This is a very rare autosomal recessive disorder characterized by growth failure leading to extremely short stature, evident within the first few years after birth (described as “cachectic dwarfism”), lack of subcutaneous fat, cutaneous photosensitivity, deafness, progressive optic atrophy, neurological deterioration with a leukodystrophy, and mental retardation. There is brain dysmyelination with calcium deposits. There is a typical “salt and pepper” retinitis and/or cataracts. These features develop from late infancy, but there is considerable variability of the phenotype, even within families (Mahmoud et al. 2002). Characteristic facial features include large ears, sunken eyes, and limbs that are relatively long. There is type II hyperlipoproteinemia. Knee contractures may occur, causing a “horse-riding stance,” and delayed neural development and neurological degeneration cause mental retardation. Mean age at death is 12.5 years but varies a great deal. There appears to be a deficiency of DNA repair after exposure to UV light and deficiency in cellular repair of oxidative DNA damage. Death usually occurs before the age of 20 years, and malignancy is not reported to be specifically increased in this condition. The disease is genetically heterogeneous, and genes for complementation groups CS-A and CS-B have been identified (Stefanini et al. 1996). Cockayne syndrome type A is caused by biallelic mutations in the gene encoding the group 8 excision repair cross-complementing protein (ERCC8; www.omim.org/entry/609412) on chromosome 5q11. Cockayne syndrome type B (CSB; www.omim.org/entry/133540) is caused by the mutation in the ERCC6 gene.
Bertola et al. (2006) analyzed the ERCC8 gene in Brazilian families with typical CSA and identified homozygosity or compound heterozygosity for ERCC8 mutations in them, with no clear genotype/phenotype correlation. The CS-B gene product is involved in transcription-coupled and/or global genome nucleotide excision repair of DNA damage induced by UV light and other oxidative DNA damage (Mahmoud et al. 2002; Osterod et al. 2002; Tuo et al. 2003). Notably, in contrast to human Cockayne syndrome, homozygous knockout mice for the murine orthologue of the human CSA gene (Csa3/3) develop skin Tumours after chronic exposure to UV light (van der Horst et al. 2002). The reason why humans with Cockayne syndrome do not develop skin cancer is not known. Interestingly, other cases of Cockayne
syndrome with features overlapping with those of xeroderma pigmentosum (XP) is due to mutations in the XPB, XPD, or XPG genes (Rapin et al. 2000). XPG and CSB mutations may also be responsible for the cerebro- oculo-facio-skeletal (COFS) syndrome (Graham et al. 2001). COFS is another autosomal recessive neurodegenerative disorder with growth failure, joint contractures, cataracts, microcornea, and optic atrophy.