SNOMEDCT: 890434000; ORPHA: 191, 90321, 90322, 90324; DO: 0080908;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 10q11.23 | Cockayne syndrome, type B | 133540 | Autosomal recessive | 3 | ERCC6 | 609413 |
A number sign (#) is used with this entry because of evidence that Cockayne syndrome B (CSB) is caused by homozygous or compound heterozygous mutation in the gene encoding the group 6 excision repair cross-complementing protein (ERCC6; 609413) on chromosome 10q11.
Cockayne syndrome B (CSB) is a multisystem disorder characterized by severe physical and mental retardation, microcephaly, progressive neurologic and retinal degeneration, skeletal abnormalities, gait defects, and sun sensitivity with no increased frequency of cancer (summary by Mallery et al., 1998).
Cockayne syndrome 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.
Falik-Zaccai et al. (2008) reported a large, highly consanguineous Druze kindred from northern Israel in which 6 members had Cockayne syndrome 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.
Wilson et al. (2016) reviewed the features and made recommendations regarding the evaluation of 102 patients, 44 females and 58 males, with Cockayne syndrome A or B. The mean age of recruited individuals was 11.5 years, with a range of 3 months to 39 years. All patients were microcephalic and had growth failure leading to proportionate short stature. At the time of the analysis, 28 individuals had died, with a mean age of death of 8.4 years with a range of 17 months to 30 years. The most prevalent features were cold extremities and abnormal brain imaging present in over 80% of individuals, followed by weakness, hearing loss, clinical photosensitivity, tremor, joint contractures, abnormal liver function tests, and abnormal bowel movements, present in over 60% but less than 80%. Cataracts were present in about 50% and were likely to be seen by age 4 years. The majority of patients with abnormal brain imaging had calcifications and white matter changes, with a minority having cerebellar corpus callosum or ventriculomegaly abnormalities. Lower extremity joint contractures were more common than upper extremity ones. Cataracts were more likely to be bilateral. Most patients had low-normal birth growth parameters but rapidly fell off the growth charts postnatally. The authors noted that early development may appear to be normal and suggested that developmental delay may be a poor discriminating factor for early diagnosis. The authors suggested that Cockayne syndrome should be suspected in any child with postnatal growth failure, microcephaly, and any 2 of the following: persistently cold hands and feet, bilateral hearing loss, dermal photosensitivity, intention tremor, joint contractures, progressive loss of body fat, cataracts, or typical facial features. Using these criteria increased clinical recognition of Cockayne syndrome in their cohort of 102 patients to around 90%. The authors cautioned that metronidazole causes acute hepatic failure in Cockayne syndrome, which may be fatal and should be avoided in anyone with a suspected diagnosis of Cockayne syndrome. The authors noted that the phenotypic discordance between sibs is not unusual. The only identified association with younger age at death in Cockayne syndrome was with early onset of cataracts (less than 3 years of age). This association was statistically significant (p = 1.36 x 10(-6)); at 5 years, survival is about 60% for those patients with early cataracts and 95% for those without. Wilson et al. (2016) also found a significant association between early cataracts and the time to development of hearing loss and of contractures, but not of tremor or loss of subcutaneous fat. Degree of photosensitivity was not associated with survival or time until the onset of tremor.
Clinical Variability
Miyauchi et al. (1994) described 2 brothers with biochemical evidence of Cockayne syndrome 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.
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.
The transmission pattern of CSB in the families reported by Mallery et al. (1998) was consistent with autosomal recessive inheritance.
In 16 patients with Cockayne syndrome B, 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 compound heterozygous for 2 mutations.
In 3 affected members of a large Druze kindred with severe Cockayne syndrome 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.
Colella, S., Nardo, T., Mallery, D., Borrone, C., Ricci, R., Ruffa, G., Lehmann, A. R., Stefanini, M. Alterations in the CSB gene in three Italian patients with the severe form of Cockayne syndrome (CS) but without clinical photosensitivity. Hum. Molec. Genet. 8: 935-941, 1999. [PubMed: 10196384] [Full Text: https://doi.org/10.1093/hmg/8.5.935]
Falik-Zaccai, T. C., Laskar, M., Kfir, N., Nasser, W., Slor, H., Khayat, M. Cockayne syndrome type II in a Druze isolate in northern Israel in association with an insertion mutation in ERCC6. Am. J. Med. Genet. 146A: 1423-1429, 2008. [PubMed: 18446857] [Full Text: https://doi.org/10.1002/ajmg.a.32309]
Fryns, J. P., Bulcke, J., Verdu, P., Carton, H., Kleczkowska, A., Van den Berghe, H. Apparent late-onset Cockayne syndrome and interstitial deletion of the long arm of chromosome 10 del(10)(q11.23q21.2). Am. J. Med. Genet. 40: 343-344, 1991. [PubMed: 1951442] [Full Text: https://doi.org/10.1002/ajmg.1320400320]
Licht, C. L., Stevnsner, T., Bohr, V. A. Cockayne syndrome group B cellular and biochemical functions. Am. J. Hum. Genet. 73: 1217-1239, 2003. [PubMed: 14639525] [Full Text: https://doi.org/10.1086/380399]
Mallery, D. L., Tanganelli, B., Colella, S., Steingrimsdottir, H., van Gool, A. J., Troelstra, C., Stefanini, M., Lehmann, A. R. Molecular analysis of mutations in the CSB (ERCC6) gene in patients with Cockayne syndrome. Am. J. Hum. Genet. 62: 77-85, 1998. Note: Erratum: Am. J. Hum. Genet. 64: 1491 only, 1999. [PubMed: 9443879] [Full Text: https://doi.org/10.1086/301686]
Miyauchi, H., Horio, T., Akaeda, T., Asada, Y., Chang, H. R., Ishizaki, K., Ikenaga, M. Cockayne syndrome in two adult siblings. J. Am. Acad. Derm. 30: 329-335, 1994. [PubMed: 8294592] [Full Text: https://doi.org/10.1016/s0190-9622(94)70034-6]
Wilson, B. T., Stark, Z., Sutton, R. E., Danda, S., Ekbote, A. V., Elsayed, S. M., Gibson, L., Goodship, J. A., Jackson, A. P., Keng, W. T., King, M. D., McCann, E., Motojima, T., Murray, J. E., Omata, T., Pilz, D., Pope, K., Sugita, K., White, S. M., Wilson, I. J. The Cockayne Syndrome Natural History (CoSyNH) study: clinical findings in 102 individuals and recommendations for care. Genet. Med. 18: 483-493, 2016. [PubMed: 26204423] [Full Text: https://doi.org/10.1038/gim.2015.110]