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Mental Retardation, X-Linked 99 OMIM

A number sign (#) is used with this entry because of evidence that X-linked mental retardation-99 (MRX99) is caused by mutation in the USP9X gene (300072) on chromosome Xp11. Heterozygous mutation in the USP9X gene can also cause female-restricted X-linked syndromic mental retardation-99 (MRXS99F; 300968). Clinical Features Homan et al. (2014) reported 4 patients from 3 unrelated families with X-linked recessive mental retardation. ... Molecular Genetics In affected male members of 2 unrelated families with X-linked recessive nonsyndromic mental retardation-99, Homan et al. (2014) identified 2 different hemizygous mutations in the USP9X gene (L2093H; 300072.0001 and c.7574delA; 300072.0003).

IQSEC2, DLG3, GDI1, PAK3, ACSL4, ARX, MECP2, RPS6KA3, HCFC1, IL1RAPL1, TSPAN7, FTSJ1, ZNF41, DMD, CNKSR2, MID2, AGTR2, UPF3B, CXorf56, FRMPD4, ALG13, SLC9A7, RAB39B, PTCHD1, ZNF81, MED12, ZNF711, ARHGEF6, SYP, CLCN4, USP27X, USP9X, ABCG2, FRAXE, AFF2, STS, OPHN1, ALAS2, POU3F4, SERPINA4, RPS6KA6, THOC2, ANOS1, FMR1, ELK1
- Mental Retardation, X-Linked 63 OMIM
  
  A number sign (#) is used with this entry because of evidence that X-linked mental retardation-63 can be caused by mutation in the ACSL4 (300157) gene. Clinical Features Raynaud et al. (2000) reported a 4-generation family with nonspecific nonsyndromic X-linked mental retardation. Affected males showed nonprogressive mental retardation ranging from severe to moderate, without seizures, whereas carrier females showed highly variable cognitive capacities, ranging from moderate mental retardation to normal intelligence. Mapping Raynaud et al. (2000) reported a 4-generation family with nonspecific nonsyndromic X-linked mental retardation mapped between DXS990 and DXS1227 (Xq21.33-q27.1) with a maximum lod at theta = 0.0 of 2.14 at DXS1001. Molecular Genetics In the proband of the family reported by Raynaud et al. (2000) as MRX63, Meloni et al. (2002) identified a mutation in the ACSL4 gene (300157.0001).
- Mental Retardation, X-Linked 73 OMIM
  
  Clinical Features Martinez et al. (2001) reported a 4-generation family in which 5 males had mild to moderate nonspecific mental retardation. Brain CT scan performed in 1 patient was normal. Inheritance The pedigree pattern in the family with mental retardation reported by Martinez et al. (2001) was consistent with X-linked inheritance. Mapping By typing of markers throughout the X chromosome in a 4-generation family with nonsyndromic mental retardation, Martinez et al. (2001) mapped the phenotype locus to a 2-cM interval between markers DXS8019 and DXS365 on chromosome Xp22.2. Molecular Genetics Exclusion Studies In a family with nonsyndromic mental retardation mapping to Xp22.2, Martinez et al. (2001) performed direct sequencing of the RSK2 gene (300075) but found no causal mutation. They concluded that another unidentified gene for X-linked mental retardation is located near RSK2.
- Mental Retardation, X-Linked 104 OMIM
  
  A number sign (#) is used with this entry because of evidence that X-linked mental retardation-104 (MRX104) is caused by mutation in the FRMPD4 gene (300838) on chromosome Xp22. Clinical Features Hu et al. (2016) reported a large family (P58) in which 5 males had mild to severe intellectual disability with variable seizures, poor or absent speech, and behavioral problems. They also reported an unrelated patient (L87) who presented at age 17 years with significant developmental delay, absence of speech, and autism spectrum disorder. Piard et al. (2018) reported follow-up of the patients reported by Hu et al. (2016) and identified 4 additional male patients from 2 additional unrelated families. Including the previous report, there were 10 affected males from 4 unrelated families with patients ranging from 4 to 66 years of age.
- Mental Retardation, X-Linked 90 OMIM
  
  A number sign (#) is used with this entry because X-linked mental retardation-90 (MRX90) is caused by mutation in the DLG3 (300189) gene on chromosome Xq13. Clinical Features Tarpey et al. (2004) reported 4 families in each of which at least 2 males had moderate to severe nonsyndromic X-linked mental retardation. Philips et al. (2014) reported 2 unrelated Finnish families with MRX90. Three affected males in 1 family (D172) had delayed psychomotor development with speech delay, mild to moderate intellectual disability, narrow thorax, molar hypoplasia, short and upslanting palpebral fissures, high-arched palate, and hypotonia. Five males in the second family (D301) had delayed motor and language development with moderate to severe mental retardation.
- Mental Retardation, X-Linked 41 OMIM
  
  A number sign (#) is used with this entry because this form of X-linked mental retardation, referred to as MRX41 or MRX48, is caused by mutation in the GDI1 gene (300104) on chromosome Xq28. Clinical Features Hamel et al. (1996) reported a family segregating mild to moderate mental retardation as an X-linked trait (MRX41). Des Portes et al. (1997) reported a large 3-generation family segregating nonspecific X-linked mental retardation (MRX48). The pedigree suggested X-linked semidominant inheritance: moderate to severe mental retardation was found in 7 males and milder intellectual impairment in 2 females, without any specific clinical, radiologic, or biologic features. Bienvenu et al. (1998) reported a large French family (family R) in which all affected males showed moderate to severe mental retardation.
- Mental Retardation, X-Linked 21 OMIM
  
  A number sign (#) is used with this entry because X-linked mental retardation-21 (MRX21) is caused by mutation in the IL1RAPL1 gene (300206) on chromosome Xp21. Description This form of nonsyndromic X-linked mental retardation is characterized by a spectrum of cognitive neurologic impairments or disabilities ranging from moderate mental retardation to high-functioning autism. Males are typically severely affected, but some carrier females may manifest milder deficits (summary by Piton et al., 2008). Clinical Features Kozak et al. (1993) reported a 3-generation Italian family in which 4 male patients had moderate mental retardation without any specific or consistent phenotypic abnormalities. One obligate female carrier had mild retardation and another 2 had normal intelligence, suggesting incomplete penetrance in females.
- Mental Retardation, X-Linked 42 OMIM
  
  Clinical Features Golla et al. (2002) reported a family in which 4 males had mild to moderate nonspecific X-linked mental retardation, with no intellectual impairment in their obligate carrier mothers. Mapping By linkage analysis in a family in which 4 affected males had nonsyndromic mental retardation, Golla et al. (2002) obtained the same multipoint lod score of 2.08 for 2 intervals on the X chromosome: one in the pericentromeric region and the other at Xq26. Since the responsible gene was not characterized, haplotyping was the only means available for carrier and prenatal testing for this form of MRX, which they designated MRX42. Carrier risk estimation using pedigree and haplotype data for 5 females at risk was presented, and the difficulties of prenatal diagnosis given linkage to 2 different regions was discussed.
- Raynaud-Claes Syndrome OMIM
  
  A number sign (#) is used with this entry because of evidence that Raynaud-Claes syndrome (MRXSRC) is caused by mutation in the CLCN4 gene (302910) on chromosome Xp22. Description Raynaud-Claes syndrome is an X-linked intellectual developmental disorder characterized by borderline to severe intellectual disability and impaired language development. Additional features include behavioral problems, psychiatric disorders, seizures (variable forms), progressive ataxia, brain abnormalities, and facial dysmorphisms. Some heterozygous females are unaffected, whereas others are affected with a severity spectrum similar to that seen in males (summary by Palmer et al. (2018)). Clinical Features Raynaud et al. (1996) reported a French family (MRX15) in which 5 males spanning 2 generations had nonsyndromic X-linked mental retardation.
- Mental Retardation, X-Linked 1 OMIM
  
  A number sign (#) is used with this entry because of evidence that X-linked mental retardation-1 (MRX1) is caused by hemizygous or heterozygous mutation in the IQSEC2 gene (300522) on chromosome Xp11. Clinical Features Suthers et al. (1988) reported a large family in which multiple males spanning several generations had nonsyndromic X-linked mental retardation. Two developed psychiatric problems and 1 had infrequent seizures. Carrier females were 'less academically able compared to their non-carrier sibs' (Shoubridge et al., 2010). Shoubridge et al. (2010) provided follow-up of a family with X-linked mental retardation reported by Gedeon et al. (1994) as MRX18. Affected males had moderate to severe intellectual disability, and some had seizures.
- Mental Retardation, X-Linked 9 OMIM
  
  A number sign (#) is used with this entry because this form of nonspecific X-linked mental retardation is caused by mutation in the FTSJ1 gene (300499). Clinical Features Nonspecific X-linked mental retardation (MRX) includes several distinct entities with mental retardation but without additional distinguishing features. Hamel et al. (1999) described a 4-generation family segregating X-linked mental retardation. Affected members had nonprogressive mental retardation noted during childhood, and several demonstrated aggressive behavior. The mental retardation in tested members of the family was moderate to severe; none of the patients was able to read, write, or solve simple arithmetic problems.
- Tonne-Kalscheuer Syndrome OMIM
  
  A number sign (#) is used with this entry because of evidence that Tonne-Kalscheuer syndrome (TOKAS) is caused by hemizygous mutation in the RLIM gene (300379) on chromosome Xq13. Description Tonne-Kalscheuer syndrome (TOKAS) is an X-linked recessive multiple congenital anomaly disorder with 2 main presentations. Most patients exhibit global developmental delay apparent from early infancy, impaired intellectual development, speech delay, behavioral abnormalities, and abnormal gait. Affected individuals also have dysmorphic facial features that evolve with age, anomalies of the hands, feet, and nails, and urogenital abnormalities with hypogenitalism. A subset of more severely affected males develop congenital diaphragmatic hernia in utero, which may result in perinatal or premature death.
- Mental Retardation, X-Linked 30 OMIM
  
  A number sign (#) is used with this entry because this form of nonsyndromic X-linked mental retardation is caused by mutation in the gene encoding p21-activated kinase-3 (PAK3; 300142). Clinical Features Des Portes et al. (1997) reported a French family in which 6 males in 2 generations had nonsyndromic X-linked mental retardation. All affected males had moderate to severe mental retardation without seizures, statural growth deficiencies, or other physical abnormalities. Gedeon et al. (2003) reported an Australian family with nonsyndromic MRX affecting 19 males in 5 generations. Some of the patients had relatively long ears, but no other physical abnormalities.
- Mental Retardation, X-Linked 105 OMIM
  
  A number sign (#) is used with this entry because of evidence that X-linked mental retardation-105 (MRX105) is caused by mutation in the USP27X gene (300975) on chromosome Xp11. Clinical Features Hu et al. (2016) reported 2 unrelated families (D177 and L75) in which a total of 7 males had borderline to moderate intellectual disability, variable poor or absent speech, and behavioral problems. No additional clinical details were provided. Inheritance The transmission pattern of MRX105 in the families reported by Hu et al. (2016) was consistent with X-linked recessive inheritance. Molecular Genetics In 3 affected males from a family (D177) with MRX105, Hu et al. (2016) identified a hemizygous truncating mutation in the USP27X gene (300975.0001). An unrelated male patient (family L75) with MRX105 was found to carry a hemizygous missense mutation in the USP27X gene (Y381H; 300975.0002); 3 others males in this family were affected, but genetic studies were not performed.
- Mental Retardation, X-Linked 88 OMIM
  
  Clinical Features Vervoort et al. (2002) reported 9 male patients with a mutation in the AGTR2 gene who had moderate to severe mental retardation. Five of the patients had seizures and, with the exception of 1 patient, they were not hypertensive. Two patients also showed autistic behavior. Cytogenetics Vervoort et al. (2002) analyzed a de novo balanced translocation 46,X,t(X;7)(q24;q22) in a female patient with moderate mental retardation. This patient had completely skewed X inactivation. They mapped the X-chromosome breakpoint and demonstrated by RT-PCR that the AGTR2 gene was silenced in this patient. History Vervoort et al. (2002) screened affected males from 33 families with possible X-linked MR but no definitive linkage data, and a large cohort of 552 unrelated male patients with MR of unknown cause but negative for the FMR1 expansion.
- Mental Retardation, X-Linked 19 OMIM
  
  A number sign (#) is used with this entry because this form of X-linked mental retardation (MRX19) is caused by mutation in the RPS6KA3 gene (300075). Description X-linked mental retardation-19 (MRX19) is a nonsyndromic form of mild to moderate mental retardation. Carrier females may be mildly affected. Mutation in the RPS6KA3 gene also causes Coffin-Lowry syndrome (CLS; 303600), a mental retardation syndrome with dysmorphic facial features and skeletal anomalies. Some patients with RPS6KA3 mutations have an intermediate phenotype with mental retardation and only mild anomalies reminiscent of CLS. These individuals have mutations resulting in some residual protein function, which likely explains the milder phenotype (summary by Field et al., 2006).
- Mental Retardation, X-Linked 89 OMIM
  
  Clinical Features Shoichet et al. (2003) reported a 7-year-old girl with severe developmental delay who had a de novo balanced chromosome rearrangement, t(X;7)(p11.3;q11.21). At age 2 years, she did not yet walk or speak, and she exhibited clearly delayed psychomotor development. At age 3 years 9 months, occasional convulsions, predominantly localized to the shoulders and upper back, were reported, which led to the diagnosis of myoclonic epilepsy. At age 5 years 6 months, her physical development was in the normal range. She had no dysmorphic features. Screening for inborn errors of metabolism resulted in no indication of amino acidopathies or organic acidurias.
- Mental Retardation, X-Linked 95 OMIM
  
  Clinical Features Molinari et al. (2008) reported an Australian family with nonsyndromic X-linked mental retardation. Of 5 sibs, there was 1 healthy girl, 2 girls with mild mental retardation, and 2 boys with severe mental retardation. The 2 affected males had a similar phenotype with the same degree of handicap. Both were in educational classes for the moderately handicapped and were able to hold a limited conversation; however, neither learned to read or write. Both were on disability pensions as adults. Their mother was described as slow and was found to carry the mutation.
- Mental Retardation, X-Linked 81 OMIM
  
  Clinical Features Annunziata et al. (2003) reported an Italian family in which 9 males in 2 generations had nonspecific moderate to severe mental retardation. Mapping In an Italian family in which 9 males in 2 generations had nonspecific mental retardation, Annunziata et al. (2003) found linkage of the disorder to the pericentromeric region of the X chromosome. Haplotype construction delineated an 8-cM critical region for the locus, which they designated MRX81, at Xp11.2-q12 between DXS1039 and DXS1216. Molecular Genetics Exclusion Studies Annunziata et al. (2003) excluded 2 candidate genes for MRX81: oligophrenin-1 (300127) and ephrin-B1 (300035). INHERITANCE - X-linked recessive NEUROLOGIC Central Nervous System - Mental retardation, moderate to severe MISCELLANEOUS - Based on a report of 9 affected males from one Italian family - No consistent features other than mental retardation - Obligate carrier females have normal intelligence ▲ Close
- Mental Retardation, X-Linked 96 OMIM
  
  A number sign (#) is used with this entry because of evidence that X-linked mental retardation-96 (MRX96) is caused by mutation in the SYP gene (313475). Clinical Features Tarpey et al. (2009) identified 4 families with X-linked mental retardation who had mutations in the SYP gene. In 3 families, all with truncating mutations, mental retardation was mild to moderate and there were no consistent additional features, although epilepsy was noted in some individuals. Female carriers had no manifestations. Molecular Genetics The SYP mutations found by Tarpey et al. (2009) in 4 unrelated families with mental retardation included 3 truncating mutations and a missense mutation (313475.0001-313475.0002). INHERITANCE - X-linked recessive NEUROLOGIC Central Nervous System - Mental retardation, mild to moderate - Epilepsy (in some patients) MOLECULAR BASIS - Caused by mutation in the synaptophysin gene (SYP, 313475.0001 ) ▲ Close
- Chromosome Xp11.22 Duplication Syndrome OMIM
  
  A number sign (#) is used with this entry because of evidence that the phenotype is caused by microduplications within a region of chromosome Xp11.22 (chrX:53.0-54.3 Mb) that involve the HSD17B10 (300256) and HUWE1 (300697) genes. Increased dosage of HUWE1 is believed to be responsible for the phenotype (Froyen et al., 2012). Point mutations in the HSD17B10 and HUWE1 genes have been found to cause syndromic forms of mental retardation, MRXS10 (see 300438) and MRXST (309590), respectively. Clinical Features Gedeon et al. (1994) reported a family in which 6 males spanning 3 generations had moderate mental retardation with slow speech development inherited in an X-linked pattern. No significant common dysmorphic features were noted. Donnelly et al. (1996) reported a 4-generation family with multiple males affected with global retardation that became apparent between ages 2 and 4 years.
- Mental Retardation, X-Linked 45 OMIM
  
  Clinical Features Hamel et al. (1999) described a 6-generation family segregating X-linked mental retardation. Affected members demonstrated nonprogressive mental retardation during childhood and had large, simple ears, relatively large hands, and normal behavior. The propositus also had clinodactyly of the fifth fingers and flat feet; findings in other affected individuals included short stature, high-arched palate, high nasal bridge, full lips, and large testes. The mental retardation in family MRX45 ranged from mild to severe: most affected members showed higher adaptive than intellectual functioning, and most could read, write, and solve simple arithmetic problems. Cytogenetics In a female patient with severe mental retardation and a de novo translocation t(X;9)(p11.23;q34.3), Kleefstra et al. (2004) characterized the breakpoints and found that the translocation disrupted the ZNF81 gene.
- Mental Retardation, X-Linked 77 OMIM
  
  Clinical Features Sismani et al. (2003) reported a Greek family with apparently nonsyndromic X-linked mental retardation. The affected males had moderate to severe mental retardation, severe speech problems, and aggressive behavior. Mapping Sismani et al. (2003) performed linkage analysis on a Greek family with apparently nonsyndromic X-linked mental retardation. Two-point linkage analysis with 26 polymorphic markers spanning the entire X chromosome allowed assignment of the causative gene to a 27-Mb interval in Xq12-q21.3. Molecular Genetics Exclusion Studies In affected members of a family segregating X-linked mental retardation, Sismani et al. (2003) performed DNA analysis of 3 known or candidate MRX genes from the Xq12-q21 region, OPHN1 (300127), ATRX (300032), and RSK4 (300303), and found no mutations.
- Mental Retardation, X-Linked 46 OMIM
  
  Clinical Features Yntema et al. (1998) reported a large Dutch family in which 12 males in 3 generations were affected with nonspecific X-linked mental retardation. Of 9 examined patients, 6 showed moderate mental retardation, and 1 each showed mild, severe, and profound mental retardation. Obligate female carriers were all normal. Mapping Linkage analysis of the family reported by Yntema et al. (1998) yielded a maximum lod score of 5.12 at HPRT between DXS8072 and DXS294 at Xq25-q26. Cytogenetics Kutsche et al. (2000) studied a male patient with severe mental retardation, mildly dysmorphic features, and sensorineural hearing loss who carried an apparently balanced X;21 translocation with breakpoints in Xq26 and 21p11. His unaffected mother carried the same translocation (von Ballestrem et al., 1996).
- Mental Retardation, X-Linked 23 OMIM
  
  Clinical Features Lehrke (1974) described a nonspecific form of X-linked mental retardation in a large kindred designated family 1. The pedigree was updated by Howard-Peebles and Roberts (1984). Affected males had lower verbal IQs than performance IQs. Several of the affected males had performance IQs above 80; however, because of the lower (12.3 points on average) verbal IQs, they were considered retarded. Mapping Gregg et al. (1996) mapped the gene for this form of X-linked mental retardation, designated MRX23, to Xq23-q24 by linkage studies in the large kindred (family 1) of Lehrke (1974). Multipoint linkage analysis gave a maximum lod score of 6.7 between markers DXS1220 and DXS424.
- Mental Retardation, X-Linked 72 OMIM
  
  A number sign (#) is used with this entry because of evidence that X-linked mental retardation-72 (MRX72) is caused by hemizygous mutation in the RAB39B gene (300774) on chromosome Xq28. Mutation in the RAB39B gene can also cause X-linked recessive mental retardation with early-onset Parkinson disease, known as Waisman syndrome (WSMN; 311510). Clinical Features Russo et al. (2000) reported a 3-generation Sardinian family segregating X-linked mental retardation. Three affected individuals had seizures and 1 had features of autism (see 209850). Giannandrea et al. (2010) reported a large family with X-linked mental retardation spanning 2 generations.
- Mental Retardation, X-Linked 58 OMIM
  
  A number sign (#) is used with this entry because nonsyndromic X-linked mental retardation-58 is caused by mutation in the TM4SF2 gene (TSPAN7; 300096) on chromosome Xp11. Clinical Features Holinski-Feder et al. (1999) described an Austrian family with nonsyndromic X-linked mental retardation. The 5 affected males in the family had mild to moderate mental retardation and no consistent dysmorphic features, while obligatory carrier females were normal. Mapping By linkage analysis in an Austrian family with nonsyndromic X-linked mental retardation, Holinski-Feder et al. (1999) mapped the disorder locus to an X pericentromeric location, with flanking markers DXS989 and DXS1111, with a maximum multipoint lod score of 2.09. Molecular Genetics In the affected family reported by Holinski-Feder et al. (1999), Abidi et al. (2002) identified a 2-bp deletion (300096.0003) in the TM4SF2 gene, resulting in a premature stop codon and truncated protein.
- Mental Retardation, X-Linked 14 OMIM
  
  Clinical Features Gendrot et al. (1994) reported a French family in which 9 persons had moderate mental deficiency and poor speech in 3 generations. Some of the patients had facial dysmorphism, epilepsy, and macroorchidism. Mapping By linkage analysis in a family segregating mental retardation, Gendrot et al. (1994) found no recombination between the disease locus, designated MRX14, and 2 loci: DXS255 at Xp11.22 (maximum lod = 3.31 at theta = 0) and PGKP1 at Xq11.2-q12 (maximum lod = 3.08 at theta = 0). In a note added in proof, Gendrot et al. (1994) stated that they had found a recombination with MAOB (309860) at Xp11.3, reducing the linkage interval to Xp11.3-q13.3. GU - Macroorchidism Neuro - Moderate mental deficiency - Poor speech - Epilepsy Facies - Facial dysmorphism Inheritance - X-linked ▲ Close
- Iqsec2 GARD
  
  IQSEC2 is a genetic condition that causes intellectual disability and sometimes other physical, neurological, or psychiatric symptoms. People with this condition can have seizures that are often difficult to control with medications. Other symptoms may include motor and language development delay, regression of learning abilities, autistic-like behavior, characteristic hand movements, and behavioral problems. Physical features may include abnormal head shape (plagiocephaly), very small head (microcephaly), reduced muscle tone (hypotonia), and crossed eyes (strabismus). This condition is caused by mutations in the IQSEC2 gene, which is located on chromosome X .
- Mental Retardation, X-Linked 101 OMIM
  
  A number sign (#) is used with this entry because of evidence that X-linked mental retardation-101 (MRX101) is caused by mutation in the MID2 gene (300204) on chromosome Xq22. One such family has been reported. Clinical Features Geetha et al. (2014) reported a large family from northern India in which 11 males spanning 3 generations had mental retardation. All 6 patients evaluated had global developmental delay. Facial dysmorphism was not prominent, but several patients had long face, prominent ears, and squint or strabismus. Two had seizures. Most also had hyperactivity, often with aggressive outbursts. Inheritance The transmission pattern in the family with MRX101 reported by Geetha et al. (2014) was consistent with X-linked recessive inheritance.
- Mental Retardation, X-Linked 107 OMIM
  
  A number sign (#) is used with this entry because of evidence that X-linked mental retardation-107 (MRX107) is caused by hemi- or heterozygous mutation in the CXORF56 gene (301012) on chromosome Xq24. One such family has been reported. Clinical Features Verkerk et al. (2018) reported a large 3-generation Dutch family in which 5 males and 1 female had mild to moderate intellectual disability. The patients had delayed development but were able to attend special schools, and some were able to work in a sheltered environment. Two males had significant behavioral problems, such as pervasive developmental disorder, attention disorder, hyperactivity, and transgressive behavior. The patients had variable dysmorphic facial features, including long, narrow face, prominent chin, upward slanting palpebral fissures, flat philtrum, narrow upper lip, and large ears with prominent cruxes.
- Mental Retardation, X-Linked 92 OMIM
  
  Clinical Features Lugtenberg et al. (2006) studied a family in which 6 males in 3 generations had moderate to severe nonsyndromic mental retardation in an X-linked pattern of inheritance (XLMR). The 17-year-old proband had an IQ of 45. His mother had normal intelligence. He was the second son of unrelated parents and had 1 affected brother, 3 healthy sisters, and 1 carrier sister with borderline intelligence. Mapping The family reported by Lugtenberg et al. (2006) segregating X-linked mental retardation had previously been studied (family T40) by Raynaud et al. (2000), who found evidence of linkage of mental retardation to Xp11.3. History In a family in which 6 males in 3 generations had moderate to severe nonsyndromic mental retardation in a pattern consistent with X-linked recessive inheritance, Lugtenberg et al. (2006) identified a 352G-T transversion in exon 6 of ZNF674 cDNA, predicted to result in a glu118-to-ter (E118X; 300573.0001) truncated protein containing the Kruppel-associated box domains but lacking the zinc finger domains, which are crucial for DNA binding.
- Mental Retardation, X-Linked 97 OMIM
  
  A number sign (#) is used with this entry because of evidence that this form of nonsyndromic X-linked mental retardation (MRX97) is caused by hemizygous mutation in the ZNF711 gene (314990) on chromosome Xq21. Clinical Features Yntema et al. (1999) reported a family (MRX65) in which 6 males in 3 generations had mild to moderate intellectual disability with speech delay. Four patients were obese. Van der Werf et al. (2017) provided follow-up of this family, noting that dysmorphic features included a broad face and prominent forehead. Van der Werf et al. (2017) reported another 4-generation family in which 5 males had mild to moderate intellectual disability, most often with motor delay and poor speech. Two had autistic features. Variable dysmorphic features included long face, synophrys, and relatively large ears.
- Mental Retardation, X-Linked 82 OMIM
  
  Clinical Features Martinez et al. (2004) described a Basque family in which 5 males in 4 sibships in 2 generations had nonsyndromic mental retardation. Mapping In a Basque family with nonsyndromic mental retardation, Martinez et al. (2004) found linkage to Xq24-q25 with a maximum lod score of 2.4. Haplotype studies and multipoint linkage analysis suggested a localization of the MRX82 locus to an interval of 7.6 Mb defined by markers DXS6805 and DXS7346, in Xq24 and Xq25, respectively. The linked interval contained the gene encoding glutamate receptor-3 (GRIA3; 305915), but mutation analysis showed no pathologic changes. INHERITANCE - X-linked recessive SKELETAL Spine - Kyphosis - Scoliosis NEUROLOGIC Central Nervous System - Mental retardation, mild to profound - Seizures (patient A) - Abnormal EEG (patient B) - Postnatal hypotonia (patient A) - Normal cerebral CT scan (patient A) Behavioral Psychiatric Manifestations - Autistic behavior (patient A) MISCELLANEOUS - Based on a report of an extended ethnically Basque family ▲ Close
- Mental Retardation, X-Linked 84 OMIM
  
  Clinical Features Zhang et al. (2004) reported a Chinese family in which 3 males in 3 generations had nonspecific X-linked mental retardation. The obligate carrier females were not affected. Mapping By 2-point linkage analysis, Zhang et al. (2004) demonstrated linkage of nonspecific mental retardation in a Chinese family to several markers located at Xq22.2, with a maximum lod score of 2.41 at theta = 0.0 for 2 adjacent markers (DXS1191 and DXS1230). Recombination events were observed with flanking markers DXS8080 and DXS456, located at Xp11.3 and Xq22.3, respectively, and a region of approximately 22.3 cM was defined. The localized region observed in this family overlapped with 29 other MRX loci previously reported in Xp11.3-q22.3. INHERITANCE - X-linked recessive GROWTH Height - Short stature HEAD & NECK Face - Broad forehead NEUROLOGIC Central Nervous System - Mental retardation, mild to moderate MISCELLANEOUS - No characteristic pattern of anomalies ▲ Close
- Mental Retardation, X-Linked 2 OMIM
  
  Clinical Features Proops et al. (1983) reported a Japanese family (family F) living in Hawaii with mental retardation in 3 generations. Affected males were mildly or moderately retarded, while a number of heterozygous females were mildly retarded. The affected males were relatively short with a large head, highly arched palate, square face, prominent ears, and large testicular volumes. Their speech was limited and characterized by repetitive phrases or inflections. Affected males and females were described as having a pleasant demeanor.
- Mental Retardation, X-Linked, With Or Without Seizures, Arx-Related OMIM
  
  A number sign (#) is used with this entry because this form of nonspecific X-linked mental retardation is caused by mutation in the ARX gene (300382) on chromosome Xp21. Description ARX-related mental retardation is a form of nonsyndromic X-linked mental retardation. It is part of a phenotypic spectrum of disorders caused by mutation in the ARX gene comprising a nearly continuous series of developmental disorders ranging from lissencephaly (LISX2; 300215) to Proud syndrome (300004) to infantile spasms without brain malformations (EIEE1; 308350) to Partington syndrome (309510) (Kato et al., 2004; Wallerstein et al., 2008). Clinical Features Hamel et al. (1999) described a two 4-generation families (MRX43 and MRX52) segregating X-linked mental retardation. Affected members in family MRX43 had moderate to profound nonprogressive mental retardation recognized in early childhood.
- Mental Retardation, X-Linked 53 OMIM
  
  Clinical Features Ahmad et al. (2001) described a large Pakistani family with X-linked nonspecific mental retardation. Mapping By linkage analysis in a Pakistani family segregating nonsyndromic mental retardation, Ahmad et al. (2001) identified a novel disease locus, MRX53, located in a critical region spanning approximately 15 cM between DXS1210 and DXS1047 on Xq22.2-q26. A lod score of 3.34 at no recombination was obtained with markers DXS1072 and DXS8081. INHERITANCE - X-linked recessive NEUROLOGIC Central Nervous System - Mental retardation (IQ between 45-50) - Normal gross motor development MISCELLANEOUS - Based on a report of 8 affected males in one Pakistani family ▲ Close
- Mental Retardation, X-Linked 50 OMIM
  
  Clinical Features Claes et al. (1997) added 2 families to the growing list of nonspecific X-linked mental retardation (XLMR) families in which the disease gene could be mapped to a specific site on the X chromosome. The first family reported was designated MRX49 (300114). The second of these families, designated MRX50, contained 4 males in 2 generations showing moderate mental retardation. Mapping Linkage analysis in the MRX50 family by Claes et al. (1997) showed location of the locus at Xp11.3-p11.21 in the pericentromeric part of the short arm of the X chromosome, overlapping with a large number of other MRX gene regions: MRX1 (309530), MRX5, MRX7, MRX8, MRX9 (309549), MRX10, MRX11, MRX12 (300957), MRX13, MRX14 (300062), MRX15, MRX18, MRX22, MRX26, MRX31, and MRX38 (see 300419). Gedeon et al. (1996) hypothesized that all of the MRX assignments clustered on the pericentromeric part of Xp could be accounted for by 2 gene locations, namely the MRX1 and the MRX10 locations. Some of these families with pericentromeric gene locations show additional characteristic abnormalities and some of them show manifestations of disease in heterozygous carriers.
- Mental Retardation, X-Linked 20 OMIM
  
  Description Impaired mental functioning occurs as an isolated feature or as part of many syndromes listed in the X-linked catalog. Mental retardation that is not associated with other distinguishing features is referred to as 'nonspecific.' The Human Gene Mapping Nomenclature Committee (Mulley et al., 1992) proposed to designate each newly reported apparently unique X-linked mental retardation (MRX) family with gene symbols (e.g., MRX1, MRX2) if a minimal lod score of 2.0 was demonstrated between the MR locus and 1 or more X chromosome markers. Mapping Lazzarini et al. (1995) reported a family with MRX20. Fragile X syndrome was excluded cytogenetically and by absence of linkage to the Xq27.3 region. On the other hand, linkage studies using short tandem repeat polymorphism (STRP) markers indicated that the mutation is at a locus in the centromeric region of the X chromosome.
Deafness, Autosomal Recessive 99 OMIM

A number sign (#) is used with this entry because of evidence that autosomal recessive deafness-99 (DFNB99) is caused by homozygous mutation in the TMEM132E gene (616178) on chromosome 17q12.
Vici Syndrome Wikipedia

These include [ citation needed ] Agenesis of the corpus callosum (80–99% patients) Hypopigmentation of the eyes and hair (80–99% patients) Cardiomyopathy (80–99% patients) Combined immunodeficiency (80–99% patients) Muscular hypotonia (80–99% patients) Abnormality of retinal pigmentation (80–99% patients) Recurrent chest infections (80–99% patients) Abnormal EEG (80–99% patients) Intellectual disability (80–99% patients) Cataracts (75%) Seizures (65%) Renal abnormalities (15%) Infections of the gastrointestinal and urinary tracts are common.

EPG5, RAB7A, RAB7B, EPGN
- Vici Syndrome MedlinePlus
  
  Vici syndrome is a severe disorder that begins early in life and affects many body systems. It is characterized by abnormalities of the brain, immune system, heart, skin, and eyes. Other organs and tissues are less commonly affected. A characteristic feature of Vici syndrome is a brain abnormality called agenesis of the corpus callosum, in which the tissue that connects the left and right halves of the brain (the corpus callosum ) fails to form normally during the early stages of development before birth. Other brain abnormalities can occur in Vici syndrome, including underdevelopment of a region of the brain known as the pons (pontine hypoplasia) and reduced myelin , which is a fatty substance that covers and protects nerve cells. In addition to problems with brain development, breakdown (degeneration) of brain tissue may occur over time, resulting in an unusually small head size (microcephaly ).
- Vici Syndrome GARD
  
  Vici syndrome is a multisystem disorder characterized by agenesis (failure to develop) of the corpus callosum, cataracts , hypopigmentation of the eyes and hair, cardiomyopathy, and combined immunodeficiency. Hearing loss, seizures, and delayed motor development have also been reported. Swallowing and feeding difficulties early on may result in a failure to thrive. Recurrent infections of the respiratory, gastrointestinal, and urinary tracts are common. Vici syndrome is caused by mutations in the EPG5 gene and is inherited in an autosomal recessive manner.
- Vici Syndrome OMIM
  
  A number sign (#) is used with this entry because Vici syndrome (VICIS) is caused by homozygous or compound heterozygous mutation in the EPG5 gene (615068) on chromosome 18q. Description Vici syndrome is a rare congenital multisystem disorder characterized by agenesis of the corpus callosum (ACC), cataracts, pigmentary defects, progressive cardiomyopathy, and variable immunodeficiency. Affected individuals also have profound psychomotor retardation and hypotonia due to a myopathy (summary by Finocchi et al., 2012). Clinical Features Dionisi Vici et al. (1988) described 2 brothers with a malformation syndrome consisting of agenesis of the corpus callosum, cutaneous hypopigmentation, bilateral cataract, cleft lip and palate, and combined immunodeficiency. The sibs suffered from severe psychomotor retardation, seizures, recurrent severe respiratory infections, and chronic mucocutaneous candidiasis.
- Vici Syndrome Orphanet
  
  Vici syndrome is a very rare and severe congenital multisystem disorder characterized by the principal features of agenesis of the corpus callosum, cataracts, oculocutaneous hypopigmentation, cardiomyopathy and combined immunodeficiency. Epidemiology Prevalence is unknown. Only 20 cases have been reported to date. Clinical description Vici syndrome is usually diagnosed in the first years of life. The phenotype is variable but the principal diagnostic features are almost always present at onset or evolve over time. Swallowing and feeding difficulties may be noted early on and may lead to failure to thrive.
Mental Retardation, X-Linked 99, Syndromic, Female-Restricted OMIM

A number sign (#) is used with this entry because of evidence that female-restricted X-linked syndromic mental retardation-99 (MRXS99F) is caused by heterozygous mutation in the USP9X gene (300072) on chromosome Xp11. ... Description Female-restricted X-linked syndromic mental retardation-99 is an X-linked dominant neurodevelopmental disorder characterized by delayed psychomotor development and mild to moderate intellectual disability.

USP9X
- X-Linked Female Restricted Facial Dysmorphism-Short Stature-Choanal Atresia-Intellectual Disability Orphanet
  
  A rare genetic multiple congenital anomalies/dysmorphic syndrome characterized by global developmental delay, intellectual disability, and dysmorphic facial features (such as facial asymmetry, prominent forehead, short palpebral fissures, low nasal bridge, smooth and long philtrum, thin upper lip, and low-set, posteriorly rotated, dysplastic ears), exclusively affecting females. Additional reported manifestations include short stature, choanal atresia, scoliosis, congenital ocular, dental, cardiac, and urogenital anomalies, as well as hypotonia, seizures, and structural brain abnormalities, among others.
Iris Pattern OMIM

Inheritance From a study of 100 monozygotic twin pairs, 99 dizygotic twin pairs, and 99 unrelated randomly paired age-matched German subjects, Larsson et al. (2003) concluded that variations in characteristic patterns of the human iris are under strong genetic influence.
Ectodermal Dysplasia, Hypohidrotic, With Hypothyroidism And Agenesis Of The Corpus Callosum OMIM

A thyroid scintigram with technetium 99 showed absence of normal thyroid gland tissue and the presence of an ectopic goiter at the base of the tongue. ... Radiology - Absent normal thyroid and ectopic goiter on technetium 99 thyroid scintigram Neuro - Severe mental retardation - Agenesis of corpus callosum Inheritance - Autosomal recessive vs.
- Ectodermal Dysplasia-Intellectual Disability-Central Nervous System Malformation Syndrome Orphanet
  
  Ectodermal dysplasia-intellectual disability-central nervous system malformation syndrome is a rare, multiple developmental anomalies syndrome characterized by the triad of ectodermal dysplasia (mostly hypohidrotic with dry skin and reduced sweating and sparse, fair scalp hair, eyebrows and eyelashes), severe intellectual disability and variable central nervous system anomalies (cerebellar hypoplasia, dilatation of ventricles, corpus callosum agenesis, Dandy-Walker malformation). Distinct craniofacial dysmorphism with macrocephaly, frontal bossing, midfacial hypoplasia and high arched or cleft palate, as well as cryptorchidism, feeding difficulties and hypotonia, are associated. There have been no further descriptions in the literature since 1998.
Pachyonychia Congenita GeneReviews

Molecular Genetic Testing Used in Pachyonychia Congenita (PC) View in own window Gene 1 Proportion of PC Attributed to Pathogenic Variants in Gene 2, 3 Proportion of Pathogenic Variants 4 Detectable by Method Sequence analysis 5 Gene-targeted deletion/duplication analysis 6 KRT6A 304/774 (39%) >99% Unknown 7 KRT6B 70/774 (9%) >99% Unknown 7 KRT6C 22/774 (3%) >99% Unknown 7 KRT16 247/774 (32%) >99% Unknown 7 KRT17 8 130/774 (17%) >99% Unknown 7 1. ... International Pachyonychia Congenita Research Registry (IPCRR) Data Summary (as of 10 May 2017) View in own window Gene in Which Pathogenic Variants Were Confirmed KRT6A KRT6B KRT6C KRT16 KRT17 TOTAL Number evaluated for finding 1 304 71 22 247 130 774 Toenails thickened 10 toenails 286 (94%) 26 (37%) 0 (00%) 99 (40%) 100 (77%) 511 (66%) 7-9 toenails 9 (03%) 14 (20%) 0 (00%) 52 (21%) 11 (08%) 86 (11%) 4-6 toenails 2 (01%) 21 (30%) 3 (14%) 63 (26%) 7 (05%) 96 (12%) 1-3 toenails 4 (01%) 9 (13%) 10 (45%) 44 (18%) 8 (06%) 75 (10%) Total w/toenails thickened 301 (99%) 70 (99%) 13 (59%) 238 (96%) 126 (97%) 748 (97%) Age at onset Birth - <1 yr 264 (88%) 10 (14%) 1 (08%) 45 (19%) 92 (73%) 412 (54%) 1-4 yrs 33 (11%) 19 (27%) 6 (46%) 78 (33%) 24 (19%) 160 (21%) 5-14 yrs 4 (01%) 34 (49%) 4 (31%) 74 (31%) 10 (08%) 126 (17%) ≥15 yrs 0 (00%) 7 (10%) 2 (15%) 43 (18%) 1 (01%) 53 (07%) Fingernails thickened 10 fingernails 271 (89%) 4 (06%) 0 (00%) 73 (30%) 62 (48%) 410 (53%) 7-9 fingernails 10 (03%) 4 (06%) 0 (00%) 11 (04%) 13 (10%) 38 (05%) 4-6 fingernails 14 (05%) 17 (24%) 0 (00%) 30 (12%) 28 (22%) 89 (11%) 1-3 fingernails 6 (02%) 7 (10%) 0 (00%) 28 (11%) 9 (07%) 50 (06%) Total w/fingernails thickened 301 (99%) 32 (45%) 0 (00%) 142 (57%) 112 (86%) 587 (76%) Age at onset Birth - <1 yr 267 (89%) 4 (13%) 0 (00%) 33 (23%) 85 (76%) 389 (66%) 1-4 yrs 30 (10%) 8 (25%) 0 (00%) 42 (30%) 19 (17%) 99 (17%) 5-14 yrs 3 (01%) 11 (34%) 0 (00%) 34 (24%) 6 (05%) 54 (09%) ≥15 yrs 1 (00%) 10 (31%) 0 (00%) 34 (24%) 3 (03%) 48 (08%) Plantar keratoderma Always (never completely goes away) 254 (84%) 67 (94%) 19 (86%) 240 (97%) 86 (66%) 666 (86%) Sometimes (feet clear up completely at times) 7 (02%) 1 (01%) 0 (00%) 1 (00%) 14 (11%) 23 (03%) Seldom (feet usually clear of symptoms) 5 (02%) 0 (00%) 0 (00%) 0 (00%) 4 (03%) 9 (01%) Total w/plantar keratoderma 266 (88%) 68 (96%) 19 (86%) 241 (98%) 104 (80%) 698 (90%) Age at onset Birth - <1 yr 39 (15%) 2 (03%) 1 (05%) 23 (10%) 12 (12%) 77 (11%) 1-4 yrs 152 (57%) 23 (34%) 9 (47%) 130 (54%) 35 (34%) 349 (50%) 5-14 yrs 70 (26%) 42 (62%) 9 (47%) 82 (34%) 43 (41%) 246 (35%) ≥15 yrs 5 (02%) 1 (01%) 0 (00%) 8 (03%) 15 (14%) 29 (04%) Plantar pain w/plantar keratoderma 2 Often require medication for pain 65 (24%) 12 (18%) 5 (26%) 74 (31%) 19 (18%) 175 (25%) Very painful, but do not use medication 114 (43%) 32 (47%) 11 (58%) 111 (46%) 34 (33%) 302 (43%) Somewhat painful 77 (29%) 24 (35%) 3 (16%) 50 (21%) 36 (35%) 190 (27%) Total w/plantar keratoderma/pain 256 (96%) 68 (100%) 19 (100%) 235 (98%) 89 (86%) 667 (96%) Palmar keratoderma Always (never completely goes away) 86 (28%) 11 (15%) 2 (09%) 148 (60%) 21 (16%) 268 (35%) Sometimes (hands clear up completely at times) 32 (11%) 7 (10%) 1 (05%) 15 (06%) 22 (17%) 77 (10%) Seldom (hands usually clear of symptoms) 49 (16%) 13 (18%) 3 (14%) 22 (09%) 27 (21%) 114 (15%) Total w/palmar keratoderma 167 (55%) 31 (44%) 6 (27%) 185 (75%) 70 (54%) 459 (59%) Additional findings Oral leukokeratosis 269 (88%) 18 (25%) 4 (18%) 88 (36%) 34 (26%) 413 (53%) Cysts 188 (62%) 49 (69%) 4 (18%) 64 (26%) 121 (93%) 426 (55%) Follicular hyperkeratosis 162 (53%) 30 (42%) 0 (00%) 30 (12%) 86 (66%) 308 (40%) Natal or prenatal teeth 12 (04%) 0 (00%) 0 (00%) 0 (00%) 99 (76%) 111 (14%) 1.

KRT17, KRT16, KRT6A, KRT6B, KRT10, KRT6C, KRT80, SLURP1, PNOC, NFE2L2, AQP5, FLG, KRT1, KLKB1, GJB2, GABPA, MTOR, KRT9
- Pachyonychia Congenita 4 OMIM
  
  A number sign (#) is used with this entry because pachyonychia congenita-4 (PC4) is caused by heterozygous mutation in the KRT6B gene (148042) on chromosome 12q13. Description Pachyonychia congenita (PC) is an autosomal dominant genodermatosis with the main clinical features of hypertrophic nail dystrophy, painful and highly debilitating plantar keratoderma, oral leukokeratosis, and a variety of epidermal cysts. Although the condition had previously been subdivided clinically into Jadassohn-Lewandowsky PC type 1 and Jackson-Lawler PC type 2, patients with PC were later found to have a mixed constellation of both types, leading to a classification of PC based on genotype (summary by Sybert, 2010; Eliason et al., 2012; McLean et al., 2011). For a discussion of genetic heterogeneity of pachyonychia congenita, see 167200. Historical Classification of Pachyonychia Congenita Gorlin et al. (1976) suggested that 2 distinct syndromes are subsumed under the designation pachyonychia congenita.
- Pachyonychia Congenita Orphanet
  
  Pachyonychia congenita (PC) is a rare genodermatosis predominantly featuring painful palmoplantar keratoderma, thickened nails, cysts and whitish oral mucosa. Epidemiology The prevalence is not known but approximately 1000 patients have been registered to date worldwide. Clinical description PC presents clinically as a spectrum of conditions. PC onset is variable with most cases manifesting soon after birth, others becoming clinically apparent only in late childhood and rarely in adulthood. The first signs of the disease usually are thickened nails or neonatal teeth.
- Pachyonychia Congenita GARD
  
  Pachyonychia congenita (PC) is a rare inherited condition that primarily affects the nails and skin. The fingernails and toenails may be thickened and abnormally shaped . Affected people can also develop painful calluses and blisters on the soles of their feet and less frequently on the palms of their hands ( palmoplantar keratoderma ). Additional features include white patches on the tongue and inside of the mouth (leukokeratosis); bumps around the elbows, knees, and waistline (follicular hyperkeratosis); and cysts of various types including steatocystoma. Features may vary among affected people depending on their specific mutation.
- Pachyonychia Congenita, Autosomal Recessive OMIM
  
  For a phenotypic description and a discussion of genetic heterogeneity of pachyonychia congenita, see 167200. Inheritance Chong-Hai and Rajagopalan (1977) suggested autosomal recessive inheritance of pachyonychia congenita in a 4-year-old Malaysian girl with first-cousin parents, although they recognized new dominant mutation as a possibility. See also Sivasundram et al. (1985). INHERITANCE - Autosomal recessive HEAD & NECK Mouth - No oral leukoplakia SKIN, NAILS, & HAIR Skin - Horny papules (face, leg, buttocks) - No palmoplantar hyperkeratosis - No hyperhidrosis Nails - Episodic inflammatory swelling of nail bed - Recurrent shedding of nails - Hard,thickened nails (pachyonychia) - Subungual hyperkeratosis MISCELLANEOUS - See also pachyonychia congenita, type 3 (PC1, 167200 ) ▲ Close
- Pachyonychia Congenita 3 OMIM
  
  A number sign (#) is used with this entry because pachyonychia congenita-3 (PC3) is caused by heterozygous mutation in the keratin-6a gene (KRT6A; 148041) on chromosome 12q13. Description Pachyonychia congenita (PC) is an autosomal dominant genodermatosis with the main clinical features of hypertrophic nail dystrophy, painful and highly debilitating plantar keratoderma, oral leukokeratosis, and a variety of epidermal cysts. Although the condition had previously been subdivided clinically into Jadassohn-Lewandowsky PC type 1 and Jackson-Lawler PC type 2, patients with PC were later found to have a mixed constellation of both types, leading to a classification of PC based on genotype (summary by Sybert, 2010; Eliason et al., 2012; McLean et al., 2011). For a discussion of genetic heterogeneity of pachyonychia congenita, see 167200. Historical Classification of Pachyonychia Congenita Gorlin et al. (1976) suggested that 2 distinct syndromes are subsumed under the designation pachyonychia congenita.
- Pachyonychia Congenita 2 OMIM
  
  A number sign (#) is used with this entry because of evidence that pachyonychia congenita-2 (PC2) is caused by heterozygous mutation in the KRT17 gene (148069) on chromosome 17q21. Description Pachyonychia congenita (PC) is an autosomal dominant genodermatosis with the main clinical features of hypertrophic nail dystrophy, painful and highly debilitating plantar keratoderma, oral leukokeratosis, and a variety of epidermal cysts. Although the condition had previously been subdivided clinically into Jadassohn-Lewandowsky PC type 1 and Jackson-Lawler PC type 2, patients with PC were later found to have a mixed constellation of both types, leading to a classification of PC based on genotype (summary by Sybert, 2010; Eliason et al., 2012; McLean et al., 2011). For a discussion of genetic heterogeneity of pachyonychia congenita, see 167200. Historical Classification of Pachyonychia Congenita Gorlin et al. (1976) suggested that 2 distinct syndromes are subsumed under the designation pachyonychia congenita.
- Pachyonychia Congenita 1 OMIM
  
  A number sign (#) is used with this entry because pachyonychia congenita-1 (PC1) is caused by heterozygous mutation in the keratin-16 gene (KRT16; 148067) on chromosome 17q21. Description Pachyonychia congenita (PC) is an autosomal dominant genodermatosis with the main clinical features of hypertrophic nail dystrophy, painful and highly debilitating plantar keratoderma, oral leukokeratosis, and a variety of epidermal cysts. Although the condition had previously been subdivided clinically into Jadassohn-Lewandowsky PC type 1 and Jackson-Lawler PC type 2, patients with PC were later found to have a mixed constellation of both types, leading to a classification of PC based on genotype (summary by Sybert, 2010; Eliason et al., 2012; McLean et al., 2011). Historical Classification of Pachyonychia Congenita Gorlin et al. (1976) suggested that 2 distinct syndromes are subsumed under the designation pachyonychia congenita. PC type 1, the Jadassohn-Lewandowsky type, shows oral leukokeratosis.
Mecp2 Disorders GeneReviews

MECP2 disorders are inherited in an X-linked manner. More than 99% are simplex cases (i.e., a single occurrence in a family), resulting from a de novo pathogenic variant or possibly from inheritance of the pathogenic variant from a parent who has germline mosaicism. ... Features of MECP2 Disorders in Females View in own window Phenotype Feature % of Persons with Feature MECP2 classic Rett syndrome Regression followed by recovery or stabilization 99% Deceleration of head growth 80% Gait abnormalities 99% Seizures 60%-80% Hand stereotypies & loss of purposeful hand skills 100% 1 Absence of speech; high-pitched crying 99% Cold extremities 99% Irregular breathing 99% Variant Rett syndrome Regression followed by recovery or stabilization 99% Gait abnormalities 80%-99% Sleep disturbences 80%-99% seizures 6%-80% Hand stereotypies & loss of purposeful hand skills 97.3% Breathing irregularities 80%-99% Agitation 80%-99% Gold et al [2018], Einspieler & Marschik [2019], Stallworth et al [2019] 1.
Meckel Diverticulum OMIM

The proband, born in 1980, complained of recurrent abdominal pain that was incompletely relieved by aluminum hydroxide and magnesium hydroxide. Although scans using technetium 99 were negative, surgery was undertaken because of the family history.

AGTR2, FANCL, ZNF41, USP9X, ARHGEF6, FRMPD4, RBM8A, MED12, MAD2L2, MID2, IL1RAPL1, CNKSR2, IQSEC2, FTSJ1, UBE2T, RFWD3, XRCC2, FANCI, FANCM, CXorf56, UPF3B, PALB2, ALG13, BRIP1, SLX4, SLC9A7, RAB39B, PTCHD1, ARX, ZNF81, ZNF711, TSPAN7, BRCA1, SYP, BRCA2, CLCN4, DLG3, DMD, ERCC4, FANCA, FANCC, FANCD2, FANCE, ACSL4, FANCB, FANCF, FANCG, GPC4, FGFR1, FOXF1, GDI1, GPC3, HCFC1, MECP2, PAK3, RAD51, RAD51C, RPS6KA3, USP27X, GAST, EPHB1, ELK3, SLC6A2
- Meckel's Diverticulum Wikipedia
  
  Journal of the Royal Society of Medicine . 99 (10): 501–505. doi : 10.1258/jrsm.99.10.501 .
Periodic Fever, Aphthous Stomatitis, Pharyngitis And Adenitis Wikipedia

The Journal of Pediatrics . 135 (1): 15–21. doi : 10.1016/S0022-3476(99)70321-5 . ISSN 0022-3476 . PMID 10393598 . ^ a b Padeh, Shai; et al. (1999). ... Mosby, Inc. 135 (1): 98–101. doi : 10.1016/S0022-3476(99)70335-5 . PMID 10393612 . Archived from the original on 2013-02-22 . ... Mosby, Inc. 135 (1): 1–5. doi : 10.1016/S0022-3476(99)70316-1 . PMID 10393593 . Archived from the original on 2008-05-12 .

MEFV, COL11A1, COL2A1, CRP, IL1B, SPAG7, CARD8, NLRP3
- Pfapa Syndrome Orphanet
  
  PFAPA (Periodic fever - aphthous stomatitis- pharyngitis - adenopathy) syndrome is an auto inflammatory syndrome characterized by recurrent febrile episodes associated with aphthous stomatitis, pharyngitis and cervical adenitis. Epidemiology Prevalence of PFAPA is unknown, over 500 cases have been reported and patients are predominantly male (>60%). Clinical description PFAPA usually presents during early childhood (<5 years old) with recurrent episodes of fever (>39°C) lasting 3-7 days, during which children appear very ill. Aphthous stomatitis is characterized by relatively painless small, round and shallow lesions on the tongue and oral mucosa (70% of cases) that recover completely in 10-14 days. Most patients present with tonsillitis, occasionally with white exudates (mimicking streptococci infection), and a general pharyngitis (75% of cases) with diffuse hyperemia of the entire palate.
Wilson–mikity Syndrome Wikipedia

"A new form of respiratory disease in premature infants". Am J Dis Child . 99 (4): 489–99. doi : 10.1001/archpedi.1960.02070030491011 .
Pituitary Stalk Interruption Syndrome Wikipedia

Some PSIS-affected individuals may also present with adrenal hypoplasia (5-29%), diabetes insipidus (5-29%), primary amenorrhea (5-29%), hypothyroidism (30-79%), failure to thrive (80-99%), septooptic dysplasia (5-29%), and Fanconi anaemia . PSIS may be isolated, or, commonly, present with extra-pituitary malformations. [1] [2] [3] PSIS features in neonates (may) include: [1] [2] [3] hypoglycaemia (30-79%) (prolonged) jaundice micropenis (30-79%) cryptorchidism (5-29%) delayed intellectual development death in infancy (5-29%) congenital abnormalities PSIS features in later childhood (may) include: [1] [2] [3] short stature (80-99%) seizures (5-29%) hypotension delayed intellectual development delayed puberty (30-79%) PSIS is associated with a higher frequency of breech presentation , Caeserian section , and/or low Apgar score , though these are likely consequences rather than causes. [3] Cause [ edit ] The cause of the condition is as of yet unknown.

GPR161, ROBO1, HESX1, PROKR2, CDON, WDR11, LHX4, POMC, GH1, OTX2, SOX3, GLI2, SIX3, DCHS1, KIF14, CCDC88C
- Pickardt Syndrome Wikipedia
  
  Rare form of tertiary hypothyroidism Pickardt–Fahlbusch syndrome Other names Pickardt's syndrome or Pickardt–Fahlbusch syndrome An interupption of the hypophyseal portal system causes Pickardt's syndrome Specialty Endocrinology Pickardt syndrome denotes a rare form of tertiary hypothyroidism that is caused by interruption of the portal veins connecting hypothalamus and pituitary . It was characterized in 1972 and 1973 by Renate Pickardt and Rudolf Fahlbusch . [1] [2] Contents 1 Cause 1.1 Endocrine consequences 2 Diagnosis 3 Treatment 4 References 5 External links Cause [ edit ] Interruption of the portal system may be caused by tumors compressing the infundibulum. Other causes for Pickardt's syndrome are inflammatory disorders and traumatic brain injury . An inborn variant of Pickardt's syndrome that is associated with certain mutations ( HESX1 [3] or LHX4 ) is referred to as pituitary stalk interruption syndrome (PSIS) . Endocrine consequences [ edit ] Typical manifestations of Pickardt–Fahlbusch syndrome are hypothyroidism with reduced TSH values and functional hyperprolactinemia (which is caused by disinhibition of prolactin release).
- Pituitary Stalk Interruption Syndrome Orphanet
  
  Pituitary stalk interruption syndrome (PSIS) is a congenital abnormality of the pituitary that is responsible for pituitary deficiency and is usually characterized by the triad of a very thin or interrupted pituitary stalk, an ectopic (or absent) posterior pituitary (EPP) and hypoplasia or aplasia of the anterior pituitary visible on MRI. In some patients the abnormality may be limited to EPP (also called ectopic neurohypophysis) or to an interrupted pituitary stalk. Epidemiology The prevalence of PSIS is unknown but to date around 1,000 cases with and without the full triad have been reported. Clinical description In the neonatal period, PSIS presents with hypoglycemia, prolonged jaundice, congenital abnormalities and microphallus and/or cryptorchidism, which are all suggestive of hypothalamic-pituitary deficiency. PSIS is also associated with higher than normal frequency of breech presentation, Cesarean section and/or low Apgar score.
- Pituitary Stalk Interruption Syndrome GARD
  
  Pituitary stalk interruption syndrome (PSIS) is a congenital abnormality of the pituitary gland characterized by the triad of a very thin or interrupted pituitary stalk , a misplaced (ectopic) or absent posterior pituitary and a small or absent anterior pituitary , with permanent growth hormone (GH) deficit. Signs and symptoms in newborns include low blood sugar levels (hypoglycemia), jaundice, congenital abnormalities and small penis (micropenis) and/or testis that are not in the scrotal sac (cryptorchidism). Later in childhood, signs may include short stature, seizures, low arterial pressure (hypotension) and/or intellectual delay. Some people can also have vision problems ( septooptic dysplasia ) and Fanconi anemia . The cause of this condition is unknown. Rare mutations in the HESX1 , LHX4 , OTX2 , SOX3 , and PROKR2 genes can be the cause in familial cases.
Actinomycetoma Wikipedia

"Actinomycetoma: an update on diagnosis and treatment". Cutis . 99 (2): –11–E15. ISSN 2326-6929 . PMID 28319638 .
Hypertensive Nephropathy OMIM

Mapping By linkage analysis in an African American family segregating hypertensive nephropathy, Chung et al. (2003) found a maximum multipoint lod score of 5.4 in the 9q31-q32 region under an autosomal dominant model with 99% penetrance. The locus, which the authors termed HNP1, was narrowed to an 8-cM region.

INF2, NPHS2, UMOD, SLC3A1, COL4A3, COL4A4, AGT, POSTN, PPARA, AGTR1, SHC1, CFL1, RAG1, COL1A1, HP, ACE, HNP1, CHGA, FHL2, SMAD3, REN, B2M, RAC1, CYP4A11, HAVCR1, BASP1, ANGPT2, SYNPO, SIRT3, BRD4, KLF15, ACE2, ALB, SMURF2, DNER, MIR107, MIR29A, APOL1, TNF, VEGFA, C3, CYP3A5, TLR4, SLC5A2, VPS51, CD40, RARRES2, KLF6, NT5E, SMAD7, CYP3A4, NR4A1, EPAS1, ELAVL2, ACTN4
Mental Retardation, Autosomal Dominant 9 OMIM

Molecular Genetics In a patient with nonsyndromic intellectual disability, Hamdan et al. (2011) identified a de novo C-to-T transition at nucleotide 296 of the KIF1A gene resulting in a threonine-to-methionine substitution at codon 99 (T99M; 601255.0004). The mutation was not identified in 285 control samples. The threonine at position 99 lies in the highly conserved P loop consensus ATP-binding site of the KIF1A motor domain.
Zirconium Granuloma Wikipedia

Aluminium, antiperspirants and breast cancer . Journal of Inorganic Biochemistry 99:9. ^ Fischer's Contact Dermatitis .
Thoracic Outlet Syndrome Orphanet

Neurogenic TOS is the most frequently observed form accounting for 95% of all cases with 99% of these being disputed NTOS. Clinical description Compression typically occurs at the interscalene triangle, the costoclavicular space between the first thoracic rib and clavicle, or the subcoracoid space beneath the pectoralis minor tendon causing pain, paresthesias and weakness in the upper extremities.

FOXO3, RPTOR
- Thoracic Outlet Syndrome Mayo Clinic
  
  Overview Thoracic outlet syndrome (TOS) is a group of disorders that occur when blood vessels or nerves in the space between your collarbone and your first rib (thoracic outlet) are compressed. This can cause shoulder and neck pain and numbness in your fingers. Common causes of thoracic outlet syndrome include physical trauma from a car accident, repetitive injuries from job- or sports-related activities, certain anatomical defects (such as having an extra rib), and pregnancy. Sometimes doctors don't know the cause of thoracic outlet syndrome. Treatment for thoracic outlet syndrome usually involves physical therapy and pain relief measures. Most people improve with these treatments. In some cases, however, your doctor may recommend surgery. Symptoms There are three general types of thoracic outlet syndrome: Neurogenic (neurologic) thoracic outlet syndrome.
- Thoracic Outlet Syndrome Wikipedia
  
  "NTOS" redirects here. For the Windows NT microkernel used in computing, see Windows NT kernel . Thoracic outlet syndrome The right brachial plexus , viewed from in front. Specialty Vascular surgery , thoracic surgery Symptoms Pain, weakness, loss of muscle at the base of the thumb , swelling, paleness, bluish coloration [1] [2] Usual onset 20 to 50 years of age [1] Types Neurogenic , venous , arterial [1] Causes Compression of the nerves, arteries, or veins in the passageway from the lower neck to the armpit [1] Risk factors Trauma , repetitive arm movements , tumors , pregnancy , cervical rib [1] Diagnostic method Nerve conduction studies , medical imaging [1] Differential diagnosis Rotator cuff tear , cervical disc disorders, fibromyalgia , multiple sclerosis , complex regional pain syndrome [1] Treatment Pain medication, surgery [1] [2] Frequency ~1% [3] Thoracic outlet syndrome ( TOS ) is a condition in which there is compression of the nerves, arteries, or veins in the passageway from the lower neck to the armpit . [1] There are three main types: neurogenic , venous , and arterial . [1] The neurogenic type is the most common and presents with pain, weakness, and occasionally loss of muscle at the base of the thumb . [1] [2] The venous type results in swelling , pain, and possibly a bluish coloration of the arm. [2] The arterial type results in pain, coldness, and paleness of the arm. [2] TOS may result from trauma , repetitive arm movements , tumors , pregnancy , or anatomical variations such as a cervical rib . [1] The diagnosis may be supported by nerve conduction studies and medical imaging . [1] Other conditions that can produce similar symptoms include rotator cuff tear , cervical disc disorders, fibromyalgia , multiple sclerosis , and complex regional pain syndrome . [1] Initial treatment for the neurogenic type is with exercises to strengthen the chest muscles and improve posture. [1] NSAIDs such as naproxen may be used for pain. [1] Surgery is typically done for the arterial and venous types and for the neurogenic type if it does not improve with other treatments. [1] [2] Blood thinners may be used to treat or prevent blood clots . [1] The condition affects about 1% of the population. [3] It is more common in women than men and it occurs most commonly between 20 and 50 years of age. [1] The condition was first described in 1818 and the current term "thoracic outlet syndrome" first used in 1956. [2] [4] Contents 1 Signs and symptoms 2 Causes 3 Diagnosis 3.1 Classification 3.1.1 By structures affected and symptomatology 3.1.2 By event 3.1.3 By structure causing constriction 4 Treatment 4.1 Physical measures 4.2 Medications 4.3 Surgery 5 Notable cases 6 See also 7 References 8 External links Signs and symptoms [ edit ] TOS affects mainly the upper limbs, with signs and symptoms manifesting in the shoulders, neck, arms and hands. Pain can be present on an intermittent or permanent basis. It can be sharp/stabbing, burning, or aching. TOS can involve only part of the hand (as in the pinky and adjacent half of the ring finger), all of the hand, or the inner aspect of the forearm and upper arm.
Dahlberg Borer Newcomer Syndrome Wikipedia

American Journal of Medical Genetics . 16 (1): 99–104. doi : 10.1002/ajmg.1320160115 .
- Dahlberg-Borer-Newcomer Syndrome Orphanet
  
  A rare multiple congenital anomalies/dysmorphic syndrome characterized by the association of congenital hypoparathyroidism, nephropathy, congenital lymphedema, mitral valve prolapse and brachytelephalangy. Additional features include mild facial dysmorphism, hyperthricoses, and nail abnormalities. There have been no further descriptions in the literature since 1993.
- Lymphedema-Hypoparathyroidism Syndrome OMIM
  
  Dahlberg et al. (1983) described 2 adult brothers with congenital lymphedema, hypoparathyroidism, nephropathy, mitral valve prolapse and brachytelephalangy. The older sib was found to have bilateral cataracts on routine examination at age 19 years. Swelling of his arms and legs, noted soon after his birth, increased after he began walking. Progressive renal failure necessitated renal transplantation at age 26 years. The brother had similar findings. Both have a broad nasal bridge and lateral displacement of the inner canthi.
Hypothyroidism, Congenital, Nongoitrous, 5 OMIM

Molecular Genetics Dentice et al. (2006) screened for mutations in the coding region of the NKX2-5 gene (600584) in 241 patients with congenital nongoitrous hypothyroidism, including 53 with athyreosis, 99 with thyroid ectopy, and 15 with hypoplasia, and identified 3 different heterozygous missense mutations in 4 of the patients: 2 of the mutations were novel (600584.0015-600584.0016) and the other had previously been identified in patients with congenital heart disease (600584.0004).

TSHR, PAX8, SLC26A4, NKX2-5, GLI3, TCOF1, POLR1C, KAT6B, POLR1D, ADAMTSL1, FOXE1, TPO, EIF2AK3, CHNG3
- Hypothyroidism, Congenital, Nongoitrous, 2 OMIM
  
  A number sign (#) is used with this entry because of evidence that congenital nongoitrous hypothyroidism-2 (CHNG2) is caused by heterozygous mutation in the PAX8 gene (167415) on chromosome 2q14. For a general phenotypic description and a discussion of genetic heterogeneity of congenital nongoitrous hypothyroidism, see 275200. Description In 80 to 85% of cases, congenital hypothyroidism is associated with, and presumably is a consequence of, thyroid dysgenesis. In these cases, the thyroid gland can be absent (agenesis), ectopically located, and/or severely reduced in size (hypoplasia). When thyroid hormone therapy is not initiated within the first 2 months of life, congenital hypothyroidism can cause severe neurologic, mental, and motor damage (Macchia et al., 1998).
- Thyroid Hypoplasia Orphanet
  
  Thyroid hypoplasia is a form of thyroid dysgenesis (see this term) characterized by incomplete development of the thyroid gland that results in primary congenital hypothyroidism (see this term), a permanent thyroid deficiency that is present from birth. Epidemiology Prevalence is estimated at around 1/28,000. Thyroid hypoplasia and athyreosis (see this term) combined account for one-third of cases of thyroid dysgenesis. Clinical description Clinical manifestations of thyroid hypoplasia are often subtle or not present at birth, 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 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.
- Thyroid Dysgenesis Wikipedia
  
  Thyroid dysgenesis Other names Thyroid agenesis CT scan and scintigraphy images of lingular ectopic thyroid Specialty Endocrinology Thyroid dysgenesis is a cause of congenital hypothyroidism [1] where the thyroid is missing, ectopic , or severely underdeveloped.It should not be confused with iodine deficiency , or with other forms of congenital hypothyroidism , such as thyroid dyshormonogenesis , where the thyroid is present but not functioning correctly. Congenital hypothyroidism caused by thyroid dysgenesis can be associated with PAX8 . [2] Contents 1 Ectopic thyroid 2 References 3 External links Ectopic thyroid [ edit ] An ectopic thyroid , also called accessory thyroid gland , is a form of thyroid dysgenesis in which an entire or parts of the thyroid located in another part of the body than what is the usual case. A completely ectopic thyroid gland may be located anywhere along the path of the descent of the thyroid during its embryological development , although it is most commonly located at the base of the tongue, just posterior to the foramen cecum of the tongue . In this location, an aberrant or ectopic thyroid gland is known as a lingual thyroid . [3] If the thyroid fails to descend to even higher degree, then the resulting final resting point of the thyroid gland may be high in the neck, such as just below the hyoid bone . [3] Parts of ectopic thyroid tissue ("accessory thyroid tissue") can also occur, and arises from remnants of the thyroglossal duct , and may appear anywhere along its original length. [3] Accessory thyroid tissue may be functional, but is generally insufficient for normal function if the main thyroid gland is entirely removed. [3] Lingual thyroid is 4-7 times more common in females, with symptoms developing during puberty, pregnancy or menopause. Lingual thyroid may be asymptomatic, or give symptoms such as dysphagia (difficulty swallowing), dysphonia (difficulty talking) and dyspnea (difficulty breathing). [4] References [ edit ] ^ Castanet M, Park SM, Smith A, et al.
Corectopia Wikipedia

Journal of Cataract & Refractive Surgery . 25 (5): 709–11. doi : 10.1016/S0886-3350(99)00018-8 . PMID 10330650 . ^ Atkinson, C Scott; Brodsky, Michael C; Hiles, David A; Simon, John W (1994).

TBX2, FOXC2, PAX6
- Ectopia Pupillae OMIM
  
  Description Ectopia pupillae is a congenital eye malformation in which the pupils are displaced from their normal central position. Inheritance Whether familial ectopic pupil occurs as an isolated anomaly is not certain. It is a feature of ectopia lentis et pupillae (225200) and of ptosis, strabismus, and ectopic pupils (178330). In either of these conditions, individuals or part of a kindred might show only ectopic pupil. Hanson et al. (1999) found ectopia pupillae in a child with 'atypical aniridia'; see 106210 and (607108.0013).