Case Report: Compound heterozygous variants in LSS and TSPEAR genes causing hypotrichosis type 14 complicated with...

To describe the clinical features and genetic findings in a child with hypotrichosis type 14 (HYPT14, OMIM: 618275) complicated by ectodermal dysplasia type 14 (ED14, OMIM: 618180) harboring compound heterozygous variants in LSS (OMIM: 600909) and a heterozygous variant in TSPEAR (OMIM: 612920), to summarize the potential phenotypic impact of concurrent variants in both genes, and to provide evidence relevant to diagnosis and mechanistic investigation of related diseases.

Clinical data were collected. Peripheral blood samples from the child and his mother were obtained for next-generation sequencing-based variant screening. Sanger sequencing was used for segregation analysis of candidate variants. In addition, relevant studies were reviewed to contextualize the reported phenotypes associated with LSS and TSPEAR variants and to discuss potential biological interactions.

The child carried compound heterozygous variants in LSS: c.1025T>G; p.(Ile342Ser) and c.3G>A (maternally inherited), and a heterozygous variant in TSPEAR, c.872G>A; p.(Arg291Gln). All variants were classified as variants of uncertain significance (VUS) under current ACMG criteria, and a definitive causal relationship with the phenotype cannot be established at present. Nevertheless, the patient's phenotype showed overlap with reported features of HYPT14 and ED14 and adds clinical data that may support future variant reclassification as additional evidence accumulates. Immunomodulatory therapy, including a JAK inhibitor, produced only a transient response and did not result in sustained hair regrowth.

Coexisting LSS and TSPEAR variants may contribute to a phenotype of HYPT14 complicated by ED14 in this child. Because the variants remain VUS, genotype-phenotype inferences should be made cautiously. The findings raise the possibility that oligogenic effects may exacerbate ectodermal abnormalities. To our knowledge, this is the first reported case of digenic inheritance involving LSS and TSPEAR, which expands the clinical spectrum of LSS- and TSPEAR-associated disorders and supports consideration of broader genetic testing in children with congenital hypotrichosis and ectodermal features.