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At a glance

A complex inherited disorder characterized by the association of dwarfism, deafness, microcephaly, facial anomalies, ataxia, photosensitivity, retinal atrophy, and renal insufficiency with premature aging and atherosclerosis.

Synonyms

Deafness-Dwarfism-Retinal Atrophy; Dwarfism with Renal Atrophy and Deafness; Neill-Dingwall Syndrome; Progeroid Nanism.

History

First described in 1936 by the English Physician Edward Alfred Cockayne.

Incidence

Estimated to be in the range of 0.5-1:200,000 live births. No ethnic or sexual predilection has been reported.

Genetic inheritance

Autosomal recessive. Cockayne Syndrome (CS) Type I (also called Type A, see “Clinical Aspects”) results from a defect in the ERCC8 (Excision Repair Cross-Complementing, Group 8) gene (also known as CSA gene), which is located on chromosome 5q12.1. Cells carrying the mutated ERCC8 gene exhibit a hypersensitivity to ultraviolet light and after exposure to it, these cells fail to recover their ability to synthesize RNA and to repair or excise and degrade lesions in DNA strands. In CS Type II (Type B), the mutations affect the ERCC6 (Excision Repair Cross-Complementing, Group 6) gene (also known as CSB gene), which has been mapped to chromosome 10q11.23. In two-thirds of the CS patients the mutations are located in the ERCC6 gene, and in one-third they are found in the ERCC8 gene.

Pathophysiology

CS is considered a nucleotide excision repair disorder. The transcription-coupled repair of oxidative damages to the DNA is defective and contributes to developmental defects.

Diagnosis

In classic CS I, the diagnosis is based on the clinical findings, whereas the “non-classic” form is confirmed by DNA repair assays in lymphoblasts or skin fibroblasts. In older children, classic CS I should be suspected in the presence of both major and three minor criteria (see below). In infants or toddlers, the diagnosis is likely when one minor and both major criteria are fulfilled and abnormalities in DNA repair are present. The major criteria consist of (1) postnatal growth retardation (height and weight below the 5th percentile at 2 years of age resulting in “cachectic dwarfism” appearance) and (2) progressive neurologic dysfunction (early developmental delay and progressive deterioration). Intracranial pericapillary calcifications (in cortex and basal ganglia), leukodystrophy with scattered neuronal loss, and normal pressure hydrocephalus may be present. The seven minor criteria are (1) dermal photosensitivity (poikiloderma), (2) pigmentary retinopathy, blindness, and/or cataracts, (3) diffuse and segmental peripheral demyelination with decreased nerve conduction velocity, (4) sensorineural hearing loss, (5) sclerotic epiphyses, vertebral and pelvic abnormalities, thickening of the calvarium, (6) thin skin and brittle hair, sunken eyes (enophthalmia), and stooped standing posture, and (7) dental cavities. In CS II, the diagnosis is based on the findings of failure to thrive beginning right after birth with severely delayed gains in height and weight combined with absent or minimal progress ...

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