TGFBR1 – Multiple Self-Healing Squamous Epithelioma

Multiple self-healing squamous epithelioma (MSSE), also known as Ferguson-Smith disease, is characterized by multiple cutaneous squamous-carcinoma-like lesions that involute spontaneously, leaving atrophic scars. Pathogenic variants in TGFBR1 cause MSSE via an autosomal dominant mechanism with high penetrance and variable expressivity.

A 37-year-old woman with recurrent facial SCC-like lesions and a positive maternal history was found to carry a heterozygous TGFBR1 pathogenic variant, confirming autosomal dominant inheritance (1 proband, 1 affected relative) ([PMID:22758773]).

High-throughput sequencing of 24.2 Mb of chromosome 9 in three initial families, followed by dideoxy sequencing in an additional 15 families, identified 11 distinct monoallelic loss-of-function mutations in 18 unrelated MSSE families, firmly establishing TGFBR1 as the causative gene ([PMID:21358634]).

The mutation spectrum comprises extracellular‐domain splice-site variants (e.g., c.806-2A>C (p.Haploinsufficiency)), truncating mutations (frameshift and nonsense) and a novel missense allele, c.664G>C (p.Gly222Arg), which in one pedigree presents with overlapping Loeys-Dietz features ([PMID:30513140]).

Splicing assays of MSSE-associated intronic variants demonstrate activation of cryptic acceptor sites, producing out-of-frame transcripts (r.807_882del, p.Asn270ThrfsTer8) and loss of function in mammalian cells, consistent with haploinsufficiency as the disease mechanism ([PMID:29706644]).

Integration of genetic segregation in 18 families, concordant functional data, and replication over >10 years support a Definitive gene-disease association. TGFBR1 analysis is critical for diagnosis, informs surveillance strategies, and enables accurate genetic counseling.

References

• The Australasian journal of dermatology • 2013 • A puzzling case: SCC or not? PMID:22758773
• Nature genetics • 2011 • Multiple self-healing squamous epithelioma is caused by a disease-specific spectrum of mutations in TGFBR1. PMID:21358634
• European journal of human genetics : EJHG • 2018 • Distinct variants affecting differential splicing of TGFBR1 exon 5 cause either Loeys-Dietz syndrome or multiple self-healing squamous epithelioma. PMID:29706644
• American journal of medical genetics. Part A • 2018 • Features of multiple self-healing squamous epithelioma and Loeys-Dietz syndrome in a patient with a novel TGFBR1 variant. PMID:30513140

Evidence Based Scoring (AI generated)