Multiple Self-Healing Squamous Epithelioma (MSSE): A Digenic Trait Associated with Loss of Function Mutations in TGFBR1 and Variants at a Second Linked Locus on the Long Arm of Chromosome 9

Abstract

MSSE (Ferguson-Smith disease) is a rare familial condition in which multiple skin tumors resembling squamous carcinomas invade locally and then regress spontaneously after several months, leaving disfiguring scars. We review evidence from haplotype studies in MSSE families with common ancestry that the condition is caused by loss of function mutations in TGFBR1 interacting with permissive variants at a second linked locus on the long arm of chromosome 9. The spectrum of TGFBR1 mutations in MSSE and the allelic disorder Loeys Dietz syndrome (characterized by developmental anomalies and thoracic aortic aneurysms) differ. Reports of patients with both MSSE and Loeys Dietz syndrome are consistent with variants at a second locus determining whether self-healing epitheliomas occur in patients with the loss of function mutations found in most MSSE patients or the missense mutations in the intracellular kinase domain of TGFBR1 that characterize Loeys Dietz syndrome.