SG15 Superimposed mosaicism in tuberous sclerosis complex presenting as unilateral facial angiofibromas

Abstract

Tuberous sclerosis complex (TSC) is inherited as an autosomal dominant disorder caused by pathogenic variants in TSC1 or TSC2, resulting in hamartomatous lesions affecting multiple organ systems. Mosaic forms of TSC contribute substantially to phenotypic variability and diagnostic delay. While simple segmental mosaicism is well recognized, superimposed mosaicism – characterized by a pronounced segmental manifestation on a background of clinically subtle or occult disease – remains under-reported and under-recognized in clinical practice. Distinguishing simple segmental from superimposed mosaicism remains challenging, and cases may be overlooked due to overlapping clinical and radiological features. We report a 9-year-old boy presenting with unilateral, linearly distributed facial angiofibromas confined to the right nasal bridge. The lesions had been present since early childhood and demonstrated sharp midline demarcation. No additional cutaneous stigmata of TSC were identified, and neurodevelopment was normal. Histopathological examination confirmed angio­fibromas. Blood-based whole-exome sequencing did not detect pathogenic germline variants in TSC1 or TSC2. However, molecular analysis of affected skin revealed two pathogenic low-level somatic TSC1 variants: a mosaic deletion encompassing the entire TSC1 gene and a mosaic nonsense variant (c.2389C>T, p.Gln797*), both absent in unaffected tissue. Systemic evaluation was largely unremarkable; however, brain magnetic resonance imaging demonstrated subtle, nonprogressive periventricular T2 hyperintensities with a possible radial migration line. The combination of a pronounced unilateral cutaneous segment, multiple somatic second-hit events confined to affected tissue, and subtle extracutaneous radiological findings supports classification as superimposed mosaicism. This case demonstrates that superimposed mosaicism in TSC may present with minimal systemic involvement and negative blood-based genetic testing, contributing to its under-representation in the literature. Recognition of superimposed mosaicism is essential to accurately characterize the full phenotypic spectrum of TSC. Tissue-specific genetic analysis plays a critical role in diagnosis, classification and genetic counselling. Increased awareness may reveal that this entity is more prevalent than currently appreciated.