Cockayne syndrome (ORPHA:191)
Cockayne syndrome (CS) is a multisystem condition characterized by short stature, a characteristic facial appearance, premature aging, photosensitivity, progressive neurological dysfunction, and intellectual deficit.
Epidemiology
The annual incidence of CS is close to 1/200,000 in European countries.
Clinical description
Disease severity and the age of onset are variable. In classical type I CS, the first symptoms usually appear during the first year of life. Early-onset cases with more severe symptoms (type II) and late-onset cases with milder symptoms (type III) have also been described. Common signs of the disease include progressive growth failure, intellectual deficit, cerebellar ataxia, spasticity, peripheral demyelinating neuropathy, pigmentary retinopathy, sensorineural hearing loss and dental anomalies (presence of caries). The typical facial appearance includes microcephaly, large ears, a thin nose, and enophthalmia. Cataracts and cutaneous photosensitivity are observed in some patients. Subcutaneous lipoatrophy is present and can lead to signs of premature aging of the skin. COFS syndrome (see this term) is the extreme prenatal form of the CS clinical spectrum characterized by congenital microphthalmia and arthrogryposis.
Etiology
CS belongs to the family of NER (nucleotide excision repair)-related disorders together with xeroderma pigmentosum and trichothiodystrophy (see these terms). CS cells show a specific defect in transcription-coupled DNA repair (TCR), a subpathway of NER involved in the removal of UV-induced DNA lesions in actively transcribed genes. Additional defects in basal transcription or in oxidative repair have also been put forward to account for the noncutaneous symptoms of CS. Mutations have been described in two major genes, ERCC6 (CSB; 10q11) and ERCC8 (CSA; 5q12.1). So far, no correlation was found between the three types of CS and the genes involved.
Diagnostic methods
Diagnosis is based on detection of the specific TCR defect that can be identified using a radioactive assay in cultured fibroblasts that measures the recovery of RNA synthesis after UV irradiation. This DNA repair test is a decisive tool for the diagnosis of CS. Brain imaging reveals diffuse hypomyelination of the cerebral white matter, calcifications in the putamen, and vermian atrophy.
Differential diagnosis
The differential diagnosis mainly includes mitochondrial diseases that may show similar clinical features to those seen in CS.
Antenatal diagnosis
Prenatal diagnosis can be performed on amniocytes or chorionic cells (using the same cellular test as that employed in fibroblasts) or by direct molecular sequencing if the causative mutations in the family have already been identified.
Genetic counseling
Transmission is autosomal recessive.
Management and treatment
Management is purely supportive and includes physiotherapy, sun protection, hearing aids and often tube feeding or gastrostomy.
Prognosis
In CS type I, death occurs before the end of the second decade as a result of progressive neurologic degeneration. Patients with type II present with a more severe prognosis, whereas patients with type III live into adulthood.

                            Last update: 
                            May 2009


                            - Expert reviewer(s): 
                            Pr Hélène DOLLFUS  - Pr Vincent LAUGEL