Cerebrooculofacioskeletal Syndrome (COFS) is a lethal and rapidly progressive disorder, involving neuromuscular defects. Characteristic clinical features are numerous and include facial (low set ears, a sloping forehead, abnormally small head and jaws, and a prominent nasal bridge), ocular (deep set eyes, small eyes, cataract, nystagmus and other vision impairments, involuntary eye movements) neurological (hypotonia, moderate to severe mental retardation, and multiple joint contractures) and skeletal (osteoporosis, kyphoscoliosis, camptodactyly, and coxa valga among others) abnormalities. Respiratory infections are frequent. These symptoms present at birth, or are evident, at the most, by a few weeks of age. Clinical symptoms of COFS appear very similar to those of Cockayne Syndrome, and in fact, many geneticists are of the opinion that COFS is a part of the spectrum of Cockayne Syndrome.
The condition can be diagnosed prenatally through transabdominal ultrasound analysis. Differential diagnoses include Cockayne Syndrome (CS), Pena-Shokeir Syndrome I, Multiple Pterygium Syndrome, and Seckel Syndrome. However, the condition can be differentiated from CS by the presence of extensive calcifications in the brain and evidence of brain atrophy in CT scans. Respiratory complications of the condition are the most serious aspects, and most infants usually succumb to these before reaching five years of age. Treatment can only be supportive and is aimed at reducing the severity of the symptoms. Affected children may need a feeding tube.
COFS1 is caused by mutations in the ERCC6 (Excision Repair Cross-complementing Rodent Repair Deficiency, Complementation Group 6) gene. This is the same gene that is responsible for Cockayne Syndrome 2. The protein coded for by this gene is presumed to have a DNA or RNA unwinding function, and is involved in the preferential repair of active genes. It is not clear how these mutations exactly work towards the development of COFS1.
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 pinna, 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.
Sawardekar (2005) conducted a study to establish the prevalence of major congenital malformations in children born during a 10-year period in Nizwa Hspital. Of the 21,988 total births in the hospital, two children were born with COFS. Sawardekar (2005) hinted for a possible genetic contribution in these children.
Rafique and Zia (2012) described an 8-month old Saudi girl born to healthy consanguineous parents. The patient had two healthy older siblings, while a third sibling had died of unknown causes at the age of 2-years. The patient was born full term via vaginal delivery but had a birth weight of 2 kg. She showed a failure to thrive with severe developmental delays. Her anthropometric measurements at 8-months of age were all below the 3rd centile. On clinical examination, she was found to be microcephalic with deep set eyes. Facial dysmorphic features also included microphthalmia, low-set large ears, a beaked nose, a long philtrum, micrognathia and an overhanging upper lip. She displayed knee flexion contractures and her legs were in scissoring position. She was also found to suffer from hypertonia and hyperreflexia in all four limbs. Ophthalmological findings included strabismus and the inability to fixate her eyes. Neurological investigations suggested the presence of cerebral atrophy, increased extra-ventricular CSF spaces, demyelination of white matter and enhancement of basal ganglia. Based on these clinical findings, the patient was diagnosed with cerebrooculofacioskeletal syndrome.