Trichothiodystrophy: Current Concepts

Background: Trichothiodystrophy (TTD) is a rare, autosomal recessive disorder in which the hair identifies a group of genetic disorders with deficient high-sulfur matrix proteins, and a defect in excision repair of ultraviolet damage in fibroblasts of most patients. TTD patients may be grouped as follows: (1) the major group with defects in the excision repair cross-complementing gene ERCC2, the gene for xeroderma pigmentosum group D (XP-D); (2) those with defects in ERCC3, the gene for XP-B; and (3) those with a repair defect distinct from those in XP-D and XP-B. In contrast to XP patients, TTD patients have no increased frequency of skin cancers. Objective: The article explains the relationship of TTD and XP and helps clarify why TTD patients with defects in the same gene(s) as those with XP do not have increased skin cancers. Methods: Methods include biochemical studies, mutational analysis, and genomic sequence analysis of cell lines from skin biopsies of TTD and XP patients. Results: The ERCC2 gene is a component of the TFIIH complex which controls two distinct DNA-metabolizing processes, transcription initiation and nucleotide excision repair. Conclusion: In TTD, the major defect is in transcription initiation, whereas in XP-D, DNA repair is primarily altered.