315 Cerebriform sebaceous nevus is caused by the specific postzygotic FGRF2 p.(Cys382Arg) variation

Abstract

Postzygotic FGFR2 variations are responsible for mosaic forms of acne, keratinocytic epidermal nevus (KEN), and nevoid acanthosis nigricans (NAN). We showed the implication of the postzygotic FGRF2 p.(Cys382Arg) variation in 2 fetuses with papillomatous pedunculated sebaceous nevus (PPSN). We found the same variation in 3 patients with a cerebriform sebaceous nevus (CSN) using ultradeep FGFR2 targeted next-generation sequencing (NGS). Overall, the p.(Cys382Arg) variation was identified in 62.5% (5/8) of our patients. PPSN and CSN seem to be the same clinical entity, differing only by the severity of the phenotype in relation with a more precocious variation in PPSN. Germline FGFR2 p.(Tyr375Cys) and p.(Ser372Cys) variations cause Beare-Stevenson cutis gyrata (BSCG) syndrome, which shows a strikingly comparable cerebriform pattern as CSN, although in a different scale. BSCG syndrome shows excessive growth of the entire scalp, with the formation of convoluted folds and furrows, whereas CSN is limited to a fraction of the scalp. The mutational spectrum in mosaic diseases varies from extreme allelic heterogeneity as it is the case in PIK3CA related overgrowth spectrum, to unique variations being the cause of the disease, but the most frequent situation is represented by several hotspot variations. Whereas there is allelic heterogeneity in KEN, which can be caused by different FGFR2 variations, there is only one recurrent hotspot variation in CSN as it is the case in Proteus syndrome. This discrepancy between allelic heterogeneity or not in mosaic diseases could be explained by a very specific gain of function variation when it is unique. Other FGFR2 variations different from the p.(Cys382Arg) variation have been identified in mosaic forms of acne, KEN, and NAN. Hence, our findings confirm a distinct clinical and molecular subgroup of sebaceous nevus related to FGFR2, being part of the group of the “mosaic signalopathies” proposed earlier.