PD04 Clinical spectrum and outcomes in a cohort of patients with trichothiodystrophy: a single-centre experience

Abstract

Trichothiodystrophy (TTD) is a rare, autosomal recessive, multisystem disorder, characterized by brittle sulfur-deficient hair with ‘tiger tail’ banding on polarized light microscopy. TTD results from pathogenic variants in DNA repair or transcription genes (ERCC2, ERCC3, GTF2H5), which encode components of transcription factor IIH, and MPLKIP, a gene implicated in mRNA splicing. The existing literature is largely limited to small case series or systematic reviews with incomplete phenotypic data. We aimed to characterize phenotypic variability and genotype correlations within a UK national service, highlighting the spectrum of dermatological findings. This retrospective observational study included patients with genetically confirmed TTD receiving multidisciplinary care within a UK national service (2017–2026). Data on demographics, genotype, cutaneous and extracutaneous manifestations, infection burden and mortality were extracted from clinical records. Sixteen patients were identified (7 male; median age 13 years, range 3–41); 11 had pathogenic variants in ERCC2, 3 in GTF2H5 and 2 in MPLKIP. All had brittle hair, with 15 of 16 demonstrating ‘tiger tail’ banding. Photosensitivity was present in 13 of 14 with ERCC2 and GTF2H5 variants, while those with MPLKIP variants were not photosensitive. Maternal pregnancy complications, collodion membrane at birth and subsequent ichthyosis were reported in all with ERCC2 and GTF2H5 variants, but none with MPLKIP variants. Nail abnormalities affected 13 of 16. Neurological abnormalities with global developmental delay were universal. Ocular abnormalities occurred in 11 of 14 with ERCC2 or GTF2H5 variants, most commonly congenital cataracts. All patients had short stature and 12 of 16 were microcephalic. Recurrent infections affected 11 of 14 with ERCC2 and GTF2H5 variants, but none with MPLKIP variants. Three patients with ERCC2 variants died (ages 1.5–28 years), two from pneumonia. This cohort represents one of the larger contemporary TTD cohorts and highlights the clinical spectrum of cutaneous findings that are often presenting features. Coordinated multidisciplinary care is essential to manage the significant neurological and immunological complications.