Mdb-24. shh medulloblastoma with smo mutation before the age of 5years old

SHH medulloblastomas represent around 30% of MB’s and occur mostly in infants and adults with an intermediate prognosis. The driving mutations concern mostly PTCH1(43%), SUFU(10%) or SMO(9%). SMO activating mutations have been described almost exclusively in adults, and is extremely rare in infants. The features and outcome of SMO mutated infant MB are not known so far. We did a national retrospective analysis of children under 5 years with a SHH medulloblastoma and a somatic SMO mutation. We collected clinical, radiological and biological data (centralised reviews) with addition of methyloma, aiming to depict the clinico-molecular features and the outcome of these rare MB. We identified 6 patients from 2014 to 2020. The median age at diagnosis was 3.2years. No evidence of metastatic disease was found for 5/6 patients and one had a positive CSF cytology. All patients underwent a complete removal. All had an extensive nodularity histologic subtype, no specific alterations in CGH apart from gains of all chromosomes 2,7 and,15. Methyloma classified 4/6 in subgroup SHH-1 and 2 in subgroup SHH-2. One patient had a second cerebellar lesion with a different radiological aspect; histological analysis and methylation profiling revealed a subependymoma, sharing the same SMO mutation than the MB ((c.1604G>T/p.(Trp535Leu)), suggesting a mosaicism. Another patient presented a polymalformative disorder diagnosed as a Curry-Jones syndrome, in agreement with the finding of mosaic SMO variant (c.1234C>T(p.Leu412Phe)). All patients received several cycles of chemotherapy, and no radiotherapy. With a median follow-up of 3.9 years, all patients were alive in complete remission with no relapse. This data suggests that an underlying mosaicism must be sought in these very rare patients, and that the outcome seems overall similar to other infants with SHH medulloblastoma and more classical SUFU or PTCH1 mutations.