Segmental basaloid follicular hamartomas derive from a post-zygotic SMO p.L412F pathogenic variant and express hair follicle development-related proteins in a pattern that distinguish them from basal cell carcinomas

Am J Med Genet A. 2022 Dec;188(12):3525-3530. doi: 10.1002/ajmg.a.62951. Epub 2022 Aug 16.

Abstract

Basaloid follicular hamartomas (BFH) are benign small basaloid skin tumors that can present as solitary or multiple lesions. Congenital BFH lesions arranged in a segmental distribution have been described, suggesting they derive from a somatic post-zygotic mutational event. Previously, BFH were described in Happle-Tinschert syndrome, which results from a post-zygotic SMO variant and is characterized by segmental BFH with variable involvement of the teeth, skeleton, and central nervous system. Here, we describe two patients with isolated segmental BFH and no systemic involvement. Paired whole exome sequencing of BFH and normal tissue revealed a pathogenic SMO c.1234 C>T, p.L412F variant restricted to BFH tissue. We characterized the proliferation index and expression of Hedgehog and Wnt/beta-catenin pathway related proteins in segmental BFH compared to sporadic basal cell carcinomas (BCCs) and found that segmental BFH had a lower proliferation index. Although segmental BFH expressed a similar level of Gli-1 compared to BCCs, levels of LEF-1 and SOX-9 expression in BFH were weaker for both and patchier for LEF-1. Our results show that a somatic SMO activating variant causes segmental BFH. Since these patients are prone to developing BCCs, differences in SOX9, LEF1, and Ki-67 expression can help distinguish between these two basaloid lesions.

Keywords: basal cell carcinoma; genetic skin disease; mosaicism.

Publication types

  • Case Reports
  • Research Support, N.I.H., Extramural

MeSH terms

  • Carcinoma, Basal Cell* / diagnosis
  • Carcinoma, Basal Cell* / genetics
  • Carcinoma, Basal Cell* / metabolism
  • Hair Follicle / abnormalities
  • Hair Follicle / metabolism
  • Hair Follicle / pathology
  • Hamartoma* / diagnosis
  • Hamartoma* / genetics
  • Hamartoma* / metabolism
  • Hedgehog Proteins / genetics
  • Hedgehog Proteins / metabolism
  • Humans
  • Skin Diseases* / pathology
  • Skin Neoplasms* / diagnosis
  • Skin Neoplasms* / genetics
  • Skin Neoplasms* / metabolism
  • Smoothened Receptor / genetics

Substances

  • Hedgehog Proteins
  • SMO protein, human
  • Smoothened Receptor