| #133540 | ||||||||||||||||||
| COCKAYNE SYNDROME, TYPE B; CSB | ||||||||||||||||||
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| CKN2 | ||||||||||||||||||
| Phenotype Gene Relationships | ||||||||||||||||||
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| Clinical Synopsis | ||||||||||||||||||
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| A number sign (#) is used with this entry because Cockayne syndrome type B (CSB) is caused by mutation in the gene encoding the group 6 excision-repair cross-complementing protein (ERCC6; 609413). Cockayne syndrome type A (CSA; 216400) is caused by mutation in the ERCC8 gene (609412) on chromosome 5q11. Among patients with Cockayne syndrome, approximately 80% have mutations in the ERCC6 gene (Licht et al., 2003). For a phenotypic description and a discussion of genetic heterogeneity of Cockayne syndrome, see 216400. | ||||||||||||||||||
| Clinical Features | ||||||||||||||||||
| Falik-Zaccai et al. (2008) reported a large, highly consanguineous Druze kindred from northern Israel in which 6 members had Cockayne syndrome type B. All 6 presented with the congenital severe phenotype that included severe failure to thrive, severe mental retardation, congenital cataracts, loss of adipose tissue, joint contractures, distinctive face with small, deep-set eyes and prominent nasal bridge, kyphosis, and cachectic dwarfism. They had sensorineural hearing loss, no language skills, could not sit or walk independently, and died by the age of 5 years. Cellular studies of the fibroblasts from 3 patients studied in detail showed that transcription-coupled DNA repair was about 18% of normal controls; this defect was corrected by a plasmid containing the cDNA of the ERCC6 gene. Patient cells also showed significantly increased sensitivity to radiation compared to control cells. Prenatal diagnosis of subsequent pregnancies using amniotic cell culture and chorionic villi sampling identified 1 affected infant. | ||||||||||||||||||
| Heterogeneity | ||||||||||||||||||
| Clinical Heterogeneity Miyauchi et al. (1994) described 2 brothers with biochemical evidence of Cockayne syndrome type B who survived to ages 42 and 55 years. Clinical features appeared in childhood and included growth retardation, mild mental retardation, slowly progressive gait disturbance, and tremor. The proband had characteristic facial features, such as aged appearance, beak-like nose, mandibular prognathia, cataracts, and mild hearing loss. Brain CT scan showed brain atrophy and calcifications. His brother was less severely affected. Their cultured skin fibroblasts showed extreme UV sensitivity but almost normal UV-induced unscheduled DNA synthesis. The patients were classified as genetic complementation group B after study of the recovery of RNA synthesis after UV irradiation of fused cells. Clinical phototesting revealed a reduced threshold for UVB erythema. | ||||||||||||||||||
| Cytogenetics | ||||||||||||||||||
| Fryns et al. (1991) reported a 24-year-old man with clinical and neurologic manifestations suggestive of late-onset Cockayne syndrome. Prometaphase chromosome studies demonstrated an interstitial 10q21.1 deletion in all cells, suggesting that the responsible gene is located in this region. | ||||||||||||||||||
| Molecular Genetics | ||||||||||||||||||
| In 16 patients with type B Cockayne syndrome, Mallery et al. (1998) identified 18 inactivating mutations in the ERCC6 gene (see, e.g., 609413.0001-609413.0003). Neither the site nor the nature of the mutation correlated with the severity of the clinical features; severe truncations were found in different patients with either classic or early-onset forms of the disease. Colella et al. (1999) reported a cellular and molecular analysis of 3 Italian CS patients who were of particular interest because none of them was sun-sensitive, despite showing most of the features of the severe form of CS, including the characteristic cellular sensitivity to UV irradiation. Two related patients were homozygous for a nonsense mutation in the ERCC6 gene (609413.0004). A third patient was a compound heterozygote for 2 mutations. In 3 affected members of a large Druze kindred with severe Cockayne syndrome type B, Falik-Zaccai et al. (2008) identified a homozygous mutation in the ERCC6 gene (609413.0011). The mutation was identified in 7 of 106 healthy Druze individuals from the same village, indicating a high carrier frequency of 1:15. | ||||||||||||||||||
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