Alternative titles; symbols
ORPHA: 1466, 191; DO: 0080911;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 10q11.23 | Cerebrooculofacioskeletal syndrome 1 | 214150 | Autosomal recessive | 3 | ERCC6 | 609413 |
A number sign (#) is used with this entry because of evidence that cerebrooculofacioskeletal syndrome-1 (COFS1) is caused by homozygous or compound heterozygous mutation in the ERCC6 gene (609413) on chromosome 10q11.
Cockayne syndrome type B (CSB; 133540) is an allelic disorder.
Cerebrooculofacioskeletal syndrome (COFS) is an autosomal recessive progressive neurodegenerative disorder characterized by microcephaly, congenital cataracts, severe mental retardation, facial dysmorphism, and arthrogryposis (summary by Jaakkola et al., 2010).
Genetic Heterogeneity of Cerebrooculofacioskeletal Syndrome
See also COFS2 (610756), caused by mutation in the ERCC2 gene (126340); COFS3 (616570), caused by mutation in the ERCC5 gene (133530); and COFS4 (610758), caused by mutation in the ERCC1 gene (126380).
Pena and Shokeir (1974) observed 10 patients in 3 kindreds with a syndrome composed of microcephaly, hypotonia, failure to thrive, arthrogryposis, eye defects, prominent nose, large ears, overhanging upper lip, micrognathia, widely set nipples, kyphoscoliosis, and osteoporosis. The first 2 kindreds were American Indian with French admixture and much consanguinity in the first of these. Preus and Fraser (1974) described a single case in an offspring of first-cousin parents of Italian extraction. One of Pena and Shokeir's affected sibships (2 affected out of 6 children) had brother-sister parents. Surana et al. (1978) described COFS syndrome in a black American infant.
Lerman-Sagie et al. (1987) described an infant with COFS manifestations plus radiologic and pathologic findings of osteopetrosis and severe degeneration of skeletal muscles. The muscular changes appeared to be the cause of the flexion contractures present at birth. Gershoni-Baruch et al. (1991) reported the case of an infant born of first-cousin parents who had findings of congenital muscular dystrophy. Laugel et al. (2008) questioned the diagnosis of COFS in the patient reported by Gershoni-Baruch et al. (1991).
The patients studied by Meira et al. (2000), the surviving boy of a dizygotic male-female twin pair and a girl who was not closely related, were related to the Manitoba aboriginal population group within which COFS syndrome was originally reported by Lowry et al. (1971) and Pena and Shokeir (1974). The twins had microcephaly, deep-set eyes, bilateral microphthalmia and cataracts, overhanging upper lips, and prominent noses, and the boy had undescended testes. They showed failure to thrive, recurrent pneumonias, axial hypotonia, appendicular hypertonia, hyperreflexia, and progressive contractures. Both were considered to have typical COFS syndrome. The girl died at age 5 years. Cranial computed tomography (CT) had shown enlargement of the ventricles and subarachnoid spaces, with calcifications in the periventricular frontal white matter and basal ganglia. Autopsy showed severe neurodegeneration, with markedly reduced brain weight, patchy demyelination in the cerebrum and hindbrain, neuronal loss and gliosis in the cerebral cortex, and pericapillary and parenchymal mineralization in the cortex and basal ganglia; this was case 7 in the study of Del Bigio et al. (1997). The boy showed normal hearing at age 2 years, but profound hearing loss by age 6 years, when he was found to have insulin resistance. At age 7 years he had CT changes similar to those in his sister. He never manifested cutaneous photosensitivity or actinic keratoses, but at age 10 years he had ocular photosensitivity with consistently constricted pupils. The boy died at age 11 years. In the third patient reported by Meira et al. (2000), the diagnosis of COFS syndrome was made at 2 years. The patient was the daughter of aboriginal parents from the same population as the dizygotic twins, although they were not known to be related. She presented at birth with growth deficiency, microcephaly, and bilateral microphthalmia with cataracts.
Jaakkola et al. (2010) reported a large multigenerational consanguineous Finnish kindred in which 6 individuals had COFS1. Two deceased patients had originally been reported by Linna et al. (1982) as having COFS, 1 of whom had intracranial calcifications. Two patients, a boy and a girl, were reported in detail. Clinical features included failure to thrive, poor growth, lack of psychomotor development with inability to sit independently or speak, and arthrogryposis. Facial dysmorphism included microcephaly, deep-set eyes, cataracts, prominent nasal bridge, micrognathia, large ear pinna, and upper lip overlapping the lower lip. Both also had hearing loss and nystagmus; 1 developed seizures. Brain MRI showed hypoplasia of the corpus callosum, ventriculomegaly, and delayed myelination. The boy had cryptorchidism. The other family members had a similar phenotype. All patients died between ages 3 and 9 years. Cultured fibroblasts from the 2 patients reported in detail showed 3.6- to 5.4-fold hypersensitivity to UV irradiation due to a defect in transcription-coupled nucleotide excision repair (TC-NER). Complementation analysis showed that the gene responsible was ERCC6.
Laugel et al. (2008) proposed that diagnosis of COFS syndrome should require the following criteria: congenital microcephaly, congenital cataracts and/or microphthalmia, arthrogryposis, severe developmental delay, severe postnatal growth failure, and facial dysmorphism with prominent nasal root and/or overhanging upper lip, as well as a DNA repair defect in the transcription coupled repair pathway.
Temtamy et al. (1996) described a 3-year-old Egyptian girl, the only child of healthy first-cousin parents, with phenotypic abnormalities of the COFS syndrome. She had microcephaly, bilateral congenital cataract, nystagmus, long ear pinnae, camptodactyly, prominent heels, coxa valga, kyphosis, and flexure contracture of the elbows and knees. CT scan showed bilateral symmetric intracranial calcifications. In addition, she had an apparently balanced translocation: 46,XX,t(1;16)(q23;q13) in all cells. The translocation was transmitted from the phenotypically normal mother who was a mosaic for the translocation. Temtamy et al. (1996) suggested that a gene for COFS may be located on 1q23 or 16q13.
The transmission pattern of COFS in the family reported by Meira et al. (2000) was consistent with autosomal recessive inheritance.
Meira et al. (2000) presented evidence that 2 probands related to the Manitoba aboriginal population group within which COFS syndrome was originally reported by Lowry et al. (1971) and Pena and Shokeir (1974) had cellular phenotypes indistinguishable from those in Cockayne syndrome cells. Furthermore, the patients had an identical homozygous mutation in the ERCC6 gene (609413.0007).
In 3 unrelated patients with COFS syndrome, Laugel et al. (2008) identified biallelic mutations in the ERCC6 gene (see, e.g., 609413.0012-609413.0014). All patients showed classic clinical features of the disorder and cultured fibroblasts showed defective DNA repair.
In 3 of 6 patients with COFS1 from a consanguineous Finnish family, Jaakkola et al. (2010) identified a homozygous mutation in the ERCC6 gene (R1288X; 609413.0015). Fibroblast studies showed that the mutation caused a severe reduction of the encoded protein to 20% of controls. Genealogic analysis revealed that common ancestors for all the patients lived in the 18th century in a small village in northern Finland, consistent with a founder effect.
Shokeir (1982) suggested that there are two types of Pena-Shokeir syndrome: type I (208150), which shows multiple ankyloses, camptodactyly, facial anomalies and pulmonary hypoplasia (Pena and Shokeir (1974, 1976)); and type II, also known as the COFS syndrome. In the third edition of Recognizable Patterns of Human Malformations, Smith (1982) also suggested that COFS be called Pena-Shokeir syndrome II. Because of potential confusion, this seems best avoided and the designation COFS used instead. Silengo et al. (1984) reported a newborn female with a phenotype intermediate between the Neu-Laxova (256520) and COFS syndromes. They espoused the notion, stated earlier by Preus and Fraser (1974) and by Temtamy and McKusick (1978), that these two separately named syndromes represent different degrees of clinical expressivity of the same autosomal recessive mutation.
Del Bigio, M. R., Greenberg, C. R., Rorke, L. B., Schnur, R., McDonald-McGinn, D. M., Zackai, E. H. Neuropathological findings in eight children with cerebro-oculo-facio-skeletal (COFS) syndrome. J. Neuropath. Exp. Neurol. 56: 1147-1157, 1997. [PubMed: 9329459] [Full Text: https://doi.org/10.1097/00005072-199710000-00009]
Gershoni-Baruch, R., Ludatscher, R. M., Lichtig, C., Sujov, P., Machoul, I. Cerebro-oculo-facio-skeletal syndrome: further delineation. Am. J. Med. Genet. 41: 74-77, 1991. [PubMed: 1951466] [Full Text: https://doi.org/10.1002/ajmg.1320410119]
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Jaakkola, E., Mustonen, A., Olsen, P., Miettinen, S., Savuoja, T., Raams, A., Jaspers, N. G. J., Shao, H., Wu, B. L., Ignatius, J. ERCC6 founder mutation identified in Finnish patients with COFS syndrome. Clin. Genet. 78: 541-547, 2010. [PubMed: 20456449] [Full Text: https://doi.org/10.1111/j.1399-0004.2010.01424.x]
Laugel, V., Dalloz, C., Tobias, E. S., Tolmie, J. L., Martin-Coignard, D., Drouin-Garraud, V., Valatannopoulos, V., Sarasin, A., Dollfus, H. Cerebro-oculo-facio-skeletal syndrome: three additional cases with CSB mutations, new diagnostic criteria and an approach to investigation. J. Med. Genet. 45: 564-571, 2008. [PubMed: 18628313] [Full Text: https://doi.org/10.1136/jmg.2007.057141]
Lerman-Sagie, T., Levi, Y., Kidron, D., Grunebaum, M., Nitzan, M. Syndrome of osteopetrosis and muscular degeneration associated with cerebro-oculo-facio-skeletal changes. Am. J. Med. Genet. 28: 137-142, 1987. [PubMed: 3674107] [Full Text: https://doi.org/10.1002/ajmg.1320280120]
Linna, S.-L., Finni, K., Simila, S., Kouvalainen, K., Laitinen, J. Intracranial calcifications in cerebro-oculo-facio-skeletal (COFS) syndrome. Pediat. Radiol. 12: 28-30, 1982. [PubMed: 7063265] [Full Text: https://doi.org/10.1007/BF01221707]
Lowry, R. B., MacLean, R., McLean, D. M., Tischler, B. Cataracts, microcephaly, kyphosis, and limited joint movement in two siblings: a new syndrome. J. Pediat. 79: 282-284, 1971. [PubMed: 5560051] [Full Text: https://doi.org/10.1016/s0022-3476(71)80114-2]
Lurie, I. W., Cherstvoy, E. D., Lazjuk, G. I., Nedzved, M. K., Usoev, S. S. Further evidence for the autosomal-recessive inheritance of the COFS syndrome. Clin. Genet. 10: 343-346, 1976. [PubMed: 825334] [Full Text: https://doi.org/10.1111/j.1399-0004.1976.tb00059.x]
Meira, L. B., Graham, J. M., Jr., Greenberg, C. R., Busch, D. B., Doughty, A. T. B., Ziffer, D. W., Coleman, D. M., Savre-Train, I., Friedberg, E. C. Manitoba aboriginal kindred with original cerebro-oculo-facio-skeletal syndrome has a mutation in the Cockayne syndrome group B (CSB) gene. Am. J. Hum. Genet. 66: 1221-1228, 2000. [PubMed: 10739753] [Full Text: https://doi.org/10.1086/302867]
Pena, S. D. J., Evans, J., Hunter, A. G. W. COFS syndrome revisited. Birth Defects Orig. Art. Ser. XIV(6B): 205-213, 1978. [PubMed: 728562]
Pena, S. D. J., Shokeir, M. H. K. Autosomal recessive cerebro-oculo-facio-skeletal (COFS) syndrome. Clin. Genet. 5: 285-293, 1974. [PubMed: 4211825] [Full Text: https://doi.org/10.1111/j.1399-0004.1974.tb01695.x]
Pena, S. D. J., Shokeir, M. H. K. Syndrome of camptodactyly, multiple ankyloses, facial anomalies, and pulmonary hypoplasia: a lethal condition. J. Pediat. 85: 373-375, 1974. [PubMed: 4431498] [Full Text: https://doi.org/10.1016/s0022-3476(74)80119-8]
Pena, S. D. J., Shokeir, M. H. K. Syndrome of camptodactyly, multiple ankyloses, facial anomalies and pulmonary hypoplasia: further delineation and evidence for autosomal recessive inheritance. Birth Defects Orig. Art. Ser. XII(5): 201-208, 1976. [PubMed: 953225]
Preus, M., Fraser, F. C. The cerebro-oculo-facio-skeletal syndrome. Clin. Genet. 5: 294-297, 1974. [PubMed: 4212394] [Full Text: https://doi.org/10.1111/j.1399-0004.1974.tb01696.x]
Preus, M., Kaplan, P., Kirkham, T. H. Renal anomalies and oligohydramnios in the cerebro-oculo-facio-skeletal syndrome. Am. J. Dis. Child. 131: 62-64, 1977. [PubMed: 402067] [Full Text: https://doi.org/10.1001/archpedi.1977.02120140064010]
Shokeir, M. H. K. Cerebro-oculo-facioskeletal (COFS) syndrome (Pena-Shokeir syndrome). In: Vinken, P. J.; Bruyn, G. W. (eds.): Handbook of Clinical Neurology. Neurogenetic Directory. Vol. 45. Part II. Amsterdam: North Holland (pub.) 1982. Pp. 341-343.
Silengo, M. C., Davi, G., Bianco, R., Biagioli, M., Franceschini, P., Cavallo, M., Bussi, G. The NEU-COFS (cerebro-oculo-facio-skeletal) syndrome: report of a case. Clin. Genet. 25: 201-204, 1984. [PubMed: 6705255] [Full Text: https://doi.org/10.1111/j.1399-0004.1984.tb00486.x]
Smith, D. W. Recognizable Patterns of Human Malformations. (3rd ed.) Philadelphia: W. B. Saunders (pub.) 1982. Pp. 136-137.
Surana, R. B., Fraga, J. R., Sinkford, S. M. The cerebro-oculo-facio-skeletal syndrome. Clin. Genet. 13: 486-488, 1978. [PubMed: 97035] [Full Text: https://doi.org/10.1111/j.1399-0004.1978.tb01203.x]
Temtamy, S. A., McKusick, V. A. The Genetics of Hand Malformations. New York: Alan R. Liss (pub.) 1978. P. 465.
Temtamy, S. A., Meguid, N. A., Mahmoud, A., Afifi, H. H., Gerzawy, A., Zaki, M. S. COFS syndrome with familial 1;16 translocation. Clin. Genet. 50: 240-243, 1996. [PubMed: 9001808] [Full Text: https://doi.org/10.1111/j.1399-0004.1996.tb02635.x]