Eroderma Pigmentosum, Trichothiodystrophy Nd Cockayne Syndrome: a Complex Enotype–phenotype Relationship

bstract—Patients with the rare genetic disorders, xeroerma pigmentosum (XP), trichothiodystrophy (TTD) and ockayne syndrome (CS) have defects in DNA nucleotide xcision repair (NER). The NER pathway involves at least 28 enes. Three NER genes are also part of the basal transcripion factor, TFIIH. Mutations in 11 NER genes have been ssociated with clinical diseases with at least eight overlaping phenotypes. The clinical features of these patients have ome similarities but also have marked differences. NER is nvolved in protection against sunlight-induced DNA damge. While XP patients have 1000-fold increase in susceptiility to skin cancer, TTD and CS patients have normal skin ancer risk. Several of the genes involved in NER also affect omatic growth and development. Some patients have short tature and immature sexual development. TTD patients have ulfur deficient brittle hair. Progressive sensorineural deafess is an early feature of XP and CS. Many of these clinical iseases are associated with developmental delay and proressive neurological degeneration. The main neuropatholgy of XP is a primary neuronal degeneration. In contrast, CS nd TTD patients have reduced myelination of the brain. hese complex neurological abnormalities are not related to unlight exposure but may be caused by developmental deects as well as faulty repair of DNA damage to neuronal cells nduced by oxidative metabolism or other endogenous rocesses. © 2006 IBRO. Published by Elsevier Ltd. All rights eserved.