OMIM (Online Mendellian Inheritance in Man)
214150 CEREBROOCULOFACIOSKELETAL SYNDROME 1; COFS1A number sign (#) is used with this entry because of evidence that COFS syndrome in patients from the Manitoba aboriginal population group within which Pena and Shokeir (1974) originally described the disorder is due to a homozygous mutation in the ERCC6 gene (609413). Mutations in the same gene cause Cockayne syndrome type B (133540).
Other forms of COFS syndrome have been identified: COFS2 (610756), which is caused by mutation in the ERCC2 gene (126340); COFS3, also known as XPG/CS syndrome (see 278780), which is caused by mutation in the ERCC5 gene (133530); and COFS4 (610758), which is caused by mutation in the ERCC1 gene (126380).
Pena and Shokeir (1974) observed 10 patients in 3 kindreds with a syndrome comprised 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.
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.
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 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.
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.
Central nervous system
Mental retardation,Optic tract and chiasm hypoplasia,Focal microgyria,Agenesis of corpus callosum,Infantile spasm,Hypotonia,Cerebellar hypoplasia,Subcortical gliosis,Third ventricle subependymal focal gliosis
Coxa valga,Shallow acetabular angle,Limbs
Elbow flexion contracture,Knee flexion contracture,Hands
Vertical talus,Rocker-bottom feet,Longitudinal groove on soles,Second metatarsal posteriorly placed
Widely spaced nipples
Normal birth weight,Failure to thrive
SKIN, NAILS, HAIR
Caused by mutation in the excision repair cross complementing rodent, repair deficiency, complementation group 6 gene (ERCC6, 133540.0007)
Death before age 5, Genetic heterogeneity (see 610756, 133530, 610758)
HEAD AND NECK
Micrognathia, Sloping forehead, Long philtrum, Ears
Large ear pinnae, Eyes
Cataracts, Blepharophimosis, Microphthalmia, Deep-set eyes, Nystagmus, Nose
Prominent nasal root, Mouth
Upper lip overlaps lower lip