally. This causes, nitrogen to accumulate in the bloodstream in the form of toxic ammonia instead of being converted to less toxic urea and being excreted. Ammonia is especially damaging to the brain, and excess ammonia causes neurological problems and other signs and symptoms of ornithine translocase deficiency. Byproducts of impaired ornithine transport in people with this condition include the accumulation of a substance called ornithine in the blood (hyperornithinemia) and the excretion of a substance called homocitrulline in the urine (homocitrullinuria). Another version of the mitochondrial ornithine transporter protein is produced by a different gene. While this protein is not as abundant as mitochondrial ornithine transporter 1, it is thought that this other version of the protein may partially compensate for the loss of mitochondrial ornithine transporter 1 and contribute to the late age of onset and mild signs and symptoms in some affected individuals. Other factors, many unknown, also contribute to the variable severity of ornithine translocase deficiency. Because ornithine translocase deficiency is caused by problems with the urea cycle, it belongs to a class of genetic diseases called urea cycle disorders. ### Learn more about the gene associated with Ornithine translocase deficiency * SLC25A15 ## 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	Ornithine translocase deficiency	c0268540	3,410	medlineplus	https://medlineplus.gov/genetics/condition/ornithine-translocase-deficiency/	2021-01-27T08:24:52	{"gard": ["2830"], "mesh": ["C538380"], "omim": ["238970"], "synonyms": []}
Juvenile polyposis syndrome is a disorder characterized by multiple noncancerous (benign) growths called juvenile polyps. People with juvenile polyposis syndrome typically develop polyps before age 20; however, in the name of this condition "juvenile" refers to the characteristics of the tissues that make up the polyp, not the age of the affected individual. These growths occur in the gastrointestinal tract, typically in the large intestine (colon). The number of polyps varies from only a few to hundreds, even among affected members of the same family. Polyps may cause gastrointestinal bleeding, a shortage of red blood cells (anemia), abdominal pain, and diarrhea. Approximately 15 percent of people with juvenile polyposis syndrome have other abnormalities, such as a twisting of the intestines (intestinal malrotation), heart or brain abnormalities, an opening in the roof of the mouth (cleft palate), extra fingers or toes (polydactyly), and abnormalities of the genitalia or urinary tract. Juvenile polyposis syndrome is diagnosed when a person has any one of the following: (1) more than five juvenile polyps of the colon or rectum; (2) juvenile polyps in other parts of the gastrointestinal tract; or (3) any number of juvenile polyps and one or more affected family members. Single juvenile polyps are relatively common in children and are not characteristic of juvenile polyposis syndrome. Three types of juvenile polyposis syndrome have been described, based on the signs and symptoms of the disorder. Juvenile polyposis of infancy is characterized by polyps that occur throughout the gastrointestinal tract during infancy. Juvenile polyposis of infancy is the most severe form of the disorder and is associated with the poorest outcome. Children with this type may develop a condition called protein-losing enteropathy. This condition results in severe diarrhea, failure to gain weight and grow at the expected rate (failure to thrive), and general wasting and weight loss (cachexia). Another type called generalized juvenile polyposis is diagnosed when polyps develop throughout the gastrointestinal tract. In the third type, known as juvenile polyposis coli, affected individuals develop polyps only in their colon. People with generalized juvenile polyposis and juvenile polyposis coli typically develop polyps during childhood. Most juvenile polyps are benign, but there is a chance that polyps can become cancerous (malignant). It is estimated that people with juvenile polyposis syndrome have a 10 to 50 percent risk of developing a cancer of the gastrointestinal tract. The most common type of cancer seen in people with juvenile polyposis syndrome is colorectal cancer. ## Frequency Juvenile polyposis syndrome occurs in approximately 1 in 100,000 individuals worldwide. ## Causes Mutations in the BMPR1A and SMAD4 genes cause juvenile polyposis syndrome. These genes provide instructions for making proteins that are involved in transmitting chemical signals from the cell membrane to the nucleus. This type of signaling pathway allows the environment outside the cell to affect how the cell produces other proteins. The BMPR1A and SMAD4 proteins work together to help regulate the activity of particular genes and the growth and division (proliferation) of cells. Mutations in the BMPR1A gene or the SMAD4 gene disrupt cell signaling and interfere with their roles in regulating gene activity and cell proliferation. This lack of regulation causes cells to grow and divide in an uncontrolled way, which can lead to polyp formation. ### Learn more about the genes associated with Juvenile polyposis syndrome * BMPR1A * SMAD4 ## Inheritance Pattern Juvenile polyposis syndrome is inherited in an autosomal dominant pattern, which means one copy of the altered gene in each cell is sufficient to cause the disorder. In approximately 75 percent of cases, an affected person inherits the mutation from one affected parent. The remaining 25 percent of cases result from new mutations in the gene and occur in people with no history of the disorder in their family. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [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	Juvenile polyposis syndrome	c0345893	3,411	medlineplus	https://medlineplus.gov/genetics/condition/juvenile-polyposis-syndrome/	2021-01-27T08:25:28	{"gard": ["3065"], "mesh": ["C537702"], "omim": ["174900"], "synonyms": []}
A rare genetic disorder of pyrimidine metabolism characterized by early onset of megaloblastic anemia, global developmental delay, and failure to thrive, associated with massive urinary overexcretion of orotic acid (sometimes with orotic acid crystalluria). Patients without megaloblastic anemia, but with additional manifestations such as epilepsy, have also been reported. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [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 orotic aciduria	c0220987	3,412	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=30	2021-01-23T17:56:57	{"gard": ["5429"], "mesh": ["C537136"], "omim": ["258900"], "umls": ["C0220987", "C0268130"], "icd-10": ["E79.8"], "synonyms": ["Orotidylic decarboxylase deficiency", "Uridine monophosphate synthetase deficiency"]}
Familial juvenile hyperuricemic nephropathy type 2 is a rare autosomal dominantly inherited disease of childhood characterized by hypoproliferative anemia, hyperuricemia and slowly progressing kidney failure due to dysregulation of the renin-angiotensin system (RAS). [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: 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	REN-related autosomal dominant tubulointerstitial kidney disease	c2751310	3,413	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=217330	2021-01-23T18:48:50	{"mesh": ["C567760"], "omim": ["613092"], "umls": ["C2751310"], "synonyms": ["ADTKD-REN", "FJHN type 2", "Familial juvenile hyperuricemic nephropathy type 2", "REN-associated FJHN", "REN-associated familial juvenile hyperuricemic nephropathy", "REN-associated kidney disease"]}
Waldenstrom macroglobulinemia is a chronic, slow-growing lymphoproliferative disorder. It usually affects older adults and is primarily found in the bone marrow, although lymph nodes and the spleen may be involved. Affected individuals have a high level of an antibody called immunoglobulin M (IgM) in their blood, which can cause thickening of the blood (hyperviscosity). Although some individuals initially do not have symptoms and are diagnosed from routine blood work, common symptoms may include weakness, appetite loss and weight loss. Other symptoms may include peripheral neuropathy, fever, Raynaud's phenomenon, and mental status changes. Hyperviscosity of the blood may cause nosebleeds, headaches, dizziness, and blurring or loss of vision. The cause of the condition is not known but environmental, genetic, and viral factors have been suggested. There have been some reports of familial cases suggesting a genetic predisposition. Treatment is often reserved for those with symptoms and may include various medications including corticosteroids, alkylating agents, biologic response modifiers and purine analogues. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: 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	Waldenstrom macroglobulinemia	c1835192	3,414	gard	https://rarediseases.info.nih.gov/diseases/7872/waldenstrom-macroglobulinemia	2021-01-18T17:57:08	{"omim": ["153600"], "synonyms": ["Waldenstrom's macroglobulinaemia", "Lymphoplasmacytic lymphoma", "Waldenstrom's syndrome", "Macroglobulinemia of Waldenstrom"]}
Pulmonary capillary hemangiomatosis Pulmonary capillary hemangiomatosis is inherited in an autosomal recessive manner. SpecialtyPulmonology Pulmonary capillary hemangiomatosis (PCH) is a disease affecting the blood vessels of the lungs, where abnormal capillary proliferation and venous fibrous intimal thickening result in progressive increase in vascular resistance.[1] It is a rare cause of pulmonary hypertension, and occurs predominantly in young adults.[2][3] Together with pulmonary veno-occlusive disease, PCH comprises WHO Group I' causes for pulmonary hypertension. Indeed, there is some evidence to suggest that PCH and pulmonary veno-occlusive disease are different forms of a similar disease process.[4] ## Contents * 1 Presentation * 2 Genetics * 3 Diagnosis * 3.1 Investigations * 3.2 Differential diagnosis * 3.3 Associations * 4 Treatment * 5 Epidemiology * 6 History * 7 Animals * 8 References * 9 External links ## Presentation[edit] These are non specific. Typical symptoms include dyspnea, cough, chest pain and fatigue.[5] ## Genetics[edit] At least some cases appear to be due to mutations in the eukaryotic translation initiation factor 2-alpha kinase 4 (EIF2AK4) gene.[6] ## Diagnosis[edit] Lung biopsy is essential to make this diagnosis. This can be difficult if the pulmonary pressure is high.[citation needed] ### Investigations[edit] Chest X ray may show enlargement of the heart and ill-defined patchy lesions in the lung fields. CT chest typically shows wide spread ill-defined centrilobular nodules of ground glass opacity. This is a nonspecific finding and may be seen in a number of pulmonary diseases. CT pulmonary angiography usually shows enlargement of the main pulmonary artery. When measured by echocardiography or pulmonary angiography, the pulmonary arterial pressure is typically elevated. ### Differential diagnosis[edit] * Pulmonary veno-occlusive disease ### Associations[edit] This condition has been reported in patients with Ehlers Danlos syndrome,[7] CREST syndrome[8] and scimitar syndrome.[9] ## Treatment[edit] The only definitive treatment for this condition currently is lung transplantation. Median survival without treatment is 3 years.[10] Imatinib may be of use.[11] Epoprostenol does not appear to be of use.[12] ## Epidemiology[edit] The prevalence of this disease is estimated to be < 1/million.[13]The usual age at presentation is between 20 and 40 but it has been reported in the newborn.[14] ## History[edit] This condition was first described in 1978.[15] ## Animals[edit] This condition has been reported in cats.[16] and dogs.[17] ## References[edit] 1. ^ Ortiz-Bautista C, Hernández-González I, EscribanoSubías P. Enfermedad venooclusiva pulmonar y hemangiomatosis capilar pulmonar. Med Clin (Barc). 2017;148:265–270. 2. ^ Masur Y, Remberger K, Hoefer M (1996). "Pulmonary capillary hemangiomatosis as a rare cause of pulmonary hypertension". Pathol Res Pract. 192 (3): 290–5, discussion 296–9. doi:10.1016/S0344-0338(96)80232-9. PMID 8739476. 3. ^ El-Gabaly M, Farver CF, Budev MA, Mohammed TL (2007). "Pulmonary capillary hemangiomatosis imaging findings and literature update". J Comput Assist Tomogr. 31 (4): 608–10. doi:10.1097/01.rct.0000284393.76073.87. PMID 17882042. S2CID 35199069. 4. ^ Lantu??joul, Sylvie; Sheppard, Mary N.; Corrin, Bryan; Burke, Margaret M.; Nicholson, Andrew G. (2006). "Pulmonary Veno-occlusive Disease and Pulmonary Capillary Hemangiomatosis". The American Journal of Surgical Pathology. 30 (7): 850–857. doi:10.1097/01.pas.0000209834.69972.e5. PMID 16819327. S2CID 25595167. 5. ^ Chaisson NF, Dodson MW, Elliott CG (2016) Pulmonary Capillary Hemangiomatosis and Pulmonary Veno-occlusive Disease. Clin Chest Med 37(3):523-534 6. ^ Best DH, Sumner KL, Smith BP, Damjanovich-Colmenares K, Nakayama I, Brown LM, Ha Y, Paul E, Morris A, Jama MA, Dodson MW, Bayrak-Toydemir P, Elliott CG (2017) EIF2AK4 Mutations in patients diagnosed With pulmonary arterial hypertension. Chest 151(4):821-828 7. ^ Park MA, Shin SY, Kim YJ, Park MJ, Lee SH (2017) Vascular Ehlers-Danlos syndrome with cryptorchidism, recurrent pneumothorax, and pulmonary capillary hemangiomatosis-like foci: A case report.Medicine (Baltimore) 96(47):e8853 8. ^ Diao XL, Mu XD, Jin ML (2017) Pulmonary capillary hemangiomatosis associated with CREST syndrome: A challenge of diagnosis and treatment. Chin Med J (Engl) 130(21):2645-2646 9. ^ Güttinger E, Vrugt B, Speich R, Ulrich S, Schwitz F, Arrigo M, Huber LC (2016) Reactive pulmonary capillary hemangiomatosis and pulmonary veno-acclusive disease in a patient with repaired scimitar syndrome. Case Rep Cardiol 2016:9384126 10. ^ Ma L, Bao R (2015) Pulmonary capillary hemangiomatosis: a focus on the EIF2AK4 mutation in onset and pathogenesis. Appl Clin Genet 8:181-8 11. ^ Ogawa A, Miyaji K, Matsubara H (2017) Efficacy and safety of long-term imatinib therapy for patients with pulmonary veno-occlusive disease and pulmonary capillary hemangiomatosis. Respir Med 131:215-219 12. ^ Akagi S, Nakamura K, Matsubara H, Ogawa A, Sarashina T, Ejiri K, Ito H (2015) Epoprostenol therapy for pulmonary arterial hypertension. Acta Med Okayama 69(3):129-136 13. ^ Szturmowicz M, Kacprzak A, Szołkowska M, Burakowska B, Szczepulska E, Kuś J (2018) Pulmonary veno-occlusive disease: pathogenesis, risk factors, clinical features and diagnostic algorithm - state of the art. Adv Respir Med 86(3) 14. ^ Sposito Cavallo SL, Macias Sobrino LA, Marenco Altamar LJ, Mejía Alquichire AF (2017) Congenital pulmonary capillary hemangiomatosis in a newborn. Arch Argent Pediatr 115(1):e17-e20 15. ^ Wagenvoort CA, Beetstra A, Spijker J (1978) Capillary haemangiomatosis of the lungs. Histopathology 2:401–6 16. ^ Jenkins TL, Jennings RN (2017) Pulmonary capillary hemangiomatosis and hypertrophic cardiomyopathy in a Persian cat. J Vet Diagn Invest 29(6):900-903 17. ^ Reinero CR, Jutkowitz LA, Nelson N, Masseau I, Jennings S, Williams K (2018) Clinical features of canine pulmonary veno-occlusive disease and pulmonary capillary hemangiomatosis. J Vet Intern Med ## External links[edit] Classification D * ICD-10: D18.0 * OMIM: 234810 * MeSH: C535861 External resources * Orphanet: 199241 [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: 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	Pulmonary capillary hemangiomatosis	c0340548	3,415	wikipedia	https://en.wikipedia.org/wiki/Pulmonary_capillary_hemangiomatosis	2021-01-18T18:45:56	{"gard": ["8527"], "mesh": ["C535861"], "umls": ["C0340548"], "orphanet": ["199241"], "wikidata": ["Q7259524"]}
This article includes a list of general references, but it remains largely unverified because it lacks sufficient corresponding inline citations. Please help to improve this article by introducing more precise citations. (May 2014) (Learn how and when to remove this template message) Sulfuric acid poisoning SpecialtyToxicology Sulfuric acid poisoning refers to ingestion of sulfuric acid, found in lead-acid batteries and some metal cleaners, pool cleaners, drain cleaners and anti-rust products. ## Contents * 1 Signs and symptoms * 2 Treatment * 3 Society and culture * 4 References * 5 External links ## Signs and symptoms[edit] * Brown to black streak from angle of mouth * Brown to black vomitus * Brown to black stomach wall * Black swollen tongue * White (chalky white) teeth * Blotting paper appearance of stomach mucosa * Ulceration of esophagus (fibrosis and stricture) * Perforation of stomach. * The stomach resembles a black spongy mass on post mortem ## Treatment[edit] For superficial injuries, washing (therapeutic irrigation) is important. Emergency treatments include protecting the airway, which might involve a tracheostomy. Further treatment will vary depending on the severity, but might include investigations to determine the extent of damage (bronchoscopy for the airways and endoscopy for the gastrointestinal tract), followed by treatments including surgery (to debride and repair) and intravenous fluids.[1] Gastric lavage is contraindicated in corrosive acid poisoning like sulfuric acid poisoning. Bicarbonate is also contraindicated as it liberates carbon dioxide which can cause gastric dilatation leading to rupture of stomach. ## Society and culture[edit] Vitriolage is the act of throwing sulfuric acid or other corrosive acids on somebody's face. ## References[edit] 1. ^ Heller, J.L. "Sulfuric acid poisoning". Medline Plus. U.S National Library of Medicine. Retrieved 26 January 2016. ## External links[edit] Classification D External resources * MedlinePlus: 002492 * Sulphuric acid: Toxicological overview * Sulfuric acid poisoning on Penn Medicine * Sulfuric acid poisoning on Medline Plus * 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	Sulfuric acid poisoning	None	3,416	wikipedia	https://en.wikipedia.org/wiki/Sulfuric_acid_poisoning	2021-01-18T18:59:09	{"wikidata": ["Q18386197"]}
## Summary ### Clinical characteristics. STXBP1 encephalopathy with epilepsy is characterized by early-onset encephalopathy with epilepsy (i.e., moderate to severe intellectual disability, refractory seizures, and ongoing epileptiform activity). The median age of onset of seizures is six weeks (range 1 day to 13 years). Seizure types can include infantile spasms; generalized tonic-clonic, clonic, or tonic seizures; and myoclonic, focal, atonic, and absence seizures. Epilepsy syndromes can include Ohtahara syndrome, West syndrome, Lennox-Gaustaut syndrome, and Dravet syndrome (not SCN1A-related), classic Rett syndrome (not MECP2-related), and atypical Rett syndrome (not CDKL5-related). The EEG is characterized by focal epileptic activity, burst suppression, hypsarrhythmia, or generalized spike-and-slow waves. Other findings can include abnormal tone, movement disorders (especially ataxia and dystonia), and behavior disorders (including autism spectrum disorder). Feeding difficulties are common. ### Diagnosis/testing. The diagnosis is established in a proband by identification of a heterozygous intragenic pathogenic variant in STXBP1 or a contiguous gene deletion that includes STXBP1 and adjacent genes on molecular genetic testing. ### Management. Treatment of manifestations: Developmental delay, cognitive dysfunction, and intellectual disability are managed in the usual manner. The most commonly used antiepileptic drugs (AEDs) are phenobarbital, valproic acid, and vigabatrin; an estimated 20% of individuals require more than one AED and approximately 25% are refractory to AED therapy. Severe dystonia, dyskinesia, and choreoathetosis can be treated with monoamine depleters or dopaminergic agents. Behavior disorders and feeding difficulties are managed symptomatically in the usual manner. Surveillance: Neuropsychological assessment and EEG are performed as needed. ### Genetic counseling. STXBP1 encephalopathy with epilepsy is inherited in an autosomal dominant manner. To date, most probands represent simplex cases (i.e., a single occurrence in a family) and have the disorder as a result of a de novo STXBP1 pathogenic variant. Individuals with STXBP1 encephalopathy with epilepsy are not known to reproduce. Once the STXBP1 pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing are possible. ## Diagnosis No formal diagnostic criteria for STXBP1 encephalopathy with epilepsy have been published. ### Suggestive Findings STXBP1 encephalopathy with epilepsy should be considered in individuals with early-onset encephalopathy with epilepsy (i.e., developmental delay, cognitive dysfunction, or intellectual disability associated with refractory seizures, and ongoing epileptiform activity), particularly those with the following epilepsy features, seizure types, and/or epilepsy syndromes. Epilepsy features * Median age of onset six weeks (range 1 day to 13 years) * EEG characterized by focal epileptic activity, burst suppression, hypsarrhythmia, or generalized spike-and-slow waves Seizure types * Infantile spasms * Generalized tonic-clonic, clonic, or tonic seizures * Myoclonic seizures * Atonic seizures * Absence seizures * Focal seizures Epilepsy syndromes * Ohtahara syndrome * West syndrome * Early myoclonic epileptic encephalopathy * Lennox-Gaustaut syndrome * Dravet syndrome not caused by mutation of SCN1A * Rett syndrome phenotype not caused by mutation of MECP2 or CDKL5 Other features * Moderate to profound intellectual disability * Behavior disorders, including autism spectrum disorder * Abnormal tone: spasticity, hypotonia * Movement disorders including ataxia, dystonia, dyskinesia, tremor, or choreoathetosis ### Establishing the Diagnosis The diagnosis of STXBP1 encephalopathy with epilepsy is established in a proband with suggestive findings and identification by molecular genetic testing of a heterozygous intragenic pathogenic variant in STXBP1 or a contiguous gene deletion that includes STXBP1 and adjacent genes (see Table 1). Molecular genetic testing approaches can include a combination of gene-targeted testing (multigene panel or single-gene testing) or genomic testing (chromosomal microarray analysis [CMA] or comprehensive genomic sequencing). Gene-targeted testing requires the clinician to determine which gene(s) are likely involved, whereas genomic testing may not. Because the phenotypes of many genetic epileptic encephalopathies overlap, most children with STXBP1 encephalopathy with epilepsy are diagnosed by the following recommended testing (a multigene panel or CMA) or testing to be considered (comprehensive genomic sequencing). #### Recommended Testing A multigene panel that includes STXBP1 and other genes of interest (see Differential Diagnosis) should be considered. For STXBP1 encephalopathy, a panel that includes gene-targeted deletion/duplication analysis is recommended to detect the 5% of STXBP1 pathogenic variants due to intragenic deletions. 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. If STXBP1 encephalopathy is suspected, testing that includes sequencing as well as gene-targeted deletion/duplication analysis is recommended to detect the 5% of STXBP1 variants that are due to intragenic deletions or duplications. For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here. Chromosomal microarray analysis (CMA). A contiguous gene deletion (≤4 MB) that encompasses STXBP1 along with as many as 92 contiguous genes has been reported in 20 affected individuals [Saitsu et al 2008, Mignot et al 2011, Campbell et al 2012, Saitsu et al 2012, Mastrangelo et al 2013, Barcia et al 2014, Matsumoto et al 2014, Di Meglio et al 2015, Ehret et al 2015, Nicita et al 2015, Nambot et al 2016, Stamberger et al 2016]. #### Testing to Consider Comprehensive genomic testing (when available) including exome sequencing and genome sequencing may be considered if the phenotype is indistinguishable from other inherited disorders (or the phenotype alone is insufficient to support gene-targeted testing). For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here. Note: Single-gene testing (sequence analysis of STXBP1, followed by gene-targeted deletion/duplication analysis) is rarely useful and typically NOT recommended. Because the phenotype of STXBP1 encephalopathy with epilepsy overlaps with that of other genetic epileptic encephalopathies, the recommended testing and testing to consider are typically used in lieu of single-gene testing. ### Table 1. Molecular Genetic Testing Used in STXBP1 Encephalopathy with Epilepsy View in own window Gene 1MethodProportion of Probands with a Pathogenic Variant 2 Detectable by Method STXBP1Sequence analysis 383% Gene-targeted deletion/duplication analysis 45% CMA 512% 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. Cases involving large deletions encompassing STXBP1 as well as other genes were excluded. 4\. Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and gene-targeted array CGH (a gene-targeted microarray designed to detect single-exon deletions or duplications). 5\. Deletion/duplication analysis (genomic approach) detects deletion of STXBP1 and other contiguous genes using a chromosomal microarray (CMA) that specifically includes this gene/chromosome segment. ## Clinical Characteristics ### Clinical Description Since the original description of STXBP1 encephalopathy with epilepsy in five individuals with Ohtahara syndrome [Saitsu et al 2008], approximately 200 affected individuals have been reported [Vatta et al 2012, Allen et al 2013, Tucker et al 2014, Ehret et al 2015, Kwong et al 2015, Dilena et al 2016, Guacci et al 2016, Helbig 2016, Marchese et al 2016]; see also Di Meglio et al [2015], Allen et al [2016], Nambot et al [2016], Yamamoto et al [2016], Lopes et al [2016] and references therein. All affected individuals have developmental delay, cognitive dysfunction, or intellectual disability. The majority of affected individuals have presented with seizures. Developmental delay, cognitive dysfunction, or intellectual disability, present in all individuals with STXBP1 encephalopathy with epilepsy, range from moderate to severe in more than 90% of individuals. Seizures are the second most common clinical feature in STXBP1 encephalopathy with epilepsy. Although the majority of affected individuals presented with seizures, ten (6%) had no history of seizures [Hamdan et al 2011, Rauch et al 2012, Gburek-Augustat et al 2016, Stamberger et al 2016]. Onset of seizures ranges from ages six hours to 13 years [Milh et al 2011, Di Meglio et al 2015]. About half of affected children had seizures in the neonatal period. Approximately 40% had seizures between ages one month and 12 months. In fewer than 10% of affected individuals, seizure onset was after age one year. Seizure types include infantile spasms and generalized tonic-clonic, generalized clonic, generalized tonic, myoclonic, atonic, and absence seizures. More than 60% of affected individuals had more than one seizure type during their lifetime. Focal seizures were reported in about 10% of affected individuals. Epilepsy syndromes * Ohtahara syndrome (OMIM 308350) is characterized by frequent generalized tonic refractory seizures and burst suppression patterns on EEG. Age of onset is neonatal or early infantile. Approximately 20% of individuals with a STXBP1 pathogenic variant were reported to have the clinical phenotype of Ohtahara syndrome, either as single case reports or small cohorts of epileptic encephalopathy [Otsuka et al 2010, Saitsu et al 2012, Kodera et al 2013, Weckhuysen et al 2013, Tso et al 2014, Di Meglio et al 2015, Allen et al 2016, Stamberger et al 2016]. * West syndrome (OMIM 308350) is characterized by tonic spasms with clustering, arrest of psychomotor development, and hypsarrhythmia on EEG. Five of 192 individuals with infantile spasms had STXBP1 encephalopathy with epilepsy [Otsuka et al 2010, Allen et al 2013]. 13 individuals with a STXBP1 pathogenic variant were reported with clinical phenotype of infantile spasms, either as single case reports or small cohorts of epileptic encephalopathy [Saitsu et al 2008, Deprez et al 2010, Saitsu et al 2010, Weckhuysen et al 2013, Di Meglio et al 2015, Romaniello et al 2015, Lopes et al 2016]. * Early myoclonic epileptic encephalopathy, characterized by myoclonic seizures and burst suppression pattern in sleep on EEG, was identified in two individuals with STXBP1 encephalopathy with epilepsy [Saitsu et al 2012, Kodera et al 2013]. * Dravet syndrome (OMIM 607208) is characterized by fever-induced refractory seizures with age of onset usually within the first year of life. EEG patterns typically show generalized spike-wave activity as seizures progress. Three of 80 individuals with Dravet syndrome were identified with STXBP1 encephalopathy with epilepsy [Carvill et al 2014]. * Lennox-Gaustaut syndrome is characterized by multiple seizure types particularly tonic and myoclonic refractory epilepsy. EEG shows slow background and spike-wave bursts at frequencies less than 2.5 per second. One of 115 individuals with Lennox-Gaustaut syndrome was identified with STXBP1 encephalopathy with epilepsy [Allen et al 2013]. * Rett syndrome phenotype. Three individuals with the Rett syndrome phenotype have been identified with STXBP1 encephalopathy with epilepsy [Olson et al 2015, Romaniello et al 2015, Lopes et al 2016]. Electroencephalography (EEG) abnormalities were reported in the majority of affected individuals. The two most common EEG abnormalities were burst suppression pattern (42 affected individuals) and hypsarrhythmia (37 affected individuals) [Saitsu et al 2012, Allen et al 2013, Kim et al 2013, Di Meglio et al 2015, Sampaio et al 2015, Allen et al 2016, Guacci et al 2016]; see also Yamamoto et al [2016] and references therein. Other EEG abnormalities included focal and multifocal discharges, spike-and-slow wave activity, poly-spike waves, theta and delta waves, paroxysmal activity, and low-amplitude fast rhythms. Background activity was frequently described as slow or poorly organized. Brain magnetic resonance imaging (MRI) was reported in more than 75% of affected individuals. In about half of these individuals, brain MRI showed various abnormalities including diffuse cerebral atrophy, delayed myelination, or thinning of the corpus callosum. Hypotonia or absence of head control was reported in fewer than 50% of affected individuals. Movement disorders were observed in fewer than 50 affected individuals. Ataxia, the most common movement disorder, was either isolated or in combination with other movement disorders including dyskinesia, dystonia, tremor, or choreoathetosis [Campbell et al 2012, Rauch et al 2012, Keogh et al 2015, Mercimek-Mahmutoglu et al 2015, Olson et al 2015, Romaniello et al 2015]; see also Di Meglio et al [2015] and references therein. Dystonia, the second most common movement disorder, was present in fewer than ten individuals, sometimes occurring in combination with tremor, rigidity, or dyskinesia [Milh et al 2011, Rauch et al 2012, Barcia et al 2013, Di Meglio et al 2015, Keogh et al 2015, Kwong et al 2015, Sampaio et al 2015, Guacci et al 2016, Stamberger et al 2016]. Behavior disorders including autism spectrum disorder, autistic-like features, hyperactivity, or self-aggressive behavior were seen in fewer than 40 affected individuals. Autistic features were the most common behavior disorder [Campbell et al 2012, Allen et al 2013, Weckhuysen et al 2013, Boutry-Kryza et al 2015, Mercimek-Mahmutoglu et al 2015, Romaniello et al 2015, Allen et al 2016]; see also Lopes et al [2016] and references therein. Other features * Microcephaly was found in fewer than ten individuals [Kwong et al 2015, Allen et al 2016, Stamberger et al 2016]; see also Yamamoto et al [2016] and references therein. * Failure to thrive was reported in a small number of affected individuals [Milh et al 2011, Weckhuysen et al 2013, Kwong et al 2015, Nambot et al 2016]. * Strabismus was reported in two affected individuals [Boutry-Kryza et al 2015, Dilena et al 2016]. * Findings other than mild dysmorphic facial features in individuals with a contiguous gene deletion: * Absent thumbnails and hypoplastic second fingernails (1 individual) [Mignot et al 2011] * Cleft lip and palate, ventricular septal defect, overlapping fingers, small penis (1 individual) [Saitsu et al 2012] * Short and broad fingers and broad feet [Campbell et al 2012] * Dysplastic right kidney, ureterocele, umbilical hernia (1 individual) [Matsumoto et al 2014] * Cleft lip/palate, umbilical hernia, mild dysmorphic facial features, dilated renal pelvis, microcephaly (1 individual) [Nicita et al 2015] ### Genotype-Phenotype Correlations Carvill et al [2014] reviewed more than 50 individuals with STXBP1 encephalopathy with epilepsy and found no correlation between pathogenic variant (including splice, nonsense, and deletion/duplication) or missense variant and phenotype. Stamberger et al [2016] reviewed 147 individuals with STXBP1 encephalopathy with epilepsy and found no correlation between the type of pathogenic variant (missense or truncating) and cognitive abilities or response to antiepileptic drugs (AEDs). ### Penetrance Almost all individuals with pathogenic variants in STXBP1 had developmental delay, cognitive dysfunction, intellectual disability, and/or epilepsy. ### Prevalence Fewer than 200 individuals with an STXBP1 pathogenic variant have been reported, including isolated STXBP1 encephalopathy with epilepsy and contiguous gene deletion syndromes. Stamberger et al [2016] estimated the prevalence of STXBP1 encephalopathy with epilepsy at 1:91,862 individuals in the Danish population. ## Differential Diagnosis Phenotypic and EEG features associated with STXBP1 pathogenic variants are not sufficient to diagnose STXBP1 encephalopathy with epilepsy. All genes known to be associated with early-infantile epileptic encephalopathy (>30 have been identified; see OMIM Phenotypic Series) should be included in the differential diagnosis of STXBP1 encephalopathy with epilepsy. Treatable neurometabolic disorders causing early infantile-onset epileptic encephalopathy should be included in the differential diagnosis. These disorders include: * Pyridoxine-dependent epilepsy * Pyridoxamine 5'-phosphate oxidase deficiency (OMIM 610090) * Biotinidase deficiency * Glucose transporter 1 deficiency syndrome * Creatine deficiency syndromes * Holocarboxylase synthetase deficiency (OMIM 253270) * Serine biosynthesis disorders including: * Phosphoglycerate dehydrogenase deficiency (OMIM 601815) * Phosphoserine aminotransferase deficiency (OMIM 610992) * Phosphoserine phosphate deficiency (OMIM 614023) ## Management ### Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with STXBP1 encephalopathy with epilepsy, the following evaluations are recommended: * Neurologic evaluation * Epilepsy consultation (if not done at the time of initial assessment) * Consultation with a clinical geneticist and/or genetic counselor ### Treatment of Manifestations Developmental delay, cognitive dysfunction, and intellectual disability. Physiotherapy, occupational therapy, and speech-language therapy can be beneficial. Seizure management is symptomatic. The most commonly used AEDs were phenobarbital, valproic acid, and vigabatrin. Clobazam, zonisamide, lamotrigine, and oxcarbamazepine have also been used. In single cases, a response to vigabatrin, carbamazepine, phenobarbital, or valproic acid and levetiracetam has been reported [Hamdan et al 2009, Deprez et al 2010, Saitsu et al 2010, Mignot et al 2011, Weckhuysen et al 2013, Barcia et al 2014, Romaniello et al 2014, Keogh et al 2015, Romaniello et al 2015, Dilena et al 2016, Yamamoto et al 2016]. In more than 20% of affected individuals, two or more AEDs were used in combination. About 25% of affected individuals were refractory to AED therapy. In approximately 20% of affected individuals, seizures were controlled with one or more than one combined anti-seizure medication. In individuals who became seizure-free, AEDs were discontinued between one month and 5.5 years after treatment began [Deprez et al 2010, Romaniello et al 2015, Sampaio et al 2015]. The longest seizure-free period documented following discontinuation of AEDs was approximately 11 years [Deprez et al 2010]. In about 1% of affected individuals, the ketogenic diet was used for seizure management. Response to the ketogenic diet was either slight or none [Saitsu et al 2011, Weckhuysen et al 2013]. Epilepsy surgery was the treatment of choice in two affected individuals: one became seizure-free following corpus callosotomy [Otsuka et al 2010]; the other had a significant reduction in seizure frequency following resection of focal cortical dysplasia [Weckhuysen et al 2013]. Other neurologic findings * Severe dystonia, dyskinesia, or choreoathetosis can be treated with monoamine depleters or dopaminergic agents. * Hypotonia may lead to feeding difficulties and associated recurrent aspiration pneumonia, which may require G-tube placement. Behavior disorders can be managed symptomatically with behavioral therapies by psychologists or behavior therapists. ### Surveillance There are no published guidelines for surveillance of individuals diagnosed with STXBP1 encephalopathy with epilepsy. The following assessments and investigations can be performed as needed: * Neuropsychological assessment * EEG ### Evaluation of Relatives at Risk See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes. ### Therapies Under Investigation Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	STXBP1 Encephalopathy with Epilepsy	c2677326	3,417	gene_reviews	https://www.ncbi.nlm.nih.gov/books/NBK396561/	2021-01-18T20:58:19	{"mesh": ["C567404"], "synonyms": ["Early-Infantile Epileptic Encephalopathy 4 (EIEE4)", "STXBP1 Epileptic Encephalopathy"]}
A rare form of primordial dwarfism, often microcephalic, characterized by short stature, global developmental delay, variable intellectual disability and recognizable dysmorphic facial features (triangular face, prominent forehead, deeply set eyes, low-set ears, wide nose, malar hypoplasia, wide mouth, thick lips, and widely spaced teeth). ## Epidemiology To date, less than 30 affected individuals reported worldwide, about half of which belong to a few consanguineous families. ## Clinical description Alazami syndrome is a genetic developmental defect characterized by mild to severe short stature, head circumference below the 50th centile, microcephaly in half of the individuals, and global developmental delay with moderate to severe intellectual disability. Speech can be absent or delayed (mainly expressive rather than receptive language delay in milder cases). Short stature and reduced head circumference are progressive, but usually already apparent at birth; endocrinological testing is normal in the majority of examined patients, with only a slight reduction of IGF-1 in some. Most individuals have distinctive facial features: triangular face, prominent forehead, deeply set eyes (often with narrow palpebral fissures), low-set ears, wide nose, malar hypoplasia, wide mouth, thick lips, widely spaced teeth. Scoliosis and strabismus are reported in one third of affected individuals. Several patients display autistic and/or maladaptive behaviors, including stereotypies similar to hand-washing. All features show inter- and intrafamilial variability. Additional, variable features may also include congenital heart defects such as pulmonary artery stenosis or atrial septal defect, seizures, aplasia/hypoplasia of the corpus callosum or other brain MRI anomalies, and accelerated skeletal maturation. Features more rarely reported include cleft palate, brachydactyly, prominent interphalangeal joints, 2-3 toe syndactyly, metaphyseal dysplasia, hydronephrosis due ureteropelvic junction stenosis, and hypospadias. ## Etiology The syndrome is caused by biallelic loss-of-function variants in the LARP7>/i> gene (4q25), which encodes a protein involved in the regulation of RNA transcription and splicing. At least one variant retaining partial protein function has been described, but no specific genotype-phenotype correlation could be established. DIAGNOSTIC METHODS Diagnosis is based on clinical examination and can be confirmed by molecular testing through sequencing. Chromosomal microarrays may also be considered since large deletions encompassing LARP7 cannot be excluded, although none have been reported in affected individuals to date. ## Diagnostic methods Diagnosis is based on clinical examination and can be confirmed by molecular testing through sequencing. Chromosomal microarrays may also be considered since large deletions encompassing LARP7 cannot be excluded, although none have been reported in affected individuals to date. ## Differential diagnosis Differential diagnosis includes other syndromes characterized by intellectual disability and short stature. ## Antenatal diagnosis Prenatal diagnosis is available for at-risk pregnancies, if a pathogenic variant has been identified in a member of the affected family. ## Genetic counseling Alazami syndrome is an autosomal recessive disorder, with homozygous and compound heterozygous variants described. It is expected to have increased frequency in populations where consanguineous couples are frequent. Genetic counseling should be offered to at-risk couples (both carriers of a disease-causing variant) informing them that there is a 25% risk of having an affected child at each pregnancy. ## Management and treatment Management is multidisciplinary, based on the clinical manifestations, with lifelong follow-up. Most patients will require various degrees of assistance with day-to-day activities. Neuropsychiatric assistance, speech therapy and educational support may be effective. ## Prognosis Life expectancy is currently unknown. Affected individuals have been reported to live into early adulthood, and only a few of the known associated clinical features can pose a life-threatening risk. There is only one report indicating a possible increase in tumor susceptibility. The level of autonomy is dependent on the severity of intellectual disability and language delay. * European Reference Network [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [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	Alazami syndrome	c3554439	3,418	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=319671	2021-01-23T18:00:49	{"omim": ["615071"], "icd-10": ["Q87.1"], "synonyms": ["Microcephalic primordial dwarfism, Alazami type"]}
A number sign (#) is used with this entry because of evidence that axial spondylometaphyseal dysplasia (SMDAX) is caused by homozygous or compound heterozygous mutation in the C21ORF2 gene (CFAP410; 603191) on chromosome 21q22. Biallelic mutations in C21ORF2 have also been reported in patients with isolated retinal dystrophy (RDMS; 617547). Description Axial spondylometaphyseal dysplasia (SMDAX) is characterized by postnatal growth failure, including rhizomelic short stature in early childhood that evolves into short trunk in late childhood, and thoracic hypoplasia that may cause mild to moderate respiratory problems in the neonatal period and later susceptibility to airway infection. Impaired visual acuity comes to medical attention in early life and vision rapidly deteriorates. Retinal changes are diagnosed as retinitis pigmentosa or pigmentary retinal degeneration on funduscopic examination and as cone-rod dystrophy on electroretinogram. Radiologic hallmarks include short ribs with flared and cupped anterior ends, mild spondylar dysplasia, lacy iliac crests, and metaphyseal irregularities essentially confined to the proximal femora (summary by Suzuki et al., 2011). Clinical Features Ehara et al. (1997) presented a previously undescribed, probably autosomal recessive skeletal dysplasia characterized by mild platyspondyly, small thorax with cupping of the anterior ends of the ribs, irregular proximal femoral metaphyses, and lacy appearance of the iliac wings. The 3 patients were a Korean brother and sister and an unrelated 5-year-old Japanese girl. Retinitis pigmentosa (RP) and optic atrophy were associated findings. The lacy appearance of the iliac crest is a feature also of Dyggve-Melchior-Claussen syndrome (223800), but Ehara et al. (1997) pointed out that the severe epiphyseal dysplasia of the proximal femurs and marked platyspondyly with particular double-hump appearance of the vertebral bodies seen in DMC syndrome were not present in their patients. The parents in both cases were nonconsanguineous. The authors excluded other rare forms of SMD. Because the metaphyseal abnormalities were almost exclusively confined to the thorax, spine, and pelvis, they proposed the designation 'axial SMD' for this disorder. Isidor et al. (2010) reported 2 unrelated French boys with short stature, femoral metaphyseal abnormalities, platyspondyly, and RP. The first boy, born of consanguineous parents, was evaluated at 7.5 years of age for short stature and found to have frontal bossing, a narrow bell-shaped thorax with prominent sternum, and rhizomelic shortening of the limbs. Radiologic examination showed moderate platyspondyly with ovoid vertebral bodies and enlarged short ribs, irregular iliac crest, and very abnormal femoral metaphyses with short and enlarged femoral neck. Bone age was moderately delayed. By 14.8 years of age, he had developed photophobia; ophthalmoscopy showed bilateral pale papillae, normal maculae, and diffuse atrophy of the pigmentary epithelium. Goldman visual fields were normal, whereas electroretinography (ERG) showed a 50% decrease in scotopic white and red waves. Cerebral MRI showed slight bilateral optic nerve atrophy. The other boy, born of healthy nonconsanguineous parents, was evaluated at 6.5 years of age for growth failure and noted to have delayed bone age, telecanthus and hypertelorism with antimongoloid palpebral fissures, slight eversion of the inferior eyelids, and short nose with anteverted nares. The thorax was very narrow with a bell-shaped thoracic cage, and he had rhizomelic shortening of the limbs; radiography showed spondylometaphyseal dysplasia, predominating in the pelvis and femoral neck, with lacy iliac wings. Ophthalmologic examination revealed bilateral symmetric cone-rod dystrophy without optic atrophy, and ERG showed a very severe defect of cone function and a small defect of the rods. Optical coherence tomography (OCT) was normal. At 15 years of age, the visual fields remained stable, but his facial features were unusual, with proptosis, hypertelorism, and frontal bossing. Radiography showed platyspondyly with 'codfish' appearance in the thoracic region, but disappearance of the irregularities of the iliac crest. Isidor et al. (2010) proposed that these 2 patients and the 3 patients described by Ehara et al. (1997) shared a distinctive phenotype, with major features consisting of postnatal growth deficiency, mild short stature, rhizomelic shortening of the limbs without bowing of the long bones of the legs, axial metaphyseal abnormalities with progressive mild platyspondyly, progressive femoral metaphyseal changes, decreased anteroposterior diameter of the thorax with markedly flared anterior ends of the ribs, normal tubular bones, and early onset and progressive visual impairment, with cone-rod dystrophy and/or optic atrophy. Taniai et al. (2001) reported a Japanese sister and brother with 'osteochondrodysplasia' and RP. The 9-year-old sister had low height (-2 SD for age) and weight as well as progressive deformation of the thorax from the age of 8 months, with pneumonia at age 3 years due to reduced respiratory function. She also exhibited night blindness, and funduscopy was consistent with early RP. Her 3-year-old brother was similarly affected with low height and weight, thorax deformation from 1 year of age that was associated with bronchitis and pneumonia, and retinal degeneration. Examination showed precordial stenosis in both sibs, with protruding breastbone and concave thorax. X-rays showed lack of physiologic thoracic kyphosis with flat thoracic vertebrae, and distal metaphyseal bone trabeculae of the femur were obscure. Dark-adapted ERGs showed severe reduction of both a- and b-waves, which were more reduced in the sister than her brother. Suga et al. (2016) restudied these sibs and noted bilateral shortening of the metacarpals in the sister, involving the fifth metacarpal on the right and the third and fifth metacarpals on the left. Ocular findings were similar in both sibs, including funduscopy that showed salt-and-pepper appearance of the peripheral retina and narrowing of retinal vessels, with visual field tests showing loss of the middle peripheral area and decreased sensitivity in the central area in both eyes. Flash ERGs of the combined rod and cone response were nonrecordable, and OCT showed thinning and disorganization of the photoreceptor layer outside the macular area. Suzuki et al. (2011) described clinical and radiologic findings in 7 affected individuals with SMDAX from 5 families of varying ethnicities, including Japanese, Korean, and Saudi Arabian, and tabulated the findings from all reported patients. The clinical hallmarks were postnatal growth deficiency, thoracic hypoplasia, and retinal abnormalities. Birth lengths were in the normal range, but short stature with rhizomelic limb shortening became apparent during childhood, with ultimate stature in adulthood sometimes less than -5 SD. Progressive shortening of the trunk resulted in short-trunk body proportion. Thoracic hypoplasia was present in all patients, associated with mild to moderate neonatal respiratory distress and susceptibility to airway infections in some patients. Pigmentary retinal degeneration was detectable in childhood, with RP diagnosed by 8 years of age; visual acuity worsened and vision was severely impaired within the first decade of life, with low to no night vision. Suzuki et al. (2011) stated that the patient reported by Megarbane et al. (2004) with rhizomelic skeletal dysplasia and RP (see 609047) might represent the same disorder. Wang et al. (2016) studied 13 patients from 9 families, including the Korean sibs and Japanese girl originally reported by Ehara et al. (1997); a French boy previously reported by Isidor et al. (2010); and 2 Saudi Arabian sibs (patients 2 and 3), a Korean boy (patient 4), and a Japanese boy (patient 5) previously reported by Suzuki et al. (2011). The common clinical findings among the patients included mild postnatal growth failure and severe thoracic deformity, as well as impaired visual acuity and retinal dystrophy, diagnosed as RP or cone-rod dystrophy. In all patients, impaired visual acuity came to medical attention early in life, and retinal function deteriorated rapidly. Thoracic hypoplasia, due to severe shortening of the ribs, was also observed in all patients. Radiologic features of the patients included cupped and flared anterior ends of ribs and lacy ilia (serrated iliac crests). Mild platyspondyly was common, but the height of vertebral bodies was sometimes normal. Proximal femoral metaphyses were irregular and enchondroma-like, and there was often progressive shortening of the femoral neck, resulting in mild coxa vara in older patients; however, metaphyseal dysplasia was rarely seen in other long tubular bones. McInerney-Leo et al. (2017) reported a 30-year-old woman who exhibited features of both Jeune asphyxiating thoracic dysplasia (JATD; see 208500) and SMDAX, including short stature with shortened limbs, narrowing of the thorax that required chest expansion surgery, severe scoliosis, and retinal dystrophy. Eye findings included reduced visual acuity (20/200), pigment displacement, and significantly reduced responses on electroretinography. In addition, she had delayed puberty, with menarche occurring at age 18 years. Inheritance Suzuki et al. (2011) noted that equally affected sib pairs of opposite genders and parental consanguinity were strongly suggestive of autosomal recessive inheritance of SMDAX. Molecular Genetics Wheway et al. (2015) cross-compared validated ciliogenesis candidate genes with whole-exome data from a cohort of patients with shortened limbs and ribs, narrow chest, and retinal degeneration, who had been clinically diagnosed as having JATD, and identified homozygous or compound heterozygous mutations in the C21ORF2 gene in affected individuals from 3 unrelated families (see, e.g., 603191.0001 and 603191.0002). In addition, homozygosity for a 1-bp deletion in C21ORF2 (603191.0003) was detected in a patient (CR-F024.1) previously reported by Abu-Safieh et al. (2013) as having isolated cone-rod dystrophy (see 617547), but in whom later reassessment showed deformation of the thorax and very short stature. Wang et al. (2016) performed whole-exome sequencing in 8 families with axial SMD and identified biallelic mutations in the C21ORF2 gene in patients from 5 of the families, including a French boy originally described by Isidor et al. (2010) (603191.0006); 2 Saudi Arabian sibs (patients 2 and 3; 603191.0007) and a Korean boy (patient 4; 603191.0008-603191.0009) previously studied by Suzuki et al. (2011); and a Swedish woman and affected members of a Turkish family with the recurrent R73P mutation (603191.0001). Wang et al. (2016) stated that the skeletal phenotypes of the patients reported by Wheway et al. (2015) with the R73P mutation, who were studied as part of a Jeune syndrome (see 208500) cohort, were similar to their own axial SMD patients carrying the R73P variant. In 147 Japanese families with inherited retinal diseases, Suga et al. (2016) performed whole-exome sequencing and identified compound heterozygosity for missense mutations in the C21ORF2 gene (603191.0008; 603191.0010) in a Japanese sister and brother with SMDAX originally reported by Taniai et al. (2001). From the same cohort, Suga et al. (2016) also detected biallelic C21ORF2 mutations in 2 Japanese sibs with isolated retinal dystrophy (see 617547). In a 30-year-old woman with short stature, extremely narrow thorax, severe scoliosis, and retinal dystrophy, McInerney-Leo et al. (2017) identified homozygosity for the recurrent R73P mutation in the C21ORF2 gene. The authors noted that the R73P variant had been associated with patients with clinical diagnoses of JATD, SMDAX, and isolated retinal dystrophy, and stated that in this patient, who exhibited features of both JATD and SMDAX, the severity of thoracic restriction added to the phenotypic spectrum attributable to C21ORF2 mutations. McInerney-Leo et al. (2017) tabulated the clinical findings in reported patients with C21ORF2 mutations and noted that all cases had retinal disease, none had renal disease, and the skeletal phenotype was variable. ### Exclusion Studies Wang et al. (2016) did not find C21ORF2 mutations in the Korean sibs or Japanese girl described by Ehara et al. (1997), or in the Japanese boy (patient 5) reported by Suzuki et al. (2011). Haplotype analysis excluded C21ORF2 as the causative gene in the Korean sibs, and Sanger sequencing, RT-PCR, and SNP analysis showed that C21ORF2 was unlikely to be the disease gene in the Japanese families. Wang et al. (2016) concluded that there was genetic heterogeneity in axial SMD. INHERITANCE \- Autosomal recessive GROWTH Height \- Short stature HEAD & NECK Eyes \- Low to no night vision \- Reduced visual fields \- Progressive loss of visual acuity \- Nystagmus \- Pigmentary retinal degeneration \- Salt-and-pepper appearance of peripheral retina \- Narrowing of retinal vessels \- Optic atrophy \- Cone-rod dystrophy seen on electroretinography \- Reduced to nonrecordable electroretinograms \- Thinning of photoreceptor layer outside of the macular area \- Disorganization of photoreceptor layer outside the macular area RESPIRATORY Lung \- Respiratory distress in neonatal period (in some patients) \- Pneumonia, recurrent (in some patients) CHEST External Features \- Small chest \- Thoracic deformation \- Harrison grooves (in some patients) Ribs Sternum Clavicles & Scapulae \- Anterior cupping of ribs \- Widened anterior ribs ABDOMEN Spleen \- Splenomegaly (in some patients) GENITOURINARY Internal Genitalia (Male) \- Reduced sperm motility SKELETAL \- Spondylometaphyseal dysplasia Spine \- Mild platyspondyly Pelvis \- Lacy iliac wings \- Narrow sacrosciatic notch Limbs \- Irregular proximal femoral metaphyses \- Short femoral necks \- Coxa vara \- Rhizomelic limb shortening Hands \- Metacarpal shortening (in some patients) MISCELLANEOUS \- Variable skeletal phenotype MOLECULAR BASIS \- Caused by mutation in the chromosome 21 open reading frame-2 gene (C21orf2, 603191.0001 ) ▲ 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	SPONDYLOMETAPHYSEAL DYSPLASIA, AXIAL	c1865695	3,419	omim	https://www.omim.org/entry/602271	2019-09-22T16:13:52	{"mesh": ["C535795"], "omim": ["602271"], "orphanet": ["168549"], "synonyms": ["Alternative titles", "SMD, AXIAL", "AXIAL SMD"]}
Horner's syndrome Other namesBernard-Horner syndrome (BH), oculosympathetic palsy Left-sided Horner's syndrome SpecialtyNeurology Horner's syndrome, also known as oculosympathetic paresis,[1] is a combination of symptoms that arises when a group of nerves known as the sympathetic trunk is damaged. The signs and symptoms occur on the same side (ipsilateral) as it is a lesion of the sympathetic trunk. It is characterized by miosis (a constricted pupil), partial ptosis (a weak, droopy eyelid), apparent anhydrosis (decreased sweating), with apparent enophthalmos (inset eyeball).[2] The nerves of the sympathetic trunk arise from the spinal cord in the chest, and from there ascend to the neck and face. The nerves are part of the sympathetic nervous system, a division of the autonomic (or involuntary) nervous system. Once the syndrome has been recognized, medical imaging and response to particular eye drops may be required to identify the location of the problem and the underlying cause.[3] ## Contents * 1 Signs and symptoms * 2 Causes * 3 Pathophysiology * 4 Diagnosis * 5 History * 6 Children * 7 See also * 8 References * 9 External links ## Signs and symptoms[edit] Signs that are found in people with Horner's syndrome on the affected side of the face include the following: * ptosis (drooping of the upper eyelid)[3] * anhidrosis (decreased sweating)[4] * miosis (constriction of the pupil)[4] * sinking of the eyeball into the face[4] * inability to completely close or open the eyelid[4] * facial flushing[4] * headaches[4] * loss of ciliospinal reflex * bloodshot conjunctiva, depending on the site of lesion. * unilateral straight hair (in congenital Horner's syndrome); the hair on the affected side may be straight in some cases. * heterochromia iridum (in congenital Horner's syndrome)[4] Interruption of sympathetic pathways leads to several implications. It inactivates the dilator muscle and thereby produces miosis. It inactivates the superior tarsal muscle which produces ptosis. It reduces sweat secretion in the face. Patients may have apparent enophthalmos (affected eye looks to be slightly sunken in) but this is not the case. The ptosis from inactivation of the superior tarsal muscle causes the eye to appear sunken in, but when actually measured, enophthalmos is not present. The phenomenon of enophthalmos is seen in Horner's syndrome in cats, rats, and dogs.[5] Sometimes there is flushing on the affected side of the face due to dilation of blood vessels under the skin. The pupil's light reflex is maintained as this is controlled via the parasympathetic nervous system. In children, Horner's syndrome sometimes leads to heterochromia, a difference in eye color between the two eyes.[3] This happens because a lack of sympathetic stimulation in childhood interferes with melanin pigmentation of the melanocytes in the superficial stroma of the iris. In veterinary medicine, signs can include partial closure of the third eyelid, or nictitating membrane. ## Causes[edit] Scheme showing sympathetic and parasympathetic innervation of the pupil and sites of a lesion in Horner's syndrome. Horner's syndrome is usually acquired as a result of disease, but may also be congenital (inborn, associated with heterochromatic iris) or iatrogenic (caused by medical treatment). In rare cases, Horner's syndrome may be the result of repeated, minor head trauma, such as being hit with a soccer ball. Although most causes are relatively benign, Horner's syndrome may reflect serious disease in the neck or chest (such as a Pancoast tumor (tumor in the apex of the lung) or thyrocervical venous dilatation). Causes can be divided according to the presence and location of anhidrosis: * Central (anhidrosis of face, arm and trunk) * Syringomyelia * Multiple sclerosis * Encephalitis * Brain tumors * Lateral medullary syndrome * Preganglionic (anhidrosis of face) * Cervical rib traction on stellate ganglion * Thyroid carcinoma * Thyroidectomy * Goiter * Bronchogenic carcinoma of the superior fissure (Pancoast tumor) on apex of lung * Klumpke paralysis * Trauma \- base of neck, usually blunt trauma, sometimes surgery. * As a complication of tube thoracostomy * Thoracic aortic aneurysm * Postganglionic (no anhidrosis) * Cluster headache \- combination termed Horton's headache * An episode of Horner's syndrome may occur during a migraine attack and be relieved afterwards[6] * Carotid artery dissection/carotid artery aneurysm * Cavernous sinus thrombosis * Middle ear infection * Sympathectomy * Nerve blocks, such as cervical plexus block, stellate ganglion or interscalene block ## Pathophysiology[edit] Horner syndrome is due to a deficiency of sympathetic activity. The site of lesion to the sympathetic outflow is on the ipsilateral side of the symptoms. The following are examples of conditions that cause the clinical appearance of Horner's syndrome: * First-order neuron disorder: Central lesions that involve the hypothalamospinal tract (e.g. transection of the cervical spinal cord). * Second-order neuron disorder: Preganglionic lesions (e.g. compression of the sympathetic chain by a lung tumor) that releases acetylcholine. * Third-order neuron disorder: Postganglionic lesions at the level of the internal carotid artery (e.g. a tumor in the cavernous sinus or a carotid artery dissection) that releases norepinephrine. * Partial Horner's syndrome: In case of a third-neuron disorder, anhidrosis is limited to the middle part of the forehead or can be absent, resulting in a partial Horner's syndrome.[7] If patients have impaired sweating above the waist affecting only one side of the body, and they do not have clinically apparent Horner's syndrome, then their lesions are just below the stellate ganglion in the sympathetic chain. ## Diagnosis[edit] Left-sided Horner's syndrome in a cat as a result of trauma, demonstrating miosis in left pupil. Three tests are useful in confirming the presence and severity of Horner syndrome: * Cocaine drop test: Cocaine eyedrops block the reuptake of post-ganglionic norepinephrine resulting in the dilation of a normal pupil from retention of norepinephrine in the synapse. However, in Horner's syndrome the lack of norepinephrine in the synaptic cleft causes mydriatic failure. A more recently introduced approach that is more dependable and obviates the difficulties in obtaining cocaine is to apply the alpha-agonist apraclonidine to both eyes and observe the increased mydriatic effect (due to hypersensitivity) on the affected side of Horner syndrome (the opposite effect to what the cocaine test would produce in the presence of Horner's).[citation needed] * Paredrine test: This test helps to localize the cause of the miosis. If the third order neuron (the last of three neurons in the pathway which ultimately discharges norepinephrine into the synaptic cleft) is intact, then the amphetamine causes neurotransmitter vesicle release, thus releasing norepinephrine into the synaptic cleft and resulting in robust mydriasis of the affected pupil. If the lesion itself is of the third order neuron, then the amphetamine will have no effect and the pupil remains constricted. There is no pharmacological test to differentiate between a first and second order neuron lesion.[7] * Dilation lag test[clarification needed] It is important to distinguish the ptosis caused by Horner's syndrome from the ptosis caused by a lesion to the oculomotor nerve. In the former, the ptosis occurs with a constricted pupil (due to a loss of sympathetics to the eye), whereas in the latter, the ptosis occurs with a dilated pupil (due to a loss of innervation to the sphincter pupillae). In a clinical setting, these two ptoses are fairly easy to distinguish. In addition to the blown pupil in a CNIII (oculomotor nerve) lesion, this ptosis is much more severe, occasionally occluding the whole eye. The ptosis of Horner syndrome can be quite mild or barely noticeable (partial ptosis).[citation needed] When anisocoria occurs and the examiner is unsure whether the abnormal pupil is the constricted or dilated one, if a one-sided ptosis is present then the abnormally sized pupil can be presumed to be on the side of the ptosis.[citation needed] ## History[edit] The syndrome is named after Johann Friedrich Horner, the Swiss ophthalmologist who first described the syndrome in 1869.[8][9] Several others had previously described cases, but "Horner's syndrome" is most prevalent. In France and Italy, Claude Bernard is also eponymized with the condition (Claude Bernard–Horner syndrome, abbreviated CBH[10]). In France, Francois Pourfour du Petit is also credited with describing this syndrome. ## Children[edit] The most common causes in young children are birth trauma and a type of cancer called neuroblastoma.[11] The cause of about a third of cases in children is unknown.[11] ## See also[edit] * Anisocoria * Harlequin syndrome ## References[edit] 1. ^ "Horner syndrome: MedlinePlus Medical Encyclopedia". medlineplus.gov. Retrieved 2019-05-06. 2. ^ Reference, Genetics Home. "Horner syndrome". Genetics Home Reference. Retrieved 2019-05-06. 3. ^ a b c Ropper AH, Brown RH (2005). "14: disorders of ocular movement and pupillary function". In Ropper AH, Brown RH (eds.). Adams and Victor's Principles of Neurology (8th ed.). New York: McGraw-Hill Professional. pp. 222–45. doi:10.1036/0071469710 (inactive 2021-01-11). ISBN 0-07-141620-X.CS1 maint: DOI inactive as of January 2021 (link) 4. ^ a b c d e f g "Horner's syndrome \| Genetic and Rare Diseases Information Center (GARD) – an NCATS Program". rarediseases.info.nih.gov. Retrieved 2019-10-15. 5. ^ Daroff R (April 2005). "Enophthalmos is not present in Horner syndrome". PLOS Medicine. 2 (4): e120. doi:10.1371/journal.pmed.0020120. PMC 1087222. PMID 15839747. 6. ^ Laing C, Thomas DJ, Mathias CJ, Unwin RJ (October 2000). "Headache, hypertension and Horner's syndrome". Journal of the Royal Society of Medicine. 93 (10): 535–6. doi:10.1177/014107680009301010. PMC 1298129. PMID 11064693.. 7. ^ a b Lee JH, Lee HK, Lee DH, Choi CG, Kim SJ, Suh DC (January 2007). "Neuroimaging strategies for three types of Horner syndrome with emphasis on anatomic location". AJR. American Journal of Roentgenology. 188 (1): W74-81. doi:10.2214/AJR.05.1588. PMID 17179330. 8. ^ Horner JF (1869). "Über eine Form von Ptosis". Klin Monatsbl Augenheilk. 7: 193–8. 9. ^ synd/1056 at Who Named It? 10. ^ Logan, Carolynn M.; Rice, M. Katherine (1987). Logan's Medical and Scientific Abbreviations. J. B. Lippincott and Company. pp. 58. ISBN 0-397-54589-4. 11. ^ a b Kennard C, Leigh RJ (2011-06-28). Neuro-ophthalmology: Handbook of Clinical Neurology (Series Editors: Aminoff, Boller and Swaab). Elsevier. p. 452. ISBN 9780702045479. ## External links[edit] Classification D * ICD-10: G90.2 * ICD-9-CM: 337.9 * OMIM: 143000 * MeSH: D006732 * DiseasesDB: 6014 * SNOMED CT: 12731000 External resources * MedlinePlus: 000708 * eMedicine: med/1029 oph/336 * Patient UK: Horner's syndrome * v * t * e Diseases of the autonomic nervous system General * Dysautonomia * Autonomic dysreflexia * Autonomic neuropathy * Pure autonomic failure Hereditary * Hereditary sensory and autonomic neuropathy * Familial dysautonomia * Congenital insensitivity to pain with anhidrosis Orthostatic intolerance * Orthostatic hypotension * Postural orthostatic tachycardia syndrome Other * Horner's syndrome * Multiple system atrophy [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Horner's syndrome	c0019937	3,420	wikipedia	https://en.wikipedia.org/wiki/Horner%27s_syndrome	2021-01-18T18:44:48	{"gard": ["6670"], "mesh": ["D006732"], "umls": ["C0019937"], "icd-9": ["337.9"], "wikidata": ["Q1126839"]}
Bladder syndrome Male urinary bladder Underactive bladder Other namesDetrusor underactivity Underactive bladder syndrome (UAB) describes symptoms of difficulty with bladder emptying, such as hesitancy to start the stream, a poor or intermittent stream, or sensations of incomplete bladder emptying. The physical finding of detrusor activity of insufficient strength or duration to ensure efficient bladder emptying is properly termed "detrusor underactivity" (DU).[1] Historically, UAB and DU (as well as others such as 'bladder underactivity') have been often used interchangeably,[2] leading to both terminologic and pathophysiologic confusion. Patients with underactive bladder have a diminished sense of bladder filling and consequently are often found to have DU as an underlying finding, however bladder outlet obstruction and less frequently volume hypersensitivity ("OAB") can be associated with UAB symptoms[3] ## Contents * 1 Causes * 2 Diagnosis * 3 Treatment * 4 See also * 5 References ## Causes[edit] Without diagnostic evaluation, the cause of underactive bladder is unclear, as there are multiple possible causes. UAB symptoms can accurately reflect impaired bladder emptying due either to DU or obstruction (normal or large storage volumes, elevated post-void residual volume), or can result from a sense of incomplete emptying of a hypersensitive bladder (small storage volumes, normal or elevated postvoid residual volume). UAB potentially might also result from inaccurate perceptions of bladder function, such as in neurologic or psychiatric disease. DU itself is often linked to a weak detrusor muscle (impaired contractility), however this association is weak. Both UAB and DU have been associated with diminished sensitivity to bladder volumes rather than objective detrusor weakness, suggesting both symptoms (UAB) and function (DU) have a significant component of sensory dysfunction, leading to impaired bladder sensations and control (Smith et al., 2015). The underlying contributors to UAB include neurologic disease, metabolic disease (e.g. diabetes), chronic bladder outlet obstruction (e.g. obstructive BPH or complications of anterior vaginal surgery), cognitive decline (such as with aging), psychiatric disorders, and adverse effects of medications. Additionally, structural abnormalities expanding the urinary reservoir beyond the bladder, such as massive vesicoureteral reflux or large bladder diverticulae, can result in UAB. While aging itself is often associated with UAB (and DU), there is scant evidence to support this claim. ## Diagnosis[edit] There is no standardized evaluation of the symptoms of UAB, in part due to the historic terminologic confusion. A thorough history aimed at detecting underlying disease or prior pelvic surgeries is certainly necessary. As a perception of volume mishandling, a voiding diary (to assess voided volumes and frequency of voiding) and a post-void residual volume would be valuable information. Uninstrumented uroflow, neurologic and pelvic examination may contribute valuable information. Imaging looking for abnormal bladder morphology or vesicoureteral reflux/hydronephrosis may be helpful. If low-pressure urine storage can be assured, and the urinary reservoir is known to be limited to the bladder, the general value of urodynamic study in UAB is unclear. In specific situations, invasive urodynamics may be helpful to distinguish bladder outlet obstruction from DU, although this distinction can be difficult. ## Treatment[edit] Therapy for UAB is often dependent on factors such as age, health, symptoms, and cause of the condition. Treatment frequently includes lifestyle modification (fluid restriction, bladder retraining). Bethanechol is a prescription medication used for treatment, bethanechol can stimulate the nerves of the bladder, making them more responsive to stimulus. With UAB, it is common for patients to utilize a urinary catheter to void. Surgical options are also options, with a cuff or stent placed around or in the neck of the bladder to aid the emptying and leakage of urine. Neuromodulatory techniques such as sacral nerve or posterior tibial nerve stimulation may be of value in selected cases. However, current therapies are considered inadequate and there is a strong need for new research and attention.(Van Koeveringe et al., 2011; Tyagi et al. 2015). ## See also[edit] * Urinary retention * Overactive bladder * Urinary incontinence * International Continence Society ## References[edit] 1. ^ Abrams, Paul; Cardozo, Linda; Fall, Magnus; Griffiths, Derek; Rosier, Peter; Ulmsten, Ulf; Kerrebroeck, Philip Van; Victor, Arne; Wein, Alan (2003-01-01). "The standardisation of terminology in lower urinary tract function: report from the standardisation sub-committee of the International Continence Society". Urology. 61 (1): 37–49. doi:10.1016/S0090-4295(02)02243-4. ISSN 0090-4295. 2. ^ Rigby, Deborah. "Underactive bladder syndrome". journals.rcni.com. doi:10.7748/ns2005.05.19.35.57.c3866. Retrieved 2020-03-25. 3. ^ Chapple, Christopher R.; Osman, Nadir I.; Birder, Lori; van Koeveringe, Gommert A.; Oelke, Matthias; Nitti, Victor W.; Drake, Marcus J.; Yamaguchi, Osamu; Abrams, Paul; Smith, Philip P. (2015-09-01). "The Underactive Bladder: A New Clinical Concept?". European Urology. 68 (3): 351–353. doi:10.1016/j.eururo.2015.02.030. ISSN 0302-2838. Smith, P. P., G. Pregenzer, et al. (2015). "Underactive bladder and detrusor underactivity represent different facets of volume hyposensitivity and not impaired contractility." Bladder 2(2): e17. Tyagi, P., P. P. Smith, et al. (2014). "Pathophysiology and animal modeling of underactive bladder." Int Urol Nephrol 46 Suppl 1: 11–21. van Koeveringe, G. A., K. L. Rademakers, et al. (2014). "Detrusor underactivity: Pathophysiological considerations, models and proposals for future research. ICI-RS 2013." Neurourol Urodyn 33(5): 591–596. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: 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	Underactive bladder	c0403644	3,421	wikipedia	https://en.wikipedia.org/wiki/Underactive_bladder	2021-01-18T18:31:25	{"mesh": ["D000077295"], "umls": ["C0403644"], "wikidata": ["Q7883430"]}
A number sign (#) is used with this entry because of evidence that hypotrichosis, or woolly hair with or without hypotrichosis, can be caused by homozygous or compound heterozygous mutation in the LIPH (607365) gene on chromosome 3q27. For a discussion of genetic heterogeneity of localized hypotrichosis, see LAH1 (607903). For a discussion of genetic heterogeneity of nonsyndromic hypotrichosis, see 605389. For a general phenotypic description and a discussion of genetic heterogeneity of autosomal recessive woolly hair, see 278150. Clinical Features Rogaev et al. (1999) described a hereditary form of hypotrichosis that is common in the Mari population, a large aboriginal Finno-Ugric population in the Volga-Ural region of Russia. They found 21 families with 26 affected individuals during a medical genetic study of this population. In each family, the parents of the proband were normal, and both sexes were affected, consistent with autosomal recessive inheritance. The frequency of the mutated gene for hypotrichosis in the Mari population was estimated to be 1% or higher. The affected Mari individuals had congenital hypotrichosis of the scalp hairs; any hair present was wiry and twisted. Eyebrows and eyelashes were absent after the first year of life, and remained sparse in adults. Pubic and axillary hairs were practically absent, and body hairs were scarce and thin. Nails and teeth, as well as other epidermal structures, were normal, with one exception: 2 sisters from 1 family with a hair abnormality also had follicular hyperkeratosis. However, ichthyosis and follicular hyperkeratosis appeared to be common abnormalities in the Mari population, and were thought to be associated with hypotrichosis in these sisters by chance. Aslam et al. (2004) described a consanguineous Pakistani family segregating autosomal recessive hypotrichosis. At birth, sparse hair was present on the scalp but did not regrow after ritual shaving, which was usually performed 1 week after birth. The affected individuals were nearly devoid of normal eyebrows, eyelashes, axillary hair, and body hair. Affected male individuals of the family had normal beard hair; however, hair was absent on their legs and arms. Teeth and nails were normal in all affected individuals. Ali et al. (2007) reported a consanguineous Pakistani family in which 3 sibs had autosomal recessive hypotrichosis. Hair was present on the scalp at birth but regrew sparsely after ritual shaving. Affected individuals were nearly devoid of normal eyebrows, eyelashes, axillary hair, and body hair. Teeth, nails, sweating, and hearing were all normal. Heterozygous carriers had normal hair. Skin biopsy from an affected individual showed absence of normal hair follicle structures replaced by comedo-like remnant hair follicles. Shimomura et al. (2009) studied 11 consanguineous Pakistani families with woolly hair and/or hypotrichosis in whom homozygosity for mutations in the LIPH gene were identified (see MOLECULAR GENETICS). The 11 families showed a wide variation in phenotype, ranging from woolly hair to sparse hair between families and even within a single family, although all affected individuals had slow hair growth that stopped at a few inches. The woolly hair of some individuals was light-colored compared to the dark brown/black hair typical in this population. Facial and body hair was normal in patients with woolly hair, whereas eyebrows, eyelashes, and body hair were sparse in the patients with hypotrichosis. Affected individuals from all 11 families had normal teeth, nails, and sweating, did not display palmoplantar hyperkeratosis, and had no family history of heart disease, cancers, or neurologic abnormalities. Shimomura et al. (2009) stated that the key observation uniting these variable phenotypes was that all affected individuals had woolly hair at birth and/or during early childhood, and some, but not all, progressed to show different degrees of hypotrichosis. Shimomura et al. (2009) reported 3 Japanese probands with woolly hair and hypotrichosis who came from families of the Niigata prefecture in Japan. One proband, a 4-year-old boy, had tightly curled hair at birth that at 2 years of age became thinner and stopped growing at a few inches. Eyebrows and eyelashes were thin and sparse. Small pale follicular papules were diffusely distributed on the scalp. Skin biopsy of scalp showed an enlarged infundibulum with keratotic plugs and a miniaturized bulb portion without obvious structural anomalies. The other 2 probands, 3- and 4-year-old girls, respectively, had similar clinical features. Khan et al. (2011) studied 17 Pakistani families with the hypotrichosis/woolly hair phenotype. At birth, patients had sparse hair. Affected members of 8 families had features of hypotrichosis, with sparse fragile hair on the scalp and sparse to absent eyebrows, eyelashes, and axillary, pubic, and body hair. In 6 families, affected members exhibited features of woolly hair on the scalp, with sparse to absent eyebrows, eyelashes, and body hair. In the remaining 3 families, some affected individuals had features of hypotrichosis and others had woolly scalp hair. All male members in all 17 families had normal beard and moustache hair. Mapping Aslam et al. (2004) performed haplotype analysis in affected members of a consanguineous Pakistani family with hereditary hypotrichosis and excluded linkage to 14 hair loss and ectodermal dysplasia loci. A genome scan using the DNA samples of 4 affected individuals yielded a maximum multipoint lod score of 6.0 for marker D3S3592. The region of homozygosity was flanked by markers D3S2314 and D3S1602, a 7.1-cM region on chromosome 3q26.33-q27.3, referred to by the authors as 'AH.' Kazantseva et al. (2006) performed linkage analysis on 14 Mari families with hypotrichosis and showed potential linkage to chromosome 3q26-q27. Using novel simple tandem repeat markers (STRs) and combining the data with haplotype mapping from 36 Chuvash families with hypotrichosis, they narrowed the interval to a 350-kb region on chromosome 3q27 containing 4 genes. In 2 large unrelated consanguineous Pakistani families with woolly hair/hypotrichosis, Petukhova et al. (2009) performed genomewide analysis that failed to identify significant regions of autozygosity or linkage; however, parametric analysis in 1 of the families showed evidence for linkage on chromosome 3q27. Haplotype analysis using microsatellite markers within the LIPH gene demonstrated that 2 haplotypes, designated A and B, were segregating with the phenotype in each of these families, and every affected individual was either homozygous for A or B, or compound heterozygous for A and B. Petukhova et al. (2009) cautioned against making the a priori assumption of identity by descent in consanguineous families, noting that their data illustrated that evidence for linkage in the absence of evidence for homozygosity points to the possibility of allelic heterogeneity. Molecular Genetics In 14 Mari families and 36 Chuvash families with hypotrichosis mapping to chromosome 3q26-q27, Kazantseva et al. (2006) sequenced the entire coding regions of all 4 genes within the critical interval for hypotrichosis and found no point mutations. However, they were unable to amplify exon 4 of the candidate gene LIPH (607365) in affected individuals, although it was detectable in their parents, suggesting that deletion of exon 4 was present in homozygosity in affected individuals and in heterozygosity in their parents. Kazantseva et al. (2006) determined that an approximately 985-bp deletion (607365.0001) eliminated exon 4 and flanking intronic sequences. In 3 sibs, born of consanguineous Pakistani parents, with autosomal recessive hypotrichosis, Ali et al. (2007) identified a homozygous mutation in the LIPH gene (607365.0002). In affected members of 2 unrelated consanguineous Pakistani families with autosomal recessive hypotrichosis, Jelani et al. (2008) identified a homozygous mutation in the LIPH gene (607365.0003). gene. Affected individuals were nearly devoid of normal eyebrows, eyelashes, axillary hair, and body hair. Adult males had normal beard hair but sparse scalp hair. There were no other clinical abnormalities. Shimomura et al. (2009) studied 11 consanguineous Pakistani families with woolly hair and/or hypotrichosis that were negative for mutation in the P2RY5 gene (609239). Because 1 of the families showed linkage to chromosome 3q27 in the region of the LIPH gene, the authors performed direct sequencing of LIPH and identified 5 different homozygous mutations among the 11 families, (see, e.g., 607365.0003-607365.0005). Shimomura et al. (2009) noted that the 11 families with LIPH mutations in this study showed a wide variation in phenotype, even within a single family. In 2 large, unrelated consanguineous Pakistani families with woolly hair/hypotrichosis showing linkage to the LIPH gene, in which microsatellite marker analysis demonstrated segregation of 2 distinct disease alleles within each family, Petukhova et al. (2009) identified 2 different LIPH mutations: a known 2-bp deletion (607365.0003) and a 90-bp duplication (607365.0006). Affected individuals were either homozygous for the deletion or the duplication, or compound heterozygous for both. In probands from 3 Japanese families, who were born with tightly curled hair and developed hypotrichosis in the second year of life, Shimomura et al. (2009) identified homozygosity or compound heterozygosity for 2 missense mutations in the LIPH gene (607365.0007, 607365.0008). The authors stated that this was the first report of LIPH mutations in the Japanese population. Khan et al. (2011) performed microsatellite genotyping in 17 Pakistani families with the hypotrichosis/woolly hair phenotype and found linkage to the LIPH gene in 9 families and to the LPAR6 gene (609239) in 8 families (see HYPT8; 278150). Sequence analysis of LIPH in the 9 linked families revealed 2 recurrent homozygous mutations (607365.0003, 607365.0005) in families with hypotrichosis, woolly hair with or without hypotrichosis, or a mixed phenotype. Khan et al. (2011) observed no difference in severity of hair loss in patients carrying different mutations in either LIPH or LPAR6, and there were no clear genotype/phenotype correlations. Population Genetics Kazantseva et al. (2006) tested 2,292 chromosomes in population samples collected irrespective of the hypotrichosis phenotype from Volga-Ural and other regions of Russia. Among the Chuvash people the mutant allele frequency was 0.033 and among the Mari it was 0.030. No mutant allele was found in other Finno-Ugric populations or Russian populations from distant geographic regions. Kazantseva et al. (2006) suggested that there may be more than 98,000 heterozygous mutant carriers and 1,500 homozygous affected individuals in populations of Mari and Chuvash descent. Nomenclature Wali et al. (2007) noted clinical similarities among 3 genetically distinct forms of hypotrichosis, with affected individuals having normal beard hair (in men) and sparse to absent eyebrows, eyelashes, and body hair; they suggested that the form mapped to chromosome 18 be designated LAH1 (HYPT6; 607903), the form mapped to chromosome 3q27 be designated LAH2, and the form mapped to 13q14-q21 be designated LAH3 (HYPT8; 278150). INHERITANCE \- Autosomal recessive HEAD & NECK Eyes \- Sparse eyebrows \- Sparse eyelashes Teeth \- Normal teeth SKIN, NAILS, & HAIR Skin \- Normal skin \- Normal sweating Nails \- Normal nails Hair \- Sparse scalp hair from birth (in some patients) \- Woolly hair (in some patients) \- Sparse to no eyebrows (in some patients) \- Sparse to no eyelashes (in some patients) \- Sparse to no axillary hair (in some patients) \- Sparse to no body hair (in some patients) \- Twisted hair shaft \- Trichorrhexis nodora-like anomaly \- Tapered distal end \- Comedo-like remnant hair follicles (on skin biopsy) MISCELLANEOUS \- Variable phenotype ranging from woolly to sparse hair, even within a single family MOLECULAR BASIS \- Caused by mutation in the lipase H gene (LIPH, 607365.0001 ) ▲ 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	HYPOTRICHOSIS 7	c1854310	3,422	omim	https://www.omim.org/entry/604379	2019-09-22T16:12:00	{"doid": ["0110704"], "mesh": ["C537160"], "omim": ["604379"], "orphanet": ["55654", "170"], "synonyms": ["Alternative titles", "HYPOTRICHOSIS, LOCALIZED, AUTOSOMAL RECESSIVE 2", "HYPOTRICHOSIS, AUTOSOMAL RECESSIVE", "HYPOTRICHOSIS, TOTAL, MARI TYPE"]}
Distal intestinal obstruction syndrome Small intestine(at center) Distal intestinal obstruction syndrome (DIOS) involves obstruction of the distal part of the small intestines by thickened intestinal content and occurs in about 20% of mainly adult individuals with cystic fibrosis.[1] DIOS was previously known as meconium ileus equivalent, a name which highlights its similarity to the intestinal obstruction seen in newborn infants with cystic fibrosis.[2] DIOS tends to occur in older individuals with pancreatic insufficiency. Individuals with DIOS may be predisposed to bowel obstruction, though it is a separate entity than true constipation.[2] ## Contents * 1 Signs and symptoms * 2 Diagnosis * 3 Classification * 3.1 Differential diagnosis * 4 Management * 5 References * 6 External links ## Signs and symptoms[edit] Signs and symptoms of DIOS include a sudden onset of crampy abdominal pain, vomiting, and a palpable mass (often in the right lower quadrant) in the abdomen. The characteristic abdominal pain is typically located in the center or right lower quadrant of the abdomen.[1] X-rays of the abdomen may reveal stool in the colon and air-fluid levels in the small intestines. ## Diagnosis[edit] A complete history and physical examination can be suggestive, especially if a palpable mass in the right lower quadrant of the abdomen is present (though this can be present in the absence of DIOS). Ultrasound and computed tomography (CT) imaging of the abdomen can confirm the diagnosis by demonstrating dilated loops of intestine with material in the intestinal lumen with bubbles.[1] Air-fluid levels may be seen in those affected by DIOS.[1] ## Classification[edit] DIOS is sometimes classified by the degree of obstruction as incomplete or complete DIOS.[3] ### Differential diagnosis[edit] Additional diagnoses which may present with similar symptoms to DIOS include severe constipation, appendicitis, and intussusception.[1] ## Management[edit] Differentiation of DIOS from constipation is generally performed by unit specializing in the treatment of cystic fibrosis. Adequate hydration and an aggressive regimen of laxatives are essential for treatment and prevention of DIOS. Osmotic laxatives such as polyethylene glycol are preferred.[1] Individuals prone to DIOS tend to be at risk for repeated episodes and often require maintenance therapy with pancreatic enzyme replacement, hydration and laxatives (if the symptoms are also mild).[4][5] Oral contrast instillation into the colon/ileum under radiological control has been found to reduce the need for surgical intervention. ## References[edit] 1. ^ a b c d e f Kelly, T; Buxbaum, J (July 2015). "Gastrointestinal Manifestations of Cystic Fibrosis". Digestive Diseases and Sciences (Review). 60 (7): 1903–13. doi:10.1007/s10620-015-3546-7. PMID 25648641. 2. ^ a b Stringer, David A.; Babyn, Paul S. (2000). Pediatric Gastrointestinal Imaging and Intervention. PMPH-USA. p. 347. ISBN 9781550090796. 3. ^ Feldman, Mark; Friedman, Lawrence S.; Brandt, Lawrence J. (2010). Sleisenger and Fordtran's Gastrointestinal and Liver Disease E-Book: Pathophysiology, Diagnosis, Management, Expert Consult Premium Edition - Enhanced Online Features. Elsevier Health Sciences. p. 945. ISBN 1437727670. 4. ^ Ludwig, Stephen (2008). Visual Handbook of Pediatrics and Child Health: The Core. Lippincott Williams & Wilkins. p. 283. ISBN 9780781795050. 5. ^ Mighten, Janice (2012). Children's Respiratory Nursing. John Wiley & Sons. ISBN 9781118278277. ## External links[edit] * http://www.cfmedicine.com/htmldocs/CFText/dios.htm * http://www.rbht.nhs.uk/healthprofessionals/clinical-departments/cystic-fibrosis/clinical-guidelines/nutritional-and-gastrointestinal-care/constipation-and-distal-intestinal-obstructive-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	Distal intestinal obstruction syndrome	c0398349	3,423	wikipedia	https://en.wikipedia.org/wiki/Distal_intestinal_obstruction_syndrome	2021-01-18T18:28:54	{"umls": ["C0398349"], "wikidata": ["Q5282842"]}
A number sign (#) is used with this entry because of evidence that aggressive periodontitis-1 is caused by homozygous mutation in the CTSC gene (602365) on chromosome 11q14. Description Aggressive periodontitis, which may be generalized or localized, is characterized by severe and protracted gingival infections, leading to tooth loss. Amounts of microbial deposits are generally inconsistent with the severity of periodontal tissue destruction and the progression of attachment and bone loss may be self arresting (American Academy of Periodontology, 2000). The term 'aggressive periodontitis' replaced the terms 'early-onset,' 'prepubertal,' or 'juvenile periodontitis' at a 1999 International workshop for a classification of periodontal disease and conditions, where it was decided that the classification terminology should not be age dependent or require knowledge of rates of progression (Armitage, 1999). ### Genetic Heterogeneity of Aggressive Periodontitis Aggressive periodontitis-2 (608526) has been mapped to chromosome 1q25. Clinical Features Jorgenson et al. (1975) described periodontitis in 3 (1 male) of 7 sibs in a black family. They found 12 reports of families with more than 1 affected child and unaffected parents. In 3 of the families the parents were first cousins. In 1 family, a first cousin was affected. Three pairs of like-sex twins were concordant for the trait. Rao et al. (1979) could detect no evidence of significant heritability. Saxen and Nevanlinna (1984) studied 30 families. None of the 60 parents had any sign of the disorder. Of the 52 sibs, 9 (in 7 families) were affected. The findings were considered compatible with autosomal recessive inheritance. Long et al. (1987) studied 37 kindreds with 2 rare types of familial periodontitis: a localized form usually diagnosed in late adolescence and a more generalized form with a later mean age of diagnosis. They found several families in which both forms occurred, making it unlikely that these 2 varieties have unrelated genetic causes. Shapira et al. (1997) described a family with prepubertal periodontitis in several members in 3 generations. Localized and generalized forms were found in sibs. Variability in disease expression was further indicated by the fact that a pair of monozygotic twins were similarly but not identically affected. Inheritance Beaty et al. (1987) performed segregation analysis of data from 28 families ascertained through a proband with juvenile periodontitis. There was strong evidence of familial aggregation. The best fitting model was an autosomal recessive one. Long et al. (1987) favored autosomal recessive inheritance for early-onset periodontitis. Melnick et al. (1976) concluded that juvenile periodontitis is probably inherited as an X-linked, dominant trait with decreased penetrance but relatively consistent gene expressivity, They stated that no male-to-male transmission had been reported and cited a female:male ratio of affected persons of about 2:1. However, Hart et al. (1991, 1992) noted that more complete family data document father-to-son transmission and that when the proportions of affected males and females are examined, rather than total numbers of affected individuals, the proportion of affected males and females is similar. They found no female preponderance after correction for ascertainment bias. Biochemical Features Exposure of polymorphonuclear leukocytes (PMNs) to N-formyl peptides stimulates these cells to migrate in a directed fashion (i.e., respond chemotactically) as well as release selectively a portion of their lysosomal contents (i.e., degranulate) and generate highly reactive oxygen-derived free radicals such as superoxide anion. These processes are initiated by the binding of formyl peptides to specific receptors on the PMN membrane. Van Dyke et al. (1980) demonstrated that PMNs from some patients with JP exhibit abnormal chemotactic responses when challenged with the synthetic chemotactic peptide FMLP. Furthermore, Van Dyke et al. (1981) reported that the PMNs from some JP patients show a diminution in their ability to bind radiolabeled FMLP indicating a decrease in receptor number. Perez et al. (1991) found a patient with JP in whom abnormal PMN chemotactic responsiveness to formyl peptide was associated with a defective population of formyl peptide receptors (FPRs). The PMNs failed to respond chemotactically when challenged with FMLP, but exhibited normal chemotactic responses upon exposure to purified human C5a (120900). Furthermore, the patient's PMNs were capable of degranulating and generating superoxide anion radicals as well as normal PMNs upon exposure to FMLP. Binding studies showed that the patient's PMNs had a reduction in the number of high-affinity FPRs. Mapping Hart et al. (2000) reported a consanguineous Jordanian family in which 4 members had prepubertal periodontitis. All 4 had gingival inflammation and radiographic evidence of alveolar bone loss. Hart et al. (2000) localized a gene of major effect for PPP in this kindred to a 14-cM genetic interval on chromosome 11q14 flanked by D11S916 and D11S1367 (maximum lod = 3.55 for D11S901). This interval overlapped the region of chromosome 11q14 containing the CTSC gene (602365), mutations in which can cause Papillon-Lefevre (245000) and Haim-Munk (245010) syndromes. ### Genetic Heterogeneity Roulston et al. (1985) studied dentinogenesis imperfecta (DGI; 125490) in the triracial population of Brandywine, Maryland, and found that a localized form of juvenile periodontitis (JP) was cosegregating. Discovery of 2 recombinant offspring supported linkage, not pleiotropism. In the full data, reported by Boughman et al. (1986), the maximum lod score for JP and group-specific complement (GC; 139200) was 3.1 at theta 0.05 and that for DGI and GC was 2.0 at theta 0.12. The lod score of 0.9 at theta 0.20 for linkage of DGI and JP suggested that GC is located between the 2 dental disease loci on chromosome 4q. The study suggested that types II and III DGI are allelic or perhaps the same disorder. (According to the classification of Shields et al. (1973), type I DGI is the form that occurs with osteogenesis imperfecta. Type II DGI (125490) is the form first shown to be linked to GC; confusion is possible because the official gene symbol for this form is DGI1. Shields type III DGI is the Brandywine form (125500) which was originally studied by Witkop and his colleagues (Hursey et al., 1956).) Since the linkage of early-onset or juvenile periodontitis to GC was based on linkage studies in 1 large kindred, Hart et al. (1993) evaluated the generality of the finding by studying 19 unrelated families with 2 or more affected individuals. Twelve genetic models that varied in diagnostic classification, penetrance, and mode of inheritance were evaluated. Results for all models strongly excluded linkage between a periodontitis susceptibility gene and the proximal region of 4q, assuming locus homogeneity. The data statistically excluded the possibility that more than 40% of the families were linked to this candidate region for one model tested. Linkage under heterogeneity was excluded less strongly for other models, but no significant evidence in support of linkage was obtained for any model. Hart et al. (1993) concluded, therefore, that either the previous report of linkage was a false positive or that there are 2 or more unlinked forms of JPD, with the form located at 4q12-q13 being less common. ### Association Pending Confirmation In 159 German patients with generalized aggressive periodontitis, Schaefer et al. (2009) analyzed 3 SNPs on chromosome 9p21.3, rs2891168, rs1333042, and rs1333048, known to be in linkage disequilibrium with SNPs previously associated with coronary heart disease (see CHDS8, 611139), and found that the 3 SNPs tested were all associated with periodontitis (adjusted p = 0.0036 to 0.0077). The association was replicated in an independent population of 146 German patients with less severe localized aggressive periodontitis (adjusted p = 0.021 to 0.071). The region of association maps to the sequence of a large antisense noncoding RNA, ANRIL (CDKN2BAS; 613149), which partly overlaps regulatory and coding sequences of the CDKN2A (600160) and CDKN2B (600431) genes. A closely located type 2 diabetes-associated variant (see 125853) was independent of the CHD and periodontitis risk haplotypes. Schaefer et al. (2009) concluded that CHD and periodontitis are genetically related by at least 1 susceptibility locus. Schaefer et al. (2010) conducted a genomewide association study in German patients with aggressive periodontitis. The phenotype was strongly associated with the intronic SNP rs1537415 in the GLT6D1 gene (613699). In a combined analysis with the addition of a Dutch cohort (n = 1758), rs1537415 reached a genomewide significance level of P = 5.51 x 10(9), OR = 1.59 (95% CI 1.36-1.86). The associated rare G allele of rs1537415 showed an enrichment of 10% in periodontitis cases (48% in comparison with 39% in controls). Fine-mapping and haplotype analysis indicated that rs1537415 showed the strongest association signal; sequencing identified no further associated variant. Tissue-specific expression analysis of GLT6D1 indicated high transcript levels in testis, leukocytes, and gingiva. Analysis of potential transcription factor binding sites at the locus predicted a significant reduction of GATA3 (131320) binding affinity, and EMSA analysis indicated a T cell-specific reduction of protein binding for the G allele. Overexpression of GATA3 in HEK293 cells resulted in allele-specific binding of GATA3, indicating the identity of GATA3 as the binding protein. Schaefer et al. (2010) concluded that GLT6D1 is an important susceptibility factor for aggressive periodontitis and suggested that GATA3 may be a potential signaling component in the pathophysiology of periodontitis. Molecular Genetics By sequence analysis of the CTSC gene in a family segregating prepubertal periodontitis, Hart et al. (2000) found that all affected members were homozygous for a missense mutation (602365.0013). None of those affected had palmoplantar keratoderma. Hewitt et al. (2004) identified a mutation in the CTSC gene (602365.0012) in only 1 of 2 families with juvenile periodontitis. They suggested that the disorder is genetically heterogeneous and that one form represents a partially penetrant Papillon-Lefevre syndrome. ### Association Studies Amer et al. (1988) reported evidence for an association between HLA alleles and susceptibility to periodontitis. They studied 49 patients with severe periodontal disease, an elderly group with minimal disease, and a young group with minimal disease. The HLA-A9 antigen was present in 36.7% of the patients with severe disease and only 2.5% of the elderly patients with minimal disease, whereas the HLA-A10 antigen was present in 30% of the resistant group and was absent from the patient group. The authors concluded that A10 may play a role in resistance to periodontal disease, whereas A9 may confer additional susceptibility. Nomenclature Periodontosis was at one time considered to be an idiopathic destruction of alveolar bone distinct from periodontitis. Periodontosis and periodontitis were later found to be the same disorder (Boughman, 1987). INHERITANCE \- Autosomal recessive HEAD & NECK Mouth \- Severe, early-onset periodontitis \- Alveolar bone destruction \- Gingival recession Teeth \- Premature tooth loss SKIN, NAILS, & HAIR Skin \- No palmoplantar keratosis MISCELLANEOUS \- Genetic heterogeneity \- Allelic to Papillon-Lefevre syndrome ( 245000 ) and Haim-Munk syndrome ( 245010 ) MOLECULAR BASIS \- Caused by mutation in the cathepsin C gene (CTSC, 602365.0012 ) ▲ 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	PERIODONTITIS, AGGRESSIVE, 1	c0031106	3,424	omim	https://www.omim.org/entry/170650	2019-09-22T16:36:20	{"doid": ["1474"], "mesh": ["D010520"], "omim": ["170650"], "icd-10": ["K05.2"], "synonyms": ["Alternative titles", "PERIODONTITIS, JUVENILE", "PERIODONTITIS, PREPUBERTAL"]}
A number sign (#) is used with this entry because of evidence that lissencephaly-8 (LIS8) is caused by homozygous or compound heterozygous mutation in the TMTC3 gene (617218) on chromosome 12q21. Description Lissencephaly-8 is an autosomal recessive neurologic disorder characterized by delayed psychomotor development, intellectual disability with poor or absent speech, early-onset refractory seizures, and hypotonia. Brain imaging shows variable features, including cortical gyral abnormalities and hypoplasia of the corpus callosum, brainstem, and cerebellum (summary by Jerber et al., 2016). For a general description and a discussion of genetic heterogeneity lissencephaly, see LIS1 (607432). Clinical Features Jerber et al. (2016) reported 9 children from 6 consanguineous families, mostly of Arab descent, with lissencephaly-8. All had delayed psychomotor development with poor or absent language, intellectual disability, truncal hypotonia, and appendicular spasticity. Six patients developed refractory generalized or myoclonic seizures in infancy. Two patients had microcephaly (-7.5 SD and -4 SD, respectively), 2 had autistic features, and 2 had clubfeet. Ophthalmologic abnormalities were rare: only 2 patients had cataracts, one of whom also had optic atrophy and the other microphthalmia. Brain imaging, performed in all patients, showed common but somewhat variable features, including agyria, cobblestone lissencephaly, polymicrogyria, ventriculomegaly, hypoplasia of the corpus callosum, and hypoplasia/dysplasia of the brainstem and cerebellum. Two patients had occipital encephalocele. Two patients had increased serum creatine kinase, which was associated with mild myopathic changes on muscle biopsy in 1 patient. Muscle biopsy was not routinely performed. Inheritance The transmission pattern of LIS8 in the families reported by Jerber et al. (2016) was consistent with autosomal recessive inheritance. Molecular Genetics In 9 children from 6 consanguineous families, mostly of Arab origin, with LIS8, Jerber et al. (2016) identified biallelic mutations in the TMTC3 gene (see, e.g., 617218.0001-617218.0005). The mutations, which were found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the families. Most of the mutations resulted in a truncated protein, although 2 affected sibs carried a homozygous missense mutation. Functional studies of the variants and studies of patient cells were not performed, but Jerber et al. (2016) postulated a loss-of-function effect. INHERITANCE \- Autosomal recessive HEAD & NECK Head \- Microcephaly (in some patients) Eyes \- Ophthalmologic abnormalities are rare \- Cataracts (in some patients) \- Optic atrophy (in 1 patient) SKELETAL Feet \- Club feet (in some patients) MUSCLE, SOFT TISSUES \- Truncal hypotonia \- No muscle atrophy NEUROLOGIC Central Nervous System \- Delayed psychomotor development \- Delayed walking \- Intellectual disability \- Poor or absent speech \- Seizures \- Appendicular spasticity \- Lissencephaly, cobblestone \- Polymicrogyria \- Ventriculomegaly \- Abnormal myelination (in some patients) \- Hypoplasia of the corpus callosum \- Hypoplasia of the brainstem \- Hypoplasia of the cerebellum \- Dysplasia of the brainstem \- Dysplasia of the cerebellum \- Occipital encephalocele (in some patients) Behavioral Psychiatric Manifestations \- Autistic features (in some patients) LABORATORY ABNORMALITIES \- Increased serum creatine kinase (rare) MISCELLANEOUS \- Onset in infancy MOLECULAR BASIS \- Caused by mutation in the transmembrane and tetratricopeptide repeat domains-containing protein 3 gene (TMTC3, 617218.0001 ) ▲ 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	LISSENCEPHALY 8	c4310646	3,425	omim	https://www.omim.org/entry/617255	2019-09-22T15:46:20	{"omim": ["617255"]}
Hypothyroidism due to mutations in transcription factors involved in pituitary development or function is a type of central congenital hypothyroidism (see this term), a permanent thyroid deficiency that is present from birth, characterized by low levels of thyroid hormones caused by disorders in the development or function of the pituitary. ## Epidemiology Prevalence is unknown. ## Clinical description The clinical manifestations can be subtle, probably as a result of trans-placental passage of some maternal thyroid hormone or due to the fact that many infants have some thyroid production of their own. More specific symptoms and signs often do not develop until several months of age. Common clinical features and signs include decreased activity and increased sleep, feeding difficulty and constipation, prolonged jaundice, myxedematous facies, large fontanels (especially posterior), macroglossia, a distended abdomen with umbilical hernia, and hypotonia. Goiter is always absent. Slow linear growth and developmental delay are usually apparent by 4-6 months of age. Without treatment hypothyroidism results in severe intellectual deficit and short stature. Clinical manifestations may often include signs of hypopituitarism including septo-optic dysplasia or cleft lip and/or palate among others. ## Etiology The hypothyroidism is caused by mutations in genes regulating pituitary gland development including HESX1, LHX3, LHX4, POU1F1 and PROP1 (3p21.2-p21.1, 9q34.3, 1q25, 3p11 and 5q) . [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: 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	Hypothyroidism due to deficient transcription factors involved in pituitary development or function	None	3,426	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=226307	2021-01-23T17:12:35	{"icd-10": ["E03.1"]}
Non-syndromic male infertility due to sperm motility disorder is a rare, genetic, non-syndromic male infertility disorder characterized by infertility due to sperm with defects in their cilia/flagella structure, leading to absent motility or reduced forward motility in fresh ejaculate. Reduced semen volume, oligospermia and an increased number of abnormally structured spermatozoa is often present. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Non-syndromic male infertility due to sperm motility disorder	c1847540	3,427	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=276234	2021-01-23T17:40:16	{"mesh": ["C564665"], "omim": ["606766", "612997", "614822", "617576", "617592", "617593", "617965", "618152", "618153", "618429", "618433", "618643", "618664", "618670", "618745", "618751"], "icd-10": ["N46"], "synonyms": ["Non-syndromic male infertility due asthenozoospermia"]}
Hughes-Stovin syndrome (HSS) is a life-threatening disorder, believed to be a cardiovascular clinical variant manifestation of Behçet's disease (BD; see this term). It is characterized by the association of multiple pulmonary artery aneurysms (PAAs) and peripheral venous thrombosis. ## Epidemiology Prevalence is unknown but fewer than 30 cases have been reported in the literature since its first description in 1959 by Hughes and Stovin. ## Clinical description Patients (mostly men aged 12-40 years) generally present with the nonspecific signs of PAA (hemoptysis, cough, dyspnea, chest pain, and signs of pulmonary hypertension), following a history of peripheral venous thrombosis. Other associated signs may include fever and intracranial hypertension. Aneurysms usually involve the pulmonary arteries and the bronchial arteries resulting in subsequent hemoptysis. However, they can occur anywhere in systemic circulation. Recurrent phlebitis also commonly involves the large vessels, resulting in thrombus formation. In general, there is a predisposition for thrombus formation affecting the peripheral veins. Thrombosis of the vena cava and of the right atrium has also been described. ## Etiology The etiology of HSS is unknown; however, it is assumed that HSS is a form of vasculitis following a similar mechanism of pathogenesis to that thought to be involved in BD. ## Diagnostic methods Diagnosis of HSS is made on the basis of the clinical picture (association of venous thrombosis and PAAs in a young patient), patient history and imaging studies (chest radiographs, conventional angiography or helical computed tomography) for detection and evaluation of the PAAs. Histologic studies show destruction of the arterial wall and perivascular lymphomonocytic infiltration of capillaries and venules. ## Differential diagnosis The pulmonary manifestations of HSS and BD have been reported to be identical, but the two syndromes can be distinguished on the basis of the absence of mucocutaneous findings in HSS. ## Management and treatment Initial management of HSS often involves administration of corticosteroids, usually in combination with cytotoxic agents (intravenous cyclophosphamide followed by oral azathioprine) to stabilize the PAAs. Despite the presence of thrombosis, anticoagulants are contraindicated due to the risk of life-threatening PAA rupture. Surgical resection provides an effective treatment option for patients with unilateral or localized PAAs and less invasive approaches such as transcatheter embolization may be feasible in some cases. ## Prognosis As most patients with HSS are diagnosed late in the disease course, the syndrome is associated with significant mortality due to massive hemoptysis resulting from PAA rupture or systemic bronchial artery hypertrophy secondary to ischemia related to the pulmonary artery occlusion. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: 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	Hughes-Stovin syndrome	None	3,428	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=228116	2021-01-23T17:26:54	{"icd-10": ["I28.8"]}
A number sign (#) is used with this entry because of evidence that the form of recessive achromatopsia present in high incidence among Pingelapese islanders, here designated achromatopsia-3 (ACHM3), is caused by homozygous or compound heterozygous mutation in the CNGB3 gene (605080), which encodes the beta subunit of the cone cyclic nucleotide-gated cation channel, on chromosome 8q21. A form of achromatopsia designated ACHM1 was later found to be the same as ACHM3, caused by mutation in the CNGB3 gene (605080.0002). For a general description and a discussion of genetic heterogeneity of achromatopsia, see ACHM2 (216900). Clinical Features Brody et al. (1970) described in Pingelapese people of the eastern Caroline Islands in the Pacific, a severe ocular abnormality manifested by horizontal pendular nystagmus, photophobia, amaurosis, colorblindness, and gradually developing cataract. From 4 to 10% of Pingelapese people are blind from infancy. Segregation analysis and equal sex distribution supported recessive inheritance. The high gene frequency was attributed to reduction in the population to about 9 surviving males by a typhoon (about 1780), combined with subsequent isolation. Whether the disorder is a form of congenital achromatopsia or a tapetoretinal degeneration with primary involvement of the cones was not clear. Carr et al. (1970) studied the same group and concluded that it is congenital complete achromatopsia. The impression of tapetoretinal degeneration was based, they thought, on severe myopia which was found in a majority of the affected persons. The disorder is nonprogressive. Compare retinal cone degeneration (180020). Maumenee (1977) concluded that Pingelapese blindness is distinct from total colorblindness (216900), mainly because of the consistent concurrence of severe myopia in the Pingelapese disease. Refraction is usually normal in total colorblindness. Pentao et al. (1992) described a 20-year-old white female with rod monochromacy who presented with short stature (less than 5th percentile), mild developmental delay, premature puberty, small hands and feet (length less than 5th percentile), and a history of 3 consecutive first-trimester miscarriages. Cytogenetic analysis showed a 14;14 Robertsonian translocation; haplotype analysis was consistent with maternal isodisomy for all portions of chromosome 14 tested by SNP markers. The finding suggested that a form of rod monochromacy, designated ACHM1, mapped to chromosome 14; however, Wiszniewski et al. (2007) restudied this patient and identified homozygosity for a 1-bp deletion in the CNGB3 gene (1148delC; 605080.0002). Using optical coherence tomography (OCT), Varsanyi et al. (2007) examined in vivo the anatomic structure of the retina in patients with achromatopsia and controls. In patients with achromatopsia, statistically significant reductions were found in total macular volume and in the thickness of the central retina compared with controls. Varsanyi et al. (2007) stated that a possible reason for the structural alteration is the qualitative and/or quantitative disorder of the cone photoreceptors, as the morphologic change is most expressed in the foveola. Lee et al. (2015) studied retinal development in 10 children with achromatopsia (8 with ACHM3 and 2 with ACHM2) in comparison with 59 age-, gender-, and race-matched controls. Longitudinal data were available for 7 of the patients, with mean follow-up of 18.9 months (range, 5.3-35.5). In all of the participants with ACHM, there was evidence of foveal hypoplasia at each visit on OCT examination. A delay in migration of the photoreceptors into the central fovea was evident in the youngest patients. There was evidence of photoreceptor disruption (ellipsoid disruption and/or a hyporeflective zone) in the ACHM group, with variable severity. Retinal development occurred at a reduced rate and magnitude in children with ACHM in comparison with controls, with consequences for all retinal layers. Inheritance Achromatopsia-3 is an autosomal recessive disorder (Sundin et al., 2000). Mapping Winick et al. (1999) performed a genomewide search for linkage in 3 Pingelapese kindreds with achromatopsia. A 2-step search was used with a DNA pooling strategy, followed by genotyping of individual family members. Genetic markers that displayed a shift toward homozygosity in the affected DNA pool were used to genotype individual members of the kindreds, and an achromatopsia locus was identified at 8q21-q22. A maximal multipoint lod score of 9.5 was observed with marker D8S1707. Homozygosity was seen in 3 adjacent markers (D8S275, D8S1119, and D8S1707), whereas recombination was observed with the flanking markers D8S1757 and D8S270, defining the outer boundaries of the disease locus that spans a distance of less than 6.5 cM. Milunsky et al. (1999) used linkage mapping to locate a gene for achromatopsia on 8q in a kindred with Irish ancestry. Five of 12 sibs were affected. A maximal multipoint lod score of 3.283 was observed near marker D8S271. Milunsky et al. (1999) raised the possibility that sailors of English/Irish descent introduced the 8q gene to the South Pacific Island of Pingelap. Molecular Genetics To refine the position of the ACHM3 locus by homozygosity mapping, Sundin et al. (2000) genotyped 60 affected individuals and narrowed the disease locus to a 1.4-cM interval, estimated at 2 Mb. Sundin et al. (2000) found that the genetic basis of Pingelapese achromatopsia at 8q21-q22 is a recessive point mutation in the CNGB3 gene that changes serine at residue 435 to phenylalanine in a highly conserved site in the S6 membrane-spanning domain (605080.0001). Two brothers in 1 family were found to be compound heterozygotes for 2 small frameshift deletions (e.g., 1148delC). The findings established that classic achromatopsia results from a complete loss of CNGB3 function and that this gene is not required for vital processes outside the visual system. Thus, CNGA3 and CNGB3 encode the alpha and beta subunits of a single cyclic nucleotide-gated channel that is located in the photoreceptor plasma membrane and is essential for the generation of light-evoked electrical responses in the red-, green-, and blue-sensitive cones. Wiszniewski et al. (2007) analyzed the CNGA3, CNGB3, and GNAT2 genes in 16 unrelated patients with autosomal recessive ACHM: 10 patients had mutations in CNGB3, 3 had mutations in CNGA3, and no coding region mutations were found in 3 patients. The 1148delC mutation accounted for 75% (18/24) of disease-associated alleles and was found in 10 patients, including a homozygous female with achromatopsia previously reported by Pentao et al. (1992), who also had systemic features associated with maternal uniparental disomy (UPD) for chromosome 14. Analysis of intragenic SNPs in unrelated patients revealed transmission of a common haplotype consistent with a founder effect for the 1148delC mutation. Wiszniewski et al. (2007) concluded that CNGA3 and CNGB3 mutations are responsible for the substantial majority of achromatopsia. Population Genetics Among 798 individuals of south Asian origin, Lazarin et al. (2013) determined that the carrier frequency for achromatopsia caused by CNGB3 mutation was approximately 1 in 24. Among 15,798 ethnically diverse individuals screened, 162 carriers were identified (1%), for a carrier frequency of approximately 1 in 98. Animal Model Sidjanin et al. (2002) identified mutations in the canine homolog of CNGB3 in Alaskan malamutes and German shorthaired pointers affected with cone degeneration. History For a popular account of the Pingelapese people, see 'The Island of the Colorblind' by Oliver Sacks (1997). INHERITANCE \- Autosomal recessive HEAD & NECK Eyes \- Horizontal pendular nystagmus \- Photophobia \- Amaurosis \- Colorblindness \- Congenital complete achromatopsia \- Cataract \- Severe myopia \- Decreased foveolar thickness MOLECULAR BASIS \- Caused by mutation in the cyclic nucleotide-gated channel, beta-3 gene (CNGB3, 605080.0001 ) ▲ 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	ACHROMATOPSIA 3	c0152200	3,429	omim	https://www.omim.org/entry/262300	2019-09-22T16:23:28	{"doid": ["0110008"], "mesh": ["D003117"], "omim": ["262300"], "orphanet": ["49382"], "synonyms": ["Alternative titles", "PINGELAPESE BLINDNESS", "TOTAL COLORBLINDNESS WITH MYOPIA", "ACHROMATOPSIA WITH MYOPIA", "ACHM1, FORMERLY", "ROD MONOCHROMATISM 1, FORMERLY", "ROD MONOCHROMACY 1, FORMERLY"], "genereviews": ["NBK1418"]}
A number sign (#) is used with this entry because of evidence that autosomal recessive deafness-49 (DFNB49) is caused by homozygous mutation in the gene encoding tricellulin (MARVELD2; 610572) on chromosome 5q13. Mapping Ramzan et al. (2005) reported 2 large consanguineous Pakistani families (PKDF041 and PKDF141) with autosomal recessive congenital profound sensorineural hearing loss of all frequencies. Genomewide linkage analysis followed by fine mapping of both families showed linkage to a candidate disease locus, termed DFNB49, on chromosome 5q12.3-q14.1 (maximum 2-point lod scores of 4.44 and 5.94 at D5S2055 and D5S424 in the 2 families, respectively). Haplotype analysis delineated an 11-cM interval flanked by D5S647 and D5S1501. Direct sequencing excluded mutations in coding regions of the SLC30A5 (607819) and SLC12A2 (600840) genes. One of the families (PKDF041) was later found to carry a homozygous mutation in the PPIP5K2 gene (611648.0001), consistent with a diagnosis of DFNB100 (618422). Riazuddin et al. (2006) identified 6 additional DFNB49 families and refined the critical interval to 2.4 Mb. They found homozygous mutations in the MARVELD2 gene to be the cause of the disorder in all families. Four families were homozygous for the same disease haplotype and carried the same mutation located in the splice donor site of exon 4 (610572.0003). Two families segregated a deletion of this same splice donor site (610572.0002), and 1 family segregated a mutation in the splice acceptor site of exon 4 (610572.0001). Affected members of the remaining family carried a nonsense mutation in exon 5 (610572.0004). All of these mutations resulted in proteins that lacked the ability to bind to the scaffolding protein ZO1 (601009) because of the loss of the conserved C-terminal occludin-ELL domain. Molecular Genetics In affected members of 3 consanguineous Pakistani kindreds with autosomal recessive nonsyndromic deafness, Chishti et al. (2008) identified 2 different homozygous mutations in the MARVELD2 gene (612572.0003, 610572.0005), one of which had previously been reported. The authors estimated that the prevalence of autosomal recessive deafness due to MARVELD2 mutations in Pakistani families is 1.06%. INHERITANCE \- Autosomal recessive HEAD & NECK Ears \- Deafness, prelingual, profound (affects all frequencies) MOLECULAR BASIS \- Caused by mutations in the marvel domain-containing protein 2 gene (MARVELD2, 610572.0001 ) ▲ 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	DEAFNESS, AUTOSOMAL RECESSIVE 49	c1857811	3,430	omim	https://www.omim.org/entry/610153	2019-09-22T16:05:01	{"doid": ["0110506"], "mesh": ["C565717"], "omim": ["610153"], "orphanet": ["90636"], "synonyms": ["Autosomal recessive isolated neurosensory deafness type DFNB", "Autosomal recessive isolated sensorineural deafness type DFNB", "Autosomal recessive non-syndromic neurosensory deafness type DFNB"], "genereviews": ["NBK1434"]}
A form of von Willebrand disease (VWD) characterized by a bleeding disorder associated with a qualitative deficiency and functional anomalies of the Willebrand factor (VWF). Depending on the type of functional abnormalities, this form is classified as type 2A, 2B, 2M or 2N. ## Epidemiology The subtypes of type 2 VWD account for between 20-45% of cases of VWD. ## Clinical description Age of onset of the bleeding anomalies varies, with earlier onset being associated with more severe VWF deficiency. Four type 2 VWD subtypes have been described: types 2A, 2B and 2M are characterized by mucocutaneous manifestations (menorrhagia, epistaxis, gastrointestinal hemorrhage etc.); type 2N is mainly characterized by post traumatic soft tissue bleedings. There is an increased risk of abnormal bleeding following an invasive procedure associated with all type 2 subtypes. ## Etiology The VWF gene (12p13.3) anomalies that lead to type 2 VWD involve the well-defined functional domains of the VWF protein. Three of these subtypes are associated with anomalies in the interaction of VWF with platelets and/or the subendothelium, and are caused by decreased affinity for platelets in combination with VWF multimerization anomalies (type 2A), increased VWF affinity for platelets (type 2B), or decreased VWF affinity for platelets or collagen and normal VWF multimerization (type 2M). The fourth subtype (type 2N) is associated with decreased VWF affinity for factor VIII (FVIII); the interactions between the platelets and the vessel walls are often normal and the FVIII deficiency is usually only moderate. ## Diagnostic methods For subtypes 2A, 2B and 2M, diagnosis is suspected following detection of a notably more profound decrease in functional VWF levels than in VWF antigen levels. This discrepancy between the functional VWF levels and VWF antigen levels also allows the type 2 disease to be distinguished from VWD type 1. However, more specific laboratory tests (analysis of the structure and distribution of the multimers) are required to diagnose the exact type 2 subtype. A thrombocytopenia can be observed in type 2B. Diagnosis of type 2N is suspected when the decrease in FVIII levels is much greater than that of VWF, and confirmed by a factor VIII binding assay. ## Differential diagnosis Subtypes 2A, 2B and 2M can be differentiated from acquired von Willebrand syndrome (AVWS), clinically by the onset of bleeding manifestations at a young age, a family history of the disease and the absence of an underlying pathology, and through molecular analysis revealing a mutation in the VWF gene. The factor VIII binding assay, together with molecular analysis of the VWF gene, allows type 2N VWD to be distinguished from mild hemophilia A. ## Genetic counseling Most subtypes of type 2 VWD are transmitted in an autosomal dominant manner except for type 2N and some rare forms of type 2A which are autosomal recessive. Genetic counseling should be proposed to inform patients about the severity of the disease and the associated risks, and to allow screening for detection of other affected family members. In case of recessive transmission where both parents are carriers of the disease-causing mutation, the at-risk couple should be informed that there is a 25% risk of having an affected child at each pregnancy. ## Management and treatment Medication (such as tranexamic acid for ENT (ear, nose and throat) bleeding anomalies and estrogen-progesterone therapy for menorrhagia) provides an effective treatment and may be prescribed alone or as an adjuvant therapy. The response to desmopressin varies depending on the type 2 subtype, as the endogenous VWF released from the endothelial cells in response to this treatment displays the same functional anomalies as plasmatic VWF. Desmopressin is contraindicated in patients with subtype 2B. Preventative or curative treatment for abnormal bleeding events often involves substitution therapy with purified human VWF. Platelet concentrates may have to be transfused in some patients with type 2B. ## Prognosis For patients managed within specialized hemostasis hospital centers, the prognosis is favorable, even for those with the most severe forms 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	Von Willebrand disease type 2	c1264040	3,431	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=166081	2021-01-23T19:12:47	{"mesh": ["D056728"], "omim": ["613554"], "umls": ["C1264040"], "icd-10": ["D68.0"]}
A number sign (#) is used with this entry because of evidence that metaphyseal dysplasia and maxillary hypoplasia with or without brachydactyly (MDMHB) is caused by heterozygous duplication resulting in a gain of function in the RUNX2 gene (600211) on chromosome 6p21. Heterozygous loss-of-function mutation in the RUNX2 gene results in cleidocranial dysplasia (CCD; 119600). Description Metaphyseal dysplasia and maxillary hypoplasia with or without brachydactyly (MDMHB) is an autosomal dominant bone dysplasia characterized by metaphyseal flaring of long bones, enlargement of the medial halves of the clavicles, maxillary hypoplasia, variable brachydactyly, and dystrophic teeth (summary by Moffatt et al., 2013). Clinical Features Halal et al. (1982) reported a characteristic syndrome in 4 generations of a French Canadian family. The features were metaphyseal dysplasia with short stature (about 152 cm in both sexes); beaked nose, short philtrum, thin lips, maxillary hypoplasia, 'dystrophic' yellowish teeth with early loss and short metacarpal 5 and/or short middle phalanx of fingers 2 and 5. Skeletal roentgenograms in adults showed 'massive enlargement of the sternal ends of the clavicles; flaring of the metaphyses with thin cortex and osteoporosis most striking in the proximal humerus, distal femur and proximal tibia; platyspondyly, multiple small vertebral fractures, and osteoporosis of the vertebrae.' Male-to-male transmission was observed in 2 instances. Similarities to oculodentodigital dysplasia (164200) were noted, but important differences, particularly lack of ocular manifestations, in this syndrome speak for its distinctness. Moffatt et al. (2013) studied a 4-generation French Canadian family that was from the same region of Quebec (Gaspesie) as the family reported by Halal et al. (1982) and had a very similar phenotype. Histomorphometric analysis of transiliac bone biopsy samples showed thin cortices and a low amount of trabecular bone. Mineral apposition rate, a marker of bone formation, was low, suggesting a defect in osteoblast function, whereas osteoclast surface, a marker of bone resorption, was normal. Biochemical parameters of bone and mineral metabolism were mostly within normal limits. Lumbar spine bone mineral density was low in some affected individuals but normal in others; however, peripheral quantitative CT of the radius showed that cortices were very thin at both the metaphysis and the diaphysis. In affected individuals, osteocyte density was 32% lower than that of age-matched controls, although the material density of trabecular bone was slightly increased compared to controls. Moffatt et al. (2013) noted that brachydactyly, which was an inconsistent feature in the family described by Halal et al. (1982), was not observed in affected individuals from this family. Avela et al. (2014) described a 20-year-old Finnish patient with clinical and radiologic findings of MDMHB. The patient had a normal birth length, but by age 20 years, her height was at the 3rd centile. She had frequent bone pain, especially affecting her knees. Facial features included micrognathia, beaked nose, and thin lips. Radiographs showed a thick cranial vault, bilateral brachydactyly, metaphyseal flaring at multiple locations, widened clavicles, and irregularly shaped vertebrae. Bones were osteoporotic based on radiographs and bone densitometry. Teeth were small and fragile. Primary tooth resorption was deficient, requiring extraction, and eruption of permanent teeth was delayed. No teeth were missing congenitally. The patient also had a hypoplastic maxilla and retrognathic mandible. Her mother, who had short stature (155 cm at age 46 years), had no brachydactyly on clinical exam, but had oligodontia with 5 congenitally missing teeth. Teeth were small with browning enamel and short roots. She had a progenic mandible and retrusive maxilla. Both mother and daughter had normal psychomotor development. Al-Yassin et al. (2018) reported 3 affected female members of a 3-generation family with MDMHB. The proband, her mother, and her materal grandmother were short, with heights at the 0.4th, 9th, and 2nd centile, respectively. All 3 had dystrophic yellowish teeth, maxillary hypoplasia, metaphyseal dysplasia, and clavicular broadening. Two patients had delayed closure of the anterior fontanel, and 1 had osteoporosis and brachydactyly Al-Yassin et al. (2018) emphasized the importance of considering an underlying skeletal dysplasia in patients with significant dental problems and other suggestive features, including disproportionate short stature and digital anomalies. Mapping Using DNA from 5 affected and 4 unaffected members of a 4-generation French Canadian family segregating autosomal dominant metaphyseal dysplasia and maxillary hypoplasia with or without brachydactyly (MDMHB), Moffatt et al. (2013) performed whole-genome SNP genotyping and obtained the maximum achievable lod score of 2.1 for regions on chromosomes 6, 11, and 15. Molecular Genetics In a 4-generation French Canadian family with MDMHB, Moffatt et al. (2013) analyzed SNP array data for copy number variation and found that all affected individuals had a 105-kb duplication within the linked region on chromosome 6 (chr6:45,308,920-45,413,885, GRCh37), comprising exons 3 to 5 of the RUNX2 gene (600211.0014), that was absent in unaffected family members. In a 20-year-old Finnish woman with MDMHB, Avela et al. (2014) identified heterozygosity for an intragenic duplication in RUNX2 encompassing exons 3 to 5. Similar to the duplication reported by Moffatt et al. (2013), the duplication breakpoints were in intron 2 and intron 5; the location of the breakpoints differed, but the exact breakpoints in the Finnish patient were not identified. In 3 affected members of a 3-generation family with MDMHB, Al-Yassin et al. (2018) identified heterozygosity for an intragenic tandem duplication of RUNX2 exons 3-6 (600211.0015). Further analysis showed that exon 3 was spliced to exon 6, confirming a tandem duplication, which was predicted to be in-frame. Radiology \- Enlarged sternal ends of clavicles \- Flared metaphyses with thin cortex and osteoporosis, esp \- proximal humerus, distal femur and proximal tibia \- Platyspondyly \- Multiple small vertebral fractures \- Osteoporosis of vertebrae Skel \- Metaphyseal dysplasia Limbs \- Short fifth metacarpal \- Short middle phalanx of fingers 2 and 5 Growth \- Short stature Mouth \- Thin lips Facies \- Maxillary hypoplasia \- Short philtrum Teeth \- Dystrophic yellowish teeth \- Early tooth loss Inheritance \- Autosomal dominant Nose \- Beaked nose ▲ 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	METAPHYSEAL DYSPLASIA WITH MAXILLARY HYPOPLASIA WITH OR WITHOUT BRACHYDACTYLY	c3549874	3,432	omim	https://www.omim.org/entry/156510	2019-09-22T16:38:15	{"omim": ["156510"], "orphanet": ["2504"], "synonyms": []}
For a phenotypic description and a discussion of episodic ataxia, see EA1 (160120). Clinical Features Kerber et al. (2007) reported a 4-generation family in which 7 members had episodic ataxia. Inheritance was autosomal dominant. Onset occurred before age 20 years, and attacks lasted hours to days and were associated with weakness and dysarthria. Triggers included exercise and excitement. Two affected family members reported vertigo during attacks. Frequency ranged from monthly to yearly and tended to decrease with age. Two affected family members had migraine headaches that were not associated with episodic ataxia. There were no interictal findings on neurologic examination. Mapping By genomewide linkage and haplotype analysis of a family with episodic ataxia, Kerber et al. (2007) identified a 10-cM candidate region, termed EA7, between rs1366444 and rs952108 on chromosome 19q13 (maximum lod score of 3.28). No mutations were identified in the KCNC3 (176264) or SLC17A7 (605208) genes. INHERITANCE \- Autosomal dominant NEUROLOGIC Central Nervous System \- Ataxia, episodic (episodes last from hours to days) \- Weakness \- Dysarthria \- Vertigo \- Normal interictal neurologic examination MISCELLANEOUS \- Onset before age 20 years \- Symptoms precipitated by exercise and excitement \- Episode frequency is monthly to yearly, and decreases with age ▲ 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	EPISODIC ATAXIA, TYPE 7	c2677843	3,433	omim	https://www.omim.org/entry/611907	2019-09-22T16:02:38	{"doid": ["0050995"], "mesh": ["C567459"], "omim": ["611907"], "orphanet": ["209970"]}
A rare, genetic, alpha-crystallinopathy disease characterized by adult-onset myofibrillar myopathy, variably associated with cardiomyopathy and/or posterior pole cataracts. Patients typically present progressive proximal and distal muscle weakness and wasting of lower and upper limbs, often with velopharyngeal involvement including dysphagia, dysphonia and ventilatory insufficiency. Electromyography shows myopathic features and muscle biopsy reveals myofibrillar myopthay changes. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: 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	Alpha-B crystallin-related late-onset myopathy	c1837317	3,434	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=399058	2021-01-23T18:19:20	{"mesh": ["C563848"], "omim": ["608810"], "icd-10": ["G71.0"], "synonyms": ["Alpha-B crystallin-related late-onset distal myopathy", "Late-onset distal crystallinopathy"]}
Personality disorder characterized by procrastination, covert obstructionism, inefficiency and stubbornness Passive–aggressive personality disorder SpecialtyPsychiatry, clinical psychology Personality disorders Cluster A (odd) * Paranoid * Schizoid * Schizotypal Cluster B (dramatic) * Antisocial * Borderline * Histrionic * Narcissistic Cluster C (anxious) * Avoidant * Dependent * Obsessive–compulsive Not specified * Depressive * Haltlose * Immature * Passive–aggressive * Cyclothymic * Psychopathy * v * t * e The current version of the Diagnostic and Statistical Manual of Mental Disorders no longer uses this phrase or label, and it is not one of the ten listed specific personality disorders. The previous edition, the revision IV (DSM-IV) describes passive–aggressive personality disorder as a proposed disorder involving a "pervasive pattern of negativistic attitudes and passive resistance to demands for adequate performance" in a variety of contexts.[1]:734–735 Passive-aggressive behavior is the obligatory symptom of the passive–aggressive personality disorder. Persons with passive–aggressive personality disorder are characterized by procrastination, covert obstructionism, inefficiency and stubbornness.[2] ## Contents * 1 Causes * 2 Diagnosis * 2.1 Diagnostic and Statistical Manual * 2.2 ICD-10 * 2.3 Millon's subtypes * 3 Treatment * 4 History * 5 References * 6 Bibliography * 7 External links ## Causes[edit] Passive–aggressive disorder may stem from a specific childhood stimulus[3] (e.g., alcohol/drug addicted parents, bullying, abuse) in an environment where it was not safe to express frustration or anger. Families in which the honest expression of feelings is forbidden tend to teach children to repress and deny their feelings and to use other channels to express their frustration. For example, if physical and psychological punishment were to be dealt to children who express anger, they would be inclined to be passive aggressive. Children who sugarcoat hostility may have difficulties being assertive, never developing better coping strategies or skills for self-expression. They can become adults who, beneath a "seductive veneer," harbor "vindictive intent," in the words of Timothy F. Murphy and Loriann Oberlin.[4] Alternatively individuals may simply have difficulty being as directly aggressive or assertive as others. Martin Kantor suggests three areas that contribute to passive–aggressive anger in individuals: conflicts about dependency, control, and competition, and that a person may be termed passive–aggressive if they behave so to few people on most occasions.[5] Murphy and Oberlin also see passive aggression as part of a larger umbrella of hidden anger stemming from ten traits of the angry child or adult. These traits include making one's own misery, the inability to analyze problems, blaming others, turning bad feelings into angry ones, attacking people, lacking empathy, using anger to gain power, confusing anger with self-esteem, and indulging in negative self-talk. Lastly, the authors point out that those who hide their anger can be nice when they wish to be.[6] ## Diagnosis[edit] ### Diagnostic and Statistical Manual[edit] With the publication of the DSM-5, this label has been largely disregarded. The equivalent DSM-5 diagnostic label would be “Other specified personality and unspecified personality disorder,” as the individual may meet general criteria for a personality disorder, but does not meet the trait-based diagnostic criteria for any specific personality disorder (p645). Passive–aggressive personality disorder was listed as an Axis II personality disorder in the DSM-III-R, but was moved in the DSM-IV to Appendix B ("Criteria Sets and Axes Provided for Further Study") because of controversy and the need for further research on how to also categorize the behaviors in a future edition. According to DSM-IV, people with passive–aggressive personality disorder are "often overtly ambivalent, wavering indecisively from one course of action to its opposite. They may follow an erratic path that causes endless wrangles with others and disappointment for themselves." Characteristic of these persons is an "intense conflict between dependence on others and the desire for self-assertion." Although exhibiting superficial bravado, their self-confidence is often very poor, and others react to them with hostility and negativity. This diagnosis is not made if the behavior is exhibited during a major depressive episode or can be attributed to dysthymic disorder.[1] ### ICD-10[edit] The 10th revision of the International Classification of Diseases (ICD-10) of the World Health Organization (WHO) includes passive–aggressive personality disorder in the "other specific personality disorders" rubric (description: "a personality disorder that fits none of the specific rubrics: F60.0–F60.7"). ICD-10 code for "other specific personality disorders" is F60.8. For this psychiatric diagnosis a condition must meet the general criteria for personality disorder listed under F60 in the clinical descriptions and diagnostic guidelines. The general criteria for personality disorder includes markedly disharmonious behavior and attitudes (involving such areas of functioning as affectivity – ability to experience affects: emotions or feelings, involving ways of perceiving and thinking, impulse control, arousal, style of relating to others), the abnormal behavior pattern (enduring, of long standing), personal distress and the abnormal behavior pattern must be clearly maladaptive and pervasive.[7] Personality disorder must appear during childhood or adolescence and continue into adulthood.[7] Specific diagnostic criteria of the passive–aggressive personality disorder in the "Diagnostic criteria for research" by WHO is not presented.[8] ### Millon's subtypes[edit] The psychologist Theodore Millon has proposed four subtypes of 'negativist' ('Passive–aggressive').[9] Any individual negativist may exhibit none or one of the following: Subtype Description Personality traits Vacillating negativist Including borderline features Emotions fluctuate in bewildering, perplexing, and enigmatic ways; difficult to fathom or comprehend own capricious and mystifying moods; wavers, in flux, and irresolute both subjectively and intrapsychically. Discontented negativist Including depressive features Grumbling, petty, testy, cranky, embittered, complaining, fretful, vexed, and moody; gripes behind pretense; avoids confrontation; uses legitimate but trivial complaints. Circuitous negativist Including antisocial and dependent features Opposition displayed in a roundabout, labyrinthine, and ambiguous manner, e.g., procrastination, dawdling, forgetfulness, inefficiency, neglect, stubbornness, indirect and devious in venting resentment and resistant behaviors. Abrasive negativist Including sadistic features Contentious, intransigent, fractious, and quarrelsome; irritable, caustic, debasing, corrosive, and acrimonious, contradicts and derogates; few qualms and little conscience or remorse. (no longer a valid diagnosis in DSM) ## Treatment[edit] Psychiatrist Kantor suggests a treatment approach using psychodynamic, supportive, cognitive, behavioral and interpersonal therapeutic methods. These methods apply to both the passive–aggressive person and their target victim.[10] ## History[edit] In the first version of the Diagnostic and Statistical Manual of Mental Disorders, DSM-I, in 1952, the Passive–aggressive was defined in a narrow way, grouped together with the passive-dependent. The DSM-III-R stated in 1987 that Passive–aggressive disorder is typified by, among other things, "fail[ing] to do the laundry or to stock the kitchen with food because of procrastination and dawdling."[11] ## References[edit] 1. ^ a b American Psychiatric Association (2000). Diagnostic and Statistical Manual of Mental Disorders-IV. Washington, DC: American Psychiatic Association. pp. 733–34. ISBN 978-0-89042-024-9. 2. ^ Benjamin J. Sadock, Virginia A. Sadock (2008). Kaplan & Sadock's Concise Textbook of Clinical Psychiatry. Lippincott Williams & Wilkins. ISBN 978-0-7817-8746-8.[page needed] 3. ^ Johnson, JG; Cohen, P; Brown, J; Smailes, EM; Bernstein, DP (July 1999), "Childhood maltreatment increases risk for personality disorders during early adulthood", Arch. Gen. Psychiatry, 56 (7): 600–06, doi:10.1001/archpsyc.56.7.600, PMID 10401504 4. ^ Tim, Murphy; Hoff Oberlin, Loriann (2005), Overcoming passive aggression: how to stop hidden anger from spoiling your relationships, career and happiness, New York: Marlowe & Company, p. 48, ISBN 978-1-56924-361-9, retrieved April 27, 2010 5. ^ Kantor 2002, pp. xvi–xvii, 5. 6. ^ Tim, Murphy; Hoff Oberlin, Loriann (2005).[page needed] 7. ^ a b "Disorders of adult personality and behaviour (F60–F69). F60 Specific personality disorders" (PDF). The ICD-10 Classification of Mental and Behavioural Disorders – Clinical descriptions and diagnostic guidelines. Geneva: World Health Organization. pp. 157–58. Archived (PDF) from the original on 2014-03-23. Retrieved 2017-12-06. 8. ^ "Disorders of adult personality and behaviour (F60–F69). F60.8 Other specified personality disorders" (PDF). The ICD-10 Classification of Mental and Behavioural Disorders – Diagnostic criteria for research. Geneva: World Health Organization. p. 157. Archived (PDF) from the original on 2016-06-18. Retrieved 2017-12-06. 9. ^ Theodore Millon, Carrie M. Millon, Sarah E. Meagher; et al. (2012). Personality Disorders in Modern Life. John Wiley & Sons. pp. 529–31. ISBN 978-1-118-42881-8.CS1 maint: multiple names: authors list (link) 10. ^ Kantor 2002, p. 115. 11. ^ Lane, C (1 February 2009), "The Surprising History of Passive–aggressive Personality Disorder" (PDF), Theory & Psychology, 19 (1): 55–70, CiteSeerX 10.1.1.532.5027, doi:10.1177/0959354308101419, S2CID 147019317, archived (PDF) from the original on 2017-09-23, retrieved 2017-12-06 ## Bibliography[edit] * Kantor, Martin (2002), Passive-aggression: a guide for the therapist, the patient and the victim, Westport, CT: Praeger Publishers, ISBN 978-0-275-97422-0, retrieved December 6, 2017. ## External links[edit] Classification D * ICD-10: F60.8 * ICD-9-CM: 301.84 * MeSH: D010324 * v * t * e DSM personality disorders DSM-III-R only * Sadistic * Self-defeating (masochistic) DSM-IV only Personality disorder not otherwise specified Appendix B (proposed) * Depressive * Negativistic (passive–aggressive) DSM-5 (Categorical model) Cluster A (odd) * Paranoid * Schizoid * Schizotypal Cluster B (dramatic) * Antisocial * Borderline * Histrionic * Narcissistic Cluster C (anxious) * Avoidant * Dependent * Obsessive-compulsive DSM-5 Alternative hybrid categorical and dimensional model in Section III included to stimulate further research * v * t * e Personality disorders Schizotypal * Schizotypal Specific * Anankastic * Anxious (avoidant) * Dependent * Dissocial * Emotionally unstable * Histrionic * Paranoid * Schizoid * Other * Eccentric * Haltlose * Immature * Narcissistic * Passive–aggressive * Psychoneurotic Organic * Organic Unspecified * Unspecified [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: 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	Passive–aggressive personality disorder	c0030631	3,435	wikipedia	https://en.wikipedia.org/wiki/Passive%E2%80%93aggressive_personality_disorder	2021-01-18T18:39:01	{"mesh": ["D010324"], "icd-10": ["F60.8"], "wikidata": ["Q28823477"]}
A number sign (#) is used with this entry because the disorder is caused by mutation in the mitochondrial complex I, subunit ND6 gene (MTND6; 516006), the complex I, subunit ND4 gene (MTND4; 516003), the complex I, subunit ND1 gene (MTND1; 516000), and the MTND3 gene (516002). Clinical Features Marsden et al. (1986) reported a unique disorder in 7 members of 2 families in whom dystonia was variably associated with subacute visual loss or asymptomatic optic atrophy, and striking bilateral symmetric lucencies, especially in the putamen, were found on computerized tomography. Marsden et al. (1986) suggested that the disorder in a family reported by Miyoshi et al. (1969) may have been the same, as well as that in the large kindred reported by Novotny et al. (1985). Novotny et al. (1986) reported an American Hispanic family with Leber hereditary optic neuropathy (LHON; 535000) in which maternal relatives in the pedigree ranged from normal, to adult-onset optic atrophy, to pediatric dystonia associated with bilateral striatal necrosis. The later individuals experienced early-onset dementia with asymmetric dystonia, bulbar dysfunction, corticospinal tract abnormalities, and short stature. Computerized tomography and magnetic resonance imaging of the brain showed basal ganglia abnormalities, designated as 'infantile bilateral striatal necrosis,' with the onset of striatal necrosis between ages 1.5 and 9 years. One severely affected individual developed bilateral striatal necrosis, and later developed optic atrophy. Muscle biopsy of 1 severely affected individual showed excessive variation in fiber size and increased central nuclei, but no ragged-red fibers or ultrastructural abnormalities of mitochondria. One interesting feature of this pedigree is that LHON predominated in the earlier generations while dystonia predominated in the more recent generations. In generations I to III, of 22 maternal relatives, 7 (32%) had LHON while 2 (9%) had dystonia. By contrast, of the 20 maternal relatives in generation IV and V, 1 (5%) had LHON, 1 (5%) had both LHON and dystonia, and 12 (60%) had dystonia (Novotny et al., 1986; Wallace et al., 1985). Spruijt et al. (2007) reported a 35-year-old woman with sequential left and right vision loss, optic nerve atrophy, and bilateral central scotoma consistent with LHON. Serum and CSF lactate levels were increased, and brain MRI showed a few punctate white matter abnormalities. Her 34-year-old brother had developed progressive spastic dystonia beginning at age 3 years. Since age 27, he was wheelchair-bound with mental retardation, scoliosis, dysarthria, strabismus without ophthalmoplegia, and accumulation of abnormal mitochondria on sural nerve biopsy. His brain MRI showed bilateral hyperintensities in the putamen. Muscle biopsies from the sister and brother showed 8% and 16% residual complex I activity, respectively. Wang et al. (2009) reported a large Chinese Han family in which 6 members had Leber optic atrophy and dystonia. The proband, who was most severely affected, developed an abnormal gait at age 5 years after a bout of diarrhea. At age 14 years, he had painless and progressive visual loss, and lost ambulation due to dystonia. There was no evidence of mental or psychomotor retardation. By the third decade, he was unable to stand or speak clearly. Neurologic exam showed generalized spastic dystonia involving the limbs, trunk, neck, and face, with diffuse muscle wasting. Brain MRI showed abnormal signals in the basal ganglia. Other family members had a similar, but less severe, disease course with spastic gait, dystonia, visual loss, and basal ganglia lesions. Nine additional family members had sudden onset of painless vision loss due to optic atrophy between ages 14 and 30 years, but without other symptoms. A tenth patient had loss of vision and was found to have postural tremor, hyperreflexia, and unstable gait. The phenotype was variable within this family. Inheritance In Marsden's family 1, all 3 sibs were affected; the mother had parkinsonism. In his second family, 4 persons in 3 separate sibships were affected; 2 of the sibships were related as double first cousins and the single affected person of the third sibship was related as a second cousin to the others. Mitochondrial inheritance was discussed as a possibility; however, one of the affected was related to the others through his father. On full presentation of the data in their family, Novotny et al. (1986) concluded that it was probably a mitochondrial disease. Molecular Genetics The family reported by Novotny et al. (1986) was found by Jun et al. (1994) to harbor a Native American mtDNA and was heteroplasmic for a MTND6LDYT14459A mutation (516006.0002) arising on the Native American haplogroup D mtDNA background. It was not found on any of 38 related mtDNA haplotypes nor in 310 control mtDNAs representing the major ethnic groups. The penetrance was high when the mutation approached homoplasmy, with 48% of maternal relatives manifesting pediatric dystonia, 10% LHON, and 3% LHON plus dystonia (Novotny et al., 1986: Wallace et al., 1985). Since the MTND6LDYT14459A mutation is heteroplasmic in this family and approaches homoplasmy in the recent generations Jun et al. (1994) suggested that the increased severity correlated with the segregation of the mutant mtDNAs. In a large Dutch kindred in which Leber optic atrophy was associated with hereditary spastic dystonia in some members whereas only 1 type of abnormality was found in others, De Vries et al. (1996) found 2 previously unreported mtDNA mutations: a heteroplasmic mutation in the MTND4 gene (11696A-G; 516003.0003) and a homoplasmic mutation in the MTND6 gene (14596T-A; 516006.0003). Watanabe et al. (2006) identified the 14459G-A mutation in the MTND6 gene in 2 Japanese sisters with childhood-onset dystonia, mental deterioration, adult-onset LHON, and basal ganglia lesions. In a woman with optic neuropathy and her brother with spastic dystonia, Spruijt et al. (2007) identified a heteroplasmic 3697G-A transition in the MTND1 gene (516000.0012). The mutation load was greater than 97% in muscle tissues of the woman with LHON and 88% in the blood of her brother. In affected members of a Chinese Han family with Leber optic atrophy and dystonia, Wang et al. (2009) identified a homoplasmic 10197G-A mutation in the MTND3 gene (516002.0004). The mutation occurred on mitochondrial haplogroup D4b. The mutation was homoplasmic in all affected individuals and in 2 unaffected family members, indicating reduced penetrance. INHERITANCE \- Mitochondrial HEAD & NECK Eyes \- Loss of vision \- Optic atrophy \- Abnormal extraocular movements SKELETAL Spine \- Scoliosis MUSCLE, SOFT TISSUES \- Amyotrophy NEUROLOGIC Central Nervous System \- Dystonia \- Dysphagia \- Dysarthria \- Mental retardation \- Normal cognition (reported in some patients) \- Dementia \- Bulbar dysfunction \- Spasticity \- Corticospinal tract dysfunction \- Bradykinesia \- Athetosis \- Bilateral striatal lucencies on imaging LABORATORY ABNORMALITIES \- Increased serum and CSF lactate \- Decreased mitochondrial complex I activity MISCELLANEOUS \- Onset of dystonia is in childhood \- Onset of optic neuropathy is usually in early adulthood \- Patients may show both optic neuropathy and dystonia or only 1 disorder \- Considered part of a spectrum of Leber hereditary optic atrophy (LHON, 535000 ) MOLECULAR BASIS \- Caused by mutation in the mitochondrial complex I, subunit ND1 gene (MTND1, 516000.0012 ) \- Caused by mutation in the mitochondrial complex I, subunit ND3 gene (MTND3, 516002.0004 ) \- Caused by mutation in the mitochondrial complex I, subunit ND4 gene (MTND4, 516003.0003 ) \- Caused by mutation in the mitochondrial complex I, subunit ND6 gene (MTND6, 516006.0002 ) ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	LEBER OPTIC ATROPHY AND DYSTONIA	c1839040	3,436	omim	https://www.omim.org/entry/500001	2019-09-22T16:16:57	{"mesh": ["C536024"], "omim": ["500001"], "orphanet": ["99718"], "synonyms": ["LHON plus disease", "Alternative titles", "MARSDEN SYNDROME", "DYSTONIA, FAMILIAL, WITH VISUAL FAILURE AND STRIATAL LUCENCIES", "LEBER HEREDITARY OPTIC NEUROPATHY WITH DYSTONIA"]}
Tetrasomy X is a chromosome disorder that only affects females and is caused by having four copies of the X chromosome instead of two. Females with tetrasomy X have a total of 48 chromosomes in their cells, so this condition is sometimes written as 48, XXXX. The signs and symptoms of tetrasomy X vary, but can include mild to moderate speech and learning difficulties; developmental delay; distinctive facial features; dental abnormalities; hypotonia and joint laxity; radioulnar synostosis; heart defects; hip dysplasia; and problems with ovarian function. An increased risk of childhood infections has also been reported. Tetrasomy X is caused by a random error that occurs during the development of an egg cell and is not caused by anything a mother does during her pregnancy. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: 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	Tetrasomy X	c0265496	3,437	gard	https://rarediseases.info.nih.gov/diseases/7754/tetrasomy-x	2021-01-18T17:57:23	{"mesh": ["C536502"], "umls": ["C0265496"], "orphanet": ["9"], "synonyms": ["48 XXXX", "48 XXXX syndrome", "Tetra X", "48,XXXX syndrome", "Quadruple X"]}
For other uses, see Infantilism (disambiguation). Look up infantilism or infantile in Wiktionary, the free dictionary. In medicine, Infantilism is an obsolete term for various, often unrelated disorders of human development, up to developmental disability, which consist of retention of the physical and/or psychological characteristics of early developmental stages (infant, child) into a relatively advanced age.[1] Various types of infantilism were recognized, lumped together in the above superficial description. With better understanding of the endocrine system and genetic disorders, various disorders which included the word "infantilism" received other names. For example, Brissaud's infantilism, described by Édouard Brissaud in 1907 is now known as myxedema (a form of hypothyroidism); "intestinal infantilism" of Christian Archibald Herter is called coeliac disease. The Turner syndrome was described as "a syndrome of infantilism" by Henry Turner himself.[2] Terms such as "genital infantilism" (infantilism in development of genitals, hypogenitalism), or "sexual infantilism" (lack of sexual development after expected puberty or delayed puberty) may still be seen, and are considered to be synonyms of hypogonadism. "Somatic infantilism" refers to infantilism of overall bodily development. Speech infantilism is a speech disorder. Similarly to some other medical terms (cretinism, idiotism), "infantilism"/"infantile" may be used pejoratively (synonymous to "immature").[3] ## References[edit] 1. ^ Ronald Grey Gordon (a 1999 reprint) "Personality", Routledge, ISBN 0-415-21057-7, p.77 2. ^ Turner HH. (1938). A syndrome of infantilism, congenital webbed neck, and cubitus valgus. Endocrinology. 23:566-574. 3. ^ "Infantilism", a dictionary entry [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: 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	Infantilism (physiological disorder)	None	3,438	wikipedia	https://en.wikipedia.org/wiki/Infantilism_(physiological_disorder)	2021-01-18T18:56:49	{"wikidata": ["Q1662323"]}
Classic endocrine tumor of the appendix is a type of endocrine tumor of the appendix (see this term), seen twice as frequently in females than in males, and usually presenting before the fifth decade of life. Classic endocrine tumor of the appendix is usually asymptomatic when located in the tip of the appendix (without obstruction), but acute appendicitis is often associated. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Classic neuroendocrine tumor of appendix	None	3,439	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=329977	2021-01-23T17:39:45	{"icd-10": ["D37.3"], "synonyms": ["Classic appendiceal neuroendocrine tumor", "Classic appendix neuroendocrine tumor"]}
A rare inborn error of metabolism characterized by abnormal accumulation of plasma cystathionine and subsequent increased urinary excretion due to cystathionine gamma-lyase deficiency. The condition is considered benign without pathological relevance. Mode of inheritance 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	Cystathioninuria	c0220993	3,440	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=212	2021-01-23T19:03:54	{"gard": ["2428"], "mesh": ["C535408"], "omim": ["219500"], "umls": ["C0220993", "C0268616"], "icd-10": ["E72.1"], "synonyms": ["Cystathionase deficiency", "Cystathionine gamma-lyase deficiency syndrome", "Gamma-cystathionase deficiency"]}
A rare, congenital, non-syndromic heart malformation characterized by more or less than one coronary ostium at the left and at the right aortic sinus of Valsalva. It may be asymptomatic or it leads to myocardial ischemia and technical difficulties during coronary angiography. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: 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	Abnormal number of coronary ostia	None	3,441	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=99089	2021-01-23T19:00:00	{"icd-10": ["Q24.5"]}
A number sign (#) is used with this entry because thyroid dyshormonogenesis-2A (TDH2A) is caused by homozygous or compound heterozygous mutation in the thyroid peroxidase gene (TPO; 606765) on chromosome 2p25. For a general phenotypic description and a discussion of genetic heterogeneity of thyroid dyshormonogenesis, see TDH1 (274400). Description Approximately 10% of patients with congenital hypothyroidism harbor inborn errors of metabolism in one of the steps for thyroid hormone synthesis in thyrocytes (Vono-Toniolo et al., 2005). The most prevalent cause of thyroid dyshormonogenesis is TPO deficiency (Park and Chatterjee, 2005). Defects in TPO cause a severe form of congenital hypothyroidism characterized by a complete and immediate release of accumulated radioiodide from the thyroid after sodium perchlorate administration (Bakker et al., 2000). This release of radioiodide represents total iodine organification defect (TIOD), a disruption of the process by which iodide present in the thyroid is oxidized by hydrogen peroxide and bound to tyrosine residues in thyroglobulin (TG; 188450) to form iodotyrosine. Clinical Features Haddad and Sidbury (1959) first demonstrated an in vitro deficiency of thyroid peroxidase activity in a patient with a thyroid hormone organification defect. A peroxide generating system did not improve activity. Hagen et al. (1971) described an intelligent, euthyroid child of normal stature with recurrent goiter. She and her similarly affected sister had normal hearing. Like patients with Pendred syndrome (274600), she discharged 50% of the thyroidal iodide after perchlorate. Her thyroid tissues showed no iodide peroxidation or tyrosine iodination activity. Addition of excessive hematin, the prosthetic group of peroxidase, restored tyrosine iodination. Niepomniszcze et al. (1973) described a cretinous child with a goiter who completely discharged radioiodide after administration of perchlorate. The total in vitro peroxidase deficiency was not improved by peroxide, hematin, or enzyme solubilization. Pommier et al. (1974) found that tissue from a euthyroid woman with a recurrent goiter and partial iodide discharge had normal iodide peroxidation but deficient thyroglobulin iodination. Partial solubilization of the enzyme resulted in a 3-fold increase in thyroglobulin iodination activity. Wolff (1983) stated that only 22 persons with this abnormality had been reported. Inheritance Perez-Cuvit et al. (1977) described partial iodide discharge in the euthyroid, identical twin grandnieces of a normal member of a sibship which included 4 children with severe retardation and complete thyroid iodide organification defect. The twins' hearing was normal and their parents were unrelated. The findings were interpreted as indicating a partial peroxidase defect resulting from compound heterogeneity for 2 different abnormal alleles. Medeiros-Neto et al. (1982) described thyroid peroxidase deficiency in a congenitally goitrous, mentally retarded, hypothyroid child, whose parents were first cousins. Both parents showed a thyroid abnormality. Couch et al. (1985) reported a Hutterite kindred with 9 affected persons including identical twins. Population Genetics Total iodide organification defect, in which iodide taken up by the thyroid gland cannot be oxidized and bound to protein, was found by Bikker et al. (1995) to be the most common hereditary inborn error causing congenital hypothyroidism in the Netherlands. Bakker et al. (2000) established the incidence of TIOD in the Netherlands to be 1 in 66,000. Mapping In 5 families, which included 9 goitrous subjects with complete or partial TPO deficiency, Mangklabruks et al. (1991) found a lod score (2.08) compatible with linkage of the disorder to a RFLP in the TPO gene in 1 family with inbreeding. In 2 other families, the lod score was inconsistent with linkage between the disease and the TPO gene. In a fourth family, partial deletion of the TPO gene was suggested by Southern blotting. Anker et al. (1992) identified a tetranucleotide repeat (AATG) in intron 10 of the TPO gene. By study of CEPH pedigrees, they found a heterozygosity of 67% and a PIC value of 0.61. By linkage studies, they subregionalized TPO to 2pter-p23. Molecular Genetics In a patient with partial iodide organification defect, Abramowicz et al. (1992) identified a mutation in the TPO gene (606765.0001). In a patient with congenital hypothyroidism, a large nodular goiter, and a total iodide organification defect, Bikker et al. (1994) found homozygosity for a 20-bp duplication in the TPO gene (606765.0002) Both parents of the patient were heterozygous for the mutation. Hypothyroidism had been discovered at the age of 4 months, the neonatal period having been complicated by prolonged icterus. In a family with 2 of 5 sibs affected with severe congenital hypothyroidism, Bikker et al. (1996) identified homozygosity for a nonsense mutation in the TPO gene (606765.0003). Thyroid tissue from 1 patient was available for study; TPO activity was absent and thyroglobulin (188450) was not iodinated, showing that iodination in vivo did not occur. Pannain et al. (1999) performed genomewide homozygosity analysis in the youngest generation of 5 nuclear families belonging to an inbred Amish kindred segregating a complete iodide organification defect, which localized the defect close to the TPO gene. Sequencing of the TPO gene revealed 2 missense mutations, E799K (606765.0007) and R648Q (606765.0009); the former was found in homozygosity in 11 affected individuals and both mutations were present in 3 affected compound heterozygotes. One family member with hypothyroidism who had no mutation in the TPO gene also had insignificant discharge of radioiodide after administration of sodium perchlorate, indicating a different etiology for his thyroid hormone deficiency. Medeiros-Neto et al. (1998) reported an infant girl born with a large cervical tumor that extended to the upper mediastinum. Pathologic examination after thyroidectomy revealed a follicular carcinoma of the thyroid (see 188470) and probable dyshormonogenetic hyperplastic goiter; she was subsequently found to have lung and bone metastases. DGGE analysis of PCR fragments corresponding to exon 14 of the TPO gene indicated the presence of a mutant TPO allele (606765.0008) in the propositus, her father, and her paternal grandmother. The authors concluded that the aggressive thyroid metastatic carcinoma arose from a dyshormonogenetic goiter caused by a defective TPO protein. History Nunez et al. (1976) showed that thyroid peroxidase catalyzes 3 different reactions and exists in 2 interchangeable forms, A and B. Form A catalyzes iodide oxidation and high-rate thyroglobulin iodination, whereas form B catalyzes low-rate thyroglobulin iodination and iodotyrosyl coupling. Pommier et al. (1974) studied thyroid tissue from a euthyroid patient with a childhood goiter in whom iodide oxidation was normal and thyroglobulin iodination was only slightly reduced, yet coupling of the iodotyrosines was markedly reduced. The authors proposed that the defect in this patient was secondary to a lack of conformational change from form A to form B. Both a defect in the third peroxidase reaction (primary coupling defect) and alteration of amino acid sequence within thyroglobulin, changing the total number or the intramolecular position of the iodotyrosines (secondary coupling defect), could result in the same phenotype. Some patients have been cretinous while others only had goiters; therefore, heterogeneity may exist in this group of patients. Stanbury and Dumont (1983) indicated that the coupling defects represent a 'poorly defined group, which is almost surely heterogeneous.' Pommier et al. (1976) summarized the in vitro kinetics and proposed mechanisms for the 3 peroxidase reactions: (1) iodide oxidation, (2) thyroglobulin (TG; 188450) iodination, and (3) iodothyronine coupling. Niepomniszcze et al. (1975) called this the 'apo-enzyme-prothetic group defect' and pointed out that an organification defect may be produced by a defective or deficient iodide acceptor (i.e., thyroglobulin). Nomenclature Discharge of a significant percentage of labeled iodide from the thyroid upon administration of thiocyanate or perchlorate in a thyroid function test indicates a defect in converting accumulated iodide to organically bound iodine (iodide organification defect, or IOD). Discharge may be partial or complete, indicating partial (PIOD) or total (TIOD) iodide organification defect. Thyroid dyshormonogenesis characterized by such a discharge was originally categorized here as type 2, with type 2A representing thyroid peroxidase (TPO) deficiency and 2B representing Pendred syndrome (274600). Later molecular studies showed IODs to be related to diverse molecular mechanisms, including mutations in DUOX2 (606759) and DUOXA2 (612772) (Cavarzere et al., 2008). INHERITANCE \- Autosomal recessive HEAD & NECK Neck \- Goiter ENDOCRINE FEATURES \- Thyroid defect in oxidation and organification of iodide \- Hypothyroidism LABORATORY ABNORMALITIES \- Rapid radioactive iodide (RAI) discharge after thiocyanate or perchlorate \- Thyroid peroxidase defect \- Tyrosine iodination defect MOLECULAR BASIS \- Caused by mutations in the thyroid peroxidase gene (TPO, 606765.0001 ) ▲ 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	THYROID DYSHORMONOGENESIS 2A	c1848805	3,442	omim	https://www.omim.org/entry/274500	2019-09-22T16:21:41	{"mesh": ["C564766"], "omim": ["274400", "274500"], "orphanet": ["95716"], "synonyms": ["Alternative titles", "HYPOTHYROIDISM, CONGENITAL, DUE TO DYSHORMONOGENESIS, 2A", "Thyroid dyshormonogenesis", "THYROID HORMONOGENESIS, GENETIC DEFECT IN, 2A", "THYROID PEROXIDASE DEFICIENCY", "IODIDE PEROXIDASE DEFICIENCY"]}
Cryofibrinogenemia SpecialtyPathology Cryofibrinogenemia refers to a condition classified as a fibrinogen disorder in which the chilling of an individual's blood plasma from the normal body temperature of 37 °C to the near-freezing temperature of 4 °C causes the reversible precipitation of a complex containing fibrinogen, fibrin, fibronectin, and, occasionally, small amounts of fibrin split products, albumin, immunoglobulins and other plasma proteins. Returning this plasma to 37 °C resolubilizes the precipitate.[1][2] Cryofibrinogenmia may occur as a laboratory finding in individuals that have no evidence of precipitate-induced tissue damage (i.e. asymptomatic cryofibrinogenemia) or in individuals suffering serious consequences of cryofibrinogen precipitation, particularly pathological blood clots in small and medium size arteries and veins. The clotting disease is commonly grouped with the asymptomatic condition in the term cryofibrinogenemia but is here termed cryofibrinogenemic disease for clarity purposes. When occurring in association with another serious disease, cryofibrinogenemic disease is referred as secondary cryofibrinogenemia; in the absence of such an association, it is referred to as primary cryofibrinogenemia.[2] ## Contents * 1 Cryofibrinogen precipitation * 2 Asymptomatic cryofibrinogenemia * 3 Associated disorders * 3.1 Infection-associated cryofibrinogenemia * 3.2 Malignancy-associated cryofibrinogenemia * 3.3 Vasculitis-associated cryofibrinogenemia * 3.4 Autoimmune disease-associated cryofibrinogenemia * 4 Cryofibrinogenemic disease * 4.1 Symptoms and signs * 4.2 Diagnosis * 4.3 Treatment * 4.3.1 Primary cryofibrinogenemic disease * 4.3.2 Secondary cryofibrinogenemic disease * 4.4 Prognosis * 5 See also * 6 References * 7 Further reading * 8 External links ## Cryofibrinogen precipitation[edit] Main article: Coagulation The reasons for the cold temperature-induced in vitro as well as the in vivo precipitation of the fibrinogen-containing complex is unknown. The fibrinogen involved in precipitate formation appears to have a normal structure. This separates cryofibrinogenemia from two pathological blood-clotting/bleeding diseases that can mimic cryofibrinogenemia but are due to structurally abnormal fibrinogen viz., dysfibrinogenemia and hypodysfibrinogenemia.[3][4] Based on in vitro studies, three causes have been hypothesized for the precipitate formed in cryofibrinogenemia. 1) The blood and plasma of individuals with cryofibrinogenemia lack the fibrinolysis activity that normally degrades and thereby resolubilizes the precipitate. This hypothesis is based on the findings that some but not all individuals with the disorder have abnormally high levels of one or two of the agents, alpha-1 antitrypsin and alpha-2-Macroglobulin, which inhibit the naturally occurring fibrinolytic agent, plasmin. 2) The blood of individuals has an increased ability of the pro-coagulant thrombin to bind fibrinogen and thereby promote coagulation. 3) The blood of individuals, particularly those with cryofibriognemic disease associated with other severe disorders, has high levels of immunological elements such as immunoglobulins or immune complexes that interact with fibronectin to promote blood clotting. This hypothesis is base on findings that some patients with cyrofibrinogenemic disease improve when treated with immunosuppressive drugs.[5] Further basic research into this area is required. ## Asymptomatic cryofibrinogenemia[edit] The occurrence of cryofibrinogenemia as defined by a 4 °C-induced formation of fibrinogen-based precipitation in plasma occurs in 2% to 9% of asymptomatic individuals and 8% to 13% of hospitalized patients without symptoms attributable to this precipitation. Most of these cases have relatively low levels of cold temperature-induced fibrinogen precipitate levels (<50 milligram/liter of fibrinogen) and do not have a disorder associated with the development of cryofibrinogenmia.[2] ## Associated disorders[edit] Cryoglobulinemia may occur without evidence of an underlying associated disorders, i.e. primary cryoglobulinemia (also termed essential cryoglobulinemia) or, far more commonly, with evidence of an underlying disease, i.e. secondary cryoglobulinemia. Secondary cryofibrinogenemia can develop in individuals suffering infection (~12% of cases), malignant or premalignant disorders (21%), vasculitis (25%), and autoimmune diseases (42%). In these cases of the secondary disorder, cryofibrinogenemia may or may not cause tissue injury and/or other symptoms and the actual cause-effect relationship between these diseases and the development of cryofibrinogenemia is unclear.[2][6] Cryofibrinogenemia can also occur in association with the intake of certain drugs.[citation needed] ### Infection-associated cryofibrinogenemia[edit] Acute bacterial and mycobacterium infections are sometimes associated with cryofibriongenemia. In these cases, cryofibrinogenemia is usually transient and rapidly resolves after appropriate anti-bacterial treatment. In HIV/AIDS virus, Epstein–Barr virus, cytomegalovirus, varicella zoster virus, herpes simplex virus, and hepatitis virus infections any rise in circulating cryofibrinogen is more sustained and potentially symptomatic. For example, one large study of the most thoroughly study example of viral infection-associated cryofibrinogenmia, Hepatitis C infection, found that cryofibrinogenemia occurred in 37% of cases, was associated with concurrent cryoglobulinemia in 89% of cases, and led to significantly increased vascular disruption. Antiviral therapy resulted in complete resolution of the cryofibrinogenemia in only ~50% of these cases.[5] ### Malignancy-associated cryofibrinogenemia[edit] Lymphoproliferative disorders such as B-cell lymphomas, T-cell lymphomas, chronic lymphocytic leukemia, and various plasma cell dyscrasias (e.g. multiple myeloma, Waldenström's macroglobulinemia, and the premalignant precursors to these two diseases, MGUS, smoldering multiple myeloma, IgM MGUS, and smoldering Waldenström's macroglobulinemia as well as adenocarcinomas of the stomach, liver, lung, colon, and other solid tumor cancers have been reported to be associated with symptomatic or asymptomatic cryfibrinogenemia.[5][6] ### Vasculitis-associated cryofibrinogenemia[edit] Cryofibrinogenemia is often associated with inflammatory disease of the arteries and/or veins. These vasculitis-associated diseases include ANCA-associated vasculitides, giant cell arteritis, Behcet disease, polyarteritis nodosa, and Henoch–Schonlein purpura.[5] Cryofibrinogenemia is also often associated with the inflammatory vasculitis that accompanies mixed Cryoglobulinemia#Classification, i.e. cryoglobulinemic vasculitis, particularly but not exclusively in instances where hepatitis C virus is an underlining disease.[5] ### Autoimmune disease-associated cryofibrinogenemia[edit] A broad range of autoimmune diseases have been reported to be associated with cryofibrinogenemia. These diseases include systemic lupus erythematosus, Sjögren syndrome, rheumatoid arthritis, mixed connective tissue disease, polymyositis, dermatomyositis, systemic sclerosis, antiphospholipid antibody syndrome, Hashimoto disease, Graves' disease, sarcoidosis, pyoderma gangrenosum, spondyloarthropathy, Crohn's disease, and ulcerative colitis.[5] ## Cryofibrinogenemic disease[edit] ### Symptoms and signs[edit] Cryofibrinogenemic disease commonly begins in adults aged 40–50 years old with symptoms of the diseases occurring in the almost always affected organ, skin. Cutaneous symptoms include one or more of the following: cold contact-induced urticarial (which may be the first sign of the disease); painful episodes of finger and/or toe arterial spasms termed Raynaud phenomena; cyanosis, a palpable purpura termed cryofibrinogenemic purpura), and a lace-like purplish discoloration termed livedo reticularis all of which occur primarily in the lower extremities but some of which may occur in the nose, ears, and buttocks; non-healing painful ulcerations and gangrene of the areas impacted by the cited symptoms.[2] Patients also have a history of cold sensitivity (~25% of cases), arthralgia (14-58%), neuritis (7-19%), myalgia (0-14%); and overt thrombosis of arteries and veins (25-40%) which may on rare occasions involve major arteries such of those of the brain and kidney.[5][6][7] Signs of renal involvement (proteinuria, hematuria, decreased glomerular filtration rate, and/or, rarely, renal failure) occur in 4-25% of cases.[5][8] Compared to secondary cryofibrinogemia, primary crygofibrinogenemia has a higher incidence of cutaneous lesions, arthralgia, and cold sensitivity while having a far lower incidence of renal involvement.[5] Patients with secondary cryofibrinogenemia also exhibit signs and symptoms specific to the infectious, malignant, premalignant vasculitis, and autoimmune disorders associated with their disease.[2] While rare, individuals with cryofibrinogenemic disease may experience pathological bleeding due to the consumption of blood clotting factors consequential to the formation of cryofibrinogen precipitates.[2][5] ### Diagnosis[edit] Suggested diagnostic criteria for cryoglobulinemic disease fall into the following obligatory and additional categories:[5] * Obligatory criteria: 1) cold sensitivity; 2) cutaneous symptoms (i.e. urticaria, purpura, Raynaud phenomenon, ulceration/necrosis/gangrene, and/or livedo reticularis); 3) arterial and/or venous thrombotic events; fever; 4) arthralgia/myalgia; 5) neuritis in >1 site; and 6) renal disorder. * Additional criteria: 1) typical biopsy findings at site(s) of involvement and 2) angiogram evidence of occlusion in one or more small to medium-sized arteries. The diagnosis of secondary cryofibrinogenemia also requires evidence for the cited infectious, malignant, premalignant vasculitis, and autoimmune disorders while the diagnosis of primary cryofibriongenemia requires a lack of evidence for 1) the cited associated disorders, 2) other vascular occlusive diseases, and 3) cryoglobulinemia.[5] ### Treatment[edit] Studies on the treatment of cryofibrinoginemic disease have involved relatively few patients, are limited primarily to case reports, and differ based on whether the disease is primary or secondary. In all cases of cryofibrinogenemic disease, however, patients should avoid the exposure of afflicted body parts to cold weather or other environmental triggers of symptoms and avoid using cigarettes or other tobacco products. In severe cases, these individuals also risk developing serious thrombotic events which lead to tissue necrosis that may result in secondary bacterial infections and require intensive antimicrobial therapy and/or amputations. Careful treatment of these developments is required.[2][5] #### Primary cryofibrinogenemic disease[edit] Success in treating the primary disease has been reported using blood clot lysing agents such as anabolic steroids (e.g. danazol or stanozolol which is no longer available in the United States), streptokinase, and streptodornase; anticoagulants such as heparin and warfarin, and immunosuppressive drug regimens such as a corticosteroid (e.g. prednisone) combined with either azathioprine of chlorambucil. Very moderate cases may do well by simply avoiding cold exposure. Treatment with a corticosteroid plus low-dose aspirin followed by maintenance therapy with an anabolic steroid where necessary are recommended for moderately severe cases. Very severe cases generally require an immunosuppressive drug regimen and if extreme or life-threatening require resorting to plasmaphoresis or plasma exchange.[2][6] Cryofiltration apheresis, a method to remove plasma agents by removing cold-induced precipitated material, may be an effective alternative to plasmaphoresis and plasma exchange but is still regarded as second-line therapy for cryofibirnogenemic disease treatment.[2] During the several years following its initial diagnosis, some 27-47% of primary cryofibrinoginemic diseases are complicated by the development of a B-cell or T-cell lymphoma. That is, the cryofibrinoginemic disease may appear to precede by years the malignant disorder to which it is associated. Accordingly, patients require careful follow-up not only to treat their primary cryofibrinoginemic disease but also to monitor them for movement to the diagnosis of secondary cryofibrinoginemic disease caused by the development of one of these hematological malignancies.[2][6] #### Secondary cryofibrinogenemic disease[edit] Treatment of secondary cryofibrinoginemic disease may use the same methods used for treating the primary disease wherever necessary but focus on treating the associated infectious, malignant, premalignant, vasculitis, or autoimmune disorder with the methods prescribed for the associated disorder. Case report studies suggest that: corticosteroids and immunosuppressive drug regimens, antimicrobial therapy, and anti-neoplastic regimens can be effective treatments for controlling the cryfibrinoginemic disease in cases associated respectively with autoimmune, infectious, and premalignant/malignant disorders.[2][5][6][7] ### Prognosis[edit] While the prognosis of cryofibrinoginemic disease varies greatly depending on its severity as well as the severity of its associated disorders, satisfactory clinical outcomes are reported in 50-80% of patients with primary or secondary disease treated with corticosteroid and/or immunosuppressive regimens. However, relapses occur within the first 6 months after stopping or decreasing therapy in 40-76% of cases.[5] Sepsis resulting from infection of necrotic tissue is the most common threat to life in primary disease whereas the associated disorder is a critical determinant of prognosis in secondary disease.[2] ## See also[edit] * Cryofibrinogenemic purpura * Cryoglobulinemia * Dysfibrinogenemia * Hypodysfibrinogenemia ## References[edit] 1. ^ James, William D.; Berger, Timothy G.; et al. (2006). Andrews' Diseases of the Skin: clinical Dermatology. Saunders Elsevier. ISBN 0-7216-2921-0.:822 2. ^ a b c d e f g h i j k l m Grada A, Falanga V (2017). "Cryofibrinogenemia-Induced Cutaneous Ulcers: A Review and Diagnostic Criteria". American Journal of Clinical Dermatology. 18 (1): 97–104. doi:10.1007/s40257-016-0228-y. PMID 27734332. S2CID 39645385. 3. ^ Casini A, Brungs T, Lavenu-Bombled C, Vilar R, Neerman-Arbez M, de Moerloose P (2017). "Genetics, diagnosis and clinical features of congenital hypodysfibrinogenemia: a systematic literature review and report of a novel mutation". Journal of Thrombosis and Haemostasis. 15 (5): 876–888. doi:10.1111/jth.13655. PMID 28211264. 4. ^ Casini A, Sokollik C, Lukowski SW, Lurz E, Rieubland C, de Moerloose P, Neerman-Arbez M (2015). "Hypofibrinogenemia and liver disease: a new case of Aguadilla fibrinogen and review of the literature". Haemophilia. 21 (6): 820–7. doi:10.1111/hae.12719. PMID 25990487. 5. ^ a b c d e f g h i j k l m n o Michaud M, Pourrat J (2013). "Cryofibrinogenemia". Journal of Clinical Rheumatology. 19 (3): 142–8. doi:10.1097/RHU.0b013e318289e06e. PMID 23519183. 6. ^ a b c d e f Chen Y, Sreenivasan GM, Shojania K, Yoshida EM (2015). "Cryofibrinogenemia After a Liver Transplant: First Reported Case Posttransplant and a Case-Based Review of the Nontransplant Literature". Experimental and Clinical Transplantation. 13 (3): 290–4. doi:10.6002/ect.2014.0013. PMID 24679054. 7. ^ a b Caimi G, Canino B, Lo Presti R, Urso C, Hopps E (2017). "Clinical conditions responsible for hyperviscosity and skin ulcers complications". Clinical Hemorheology and Microcirculation. 67 (1): 25–34. doi:10.3233/CH-160218. hdl:10447/238851. PMID 28550239. 8. ^ Harris RJ, Cropley TG (2011). "Possible role of hypercoagulability in calciphylaxis: review of the literature". Journal of the American Academy of Dermatology. 64 (2): 405–12. doi:10.1016/j.jaad.2009.12.007. PMID 20708299. ## Further reading[edit] * Amdo, TD; Welker, JA (Mar 1, 2004). "An approach to the diagnosis and treatment of cryofibrinogenemia" (PDF). The American Journal of Medicine. 116 (5): 332–7. doi:10.1016/j.amjmed.2003.09.033. PMID 14984819. Archived from the original (PDF) on February 2, 2014. Retrieved January 25, 2014. * Michaud, M; Pourrat, J (Apr 2013). "Cryofibrinogenemia". Journal of Clinical Rheumatology. 19 (3): 142–8. doi:10.1097/RHU.0b013e318289e06e. PMID 23519183. * Kalbfleisch, John M.; Bird, Robert M. (3 November 1960). "Cryofibrinogenemia". New England Journal of Medicine. 263 (18): 881–886. doi:10.1056/NEJM196011032631803. PMID 13750865. * Begin, Philippe; Leclerc, Georgette (22 August 2013). "Familial Primary Cryofibrinogenemia". New England Journal of Medicine. 369 (8): e10. doi:10.1056/NEJMicm1300987. PMID 23964955. * van Geest, AJ; van Dooren-Greebe, RJ; Andriessen, MP; Blomjous, CE; Go, IH (Jan 1999). "Familial primary cryofibrinogenemia". Journal of the European Academy of Dermatology and Venereology : JEADV. 12 (1): 47–50. doi:10.1111/j.1468-3083.1999.tb00808.x. PMID 10188150. * Soyfoo, MS; Goubella, A; Cogan, E; Wautrecht, JC; Ocmant, A; Stordeur, P (15 November 2011). "Clinical Significance of Cryofibrinogenemia: Possible Pathophysiological Link with Raynaud's Phenomenon". The Journal of Rheumatology. 39 (1): 119–124. doi:10.3899/jrheum.110793. PMID 22089468. S2CID 29987316. ## External links[edit] Classification D * OMIM: 123540 * MeSH: C536218 [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: 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	Cryofibrinogenemia	c0272263	3,443	wikipedia	https://en.wikipedia.org/wiki/Cryofibrinogenemia	2021-01-18T19:01:01	{"gard": ["9908"], "mesh": ["C536218"], "umls": ["C0272263"], "wikidata": ["Q5190514"]}
## Summary ### Clinical characteristics. Lateral meningocele syndrome (LMS) is characterized by multiple lateral spinal meningoceles (protrusions of the arachnoid and dura through spinal foramina), distinctive facial features, joint hyperextensibility, hypotonia, and skeletal, cardiac, and urogenital anomalies. Neurologic sequelae of the meningoceles depend on size and location and can include neurogenic bladder, paresthesias, back pain, and/or paraparesis. Other neurologic findings can include Chiari I malformation, syringomyelia, and rarely, hydrocephalus. Additional findings of LMS include mixed or conductive hearing loss and cleft palate. Skeletal abnormalities may include scoliosis, vertebral fusion, scalloping of vertebrae, and wormian bones. Although developmental delay is common, cognition is often preserved. Feeding difficulties and gastroesophageal reflux disease (GERD) are common. ### Diagnosis/testing. The diagnosis of LMS syndrome is established in a proband with consistent clinical findings and a heterozygous pathogenic variant in NOTCH3. ### Management. Treatment of manifestations: Routine management of neurologic sequelae of lateral meningoceles (neurogenic bladder, paresthesias, back pain, and/or paraparesis). Although rarely required, surgical intervention may be necessary for neurologic manifestations secondary to meningocele size and location. As needed: management by specialists in chronic pain management or rehabilitation medicine; physiotherapy to reduce the risk for joint subluxation and dislocation. Routine management of: cleft palate, hearing loss, congenital cardiac defects, GU abnormalities, feeding difficulties. Surveillance: Ongoing monitoring by the appropriate subspecialists for neurologic, developmental, musculoskeletal, cardiovascular, genitourinary, and/or gastrointestinal issues. ### Genetic counseling. LMS is inherited in an autosomal dominant manner. Although most probands have the disorder as a result of a de novo NOTCH3 pathogenic variant, affected parent-child pairs have been reported. Each child of an individual with LMS has a 50% chance of inheriting the NOTCH3 pathogenic variant. When the NOTCH3 pathogenic variant has been identified in an affected family member, prenatal testing and preimplantation genetic testing for a pregnancy at increased risk are possible options. ## Diagnosis Formal diagnostic clinical criteria for lateral meningocele syndrome (LMS) have not been established. ### Suggestive Findings LMS should be suspected in individuals with the following findings: * Multiple lateral spinal meningoceles (protrusion of the arachnoid and dura through the spinal foramina). Present in all affected individuals (Figure 1). Associated neurologic findings can include: Chiari I malformation, hydrocephalus, syringomyelia, and neurogenic bladder. * Characteristic craniofacial appearance [Castori et al 2014, Gripp et al 2015, Ejaz et al 2016] including widely spaced eyes, highly arched eyebrows, downslanted palpebral fissures, ptosis, malar flattening, long philtrum, thin vermilion of the upper lip, high and narrow palate (cleft palate present in some individuals), micrognathia, and coarse hair with a low posterior hairline (Figure 2) * High nasal voice * Mixed or conductive hearing loss (present in some individuals) * Developmental delay or (rarely) intellectual disability * Musculoskeletal. Hypotonia, decreased muscle bulk, joint hyperextensibility with possibility of frequent dislocations, hernias, scoliosis, vertebral fusion, and scalloping of vertebrae * Congenital cardiovascular malformations. Aortic abnormalities (bicuspid aortic valve, aortic dilation, and coarctation of the aortic arch) and ventricular septal defects * Genitourinary. Cryptorchidism and hydronephrosis * Gastrointestinal. Poor feeding, dysphagia, and gastroesophageal reflux disease (GERD) #### Figure 1. Numerous lateral meningoceles (see arrows) protrude through the thoracic foramina in a sagittal view (a) and through the lumbar foramina in a sagittal (b) and axial (c) view. The curved arrow in (a) shows a meningocele protruding from the middle cranial (more...) #### Figure 2. Photographs of individuals with lateral meningocele syndrome A-D. Patient 1 at age 24 years: ### Establishing the Diagnosis The diagnosis of LMS syndrome is established in a proband with consistent clinical findings and identification of a heterozygous pathogenic variant in NOTCH3 by molecular genetic testing (see Table 1). 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 NOTCH3 is performed first, followed by gene-targeted deletion/duplication analysis if no pathogenic variant is found. Note: To date all causative pathogenic variants have been in exon 33, the last exon of NOTCH3 [Gripp et al 2015, Ejaz et al 2016]; see Molecular Genetics, Pathogenic variants. * A multigene panel that includes NOTCH3 and other genes of interest (see Differential Diagnosis) may also 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 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 if single-gene testing (and/or use of a multigene panel that includes NOTCH3) fails to confirm a diagnosis in an individual with features of LMS. 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). Note: Clinicians should ensure that exome sequencing or genome sequencing has sufficient coverage to detect small deletions in the last exon of NOTCH3 as these pathogenic variants could otherwise be missed [Ejaz et al 2016]. 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 Lateral Meningocele Syndrome View in own window Gene 1MethodProportion of Probands with a Pathogenic Variant 2 Detectable by Method NOTCH3Sequence analysis 37/8 4 Gene-targeted deletion/duplication analysis 5Unknown 6 UnknownSee footnote 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. 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\. Gripp et al [2015], Ejaz et al [2016] 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. 7\. The one individual reported by Castori et al [2014] did not have an identifiable NOTCH3 pathogenic variant [Kym Boycott, MD; email communication February 17, 2016]. ## Clinical Characteristics ### Clinical Description Lateral meningocele syndrome (LMS) is characterized by multiple lateral spinal meningoceles, distinctive facial features, joint hyperextensibility, hypotonia, and skeletal, cardiac, and urogenital anomalies. LMS is a recognizable clinical phenotype, with half of known affected individuals having a molecularly confirmed diagnosis [Gripp et al 2015]; to date, most others have not been tested for a NOTCH3 pathogenic variant. Multiple lateral spinal meningoceles (protrusions of the arachnoid and dura through the spinal foramina) are found in all affected individuals. Neurologic sequelae of the meningoceles can include neurogenic bladder, paresthesias, back pain, and/or paraparesis depending on size and location. Other neurologic findings can include Chiari I malformation (4/14), syringomyelia (3/14) and rarely, hydrocephalus [Gripp et al 1997, Castori et al 2014, Gripp et al 2015, Ejaz et al 2016]. Head and neck. Mixed or conductive hearing loss has been noted in seven of 14 individuals with LMS. Cleft palate is occasionally seen. Eye abnormalities can include iris coloboma, proptosis, and oculomotor restriction [Castori et al 2014, Gripp et al 2015, Ejaz et al 2016]. Developmental delay is frequently seen in individuals with LMS but cognition is often preserved. All seven individuals with a molecularly confirmed diagnosis had developmental delay, and one also had intellectual disability [Gripp et al 2015, Ejaz et al 2016]. Psychomotor development may vary within a family; for example, in an affected mother-daughter pair only the daughter had developmental delay [Lehman et al 1977]. Musculoskeletal. Overlap with features of connective tissue disorders include neonatal hypotonia (11/14), abdominal hernias (9/14), ligamentous laxity (12/14), keloid scars (5/14), and back pain (3/14) in later life. Nonspecific muscle or generalized pain has been described. One woman age 55 years had multiple joint dislocations [Castori et al 2014]. Many individuals have skeletal changes including scoliosis, vertebral fusion, scalloping of vertebrae, and wormian bones [Gripp et al 1997, Castori et al 2014, Gripp et al 2015]. Congenital cardiovascular malformations described in five individuals with a molecularly confirmed diagnosis include ventricular septal defect (3), bicuspid aortic valve (2), dilatation of the aorta (2), and coarctation of the aortic arch (1) [Alves et al 2013, Gripp et al 2015, Ejaz et al 2016]. Genitourinary. Cryptorchidism is frequently seen. Hydronephrosis has been occasionally reported [Castori et al 2014]. Gastrointestinal. Infants with LMS may demonstrate dysphagia with poor weight gain. Dysphagia was severe enough to warrant gastrostomy tube feeding in one [Ejaz et al 2016]. Gastroesophageal reflux disease (GERD) which can persist into adulthood has been described in a woman age 55 years, the oldest reported individual with LMS to date [Castori et al 2014]. Of note, she did not have a NOTCH3 pathogenic variant on exome sequencing and targeted sequencing [Kym Boycott, MD; email communication 2-17-16]. ### Genotype-Phenotype Correlations Given that lateral meningocele syndrome (LMS) is a rare disorder with fewer than 20 reported cases, no genotype-phenotype correlations have been determined. ### Penetrance Penetrance appears to be complete but data are limited. ### Nomenclature Lehman et al [1977] first described a woman with dysmorphic facial features, skeletal sclerosis, and multiple meningoceles, and her mother with similar craniofacial dysmorphisms. Philip et al [1995], who published a second case, named the syndrome after Lehman. The authors prefer the term "lateral meningocele syndrome" as it emphasizes the hallmark feature of the condition. ### Prevalence Lateral meningocele syndrome is very rare, with approximately 14 reported individuals, seven of whom have a molecularly confirmed diagnosis. There does not appear to be increased prevalence in specific populations. ## Differential Diagnosis The differential diagnosis for lateral meningocele syndrome (LMS) can include the following: * Hadju-Cheney syndrome (OMIM 102500), a skeletal disorder caused by a heterozygous pathogenic variant in NOTCH2, is characterized by dysmorphic facial features (e.g., malar flattening, thick eyebrows, micrognathia), osteoporosis with acro-osteolysis, wormian bones, premature loss of dentition, and joint laxity. One individual with LMS was initially misdiagnosed with Hadju-Cheney syndrome due to the presence of acro-osteolysis [Avela et al 2011, Gripp 2011]. * Marfan syndrome. LMS has significant overlap with other connective tissue disorders. Spinal meningeal anomalies, specifically dural ectasias, are frequently seen in Marfan syndrome. Individuals with Marfan syndrome may also have joint laxity, scoliosis, cardiovascular anomalies, and some shared facial features, such as malar flattening and retrognathia. Marfan syndrome is inherited in an autosomal dominant manner and is caused by mutation of FBN1. * Noonan syndrome. LMS and Noonan syndrome share similarities in their characteristic facial features (including widely spaced eyes, ptosis, epicanthus, and low-set ears with increased posterior angulation) and a low posterior hairline. Prenatal signs of Noonan syndrome, such as a nuchal edema and congenital cardiac defect, were also seen in one individual with LMS [Ejaz et al 2016]. Noonan syndrome is inherited in an autosomal dominant manner. Genes known to be associated with the disorder include PTPN11, SOS1, RAF1, RIT1, and KRAS. * Neurofibromatosis type 1. Lateral meningoceles and dural ectasia have been described in some individuals with NF1 [Ueda et al 2015]. The distincitve facial features of LMS are not seen in individuals with NF1; other distinctive characteristics of NF1 include café-au-lait spots, neurofibromas, and Lisch nodules. NF1 and LMS may also have similar skeletal and neurologic changes including scoliosis, hydrocephalus, and developmental delays. NF1 is inherited in an autosomal dominant manner and is caused by mutation of NF1. ## Management ### Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with lateral meningocele syndrome (LMS), the following evaluations are recommended: * Spine MRI to assess for meningoceles (if not performed at time of diagnosis) and neurosurgical assessment to evaluate the effect of lateral spinal meningocele size and location on neurologic function * Brain MRI to assess for Chiari I malformation or hydrocephalus, if not performed at time of diagnosis * Thorough physical and neurologic examination for signs of neuropathy, joint abnormalities, and abdominal hernias * Neurocognitive assessment * Assessment by general surgery for abdominal hernia repair * Assessment by orthopedic surgery for symptomatic skeletal deformities * Visualization of the aortic arch by echocardiogram or MRI * Urologic assessment for cryptorchidism if present * Feeding assessment * Hearing assessment * Ophthalmologic assessment * Consultation with a clinical geneticist and/or genetic counselor ### Treatment of Manifestations Specific treatment for LMS does not currently exist. Supportive management of the clinical finding depends on the involved system as outlined below. Lateral spinal meningoceles. Symptomatic treatment of neurologic sequelae (e.g., neurogenic bladder, paresthesias, back pain, and/or paraparesis) is as per routine. Although rarely required, surgical intervention may be necessary for neurologic manifestations secondary to meningocele size and location. When required, surgical approach is individualized and can include laminectomy for smaller meningoceles and costotransversectomy for larger meningoceles [Kim et al 2011]. Of note, the 55-year-old woman with LMS experienced irreversible nerve damage following surgery for two lumbosacral meningoceles (to manage back and referred neuropathic pain) [Castori et al 2014]. Psychomotor development. Provide timely supportive interventions as needed to optimize development through occupational therapy and education resources. Musculoskeletal * Management by specialists in chronic pain management or rehabilitation medicine as needed * Physiotherapy to reduce risk for joint subluxation and dislocation Routine management of the following: * Cleft palate * Hearing loss * Congenital cardiac defects * Genitourinary abnormalities * GERD. Note that a feeding tube may be necessary if persistent feeding difficulties result in failure to thrive. ### Surveillance No surveillance guidelines for LMS have been published. Ongoing monitoring by the appropriate subspecialists for neurologic, developmental, musculoskeletal, cardiovascular, genitourinary, and/or gastrointestinal issues is indicated. ### Evaluation of Relatives at Risk See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes. ### Therapies Under Investigation Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Lateral Meningocele Syndrome	c1851710	3,444	gene_reviews	https://www.ncbi.nlm.nih.gov/books/NBK368476/	2021-01-18T21:15:23	{"mesh": ["C537878"], "synonyms": ["Lehman Syndrome"]}
Congenital stromal corneal dystrophy Other namesWitschel dystrophy The cornea is particularly opaque in the anterior stroma by slit-lamp biomicroscopy Congenital stromal dystrophy. Transmission electron microscopy of the corneal stroma showing normal collagen lamellae separated by abnormal randomly distributed collagen filaments in an electron-lucent extracellular matrix. Congenital stromal corneal dystrophy (CSCD), is an extremely rare, autosomal dominant form of corneal dystrophy.[1] Only 4 families have been reported to have the disease by 2009.[2] The main features of the disease are numerous opaque flaky or feathery areas of clouding in the stroma that multiply with age and eventually preclude visibility of the endothelium. Strabismus or primary open angle glaucoma was noted in some of the patients. Thickness of the cornea stays the same, Descemet's membrane and endothelium are relatively unaffected, but the fibrils of collagen that constitute stromal lamellae are reduced in diameter and lamellae themselves are packed significantly more tightly. ## Contents * 1 Genetics * 2 Diagnosis * 3 Treatment * 4 References * 5 External links ## Genetics[edit] CSCD is associated with a mutation in the gene DCN that encodes the protein decorin, located at chromosome 12q22.[1] The disorder is inherited in an autosomal dominant manner,[1] which indicates that the defective gene responsible for a disorder is located on an autosome (chromosome 12 is an autosome), and only one copy of the gene is sufficient to cause the disorder, when inherited from a parent who has the disorder.[citation needed] ## Diagnosis[edit] This section is empty. You can help by adding to it. (July 2017) ## Treatment[edit] This section is empty. You can help by adding to it. (July 2017) ## References[edit] 1. ^ a b c Bredrup, C.; Knappskog, P. M.; Majewski, J.; Rødahl, E.; Boman, H. (February 2005). "Congenital stromal dystrophy of the cornea caused by a mutation in the decorin gene" (Free full text). Invest Ophthalmol Vis Sci. 46 (2): 420–426. doi:10.1167/iovs.04-0804. PMID 15671264. 2. ^ Klintworth GK (2009). "Corneal dystrophies". Orphanet J Rare Dis. 4: 7. doi:10.1186/1750-1172-4-7. PMC 2695576. PMID 19236704. ## External links[edit] * GeneReviews/NCBI/NIH/UW entry on Congenital Stromal Corneal Dystrophy Classification D * ICD-10: H18.5 * OMIM: 610048 * MeSH: C566452 C566452, C566452 External resources * Orphanet: 101068 * v * t * e Types of corneal dystrophy Epithelial and subepithelial * Epithelial basement membrane dystrophy * Gelatinous drop-like corneal dystrophy * Lisch epithelial corneal dystrophy * Meesmann corneal dystrophy * Subepithelial mucinous corneal dystrophy Bowman's membrane * Reis–Bucklers corneal dystrophy * Thiel-Behnke dystrophy Stroma * Congenital stromal corneal dystrophy * Fleck corneal dystrophy * Granular corneal dystrophy * Lattice corneal dystrophy * Macular corneal dystrophy * Posterior amorphous corneal dystrophy * Schnyder crystalline corneal dystrophy Descemet's membrane and endothelial * Congenital hereditary endothelial dystrophy * Fuchs' dystrophy * Posterior polymorphous corneal dystrophy * X-linked endothelial corneal dystrophy * v * t * e Diseases of collagen, laminin and other scleroproteins Collagen disease COL1: * Osteogenesis imperfecta * Ehlers–Danlos syndrome, types 1, 2, 7 COL2: * Hypochondrogenesis * Achondrogenesis type 2 * Stickler syndrome * Marshall syndrome * Spondyloepiphyseal dysplasia congenita * Spondyloepimetaphyseal dysplasia, Strudwick type * Kniest dysplasia (see also C2/11) COL3: * Ehlers–Danlos syndrome, types 3 & 4 * Sack–Barabas syndrome COL4: * Alport syndrome COL5: * Ehlers–Danlos syndrome, types 1 & 2 COL6: * Bethlem myopathy * Ullrich congenital muscular dystrophy COL7: * Epidermolysis bullosa dystrophica * Recessive dystrophic epidermolysis bullosa * Bart syndrome * Transient bullous dermolysis of the newborn COL8: * Fuchs' dystrophy 1 COL9: * Multiple epiphyseal dysplasia 2, 3, 6 COL10: * Schmid metaphyseal chondrodysplasia COL11: * Weissenbacher–Zweymüller syndrome * Otospondylomegaepiphyseal dysplasia (see also C2/11) COL17: * Bullous pemphigoid COL18: * Knobloch syndrome Laminin * Junctional epidermolysis bullosa * Laryngoonychocutaneous syndrome Other * Congenital stromal corneal dystrophy * Raine syndrome * Urbach–Wiethe disease * TECTA * DFNA8/12, DFNB21 see also fibrous proteins [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: 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 stromal corneal dystrophy	c1864738	3,445	wikipedia	https://en.wikipedia.org/wiki/Congenital_stromal_corneal_dystrophy	2021-01-18T18:39:02	{"mesh": ["C566452"], "umls": ["C1864738"], "orphanet": ["101068"], "wikidata": ["Q4127187"]}
A rare autosomal recessive cerebellar ataxia, characterized by progressive cerebellar ataxia associated with oculomotor apraxia, severe neuropathy, and hypoalbuminemia. ## Epidemiology Ataxia-oculomotor apraxia type 1 (AOA1) represents 3.6% of all autosomal recessive cerebellar ataxia (ARCA) in Portugal; in Japan, AOA1 seems to be the most frequent cause of ARCA. In a cohort of 227 patients mostly of French origin with progressive cerebellar ataxia selected after exclusion of Friedreich ataxia, the relative frequency of AOA1 was of 5%. ## Clinical description Cerebellar ataxia is the first manifestation of AOA1 with a mean age of onset of 4.3 years (2-10 years) and is characterized by progressive gait imbalance followed by dysarthria, and limb dysmetria. Later, peripheral axonal motor neuropathy dominates the clinical picture. Oculomotor apraxia (OMA; inability to coordinate eyes ± head movements: when the head turns toward a lateral target; the head reaches the target before the eyes) is present in almost all individuals with AOA1. Chorea is present at onset in 80% of patients and upper limb dystonia (see this term) occurs in about 50% of individuals. Additional features include square wave jerks, saccadic pursuit and gaze-evoked nystagmus, areflexia followed by severe peripheral neuropathy. Variable intellectual disability is observed. ## Etiology AOA1 results from mutations in APTX gene (9p13.3) encoding aprataxin which plays a role in DNA-single-strand break repair. Most mutations identified so far are localized in exons 5, 6 and 7. Some correlations between genotype and phenotype have been established: for example severe and persistent choreic phenotype is associated with mutations A198V; truncating mutations are associated with earlier onset and deletions with more severe phenotype and intellectual disability. ## Diagnostic methods Diagnosis of AOA1 is based on the clinical features, the progressive evolution, the absence of extraneurologic findings and family history. Electromyography findings reveal severe axonal sensory-motor neuropathy. Oculographic recordings demonstrate normal latencies, hypometric saccades, decrease mean gain in amplitude and broken saccades into multiple successive saccades. Cerebral magnetic resonance imagery displays cerebellar atrophy. Hypoalbuminemia and hypercholesterolemia are usual (disease duration is positively correlated with cholesterol and negatively correlated with albumin levels). Diagnosis is confirmed by molecular analysis of APTX gene. ## Differential diagnosis Differential diagnosis includes Friedreich ataxia, ataxia with vitamin E deficiency, AOA2, ataxia-telangiectasia, ataxia-telangiectasia-like disorder, autosomal recessive spastic ataxia of Charlevoix-Saguenay (see these terms). ## Antenatal diagnosis Carrier testing for at-risk family members and prenatal testing are possible if both disease-causing alleles in a family are known. ## Genetic counseling Transmission of AOA1 is autosomal recessive. Genetic counseling is recommended as each sib of an affected individual has 25% risk of being affected, 50% risk of being an asymptomatic carrier, and 25% risk of being neither affected nor a carrier. ## Management and treatment No specific treatment exists for AOA1 and management is mainly supportive. It includes physical therapy for cerebellar ataxia and disabilities resulting from peripheral neuropathy; educational support for reading and writing difficulties, speech therapy for dysarthria and cognitive impairment. Low-cholesterol diet and hypolipemiant treatment are recommended. Routine follow-up with a neurologist or neurogenetician is suggested. Some therapeutic trials are on the way such as the evaluation of efficacy of Coenzyme Q10 in evolution of the disease. ## Prognosis AOA1 is a progressive neurodegenerative disorder and most patients usually become wheelchair bound from seven to ten years after onset 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	Ataxia-oculomotor apraxia type 1	c1859598	3,446	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=1168	2021-01-23T17:25:50	{"gard": ["9283"], "mesh": ["C538013"], "omim": ["208920"], "umls": ["C1859598"], "icd-10": ["G11.3"], "synonyms": ["AOA1"]}
A rare, genetic cardiac rhythm disease characterized by a short QTc interval on the surface electrocardiogram (ECG) with a high risk of syncope or sudden death due to malignant ventricular arrhythmia. ## Epidemiology This extremely rare syndrome affects mainly young adults or infants and has been reported in nearly 80 families. The disease has been predominantly reported in males. ## Clinical description Whilst the disease may remain asymptomatic, the most common clinical presentation is a cardiac arrest (CA), with approximately 40% of patients suffering an episode of CA between birth and 40 years of age. Other symptoms include syncope and arrhythmias including atrial fibrillation, ventricular fibrillation (VF), supraventricular tachycardia (SVT), and polymorphic ventricular tachycardia. There is a high risk of recurrent arrhythmic events in symptomatic patients. The risk of sudden cardiac death (SDC) is highest in the first year of life and between 20 to 40 years. ## Etiology Mutations in the genes KCNQ1 (11p15.5), KCNH2 (7q36.1), and KCNJ2 (17q24.3), encoding cardiac ionic potassium channels, and the gene encoding the calcium channel, CACNA2D1 (7q21.11), have been identified in affected patients. 40% of patients do not have a genetic cause identified. ## Diagnostic methods According to the European Society of Cardiology Guidelines, SQTS is diagnosed by the presence of a corrected QT (QTc) interval less than or equal to 340 ms on resting 12-lead ECG or should be considered in the presence of a QTc less than or equal 360 ms and one or more of the following: a confirmed pathogenic mutation, a family history of SQTS, a family history of sudden death at young age (less than 40 years of age), or history of ventricular tachyarrhythmia/ventricular fibrillation (VT/VF) in the absence of heart disease. When a patient is diagnosed, clinical assessment is recommended in all family members, including an ECG in newborns. ## Differential diagnosis Differential diagnosis includes other repolarizing disorders such as Brugada syndrome and early repolarization syndrome. Of note, a few rare patients with Brugada syndrome have been reported to have a short QTc. ## Genetic counseling Transmission is autosomal dominant. Genetic counseling should be offered to affected families. First-degree relatives of an affected individual have a 50% risk of being affected. Sporadic cases have also been reported. ## Management and treatment Currently, an automatic implantable cardioverter-defibrillator (ICD) is recommended for patients who have experienced a sustained VT/VF episode or have survived an aborted cardiac arrest. However, ICD is complicated by a high probability of inappropriate ICD shocks, particularly in pediatric patients, and requires appropriate programming to prevent T-wave oversensing. Quinidine prophylaxis may be considered in patients where ICD is contraindicated/refused or in asymptomatic SQTS patients with a family history of SDC. Patients on quinidine should be carefully monitored for QT prolongation and possible pro-arrhythmic events. ## Prognosis The risk of sudden cardiac death is high, and a history of survived cardiac arrest at the initial presentation is a strong predictor of recurrent ventricular arrhythmias over the course of time. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: 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 short QT syndrome	c1865020	3,447	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=51083	2021-01-23T18:42:19	{"mesh": ["C566506"], "omim": ["609620", "609621", "609622"], "icd-10": ["I49.8"], "synonyms": ["SQTS"]}
A rare disorder characterized by the combination of congenital limb abnormalities and scalp defects, often accompanied by skull ossification defects. ## Epidemiology The prevalence is unknown. ## Clinical description The severity of the disorder varies greatly among affected individuals. Aplasia cutis congenita, transverse limb defects and cutis marmorata telangiectica are characteristic of this condition. The affected patients typically have malformations of the hands, arms, feet and/or legs that range from hypoplastic fingers and toes to absent hands and/or lower legs, and occasionally show intellectual deficit. AOS may be associated with a variety of physical anomalies including congenital cataract, strabismus and microphthalmia, congenital heart malformations (including tetralogy of Fallot and pulmonary atresia), and hepatoportal sclerosis. Hydrocephalus is the principal cerebral feature and epilepsy may be associated. Extensive lethal anomalies are possible. ## Etiology The etiopathogenesis remains unclear. ## Genetic counseling Most cases are transmitted as an autosomal dominant trait, but some show autosomal recessive transmission with familial or sporadic occurrence. ## Management and treatment Limb and scalp defects require orthopedic treatment. Management requires a comprehensive multidisciplinary approach. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: 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	Adams-Oliver syndrome	c0265268	3,448	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=974	2021-01-23T18:26:35	{"gard": ["5739"], "mesh": ["C538225"], "omim": ["100300", "614219", "614814", "615297", "616028", "616589"], "umls": ["C0265268"], "icd-10": ["Q87.2"], "synonyms": ["AOS", "Congenital scalp defects with distal limb anomalies", "Congenital scalp defects with distal limb reduction anomalies", "Limb, scalp and skull defects"]}
Intestinal obstruction in the newborn due to guanylate cyclase 2C deficiency is an extremely rare, autosomal recessive, gastroenterological disorder reported in three families so far that is characterized by meconium ileus without any further stigmata of cystic fibrosis (see this term) including pulmonary or pancreatic manifestations. Two of the reported patients developed chronic diarrhea in infancy. Homozygous mutations in the GUCY2C gene (12p12) leading to marked reduction or absence of enzymatic activity of guanylate cyclase 2C were found in the affected patients. The disease was reported to show partial penetrance. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: 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	Intestinal obstruction in the newborn due to guanylate cyclase 2C deficiency	c2939175	3,449	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=314376	2021-01-23T17:52:07	{"mesh": ["D000074270"], "omim": ["614665"], "icd-10": ["P76.0"], "synonyms": ["Meconium ileus due to guanylate cyclase 2C deficiency"]}
Nishimura et al. (1999) described a Japanese family in which 4 females and 2 males in 3 generations had a brittle bone disorder that appeared to be hitherto unreported. The cardinal manifestations included dolichocephaly with frontal bossing, hypoplasia of the midface, postpubertal prognathism, micromelic short stature, coarse trabeculae of the entire skeleton, and bone fragility of variable degrees. Mild spondylar modification and iliac hypoplasia were other hallmarks that were recognized in childhood. The proband, a 19-year-old male, was the most severely affected, with multiple wormian bones in the calvaria, repetitive fractures, intractable bowing of the legs and forearms, and pseudofractures of the long bones with metaphyseal narrowing. His male cousin was the next most severely affected, with angular deformity restricted to the forearm. The 4 females were much less affected, without angular deformity. There was no instance of male-to-male transmission. The mode of inheritance was thus consistent with either an autosomal dominant trait with sex influence or an X-linked semidominant trait. Histologic bone examination in the proband showed atrophy and fibrous degeneration of the lamellar trabeculae and disorganized chondroosseous junction, which implied that the disorder involved both intramembranous and enchondral ossifications. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: 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	BRITTLE BONE DISORDER	c1859069	3,450	omim	https://www.omim.org/entry/603828	2019-09-22T16:12:35	{"mesh": ["C565842"], "omim": ["603828"]}
A rare genetic neurological disorder characterized by sensorineural hearing loss, sensory neuropathy, behavioral abnormalities, and dementia. Occurrence of seizures has also been reported. Age of onset is between adolescence and adulthood. The disease is progressive, with fatal outcome typically in the fifth to sixth decade. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: 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 neuropathy-deafness-dementia syndrome	c3279885	3,451	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=456318	2021-01-23T17:48:57	{"gard": ["11927"], "mesh": ["C580162"], "omim": ["614116"], "icd-10": ["G60.8"], "synonyms": ["HSAN1E", "HSN1E", "Hereditary sensory neuropathy-sensorineural hearing loss-dementia syndrome"]}
Kindling (sedative–hypnotic withdrawal) SpecialtyNeurology, psychiatry Kindling due to substance withdrawal refers to the neurological condition which results from repeated withdrawal episodes from sedative–hypnotic drugs such as alcohol and benzodiazepines. Each withdrawal leads to more severe withdrawal symptoms than in previous episodes. Individuals who have had more withdrawal episodes are at an increased risk of very severe withdrawal symptoms, up to and including seizures and death. Long-term use of GABAergic-acting sedative–hypnotic drugs causes chronic GABA receptor downregulation as well as glutamate overactivity, which can lead to drug and neurotransmitter sensitization, central nervous system hyperexcitability, and excitotoxicity. ## Contents * 1 Symptoms * 2 Causes * 3 Pathophysiology * 3.1 Benzodiazepines * 3.2 Alcohol * 4 Diagnosis * 4.1 Definition * 5 Treatment * 6 See also * 7 References ## Symptoms[edit] Binge drinking is believed to increase impulsivity due to altered functioning of prefrontal–subcortical and orbitofrontal circuits. Binge drinking in alcoholics who have undergone repeated detoxification is associated with an inability to interpret facial expressions properly; this is believed to be due to kindling of the amygdala with resultant distortion of neurotransmission. Adolescents, females and young adults are most sensitive to the neuropsychological effects of binge drinking. Adolescence, particularly early adolescence, is a developmental stage which is particularly vulnerable to the neurotoxic and neurocognitive adverse effects of binge drinking due to it being a time of significant brain development.[1] Approximately 3 percent of people who are alcohol dependent experience psychosis during acute intoxication or withdrawal. Alcohol-related psychosis may manifest itself through a kindling mechanism. The mechanism of alcohol-related psychosis is due to distortions to neuronal membranes, gene expression, as well as thiamin deficiency. It is possible in some cases that alcohol abuse via a kindling mechanism can cause the development of a chronic substance-induced psychotic disorder, i.e. schizophrenia. The effects of an alcohol-related psychosis include an increased risk of depression and suicide as well as psychosocial impairments.[2] Repeated acute intoxication followed by acute withdrawal is associated with profound behavioural changes and neurobiological alterations in several brain regions. Much of the documented evidence of kindling caused by repeated detoxification regards increased seizure frequency. Increased fear and anxiety and cognitive impairments are also associated with alcohol withdrawal kindling due to binge drinking or alcoholics with repeated alcohol withdrawal experiences. The impairments induced by binge drinking or repeated detoxification of alcoholics cause a loss of behavioural inhibition of the prefrontal cortex; the prefrontal cortex is mediated by subcortical systems such as the amygdala. This loss of behavioral control due to brain impairment predisposes an individual to alcoholism and increases the risk of an abstaining alcoholic relapsing. This impairment may also result in long-term adverse effects on emotional behavior. Impaired associative learning may make behavioural therapies involving conditioning approaches for alcoholics less effective.[1] ## Causes[edit] Binge drinking regimes are associated with causing an imbalance between inhibitory and excitatory amino acids and changes in monoamine release in the central nervous system, which increases neurotoxicity; this may result in cognitive impairments, psychological problems, and may cause irreversible brain damage in both adolescent and adult long-term binge drinkers.[3][4] Similar to binge drinkers, individuals suffering from alcohol dependence develop changes to neurotransmitter systems, which occur as a result of kindling and sensitization during withdrawal. This progressively lowers the threshold needed to cause alcohol-related brain damage and cognitive impairments, leading to altered neurological function. The changes in activity of excitatory and inhibitory neurotransmitter systems is similar to that which occurs in individuals suffering from limbic or temporal lobe epilepsy.[5] Adaptational changes at the GABAA benzodiazepine receptor complex do not fully explain tolerance, dependence, and withdrawal from benzodiazepines. Other receptor complexes may be involved; in particular, the excitatory glutamate system is implicated. The involvement of glutamate in benzodiazepine dependence explains long-term potentiation as well as neuro-kindling phenomena. Use of a short-acting benzodiazepine at night as a sleeping pill causes repeated acute dependence followed by acute withdrawal. There is some evidence that a prior history of CNS depressant dependence (e.g. alcohol) increases the risk of dependence on benzodiazepines. Tolerance to drugs is commonly believed to be due to receptor down-regulation; however, there is very limited evidence to support this, and this hypothesis comes from animal studies using very high doses. Instead, other mechanisms, such as receptor uncoupling, may play a more important role in the development of benzodiazepine dependence; this may lead to prolonged comformational changes in the receptors or altered subunit composition of the receptors.[6] ## Pathophysiology[edit] ### Benzodiazepines[edit] Repeated benzodiazepine withdrawal episodes may result in similar neuronal kindling as that seen after repeated withdrawal episodes from alcohol, with resultant increased neuro-excitability. The glutamate system is believed to play an important role in this kindling phenomenon with AMPA receptors which are a subtype of glutamate receptors being altered by repeated withdrawals from benzodiazepines. The changes which occur after withdrawal in AMPA receptors in animals have been found in regions of the brain which govern anxiety and seizure threshold; thus kindling may result in increased severity of anxiety and a lowered seizure threshold during repeated withdrawal. Changes in the glutamate system and GABA system may play an important role at different time points during benzodiazepine withdrawal syndrome.[6] ### Alcohol[edit] See also: Alcohol-related brain damage Binge drinking may induce brain damage due to the repeated cycle of acute intoxication followed by an acute abstinence withdrawal state.[7] Based on animal studies, regular binge drinking in the long-term is thought to be more likely to result in brain damage than chronic (daily) alcoholism. This is due to the 4- to 5-fold increase in glutamate release in nucleus accumbens during the acute withdrawal state between binges but only in dose 3 g/kg, in 2 g/kg there is no increase in glutamate release. In contrast, during withdrawal from chronic alcoholism only a 2- to 3-fold increase in glutamate release occurs. The high levels of glutamate release causes a chain reaction in other neurotransmitter systems. The reason that chronic sustained alcoholism is thought by some researchers to be less brain damaging than binge drinking is because tolerance develops to the effects of alcohol and unlike binge drinking repeated periods of acute withdrawal does not occur,[3][4] but there are also many alcoholics who typically drink in binges followed by periods of no drinking.[8] Excessive glutamate release is a known major cause of neuronal cell death. Glutamate causes neurotoxicity due to excitotoxicity and oxidative glutamate toxicity. Evidence from animal studies suggests that some people may be more genetically sensitive to the neurotoxic and brain damage associated with binge drinking regimes. Binge drinking activates microglial cells which leads to the release of inflammatory cytokines and mediators such as tumour necrosis factor, and nitric oxide causing neuroinflammation leading to neuronal destruction.[3][4] Repeated acute withdrawal from alcohol which occurs in heavy binge drinkers has been shown in several studies to be associated with cognitive deficits as a result of neural kindling; neural kindling due to repeated withdrawals is believed to be the mechanism of cognitive damage in both binge drinkers and alcoholics. Neural kindling may explain the advancing pathogenesis and progressively deteriorating course of alcoholism and explain continued alcohol abuse as due to avoidance of distressing acute withdrawal symptoms which get worse with each withdrawal. Multiple withdrawals from alcohol is associated with impaired long-term nonverbal memory impairment in adolescents and to poor memory in adult alcoholics. Adult alcoholics who experienced two or more withdrawals showed more frontal lobe impairments than alcoholics who had a history of one or no prior alcohol withdrawals. The finding of kindling in alcoholism is consistent with the mechanism of brain damage due to binge drinking and subsequent withdrawal.[9] ## Diagnosis[edit] ### Definition[edit] Kindling refers to the phenomenon of increasingly severe withdrawal symptoms, including an increased risk of seizures, that occurs as a result of repeated withdrawal from alcohol or other sedative–hypnotics with related modes of action. Ethanol (alcohol) has a very similar mechanism of tolerance and withdrawal to benzodiazepines, involving the GABAA receptors, NMDA receptors and AMPA receptors, but the majority of research into kindling has primarily focused on alcohol.[6] An intensification of anxiety and other psychological symptoms of alcohol withdrawal also occurs.[10] ## Treatment[edit] Failure to manage the alcohol withdrawal syndrome appropriately can lead to permanent brain damage or death.[11] Acamprosate, a drug used to promote abstinence from alcohol, an NMDA antagonist drug, reduces excessive glutamate activity in the central nervous system and thereby may reduce excitotoxicity and withdrawal related brain damage.[12][13] ## See also[edit] * Kindling model ## References[edit] 1. ^ a b Stephens, DN.; Duka, T. (Oct 2008). "Review. Cognitive and emotional consequences of binge drinking: role of amygdala and prefrontal cortex". Philos Trans R Soc Lond B Biol Sci. 363 (1507): 3169–79. doi:10.1098/rstb.2008.0097. PMC 2607328. PMID 18640918. 2. ^ Alcohol-Related Psychosis at eMedicine 3. ^ a b c Ward, RJ.; Lallemand, F.; de Witte, P. (March–April 2009). "Biochemical and neurotransmitter changes implicated in alcohol-induced brain damage in chronic or 'binge drinking' alcohol abuse". Alcohol Alcohol. 44 (2): 128–35. doi:10.1093/alcalc/agn100. PMID 19155229. 4. ^ a b c Crews, FT.; Boettiger, CA. (Sep 2009). "Impulsivity, frontal lobes and risk for addiction". Pharmacol Biochem Behav. 93 (3): 237–47. doi:10.1016/j.pbb.2009.04.018. PMC 2730661. PMID 19410598. 5. ^ Bob, P.; Jasova, D.; Bizik, G.; Raboch, J. (2011). "Epileptiform activity in alcohol dependent patients and possibilities of its indirect measurement". PLOS ONE. 6 (4): e18678. doi:10.1371/journal.pone.0018678. PMC 3082533. PMID 21541318. 6. ^ a b c Allison C, Pratt JA (May 2003). "Neuroadaptive processes in GABAergic and glutamatergic systems in benzodiazepine dependence". Pharmacol. Ther. 98 (2): 171–95. doi:10.1016/S0163-7258(03)00029-9. PMID 12725868. 7. ^ Hunt, WA. (1993). "Are binge drinkers more at risk of developing brain damage?". Alcohol. 10 (6): 559–61. doi:10.1016/0741-8329(93)90083-Z. PMID 8123218. 8. ^ "Alcohol – Special Subjects – Merck Manuals Consumer Version". 9. ^ Courtney, KE.; Polich, J. (Jan 2009). "Binge drinking in young adults: Data, definitions, and determinants". Psychol Bull. 135 (1): 142–56. doi:10.1037/a0014414. PMC 2748736. PMID 19210057. 10. ^ Heilig M, Egli M, Crabbe JC, Becker HC (April 2010). "Acute withdrawal, protracted abstinence and negative affect in alcoholism: are they linked?". Addict Biol. 15 (2): 169–84. doi:10.1111/j.1369-1600.2009.00194.x. PMC 3268458. PMID 20148778. 11. ^ Hanwella R, de Silva V (June 2009). "Treatment of alcohol dependence". Ceylon Med J. 54 (2): 63–5. doi:10.4038/cmj.v54i2.877. PMID 19670554. 12. ^ De Witte P, Littleton J, Parot P, Koob G (2005). "Neuroprotective and abstinence-promoting effects of acamprosate: elucidating the mechanism of action". CNS Drugs. 19 (6): 517–37. doi:10.2165/00023210-200519060-00004. PMID 15963001. 13. ^ Mirijello A, D'Angelo C, Ferrulli A, Vassallo G, Antonelli M, Caputo F, Leggio L, Gasbarrini A, Addolorato G (March 2015). "Identification and management of alcohol withdrawal syndrome". Drugs. 75 (4): 353–65. doi:10.1007/s40265-015-0358-1. PMC 4978420. PMID 25666543. * 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	Kindling (sedative–hypnotic withdrawal)	None	3,452	wikipedia	https://en.wikipedia.org/wiki/Kindling_(sedative%E2%80%93hypnotic_withdrawal)	2021-01-18T18:57:08	{"wikidata": ["Q6410625"]}
Morton's neuroma Other namesMorton neuroma, Morton's metatarsalgia, Intermetatarsal neuroma, and Intermetatarsal space neuroma[1] The plantar nerves. SpecialtyNeurology Morton's neuroma is a benign neuroma of an intermetatarsal plantar nerve, most commonly of the second and third intermetatarsal spaces (between the second/third and third/fourth metatarsal heads), which results in the entrapment of the affected nerve. The main symptoms are pain and/or numbness, sometimes relieved by ceasing to wear footwear with tight toeboxes and high heels (which have been linked to the condition).[2] The condition is named after Thomas George Morton, though it was first correctly described by a chiropodist named Durlacher.[3][4] Some sources claim that entrapment of the plantar nerve resulting from compression between the metatarsal heads, as originally proposed by Morton, is highly unlikely, because the plantar nerve is on the plantar side of the transverse metatarsal ligament and thus does not come into contact with the metatarsal heads.[citation needed] It is more likely that the transverse metatarsal ligament is the cause of the entrapment.[5][6] Though the condition is labeled as a neuroma, many sources do not consider it a true tumor, but rather a perineural fibroma (fibrous tissue formation around nerve tissue). ## Contents * 1 Signs and symptoms * 2 Diagnosis * 2.1 Histopathology * 2.2 Imaging * 3 Treatment * 4 In popular culture * 5 References * 6 External links ## Signs and symptoms[edit] Symptoms include pain on weight bearing, frequently after only a short time. The nature of the pain varies widely among individuals. Some people experience shooting pain affecting the contiguous halves of two toes. Others describe a feeling akin to having a pebble in the shoe or walking on razor blades. Burning, numbness, and paresthesia may also be experienced.[7] The symptoms progress over time, often beginning as a tingling sensation in the ball of the foot.[8] Morton's neuroma lesions have been found using MRI in patients without symptoms.[9] ## Diagnosis[edit] Negative signs include a lack of obvious deformities, erythema, signs of inflammation, or limitation of movement. Direct pressure between the metatarsal heads will replicate the symptoms, as will compression of the forefoot between the finger and thumb so as to compress the transverse arch of the foot. This is referred to as Mulder’s Sign.[citation needed] There are other causes of pain in the forefoot that often lead to miscategorization as neuroma, such as capsulitis, which is an inflammation of ligaments that surround two bones at the level of the joint. If the ligaments that attach the phalanx (bone of the toe) to the metatarsal bone are impacted, the resulting inflammation may put pressure on an otherwise healthy nerve and produce neuroma-type symptoms. Additionally, an intermetatarsal bursitis between the third and fourth metatarsal bones will also give neuroma-type symptoms because it too puts pressure on the nerve. Freiberg disease, which is an osteochondritis of the metatarsal head, causes pain on weight-bearing or compression.[citation needed] Other conditions that could be clinically confused with a neuroma include stress fractures/reactions and plantar plate disruption.[10][11] ### Histopathology[edit] Microscopically, the affected nerve is markedly distorted, with extensive concentric perineural fibrosis. The arterioles are thickened and occlusion by thrombi are occasionally present.[12][13] ### Imaging[edit] Though a neuroma is a soft-tissue abnormality and will not be visualized by standard radiographs, the first step in the assessment of forefoot pain is an X-ray to detect the presence of arthritis and exclude stress fractures/reactions and focal bone lesions, which may mimic the symptoms of a neuroma. Ultrasound (sonography) accurately demonstrates thickening of the interdigital nerve within the web space of greater than 3mm, diagnostic of a Morton’s neuroma. This typically occurs at the level of the intermetatarsal ligament. Frequently, intermetatarsal bursitis coexists with the diagnosis. MRI can distinguish conditions that mimic the symptoms of Morton's neuroma, but when more than one abnormality exists, ultrasound has the added advantage of determining the precise source of the patient’s pain by applying direct pressure with the probe. Ultrasound may also be used to guide treatment such as cortisone injections into the webspace, as well as alcohol ablation of the nerve. ## Treatment[edit] Orthotics and corticosteroid injections are widely used conservative treatments for Morton’s neuroma. In addition to traditional orthotic arch supports, a small foam or fabric pad may be positioned under the space between the two affected metatarsals, immediately behind the bone ends. This pad helps to splay the metatarsal bones and create more space for the nerve so as to relieve pressure and irritation. However, it may also elicit mild uncomfortable sensations of its own, such as the feeling of having an awkward object under one's foot. Corticosteroid injections can relieve inflammation in some patients and help end the symptoms. For some patients, however, the inflammation and pain recur after some weeks or months, and corticosteroids may only be used a limited number of times because they cause progressive degeneration of ligamentous and tendinous tissues.[citation needed] Sclerosing alcohol injections are an increasingly available treatment alternative if other management approaches fail. Dilute alcohol (4%) is injected directly into the area of the neuroma, causing toxicity to the fibrous nerve tissue. Frequently, treatment must be performed two to four times, with one to three weeks between interventions. A 60–80% success rate has been achieved in clinical studies, equal to or exceeding the success rate for surgical neurectomy, with fewer risks and less significant recovery. If done with more concentrated alcohol under ultrasound guidance, the success rate is considerably higher and fewer repeat procedures are needed.[14] Radiofrequency ablation is also used in the treatment of Morton's neuroma.[15] The outcomes appear to be similar to, or even more reliable than, alcohol injections, especially if the procedure is performed under ultrasound guidance.[16] A 2019 systematic review of randomised controlled trials found that corticosteroid injections or manipulation/mobilisation reduced pain more than control, extracorporeal shockwave therapy or varus/valgus foot wedges (which did not reduce pain more than control or comparison treatment, and pain reduction was not reported in any wider foot/metatarsal padding studies). The review also found no randomised controlled trials for sclerosing alcohol injections, radiofrequency ablations, cryoneurolysis or botulinum toxin injections. These treatments have only been assessed with pre-test/post-test case series, which do not measure the benefit of treatment beyond any placebo effect, sham treatment or any natural improvement over time.[17] If such interventions fail, patients are commonly offered neurectomy, a surgery that involves removing the affected piece of nerve tissue. Postoperative scar tissue formation (known as stump neuroma) can occur in approximately 20–30% of cases, causing a return of neuroma symptoms.[18] Neurectomy may be performed using one of two general methods. Making the incision from the dorsal side (the top of the foot) is the more common method but requires cutting the deep transverse metatarsal ligament that connects the third and fourth metatarsals in order to access the nerve beneath it. This results in exaggerated postoperative splaying of the third and fourth digits (toes) resulting from the loss of the supporting ligamentous structure. This has aesthetic concerns for some patients and possible, though unquantified, long-term implications for foot structure and health. Alternatively, making the incision from the ventral side (the sole of the foot) allows more direct access to the affected nerve without cutting other structures. However, this approach requires a greater post-operative recovery time in which the patient must avoid weight-bearing on the affected foot, because the ventral aspect of the foot is more highly enervated and impacted by pressure when standing. It also carries an increased risk of scar-tissue formation in a location that causes ongoing pain.[citation needed] Cryogenic neuroablation (also known as cryoinjection therapy, cryoneurolysis, cryosurgery or cryoablation) is a lesser-known alternative to neurectomy surgery. It involves the destruction of axons to prevent them from carrying painful impulses. This is accomplished by making a small incision (~3 mm) and inserting a cryoneedle that applies extremely low temperatures of between −50 °C to −70 °C to the nerve/neuroma,[19] resulting in degeneration of the intracellular elements, axons and myelin sheath (which houses the neuroma) with wallerian degeneration. The epineurium and perineurium remain intact, thus preventing the formation of stump neuroma. The preservation of these structures differentiates cryogenic neuroablation from surgical excision and neurolytic agents such as alcohol. An initial study showed that cryoneuroablation is initially equal in effectiveness to surgery but does not have the risk of stump neuroma formation.[20] An increasing range of procedures are being performed at specialist centers to treat Morton's neuroma[8][14] under ultrasound guidance. Recent studies have shown excellent results for the treatment of the condition with ultrasound-guided sclerosing alcohol injections,[16][21] radiofrequency ablation[15] and cryoablation.[22] ## In popular culture[edit] Aerosmith frontman Steven Tyler was affected by Morton's neuroma and underwent surgery for it.[23] Near the end of the 2019 Major League Baseball season, Los Angeles Angels center fielder Mike Trout missed several September games before being scheduled for surgery to remove a Morton's neuroma in the ball of his right foot.[24] In Season 1, Episode 18 of the Golden Girls, Dorothy requires an operation due to Morton’s neuroma. ## References[edit] 1. ^ Names for Morton's neuroma The Center for Morton's Neuroma 2. ^ "Morton's neuroma - Symptoms and causes". Mayo Clinic. Retrieved 2019-03-03. 3. ^ "Thomas George Morton". Who Named It. Retrieved 2019-03-03. 4. ^ Morton's Neuroma: Interdigital Perineural Fibrosis Wheeless' Textbook of Orthopaedics 5. ^ Hochberg MC, Silman AJ, Smolen JS, Weinblatt ME, Weisman MH (2011). Rheumatology. 5th Edition, Volume 1, p. 794. Mosby Elsevier, Philadelphia. ISBN 978-0-323-06551-1 6. ^ A Scientific Discussion of Morton’s Neuroma The Center for Morton's Neuroma 7. ^ "What is Morton's Neuroma?". The Center for Morton's Neuroma. 8. ^ a b "Cryosurgery for Morton's Neuroma, UK Clinic". Cite journal requires `\|journal=` (help) 9. ^ Bencardino J, Rosenberg ZS, Beltran J, Liu X, Marty-Delfaut E (September 2000). "Morton's neuroma: is it always symptomatic?". American Journal of Roentgenology. 175 (3): 649–653. doi:10.2214/ajr.175.3.1750649. PMID 10954445.CS1 maint: uses authors parameter (link) 10. ^ Gregg JM, Schneider T, Marks P (2008). "MR imaging and ultrasound of metatarsalgia--the lesser metatarsals". Radiological Clinics of North America. 46 (6): 1061–1078. doi:10.1016/j.rcl.2008.09.004. PMID 19038613. 11. ^ Gregg JM, Marks P (2007). "Metatarsalgia: an ultrasound perspective". Australasian Radiology. 51 (6): 493–499. doi:10.1111/j.1440-1673.2007.01886.x. PMID 17958682. 12. ^ Reed, RJ; Bliss, BO (February 1973). "Morton's neuroma. Regressive and productive intermetatarsal elastofibrositis". Archives of Pathology. 95 (2): 123–129. PMID 4118941. 13. ^ Scotti, TM (January 1957). "The lesion of Morton's metatarsalgia (Morton's toe)". AMA Archives of Pathology. 63 (1): 91–102. PMID 13381291. 14. ^ a b "The Center for Morton's Neuroma". Cite journal requires `\|journal=` (help) 15. ^ a b Chuter GS1, Chua YP, Connell DA, Blackney MC. (January 2013). "Ultrasound guided radiofrequency ablation in the management of interdigital (Morton's) neuroma". Skeletal Radiol. 42 (1): 107–11. doi:10.1007/s00256-012-1527-x. PMID 23073898. S2CID 25166343.CS1 maint: multiple names: authors list (link) 16. ^ a b Hughes RJ, Ali K, Jones H, Kendall S, Connell DA (June 2007). "Treatment of Morton's neuroma with alcohol injection under sonographic guidance: follow-up of 101 cases". Acta Orthop Belg. 188 (6): 1535–9. doi:10.2214/AJR.06.1463. PMID 17515373. 17. ^ Matthews, Barry G.; Hurn, Sheree E.; Harding, Michael P.; Henry, Rachel A.; Ware, Robert S. (13 February 2019). "The effectiveness of non-surgical interventions for common plantar digital compressive neuropathy (Morton's neuroma): a systematic review and meta-analysis". Journal of Foot and Ankle Research. 12 (12): 1–21. doi:10.1186/s13047-019-0320-7. ISSN 1757-1146. PMC 6375221. PMID 30809275. 18. ^ "Morton's neuroma". www.nhs.uk. NHS choices. Retrieved 15 March 2016. 19. ^ Cryosurgery Or Sclerosing Injections: Which Is Better For Neuromas? 20. ^ A Caporusso EF, Fallat LM, Savoy-Moore R (Sep–Oct 2002). "Cryogenic Neuroablation for the treatment of lower extremity neuromas". J Foot Ankle Surg. 41 (5): 286–290. doi:10.1016/S1067-2516(02)80046-1. PMID 12400711. 21. ^ Musson RE1, Sawhney JS, Lamb L, Wilkinson A, Obaid H. (March 2012). "Ultrasound guided alcohol ablation of Morton's neuroma". Foot & Ankle International. 33 (3): 196–201. doi:10.3113/fai.2012.0196. PMID 22734280.CS1 maint: multiple names: authors list (link) 22. ^ Talia Friedman, MD, Daniel Richman, MD and Ronald Adler, MD (2012). "Sonographically Guided Cryoneurolysis Preliminary Experience and Clinical Outcomes". J Ultrasound Med. 31 (12): 2025–2034. doi:10.7863/jum.2012.31.12.2025. PMID 23197557.CS1 maint: multiple names: authors list (link) 23. ^ Steven Tyler Q&A: On Making 'Noise in My Head,' Aerosmith & 'Idol,' Johnny Depp & More 24. ^ "Trout to have surgery for nerve issue in foot". ESPN.com. September 15, 2019. Retrieved September 15, 2019. ## External links[edit] Classification D * ICD-10: G57.6 * ICD-9-CM: 355.6 * MeSH: D000070607 * DiseasesDB: 8356 External resources * MedlinePlus: 007286 * eMedicine: orthoped/623 pmr/81 radio/882 * 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]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: 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	Morton's neuroma	c0311337	3,453	wikipedia	https://en.wikipedia.org/wiki/Morton%27s_neuroma	2021-01-18T18:53:08	{"mesh": ["D000070607"], "icd-9": ["355.6"], "icd-10": ["G57.6"], "wikidata": ["Q1948740"]}
A rare, genetic, congenital disorder of glycosylation and glycogen storage disease characterized by a wide range of clinical manifestations, most commonly presenting with bifid uvula with or without cleft palate at birth, associated with growth delay, hepatopathy with elevated aminotransferase serum levels, myopathy (including exercise-related fatigue, exercise intolerance, muscle weakness), intermittent hypoglycemia, and dilated cardiomyopathy and/or cardiac arrest, due to decreased phosphoglucomutase 1 enzyme activity. Less common manifestations include malignant hyperthermia, rhabdomyolysis, and hypogonadotropic hypogonadism with delayed puberty. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: 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	PGM1-CDG	c2752015	3,454	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=319646	2021-01-23T18:37:10	{"mesh": ["C567859"], "omim": ["614921"], "umls": ["C2752015"], "icd-10": ["E77.8"], "synonyms": ["CDG syndrome type It", "CDG-It", "CDG1T", "Congenital disorder of glycosylation type 1t", "Congenital disorder of glycosylation type It", "PGM1-related congenital disorder of glycosylation", "Phosphoglucomutase-1 deficiency"]}
COG7-CDG is a congenital disorder of glycosylation characterised by dysmorphism, skeletal dysplasia, hypotonia, hepatosplenomegaly, jaundice, cardiac insufficiency, recurrent infections and epilepsy. To date, it has been described in two infants, both of whom died within the first three months of life. The syndrome is caused by a mutation in the gene encoding COG-7 (chromosome 16), a subunit of the oligomeric Golgi 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	COG7-CDG	c2931010	3,455	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=79333	2021-01-23T18:53:06	{"gard": ["9842"], "mesh": ["C535754"], "omim": ["608779"], "umls": ["C2931010"], "icd-10": ["E77.8"], "synonyms": ["CDG syndrome type IIe", "CDG-IIe", "CDG2E", "Carbohydrate deficient glycoprotein syndrome type IIe", "Congenital disorder of glycosylation type 2e", "Congenital disorder of glycosylation type IIe"]}
Parkinson-plus syndromes Other namesDisorders of multiple system degeneration SpecialtyNeurology Parkinson-plus syndromes (PPS) is a group of neurodegenerative[1] diseases featuring the classical features of Parkinson's disease (tremor, rigidity, akinesia/bradykinesia, and postural instability) with additional features that distinguish them from simple idiopathic Parkinson's disease (PD). Some consider Alzheimer's disease to be in this group.[2] Parkinson-plus syndromes are either inherited genetically or occur sporadically.[3] Atypical parkinsonism, and other Parkinson-plus syndromes are often difficult to differentiate from PD and each other. They include multiple system atrophy (MSA), progressive supranuclear palsy (PSP), and corticobasal degeneration (CBD). Dementia with Lewy bodies (DLB), may or may not be part of the PD spectrum, but it is increasingly recognized as the second-most common type of neurodegenerative dementia after Alzheimer's disease. These disorders are currently lumped into two groups, the synucleinopathies and the tauopathies.[4][5] They may coexist with other pathologies.[6] Additional Parkinson-plus syndromes include Pick's disease and olivopontocerebellar atrophy.[7] The latter is characterized by ataxia and dysarthria, and may occur either as an inherited disorder or as a variant of multiple system atrophy. MSA is also characterized by autonomic failure, formerly known as Shy–Drager syndrome.[8] ## Contents * 1 Presentation * 2 Diagnosis * 3 Treatments * 4 See also * 5 References * 6 External links ## Presentation[edit] Clinical features that distinguish Parkinson-plus syndromes from idiopathic PD include symmetrical onset, a lack of or irregular resting tremor, and a reduced response to dopaminergic drugs (including levodopa).[3] Additional features include bradykinesia, early-onset postural instability, increased rigidity in axial muscles, dysautonomia, alien limb syndrome, supranuclear gaze palsy, apraxia, involvement of the cerebellum including the pyramidal cells, and in some instances significant cognitive impairment.[3] ## Diagnosis[edit] Accurate diagnosis of these Parkinson-plus syndromes is improved when precise diagnostic criteria are used.[3] Since diagnosis of individual Parkinson-plus syndromes is difficult, the prognosis is often poor. Proper diagnosis of these neurodegenerative disorders is important as individual treatments vary depending on the condition. The nuclear medicine SPECT procedure using 123I‑iodobenzamide (IBZM), is an effective tool in the establishment of the differential diagnosis between patients with PD and Parkinson-plus syndromes.[9] ## Treatments[edit] Parkinson-plus syndromes are usually more rapidly progressive and less likely to respond to antiparkinsonian medication than PD.[10][11] However, the additional features of the diseases may respond to medications not used in PD. Current therapy for Parkinson-plus syndromes is centered around a multidisciplinary treatment of symptoms.[12][13] These disorders have been linked to pesticide exposure.[14] ## See also[edit] * Frontotemporal dementia and parkinsonism linked to chromosome 17 ## References[edit] 1. ^ Bensimon G, Ludolph A, Agid Y, Vidailhet M, Payan C, Leigh PN (January 2009). "Riluzole treatment, survival and diagnostic criteria in Parkinson plus disorders: the NNIPPS study". Brain. 132 (Pt 1): 156–71. doi:10.1093/brain/awn291. PMC 2638696. PMID 19029129. 2. ^ Cecil Textbook of Medicine, 22nd edition, ISBN 0-7216-9652-X 3. ^ a b c d Mitra K.; Gangopadhaya P. K.; Das S. K. (2003). "Parkinsonism plus syndrome—a review". Neurol India. 51 (2): 183–188. PMID 14570999. 4. ^ Mark, M. H. (2001). "Lumping and splitting the Parkinson Plus syndromes: dementia with Lewy bodies, multiple system atrophy, progressive supranuclear palsy, and cortical-basal ganglionic degeneration". Neurologic Clinics. 19 (3): 607–27. doi:10.1016/S0733-8619(05)70037-2. PMID 11532646. 5. ^ Levin J, Kurz A, Arzberger T, Giese A, Höglinger GU (February 5, 2016). "The Differential Diagnosis and Treatment of Atypical Parkinsonism". Dtsch Arztebl Int. 113 (5): 61–9. doi:10.3238/arztebl.2016.0061. PMC 4782269. PMID 26900156. 6. ^ Brittany N. Dugger; Charles H. Adler; Holly A. Shill; John Caviness; Sandra Jacobson; Erika Driver-Dunckley; Thomas G. Beach & the Arizona Parkinson’s Disease Consortium (May 2014). "Concomitant pathologies among a spectrum of parkinsonian disorders". Parkinsonism Relat Disord. 20 (5): 525–9. doi:10.1016/j.parkreldis.2014.02.012. PMC 4028418. PMID 24637124. 7. ^ Constance Ward (2006). "Characteristics and symptom management of progressive supranuclear palsy: a multidisciplinary approach" (PDF). Journal of Neuroscience Nursing. 38 (4): 242–247. doi:10.1097/01376517-200608000-00007. PMID 16925000. Archived from the original (PDF) on 2008-07-23. 8. ^ "Multiple System Atrophy with Orthostatic Hypotension Information Page". Archived from the original on 2012-05-14. Retrieved 2009-09-15. 9. ^ Hierholzer, Johannes; Cordes, Michael; Venz, Stephan; Schelosky, Ludwig; Harisch, Cordula; Richter, Wolf; Keske, Uwe; Hosten, Norbert; Mäurer, Jürgen (1998-06-01). "Loss of Dopamine-D2 Receptor Binding Sites in Parkinsonian Plus Syndromes". Journal of Nuclear Medicine. 39 (6): 954–960. ISSN 0161-5505. PMID 9627325. 10. ^ Litvan I, Campbell G, Mangone CA, Verny M, McKee A, Chaudhuri KR, Jellinger K, Pearce RK, D'Olhaberriague L (Jan 1997). "Which clinical features differentiate progressive supranuclear palsy (Steele-Richardson-Olzewski syndrome) from related disorders". Brain. 120 (1): 65–74. doi:10.1093/brain/120.1.65. PMID 9055798. 11. ^ David R. Williams & Irene Litvan (October 2013). "Parkinsonian syndromes". Continuum (Minneap Minn). 19 (5 Movement Disorders): 1189–212. doi:10.1212/01.CON.0000436152.24038.e0. PMC 4234134. PMID 24092286. 12. ^ Molloy, F. M., & Healy, D. G. (2011). Parkinsonism Plus Syndromes. In O. Hardiman & C. P. Doherty (Eds.), Neurodegenerative Disorders (181-196). London: Springer London. doi:10.1007/978-1-84996-011-3_9 13. ^ Ling H (2016). "Clinical Approach to Progressive Supranuclear Palsy". J Mov Disord. 9 (1): 3–13. doi:10.14802/jmd.15060. PMC 4734991. PMID 26828211. 14. ^ Milestones in Atypical and Secondary Parkinsonisms ## External links[edit] Classification D External resources * eMedicine: article/1154074 * 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	Parkinson plus syndrome	None	3,456	wikipedia	https://en.wikipedia.org/wiki/Parkinson_plus_syndrome	2021-01-18T18:58:24	{"wikidata": ["Q2915552"]}
Yemenite deaf-blind hypopigmentation syndrome Other namesWarburg-Thomsen syndrome[1] Yemenite deaf-blind hypopigmentation syndrome is a condition caused by a mutation on the SRY-related HMG-box gene 10[2] (not SOX10).[3] It was characterized in 1990,[4] after being seen in two siblings from Yemen who presented with a "hitherto undescribed association of microcornea, colobomata of the iris and choroidea, nystagmus, severe early hearing loss, and patchy hypo- and hyperpigmentation."[1] Some sources affirm SOX10 involvement.[5][6] ## See also[edit] * ABCD syndrome * List of cutaneous conditions ## References[edit] 1. ^ a b Lurie, Iosif W. & Victor A. McKusick (17 March 1997). "Yemenite deaf-blind hypopigmentation syndrome". Online Mendelian Inheritance in Man. Johns Hopkins University. Retrieved 25 January 2014. 2. ^ Rapini, Ronald P.; Bolognia, Jean L.; Jorizzo, Joseph L. (2007). Dermatology: 2-Volume Set. St. Louis: Mosby. p. 717. ISBN 978-1-4160-2999-1. 3. ^ Bondurand N, Kuhlbrodt K, Pingault V, et al. (September 1999). "A molecular analysis of the yemenite deaf-blind hypopigmentation syndrome: SOX10 dysfunction causes different neurocristopathies". Hum. Mol. Genet. 8 (9): 1785–9. doi:10.1093/hmg/8.9.1785. PMID 10441344. 4. ^ Warburg M, Tommerup N, Vestermark S, et al. (September 1990). "The Yemenite deaf-blind hypopigmentation syndrome. A new oculo-dermato-auditory syndrome". Ophthalmic Paediatr Genet. 11 (3): 201–7. doi:10.3109/13816819009020980. PMID 2280978. 5. ^ Lang D, Epstein JA (April 2003). "Sox10 and Pax3 physically interact to mediate activation of a conserved c-RET enhancer". Hum. Mol. Genet. 12 (8): 937–45. doi:10.1093/hmg/ddg107. PMID 12668617. 6. ^ Alexander M. Holschneider; Prem Puri (13 December 2007). Hirschsprung's Disease and Allied Disorders. シュプリンガー・ジャパン株式会社. pp. 124–. ISBN 978-3-540-33934-2. Retrieved 2 January 2011. ## External links[edit] Classification D * OMIM: 601706 * MeSH: C536771 * v * t * e Genetic disorders relating to deficiencies of transcription factor or coregulators (1) Basic domains 1.2 * Feingold syndrome * Saethre–Chotzen syndrome 1.3 * Tietz syndrome (2) Zinc finger DNA-binding domains 2.1 * (Intracellular receptor): Thyroid hormone resistance * Androgen insensitivity syndrome * PAIS * MAIS * CAIS * Kennedy's disease * PHA1AD pseudohypoaldosteronism * Estrogen insensitivity syndrome * X-linked adrenal hypoplasia congenita * MODY 1 * Familial partial lipodystrophy 3 * SF1 XY gonadal dysgenesis 2.2 * Barakat syndrome * Tricho–rhino–phalangeal syndrome 2.3 * Greig cephalopolysyndactyly syndrome/Pallister–Hall syndrome * Denys–Drash syndrome * Duane-radial ray syndrome * MODY 7 * MRX 89 * Townes–Brocks syndrome * Acrocallosal syndrome * Myotonic dystrophy 2 2.5 * Autoimmune polyendocrine syndrome type 1 (3) Helix-turn-helix domains 3.1 * ARX * Ohtahara syndrome * Lissencephaly X2 * MNX1 * Currarino syndrome * HOXD13 * SPD1 synpolydactyly * PDX1 * MODY 4 * LMX1B * Nail–patella syndrome * MSX1 * Tooth and nail syndrome * OFC5 * PITX2 * Axenfeld syndrome 1 * POU4F3 * DFNA15 * POU3F4 * DFNX2 * ZEB1 * Posterior polymorphous corneal dystrophy * Fuchs' dystrophy 3 * ZEB2 * Mowat–Wilson syndrome 3.2 * PAX2 * Papillorenal syndrome * PAX3 * Waardenburg syndrome 1&3 * PAX4 * MODY 9 * PAX6 * Gillespie syndrome * Coloboma of optic nerve * PAX8 * Congenital hypothyroidism 2 * PAX9 * STHAG3 3.3 * FOXC1 * Axenfeld syndrome 3 * Iridogoniodysgenesis, dominant type * FOXC2 * Lymphedema–distichiasis syndrome * FOXE1 * Bamforth–Lazarus syndrome * FOXE3 * Anterior segment mesenchymal dysgenesis * FOXF1 * ACD/MPV * FOXI1 * Enlarged vestibular aqueduct * FOXL2 * Premature ovarian failure 3 * FOXP3 * IPEX 3.5 * IRF6 * Van der Woude syndrome * Popliteal pterygium syndrome (4) β-Scaffold factors with minor groove contacts 4.2 * Hyperimmunoglobulin E syndrome 4.3 * Holt–Oram syndrome * Li–Fraumeni syndrome * Ulnar–mammary syndrome 4.7 * Campomelic dysplasia * MODY 3 * MODY 5 * SF1 * SRY XY gonadal dysgenesis * Premature ovarian failure 7 * SOX10 * Waardenburg syndrome 4c * Yemenite deaf-blind hypopigmentation syndrome 4.11 * Cleidocranial dysostosis (0) Other transcription factors 0.6 * Kabuki syndrome Ungrouped * TCF4 * Pitt–Hopkins syndrome * ZFP57 * TNDM1 * TP63 * Rapp–Hodgkin syndrome/Hay–Wells syndrome/Ectrodactyly–ectodermal dysplasia–cleft syndrome 3/Limb–mammary syndrome/OFC8 Transcription coregulators Coactivator: * CREBBP * Rubinstein–Taybi syndrome Corepressor: * HR (Atrichia with papular lesions) 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	Yemenite deaf-blind hypopigmentation syndrome	c1866425	3,457	wikipedia	https://en.wikipedia.org/wiki/Yemenite_deaf-blind_hypopigmentation_syndrome	2021-01-18T18:38:57	{"gard": ["5535"], "mesh": ["C536771"], "umls": ["C1866425"], "orphanet": ["3214"], "wikidata": ["Q8052144"]}
This syndrome is characterized by cardiac arrhythmias (ventricular extrasystoles manifesting as bigeminy or multifocal tachycardia with syncopal episodes), perodactyly (hypoplasia and/or agenesis of the distal phalanges of the toes) and Pierre-Robin sequence (see this term). ## Epidemiology It has initially been reported in six patients from three generations of one family. Four affected members of another family manifesting a similar constellation of clinical features have recently been reported. ## Clinical description An additional feature may be an antimongoloid slant of the palpebral fissures. ## Etiology Etiology remains unknown. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: 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	Ventricular extrasystoles with syncopal episodes-perodactyly-Robin sequence syndrome	c1860471	3,458	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=3201	2021-01-23T16:56:14	{"gard": ["5472"], "mesh": ["C537497"], "omim": ["192445"], "umls": ["C1860471", "C2931232"], "icd-10": ["Q87.8"], "synonyms": ["Stoll-Kieny-Dott syndrome"]}
A rare myelodysplastic/myeloproliferative neoplasm characterized by a proliferation primarily of granulocytic and monocytic lineages with infiltration of the liver and spleen, among other organs. Blasts and promonocytes account for less than 20% of white blood cells in peripheral blood and bone marrow. Erythroid and megakaryocytic abnormalities are often present. BCR-ABL1 fusion is absent, while somatic mutations in genes of the RAS pathway or monosomy 7 may be found. The condition may also occur in the context of neurofibromatosis type 1 or Noonan syndrome-like disorder. Children of less than three years are predominantly affected, with a clear male preponderance. Most patients present with constitutional symptoms, signs of infection, and hepatosplenomegaly. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: 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	Juvenile myelomonocytic leukemia	c0349639	3,459	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=86834	2021-01-23T18:29:10	{"gard": ["9884"], "mesh": ["D054429"], "omim": ["607785"], "umls": ["C0349639"], "icd-10": ["C93.3"], "synonyms": ["JMML", "Juvenile chronic myelomonocytic leukemia"]}
A number sign (#) is used with this entry because of the evidence that the causative mutation resides in the COL2A1 gene (120140). Clinical Features Siggers et al. (1974) reported 8 patients with Kniest dysplasia. Two were identical twins; the other cases were sporadic. All of the patients had short stature, round face with central depression, prominent eyes, enlargement and stiffness of joints, contractures of fingers, normal head circumference, bell-shaped chest, and myopia. Cleft palate was present in 5, deafness in 6, retinal detachment in 3. Cartilage obtained by biopsy felt soft. Histology showed lacunae in the cartilage, giving it a Swiss-cheese appearance. Electron microscopy showed abnormality of the collagen of cartilage. The patients cannot make a tight fist, seemingly because of thin joint spaces, and have a violaceous hue of the palms. Siggers et al. (1974) cited cases in mother and daughter known to Dr. J. Spranger of Kiel. The mean paternal age of the 8 cases was 28.5 years. Kim et al. (1975) described affected mother and daughter. Excessive urinary excretion of keratan sulfate was noted. The daughter had myopia and chorioretinal thinning. The mother had cataracts and myopia. Stanescu et al. (1976) suggested that an abnormal proteoglycan is synthesized in this disease. Horton and Rimoin (1979) described chondrocyte inclusions. Friede et al. (1985) confirmed the high excretion of keratan sulfate in the urine. Characteristic craniofacial changes were described. There was macrocephaly with increased size of the neurocranium in all 3 dimensions. The odontoid process was short and wide. At 11 years of age in the patient most extensively studied, there was bony fusion between the anterior arch of the atlas and the odontoid and between the posterior arch of the atlas and the cranial base. In all of 7 patients with Kniest dysplasia, Maumenee and Traboulsi (1985) found congenital severe myopia and vitreoretinal degeneration. Rhegmatogenous retinal detachment developed in 4 of them. Other ocular findings included cataract in 2, dislocated lenses in 1, and blepharoptosis in 1. Sayli and Brooker (1989) reported hip replacement in a 26-year-old woman with successful relief of pain and functional improvement. Gilbert-Barnes et al. (1996) reviewed the radiologic, histopathologic, and spanning electron microscopic findings in Kniest dysplasia. Pathogenesis Poole et al. (1988) studied epiphyseal cartilages from 4 cases of Kniest dysplasia and demonstrated abnormality of collagen fibril organization by electron microscopy in each. Fibrils were much thinner than normal and were irregular in shape, without the characteristic banding pattern. Furthermore, chondrocalcin was found to be absent from the extracellular matrix of epiphyseal cartilages and to be abnormally concentrated in intracellular vacuolar sites where it was not part of the procollagen molecule. Type II collagen alpha chain size was normal, indicating the formation of a triple helix; the content of type II collagen was also normal. Poole et al. (1988) believed these observations indicated that the defect in Kniest dysplasia results from the secretion of type II procollagen lacking the C-propeptide and abnormal fibril formation, and that the C-propeptide is normally required for fibril formation. Molecular Genetics Mortier et al. (1995) described a mutation in type II collagen resulting in Kniest dysplasia (120140.0022). Winterpacht et al. (1993) and Spranger et al. (1994) described COL2A1 mutations in patients with Kniest dysplasia. The patient described by Winterpacht et al. (1993) had a 28-bp deletion involving exon 12 and intron 12 in the COL2A1 gene (120140.0012). The patient described by Spranger et al. (1994) had a splice site mutation in exon 20. In each case, 1 parent was a somatic mosaic for the same mutation as seen in their children and was significantly more mildly affected. Wilkin et al. (1994) reported a single amino acid substitution in the triple helical domain of COL2A1 (120140.0020) resulting in Kniest dysplasia. Wilkin et al. (1999) pointed out that all but 2 of the previously described Kniest dysplasia mutations cause in-frame deletions in type II collagen, either by small deletions in the gene or splice site alterations. Furthermore, all but 1 of these mutations were located between exons 12 and 24 in the COL2A1 gene. Wilkin et al. (1999) used heteroduplex analysis to identify sequence anomalies in 5 individuals with Kniest dysplasia. Sequencing of the genomic DNA in each index patient identified 4 new dominant mutations in COL2A1 that resulted in Kniest dysplasia: a 21-bp deletion in exon 16, an 18-bp deletion in exon 19, and 4-bp deletions in the splice donor sites of introns 14 and 20. A previously described 28-bp deletion at the COL2A1 exon 12-intron 12 junction, deleting the splice donor site, was identified in the fifth patient. The latter 3 mutations were predicted to result in exon skipping in the mRNA encoded from the mutant allele. These data suggested that Kniest dysplasia results from shorter type II collagen monomers, and supported the hypothesis that alteration of a specific COL2A1 domain, which may span from exons 12 to 24, leads to the Kniest dysplasia phenotype. History Spranger et al. (1997) described, with a photograph, Dr. Wilhelm Kniest and the patient he described in 1952. At the time of the report, Kniest was chief resident of the Children's Hospital of the University of Jena in Thuringia. At the time of the report by Spranger et al. (1997), his patient was aged 50 years and severely handicapped with short stature, restricted joint mobility, and blindness, but was mentally alert and leading an active life. Molecular analysis of the patient's DNA showed a single base (G) deletion involving the GT dinucleotide at the start of intron 18 destroying a splice site of the COL2A1 gene (120140.0025). INHERITANCE \- Autosomal dominant GROWTH Height \- Final adult height 106-145cm \- Short stature, disproportionate (short trunk) HEAD & NECK Face \- Flat midface \- Round face Ears \- Conductive hearing loss \- Frequent otitis media Eyes \- Myopia \- Retinal detachment \- Cataracts \- Prominent eyes Nose \- Low nasal bridge Mouth \- Cleft palate Neck \- Short neck RESPIRATORY Airways \- Tracheomalacia \- Respiratory distress ABDOMEN External Features \- Inguinal hernias \- Umbilical hernias SKELETAL Spine \- Platyspondyly \- Lumbar kyphoscoliosis \- Coronal vertebral clefts \- Occipitoatlantal instability Pelvis \- Flexion contractures of hips \- Hypoplastic pelvic bones \- Hip dislocation \- Coxa vara Limbs \- Short, dumbbell appearance of long bones \- Splayed epiphyses and metaphyses \- Delayed epiphyseal ossification (early) \- Megaepiphyses (late) \- Narrowing of joint spaces \- Enlarged joints \- Limited joint mobility \- Painful joints Hands \- Flattened, squared-off epiphyses of tubular bones LABORATORY ABNORMALITIES \- Abnormal cartilage collagen on EM \- Keratan sulfaturia in some patients MISCELLANEOUS \- Delayed motor milestones \- Abnormal gait \- Parental somatic mosaicism in 2 cases produced mild phenotype in the patients MOLECULAR BASIS \- Caused by mutation in the collagen II, alpha-1 polypeptide gene (COL2A1, 120140.0012 ) ▲ 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	KNIEST DYSPLASIA	c0265279	3,460	omim	https://www.omim.org/entry/156550	2019-09-22T16:38:15	{"doid": ["0080045"], "mesh": ["C537207"], "omim": ["156550"], "orphanet": ["485"], "genereviews": ["NBK540447"]}
A number sign (#) is used with this entry because homozygous mutation in the TYRP1 gene (115501) has been shown to account for variation in hair color linked to chromosome 9p23 in Melanesians. For a general phenotypic description and a discussion of genetic heterogeneity of variation in skin, hair, and eye pigmentation, see SHEP1 (227220). Mapping Sulem et al. (2008) presented results from a genomewide association study for variants associated with human pigmentation characteristics among 5,130 Icelanders, with follow-up analyses in 2,116 Icelanders and 1,214 Dutch individuals. They found that a single-nucleotide polymorphism (SNP) near the TYRP1 on chromosome 9p23, rs1408799C, was associated with blue versus nonblue eyes (OR = 1.41, p = 1.5 x 10(-9)). The association was confirmed in both the Icelandic and Dutch replication samples with a similar effect. A suggestive association for blond versus brown hair was also observed for this SNP. The TYRP1 gene encodes a melanosomal enzyme with a role in the eumelanin pathway. Gudbjartsson et al. (2008) assessed the effect of genetic variants affecting hair, eye, and skin pigmentation of Europeans on the risk of cutaneous melanoma (155600) and basal cell carcinoma. The authors studied 2,121 individuals with cutaneous melanoma and 2,163 individuals with basal cell carcinoma, and over 40,000 controls. The SNP rs1408799C, found to be associated with blue eye color by Sulem et al. (2008), was associated with a risk of cutaneous melanoma (odds ratio = 1.15, p = 4.3 x 10(-4)). In a study of eye color variation in a cohort of 718 individuals of European descent, Pospiech et al. (2011) used multifactor dimensionality reduction and logistic regression to examine gene-gene interactions based on SNPs in 11 known pigmentation genes. A significant interaction effect was found for rs12913832 in HERC2 (605837) and rs1408799 in TYRP1 for green versus nongreen color. The interaction showed a synergistic effect. Clinical Features Kenny et al. (2012) examined the genetic basis of blond hair in Solomon Islanders, a population that differs from the general trend of darker skin and hair pigmentation near the equator where there is higher UV radiation. Although individuals from the Solomon Islands and Equatorial Oceania have the darkest skin pigmentation outside of Africa, they also have the highest prevalence of blond hair (5 to 10%) outside of Europe. Molecular Genetics Kenny et al. (2012) performed a case-control genomewide association study on 43 blond- and 42 dark-haired Solomon Islanders and observed a single strong association signal on chromosome 9p23; the most significant SNP was rs13289810 with a p value of 1.11 x 10(-19) and a frequency of 0.93 and 0.31 in blond- and dark-haired individuals, respectively. The mapping interval contained 1 known gene, TYRP1. It was known that mutations in TYRP1 lighten skin and/or hair pigmentation in several species, and that TYRP1 null alleles cause rufous albinism (OCA3; 203290) in humans. Resequencing of TYRP1 exons identified a C-to-T transition at chr9:12,694,273 (GRCh37) that corresponds to a predicted arg-to-cys mutation (R93C) in exon 2 of the TYRP1 gene at amino acid position 93 (R93C; 115501.0007). The genotype was TT in blond- and CT or CC in dark-haired individuals. The R93C mutation was more strongly associated with blond hair (p = 9.60 x 10(-23)) than the top GWA SNP, and the GWA signal was lost on conditioning for R93C, suggesting a primary role for the missense mutation. When Kenny et al. (2012) genotyped R93C in 918 Solomon Islanders for whom they had measured hair pigmentation with spectrometry, a recessive model provided the best fit for the data, and the R93C genotypes accounted for 46.4% of the variance in hair color (linear regression; p = 2.19 x 10(-90)). The frequency of the 93C allele in the Solomon Islands was 0.26, and genotyping of R93C in an additional 941 individuals from 52 worldwide populations revealed that the 93C allele is rare or absent outside of Oceania. Kenny et al. (2012) found no evidence for recent gene flow from Europe (i.e., admixture) nor a strong signature of recent positive selection for the 93C allele. Kenny et al. (2012) noted that the R93C mutation resides in an EGF-like repeat near the N terminus and is similar to a molecular alteration in TYRP1 observed in the brown(light) mouse (R38C). The R38C mutation is thought to interfere with disulfide bridges formed by the 15-cys EGF repeat. The brown(light) mouse exhibits reduced TYRP1 stability and catalytic function, resulting in decreased melanin content in hair, and Kenny et al. (2012) considered it likely that the human R93C mutation operates via a similar mechanism. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	SKIN/HAIR/EYE PIGMENTATION, VARIATION IN, 11	c2677086	3,461	omim	https://www.omim.org/entry/612271	2019-09-22T16:01:59	{"mesh": ["C567374"], "omim": ["612271"], "synonyms": ["Alternative titles", "MELANESIAN BLOND HAIR", "SKIN/HAIR/EYE PIGMENTATION 11, BLUE/NONBLUE EYES"]}
A rare mitochondrial DNA depletion syndrome characterized by congenital or early-onset lactic acidosis, hypotonia, and severe global developmental delay with feeding difficulties and failure to thrive. It is frequently associated with variable dysmorphic facial features. Additional manifestations include seizures, movement disorders, and cardiac and ophthalmologic anomalies, among others. Brain imaging may show generalized atrophy and white matter abnormalities. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Mitochondrial DNA depletion syndrome, encephalomyopathic form with variable craniofacial anomalies	c3809592	3,462	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=369897	2021-01-23T17:20:58	{"omim": ["615471"], "icd-10": ["E88.8"], "synonyms": ["mtDNA depletion syndrome, encephalomyopathic form with variable craniofacial anomalies"]}
Timothy syndrome is a disorder that affects the heart, digits (toes and fingers), and nervous system (brain and nerves). It is a type of long QT syndrome. Long QT syndrome refers to a prolonged QT interval measurement seen on the electrocardiogram. Symptoms of Timothy syndrome include fusion of the skin between fingers or toes (syndactyly), distinctive facial features, and congenital heart defects. Additional symptoms may include developmental delay, intellectual disability, and autism spectrum disorders. There are two forms of Timothy syndrome, classified based on signs and symptoms. Type 1, known as classic type, includes all of the symptoms described above. Type 2, or atypical type, causes a more severe form of long QT syndrome and does not appear to include syndactyly. Both types are caused by mutations in the CACNA1C gene and are inherited in an autosomal dominant manner. Treatment is focused on managing cardiac symptoms. This might include medications such as beta-blockers, placement of defibrillators, and pacemakers. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: 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	Timothy syndrome	c1832916	3,463	gard	https://rarediseases.info.nih.gov/diseases/9294/timothy-syndrome	2021-01-18T17:57:21	{"mesh": ["C536962"], "omim": ["601005"], "umls": ["C1832916"], "orphanet": ["65283"], "synonyms": ["Long QT syndrome 8", "LQT8", "Long QT syndrome with syndactyly"]}
Sappinia amoebic encephalitis SpecialtyInfectious disease Sappinia amoebic encephalitis (SAE) is the name for amoebic encephalitis caused by species of Sappinia.[1] The causative organism was originally identified as Sappinia diploidea,[2][3] but is now considered to be Sappinia pedata.[4] It has been treated with azithromycin, pentamidine, itraconazole, and flucytosine.[3] ## References[edit] 1. ^ Da Rocha-Azevedo, B.; Tanowitz, H.; Marciano-Cabral, F. (2009). "Diagnosis of infections caused by pathogenic free-living amoebae". Interdisciplinary Perspectives on Infectious Diseases. 2009: 1–14. doi:10.1155/2009/251406. PMC 2719787. PMID 19657454. 2. ^ Gelman, B. B.; Rauf, S. J.; Nader, R.; Popov, V.; Borkowski, J.; Chaljub, G.; Nauta, H. W.; Visvesvara, G. S. (2001). "Amoebic encephalitis due to Sappinia diploidea". JAMA: The Journal of the American Medical Association. 285 (19): 2450–2451. doi:10.1001/jama.285.19.2450. PMID 11368696. 3. ^ a b Gelman, B. B.; Popov, V.; Chaljub, G.; Nader, R.; Rauf, S. J.; Nauta, H. W.; Visvesvara, G. S. (2003). "Neuropathological and ultrastructural features of amebic encephalitis caused by Sappinia diploidea". Journal of Neuropathology and Experimental Neurology. 62 (10): 990–998. doi:10.1093/jnen/62.10.990. PMID 14575235. 4. ^ Qvarnstrom, Y.; Da Silva, A.; Schuster, F.; Gelman, B.; Visvesvara, G. (2009). "Molecular confirmation of Sappinia pedata as a causative agent of amoebic encephalitis". The Journal of Infectious Diseases. 199 (8): 1139–1142. doi:10.1086/597473. PMID 19302010. * v * t * e Amoebozoal diseases Lobosea (free-living) Centramoebida * Acanthamoeba * Acanthamoeba keratitis * Cutaneous acanthamoebiasis * Granulomatous amoebic encephalitis * Acanthamoeba infection * Balamuthia mandrillaris * Balamuthia amoebic encephalitis * Balamuthia infection Flabellinia * Sappinia diploidea/Sappinia pedata * Sappinia amoebic encephalitis Conosa/Archamoebae * Entamoeba histolytica * Amoebiasis * Amoebic dysentery * Amoebic liver abscess * Cutaneous amoebiasis * Amoebic brain abscess * Amebiasis cutis * Entamoeba gingivalis * 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 This article about a medical condition affecting the nervous 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	Sappinia amoebic encephalitis	None	3,464	wikipedia	https://en.wikipedia.org/wiki/Sappinia_amoebic_encephalitis	2021-01-18T18:50:41	{"wikidata": ["Q7421081"]}
Postoperative hematomas are a cutaneous condition characterized by a collection of blood below the skin, and result as a complication following surgery.[1] ## See also[edit] * Subungual hematoma * List of cutaneous conditions ## References[edit] 1. ^ Rapini, Ronald P.; Bolognia, Jean L.; Jorizzo, Joseph L. (2007). Dermatology: 2-Volume Set. St. Louis: Mosby. ISBN 1-4160-2999-0. This dermatology article is a stub. You can help Wikipedia by expanding it. * v * t * e [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Postoperative hematoma	c0338380	3,465	wikipedia	https://en.wikipedia.org/wiki/Postoperative_hematoma	2021-01-18T19:10:12	{"wikidata": ["Q7234429"]}
Early-1900s term for proportional dwarfism Ateliosis or ateleiosis is a diagnosis used in the early 1900s to describe patients with short stature. Ateliosis literally means "failure to achieve perfection", and was used to describe proportional dwarfism.[1] The term was popularised by Hastings Gilford, who used the term to refer to forms of dwarfism associated with and without sexual maturation.[2] Ateliosis was reported as early as 1904 in relation to progeria, a syndrome of premature aging.[3] According to the Merriam-Webster Dictionary it is, “dwarfism associated with anterior pituitary deficiencies and marked by essentially normal intelligence and proportions though often retarded sexual development”.[4] The physical characteristics include: normal facial features, childlike high pitched voice, proportioned body, and abnormal genitalia. Their mental development is normal to slightly delayed. Hastings Gilford originated the term to describe patients with "continuous youth".[5] ## References[edit] 1. ^ Merimee, T J (1 February 1974). "Isolated Growth Hormone Deficiency and Related Disorders". Annual Review of Medicine. 25 (1): 137–142. doi:10.1146/annurev.me.25.020174.001033. 2. ^ "Low Birth Weight Dwarfism". Arch Dis Child. 36 (190): 633–644. 1961. doi:10.1136/adc.36.190.633. PMC 2012814. PMID 13869653. 3. ^ Gilford H; Shepherd, RC (1904). "Ateleiosis and progeria: continuous youth and premature old age". British Medical Journal. 2 (5157): 914–8. PMC 1990667. PMID 14409225. 4. ^ "Ateliosis." Merriam Webster.com. N.p.,n.d. Web. 10 Mar. 2010. 5. ^ Worster-Drought C.,Archer BW. "A Case of Ateleiosis (Lorain’s Disease)." Proc R Soc Med 20.6 (1927): 771-773. PubMed. Web. 8 Mar. 2010. * v * t * e Growth and height disorder due to endocrine malfunction * Dwarfism * Primordial dwarfism * Laron syndrome * Psychosocial * Ateliosis * Gigantism [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: 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	Ateliosis	None	3,466	wikipedia	https://en.wikipedia.org/wiki/Ateliosis	2021-01-18T18:46:48	{"wikidata": ["Q4813037"]}
Endocardial Fibroelastosis Other namesEFE SpecialtyCardiology Endocardial fibroelastosis (EFE) is a rare heart disorder usually occurring in children two years old and younger.[1] It may also be considered a reaction to stress, not necessarily a specific disease.[2] It should not be confused with endomyocardial fibrosis. ## Contents * 1 Signs and symptoms * 2 Cause * 3 Treatment * 4 History * 5 See also * 6 References * 7 External links ## Signs and symptoms[edit] EFE is characterized by a thickening of the innermost lining of the heart chambers (the endocardium) due to an increase in the amount of supporting connective tissue and elastic fibres. It is an uncommon cause of unexplained heart failure in infants and children, and is one component of HEC syndrome. Fibroelastosis is strongly seen as a primary cause of restrictive cardiomyopathy in children, along with cardiac amyloidosis, which is more commonly seen in progressive multiple myeloma patients and the elderly.[citation needed] ## Cause[edit] A review cites references to 31 different diseases and other stresses associated with the EFE reaction.[2] These include infections, cardiomyopathies, immunologic diseases, congenital malformations, even electrocution by lightning strike. EFE has two distinct genetic forms, each having a different mode of inheritance. An X-linked recessive form,[3] and an autosomal recessive form[4] have both been observed. ## Treatment[edit] The cause should be identified and, where possible, the treatment should be directed to that cause. A last resort form of treatment is heart transplant.[5] ## History[edit] An infant with dilated, failing heart was no rarity on the pediatric wards of hospitals in the mid-twentieth century. On autopsy, most of these patients' hearts showed the thickened endocardial layer noted above. This was thought to be a disease affecting both the heart muscle and the endocardium and it was given various names such as: idiopathic hypertrophy of the heart, endocardial sclerosis, cardiac enlargement of unknown cause, etc. Some of these hearts also had overt congenital anomalies, especially aortic stenosis and coarctation of the aorta.[citation needed] The term "endocardial fibroelastosis" was introduced by Weinberg and Himmelfarb in 1943.[6] In their pathology laboratory they noted that usually the endocardium was pearly white or opaque instead of normally thin and transparent and microscopically showed a systematic layering of collagenous and elastic fibers. They felt their new term was more adequately descriptive, and, indeed it was quickly and widely adopted. Clinicians began applying it to any infant with a dilated, failing heart, in spite of the fact that the only way to definitively establish the presence of EFE was to see it at autopsy. EFE had quickly become the name of a disease, and it continues to be used by many physicians in this way, though many patients with identical symptoms do not have the endocardial reaction of EFE.[citation needed] In the latter decades of the twentieth century new discoveries and new thinking about heart muscle disease gave rise to the term "cardiomyopathy". Many of the cases of infantile cardiac failure were accordingly called "primary cardiomyopathy" as well as "primary EFE", while those with identifiable congenital anomalies stressing the heart were called "secondary EFE". In 1957 Black-Schaffer proposed a unitary explanation that stress on the ventricle, of any kind, may trigger the endocardial reaction, so that all EFE could be thought of as secondary.[7] This prescient paper convinced few readers at the time. Evidence gradually accumulated as to the role of infection as one such type of stress. The studies of Fruhling and colleagues in 1962 were critical.[8] They followed a series of epidemics of Coxsackie virus infection in their part of France. After each epidemic there were increased numbers of cases with EFE coming to autopsy. On closer study there were cases of pure acute myocarditis, cases of mixed myocarditis and EFE, and cases where myocarditis had healed, leaving just EFE. They were able to culture Coxsackie virus from the tissues of many of the cases at all stages of this apparent progression. A similar progression from myocarditis to EFE was later observed at Johns Hopkins but no virology was done.[9] Noren and colleagues at University of Minnesota, acting on an idea floated at a pediatric meeting, were able to show a relation between exposure to maternal mumps in fetal life, EFE, and a positive skin test for mumps in infants.[10] This brought on a large ongoing controversy and finally prompted a virologist colleague of theirs to inject embryonated eggs with mumps virus.[11] The chicks at first showed the changes of myocarditis, about a year later, typical EFE, and transitional changes in between. Despite this, the controversy about the role of mumps continued as the actual incidence of EFE plummeted. The proponents of mumps as a cause pointed to this as the effect of the recent implementation of widespread mumps immunization.[citation needed] Evidence that viral infection may play a role as a cause or trigger of EFE was greatly reinforced by the study directed by Towbin in the virus laboratory of Texas Children's Hospital.[12] They applied the methods of today's genetics to old preserved specimens from autopsies of patients with EFE done well before mumps immunization began and found mumps genome in the tissues of over 80% of these patients. It seems undeniable that transplacental mumps infection had been in the past the major cause of EFE, and that immunization was indeed the cause of EFE having become rare.[citation needed] Non-infectious causes of EFE have also been studied, spurred by the opening of new avenues of genetics research. Now there are specific named genes associated with certain cardiomyopathies, some of which show the characteristic reaction of EFE. A typical example is Barth syndrome and the responsible gene, tafazzin.[13] Developments in echocardiography, both the technology of the machines and the skill of the operators, have made it no longer necessary to see the endocardium at autopsy. EFE can now be found non-invasively by the recording of increased endocardial echos. Fetal echocardiography has shown that EFE can begin to accumulate as early as 14 weeks of gestation, and increase with incredible rapidity[14] and even that it can be reversed if the stress can be removed early in fetal life.[15] The North American Pediatric Cardiomyopathy Registry was founded in 2000 and has been supported since by the National Heart, Lung and Blood Institute. Because of the logic of the diagnostic tree, where EFE applies to many branches of the tree and thus cannot occupy a branch, it is not listed by the Registry as a cause but rather, "with EFE" is a modifier that can be applied to any cause.[16] Thus, the past half century has seen EFE evolve from a mysterious but frequently observed disease to a rare but much better understood reaction to many diseases and other stresses. ## See also[edit] * Papillary fibroelastoma ## References[edit] 1. ^ Cotran, Ramzi S.; Kumar, Vinay; Fausto, Nelson; Nelso Fausto; Robbins, Stanley L.; Abbas, Abul K. (2005). Robbins and Cotran pathologic basis of disease. St. Louis, Mo: Elsevier Saunders. p. 607. ISBN 978-0-7216-0187-8. 2. ^ a b Lurie PR; Béland, MJ (2010). "Changing concepts of endocardial fibroelastosis". Cardiology in the Young. 20 (2): 124–132. doi:10.1017/s1047951110000181. PMID 20405546. 3. ^ Online Mendelian Inheritance in Man (OMIM): 226000 4. ^ Online Mendelian Inheritance in Man (OMIM): 305300 5. ^ Netz H, Bauer JJ, Scheld HH, et al. (1990). "Cardiac Transplantation in a Neonate with Endocardial Fibroelastosis" (Free full text). Tex Heart Inst J. 17 (2): 122–125. PMC 326468. PMID 15227396. 6. ^ Weinberg T, Himmelfarb AJ (1943). "Endocardial fibroelastosis". Bull Johns Hopkins Hosp. 72: 299. 7. ^ Black-Schaffer B. (1957) "Infantile endocardial fibroelastosis: a suggested etiology", AMA Archives of Pathology 63::281-306. 8. ^ Fruhling L, Korn R, LaVillaureix J, Surjus A, Fousserreau S. (1962)"La myoendocardite chronique fibroélastique du nouveau-né et du nourisson" Ann d'Anat Pathol 7:227-303. 9. ^ Hutchins GM, Vie SA (1982) "The progression of interstitial myocarditis to idiopathic endocardial fibroelastosis" Am J Pathol 66: 483-492. 10. ^ Noren GR, Adams P Jr., Anderson RC (1963) "Positive skin reactivity to mumps virus antigen in endocardial fibroelastosis" J Pediat 62: 604-606. 11. ^ St. Geme JW Jr., Peralta H, Farias E, et al. (1971) "Experimental gestational mumps virus infection and endocardial fibroelastosis" Pediatrics 48: 821-828. 12. ^ Ni J, Bowles NE, Kim YH, et al. (Jan 1997). "Viral infection of the myocardium in endocardial fibroelastosis. Molecular evidence for the role of mumps virus as an etiologic agent" (Free full text). Circulation. 95 (1): 133–139. doi:10.1161/01.CIR.95.1.133. PMID 8994428. 13. ^ Bione S, D'Adamo P, Maestrini E, Gedeon AK, Bolhuis PA, Toniolo D (1996) "A novel x-linked gene, G4.5, is responsible for Barth Syndrome" Nat Genet 12: 385-389. 14. ^ Rustico MA, Benettoni A, Bussani R, Maieron A, Mandruzzato G. (1995) "Early fetal endocardial fibroelastosis and critical aortic stenosis: a case report" Ultrasound Obstet Gynecol 5: 202-205. 15. ^ Raboisson M-J, Fouron J-C, Sonesson S-E, Nyman M, Proulx F, Gamache S (2005) " Fetal Doppler echocardiographic diagnosis and successful steroid therapy of Luciani-Wenckebach phenomenon and endocardial fibroelastosis related to maternal anti-Ro and anti-La antibodies" J Am Soc Echocardiogr 18: 375-380. 16. ^ Alvarez JA, Wilkinson JD, Lipshultz SE (2007) "Outcome predictors for pediatric dilated cardiomyopathy: a systematic review" Prog Pediatr Cardiol 23: 25-32. ## External links[edit] Classification D * ICD-10: I42.4 * ICD-9-CM: 425.3 * OMIM: 226000 305300 * MeSH: D004695 * DiseasesDB: 29236 External resources * Orphanet: 2022 * v * t * e Cardiovascular disease (heart) Ischaemic Coronary disease * Coronary artery disease (CAD) * Coronary artery aneurysm * Spontaneous coronary artery dissection (SCAD) * Coronary thrombosis * Coronary vasospasm * Myocardial bridge Active ischemia * Angina pectoris * Prinzmetal's angina * Stable angina * Acute coronary syndrome * Myocardial infarction * Unstable angina Sequelae * hours * Hibernating myocardium * Myocardial stunning * days * Myocardial rupture * weeks * Aneurysm of heart / Ventricular aneurysm * Dressler syndrome Layers Pericardium * Pericarditis * Acute * Chronic / Constrictive * Pericardial effusion * Cardiac tamponade * Hemopericardium Myocardium * Myocarditis * Chagas disease * Cardiomyopathy * Dilated * Alcoholic * Hypertrophic * Tachycardia-induced * Restrictive * Loeffler endocarditis * Cardiac amyloidosis * Endocardial fibroelastosis * Arrhythmogenic right ventricular dysplasia Endocardium / valves Endocarditis * infective endocarditis * Subacute bacterial endocarditis * non-infective endocarditis * Libman–Sacks endocarditis * Nonbacterial thrombotic endocarditis Valves * mitral * regurgitation * prolapse * stenosis * aortic * stenosis * insufficiency * tricuspid * stenosis * insufficiency * pulmonary * stenosis * insufficiency Conduction / arrhythmia Bradycardia * Sinus bradycardia * Sick sinus syndrome * Heart block: Sinoatrial * AV * 1° * 2° * 3° * Intraventricular * Bundle branch block * Right * Left * Left anterior fascicle * Left posterior fascicle * Bifascicular * Trifascicular * Adams–Stokes syndrome Tachycardia (paroxysmal and sinus) Supraventricular * Atrial * Multifocal * Junctional * AV nodal reentrant * Junctional ectopic Ventricular * Accelerated idioventricular rhythm * Catecholaminergic polymorphic * Torsades de pointes Premature contraction * Atrial * Junctional * Ventricular Pre-excitation syndrome * Lown–Ganong–Levine * Wolff–Parkinson–White Flutter / fibrillation * Atrial flutter * Ventricular flutter * Atrial fibrillation * Familial * Ventricular fibrillation Pacemaker * Ectopic pacemaker / Ectopic beat * Multifocal atrial tachycardia * Pacemaker syndrome * Parasystole * Wandering atrial pacemaker Long QT syndrome * Andersen–Tawil * Jervell and Lange-Nielsen * Romano–Ward Cardiac arrest * Sudden cardiac death * Asystole * Pulseless electrical activity * Sinoatrial arrest Other / ungrouped * hexaxial reference system * Right axis deviation * Left axis deviation * QT * Short QT syndrome * T * T wave alternans * ST * Osborn wave * ST elevation * ST depression * Strain pattern Cardiomegaly * Ventricular hypertrophy * Left * Right / Cor pulmonale * Atrial enlargement * Left * Right * Athletic heart syndrome Other * Cardiac fibrosis * Heart failure * Diastolic heart failure * Cardiac asthma * Rheumatic fever * v * t * e Congenital heart defects Heart septal defect Aortopulmonary septal defect * Double outlet right ventricle * Taussig–Bing syndrome * Transposition of the great vessels * dextro * levo * Persistent truncus arteriosus * Aortopulmonary window Atrial septal defect * Sinus venosus atrial septal defect * Lutembacher's syndrome Ventricular septal defect * Tetralogy of Fallot Atrioventricular septal defect * Ostium primum Consequences * Cardiac shunt * Cyanotic heart disease * Eisenmenger syndrome Valvular heart disease Right * pulmonary valves * stenosis * insufficiency * absence * tricuspid valves * stenosis * atresia * Ebstein's anomaly Left * aortic valves * stenosis * insufficiency * bicuspid * mitral valves * stenosis * regurgitation Other * Underdeveloped heart chambers * right * left * Uhl anomaly * Dextrocardia * Levocardia * Cor triatriatum * Crisscross heart * Brugada syndrome * Coronary artery anomaly * Anomalous aortic origin of a coronary artery * Ventricular inversion [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Endocardial fibroelastosis	c0014117	3,467	wikipedia	https://en.wikipedia.org/wiki/Endocardial_fibroelastosis	2021-01-18T19:10:51	{"gard": ["2121", "6336"], "mesh": ["D004695"], "umls": ["C0014117"], "orphanet": ["2022"], "wikidata": ["Q5376225"]}
A number sign (#) is used with this entry because of evidence that progressive encephalopathy with edema, hypsarrhythmia, and optic atrophy (PEHO)-like syndrome (PEHOL) is caused by homozygous mutation in the CCDC88A gene (609736) on chromosome 2p16. One such family has been reported. Clinical Features Nahorski et al. (2016) reported 3 children from a large consanguineous Caucasian family with a severe encephalopathy, progressive microcephaly, and hypotonia beginning at birth. All developed seizures at birth or within the first month of life, which progressed to hypsarrhythmia on electroencephalogram. The seizures persisted and were difficult to control. The infants had edema of the face, hands, and feet that was present since birth and persisted. Over the first 6 months, poor visual attention, fixing, and following were noted, and all had moderate optic atrophy. They had profound cognitive delay, severe motor delay, central hypotonia, peripheral hypertonia with spasticity, and kyphoscoliosis. Microcephaly progressed to -6 SD by age 3 years. Brain imaging showed coarse pachygyria, polymicrogyria, dilated ventricles due to brain atrophy, hypoplastic corpus callosum, and hypoplastic pons. One of the 3 had a small cerebellum. The patients also had subtle dysmorphic features consistent with PEHO syndrome, including narrow forehead, epicanthal folds, short nose, open mouth, receding chin, and tapering fingers. Anttonen et al. (2017) suggested that the polymicrogyria and pachygyria observed in the individuals reported by Nahorski et al. (2016) argued against a diagnosis of PEHO syndrome (260565). Inheritance The transmission pattern of PEHO-like syndrome in the family reported by Nahorski et al. (2016) was consistent with autosomal recessive inheritance. Molecular Genetics In 3 patients from a consanguineous Caucasian family with PEHO-like syndrome, Nahorski et al. (2016) identified a homozygous truncating mutation in the CCDC88A gene (609736.0001). The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Patient cells showed presence of the mutant transcript, indicating that it is not subject to nonsense-mediated mRNA decay. However, Nahorski et al. (2016) suggested that even if the protein were produced, it would be highly disrupted due to absence of C-terminal functions. Animal Model Nahorski et al. (2016) found that Ccdc88a-null mice developed mesial temporal lobe epilepsy and showed postnatal growth retardation and postnatal lethality. Neuropathologic examination of mutant mice showed a developmental defect in the caudal end of the corpus callosum and cerebral atrophy. There was no evidence of polymicrogyria, optic nerve atrophy, or cerebellar atrophy. INHERITANCE \- Autosomal recessive HEAD & NECK Head \- Microcephaly, progressive (up to -6SD) Face \- Narrow forehead \- Sloping forehead \- Bitemporal narrowing \- Receding chin \- Full cheeks Eyes \- Epicanthal folds \- Visual fixation absent from birth or lost in first months of life \- Absent visual evoked potentials \- Optic atrophy Nose \- Short nose Mouth \- Open mouth ABDOMEN Gastrointestinal \- Poor feeding SKELETAL Hands \- Tapered digits MUSCLE, SOFT TISSUES \- Edema, peripheral \- Hypotonia, neonatal NEUROLOGIC Central Nervous System \- Lack of psychomotor development \- Infantile encephalopathy, progressive \- Hypotonia, severe \- Seizures (neonatal onset) \- Myoclonic jerks \- Status epilepticus \- Hypsarrhythmia seen on EEG \- Mental retardation, profound \- Absent speech \- Hyperreflexia \- Cerebellar atrophy, progressive \- Brain stem atrophy, progressive \- Enlarged ventricles \- Absent cortical responses of somatosensory evoked potentials \- Dysmyelination seen on MRI \- Pachygyria \- Polymicrogyria \- Lissencephaly \- Hypoplastic corpus callosum MISCELLANEOUS \- Onset in infancy or at birth \- Three patients from 1 consanguineous family have been reported (last curated July 2016) MOLECULAR BASIS \- Caused by mutation in the coiled-coil domain-containing protein 88A gene (CCDC88A, 609736.0001 ) ▲ 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	PEHO-LIKE SYNDROME	c1850056	3,468	omim	https://www.omim.org/entry/617507	2019-09-22T15:45:44	{"mesh": ["C536317"], "omim": ["617507"], "orphanet": ["99807"], "synonyms": ["Alternative titles", "PROGRESSIVE ENCEPHALOPATHY WITH EDEMA, HYPSARRHYTHMIA, AND OPTIC ATROPHY-LIKE SYNDROME"]}
Kimura disease is a benign and chronic inflammatory disorder of unknown etiology, occurring mainly in Asian countries (very rarely in Western countries) and predominantly affecting young men, that usually presents with solitary or multiple non-tender subcutaneous masses in the head and neck region (in particular the preauricular and submandibular area) and/or generalized painless lymphadenopathy, often with salivary gland involvement. Characteristic laboratory findings include blood eosinophilia and markedly elevated serum immunoglobulin E (IgE) levels. It is often associated with autoinflammatory disorders (i.e. ulcerative colitis, bronchial asthma) and a co-existing renal 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	Kimura disease	c0033838	3,469	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=482	2021-01-23T18:46:59	{"gard": ["6835"], "mesh": ["D000796"], "umls": ["C0033838"], "icd-10": ["I89.8"], "synonyms": ["Eosinophilic lymphogranuloma"]}
Menkes disease (MD) is an inherited condition that impacts the way the body processes copper levels in the body. MD primarily affects the nervous system and connective tissue with symptoms that tend to get worse over time. Symptoms of MD usually appear within the first few months of life and include sparse, kinky hair; slow growth (failure to thrive); and seizures. Additional features may include low muscle tone (hypotonia), sagging facial features, and developmental and intellectual disability. Most children with MD have severe symptoms that lead to death at an early age. Occipital horn syndrome is a less severe form of MD that begins in early to middle childhood. The adult-onset form is the least severe and primarily impacts the nerves and muscles. MD is caused by alterations (mutations) in the ATP7A gene and is inherited in an X-linked recessive pattern. MD mainly affects boys. Early treatment with copper may improve the long-term outcome in some children with this 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	Menkes disease	c0022716	3,470	gard	https://rarediseases.info.nih.gov/diseases/1521/menkes-disease	2021-01-18T17:59:10	{"mesh": ["D007706"], "omim": ["309400"], "umls": ["C0022716"], "orphanet": ["565"], "synonyms": ["Menkes syndrome", "Steely hair disease", "Menkea syndrome", "Kinky hair disease", "Copper transport disease"]}
Medical condition of the prostate gland 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: "Prostatic congestion" – news · newspapers · books · scholar · JSTOR (September 2019) Prostatic congestion is a medical condition of the prostate gland that happens when the prostate becomes swollen by excess fluid and can be caused by prostatosis. The condition often results in a person with prostatic congestion feeling the urge to urinate frequently. ## Possible causes of prostatic congestion[edit] * Benign prostatic hyperplasia * Blue balls * Chronic prostatitis (infection of the prostate) * Excessive drinking of alcoholic beverages * Prostate cancer * Urinary tract cysts ## References[edit] ## External links[edit] * NIH: Enlarged prostate * Prostatitis, prostatosis and prostalgia. Psychogenic or organic disease? * NIH: Prostatitis - chronic * 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 This medical symptom 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	Prostatic congestion	c0268890	3,471	wikipedia	https://en.wikipedia.org/wiki/Prostatic_congestion	2021-01-18T18:30:58	{"umls": ["C0268890"], "wikidata": ["Q16969121"]}
Adie's syndrome Other namesHolmes–Adie syndrome, Adie's tonic pupil, Holmes–Adie pupil Bilateral mydriasis given the observational diagnosis Adie's pupils by an ophthalmologist Pronunciation * /ˈeɪdi/ SpecialtyOphthalmology Adie syndrome, also known as Holmes-Adie syndrome, is a neurological disorder characterized by a tonically dilated pupil that reacts slowly to light but shows a more definite response to accommodation (i.e., light-near dissociation).[1] It is frequently seen in females with absent knee or ankle jerks and impaired sweating. The syndrome is caused by damage to the postganglionic fibers of the parasympathetic innervation of the eye, usually by a viral or bacterial infection that causes inflammation, and affects the pupil of the eye and the autonomic nervous system.[1] It is named after the British neurologists William John Adie and Gordon Morgan Holmes, who independently described the same disease in 1931.[2] ## Contents * 1 Signs and symptoms * 2 Pathophysiology * 3 Diagnosis * 4 Treatment * 5 Prognosis * 6 Epidemiology * 7 See also * 8 References * 9 Further reading * 10 External links ## Signs and symptoms[edit] Adie syndrome presents with three hallmark symptoms, namely at least one abnormally dilated pupil (mydriasis) which does not constrict in response to light, loss of deep tendon reflexes, and abnormalities of sweating.[1] Other signs may include hyperopia due to accommodative paresis, photophobia and difficulty reading.[3] Some individual with Adie syndrome may also have cardiovascular abnormalities.[4] ## Pathophysiology[edit] Pupillary symptoms of Holmes–Adie syndrome are thought to be the result of a viral or bacterial infection that causes inflammation and damage to neurons in the ciliary ganglion, located in the posterior orbit, that provides parasympathetic control of eye constriction. Additionally, patients with Holmes-Adie Syndrome can also experience problems with autonomic control of the body. This second set of symptoms is caused by damage to the dorsal root ganglia of the spinal cord. Adie's pupil is supersensitive to ACh so a muscarinic agonist (e.g. pilocarpine) whose dose would not be able to cause pupillary constriction in a normal patient, would cause it in a patient with Adie's Syndrome. The circuitry for the pupillary constriction does not descend below the upper midbrain, henceforth impaired pupillary constriction is extremely important to detect as it can be an early sign of brainstem herniation.[1] ## Diagnosis[edit] Clinical exam may reveal sectoral paresis of the iris sphincter or vermiform iris movements. The tonic pupil may become smaller (miotic) over time which is referred to as "little old Adie's".[5] Testing with low dose (1/8%) pilocarpine may constrict the tonic pupil due to cholinergic denervation supersensitivity.[1] A normal pupil will not constrict with the dilute dose of pilocarpine.[5] CT scans and MRI scans may be useful in the diagnostic testing of focal hypoactive reflexes.[6] ## Treatment[edit] The usual treatment of a standardised Adie syndrome is to prescribe reading glasses to correct for impairment of the eye(s).[1] Pilocarpine drops may be administered as a treatment as well as a diagnostic measure.[1] Thoracic sympathectomy is the definitive treatment of diaphoresis, if the condition is not treatable by drug therapy.[1] ## Prognosis[edit] Adie's syndrome is not life-threatening or disabling.[1] As such, there is no mortality rate relating to the condition; however, loss of deep tendon reflexes is permanent and may progress over time.[1] ## Epidemiology[edit] It most commonly affects younger women (2.6:1 female preponderance) and is unilateral in 80% of cases.[5] Average age of onset is 32 years. ## See also[edit] * Ciliary ganglion * Ross' syndrome ## References[edit] 1. ^ a b c d e f g h i j "Holmes-Adie syndrome Information Page". National Institute of Neurological Disorders and Stroke. Archived from the original on 2007-10-16. Retrieved 2008-01-21. 2. ^ Siddiqui AA, Clarke JC, Grzybowski A (November 2014). "William John Adie: the man behind the syndrome" (PDF). Clinical & Experimental Ophthalmology. 42 (8): 778–84. doi:10.1111/ceo.12301. PMID 24533698. 3. ^ Stedman's Medical Dictionary (27th ed.). 2000. ISBN 978-0-683-40007-6. 4. ^ "Adie syndrome". Genetic and Rare Diseases Information Center (GARD) – an NCATS Program. 5. ^ a b c Haines DE (2002). Fundamental Neuroscience, 2nd edition. ISBN 978-0-443-06603-0. 6. ^ "Diagnosis of Adie syndrome WrongDiagnosis.com". Retrieved 2008-01-21. ## Further reading[edit] * Estañol B, Callejas-Rojas RC, Cortés S, Martínez-Memije R, Infante-Vázquez O, Delgado-García G (2017). "Asymptomatic Severe Vagal and Sympathetic Cardiac Denervation in Holmes-Adie's Syndrome". Case Reports in Neurological Medicine. 2017: 4919758. doi:10.1155/2017/4919758. PMC 5385912. PMID 28428900. ## External links[edit] Classification D * ICD-10: H57.0 * ICD-9-CM: 379.46 * MeSH: D015845 * DiseasesDB: 29742 * 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	Adie syndrome	c0001519	3,472	wikipedia	https://en.wikipedia.org/wiki/Adie_syndrome	2021-01-18T18:52:50	{"gard": ["5749"], "mesh": ["D000270"], "umls": ["C0001519"], "orphanet": ["454718"], "wikidata": ["Q357067"]}
Epidermolysis bullosa (EB) is a group of genetic skin diseases that cause the skin to blister and erode very easily. In people with EB, blisters form in response to minor injuries or friction, such as rubbing or scratching.[2310] There are four main types of EB, which are classified based on the depth, or level, of blister formation: * Epidermolysis bullosa simplex * Dystrophic epidermolysis bullosa * Junctional epidermolysis bullosa * Kindler Syndrome EB may then be further classified based on severity and specific symptoms, such as distribution (localized or generalized) and whether parts of the body other than the skin are affected. Specific sub-types may then be determined based on identifying the exact protein that is defective in a person with EB. This may be done by tests performed on a skin biopsy, or when possible, genetic testing. Identifying the exact sub-type can be hard because there are many sub-types of EB. A person with any main type of EB may be mildly or severely affected, and the disease can range from being a minor inconvenience requiring modifying activities, to completely disabling and even fatal in some cases. EB may be caused by changes (mutations) in at least 18 genes that play various roles in the structure, integrity, and repair of the skin. Inheritance may be autosomal dominant or autosomal recessive depending on the type and subtype of EB a person has. Management involves a multidisciplinary team of health care providers and involves wound care, pain control, controlling infections, nutritional support, and prevention and treatment of complications. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [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	Epidermolysis bullosa	c0014527	3,473	gard	https://rarediseases.info.nih.gov/diseases/6359/epidermolysis-bullosa	2021-01-18T18:00:41	{"mesh": ["D004820"], "umls": ["C0014527"], "synonyms": ["EB"]}
A number sign (#) is used with this entry because of evidence that Okur-Chung neurodevelopmental syndrome (OCNDS) is caused by heterozygous mutation in the CSNK2A1 gene (115440) on chromosome 20p13. Description Okur-Chung neurodevelopmental syndrome is an autosomal dominant disorder characterized by delayed psychomotor development, intellectual disability with poor speech, behavioral abnormalities, cortical malformations in some patients, and variable dysmorphic facial features. Additional features, including microcephaly, gastrointestinal problems, and low levels of immunoglobulins, may be observed in some patients (Okur et al., 2016). Clinical Features Okur et al. (2016) reported 5 unrelated girls, ranging in age from 2 to 13 years, with a syndromic neurodevelopmental disorder. Common features included developmental delay, intellectual disability with behavioral problems and delayed speech, hypotonia, and gastrointestinal problems such as dysphagia, gastric reflux, or constipation. Three had microcephaly and 3 had pachygyria on brain imaging. Three patients had variable dysmorphic features including low-set and folded ears, arched eyebrows, mild synophrys, ptosis, epicanthal folds, hypertelorism, broad nasal bridge, upturned nose, high palate, thin upper lip, protruding tongue, clinodactyly, and brachydactyly. All patients had behavioral problems such as tantrums, volatile mood, clapping, hand-flapping, and attention deficit-hyperactivity disorder features. Three patients had scoliosis and/or joint laxity. Three patients had immunologic findings of hypogammaglobulinemia and mild IgA or IgG deficiency. Two patients had ataxia. One patient had seizures. Trinh et al. (2017) reported a 7-year-old German boy with features of OCNDS. At last examination at age 6.5 years, he had global developmental delay, impaired intellectual development, borderline microcephaly, brachycephaly, and dysmorphic features. Psychometric testing showed impaired social responsiveness. The patient had developmental delay in most areas, but average performance in articulation and receptive language. Sleeping difficulties and hyperactive behavior were also observed. EEG was unremarkable, and brain MRI showed a solid lesion of the pineal gland with minor cystic inclusions, which was not thought to be clinically significant. Chiu et al. (2018) summarized findings in their 8 patients and 6 previously reported patients with OCNDS. Common facial features included microcephaly, hypertelorism, epicanthic folds, ptosis, arched eyebrows, low-set ears, ear-fold abnormalities, broad nasal bridge, and round face. Other clinical findings included neurodevelopmental delay in 93%, gastrointestinal issues in 57%, musculoskeletal issues in 57%, and immunologic abnormalities in 43%. None of the patients were reported to have a malignancy. The male:female ratio was 1:1. Owen et al. (2018) described an additional 11 children with OCNDS from the DDD study, all of whom had impaired intellectual development and short stature. Other clinical features reported in at least 3 affected patients included neonatal hypotonia in 7, autistic spectrum traits in 4, swallowing difficulties in 3, and congenital heart disease in 3 (2 with septal defects and 1 with tetralogy of Fallot). Microcephaly was seen in only 1 patient. Shared facial features included malar flattening, depressed nasal bridge, short nose, thin upper vermilion, epicanthus, short philtrum, and widely spaced teeth, but the authors noted that there was not a recognizable facial gestalt. Recurrent infections were not reported in the patients. Brain MRI was normal in 5 of 6 patients, with delayed myelination in 1 patient. Akahira-Azuma et al. (2018) reported an 8-year-old Japanese boy with OCNDS. He had an IQ of 21-35 at age 7 years 4 months (Tanaka-Binet scale), motor and speech delay, severe growth retardation with relative macrocephaly, behavioral problems, distinctive facial features, and abnormal MRI findings. His behavior was described as hyperactive and very friendly and interactive. Facial features included synophrys, hypertrichosis, downslanting palpebral fissures, and bulbous nose. The authors noted that some of these findings were suggestive of Kleefstra syndrome (610253), Coffin-Siris syndrome (135900), or Rubinstein-Taybi syndrome (180849). Brain MRI findings included a reduced anterior pituitary gland and delayed myelination. Clinical Management Chiu et al. (2018) made the following recommendations for the management of patients with OCNDS: (1) assessment by a clinical geneticist; (2) comprehensive neurodevelopmental assessment and multidisciplinary training; (3) serial measurement of growth, nutrition and skeletal malformation; (4) serial measurement of head circumference; and (5) immunologic evaluation if any suspicion of frequent or severe infections. Molecular Genetics In 5 unrelated girls with OCNDS, Okur et al. (2016) identified de novo heterozygous mutations in the CSNK2A1 gene (115440.0001-115440.0005), including 4 missense mutations and 1 splice site mutation. Functional studies of the variants and studies of patient cells were not performed, but Okur et al. (2016) noted that the CSNK2A1 gene is expressed in the brain and encodes the catalytic subunit of protein kinase CK2, which is involved in many biologic processes. The mutations were found by whole-exome sequencing of 4,102 patients with developmental delay/intellectual disability. In a 7-year-old German boy with OCNDS, Trinh et al. (2017) identified a de novo heterozygous missense mutation (D156H; 115440.0006) in the CSNK2A1 gene. The variant was identified by trio exome sequencing and confirmed by Sanger sequencing. Chiu et al. (2018) summarized data on 16 variants in the CSNK2A1 identified in 22 patients with OCNDS. All but 2 variants were located in the large protein kinase domain that spans exons 4 to 12. The most common area for variants was in exon 9, including the most frequently observed variant, K198R (115440.0002), which was found in 5 cases. Variants were believed to be disruptive by altering highly conserved amino acids with important roles in stabilization and substrate recognition. Among 11 patients with OCNDS, Owen et al. (2018) identified 8 different de novo heterozygous missense mutations in the CSNK2A1 gene, including K198R, which was found in 4 unrelated individuals, suggesting a hotspot at this location. Akahira-Azuma et al. (2018) identified de novo heterozygosity for the recurrent K198R mutation in the CSNK2A1 gene in an 8-year-old Japanese boy with OCNDS. INHERITANCE \- Autosomal dominant GROWTH Other \- Failure to thrive (in some patients) HEAD & NECK Head \- Microcephaly (3 patients) Face \- Dysmorphic features, variable \- Micrognathia Ears \- Low-set ears \- Folded ears Eyes \- Hypertelorism \- Epicanthal folds \- Arched eyebrows \- Synophrys \- Ptosis Nose \- Broad nasal bridge \- Upturned nose Mouth \- High palate \- Thin upper lip CARDIOVASCULAR Heart \- Congenital heart defects (in some patients) ABDOMEN Gastrointestinal \- Feeding difficulties \- Constipation \- Gastric reflux SKELETAL \- Joint hyperextensibility (1 patient) Spine \- Scoliosis (1 patient) Hands \- Clinodactyly \- Brachydactyly MUSCLE, SOFT TISSUES \- Hypotonia NEUROLOGIC Central Nervous System \- Global developmental delay \- Intellectual disability \- Delayed speech \- Poor or absent speech \- Atonic seizures (1 patient) \- Pachygyria (1 patient) \- Simplified gyral pattern Behavioral Psychiatric Manifestations \- Behavioral problems \- Tantrums \- Volatile mood \- Hand-flapping \- Attention deficit-hyperactivity disorder IMMUNOLOGY \- Hypogammaglobulinemia (in some patients) \- IgA deficiency \- IgG deficiency MISCELLANEOUS \- Variable phenotype MOLECULAR BASIS \- Caused by mutation in the casein kinase II, alpha-1 gene (CSNK2A1, 115440.0001 ). ▲ 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	OKUR-CHUNG NEURODEVELOPMENTAL SYNDROME	c4310739	3,474	omim	https://www.omim.org/entry/617062	2019-09-22T15:47:11	{"omim": ["617062"]}
A number sign (#) is used with this entry because of evidence that hereditary sensory and autonomic neuropathy type VIII (HSAN8) is caused by homozygous mutation in the PRDM12 gene (616458) on chromosome 9q34. Description Hereditary sensory and autonomic neuropathy type VIII is an autosomal recessive neurologic disorder characterized by congenital insensitivity to pain resulting in ulceration to the fingers, tongue, lips, and other distal appendages. Affected individuals may also have decreased sweating and tear production (summary by Chen et al., 2015). For a discussion of genetic heterogeneity of hereditary sensory and autonomic neuropathy, see HSAN1A (162400). Clinical Features Chen et al. (2015) reported 11 families with congenital insensitivity to pain. The patients presented in the first year of life with disturbed pain and temperature sensation, resulting in lip and tongue lesions, facial scratching, finger biting, and distal ulcers and mutilations. There was also absence of the corneal reflex, resulting in corneal scarring. Most patients had skin and bone infections. Most also had reduced sweating and tear production, but additional autonomic features were not reported. Sensory nerve conduction was abnormal in those tested; sural nerve biopsy of 2 patients showed a severe loss of small myelinated A-delta fibers, whereas large-caliber axons were unaltered. Skin biopsies of 2 patients showed abnormal peripheral terminals of C fibers, with complete absence of nerve fibers crossing the basement membrane to innervate the epidermis. The subepidermal neural plexus and autonomic innervation of sweat glands were also reduced but were morphologically normal. The findings were consistent with developmental defects in the sensory neurons destined to become nociceptors. Chen et al. (2015) proposed the name congenital insensitivity to pain type 3 (CIP3) to refer to this disorder. Zhang et al. (2016) reported the clinical features of 5 adult patients with genetically confirmed HSAN8. The patients, 4 of whom came from the same consanguineous family, ranged in age from 23 to 57 years. All individuals were unable to sense acute or chronic pain from birth, although most were diagnosed after age 3. All had unusual injuries, including oral and tongue injuries and loss of terminal digits from injuries that became infected. They tended to have recurrent infections, most commonly with Staphylococcus aureus. Infections were not painful, and inflammation was always far less than expected by doctors. Corneal reflexes were absent, leading to corneal scarring. The patients were able to taste types of food commonly associated with a painful sensation, such as spicy foods being 'hot,' but were unable to identify food that was too hot by temperature. All had normal intellect and normal neurologic examination, including fine touch, deep touch, pressure, vibration, and sensation of itch and tickle. All had normal olfaction, and only 1 of the 5 had difficulties sensing ambient temperature. The patients were able to feel emotional pain. Inheritance The transmission pattern of HSAN8 in the families reported by Chen et al. (2015) was consistent with autosomal recessive inheritance. Molecular Genetics In affected members of 11 families with HSAN8, Chen et al. (2015) identified 10 different homozygous mutations in the PRDM12 gene (e.g., 616458.0001-616458.0005). Mutations in 3 families were found by exome sequencing, and mutation in another family was found by direct sequencing of the PRDM12 gene after exome sequencing failed to identify the causative mutation. The subsequent mutations were found in 7 of 158 individuals with a similar phenotype who underwent direct sequencing of the PRDM12 gene. In vitro functional expression studies showed that the mutations abrogated the histone-modifying potential of PRDM12, consistent with a loss of function. PRDM12 was expressed in nociceptors and their progenitors, and participated in the development of sensory neurons in Xenopus embryos. INHERITANCE \- Autosomal recessive HEAD & NECK Face \- Facial scratching Eyes \- Corneal ulceration \- Corneal scarring \- Absent corneal reflex \- Decreased tearing Mouth \- Lip biting \- Tongue biting SKELETAL Hands \- Recurrent infections due to painless trauma and ulceration Feet \- Recurrent infections due to painless trauma and ulceration SKIN, NAILS, & HAIR Skin \- Decreased sweating \- Painless, ulcerating lesions of distal extremities, tongue, and lips \- Recurrent infections due to painless trauma and ulceration Skin Histology \- Absence of C fiber terminals crossing the basement membrane to innervate the epidermis \- Reduction of autonomic innervation to sweat glands NEUROLOGIC Peripheral Nervous System \- Insensitivity to pain and temperature \- Sural nerve biopsy shows severe loss of small-caliber myelinated A-delta fibers \- Large-caliber axons remain intact MISCELLANEOUS \- Onset in first months of life MOLECULAR BASIS \- Caused by mutation in the PR domain-containing protein 12 gene (PRDM12, 616458.0001 ) ▲ 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	NEUROPATHY, HEREDITARY SENSORY AND AUTONOMIC, TYPE VIII	c4225308	3,475	omim	https://www.omim.org/entry/616488	2019-09-22T15:48:41	{"doid": ["0070153"], "omim": ["616488"], "orphanet": ["478664"], "synonyms": ["HSAN8", "Alternative titles", "Hereditary sensory and autonomic neuropathy type VIII", "HSAN VIII"], "genereviews": ["NBK481553"]}
A number sign (#) is used with this entry because of evidence that primary failure of tooth eruption (PFE) is caused by heterozygous mutation in the PTHR1 gene (168468) on chromosome 3p21. See also 157950 and 273050 for phenotypes with shared features of PFE. Clinical Features Shokeir (1974) described autosomal dominant inheritance of failure of eruption of permanent teeth. The primary dentition persisted in the adult; however, the proband showed complete or partial eruption of 11 permanent teeth. Proffit and Vig (1981) described the characteristic features of primary failure of tooth eruption: posterior teeth are more commonly affected, and the bite distal to the first affected tooth is usually completely open; the affected teeth may or may not have initially erupted into occlusion before submerging; deciduous teeth, especially second deciduous molars are commonly submerged; involvement may be unilateral or bilateral; involved permanent teeth may become ankylosed after failure of eruption has occurred; orthodontic extrusion is unsuccessful and usually leads to ankylosis; and although other members of the family may be affected they are not usually close relatives. Proffit and Vig (1981) noted that the radiographs of the index cases with 'reinclusion of permanent molars' (157950) studied by Bosker et al. (1978) showed the same characteristics as their own patients with primary failure of eruption (PFE). Bianchi and Roccuzzo (1991) described 3 cases and reviewed 9 published cases of primary impaction of primary second molars, in which there was no physical barrier to the eruption of the primary teeth and ankylosis appeared to be excluded. There was frequent passing of the corresponding permanent tooth and sometimes retention of the adjacent mesial bicuspid. Rasmussen and Kotsaki (1997) described 5 cases, including 2 brothers, from a collection of 14 patients who had inherited retarded eruption in the permanent dentition as well as primary failure of eruption of one or more primary second molars. In total, 14 teeth underwent primary failure of eruption (PFE): 2 of the patients had all 4 molars unerupted; the other patients had 3, 2, and 1 unerupted tooth, respectively. There were no significant differences between sexes, jaws, or sides. The unerupted teeth were always deeply seated, most often beyond the positions where they normally develop, and in most cases their axial angulation was correct. There was no evidence of post-eruption impaction due to ankylosis. In nearly all cases the impacted teeth remained deeply buried and increased their distance from the occlusal plane with increasing age, and often there remained an open 'chimney' from the occlusal surfaces of the teeth to the margins of the alveolar processes, most visible in the mandible. The eruption of the other primary teeth was reported by parents to have been uneventful. None of the unerupted primary teeth ever erupted, and there was severely retarded eruption of all teeth in the permanent dentition. Only 1 of the cases appeared to be isolated; the others had affected sibs, parents, and/or grandparents. A conspicuous feature was the high prevalence of hypodontia, which affected 3 of the 5 cases with a total of 8 missing teeth, which were all second premolars succedaneous to unerupted primary molars. Rasmussen and Kotsaki (1997) stated that pedigree analysis of previously reported families segregating primary failure of eruption in the primary dentition combined with severely retarded eruption in the permanent dentition pointed to a single gene effect with autosomal dominant transmission. O'Connell and Torske (1999) reported a 6-year-old girl with primary retention in the deciduous dentition and the entire permanent dentition, involving incisors, molars, and premolars in all quadrants. At 3.75 years of age, only 6 teeth had erupted (all central incisors and the lower lateral incisors); panoramic radiograph revealed the presence of all primary teeth and appropriate development of the permanent teeth. At 6 years of age, 13 of her primary teeth had erupted, and they were normal in size, shape, and quality of enamel. Radiographically all primary teeth were present, and the permanent tooth buds of all teeth except the upper second premolars were identified. Comparison with previous radiographs revealed that there had been little progress in tooth eruption; however, continued root development of the permanent teeth was noted, without progress toward the alveolar crest. In addition to the significant delay, the sequence of eruption was inappropriate, with the upper lateral incisors erupting more than 1 year apart and later than the cuspids and first molars. By age 10, no more teeth had erupted and the patient had shown minimal response to repeated surgical intervention exposing the permanent molars to facilitate eruption; the only occlusal contact was on the primary incisors, which had begun to exhibit resorption and mobility. She had normal growth and development otherwise, with no craniofacial, dermal, or skeletal dysmorphologies. There was 1 older brother with no dental problems, and no family history of dental anomalies. O'Connell and Torske (1999) stated that this was the first report of generalized primary retention or idiopathic failure of tooth eruption. DiBiase and Leggat (2000) reported 2 sisters with bilateral posterior open bite due to eruption failure of the permanent dentition, most notably of the first and second molars, with greater severity in the younger sister. In both cases teeth were exposed and traction placed on them with little or no effect. An unusual feature in the sisters was the normal eruption of the upper third molars, distal to the posterior open bite. There was reported eruption failure involving permanent teeth in their father, although his records were unavailable. Ahmad et al. (2006) analyzed 5 new and 35 published cases of PFE affecting teeth in the permanent dentition (other than the third molars). Cases were excluded from the study if there was evidence of a mechanical, pathologic, or systemic cause of obstruction, or evidence of successful orthodontic extrusion of the affected tooth or teeth. The authors suggested that the term PFE might incorporate 2 independent conditions, 1 with a localized complete failure of tooth eruption and 1 where there is some initial eruption of the affected tooth or teeth prior to the eruption failure, a condition also described as 'secondary retention' (see 157950); however, they also noted that PFE might represent a single disorder of tooth eruption with differing degrees of severity, a hypothesis supported by the fact that these 2 manifestations can occur the same subject. A family history of eruption failure or eruption problems in the primary dentition was present in 18 (40%) of the 40 cases in this study, in contrast to that of Proffit and Vig (1981). Hypodontia, a dental anomaly of known genetic origin (see 106600), was present in 5 (13%) of the PFE cases, suggesting that PFE might have a significant genetic component. Frazier-Bowers et al. (2007) stated that PFE describes a condition in which malfunction of the eruption mechanism causes nonankylosed teeth to fail to erupt. The primary identifying characteristic is failure of an affected tooth to move along the eruption path that has been cleared for it; involved teeth can erupt partially and then cease to erupt, becoming relatively submerged although not ankylosed. Only posterior teeth are affected, resulting in a posterior open bite, and all teeth distal to the most mesial affected tooth are also affected. The condition is rarely symmetric and frequently unilateral, but can affect any or all of the posterior quadrants. A key characteristic is an abnormal or complete lack of response to orthodontic force; the authors noted that a nonankylosed tooth with PFE is likely to become ankylosed when force is applied. Frazier-Bowers et al. (2007) studied radiographs and clinical records of 97 cases of failure of posterior eruption; 15 were familial cases from 9 families in which pedigree analysis by inspection was strongly suggestive of autosomal dominant inheritance. The authors classified 38 of the 97 cases as PFE and 19 as mechanical failure of eruption (MFE) due to ankylosis; in 32 cases, a definitive diagnosis could not be made without additional longitudinal data, and in 8 cases the affected teeth were not in occlusion but were not submerged as in PFE and MFE. The PFE group had 3 distinguishable forms: 17 of the 38 patients, designated 'type I,' had a similar lack of eruption potential of all affected teeth, with a progressive open bite from anterior to posterior; 11 patients ('type II') had variable eruption potential among the affected teeth, and displayed a tooth distal to the most mesial affected tooth with greater though inadequate eruption; and 10 patients had both types coexisting in different quadrants. There appeared to be no difference in subtypes of PFE between those with and without a family history of eruption problems. At least 1 ankylosed deciduous tooth was noted in 24 of the 97 patients, 4 patients had hypodontia, 5 had hyperdontia, and 3 had taurodontism; no other dental anomalies were noted. Other than ankylosed deciduous molars (in 5 of 15 patients), no other dental anomalies were found in the familial group. Mapping Decker et al. (2008) genotyped 8 affected and 4 unaffected members of a 3-generation German family segregating autosomal dominant PFE. Parametric linkage analysis with a dominant model revealed 2 regions with a maximum lod score of 2.41, a 31.8-Mb interval on chromosome 3p24.3-p14.3, flanked by markers rs1402366 and rs13074914, and an 8-Mb interval on chromosome 13q31.3-q33.1, flanked by markers rs1328369 and rs7988100. The latter region, containing 31 known protein-coding genes, was excluded by direct sequencing in 2 affected and 1 unaffected family member. Molecular Genetics In a 3-generation German family segregating autosomal dominant PFE mapping to a 31.8-Mb interval on chromosome 3p24.3-p14.3, Decker et al. (2008) analyzed the candidate gene PTHR1 (168468) and identified heterozygosity for a splice site mutation (168468.0001) in affected individuals. The same mutation was identified in affected individuals from another German PFE family, and a different splice splice site mutation (168468.0002) and a nonsense mutation (168468.0003) in 2 additional PFE families, respectively. The mutations, which were not found in unaffected family members or 178 German controls, were predicted to result in premature proteolytic degradation of the precursor protein or a functionless receptor, suggesting that haploinsufficiency of PTHR1 is likely to be the underlying principle of nonsyndromic PFE. INHERITANCE \- Autosomal dominant HEAD & NECK Teeth \- Primary failure of tooth eruption (1st and 2nd molar teeth most commonly affected) \- Posterior openbite \- Often unilateral, rarely symmetric \- Lack of response to orthodontic force \- Hypodontia \- Ankylosis of deciduous teeth (some) MOLECULAR BASIS \- Caused by mutation in the parathyroid hormone receptor-1 gene (PTHR1, 168468.0012 ) ▲ 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	FAILURE OF TOOTH ERUPTION, PRIMARY	c1852222	3,476	omim	https://www.omim.org/entry/125350	2019-09-22T16:42:28	{"doid": ["0111341"], "mesh": ["C565114"], "omim": ["125350"], "orphanet": ["412206"], "synonyms": ["Alternative titles", "PRIMARY FAILURE OF ERUPTION, NONSYNDROMIC", "PRIMARY RETENTION OF TEETH", "UNERUPTED SECOND PRIMARY MOLAR", "POSTERIOR OPENBITE MALOCCLUSION, FAMILIAL", "DENTAL NONERUPTION"]}
Primary ciliary dyskinesia is a disorder characterized by chronic respiratory tract infections, abnormally positioned internal organs, and the inability to have children (infertility). The signs and symptoms of this condition are caused by abnormal cilia and flagella. Cilia are microscopic, finger-like projections that stick out from the surface of cells. They are found in the linings of the airway, the reproductive system, and other organs and tissues. Flagella are tail-like structures, similar to cilia, that propel sperm cells forward. In the respiratory tract, cilia move back and forth in a coordinated way to move mucus towards the throat. This movement of mucus helps to eliminate fluid, bacteria, and particles from the lungs. Most babies with primary ciliary dyskinesia experience breathing problems at birth, which suggests that cilia play an important role in clearing fetal fluid from the lungs. Beginning in early childhood, affected individuals develop frequent respiratory tract infections. Without properly functioning cilia in the airway, bacteria remain in the respiratory tract and cause infection. People with primary ciliary dyskinesia also have year-round nasal congestion and a chronic cough. Chronic respiratory tract infections can result in a condition called bronchiectasis, which damages the passages, called bronchi, leading from the windpipe to the lungs and can cause life-threatening breathing problems. Some individuals with primary ciliary dyskinesia have abnormally placed organs within their chest and abdomen. These abnormalities arise early in embryonic development when the differences between the left and right sides of the body are established. About 50 percent of people with primary ciliary dyskinesia have a mirror-image reversal of their internal organs (situs inversus totalis). For example, in these individuals the heart is on the right side of the body instead of on the left. Situs inversus totalis does not cause any apparent health problems. When someone with primary ciliary dyskinesia has situs inversus totalis, they are often said to have Kartagener syndrome. Approximately 12 percent of people with primary ciliary dyskinesia have a condition known as heterotaxy syndrome or situs ambiguus, which is characterized by abnormalities of the heart, liver, intestines, or spleen. These organs may be structurally abnormal or improperly positioned. In addition, affected individuals may lack a spleen (asplenia) or have multiple spleens (polysplenia). Heterotaxy syndrome results from problems establishing the left and right sides of the body during embryonic development. The severity of heterotaxy varies widely among affected individuals. Primary ciliary dyskinesia can also lead to infertility. Vigorous movements of the flagella are necessary to propel the sperm cells forward to the female egg cell. Because their sperm do not move properly, males with primary ciliary dyskinesia are usually unable to father children. Infertility occurs in some affected females and is likely due to abnormal cilia in the fallopian tubes. Another feature of primary ciliary dyskinesia is recurrent ear infections (otitis media), especially in young children. Otitis media can lead to permanent hearing loss if untreated. The ear infections are likely related to abnormal cilia within the inner ear. Rarely, individuals with primary ciliary dyskinesia have an accumulation of fluid in the brain (hydrocephalus), likely due to abnormal cilia in the brain. ## Frequency Primary ciliary dyskinesia occurs in approximately 1 in 16,000 individuals. ## Causes Primary ciliary dyskinesia can result from mutations in many different genes. These genes provide instructions for making proteins that form the inner structure of cilia and produce the force needed for cilia to bend. Coordinated back and forth movement of cilia is necessary for the normal functioning of many organs and tissues. The movement of cilia also helps establish the left-right axis (the imaginary line that separates the left and right sides of the body) during embryonic development. Mutations in the genes that cause primary ciliary dyskinesia result in defective cilia that move abnormally or are unable to move (immotile). Because cilia have many important functions within the body, defects in these cell structures cause a variety of signs and symptoms. Mutations in the DNAI1 and DNAH5 genes account for up to 30 percent of all cases of primary ciliary dyskinesia. Mutations in the other genes associated with this condition are found in only a small percentage of cases. In many people with primary ciliary dyskinesia, the cause of the disorder is unknown. ### Learn more about the genes associated with Primary ciliary dyskinesia * DNAH5 * DNAI1 * OFD1 * RPGR Additional Information from NCBI Gene: * ARMC4 * CCDC103 * CCDC114 * CCDC39 * CCDC40 * CCDC65 * CFAP298 * DNAAF1 * DNAAF2 * DNAAF3 * DNAAF4 * DNAAF5 * DNAH11 * DNAH8 * DNAI2 * DNAL1 * DRC1 * HYDIN * LRRC6 * NME8 * RSPH1 * RSPH4A * RSPH9 * SPAG1 * ZMYND10 ## 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	Primary ciliary dyskinesia	c0022521	3,477	medlineplus	https://medlineplus.gov/genetics/condition/primary-ciliary-dyskinesia/	2021-01-27T08:25:14	{"gard": ["6815", "4484"], "mesh": ["D007619"], "omim": ["244400", "612518", "612649", "612650", "613193", "613807", "613808", "606763", "608644", "608646", "608647", "610852", "611884", "612274", "612444"], "synonyms": []}
Arteriovenous malformations or AVMs are rare vascular malformations (abnormal tangles of blood vessels where direct connections form between arteries and veins) which disrupt natural blood flow. AVMs most commonly affect the central nervous system (brain and spinal cord) but can involve any organ. Those affecting the face, head or neck are often called extracranial arteriovenous malformations (AVMs). Although present at birth, AVMs may not be clinically evident until childhood or adolescence. Complications may include disfigurement, destruction of tissue, obstruction of vital structures, pain, bleeding, ulceration and rarely, cardiac overload. AVMs may be treated with surgery, embolization, or both. The goal of treatment is to control rather than cure the underlying problem. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: 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	Extracranial arteriovenous malformation	None	3,478	gard	https://rarediseases.info.nih.gov/diseases/12047/extracranial-arteriovenous-malformation	2021-01-18T18:00:38	{"synonyms": ["Extracranial AVM", "Head and neck arteriovenous malformation", "Head and neck AVM"]}
Combined oxidative phosphorylation defect type 14 is a rare mitochondrial disease due to a defect in mitochondrial protein synthesis characterized by neonatal or infancy-onset of seizures that are refractory to treatment, delayed or absent psychomotor development and lactic acidosis. Additional manifestations reported include poor feeding, failure to thrive, microcephaly, hypotonia, anemia and thrombocytopenia. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: 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	Combined oxidative phosphorylation defect type 14	c3554168	3,479	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=319519	2021-01-23T17:16:47	{"omim": ["614946"], "icd-10": ["E88.8"], "synonyms": ["COXPD14"]}
A number sign (#) is used with this entry because of evidence that juvenile-onset cataract-46 (CRCT46) is caused by homozygous mutation in the LEMD2 gene (616312) on chromosome 6p21. Clinical Features Shokeir and Lowry (1985) found 9 cases in 4 sibships of an inbred Lehrerleut Hutterite group. Apart from the cataracts, all were healthy, with normal growth and development. Specifically, no metabolic disorder could be identified. Intelligence, hearing, and behavior were normal. The patients were neurologically intact. There were no ocular lesions other than the cataracts. Boone et al. (2016) reported 4 Lehrerleut Hutterite kindreds with juvenile cataract, including sibships previously studied by Shokeir and Lowry (1985) and Gerull et al. (2013). Age of cataract presentation was mostly between 3 and 7 years, although 1 individual presented at age 26. All pedigrees were consistent with autosomal recessive inheritance. In 2 of the pedigrees, 7 individuals died of sudden, apparently arrythmogenic events in the third through fifth decades; 6 of those patients also had juvenile-onset cataracts. Postmortem examination of 1 patient with juvenile cataracts showed myocardial scarring and fibrosis of the left lateral ventricular free wall, in the setting of normally distributed coronary arteries and no detectable coronary thrombi or vascular lesions. Forsius et al. (1992) found 15 cases of juvenile cataract on the Aland Islands, which have about 23,000 inhabitants. Twelve of the cases belonged to 7 sibships of 2 different pedigrees and 3 cases were apparently sporadic; there were no genealogic connections in the last 6 to 10 generations to the 2 cataract pedigrees. One of the sporadic cases presented with a corrected cleft palate and a chromosomal anomaly. In another sporadic case, the mother probably had been infected with rubella during early gestation. In the third sporadic case, the cataract was combined with partial aniridia, but the patient had several genealogic connections to one of the cataract pedigrees. Parental consanguinity was detected in 5 of the 7 sibships, in some on multiple ancestral levels. Apart from the cataracts, all patients were healthy, with normal intelligence, behavior, hearing, growth, and development. Mapping Using exome data from 3 individuals with juvenile cataracts from 2 consanguineous Lehrerleut Hutterite kindreds and their parents, Boone et al. (2016) performed genomewide autozygosity mapping and identified a 9.5-Mb autozygous region on chromosome 6p22.2-p21.31 that was shared by all 3 patients and absent from their healthy parents. SNP-based fine mapping narrowed the critical interval to a subregion of 0.5 to 2.9 Mb (6p21.32-p21.31). Molecular Genetics In 17 affected members of 4 Lehrerleut Hutterite kindreds segregating autosomal recessive juvenile cataract mapping to 6p21.32-p21.31, Boone et al. (2016) identified homozygosity for a missense mutation in the LEMD2 gene (T38G; 616312) that segregated with cataract in all 4 families and was not found in public variant databases. In 2 of the kindreds, 6 patients with juvenile cataract also experienced sudden cardiac death (SCD). In 'sibship 2' from 1 of the kindreds (AR-900), previously studied by Gerull et al. (2013) as 'family L,' homozygosity for a nonsense mutation in the DSC2 gene (Q554X; 125645.0005) had been identified in an individual who experienced SCD. However, the Q554X variant was absent in an individual with cataract from another sibship from the same Hutterite kindred who experienced SCD, and was not present in the obligate carrier parents of the 5 other cataract patients who had SCD. Boone et al. (2016) concluded that the Q554X DSC2 variant did not explain SCD in their Hutterite families, other than in the previously studied sibship 2. Noting that variable age of onset and reduced penetrance are characteristic of inherited cardiomyopathies, the authors suggested that juvenile cataracts and sudden death might both be caused by mutation in the LEMD2 gene. History Saebo (1949) studied 17 families with cases of congenital or juvenile cataracts. Two or more sibs were affected in 8 families. In 9 families the parents were related, being first cousins in 5. In 1 family the proband had retinitis pigmentosa (268000), of which cataract is a known complication. In another family the proband had retinitis pigmentosa and congenital deafness (Usher syndrome, 276900). Recessively inherited congenital cataract was found to be frequent in Cyprus by Merin et al. (1972). INHERITANCE \- Autosomal recessive HEAD & NECK Eyes \- Cataract, juvenile-onset MISCELLANEOUS \- Based on report of 4 Lehrerleut Hutterite kindreds \- Cataract develops in the first decade of life in most patients \- Sudden cardiac death at an early age has been reported in some individuals with cataract in 2 of the kindreds MOLECULAR BASIS \- Caused by mutation in the LEM domain-containing protein-2 gene ( 616312.0001 ) ▲ 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	CATARACT 46, JUVENILE-ONSET	c0220721	3,480	omim	https://www.omim.org/entry/212500	2019-09-22T16:30:03	{"doid": ["0110243"], "omim": ["212500"], "icd-10": ["Q12.0"], "orphanet": ["91492"], "synonyms": ["Alternative titles", "CATARACT, JUVENILE, HUTTERITE TYPE"]}
## Summary ### Clinical characteristics. Y chromosome infertility is characterized by azoospermia (absence of sperm), severe oligozoospermia (<1 x 106 sperm/mL semen), moderate oligozoospermia (1-5 x 106 sperm/mL semen), or mild oligozoospermia (5-20 x 106 sperm/mL semen). Males with Y chromosome infertility usually have no obvious symptoms, although physical examination may reveal small testes. ### Diagnosis/testing. The diagnosis of Y chromosome infertility is established in a male with characteristic clinical and laboratory features and by identification of a hemizygous deletion of Yq involving the AZF regions or identification of a heterozygous pathogenic variant involving USP9Y (located within AZFa). ### Management. Treatment of manifestations: Pregnancies may be achieved by in vitro fertilization using intracytoplasmic sperm injection (ICSI), an in vitro fertilization procedure in which spermatozoa retrieved from ejaculate (in males with oligozoospermia) or extracted from testicular biopsies (in males with azoospermia) are injected into an egg harvested from the reproductive partner. Other: Testicular sperm retrieval for in vitro fertilization is ineffective for males with AZFb and AZFa deletions, but has been successful for most males with AZFc deletions; in males with retrievable spermatozoa, the presence or absence of deletion of the long arm of the Y chromosome has no apparent effect on the fertilization or pregnancy rates; the risk for birth defects is the same as for any infertile couple that achieves a pregnancy using assisted reproductive technology. ### Genetic counseling. Y chromosome infertility is inherited in a Y-linked manner. Because males with Y chromosome deletions are infertile, the deletions are usually de novo and therefore not present in the father of the proband. Despite their severely impaired spermatogenesis, some males with deletion of the AZF regions have occasionally spontaneously fathered sons, who are infertile. This will occur in about 4% of couples with severe oligospermia if the female partner is young and very fertile. In pregnancies achieved using ICSI, male offspring have the same deletion as their father, with a high risk of male infertility. Note that certain Y deletions, including the most common Y deletions (gr/gr), do not necessarily cause infertility, but are only a risk factor for infertility. Female fetuses from a father with a Y chromosome deletion have no increased risk of congenital abnormalities or infertility. In pregnancies conceived through assisted reproductive technology (ART) and known to be at risk of resulting in a male with Y chromosome deletion, specific prenatal testing or preimplantation testing could be performed to determine the sex of the fetus and/or the presence of the Y chromosome deletion. ## Diagnosis ### Suggestive Findings Y chromosome infertility should be suspected in males with the following clinical and laboratory features. Clinical features * A history of infertility * Normal physical examination in ~30% * Small testes in ~70% (males with Sertoli cell-only syndrome) Laboratory features Semen analysis. Ejaculate is examined to determine the number, motility, and morphology of sperm. Semen analysis should follow the WHO guidelines, Laboratory Manual for the Examination and Processing of Human Semen [WHO 2010]. The following categories of sperm count are identified (Table 1). ### Table 1. Classification of Sperm Count View in own window Classification of Sperm Count 1Sperm Count in Millions/mL 2 Azoospermia0 Severe oligozoospermia<1 Moderate oligozoospermia1-5 Mild oligozoospermia5-20 Normal>20 1\. In each category, the morphology and/or motility of the sperm can be normal or abnormal (asthenoteratozoospermia). 2\. These estimates have a poor correlation to pregnancy rate, when the count is >5 million/mL. Other than males with gr/gr interstitial AZFc deletions, individuals with deletion of Yq involving the AZF regions never have a sperm count >2 million/mL. Testicular biopsy. Testicular biopsy may reveal either one or a combination of the following: * Sertoli cell-only (SCO) syndrome, in which azoospermia is associated with the absence of or only occasional germ cells in tubules that for the most part have only Sertoli cells lining them with no or rare spermatogenesis * Maturation arrest with spermatocytes but no spermatids or mature sperm ### Establishing the Diagnosis The diagnosis of Y chromosome infertility is established in a male with characteristic clinical and laboratory features and one of the following identified on molecular genetic testing (see Table 2): * A hemizygous deletion of Yq involving the AZF regions (see Figure 1) (~99% of affected individuals) [Colaco & Modi 2018] * A heterozygous USP9Y pathogenic variant in the AZFa region (1% of affected individuals) [Silber 2011] #### Figure 1. Schematic of the Y chromosome indicating the approximate position of the previously defined regions AZFa, AZFb, and AZFc and the position of recurrent deletions currently defined on the basis of the flanking palindromic repeats (see Establishing the Diagnosis) (more...) Molecular genetic testing approaches can include a combination of Tier 1 testing (targeted deletion/duplication analysis or chromosomal microarray analysis) and Tier 2 testing (cytogenetic analysis and single-gene testing). #### Tier 1 Testing Targeted deletion analysis to detect deletions of the AZF regions on the Y chromosome can be considered first: * Interstitial AZFa deletion (HERV15yq1-HERV15yq2; region includes USP9Y and DDX3Y) * Interstitial AZFb & AZFb+c deletions (P5/proxP1, P5/distP1, P4/distP1) * Interstitial AZFc deletion (b2/b4, gr/gr) * Terminal AZF deletion (often representing a pseudodicentric Y chromosome with duplication and deletion) Note: (1) USP9Y deletion has been found in fertile individuals (albeit with reduced spermatogenesis), and severely impaired spermatogenesis only occurs when both USP9Y and DDX3Y are deleted [Luddi et al 2009]. (2) Duplications involving the AZF regions have been reported and do not appear to affect fertility. Chromosomal microarray analysis (CMA), which uses oligonucleotide or SNP arrays to detect genome-wide deletions/duplications (including deletions or duplications of the Y chromosome) not detectable by sequence analysis, can be used to detect deletions/duplications of the AZF region (Table 2). However, interpretation of CMA for the detection of Y deletions can be complicated by the fact that many of the genes implicated in Y chromosome infertility are present in multiple copies with similar sequences (see Molecular Genetics). #### Tier 2 Testing Cytogenetic analysis. Routine cytogenetic studies including G-banded karyotype and fluorescence in situ hybridization (FISH) analyses using probes specific for Y-linked genes performed on peripheral blood can distinguish terminal deletions of Yq from complex Y chromosome rearrangements that lead to Yq deletions (e.g., pseudodicentric Y chromosome). Note: (1) A pseudodicentric Y chromosome results in both deletion of part of Yq and duplication of Yp and proximal Yq. (2) Complex Y chromosome rearrangements (e.g., pseudodicentric Y chromosomes and ring Y chromosomes) are often associated with a 45,X cell line [Lange et al 2009] and can lead to disruption of genes within the pseudoautosomal region (e.g., SHOX) and to additional phenotypes including short stature [Jorgez et al 2011] (see Genetically Related Disorders). Single-gene testing. Sequence analysis of USP9Y detects small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. Note: Complete deletion of USP9Y has been found in fertile individuals (albeit with reduced spermatogenesis), and severely impaired or totally absent spermatogenesis only occurs when both USP9Y and DDX3Y are both deleted [Luddi et al 2009]. ### Table 2. Genomic Testing Used in Y Chromosome Infertility View in own window MethodGenetic Mechanism Detected 1Total Proportion of Y Chromosome Infertility Detected by Method AZF region deletion 2Unbalanced Y-chromosome rearrangementUSP9Y pathogenic variant Targeted deletion/duplication analysis 3XX 4>90% CMA 5X>90% 6 KaryotypeXRare USP9Y sequence analysis 7X1 reported 8 1\. See Molecular Genetics for more details. 2\. AZF regions include interstitial AZFa deletion (HERV15yq1-HERV15yq2); interstitial AZFc deletion (b2/b4); interstitial AZFb & AZFb+c deletions (P5/proxP1, P5/distP1, P4/distP1); and terminal AZF deletion (often representing a pseudodicentric Y chromosome w/duplication & deletion). 3\. Targeted deletion analysis methods can include FISH, quantitative PCR (qPCR), and multiplex ligation-dependent probe amplification (MLPA), as well as other targeted quantitative methods. 4\. Two individuals with intragenic USP9Y deletions/duplications reported [Sun et al 1999, Katsumi et al 2014] 5\. Chromosomal microarray analysis (CMA) uses oligonucleotide or SNP arrays to detect genome-wide large deletions/duplications (including USP9Y and DDX3Y) that cannot be detected by sequence analysis. The ability to determine the size of the deletion depends on the type of microarray used and the density of probes in the AZF region. CMA designs in current clinical use target the AZF region. 6\. The detection rate by CMA may be higher than that of targeted deletion/duplication analysis depending on the targeted method used. 7\. 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. 8\. Sun et al [1999] ## Clinical Characteristics ### Clinical Description Males with Y chromosome infertility usually have no symptoms other than infertility. A physical examination may reveal small testes in those with Sertoli cell-only (SCO) syndrome. Physical examination is normal in approximately 30% of males with Y chromosome infertility. Males with Y chromosome infertility have azoospermia or severe, moderate, or mild oligozoospermia depending on the location and size of the Y chromosome deletion (see Genotype-Phenotype Correlations). Most males with AZFa or AZFb/c deletions have a very poor prognosis for finding any sperm with testicular sperm extraction (TESE). Males with AZFc deletions (b2/b4 or gr/gr) have an extremely favorable prognosis (87%) for finding sperm sufficient for successful intracytoplasmic sperm injection (ICSI). Oligozoospermia may be compatible with fertility when the female partner is very fertile. ### Genotype-Phenotype Correlations Each AZF region contains several genes that play a role in different stages of spermatogenesis. It is likely that future analysis of these individual genes in infertile males will result in more precise genotype-phenotype correlations. However, the multicopy and polymorphic nature of most fertility genes located on the Y chromosome makes it difficult to define their role precisely. The regions initially defined as AZFb and AZFc have been found to partially overlap (Figure 1) [Repping et al 2002]. Much of the literature still refers to these regions; thus, the authors include reference to these regions by the palindromic repeats that now define the deletions more precisely [Silber 2011]. * Interstitial or terminal deletions that include all of AZFa are rare and usually result in the severe phenotype of Sertoli cell-only (SCO) syndrome [Silber 2011] (see Differential Diagnosis). The interstitial deletions are mediated by recombination between the HERV15yq1 and HERV15yq2 repeats. One single-copy gene (USP9Y) located in AZFa has been directly implicated in the infertility phenotype, following detection of a single-nucleotide variant and a deletion limited to this gene in two infertile males with hypospermatogenesis but without SCO syndrome [Sun et al 1999]. Complete deletion of USP9Y has been found in fertile individuals, albeit with hypospermatogenesis [Luddi et al 2009], suggesting that SCO syndrome usually associated with AZFa deletion is not caused by USP9Y deletion alone but must include deletion of at least one adjacent gene, DDX3Y, to result in azoospermia. Complete AZFa deletions thus involve loss of two genes, USP9Y and DDX3Y, and result in a much more severe phenotype than mutation of USP9Y alone. * Interstitial or terminal deletions that include AZFb and/or AZFb+c (hereafter designated AZFb/c) are mediated by recombination between palindromic repeats, either P5/proxP1, P5/distP1, or P4/distP1. These deletions are uncommon and usually result in severe azoospermia due to mature arrest [Repping et al 2002, Silber 2011]. Partial deletion of AZFb that removes the entire P4 palindrome decreases spermatocyte maturation but can be transmitted [Kichine et al 2012]. * Interstitial or terminal deletions that include AZFc only are mediated by recombination between the b2/b4 palindromic repeats and result in a variable infertility phenotype, ranging from azoospermia and SCO syndrome to severe or mild oligozoospermia [Oates et al 2002, Silber 2011]. This type of deletion is common. Eighty-seven percent of males with this deletion will have some spermatozoa either in the ejaculate or at testicular sperm extraction that can lead to successful intracytoplasmic sperm injection [Silber 2011]. * Two partial deletions of AZFc, called b1/b3, b2/b3, are considered benign copy number variants (polymorphisms) [Repping et al 2003, Fernandes et al 2004, Machev et al 2004, Ferlin et al 2007]. * Another partial deletion of AZFc, gr/gr, may have some impact on fertility depending on ethnicity and geographic region [Stouffs et al 2011]. Males with gr/gr deletions can also have compensatory duplications of genes [Noordam et al 2011]. The gr/gr deletion removes two of the four copies of DAZ in the AZFc region, and is a risk factor for oligospermia. The role of DAZ in spermatogenesis is quantitative. Usually the loss of all four copies of DAZ does not prevent some spermatogenesis from occurring because of the compensatory function of DAZL on chromosome 3. * Duplication of the AZFa or AZFc regions has been reported and does not appear to be associated with an abnormal phenotype [Bosch & Jobling 2003, Giachini et al 2008]. ### Penetrance Rarely within a family, the same deletion of the Y chromosome has been reported to occasionally cause infertility in some males but not in others [Repping et al 2003]. These observations have been misinterpreted as representing variable penetrance. However, they result from the fact that even a severely oligospermic male with a Y chromosome deletion in the AZF regions can occasionally impregnate a very fertile partner. ### Prevalence The prevalence of Y chromosome deletions and microdeletions is estimated at 1:2,000 to 1:3,000 males [de Vries et al 2002; de Vries et al, personal communication]. The frequency of Yq microdeletions in males with azoospermia or severe oligozoospermia is about 5% [Kim et al 2017]. Differences in prevalence based on ethnicity have not been observed. However, the gr/gr deletion may have a different impact on fertility depending on ethnicity and geographic region [Stouffs et al 2011]. The gr/gr deletion is extremely common (25%) in Japanese men, for example, and represents simply a "risk factor" for male infertility. ## Differential Diagnosis Infertility affects 15%-20% of couples of reproductive age. Infertility, dependent to a great extent on the age of the female partner, has been estimated to be male related in about half of those couples, but this often-quoted figure is poorly documented. Most likely, oligospermia sufficiently severe to cause infertility would only be present in 10% of infertile couples. Causes of male infertility other than deletion of the Y chromosome are numerous and often controversial. In most cases, male infertility is of unknown etiology. Possible causes of male infertility other than Y chromosome deletion include the following conditions: * Obstruction of the ejaculatory ducts, which should be evaluated by physical examination [Practice Committee of the American Society for Reproductive Medicine 2004]. Congenital absence of the vas deferens (see Cystic Fibrosis and Congenital Absence of the Vas Deferens) should be considered in this evaluation. CFTR-related disorders include cystic fibrosis (CF) and congenital absence of the vas deferens (CAVD). All males with CF are infertile as a result of azoospermia caused by absent, atrophic, or fibrotic Wolffian duct structures. CAVD more commonly occurs in men without pulmonary or gastrointestinal manifestations of CF and usually results from compound heterozygosity of a classic (severe, loss-of-function) CFTR pathogenic variant with a mild (retaining some function) CFTR pathogenic variant (e.g., the 5T allele). These men make about 10% of the normal amount of CTFR protein, which is typically enough to prevent clinical CF, but not enough to allow fetal Wolffian duct development [Chillón et al 1995]. Affected men have azoospermia and are thus infertile. Homozygosity for two CFTR 5T alleles can also result in CAVD without pulmonary or gastrointestinal manifestations of CF. CF is inherited in an autosomal recessive manner. * Immunologic abnormalities caused by anti-sperm antibodies (controversial) * Infection (e.g., mumps orchitis, epididymitis, urethitis); uncommon, and can generally be differentiated from Y chromosome infertility by past history * Vascular abnormalities (varicocele); may be identified on physical examination, but their relevance to male infertility has been robustly questioned by most reproductive endocrinologists and is very controversial [Silber 2001] * Trauma; distinguished by history and very rare * Endocrine abnormalities; also rare (e.g., congenital adrenal hyperplasia [see 21-Hydroxylase-Deficient Congenital Adrenal Hyperplasia], isolated follicle-stimulating hormone (FSH) deficiency, and hyperprolactinemia). These can be differentiated through hormone studies. Kallmann syndrome (KS), the association of isolated GnRH deficiency (IGD) and anosmia (absence of smell), needs to be considered. Some males with KS have micropenis and cryptorchidism as neonates. Adults with KS have incomplete development of secondary sexual characteristics and prepubertal testicular volume (i.e., <4 mL). To date, more than 20 genes have been associated with KS. Of these, pathogenic variants in ANOS1 (KAL1) and FGFR1 account for approximately 15%-25% of KS. Non-reproductive phenotypes: * In males with ANOS1 (KAL1) pathogenic variants. Synkinesia (mirror movement) of the digits, unilateral renal agenesis, sensorineural hearing loss, high-arched palate * In males with FGFR1 pathogenic variants. Synkinesia of digits, cleft lip and/or palate, dental agenesis, brachydactyly or syndactyly, corpus callosum agenesis * Testicular tumor, or other tumor caused by exposure to toxic agents * Exposure to toxic agents such as radiation, chemotherapy; heat exposure (evaluated by full medical history) * Klinefelter syndrome (XXY), which can be detected by cytogenetic analyses or CMA in men with non-obstructive azoospermia (NOA) and severe oligospermia and accounts for approximately 8% of azoospermic men. Klinefelter syndrome can be associated with hypoandrogenism and reported reduced intellectual function. However, most men with XXY are healthy except for their infertility. * Balanced chromosomal rearrangements, which can be detected by cytogenetic evaluation in about 1.5% of men with NOA and oligospermia. In this case, there may also be a family history of multiple miscarriages and/or various phenotypic anomalies. Sertoli cell-only (SCO) syndrome is the term applied to the finding of germinal aplasia in males. It has numerous causes including Y deletion, exposure to toxic chemotherapy agents or irradiation, mumps orchitis, Down syndrome, Klinefelter syndrome (47,XXY), congenital adrenal hypoplasia, isolated FSH deficiency, and hyperprolactinemia. For each of these, the medical history, the presence of other anomalies or symptoms, or chromosome analysis should differentiate them from Y chromosome infertility. In most cases, the etiology of SCO syndrome is unknown. ## Management ### Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with Y chromosome infertility, the evaluations summarized in this section (if not performed as part of the evaluation that led to the diagnosis) are recommended: * Semen analysis to determine the number, motility, and morphology of sperm * Consultation with a clinical geneticist and/or genetic counselor ### Treatment of Manifestations A couple in which the male has Y chromosome infertility can be offered the option of in vitro fertilization using ICSI (intracytoplasmic sperm injection) [Silber 2011]. In this procedure, spermatozoa retrieved from ejaculate (in males with oligozoospermia) or extracted from testicular biopsies (in males with azoospermia) are injected by ICSI into a harvested egg by IVF (in vitro fertilization) [Silber et al 1998]. Retrieval of sperm has been successful for most males with deletions of AZFc, but rarely for males with deletions of AZFb or AZFa. The reason for this is that an autosomal copy of DAZ (DAZL) may serve as a "backup gene," which would help preserve a tiny amount of residual spermatogenesis in males with AZFc deletions that remove the DAZ genes. There are no such autosomal "backup" copies for genes in AZFa and AZFb. The definition of Sertoli cell-only (SCO) syndrome has been the subject of confusion in the literature. There are two main causes of non-obstructive azoospermia (NOA): maturation arrest and Sertoli cell-only. With maturation arrest, there is a failure of spermatocytes to progress beyond meiosis I. But in 60% of individuals, a few spermatocytes do progress to sperm and can be retrieved from the testis. Similarly, in about 60% of males with SCO syndrome a tiny number of tubules actually contain a few spermatozoa resulting from small foci of spermatogenesis. It is important to discuss the possibility of transmission of Y chromosome infertility to male offspring (see Genetic Counseling) prior to attempting fertilization by ICSI and IVF [Stouffs et al 2005]. In males with retrievable spermatozoa, the presence or absence of deletion of the long arm of the Y chromosome has no apparent effect on fertilization or pregnancy rates [Silber 2011]. The risk for birth defects is not different from that of any infertile couple that achieves a pregnancy through assisted reproductive technology [Davies et al 2012]. ### Agents/Circumstances to Avoid Hormones or nutritional supplements could reduce severe oligospermia to complete azoospermia [Hughes & Page 2015]. ### Evaluation of Relatives at Risk See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes. ### Therapies Under Investigation Ongoing studies are evaluating the use of skin biopsy in azoospermic men to make induced pluripotent stem cells (iPSC) differentiate into primordial germ cells and ultimately sperm [Author, personal communication]. 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 Testicular sperm retrieval for in vitro fertilization is ineffective for males with AZFb and AZFa deletions, but has been achieved for the majority of males with AZFc deletions [Silber 2011]. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [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	Y Chromosome Infertility	c3711648	3,481	gene_reviews	https://www.ncbi.nlm.nih.gov/books/NBK1339/	2021-01-18T20:48:00	{"mesh": ["C580551"], "synonyms": ["Y Chromosome-Related Azoospermia"]}
Of the 7 children of parents related as half first cousins, 1 boy died during a convulsion at age 2 months and the other 6, born between 1925 and 1935, had severe mental retardation and extensive calcification of the choroid plexus (Lott et al., 1979). Strabismus, hyperactive deep tendon reflexes, Babinski sign, and lalling speech were other clinical features. ('Lalling speech,' an archaic expression, was used by Friedman and Roy (1944) in first reporting this family.) CSF protein concentration was 2-3 times normal. Neuropathologic studies were done in 1 sib, who died at age 26 years of cardiovascular collapse, possibly due to an abrupt withdrawal of corticosteroids given for bronchial asthma; autopsy showed severe bilateral adrenal atrophy. Small subcortical heterotopias and atrophy of the choroid plexus with encasement by glial fibrils were found. Lott et al. (1979) postulated a hereditary disorder of the choroid plexus. In the 1 patient studied, the choroid plexus failed to take up radiolabeled (99m)Tc-pertechnetate. The only other report of this disorder seems to be that by Singh et al. (1993). Three sibs in a Saudi family had mental retardation, calcification of the choroid plexus, and increased CSF protein. Radiology \- Choroid plexus calcification Neuro \- Severe mental retardation \- Seizures \- Hyperactive deep tendon reflexes \- Babinski sign Inheritance \- Autosomal recessive Lab \- CSF protein increased \- Failure of choroid plexus to take up radiolabeled (99m) Tc-pertechnetate HEENT \- Strabismus Voice \- 'Lalling' speech ▲ 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	CHOROID PLEXUS CALCIFICATION AND MENTAL RETARDATION	c1859092	3,482	omim	https://www.omim.org/entry/215480	2019-09-22T16:29:42	{"mesh": ["C535357"], "omim": ["215480"], "orphanet": ["1313"]}
ACTG2-related disorders are a subset of visceral myopathy (a condition where the intestine is unable to push food through but where there is not a real intestinal obstruction) with variable involvement of the bladder and intestine. Bladder involvement can range from neonatal megacystis (a bladder with increased size) and megaureter (ureter abnormally wide) at the more severe end, to recurrent urinary tract infections and bladder dysfunction at the milder end. It includes three different conditions, megacystis-microcolon-intestinal hypoperistalsis syndrome (MMIHS), Prune belly sequence or syndrome and chronic intestinal pseudoobstruction (CIPO). It is caused by alterations (mutations) of the ACTG2 gene and is inherited in an autosomal dominant manner. Affected infants (with or without evidence of intestinal malrotation) often present with feeding intolerance and findings of non-mechanical bowel obstruction that persist after successful surgical correction of malrotation. Individuals who develop manifestations of CIPO in later childhood or adulthood oftenhave episodic waxing and waning of bowel motility. They may need frequent abdominal surgeries (perhaps related to intestinal malrotation or adhesions causing mechanical obstruction) resulting in resection of dilated segments of bowel, often becoming dependent on total parenteral nutrition. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: 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	ACTG2-related disorders	None	3,483	gard	https://rarediseases.info.nih.gov/diseases/12743/actg2-related-disorders	2021-01-18T18:02:19	{"synonyms": []}
Keratoacanthoma Keratoacanthoma SpecialtyDermatology, plastic surgery Types * Giant keratoacanthomas * Subungual keratoacanthoma * Multiple keratoacanthomas (Ferguson–Smith syndrome) * Keratoacanthoma centrifugum marginatum * Generalized eruptive keratoacanthoma of Grzybowski Risk factorsUltraviolet radiation, immunosuppression, genetics Diagnostic methodTissue biopsy Differential diagnosisSquamous cell skin cancer TreatmentSurgery (excision, Mohs surgery) Keratoacanthoma (KA) is a common low-grade (unlikely to metastasize or invade) rapidly-growing skin tumour that is believed to originate from the hair follicle (pilosebaceous unit) and can resemble squamous cell carcinoma.[1][2] The defining characteristic of a keratoacanthoma is that it is dome-shaped, symmetrical, surrounded by a smooth wall of inflamed skin, and capped with keratin scales and debris. It grows rapidly, reaching a large size within days or weeks, and if untreated for months will almost always starve itself of nourishment, necrose (die), slough, and heal with scarring. Keratoacanthoma is commonly found on sun-exposed skin, often face, forearms and hands.[2][3] It is rarely found at a mucocutaneous junction or on mucous membranes.[2] Keratoacanthoma may be difficult to distinguish visually from a skin cancer.[4] Under the microscope, keratoacanthoma very closely resembles squamous cell carcinoma. In order to differentiate between the two, almost the entire structure needs to be removed and examined. While some pathologists classify keratoacanthoma as a distinct entity and not a malignancy, about 6% of clinical and histological keratoacanthomas do progress to invasive and aggressive squamous cell cancers; some pathologists may label KA as "well-differentiated squamous cell carcinoma, keratoacanthoma variant", and prompt definitive surgery may be recommended.[5][6][7][8] ## Contents * 1 Classification * 2 Cause * 3 Diagnosis * 4 Treatment * 5 History * 6 See also * 7 References * 8 External links ## Classification[edit] A person with generalized eruptive keratoacanthomas Frequently reported and reclassified over the last century, keratoacanthoma can be divided into various subtypes and despite being considered benign, their unpredictable behaviour has warranted the same attention as with squamous cell carcinoma.[1] Keratoacanthomas may be divided into the following types:[9]:763–764[10]:643–646 * Giant keratoacanthomas are a variant of keratoacanthoma, which may reach dimensions of several centimeters.[9]:763 * Keratoacanthoma centrifugum marginatum is a cutaneous condition, a variant of keratoacanthomas, which is characterized by multiple tumors growing in a localized area.[9]:763[10]:645 * Multiple keratoacanthomas (also known as "Ferguson–Smith syndrome," "Ferguson-Smith type of multiple self-healing keratoacanthomas,") is a cutaneous condition, a variant of keratoacanthomas, which is characterized by the appearance of multiple, sometimes hundreds of keratoacanthomas.[9]:763[10]:644 * A solitary keratoacanthoma (also known as "Subungual keratoacanthoma") is a benign, but rapidly growing, locally aggressive tumor which sometimes occur in the nail apparatus.[9]:667,764[10]:644 * Generalized eruptive keratoacanthoma (also known as "Generalized eruptive keratoacanthoma of Grzybowski") is a cutaneous condition, a variant of keratoacanthomas, characterized by hundreds to thousands of tiny follicular keratotic papules over the entire body.[9]:763[10] :645 Treatments are not successful for many people with generalized eruptive keratoacanthoma. Use of emollients and anti-itch medications can ease some symptoms. Improvement or complete resolutions of the condition has occurred with the application of the following medications: acitretin, isotretinoin, fluorouracil, methotrexate, cyclophosphamide.[11] ## Cause[edit] Keratoacanthomas usually occurs in older individuals. A number of causes have been suggested including ultraviolet light, chemical carcinogens, recent injury to the skin, immunosuppression and genetic predisposition.[1] As with squamous cell cancer, sporadic cases have been found co-infected with the human papilloma virus (HPV).[4][12] Although HPV has been suggested as a causal factor, it is unproven.[2] Many new treatments for melanoma are also known to increase the rate of keratoacanthoma, such as the BRAF inhibitor medications vemurafenib and dabrafenib.[13] ## Diagnosis[edit] Microscopic view of a skin keratoacanthoma Keratoacanthomas presents as a fleshy, elevated and nodular lesion with an irregular crater shape and a characteristic central hyperkeratotic core. Usually the people will notice a rapidly growing dome-shaped tumor on sun-exposed skin.[14] If the entire lesion is removed, the pathologist will probably be able to differentiate between keratoacanthoma and squamous cell carcinoma. Follow-up would be required to monitor for recurrence of disease.[15] ## Treatment[edit] Excision of the entire lesion, with adequate margin, will remove the lesion, allow full tissue diagnosis, and leave a planned surgical wound which can usually be repaired with a good cosmetic result. However, removing the entire lesion (especially on the face) may present difficult problems of plastic reconstruction. (On the nose and face, Mohs surgery may allow for good margin control with minimal tissue removal, but many insurance companies require the definitive diagnosis of a malignancy before they are prepared to pay the extra costs of Mohs surgery.) Especially in more cosmetically-sensitive areas, and where the clinical diagnosis is reasonably certain, alternatives to surgery may include no treatment (awaiting spontaneous resolution).[14] On the trunk, arms, and legs, electrodesiccation and curettage often suffice to control keratoacanthomas until they regress. Other modalities of treatment include cryosurgery and radiotherapy; intralesional injection of methotrexate or 5-fluorouracil have also been used.[14] Recurrence after electrodesiccation and curettage can occur; it can usually be identified and treated promptly with either further curettage or surgical excision.[6] ## History[edit] In 1889, Sir Jonathan Hutchinson described a crateriform ulcer on the face”.[16] In 1936, the same condition was renamed "molluscum sebaceum" by MacCormac and Scarf.[17] Later, the term “keratoacanthoma” was coined by Walter Freudenthal.[18][19] and the term became established by Arthur Rook and the pathologist Ian Whimster in 1950.[16] ## See also[edit] * List of cutaneous conditions * Marian Grzybowski ## References[edit] 1. ^ a b c Zito, Patrick M.; Scharf, Richard (2018), "Keratoacanthoma", StatPearls, StatPearls Publishing, PMID 29763106, retrieved 17 September 2018 2. ^ a b c d Joseph A. Regezi; James Sciubba; Richard C. K. Jordan (2012). "6. Neoplasms". Oral Pathology - E-Book: Clinical Pathologic Correlations. Elsevier Saunders. p. 155. ISBN 978-1-4557-0262-6. 3. ^ Schwartz RA. The Keratoacanthoma: A Review. J Surg Oncol 1979; 12:305–17. 4. ^ a b "Keratoacanthoma \| DermNet New Zealand". www.dermnetnz.org. Retrieved 17 September 2018. 5. ^ Ko CJ, Keratoacanthoma: facts and controversies. Clin Dermatol. 2010; 28(3):254–61 (ISSN 1879-1131) 6. ^ a b "Keratoacanthoma: Background, Pathophysiology, Etiology". Medscape. 14 August 2018.(subscription required) 7. ^ Kossard S; Tan KB; Choy C; Keratoacanthoma and infundibulocystic squamous cell carcinoma. Am J Dermatopathol. 2008; 30(2):127–34 (ISSN 1533-0311) 8. ^ Weedon DD, et al. Squamous cell carcinoma arising in keratoacanthoma: a neglected phenomenon in the elderly. Am J Dermatopathol. 2010; 32(5):423–6 9. ^ a b c d e f Freedberg, et al. (2003). Fitzpatrick's Dermatology in General Medicine. (6th ed.). McGraw-Hill. ISBN 0-07-138076-0. 10. ^ a b c d e James, William; Berger, Timothy; Elston, Dirk (2005). Andrews' Diseases of the Skin: Clinical Dermatology. (10th ed.). Saunders. ISBN 0-7216-2921-0. 11. ^ "Grzybowski generalized eruptive keratoacanthomas \| DermNet New Zealand". www.dermnetnz.org. Retrieved 17 September 2018. 12. ^ Niebuhr M, et al. Giant keratoacanthoma in an immunocompetent patient with detection of HPV 11. Hautarzt. 2009; 60(3):229–32 (ISSN 1432-1173) 13. ^ Niezgoda, A (2015). "Novel Approaches to Treatment of Advanced Melanoma: A Review on Targeted Therapy and Immunotherapy". Biomed Res Int. 2015: 851387. doi:10.1155/2015/851387. PMC 4478296. PMID 26171394. 14. ^ a b c Keratoacanthoma. Désirée Ratner. 2004. http://www.medscape.com/viewarticle/467069 accessed 23 June 2015 15. ^ Baran, Robert; Berker, David A. R. de; Holzberg, Mark; Thomas, Luc (2012). Baran and Dawber's Diseases of the Nails and their Management. John Wiley & Sons. ISBN 9780470657355. 16. ^ a b Cerroni, Lorenzo; Kerl, Helmut (2012), Goldsmith, Lowell A.; Katz, Stephen I.; Gilchrest, Barbara A.; Paller, Amy S. (eds.), "Chapter 117. Keratoacanthoma", Fitzpatrick's Dermatology in General Medicine (8 ed.), The McGraw-Hill Companies, retrieved 2018-08-20 17. ^ Levy, Edwin J. (1954-06-05). "Keratoacanthoma". Journal of the American Medical Association. 155 (6): 562–4. doi:10.1001/jama.1954.03690240028008. ISSN 0002-9955. PMID 13162754. 18. ^ HJORTH, NIELS (August 1960). "Keratoacanthoma: A Historical Note". British Journal of Dermatology. 72 (8–9): 292–295. doi:10.1111/j.1365-2133.1960.tb13896.x. ISSN 0007-0963. S2CID 71452344. 19. ^ ROOK, ARTHUR; WHIMSTER, IAN (January 1979). "Keratoacanthoma–a thirty year retrospect". British Journal of Dermatology. 100 (1): 41–47. doi:10.1111/j.1365-2133.1979.tb03568.x. ISSN 0007-0963. PMID 427012. S2CID 27373097. ## External links[edit] Classification D * ICD-10: D23 (ILDS D23.L71) (ICD10.v4 L85.8) * ICD-9-CM: 238.2 * MeSH: D007636 * DiseasesDB: 29383 External resources * eMedicine: derm/206 * Patient UK: Keratoacanthoma * v * t * e Skin cancer of the epidermis Tumor Carcinoma BCC * Forms * Aberrant * Cicatricial * Cystic * Fibroepithelioma of Pinkus * Infltrative * Micronodular * Nodular * Pigmented * Polypoid * Pore-like * Rodent ulcer * Superficial * Nevoid basal cell carcinoma syndrome SCC * Forms * Adenoid * Basaloid * Clear cell * Signet-ring-cell * Spindle-cell * Marjolin's ulcer * Bowen's disease * Bowenoid papulosis * Erythroplasia of Queyrat * Actinic keratosis Adenocarcinoma * Aggressive digital papillary adenocarcinoma * Extramammary Paget's disease Ungrouped * Merkel cell carcinoma * Microcystic adnexal carcinoma * Mucinous carcinoma * Primary cutaneous adenoid cystic carcinoma * Verrucous carcinoma * Malignant mixed tumor Benign tumors Acanthoma * Forms * Large cell * Fissuring * Clear cell * Epidermolytic * Melanoacanthoma * Pilar sheath acanthoma * Seboacanthoma * Seborrheic keratosis * Warty dyskeratoma Keratoacanthoma * Generalized eruptive * Keratoacanthoma centrifugum marginatum * Multiple * Solitary Wart * Verruca vulgaris * Verruca plana * Plantar wart * Periungual wart Other Epidermal nevus * Syndromes * Epidermal nevus syndrome * Schimmelpenning syndrome * Nevus comedonicus syndrome * Nevus comedonicus * Inflammatory linear verrucous epidermal nevus * Linear verrucous epidermal nevus * Pigmented hairy epidermal nevus syndrome * Systematized epidermal nevus * Phakomatosis pigmentokeratotica Other nevus * Nevus unius lateris * Patch blue nevus * Unilateral palmoplantar verrucous nevus * Zosteriform speckled lentiginous nevus Ungrouped * Cutaneous horn [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: 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	Keratoacanthoma	c0022572	3,484	wikipedia	https://en.wikipedia.org/wiki/Keratoacanthoma	2021-01-18T19:01:29	{"mesh": ["D007636"], "umls": ["C0022572"], "icd-9": ["238.2"], "icd-10": ["D23"], "wikidata": ["Q785827"]}
Francois (1958) described a brother and sister, aged 50 and 35, respectively, with what he considered to be a 'new' type of hereditary corneal dystrophy. He referred to it as 'dystrophie corneenne nuageuse centrale.' Eyes \- Central corneal dystrophy Inheritance \- Autosomal recessive ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	CENTRAL CLOUDY DYSTROPHY OF FRANCOIS	c1622427	3,485	omim	https://www.omim.org/entry/217600	2019-09-22T16:29:29	{"mesh": ["C563262"], "omim": ["217600"], "orphanet": ["98972"], "synonyms": ["Alternative titles", "CORNEAL DYSTROPHY, CENTRAL TYPE"]}
Autosomal recessive spastic paraplegia type 14 is a rare, complex hereditary spastic paraplegia characterized by adulthood-onset of slowly progressive spastic paraplegia of lower limbs presenting with spastic gait, hyperreflexia, and mild lower limb hypertonicity associated with mild intellectual disability, visual agnosia, short and long-term memory deficiency and mild distal motor neuropathy. Bilateral pes cavus and extensor plantar responses are also associated. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Autosomal recessive spastic paraplegia type 14	c1854568	3,486	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=100995	2021-01-23T17:02:02	{"gard": ["9589"], "mesh": ["C537486"], "omim": ["605229"], "umls": ["C1854568"], "icd-10": ["G11.4"], "synonyms": ["SPG14"]}
A number sign (#) is used with this entry because of evidence that spinocerebellar ataxia-48 (SCA48) is caused by heterozygous mutation in the STUB1 gene (607207) on chromosome 16p13. One such family has been reported. Description SCA48 is an autosomal dominant neurodegenerative disorder characterized by onset of gait ataxia and/or cognitive-affective symptoms in mid-adulthood. Patients may present with involvement of either system, but most eventually develop impairment in both. Features include gait ataxia, dysarthria, and dysphagia, as well as anxiety and deficits in executive function. Brain imaging shows selective atrophy of the posterior areas of the cerebellar vermis (summary by Genis et al., 2018). Clinical Features Genis et al. (2018) reported a large multigenerational Spanish family in which multiple members had late-onset, progressive, cognitive decline associated with spinocerebellar ataxia at a median age of 42 years. About half of the patients presented with cognitive or affective impairment, including anxiety, agoraphobia, and declines in cognitive and executive function, before the onset of ataxia, whereas the others presented with ataxia and later developed cognitive and affective symptoms. Pure motor symptoms included ataxia, dysarthria, dysphagia, ocular dysmetria, and urinary incontinence, and some patients became wheelchair-bound after a long disease duration. Two patients had only cognitive symptoms without ataxia, and 1 younger patient had no symptoms but had cerebellar atrophy on brain imaging. Genis et al. (2018) noted that patients were anosognosic about their deficits at the time of evaluation. Brain imaging showed cerebellar atrophy particularly of the posterior area of the vermis and paravermis (lobes VI and VII), which is known to receive neocortical input from prefrontal, frontal, and other brain areas involved in higher order behavior. Inheritance The transmission pattern of SCA48 in the family reported by Genis et al. (2018) was consistent with autosomal dominant inheritance. Molecular Genetics In 9 affected members of a multigenerational family from Catalonia, Spain, with SCA48, Genis et al. (2018) identified a heterozygous frameshift mutation in the STUB1 gene (c.823_824delCT; 607207.0010). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing and linkage analysis, segregated with the disorder in the family. It was found at a low frequency (0.0000081) in the ExAC database. Functional studies of the variant and studies of patient cells were not performed. INHERITANCE \- Autosomal dominant HEAD & NECK Eyes \- Ocular dysmetria ABDOMEN Gastrointestinal \- Dysphagia GENITOURINARY Bladder \- Urinary incontinence NEUROLOGIC Central Nervous System \- Spinocerebellar ataxia \- Gait ataxia \- Dysarthria \- Cognitive dysfunction \- Cerebellar atrophy Behavioral Psychiatric Manifestations \- Anxiety \- Executive dysfunction MISCELLANEOUS \- Onset in mid-adulthood \- Progressive disorder \- Patients may present with either cognitive-affective symptoms or motor symptoms \- One Spanish family has been reported (last curated November 2018) MOLECULAR BASIS \- Caused by mutation in the STIP1 homologous and U box-containing protein 1 gene (STUB1, 607207.0010 ) ▲ 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	SPINOCEREBELLAR ATAXIA 48	None	3,487	omim	https://www.omim.org/entry/618093	2019-09-22T15:43:39	{"omim": ["618093"]}
Hemangiopericytoma Other namesHPC Haemangiopericytoma, Gomori methenamine silver stain SpecialtyOncology, rheumatology SymptomsPainless mass[1] Usual onset45 years of age (median)[1] A hemangiopericytoma is a type of soft-tissue sarcoma that originates in the pericytes in the walls of capillaries. When inside the nervous system, although not strictly a meningioma tumor, it is a meningeal tumor with a special aggressive behavior. It was first characterized in 1942.[2] ## Contents * 1 Histopathology * 2 Diagnosis * 3 Treatment * 4 Epidemiology * 5 See also * 6 References * 7 Further reading * 8 External links ## Histopathology[edit] Hemangiopericytomas are tumors that are derived from specialized spindle shaped cells called pericytes, which line capillaries.[3] ## Diagnosis[edit] Hemangiopericytoma located in the cerebral cavity is an aggressive tumor of the mesenchyme with oval nuclei with scant cytoplasm. "There is dense intercellular reticulin staining. Tumor cells can be fibroblastic, myxoid, or pericytic. These tumors, in contrast to meningiomas, do not stain with epithelial membrane antigen. They have a grade 2 or 3 biological behavior, and need to be distinguished from benign meningiomas because of their high rate of recurrence (68.2%) and metastases (Maier et al. 1992;[4] Kleihues et al. 1993 [5])." [6] ## Treatment[edit] Depending on the grade of the sarcoma, it is treated with surgery,[7] chemotherapy, and/or radiotherapy. ## Epidemiology[edit] In one series, the median age of affected individuals was 45 years, with a 10 year survival rate of 70 percent.[1] ## See also[edit] * Infantile hemangiopericytoma * List of cutaneous conditions ## References[edit] 1. ^ a b c Enzinger, FM; Smith, BH (January 1976). "Hemangiopericytoma. An analysis of 106 cases". Human Pathology. 7 (1): 61–82. doi:10.1016/s0046-8177(76)80006-8. PMID 1244311. 2. ^ Stout AP, Murray MR (1942). "Hemangiopericytoma: a vascular tumor featuring Zimmermann's pericytes". Ann Surg. 116 (1): 26–33. doi:10.1097/00000658-194207000-00004. PMC 1543753. PMID 17858068. 3. ^ Gerner, RE; Moore, GE; Pickren, JW (February 1974). "Hemangiopericytoma". Annals of Surgery. 179 (2): 128–32. doi:10.1097/00000658-197402000-00002. PMC 1355764. PMID 4359454. S2CID 220588367. 4. ^ Maier H, Ofner D, Hittmair A, Kitz K, Budka H (1992). "Classic, atypical, and anaplastic meningioma: three histopathological subtypes of clinical relevance". Journal of Neurosurgery. 77 (4): 616–23. doi:10.3171/jns.1992.77.4.0616. PMID 1527622. 5. ^ Kleihues P, Burger PC, Scheithauer BW (1993). "Histological typing of tumours of the central nervous system". World Health Organization. Berlin : Springer-Verlag (2nd ed.) (30). 6. ^ Sherman Sojka W MD; Raizer J MD; Dropcho E.J.MD. "Meningiomas". Medmerits: 2. Archived from the original on 2012-03-31. Retrieved 2011-09-19. 7. ^ Ozaki N, Mukohara N, Yoshida M, Shida T (April 2006). "Successful resection of giant hemangeopericytoma originating from the left atrium". Interact Cardiovasc Thorac Surg. 5 (2): 79–80. doi:10.1510/icvts.2005.124107. PMID 17670519.[permanent dead link] ## Further reading[edit] Schiariti, M; Goetz, P; El-Maghraby, H; Tailor, J; Kitchen, N (Mar 2011). "Hemangiopericytoma: long-term outcome revisited. Clinical article". Journal of Neurosurgery. 114 (3): 747–55. doi:10.3171/2010.6.JNS091660. PMID 20672899. ## External links[edit] Classification D * ICD-10: C49 (ILDS C49.M20) * ICD-O: M9150/1 * MeSH: D006393 * DiseasesDB: 29249 External resources * eMedicine: orthoped/500 * v * t * e Tumours of blood vessels Blood vessel * Hemangiosarcoma * Blue rubber bleb nevus syndrome * Hemangioendothelioma * Composite * Endovascular papillary * Epithelioid * Kaposiform * Infantile * Retiform) * Spindle cell * Proliferating angioendotheliomatosis * Hemangiopericytoma * Venous lake * Kaposi's sarcoma * African cutaneous * African lymphadenopathic * AIDS-associated * Classic * Immunosuppression-associated * Hemangioblastoma * Hemangioma * Capillary * Cavernous * Glomeruloid * Microvenular * Targeted hemosiderotic * Angioma * Cherry * Seriginosum * Spider * Tufted * Universal angiomatosis * Angiokeratoma * of Mibelli * Angiolipoma * Pyogenic granuloma Lymphatic * Lymphangioma/lymphangiosarcoma * Lymphangioma circumscriptum * Acquired progressive lymphangioma * PEComa * Lymphangioleiomyomatosis * Cystic hygroma * Multifocal lymphangioendotheliomatosis * Lymphangiomatosis Either * Angioma/angiosarcoma * Angiofibroma [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: 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	Hemangiopericytoma	c0018922	3,488	wikipedia	https://en.wikipedia.org/wiki/Hemangiopericytoma	2021-01-18T18:50:53	{"gard": ["2627"], "mesh": ["D006393"], "umls": ["C0018922"], "icd-10": ["C49"], "wikidata": ["Q3144913"]}
A number sign (#) is used with this entry because tetrahydrobiopterin (BH4)-deficient hyperphenylalaninemia (HPA) due to dihydropteridine reductase deficiency (HPABH4C) is caused by homozygous or compound heterozygous mutation in the QDPR gene (612676), which encodes an enzyme involved in the salvage pathway for BH4, on chromosome 4p15. For a general phenotypic description and a discussion of genetic heterogeneity of BH4-deficient hyperphenylalaninemia, see HPABH4A (261640). Clinical Features Smith et al. (1975) described 3 children, 2 of them sibs, with an unusual type of phenylketonuria. All 3 (2 of them observed from the neonatal period) had a progressive neurologic illness that did not respond to a low phenylalanine diet, unlike classic PKU (261600). The biochemical features suggested that the block in conversion of phenylalanine to tyrosine was less severe than in classic PKU. Phenylalanine hydroxylase (PAH; 612349), measured in 1 patient, was normal. Smith et al. (1975) suggested that the patients had a disorder of biopterin metabolism possibly due to a defect in the enzyme dihydropteridine reductase. Butler et al. (1975) reported dihydropteridine reductase deficiency in a patient unresponsive to dietary treatment. Biopterin is the natural cofactor for phenylalanine hydroxylase. In its active tetra-hydro form (BH4), biopterin donates hydrogen ions during the hydroxylation reaction. The same cofactor system is active in neural tissue for hydroxylation of tyrosine to dihydroxyphenylalanine (levodopa) in the synthesis of amine transmitters (dopaminine, noradrenaline, and adrenaline) and serotonin. Phenylalanine restriction would not be expected to help the neurologic problem. Basal ganglion symptoms can be related to the importance of levodopa and dopamine to that part of the brain. Kaufman et al. (1975) demonstrated absence of dihydropteridine reductase in liver, brain, and cultured skin fibroblasts of a patient with elevated blood phenylalanine and no response to diet despite good control of blood levels. Watts et al. (1979) reported a patient with hyperphenylalaninemia who had better tolerance of phenylalanine compared to patients with classic PKU. However, unlike patients with classic PKU, treatment with trimethoprim reduced the phenylalanine tolerance in this patient. Since trimethoprim inhibits 7,8-dihydrobiopterin reduction, Watts et al. (1979) speculated that the causative defect may involve the gene for dihydropteridine reductase such that it is sensitive to the reduced availability of tetrahydrobiopterin produced by trimethoprim. Woody et al. (1989) pointed out that without folinic acid therapy as a source of tetrahydrofolate, patients with DHPR deficiency show progressive basal ganglia and other subcortical calcification. The pattern of calcification resembled that seen in CNS folate deficiency, both that in the congenital form (229050) and that in the methotrexate-induced form. Larnaout et al. (1998) described 2 brothers with juvenile-onset DHPR deficiency. Both were considered normal until 6 years of age when they developed a fluctuating and progressive encephalopathy combining mental retardation, epilepsy, and pyramidal, cerebellar, and extrapyramidal signs. Diagnosis ### Prenatal Diagnosis Dahl et al. (1987, 1988) showed that RFLPs of the DHPR locus could be used for prenatal diagnosis. Clinical Management Danks et al. (1975) found that intravenous tetrahydrobiopterin (BH4) treatment was effective and resulted in a fall in serum phenylalanine. Oral therapy had no effect. Molecular Genetics In a patient with dihydropteridine reductase deficiency, the offspring of consanguineous parents, Howells et al. (1990) identified homozygosity for a mutation in the QDPR gene (612676.0001). Smooker and Cotton (1995) reviewed 12 point mutations that had been described in DHPR cDNA, all of which resulted in dihydropteridine reductase deficiency. The mutations resulted in amino acid substitutions, insertions, or premature terminations. A further 2 mutations resulted in aberrant splicing of QDPR transcripts. Romstad et al. (2000) studied 17 patients belonging to 16 Turkish families with DHPR deficiency. The patients were detected at neonatal screening for hyperphenylalaninemia or upon the development of neurologic symptoms. A mutation screen of the entire open reading frame and all splice sites of the QDPR gene identified 10 different mutations, 7 of which were novel (e.g., 612676.0007). Six of the mutations were missense, 2 were nonsense, and 2 were frameshift mutations. All patients had homoallelic genotypes, which allowed the establishment of genotype-phenotype associations. INHERITANCE \- Autosomal recessive GROWTH Other \- Poor feeding in infancy HEAD & NECK Head \- Microcephaly Mouth \- Hypersalivation ABDOMEN Gastrointestinal \- Swallowing difficulties NEUROLOGIC Central Nervous System \- Delayed development \- Psychomotor retardation \- Mental retardation \- Hypotonia, truncal \- Hypertonia of the extremities \- Uncoordinated movements \- Tremor \- Dystonia \- Seizures \- Choreoathetosis \- Intracerebral calcifications Behavioral Psychiatric Manifestations \- Irritability METABOLIC FEATURES \- Hyperthermia, episodic LABORATORY ABNORMALITIES \- Hyperphenylalaninemia \- Decreased homovanillic acid (HVA) and 5-hydroxyindoleacetic acid (5HIAA) in CSF \- Increased biopterin in urine and CSF \- Decreased or absent dihydropteridine reductase activity MISCELLANEOUS \- Onset in infancy \- Variable severity \- Progressive neurologic deterioration if untreated \- Diurnal fluctuation of neurologic symptoms \- Defect in tetrahydrobiopterin (BH4) synthesis \- Treatment with BH4 is effective \- Neurotransmitter treatment with L-dopa and serotonin or precursors is effective \- Early treatment can reduce neurologic symptoms MOLECULAR BASIS \- Caused by mutation in the quinoid dihydropteridine reductase gene (QDPR, 612676.0001 ) ▲ 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	HYPERPHENYLALANINEMIA, BH4-DEFICIENT, C	c0751436	3,489	omim	https://www.omim.org/entry/261630	2019-09-22T16:23:32	{"mesh": ["D010661"], "omim": ["261630"], "orphanet": ["238583", "226"], "synonyms": ["Alternative titles", "HYPERPHENYLALANINEMIA, TETRAHYDROBIOPTERIN-DEFICIENT, DUE TO DHPR DEFICIENCY", "DIHYDROPTERIDINE REDUCTASE DEFICIENCY", "DHPR DEFICIENCY", "QUINOID DIHYDROPTERIDINE REDUCTASE DEFICIENCY", "QDPR DEFICIENCY"]}
STAC3 Disorder is a genetic condition that affects the muscles and skeleton. The main features are muscle weakness present at birth, club foot, fixed joints (joint contractures), and curvature of the spine. The symptoms of this condition vary. The most severe complications can include feeding and breathing difficulties. Many people with this condition are at risk to have complications under general anesthesia (malignant hyperthermia). Muscle weakness may get slowly worse over time or stay the same. Most people with STAC3 disorders are shorter than average and have normal intelligence. This condition is caused by genetic alterations in the STAC3 gene and is inherited in an autosomal recessive pattern. STAC3 disorder is diagnosed based on the symptoms and confirmed by genetic testing. Treatment is based on managing the symptoms. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	STAC3 Disorder	c1850625	3,490	gard	https://rarediseases.info.nih.gov/diseases/8432/stac3-disorder	2021-01-18T17:57:31	{"mesh": ["C538343"], "omim": ["255995"], "umls": ["C1850625"], "orphanet": ["168572"], "synonyms": ["Congenital myopathy cleft palate and malignant hyperthermia", "Congenital myopathy - cleft palate - malignant hyperthermia", "Congenital myopathy-cleft palate-malignant hyperthermia syndrome", "Congenital myopathy with myopathic facies, scoliosis, and malignant hyperthermia", "Bailey-Bloch congenital myopathy", "Native American myopathy"]}
A rare otorhinolaryngologic malformation characterized by delayed speech development and hypernasal speech in the absence of overt cleft palate. Radiological examination shows a short and immobile soft palate with anatomical disproportion of the velopharyngeal structures. The condition may be an isolated finding or occur as part of velo-cardio-facial 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	Congenital velopharyngeal incompetence	c1997202	3,491	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=2291	2021-01-23T16:58:59	{"gard": ["5470"], "omim": ["167500"], "umls": ["C1997202"], "icd-10": ["J39.2"]}
A number sign (#) is used with this entry because of evidence that anauxetic dysplasia-1 (ANXD1) is caused by homozygous or compound heterozygous mutation in the RMRP gene (157660) on chromosome 9p13. Description Anauxetic dysplasia is a form of spondylometaepiphyseal dysplasia characterized by the prenatal onset of extreme short stature, an adult height of less than 85 cm, hypodontia, and mild mental retardation. Major radiographic characteristics are late-maturing ovoid vertebral bodies with concave dorsal surfaces in the lumbar region; small capital femoral epiphyses; hypoplastic femoral necks; hypoplastic iliac bodies and shallow acetabulae; irregular metaphyseal mineralization and demarcation of the long tubular bones; short first and fifth metacarpals with widened shafts; very short and broad phalanges with small, late-ossifying epiphyses and bullet-shaped middle phalanges; and midface hypoplasia. The number of chondrocytes is severely reduced in the resting and proliferating cartilage, with diminished columnization of the hypertrophic zone (summary by Thiel et al., 2005). Mutations in RMRP also cause 2 milder types of short stature with susceptibility to cancer, cartilage-hair hypoplasia (CHH; 250250) and metaphyseal dysplasia without hypotrichosis (250460). ### Genetic Heterogeneity of Anauxetic Dysplasia Anauxetic dysplasia-2 (ANXD2; 617396) is caused by mutation in the POP1 gene on chromosome 8q22. Clinical Features Menger et al. (1996) described 3 sibs born to first-cousin Jordanian parents. These children had extreme disproportionate short stature with final adult height in 1 individual being 85 cm. The children had a distinct facial appearance with hypotelorism, prognathism, and hypodontia. Three children had a short trunk with lumbar hyperlordosis, and the oldest affected individual had kyphoscoliosis. There was rhizomelic shortening of the limbs with brachydactyly of the hands and feet. The large joints were prominent and the oldest affected individual had limited extension at the elbows. Rocker-bottom feet with prominent heels were present. Pubertal development was normal. All were said to be slightly mentally retarded. Radiographs showed midface hypoplasia with a steep skull base and enlarged J-shaped sella. The vertebrae were oval-shaped in the youngest sib and foreshortened in the oldest. The lateral aspects of the iliac bodies were hypoplastic with slanting acetabular roofs; the pubic bones were gracile. The femoral heads were very small with no femoral necks present. All the tubular bones were severely short with irregular metaphyses and small, deformed epiphyses. Carpal bone age was delayed. The phalanges were short and broad and the terminal phalanges hypoplastic. Iliac crest biopsy in one of the affected children showed a severely distorted growth plate with only a few chondrocytes present. There was almost absent columnization of the hypertrophic zone and marked irregularity of the osteochondral junction. Electron microscopy showed dilation of the rough endoplasmic reticulum in the remaining hypertrophic chondrocytes with granular material present. The collagen fibrils in the surrounding matrix seemed small. One of the affected children had Fanconi anemia (see 227650); the authors believed that this was an unrelated finding. Horn et al. (2001) reported 2 brothers, born to nonconsanguineous German parents, who they believed had the same condition as that described by Menger et al. (1996). These children also had extreme disproportionate short stature with shortening of the long bones and the bones of the hands and feet, with flexion contractures of the elbows. Both boys had marked lumbar hyperlordosis, and one of them had thoracic kyphosis. Radiographic examination showed irregular and widened metaphyses with very small epiphyses and severely delayed carpal bone ossification. There was platyspondyly of the thoracic spine. The tubular bones of the hands were short and broad. Skull x-ray showed a J-shaped sella. Light microscopy of the specimens from the iliac crest, vertebral bodies, and femoral and tibial growth plates showed marked hypocellularity of the resting cartilage with rounded chondrocytes, and a reduced number of proliferating chondrocytes with diminished columnization of the hypertrophic zone. Both children had delayed development. At the age of 4 years, 1 child had developed respiratory insufficiency and quadriplegia that was attributed to cervical cord compression. After 4 months of ventilation, the child died. The second child was reported to be well at 11 years of age but at that age was found to have aortic stenosis. He was also found to have atlantoaxial subluxation and underwent cervical fusion. Mapping By genomewide homozygosity mapping in a large consanguineous family segregating anauxetic dysplasia, Thiel et al. (2005) identified linkage to a 18.7-cM region on chromosome 9p21-p13 (maximum multipoint lod of 3.0). Fine-mapping with additional members of this and another affected family refined the linkage to a 17.1-cM region between markers D9S1114 and D9S1874, resulting in an 11.15-Mb candidate region (maximum lod of 3.1). Molecular Genetics In affected individuals from 3 unrelated families with anauxetic dysplasia, including the Jordanian family originally reported by Menger et al. (1996) and the German family reported by Horn et al. (2001), Thiel et al. (2005) sequenced the candidate gene RMRP and identified homozygous or compound heterozygous mutations (157660.0018-157660.0021) that segregated with the disorder. Mutations in this gene also cause 2 milder types of short stature with susceptibility to cancer, cartilage-hair hypoplasia (CHH; 250250) and metaphyseal dysplasia without hypotrichosis (250460). Thiel et al. (2005) showed that different RMRP gene mutations lead to decreased cell growth by impairing ribosomal assembly and by altering cyclin-dependent cell cycle regulation. Clinical heterogeneity is explained by a correlation between the level and type of functional impairment in vitro and the severity of short stature or predisposition to cancer. Whereas the CHH founder mutation (157660.0001) affects both pathways intermediately, anauxetic dysplasia mutations do not affect B-cyclin (123836) mRNA levels but severely incapacitate ribosomal assembly via defective endonucleolytic cleavage. Anauxetic dysplasia mutations thus lead to poor processing of ribosomal RNA by allowing normal mRNA processing, and, therefore, genetically separate the different functions of RNase MRP. Nomenclature Horn et al. (2001) concluded that this condition is distinct from other forms of spondylometaepiphyseal dysplasia and the same as the condition described by Menger et al. (1996). Horn et al. (2001) proposed the name 'anauxetic dysplasia' (from the Greek term for 'not growing' or 'not permitting growth') on the basis of extreme dwarfism resulting from a severe pre- and postnatal disturbance of skeletal growth and differentiation. INHERITANCE \- Autosomal recessive GROWTH Height \- Severely disproportionate short stature HEAD & NECK Eyes \- Hypertelorism Teeth \- Hypodontia Neck \- Short \- Cervical subluxation SKELETAL Skull \- J-shaped sella Spine \- Platyspondyly \- Cervical subluxation Pelvis \- Hypoplastic ilia \- Slanting acetabular roots Limbs \- Rhizomelic shortening \- Metaphyseal flaring \- Small epiphyses Hands \- Brachydactyly \- Delayed carpal bone age Feet \- Brachydactyly NEUROLOGIC Central Nervous System \- Cervical cord compression \- Mental retardation LABORATORY ABNORMALITIES \- Abnormal columnization of chondrocytes \- Dilated rough endoplasmic reticulum (RER) MOLECULAR BASIS \- Caused by mutation in the mitochondrial RNA-processing endoribonuclease (RMRP, 157660.0018 ) ▲ 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	ANAUXETIC DYSPLASIA 1	c1846796	3,492	omim	https://www.omim.org/entry/607095	2019-09-22T16:09:39	{"doid": ["0050640"], "mesh": ["C538256"], "omim": ["607095"], "orphanet": ["93347"], "synonyms": ["Alternative titles", "ANAUXETIC DYSPLASIA", "SPONDYLOMETAEPIPHYSEAL DYSPLASIA, ANAUXETIC TYPE", "SPONDYLOEPIMETAPHYSEAL DYSPLASIA, ANAUXETIC TYPE", "SPONDYLOMETAEPIPHYSEAL DYSPLASIA, MENGER TYPE"], "genereviews": ["NBK84550"]}
Mycoplasma pneumonia Other namesWalking pneumonia SpecialtyInfectious disease, pulmonology Mycoplasma pneumonia (also known as "walking pneumonia") is a form of bacterial pneumonia caused by the bacterial species Mycoplasma pneumoniae.It is also known as PPLO, which is an acronym for Pleuro Pneumonia Like Organism. ## Contents * 1 Pathophysiology * 2 Diagnosis * 3 Treatment * 4 See also * 5 References * 6 External links ## Pathophysiology[edit] Mycoplasma pneumoniae is spread through respiratory droplet transmission. Once attached to the mucosa of a host organism, M. pneumoniae extracts nutrients, grows, and reproduces by binary fission. Attachment sites include the upper and lower respiratory tract, causing pharyngitis, bronchitis, and pneumonia. The infection caused by this bacterium is called atypical pneumonia because of its protracted course and lack of sputum production and wealth of extrapulmonary symptoms. Chronic Mycoplasma infections have been implicated in the pathogenesis of rheumatoid arthritis and other rheumatological diseases. Mycoplasma atypical pneumonia can be complicated by Stevens–Johnson syndrome, autoimmune hemolytic anemia, cardiovascular diseases, encephalitis, or Guillain–Barré syndrome. ## Diagnosis[edit] M. pneumoniae infections can be differentiated from other types of pneumonia by the relatively slow progression of symptoms. A positive blood test for cold-hemagglutinins in 50–70% of patients after 10 days of infection (cold-hemagglutinin-test should be used with caution or not at all, since 50% of the tests are false-positive), lack of bacteria in a Gram-stained sputum sample, and a lack of growth on blood agar. PCR has also been used.[1] ## Treatment[edit] While antibiotics with activity specifically against M. pneumoniae are often used (e.g., erythromycin, doxycycline), it is unclear if these result in greater benefit than using antibiotics without specific activity against this organism in those with an infection acquired in the community.[2] ## See also[edit] * Mycoplasmal pneumonia of swine ## References[edit] 1. ^ Waris ME, Toikka P, Saarinen T, et al. (November 1998). "Diagnosis of Mycoplasma pneumoniae pneumonia in children". J. Clin. Microbiol. 36 (11): 3155–9. doi:10.1128/JCM.36.11.3155-3159.1998. PMC 105292. PMID 9774556. 2. ^ Biondi, E; McCulloh, R; Alverson, B; Klein, A; Dixon, A (Jun 2014). "Treatment of mycoplasma pneumonia: a systematic review". Pediatrics. 133 (6): 1081–90. doi:10.1542/peds.2013-3729. PMID 24864174. ## External links[edit] Classification D * ICD-10: J15.7 * ICD-9-CM: 483.0 * MeSH: D011019 External resources * MedlinePlus: 000082 * eMedicine: emerg/467 * v * t * e * Firmicutes (low-G+C) Infectious diseases * Bacterial diseases: G+ Bacilli Lactobacillales (Cat-) Streptococcus α optochin susceptible * S. pneumoniae * Pneumococcal infection optochin resistant * Viridans streptococci: S. mitis * S. mutans * S. oralis * S. sanguinis * S. sobrinus * S. anginosus group β A * bacitracin susceptible: S. pyogenes * Group A streptococcal infection * Streptococcal pharyngitis * Scarlet fever * Erysipelas * Rheumatic fever B * bacitracin resistant, CAMP test+: S. agalactiae * Group B streptococcal infection ungrouped * Streptococcus iniae * Cutaneous Streptococcus iniae infection γ * D * BEA+: Streptococcus bovis Enterococcus * BEA+: Enterococcus faecalis * Urinary tract infection * Enterococcus faecium Bacillales (Cat+) Staphylococcus Cg+ * S. aureus * Staphylococcal scalded skin syndrome * Toxic shock syndrome * MRSA Cg- * novobiocin susceptible * S. epidermidis * novobiocin resistant * S. saprophyticus Bacillus * Bacillus anthracis * Anthrax * Bacillus cereus * Food poisoning Listeria * Listeria monocytogenes * Listeriosis Clostridia Clostridium (spore-forming) motile: * Clostridium difficile * Pseudomembranous colitis * Clostridium botulinum * Botulism * Clostridium tetani * Tetanus nonmotile: * Clostridium perfringens * Gas gangrene * Clostridial necrotizing enteritis Finegoldia (non-spore forming) * Finegoldia magna Mollicutes Mycoplasmataceae * Ureaplasma urealyticum * Ureaplasma infection * Mycoplasma genitalium * Mycoplasma pneumoniae * Mycoplasma pneumonia Anaeroplasmatales * Erysipelothrix rhusiopathiae * Erysipeloid * v * t * e Diseases of the respiratory system Upper RT (including URTIs, common cold) Head sinuses Sinusitis nose Rhinitis Vasomotor rhinitis Atrophic rhinitis Hay fever Nasal polyp Rhinorrhea nasal septum Nasal septum deviation Nasal septum perforation Nasal septal hematoma tonsil Tonsillitis Adenoid hypertrophy Peritonsillar abscess Neck pharynx Pharyngitis Strep throat Laryngopharyngeal reflux (LPR) Retropharyngeal abscess larynx Croup Laryngomalacia Laryngeal cyst Laryngitis Laryngopharyngeal reflux (LPR) Laryngospasm vocal cords Laryngopharyngeal reflux (LPR) Vocal fold nodule Vocal fold paresis Vocal cord dysfunction epiglottis Epiglottitis trachea Tracheitis Laryngotracheal stenosis Lower RT/lung disease (including LRTIs) Bronchial/ obstructive acute Acute bronchitis chronic COPD Chronic bronchitis Acute exacerbation of COPD) Asthma (Status asthmaticus Aspirin-induced Exercise-induced Bronchiectasis Cystic fibrosis unspecified Bronchitis Bronchiolitis Bronchiolitis obliterans Diffuse panbronchiolitis Interstitial/ restrictive (fibrosis) External agents/ occupational lung disease Pneumoconiosis Aluminosis Asbestosis Baritosis Bauxite fibrosis Berylliosis Caplan's syndrome Chalicosis Coalworker's pneumoconiosis Siderosis Silicosis Talcosis Byssinosis Hypersensitivity pneumonitis Bagassosis Bird fancier's lung Farmer's lung Lycoperdonosis Other * ARDS * Combined pulmonary fibrosis and emphysema * Pulmonary edema * Löffler's syndrome/Eosinophilic pneumonia * Respiratory hypersensitivity * Allergic bronchopulmonary aspergillosis * Hamman-Rich syndrome * Idiopathic pulmonary fibrosis * Sarcoidosis * Vaping-associated pulmonary injury Obstructive / Restrictive Pneumonia/ pneumonitis By pathogen * Viral * Bacterial * Pneumococcal * Klebsiella * Atypical bacterial * Mycoplasma * Legionnaires' disease * Chlamydiae * Fungal * Pneumocystis * Parasitic * noninfectious * Chemical/Mendelson's syndrome * Aspiration/Lipid By vector/route * Community-acquired * Healthcare-associated * Hospital-acquired By distribution * Broncho- * Lobar IIP * UIP * DIP * BOOP-COP * NSIP * RB Other * Atelectasis * circulatory * Pulmonary hypertension * Pulmonary embolism * Lung abscess Pleural cavity/ mediastinum Pleural disease * Pleuritis/pleurisy * Pneumothorax/Hemopneumothorax Pleural effusion Hemothorax Hydrothorax Chylothorax Empyema/pyothorax Malignant Fibrothorax Mediastinal disease * Mediastinitis * Mediastinal emphysema Other/general * Respiratory failure * Influenza * Common cold * SARS * Coronavirus disease 2019 * Idiopathic pulmonary haemosiderosis * Pulmonary alveolar proteinosis [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: 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	Mycoplasma pneumonia	c0032302	3,493	wikipedia	https://en.wikipedia.org/wiki/Mycoplasma_pneumonia	2021-01-18T18:32:20	{"gard": ["7125"], "mesh": ["D011019"], "icd-9": ["483.0"], "icd-10": ["B96.0"], "wikidata": ["Q10591185"]}
Criss cross heart (CCH) is a cardiac malformation where the inflow streams of the two ventricles cross due to twisting of the heart about its major axis. The clinical features depend on the particular cardiac defects associated, like simple or corrected transposition of the great arteries and ventricular septal defects. ## Epidemiology The birth prevalence of CCH is 1 /125, 000 live births and accounts for <0.1% of all congenital heart defects. ## Clinical description CCH is a congenital disorder which can manifest by severe dyspnea with nasal flaring, retraction of sternal notch, subcostal and intercostal indrawing, diaphoresis, cyanosis, pallor, feeding difficulty, systolic murmur at the left sternal edge and accentuated P2 heart sound, depending on the associated lesions. The most common associations are ventricular septal defect (VSD), complete or congenitally corrected transposition of the great arteries, double outlet right ventricle, pulmonary branch stenosis, straddling mitral or tricuspid valve, mitral stenosis, and subpulmonary, subaortic or supravalvular aortic stenosis (see these terms). ## Etiology CCH is caused by abnormal rotation (clockwise or counterclockwise) of the ventricular mass along its long axis during embryonic development. The developmental mechanisms and causes of CCH are still elusive but some studies in mice have linked mutations in the Gja1 gene to the pathogenesis of CCH. ## Diagnostic methods Diagnosis is confirmed by 2-dimensional and color Doppler echocardiography revealing the crossing of the atrioventricular connections, without mixing, at the level of the atrioventricular (AV) valves. Failure to obtain a characteristic 4-chamber view (4CV) is a key diagnostic feature of CCH. Biventricular function is normal but perimembranous ventricular septal defects are usually observed. MRI and angiography may be used for the diagnosis of anomalies of the coronary circulation. ## Differential diagnosis Differential diagnosis includes straddling mitral or tricuspid valve, severe forms of Ebstein malformation (the tricuspid valve opens to the infundibulum, giving the appearance of crossing the valves) (see these terms), and double atrial outlet (an outlet orifice apparently crosses the other valve). ## Antenatal diagnosis Prenatal diagnosis can be achieved with a color Doppler ultrasound, by identifying key features of CCH that include the inability to obtain a 4CV at the standard transverse plane through the fetal chest and visualization of the criss cross arrangement of the inflow tracts into the two ventricles simultaneously in the transverse plane of the fetal chest. ## Management and treatment The surgical management of CCH consists of the repair of major and limiting malformations, with ventricular rotation itself being excluded as the reason for the correction. The initial management is determined by the presence or absence of pulmonary stenosis, and its severity. Where the pulmonary flow is inadequate, early intervention with prostaglandin E1 is indicated for maintaining the patency of the patent arterial duct. When anatomic correction fails, balance in pulmonary flow can be achieved with the construction of a systemic-pulmonary shunt. The corrective surgery is determined by the potential use of both ventricles. The Fontan correction may be indicated as a palliative repair option. Jatene's surgical technique (the arterial switch operation) may be proposed to patients where CCH is associated with transposition of the great arteries, VSD, atrial septal defect and patent arterial duct (see these terms). ## Prognosis The prognosis is unfavorable without surgical treatment. However, after correction of the main defect, normal physical, psychomotor and cardiovascular development may be achieved. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: 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	Criss-cross heart	c0010334	3,494	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=1461	2021-01-23T17:12:59	{"mesh": ["D003420"], "umls": ["C0010334"], "icd-10": ["Q24.8"], "synonyms": ["Criss-cross atrioventricular relationships", "Superoinferior ventricles", "Twisted atrioventricular connections"]}
A rare X-linked disorder of purine metabolism associated with hyperuricemia and hyperuricosuria, and comprised of two forms: an early-onset severe form characterized by gout, urolithiasis, and neurodevelopmental anomalies and a mild late-onset form with no neurologic involvement. ## Epidemiology Phosphoribosylpyrophosphate (PRPP) synthetase superactivity is is a rare disorder with 30 families described in the literature to date. Males are predominantly affected. ## Clinical description Most individuals (approximately 75%) are affected by the milder form (mild PRPP synthetase superactivity), which manifests in late adolescence or early adulthood, usually with uric acid crystalluria and (kidney and/or bladder) urinary stones, followed by the development of gouty arthritis and eventually renal failure as a result of obstructive uropathy from uric acid crystal deposition. The severe form (severe PRPP synthetase superactivity) usually starts from infancy or early childhood and shares the same clinical features with the mild form but also shows neurologic impairment, mainly sensorineural hearing loss, hypotonia, ataxia, developmental delay, and /or intellectual disability. Heterozygous carrier women are either asymptomatic or display mild metabolic and neurologic symptoms. ## Etiology The disease is due to overactivity of ribose-phosphate pyrophosphokinase 1 (PRS-I), an enzyme that catalyzes the synthesis of PRPP, a cofactor involved in the synthesis of purine and pyrimidine nucleotides. PRS-I overactivity results in the overproduction of purine nucleotides and uric acid (a waste product of purine breakdown). In the severe form, PRS-I overactivity is due to gain-of-function point mutations in the open reading frame of the PRPS1 gene (Xq22.3) encoding PRS-I, that lead to defective allosteric control of PRS-I isoform activity. The exact molecular mechanism leading to the mild form is not yet well understood as no mutations have been found in PRPS1, but it seems to be linked to increased rates of PRPS1 transcription. Loss of function mutations in PRPS1 are linked to Charcot-Marie-Tooth X type 5, X-linked non-syndromic sensorineural deafness and Arts syndrome, together these diseases form part of a spectrum of PRPS1-related disorders. ## Diagnostic methods In both forms, diagnosis is based on blood and urine analysis showing hyperuricemia, hyperuricosuria, and uric acid crystalluria. Diagnosis is confirmed by a PRS enzyme assay showing increased PRS-I activity in fibroblasts, lymphoblasts, and erythrocytes. Molecular genetic testing also confirms the diagnosis in the severe form. ## Differential diagnosis Differential diagnosis includes hypoxanthine-guanine phosphoribosyltransferase deficiency and psychomotor delay due to S-adenosylhomocysteine hydrolase deficiency. ## Antenatal diagnosis Prenatal genetic testing in male fetuses are possible if the mutation has been previously identified in the family. ## Genetic counseling PRPP synthetase superactivity is an X-linked recessive disorder with complete penetrance. An affected mother has a 50% risk of transmitting the mutation to any of her offspring; an affected father transmits the mutation only to his daughters. De novo PRSP1 mutations have also been reported. Heterozygous carrier women are either asymptomatic or display mild metabolic and neurologic symptoms. ## Management and treatment Treatment of uric acid overproduction with xanthine oxidase inhibitors like allopurinol or febuxostat successfully reverses or prevents the consequences of hyperuricemia and hyperuricosuria. A high daily fluid intake is warranted; and, as needed, potassium citrate to alkalinize the urine in order to avoid the formation of kidney stones. A low-purine and low-fructose diet along with regular surveillance of serum urate concentration is essential. For patients with the severe form, regular audiometric and neurologic evaluations are also recommended. ## Prognosis The prognosis is uncertain in the severe form of the disease. Severe gout can lead to renal impairment, if not properly treated. Of note, the interventions have no known beneficial effect on hearing loss or neurologic impairment. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: 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	Phosphoribosylpyrophosphate synthetase superactivity	c1970827	3,495	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=3222	2021-01-23T17:10:10	{"mesh": ["C567064"], "omim": ["300661"], "umls": ["C1970827"], "icd-10": ["E79.8"], "synonyms": ["PRPP synthetase superactivity", "PRPS1 superactivity"]}
A disorder that caused by the Junin virus (JUNV), is an acute viral hemorrhagic disease characterized by initial fever and malaise followed by gastrointestinal symptoms and in some cases hemorrhagic and neurological manifestations. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: 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	Argentine hemorrhagic fever	c0019097	3,496	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=319223	2021-01-23T18:22:49	{"mesh": ["D006478"], "umls": ["C0019097"], "icd-10": ["A96.0"], "synonyms": ["Argentinian hemorrhagic fever", "Junin hemorrhagic fever"]}
Mead and Martin (1963) described a black family in which a mother and 4 children had aplasia of the trochlea of the humerus (the part that articulates with the ulna). Three of the children were by one father and one by another. The deformity was bilaterally symmetrical. The patient held the elbows in flexion and the forearms in pronation. The humerus was shortened. A web of soft tissue stretched across the antecubital space. The elbows could not be extended beyond a right angle but could be flexed to about 30 degrees. Pronation was moderately limited; supination was normal. The biceps brachii appeared to be either hypoplastic or absent. One of the affected children had a cleft palate. Whereas the lateral part of the distal humerus including the capitellum was essentially normal, the medial part had no trochlea or medial epicondyle. The ulna was displaced and did not articulate with the humerus. The authors suggested that this is a 'new' mutation both in the sense of having occurred first in the mother and of not having been described previously. Because of the high illegitimacy rate in blacks, new mutation is difficult to defend. It is also rash to suggest the disorder has never been reported. Certainly this must be a very rare anomaly. Limbs \- Aplasia of trochlea of humerus \- Flexed elbows \- Pronated forearms \- Short humerus \- Webbed antecubital space \- Hypoplastic/absent biceps brachii \- Aplastic humeral medial epicondyle \- Displaced nonarticulating ulna Mouth \- Cleft palate Inheritance \- ? Autosomal dominant ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	TROCHLEA OF THE HUMERUS, APLASIA OF	c1860773	3,497	omim	https://www.omim.org/entry/191000	2019-09-22T16:32:15	{"mesh": ["C566022"], "omim": ["191000"], "orphanet": ["3383"]}
Sitosterolemia is a rare autosomal recessive sterol storage disease characterized by the accumulation of phytosterols in the blood and tissues. Clinical manifestations include xanthomas, arthralgia and premature atherosclerosis. Hematological manifestations include hemolytic anemia with stomatocytosis and macrothrombocytopenia. The disease is caused by homozygous or compound heterozygous mutations in ABCG5 (2p21) and ABCG8 (2p21) genes. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: 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	Sitosterolemia	c0342907	3,498	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=2882	2021-01-23T17:08:39	{"gard": ["7653"], "mesh": ["C537345"], "omim": ["210250", "618666"], "umls": ["C0342907"], "icd-10": ["E78.0"], "synonyms": ["Phytosterolemia"]}
A number sign (#) is used with this entry because familial dysalbuminemic hyperthyroxinemia (FDAH) is caused by heterozygous mutation in the ALB gene (103600) on chromosome 4q13. Description Familial dysalbuminemic hyperthyroxinemia is an autosomal dominant condition characterized by the presence of a variant serum albumin with preferential affinity for thyroxine (T4) in clinically euthyroid individuals. Individuals have consistently elevated total T4 and elevated or normal free T4 values with normal TSH levels. The condition may be confused with hyperthyroidism or thyroid hormone resistance syndromes, prompting repeated unnecessary laboratory testing and possibly even inappropriate treatment (summary by Heufelder et al., 1995). Clinical Features Ruiz et al. (1982) studied 15 euthyroid patients from 8 families who showed elevated serum thyroxine and free-thyroxine index, both due to an abnormal serum albumin that preferentially binds thyroxine. Results of thyrotropin-releasing hormone and thyroid suppressions tests, as well as direct measurements of the free-thyroxine concentration by equilibrium dialysis were normal. Ruiz et al. (1982) noted that some of their patients had mistakenly been thought to be hyperthyroid and that some had received unnecessary treatment. Ruiz et al. (1982) called the disorder 'familial dysalbuminemic hyperthyroxinemia.' Lalloz et al. (1985) subdivided FDH into 3 types, depending on the coexistence of T3 and rT3 excess with hyperthyroxinemia. Seemingly, the binding of drugs by albumin and the release of thyroid hormone to the tissues are not altered in ways that have clinical significance. DeCosimo et al. (1987) presented evidence indicating that familial dysalbuminemic hyperthyroxinemia is unusually frequent in Hispanics of Puerto Rican origin. Yeo et al. (1987) reported the largest kindred with familial dysalbuminemic hyperthyroxinemia thus far reported. Two of the patients had mistakenly been treated for hyperthyroidism. Two women with the disorder were receiving oral contraceptives, which produced an increase in serum thyroxine-binding globulin (314200). Yeo et al. (1987) pointed out that the coexistence of acquired high TBG or significant thyroid malfunction may confound the diagnosis of dysalbuminemic hyperthyroxinemia. Yabu et al. (1987) described a variant form of albumin with a markedly enhanced binding activity for L-3,5,3-prime-triiodothyronine (T3), a somewhat increased activity for thyroxine (T4), and a normal activity for 3,3-prime,5-prime-triiodothyronine (rT3). The presence of the variant albumin was recognized in a patient with Graves disease after successful subtotal thyroidectomy. The findings could be misdiagnosed as T3 toxicosis or peripheral resistance to thyroid hormones. Premachandra et al. (1988) commented that in patients with familial dysalbuminemic hyperthyroxinemia, treatment of hypothyroidism with thyroxine has special considerations because of binding of the drug to the atypical albumin, and raised the possibility that other forms of drug therapy may require custom tailoring. Mapping In a large Amish family of Swiss descent in which 22 members had dysalbuminemic hyperthyroxinemia, Weiss et al. (1995) showed linkage between the disorder and the ALB gene, using as markers a SacI polymorphism in the coding sequence of the ALB gene and the GC gene, located less than 1 cM from the ALB gene (multipoint lod of 5.53 at theta = 0.0). Molecular Genetics In 2 unrelated patients with dysalbuminemic hyperthyroxinemia, Petersen et al. (1994) identified a heterozygous mutation in the ALB gene (R218H; 103600.0041). During the preparation of the manuscript, a third patient with the same mutation was found, suggesting that R218H may be a frequent cause of this disorder. Sunthornthepvarakul et al. (1994) identified the R218H mutation in affected members of 8 unrelated families with dysalbuminemic hyperthyroxinemia. Wada et al. (1997) documented 6 members of a Japanese family with the FDH phenotype. All were heterozygous for a missense mutation in the ALB gene (R218P; 103600.0055). Wada et al. (1997) proposed the existence of a distinct ethnic phenotype of FDH characterized by extremely elevated serum total T4 levels and relatively elevated serum total T3 and rT3 levels in the Japanese. Petitpas et al. (2003) characterized the structure of the interaction between thyroxine and albumin. Using crystallographic analyses, they identified 4 binding sites for thyroxine on albumin distributed in subdomains IIA, IIIA, and IIIB. Mutations of arg218 within subdomain IIA--i.e., arg218 to his (R218H; 103600.0041) and arg218 to pro (R218P; 103600.0055)--greatly enhanced the affinity for thyroxine and caused the elevated serum thyroxine levels associated with FDH. Structural analyses of these 2 mutants showed that this effect arises because substitution of arg218, which contacts the hormone bound in subdomain IIA, produces localized conformational changes to relax steric restrictions on thyroxine binding at this site. Petitpas et al. (2003) also found that, although fatty acid binding competes with thyroxine at all 4 sites, it induces conformational changes that create a fifth hormone-binding site in the cleft between domains I and III, at least 9 angstroms from arg218. These structural observations were consistent with binding data showing that albumin retains a high-affinity site for thyroxine in the presence of excess fatty acid that is insensitive to FDH mutations. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: 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	HYPERTHYROXINEMIA, FAMILIAL DYSALBUMINEMIC	c0342185	3,499	omim	https://www.omim.org/entry/615999	2019-09-22T15:50:15	{"mesh": ["D050010"], "omim": ["615999"], "synonyms": ["Alternative titles", "FDH", "EUTHYROID HYPERTHYROXINEMIA 1"]}

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