Complex phenotypes in trichothiodystrophy patients with XPD (ERCC2) mutations

Trichothiodystrophy (TTD), Cockayne syndrome (CS) and Cerebro-Oculo-Facial-Skeletal syndrome (COFS) are rare, autosomal recessive disorders with defective DNA repair. Overlaps of different DNA repair disorders in the same patient were reported including xeroderma pigmentosum (XP)/CS complex and XP/TTD. We describe 6 TTD patients in 5 families with XPD (ERCC2) mutations and clinical features of CS or COFS. All presented with major features of TTD (“tiger tail” banding on polarized microscopy, skin abnormalities, short stature and developmental delay). Three patients (TTD406BE and TTD407BE, 9 yo (d19 yo) and 7 yo sisters; and XP624BE, 5 yo boy) also had CS features including deep-set eyes and postnatal growth failure. TTD406BE and TTD407BE had CS type pigmentary retinopathy. Three patients (TTD373BE 13 mo girl with early death; TTD522BE 10 yo girl; and, TTD633BE 13 mo girl) also had features of COFS with microcephaly, congenital cataracts, facial dysmorphism and skeletal abnormalities. DNA sequencing revealed each patient was a compound heterozygote with mutations in XPD; TTD406BE and TTD407BE had R112H (reported in TTD, XP/TTD, XP/CS) and L461V,V716_R730del (reported in XP,TTD, XP/CS). XP624BE had L461V,V716_R730del and G675R (reported in XP/CS). TTD373BE had R616W and D681N, both reported in COFS, TTD and XP. TTD633BE had D681N and L461V,V716_R730del. TTD522BE had F568YfsX2 (reported in TTD, XP/TTD) and a novel mutation, D240G. Different XPD repair/ transcription gene defects are associated with complex clinical phenotypes and may reflect interactions of different alleles or of modifier genes. These findings may give insight into the genotype-phenotype relationship.