Expanding the Genotypic Spectrum of Bathing Suit Ichthyosis

Abstract

IMPORTANCE Bathing suit ichthyosis (BSI) is a rare congenital disorder of keratinization characterized by restriction of scale to sites of relatively higher temperature such as the trunk, with cooler areas remaining unaffected. Fewer than 40 cases have been reported in the literature. Bathing suit ichthyosis is caused by recessive, temperature-sensitive mutations in the transglutaminase-1 gene (TGM1). Clear genotype-phenotype correlations have been difficult to establish because several of the same TGM1 mutations have been reported in BSI and other forms of congenital ichthyosis. We identify novel and recurrent mutations in 16 participants with BSI. OBJECTIVE To expand the genotypic spectrum of BSI, identifying novel TGM1 mutations in patients with BSI, and to use BSI genotypes to draw inferences about the temperature sensitivity of TGM1 mutations. DESIGN, SETTING, AND PARTICIPANTS A total of 16 participants with BSI from 13 kindreds were identified from 6 academic medical centers. A detailed clinical history was obtained from each participant, including phenotypic presentation at birth and disease course. Each participant underwent targeted sequencing of TGM1. MAIN OUTCOMES AND MEASURES Phenotypic and genotypic characteristics in these patients from birth onward. RESULTS Of the 16 participants, 7 were male, and 9 were female (mean age, 12.6 years; range, 1-39 years). We found 1 novel TGM1 indel mutation (Ile469_Cys471delinsMetLeu) and 8 TGM1 missense mutations that to our knowledge have not been previously reported in BSI: 5 have been previously described in non-temperature-sensitive forms of congenital ichthyosis (Arg143Cys, Gly218Ser, Gly278Arg, Arg286Gln, and Ser358Arg), and 3 (Tyr374Cys, Phe495Leu, and Ser772Arg) are novel mutations. Three probands were homozygous for Arg264Trp, Arg286Gln, or Arg315Leu, indicating that these mutations are temperature sensitive. Seven of 10 probands with a compound heterozygous TGM1 genotype had a mutation at either arginine 307 or 315, providing evidence that mutations at these sites are temperature sensitive and highlighting the importance of these residues in the pathogenesis of BSI. CONCLUSIONS AND RELEVANCE Our findings expand the genotypic spectrum of BSI and the understanding of temperature sensitivity of TGM1 mutations. Increased awareness of temperature-sensitive TGM1 genotypes should aid in genetic counseling and provide insights into the pathophysiology of TGM1 ichthyoses, transglutaminase-1 enzymatic activity, and potential therapeutic approaches.