Cockayne syndrome

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What is Cockayne syndrome?

Cockayne syndrome is a rare genetic multisystem degenerative disorder presenting with microcephaly, growth failure, photosensitivity, and features of premature ageing.

Who gets Cockayne syndrome?

Cockayne syndrome is an autosomal recessive genetic disorder that affects all races and both sexes equally. It has a worldwide prevalence of approximately 2.5 cases per million, and an incidence of 1 in 250,000 live births.

What causes Cockayne syndrome?

Cockayne syndrome results from mutations in excision repair cross complementation (ERCC) genes. There is considerable genetic heterogeneity. It has been classified as CSA and CSB based on the affected gene, ERCC8 or ERCC6 respectively. CSB due to ERCC6 mutations accounts for 80% of cases of Cockayne syndrome. Xeroderma pigmentosum-Cockayne syndrome overlap (XP/CS) complex is a distinct genotype/phenotype with mutations in other ERCC genes (ERCC2, ERCC3, XPD).

Mutations in ERCC genes can cause defective DNA repair following UV radiation exposure. However, the pathogenesis of Cockayne syndrome is more complex than this, as changes can be seen in the fetus and at birth before there has been UV exposure, and typically involves the nervous system in cells never exposed to UV. Clinically, Cockayne syndrome resembles mitochondrial diseases.

Genetics of Cockayne syndrome 

What are the clinical features of Cockayne syndrome?

Cockayne syndrome is characterised by microcephaly and failure to grow after birth, in association with other clinical signs. It is classified into three types based on the age of presentation and clinical features, but this does not necessarily correlate with the genetic classification.

• Cockayne syndrome type 1 (CS-1) — classical form presents in early childhood (1–2 years of age) after normal intrauterine development and growth.
• Cockayne syndrome type 2 (CS-2) — severe form presents at birth or early infancy, typically with intrauterine growth failure.
• Cockayne syndrome type 3 (CS-3) — mild or atypical form with late presentation after the age of 2 years.

There is however considerable phenotypic variability even between affected siblings with the same genotype, and there is a continuous spectrum of clinical features.

Cutaneous features of Cockayne syndrome

• Photosensitivity* – major diagnostic feature but variable in degree, including sunburn on even minimal exposure.
• Cold extremities* – persistently cold hands and feet which may be disproportionately large
• Loss of subcutaneous fat*
• Premature ageing of skin with wrinkling
• Thin, dry hair with premature greying
• Hypohidrosis.

Common features of Cockayne syndrome

• Typical facial features* — beaked nose, deep sunken eyes, progeria-like features
• Bilateral sensorineural high tone hearing loss*
• Intention tremor*
• Joint contractures* — most commonly of the lower extremities
• Cataracts by 4 years of age*
• Proportionate short stature
• Early development may appear normal, but subsequent delays will result in progressive deterioration in behaviour and intellect
• Eye — in addition to cataracts, progressive ‘salt and pepper pattern’ retinal pigmentation is characteristic of Cockayne syndrome. Other eye signs reported include nystagmus and strabismus.

What are the complications of Cockayne syndrome?

Complications resulting from Cockayne syndrome can include the following:

• Dental anomalies — caries, enamel hypoplasia, abnormal tooth shape, or number
• Hypertension
• Renal failure
• Premature atherosclerosis
• Gastroesophageal reflux can be severe causing feeding difficulties
• Progressive peripheral motor and sensory neuropathy causing difficulty walking, bladder, and bowel disturbances
• Skin cancer, but not other malignancies
• Acute, sometimes fatal, liver failure due to metronidazole, which is therefore contraindicated in Cockayne syndrome.

How is Cockayne syndrome diagnosed?

Cockayne syndrome should be suspected in a child with postnatal failure to thrive, microcephaly, and two of the other starred (*) clinical findings.

Diagnosis is confirmed on genetic testing and the demonstration of mutations in the ERCC genes. This can direct parental genetic testing and prenatal diagnosis in subsequent pregnancies.

CT and MRI scans may demonstrate a variety of neuropathologies, including severe cerebral white matter atrophy leading to microcephaly, cerebellar atrophy, basal ganglia calcification, and patchy demyelination (‘tigroid leukodystrophy’).

What is the differential diagnosis for Cockayne syndrome?

• Xeroderma pigmentosum
• Progeria
• Rothmund-Thomson syndrome
• Bloom syndrome.

What is the treatment for Cockayne syndrome?

There is no cure for Cockayne syndrome. Treatment is supportive and directed at preventing and managing complications.

General measures

• Sun protection for the skin and eyes
• Physiotherapy/occupational therapy
• Nutritional support.

Specific measures

Regular surveillance is recommended for the development of complications, including:

• Dental care
• Eye care
• Hearing assessment
• Blood pressure monitoring
• Blood tests — kidney function, liver function, blood sugar.

Genetic counselling may be recommended for family members.

What is the outcome for Cockayne syndrome?

Cockayne syndrome is associated with reduced life expectancy with a mean age at death of 12 years: CS-1, 16 years; CS-2, 5 years; CS-3, above 30 years. The most common cause of death is respiratory complications such as pneumonia.