Xeroderma pigmentosum, Cockayne syndrome and trichothiodystrophy

Introduction Xeroderma pigmentosum (XP), Cockayne syndrome (CS), and trichothiodystrophy (TTD) are rare neurocutaneous disorders caused by mutations in genes involved with nucleotide excision repair (NER) and also DNA transcription. Initially these recessive disorders were categorized clinically (Table 29.1) and by complementation studies, but more recently specific genes have been identified for most of the different subtypes (Table 29.2). Genotypic and phenotypic characteristics are being studied to determine the basis for the clinical heterogeneity within each disorder and across (overlap) entities, including XP neurological (DeSanctis-Cacchione) syndrome and xeroderma pigmentosum/Cockayne syndrome (XP–CS). Thus, specific mutation sites may determine abnormal protein–protein interactions as subunits in a protein complex involved in NER and/or DNA transcription. Study of these interactions has helped to clarify the clinical features of specific disorders, including sensitivity to ultraviolet (UV) light, propensity to cutaneous neoplasms (XP disorders), overlap syndromes, and a greater appreciation of the importance of normal DNA repair mechanisms and how DNA repair, replication, transcription and translation mechanisms interact at a molecular level. Currently treatment of these disorders is limited to avoidance of sunlight or other sources of UV light, monitoring and removal of skin neoplasms, and symptomatic treatment of other features. Improved understanding of genetic and molecular mechanisms may result in innovative approaches to diagnosis, prevention, and management of these rare neurocutaneous disorders and could lead to better understanding and management of disorders of aging, neoplasia, and neural degeneration.