Cerebro-Oculo-Facio-Skeletal Syndrome

Cerebro-oculo-facio-skeletal (COFS) syndrome is a severe autosomal recessive disorder of nucleotide excision repair, due to biallelic variants in ERCC6, ERCC5, ERCC2 or ERCC1. It presents in the neonate or foetus with microcephaly, cataracts, arthrogryposis, growth failure and neurodegeneration, and it lies at the severe end of the Cockayne syndrome spectrum.

Pathophysiology. The ERCC proteins take part in transcription coupled repair and global genome repair of ultraviolet induced DNA damage. Failed repair stalls transcription and leads to neuronal loss, demyelination and early death.

Most children die in early childhood, but longer survival occurs with milder variants.

Care is supportive, with attention to avoidable harms.

• Microcephaly, often congenital, with deep set eyes, prominent nasal root, and a large pinna
• Congenital cataracts, microphthalmia, optic atrophy and nystagmus
• Arthrogryposis with contractures of the joints, rocker bottom feet, and kyphoscoliosis
• Severe growth failure and cachexia
• Profound developmental delay and hypotonia, later spasticity
• Seizures, brain calcification and white matter loss on imaging
• Feeding difficulty, reflux and aspiration
• Sensorineural hearing loss
• Photosensitivity in some, and dental caries
• Hepatic or renal dysfunction in some

• Sequencing of ERCC6, ERCC8 and the related genes (ERCC5, ERCC2, ERCC1, ERCC3), usually within a panel or exome sequencing, with deletion and duplication analysis.
• Functional assay: reduced recovery of RNA synthesis after ultraviolet exposure in fibroblasts supports the diagnosis.
• Brain MRI and CT: microcephaly, hypomyelination, and basal ganglia calcification.
• Ophthalmology, audiology, liver and renal assessment.
• Prenatal ultrasound: severe growth restriction, arthrogryposis and microcephaly in a recurrent pregnancy.
• Parental carrier testing to confirm biallelic variants.

Differential diagnosis.

• Cockayne syndrome types I to III and xeroderma pigmentosum with neurological disease
• Trichothiodystrophy
• Neu-Laxova syndrome
• Congenital infection (cytomegalovirus, Zika)
• Aicardi-Goutières syndrome

• Avoid harmful drugs: do not give metronidazole, because fatal liver failure has been reported in Cockayne syndrome. Use cautious dosing of other hepatotoxic and ototoxic drugs.
• Feeding and nutrition: dietitian input, gastrostomy for unsafe swallow, and omeprazole 0.7 to 1 mg/kg daily for reflux.
• Respiratory care: chest physiotherapy, prompt treatment of infection, and vaccination.
• Seizures: levetiracetam 10 mg/kg twice daily increasing to 30 mg/kg twice daily. Provide a rescue plan: buccal midazolam 0.3 mg/kg (maximum 10 mg) for a seizure lasting over 5 minutes.
• Contractures and spasticity: physiotherapy, positioning, orthotics and baclofen 0.3 mg/kg daily in divided doses increasing weekly to 2 mg/kg daily (maximum 60 mg).
• Eye and hearing care: cataract surgery when it will improve visual input, lubricants, hearing aids.
• Sun protection: broad spectrum sunscreen, clothing and avoidance of strong sunlight for photosensitive patients.
• Dental care: early dental review and fluoride.
• Palliative care: early involvement with symptom control (including morphine 0.05 to 0.1 mg/kg orally every 4 hours as needed for pain or dyspnoea) and support for the family.
• Genetic counselling: a 25% recurrence risk in each pregnancy; offer prenatal diagnosis once the familial variants are known.

Special groups.

• Families with a previous affected child: offer testing of chorionic villus samples or amniotic fluid.

Monitoring. Growth, feeding and respiratory status at each visit. Liver tests and hearing yearly, and symptom review frequently.

Referral and escalation. Refer to clinical genetics, paediatric palliative care and neurology. Emergency for aspiration, respiratory failure or prolonged seizures.