Alternative titles; symbols
SNOMEDCT: 773329005; ORPHA: 251383; DO: 0111898;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| Xq28 | CK syndrome | 300831 | X-linked recessive | 3 | NSDHL | 300275 |
A number sign (#) is used with this entry because of evidence that CK syndrome (CKS) is caused by hemizygous mutation in the NSDHL gene (300275) on chromosome Xq28.
CK syndrome (CKS) is an X-linked recessive disorder characterized by mild to severe cognitive impairment, seizures, microcephaly, cerebral cortical malformations, dysmorphic facial features, and thin body habitus. It is named after the first identified patient (summary by McLarren et al., 2010).
CHILD syndrome (308050) is an allelic disorder with a different phenotype.
Du Souich et al. (2009) reported a 5-generation family of Russian-Doukhobor descent with an X-linked recessive mental retardation syndrome. Affected boys had onset of seizures in the neonatal period and delayed psychomotor development associated with behavioral abnormalities, including hyperactivity, aggression, and irritability. Mental retardation ranged from mild to severe. Brain imaging of 2 affected individuals showed polymicrogyria and/or pachygyria. Other features included hypotonia, hyperextensible joints, and a thin body habitus with long limbs and digits. Dysmorphic features included microcephaly, long, narrow face, almond-shaped eyes, epicanthal folds, upslanting palpebral fissures, high nasal bridge, high-arched palate, crowded teeth, posteriorly rotated ears, micrognathia/retrognathia, and malar hypoplasia. Carrier females were unaffected. A second affected 3-generation family with similar features was reported by Tarpey et al. (2009) and McLarren et al. (2010). Laboratory studies showed that cholesterol levels in serum and cerebrospinal fluid were normal in affected individuals and carrier females.
McLarren et al. (2010) showed that inheritance in the family with CK syndrome reported by du Souich et al. (2009) and the family reported by Tarpey et al. (2009) was consistent with an X-linked recessive pattern. Obligate female carriers were unaffected.
In affected members of a 3-generation family with X-linked mental retardation, Tarpey et al. (2009) identified a 1-bp duplication in the NSDHL gene (300275.0007). In affected members of the original family with CK syndrome reported by du Souich et al. (2009), McLarren et al. (2010) identified a hemizygous truncating mutation in the NSDHL gene (300275.0008). In vitro functional expression studies showed that both mutations acted as temperature-sensitive hypomorphic alleles, resulting in a less severe phenotype than that observed with mutations associated with CHILD syndrome. Cells and cerebrospinal fluid from an affected individual showed increased methylsterol levels. McLarren et al. (2010) suggested that the phenotype resulted mainly from the accumulation of toxic methylsterols, not necessarily from cholesterol deficiency.
du Souich, C., Chou, A., Yin, J., Oh, T., Nelson, T. N., Hurlburt, J., Arbour, L., Friedlander, R., McGillivray, B. C., Tyshchenko, N., Rump, A., Poskitt, K. J., Demos, M. K., Van Allen, M. I., Boerkoel, C. F. Characterization of a new X-linked mental retardation syndrome with microcephaly, cortical malformation, and thin habitus. Am. J. Med. Genet. 149A: 2469-2478, 2009. [PubMed: 19842190] [Full Text: https://doi.org/10.1002/ajmg.a.33071]
McLarren, K. W., Severson, T. M., du Souich, C., Stockton, D. W., Kratz, L. E., Cunningham, D., Hendson, G., Morin, R. D., Wu, D., Paul, J. E., An, J., Nelson, T. N., and 28 others. Hypomorphic temperature-sensitive alleles of NSDHL cause CK syndrome. Am. J. Hum. Genet. 87: 905-914, 2010. [PubMed: 21129721] [Full Text: https://doi.org/10.1016/j.ajhg.2010.11.004]
Tarpey, P. S., Smith, R., Pleasance, E., Whibley, A., Edkins, S., Hardy, C., O'Meara, S., Latimer, C., Dicks, E., Menzies, A., Stephens, P., Blow, M., and 67 others. A systematic, large-scale resequencing screen of X-chromosome coding exons in mental retardation. Nature Genet. 41: 535-543, 2009. [PubMed: 19377476] [Full Text: https://doi.org/10.1038/ng.367]