A number sign (#) is used with this entry because of evidence that cerebrooculofacioskeletal syndrome-4 (COFS4) is caused by homozygous or compound heterozygous mutation in the ERCC1 gene (126380) on chromosome 19q13.

Cerebrooculofacioskeletal syndrome-4 (COFS4) is a severe autosomal recessive disorder characterized by growth retardation, dysmorphic facial features, arthrogryposis, and neurologic abnormalities. Cellular studies show a defect in both transcription-coupled and global genome nucleotide excision repair (TC-NER and GG-NER) (summary by Jaspers et al., 2007 and Kashiyama et al., 2013).

For a discussion of genetic heterogeneity of cerebrooculofacioskeletal syndrome, see 214150.

Jaspers et al. (2007) described a patient with COFS who was the child of nonconsanguineous white Italian parents. The patient was born after a 37-week pregnancy complicated by intrauterine growth retardation. Amniocyte analysis did not reveal any karyotypic abnormality. At birth, the patient's weight, length, and occipitofrontal circumference were below the 3rd percentile. The infant had microcephaly with premature closure of fontanels, bilateral microphthalmia, blepharophimosis, high nasal bridge, short philtrum, micrognathia, low-set and posteriorly rotated ears, arthrogryposis with rocker-bottom feet, flexion contractures of the hands, and bilateral congenital hip dislocation. On x-rays, there was no evidence for spine abnormalities. Nuclear magnetic resonance revealed a simplified gyral pattern and cerebellar hypoplasia. There was mild hypoplasia of the kidneys, with normal structure and function. Echography did not reveal any congenital heart defects. Although other dysmorphology syndromes, such as Warburg Micro syndrome (600118) and Cockayne syndrome (see 216400), were considered, COFS was the preferred diagnosis because of the absence of genital abnormalities and retinopathy. The infant failed to thrive, was tube fed, and did not pass any developmental milestone. Respiratory failure due to bilateral pneumonia was the cause of death at age 14 months. His weight was 4.5 kg and occipital frontal circumference was 38 cm at the time of death.

Kashiyama et al. (2013) reported a girl with multiple congenital anomalies. At 4 to 6 months of age, she had microcephaly, micrognathia, deep-set eyes, and contractures of the knees and elbows. Skeletal abnormalities included a dislocated radial head, camptodactyly, adducted thumbs, stiff limbs, steeply sloping acetabula, wrist contracture, slender long bones with mildly flared metaphyses, and moderate kyphoscoliosis. She was hypertonic and had brisk reflexes. Brain MRI at birth showed possible polymicrogyria; a nuclear magnetic resonance (NMR) scan at age 4 months showed no major malformations. EEG was abnormal at 9 months. At 16 months of age, she had nystagmus, but no additional ophthalmic abnormalities. She died at age 2.5 years. This patient was diagnosed as having Cockayne syndrome on the basis of impaired RNA synthesis after UV radiation, indicating a defect in TC-NER. Patient cells also showed a decrease in unscheduled DNA synthesis, indicating a defect in global genome NER (GG-NER). The cellular defects were restored by transfection with wildtype ERCC1.

The transmission pattern of COFS4 in the family reported by Jaspers et al. (2007) was consistent with autosomal recessive inheritance.

In a patient with cerebrooculofacioskeletal syndrome, Jaspers et al. (2007) detected compound heterozygosity for mutations in the ERCC1 gene. On the maternal allele, a C-to-T transition was predicted to introduce a premature stop codon (126380.0001); the paternal allele carried a missense mutation (F231L; 126380.0002).

In a patient with severe growth and skeletal abnormalities resulting in early death and associated with defective NER, Kashiyama et al. (2013) identified a homozygous F231L mutation in the ERCC1 gene. Patient cells showed decreased expression of both ERCC1 and ERCC4 (133520). The mutation was demonstrated to result in significantly decreased expression of the mutant ERCC1 protein.