Hypotrichosis 14: Novel variants of the LSS gene in five Chinese families and insights from literature review

Background: Congenital hypotrichosis 14 is a non-syndromic form of alopecia associated with mutations in the lanosterol synthase ( LSS ) gene. Recent studies have expanded the spectrum of LSS -related phenotypes, including congenital cataracts, alopecia-intellectual disability syndrome, and palmoplantar keratoderma. Currently, investigations into this disease are still limited, and its treatment remains elusive. Methods: In this study, we aimed to report six Chinese patients diagnosed with hypotrichosis 14, whose conditions were attributed to five novel and recurrent mutations in the LSS gene identified via whole exome sequencing. Moreover, published literature focusing on the LSS gene has also been reviewed. Results: We described six patients in five Chinese families presenting with hair loss, and one of them had a new accompanying phenotype of hypergonadotropic hypogonadism, which has rarely been reported. Five novel mutations were discovered in the LSS gene, including c.919_921del (p.His307del), c.1987C>T (p.Arg663Trp), c.982C>T (p.Arg328*), c.1405_1407del (p.Glu469del) and c.193_200dup (p.Pro68Argfs*14), along with recurrent mutations. We also reviewed all published literature focusing on the LSS gene and found that phenotypes included cataract alone (3/48), cataract with hypotrichosis 14 (4/48), hypotrichosis 14 alone (25/48), alopecia intellectual disability syndromes 4 (12/48), palmoplantar keratoderma-congenital alopecia syndrome type 2 (3/48) and palmoplantar keratoderma (1/48). The most frequent mutation was c.1025T>G (p.Ile342Ser). Conclusions: Our comprehensive summary of phenotypes caused by LSS gene variants not only enriches the existing knowledge on congenital hypotrichosis 14 but also provides crucial guidance for more accurate genetic counseling and potentially new directions for future research in understanding the disease mechanism and developing targeted therapies.