Early-onset sonic hedgehog medulloblastomas with Smoothened (SMO) activating pathogenic variants: wouldn’t underlying post-zygotic mosaicism be underdiagnosed?

Abstract Background Sonic Hedgehog medulloblastomas (MB-SHH) are mainly driven by PTCH1 and SUFU pathogenic variants (PV) in children, and frequently related to germline predisposition in infants. SMO activating PV are almost exclusively reported in adults and remain very rare in infants. The particularities of early-onset MB with SMO PV are poorly described. Genetic predispositions have not been thoroughly explored in this context. Methods We performed a national retrospective study of children under 5 years diagnosed with MB-SHH harbouring a somatic SMO PV MB. Results From two cohorts of 689 and 213 sequenced MB, eight patients were identified (median age 2.8 years), all had an extensive nodularity histologic subtype and a confirmed SHH group. With a median follow-up of 3.9 years, the outcome was excellent (100% 5-year event free survival) with chemotherapy. Notably, two patients developed the MB in a post-zygotic SMO PV mosaic. One patient had a apparent Curry–Jones syndrome (mosaic SMO c.1234C>T/p.(Leu412Phe) PV); another patient had a MB and a concomitant cerebellar subependymoma, both sharing the same SMO c.1604G>T/p.(Trp535Leu) PV. Clinical and imaging features of the other patients didn't reveal any abnormality. Conclusion Early onset MB-SHH with SMO PV have an overall good prognosis. SMO PV in this age range are very rare and can be associated with an underlying SMO PV mosaic that may deserve careful investigations.