Trichothiodystrophy: Update on the sulfur-deficient brittle hair syndromes

Trichothiodystrophy (TTD) refers to a heterogeneous group of autosomal rece ssive disorders that share the distinctive features of short, brittle hair and an abnormally low sulfur content. Within the spectrum of the TTD syndro mes ale numerous interrelated neuroectodermal disorders. The TTD syndromes show defective synthesis of high-sulfur matrix proteins. Abnormalities in e xcision repair of ultraviolet (UV)-damaged DNA are recognized in about half of the patients. Three distinct autosomal recessive syndromes are associat ed With nucleotide excision repair (NER) defects: the photosensitive form o f TTD, xeroderma pigmentosum, and Cockayne syndrome. The unifying feature o f these conditions is exaggerated sensitivity to sunlight and UV radiation. In contrast to patients with xeroderma pigmentosum, no increase of skin ca ncers in patients with TTD has been observed. Genetically, 3 complementatio n groups have been characterized among photosensitive patients with TTD. Mo st patients exhibit mutations on the two alleles of the XPD gene. Rarely, m utated XPB gene or an unidentified TTD-A gene may result in TTD. In UV-sens itive TTD, the TFIIH transcription factor containing XPB and XPD helicase a ctivities necessary for both transcription initiation and DNA repair is dam aged. Beyond deficiency in the NER pathway, it is hypothesized that basal t ranscription may be altered leading to decreased transcription of specific genes. Depressed RNA synthesis may account for some clinical features, such as growth retardation, neurologic abnormalities, and brittle hair and nail s. Therefore the attenuated expression of some proteins in differentiated c ells is most likely explained by a mechanism distinct from DNA repair defic iency. The first transgenic mouse models for NER deficiencies have been gen erated. The TTD mouse as well as related cell models will provide important tools to understand the complex relationships between defects in DNA repai r, low-sulfur hair shaft disorders, and the genotype-phenotype correlates. for this constellation of inherited disorders, including the lack of predis position to cancer in patients with TTD.