Two individuals with features of both xeroderma pigmentosum and trichothiodystrophy highlight the complexity of the clinical outcomes of mutations inthe XPD gene

The xeroderma pigmentosum group D (XPD) protein is a subunit of transcripti on factor TFIIH with DNA helicase activity. TFIIH has two functions, in bas al transcription and nucleotide excision repair. Mutations in XPD that affe ct DNA repair but not transcription result in the skin cancer-prone disorde r, xeroderma pigmentosum (XP). If transcription is also affected, the resul t is the multi-system disorder trichothiodystrophy (TTD), in which there is no skin cancer predisposition, or in rare cases, XP combined with Cockayne syndrome. Up till now there have been no reports of combined clinical feat ures of XP and TTD. We have now identified two patients with some features of both these disorders. One of these, XP189MA, a 3-year-old girl with sun sensitivity, mental and physical developmental delay, has XPD mutations not previously reported, and barely detectable levels of nucleotide excision r epair. The other, XP38BR, a 28-year-old woman with sun sensitivity, pigment ation changes and skin cancers typical of XP, has a mutation that has been identified previously, but only in TTD patients with no features of XP. The level of repair of UV damage in XP38BR is substantially higher than that i n other patients with the same mutation. With both patients, polarized ligh t microscopy revealed a 'tiger-tail' appearance of the hair, and amino acid analysis of the hairshafts show levels of sulfur-containing proteins inter mediate between those of normal and TTD individuals. Our findings highlight the complexities of genotype-phenotype relationships in the XPD gene.