ORPHA: 1466, 191; DO: 0080913;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 13q33.1 | Cerebrooculofacioskeletal syndrome 3 | 616570 | Autosomal recessive | 3 | ERCC5 | 133530 |
A number sign (#) is used with this entry because of evidence that cerebrooculofacioskeletal syndrome-3 (COFS3) is caused by homozygous mutation in the ERCC5 gene (133530) on chromosome 13q33.
Biallelic mutations in the ERCC5 gene can also cause Xeroderma pigmentosum, group G and/or Cockayne syndrome (278780).
Cerebrooculofacioskeletal syndrome is a severe, progressive neurologic disorder characterized by prenatal onset of arthrogryposis, microcephaly, and growth failure. Postnatal features include severe developmental delay, congenital cataracts (in some), and marked UV sensitivity of the skin. Survival beyond 6 years of age is rare. COFS represents the severe end of the spectrum of disorders caused by mutations in nucleotide excision repair (NER) genes, with Cockayne syndrome and xeroderma pigmentosum being milder NER-related phenotypes (summary by Drury et al., 2014).
For a phenotypic description and a discussion of genetic heterogeneity of cerebrooculofacioskeletal syndrome, see COFS1 (214150).
Hamel et al. (1996) and Nouspikel et al. (1997) studied a male who was born to healthy first-cousin Moroccan parents and had extremely severe early-onset Cockayne syndrome leading to death at 7 months of age. Graham et al. (2001) referred to the case reported by Hamel et al. (1996) as one of cerebrooculofacioskeletal syndrome. The patient showed prenatal-onset growth deficiency, severe microcephaly, microphthalmia with no cataracts, cleft palate, cutaneous photosensitivity, and brain atrophy with no calcifications. Skin fibroblasts showed extreme cellular sensitivity to UV, comparable to that in classic XP.
Drury et al. (2014) reported a family of Pakistani ancestry in which 5 fetuses conceived to 3 pairs of first cousins presented with abnormal ultrasound findings in the second trimester, including contractures and microcephaly. All pregnancies were terminated and underwent autopsy. Variable intracerebral findings included 2 instances of ventriculomegaly, 2 of delayed cerebral sulcation, and 2 of cerebellar hypoplasia/posterior fossa abnormalities. The 1 fetus that survived beyond 24 weeks developed progressive edema. None of the fetuses had cataracts.
The transmission pattern of COFS3 in the family reported by Drury et al. (2014) was consistent with autosomal recessive inheritance.
By linkage analysis of a consanguineous Pakistani kindred in which 5 fetuses were affected with COFS, Drury et al. (2014) found linkage to a 9.3-Mb region on chromosome 13q32.3-q33.3 (lod score of 5.0).
In a boy, born of consanguineous Moroccan parents, with COFS originally reported by Hamel et al. (1996), Nouspikel et al. (1997) identified a homozygous truncating mutation in the ERCC5 gene (133530.0003).
In 4 fetuses from a large consanguineous Pakistani kindred with COFS3, Drury et al. (2014) identified a homozygous truncating mutation in the ERCC5 gene (133530.0016) predicting the loss of the C terminus. The mutation, which was found by a combination of linkage analysis and exome sequencing, segregated with the disorder in the family. Functional studies of the variant were not performed.
Drury, S., Boustred, C., Tekman, M., Stanescu, H., Kleta, R., Lench, N., Chitty, L. S., Scott, R. H. A novel homozygous ERCC5 truncating mutation in a family with prenatal arthrogryposis--further evidence of genotype-phenotype correlation. Am. J. Med. Genet. 164A: 1777-1783, 2014. [PubMed: 24700531] [Full Text: https://doi.org/10.1002/ajmg.a.36506]
Graham, J. M., Jr., Anyane-Yeboa, K., Raams, A., Appeldoorn, E., Kleijer, W. J., Garritsen, V. H., Busch, D., Edersheim, T. G., Jaspers, N. G. J. Cerebro-oculo-facio-skeletal syndrome with a nucleotide excision-repair defect and a mutated XPD gene, with prenatal diagnosis in a triplet pregnancy. Am. J. Hum. Genet. 69: 291-300, 2001. [PubMed: 11443545] [Full Text: https://doi.org/10.1086/321295]
Hamel, B. C. J., Raams, A., Schuitema-Dijkstra, A. R., Simons, P., van der Burgt, I., Jaspers, N. G. J., Kleijer, W. J. Xeroderma pigmentosum-Cockayne syndrome complex: a further case. J. Med. Genet. 33: 607-610, 1996. [PubMed: 8818951] [Full Text: https://doi.org/10.1136/jmg.33.7.607]
Nouspikel, T., Lalle, P., Leadon, S. A., Cooper, P. K., Clarkson, S. G. A common mutational pattern in Cockayne syndrome patients from xeroderma pigmentosum group G: implications for a second XPG function. Proc. Nat. Acad. Sci. 94: 3116-3121, 1997. Note: Retraction Proc. Nat. Acad. Sci. 103: 19606 only, 2006. [PubMed: 9096355] [Full Text: https://doi.org/10.1073/pnas.94.7.3116]