LSS – Hypotrichosis Simplex

Hypotrichosis simplex is a rare form of congenital alopecia characterized by isolated scalp hair loss without systemic involvement. LSS encodes lanosterol synthase, a key enzyme in cholesterol biosynthesis necessary for hair follicle maintenance.

Initial evidence came from a Chinese Tibetan family in which two siblings with early-onset scalp hair loss were found to carry a homozygous missense variant c.812T>C (p.Ile271Thr) in LSS; their asymptomatic parents were heterozygous carriers (PMID:36685177).

A follow-up multi-patient study in two unrelated Chinese families reported three pediatric probands with hypotrichosis simplex harboring compound heterozygous LSS variants identified by exome sequencing, expanding the allelic spectrum and noting an accompanying phenotype of dental dysplasia in one patient (PMID:33222230).

In total, five probands from three unrelated families have been described, all with biallelic missense or loss‐of‐function variants consistent with autosomal recessive inheritance and no additional ectodermal abnormalities.

Functional validation using epidermis‐specific Lss knockout mice demonstrated neonatal hypotrichosis, skin barrier defects, and elevated (S)-2,3-epoxysqualene/lanosterol ratios in sebum, confirming that LSS loss-of-function underlies hair follicle pathology (PMID:32101538).

Together, the genetic and experimental data support a Moderate clinical validity for the association between LSS and hypotrichosis simplex. Key Take-home: Biallelic LSS variants cause autosomal recessive hypotrichosis simplex via enzyme deficiency, informing molecular diagnosis and genetic counseling.

References

• Frontiers in physiology • 2022 • A novel homozygous mutation in LSS gene possibly causes hypotrichosis simplex in two siblings of a Tibetan family from the western Sichuan province of China. PMID:36685177
• The Journal of dermatology • 2021 • Novel mutations in Chinese hypotrichosis simplex patients associated with LSS gene. PMID:33222230
• PLoS genetics • 2020 • Metabolic and pathologic profiles of human LSS deficiency recapitulated in mice. PMID:32101538

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