Biallelic Variants in Lanosterol Synthase (LSS) Cause Palmoplantar Keratoderma-Congenital Alopecia Syndrome Type 2

The study identified biallelic variants in the LSS gene as the cause of palmoplantar keratoderma-congenital alopecia syndrome type 2 in two unrelated cases. The LSS gene, which encodes lanosterol synthase, plays a role in the cholesterol biosynthesis pathway. The identified variants led to a decrease in LSS and lanosterol levels, indicating a loss of enzymatic activity. This resulted in abnormal cornified envelope formation in the patients' skin, severe skin hyperkeratosis affecting the palms and soles, early-onset cataracts, strabismus, alopecia, and anagenesis of the corpus callosum. The study also found that specific LSS variants, LSS-ΔN80 and Ile342Ser, led to unstable proteins that were likely degraded, causing an imbalance in skin lipids. This imbalance may contribute to conditions like alopecia and skin hyperkeratosis. The findings suggest potential therapeutic strategies targeting these LSS variants, such as the use of lanosterol to alleviate cataract severity.