Coexistence of Multiple self-healing squamous epithelioma and features of Loeys-Dietz syndrome caused by a pathogenic missense variant in the kinase domain of TGFBR1 gene

Abstract

Abstract The transforming growth factor beta receptor 1 (TGFBR1) gene is associated with two distinct clinical presentations, Multiple Self-Healing Squamous Epithelioma (MSSE) also known as Ferguson-Smith syndrome and Loeys-Dietz syndrome. MSSE is characterized by development of multiple self-healing skin tumours that may affect any part of the body. Spontaneous resolution may take several months leaving pitted scars. Most pathogenic variants in MSSE patients are truncating variants distributed throughout the gene or missense variants in the receptor domain of TGFBR1. Missense variants in the kinase domain of TGFBR1 cause LDS which is a connective tissue disorder associated with increased risk of aortic and arterial aneurysms and dissection. There are two reports in the literature of patients with both MSSE and LDS phenotype and a missense variant in the kinase domain of TGFBR1. The patient reported here has MSSE with at least 20 skin tumours (four with perineural invasion) and features of LDS. The patient harbors a heterozygous missense pathogenic variant c.1043G>A p.(Cyst348Tyr) in TGFBR1 which has previously been associated with LDS but not MSSE. This report is consistent with the hypothesis that a variant in a second locus determines whether skin tumours develop in a patient with missense variant in the kinase domain of TGFBR1 associated with LDS. It also highlights the association of more histologically aggressive keratocanthomas associated with perineural invasion in MSSE.