MB-26: SHH DESMOPLASTIC/NODULAR MEDULLOBLASTOMA AND GORLIN SYNDROME IN THE SETTING OF DOWN SYNDROME: CASE REPORT WITH MOLECULAR PROFILING

BACKGROUND: Individuals with trisomy 21 (Down syndrome, DS) have a 10- to 20- fold increased risk of acute leukemia compared with a markedly decreased incidence of solid tumors, including medulloblastoma. Only a single case report has been previously published of medulloblastoma arising in an individual with DS. Cerebellar hypoplasia and a decreased number of cerebellar granule neuron progenitor cells (CGNPs) in the external granular layer (EGL) has been described in a mouse model of DS in which sonic hedgehog (Shh) signaling pathway agonists promote normalization of CGNPs and improved cognitive functioning. On the other hand, desmoplastic/nodular medulloblastoma (DNMB) is a tumor derived from Shh dysregulation and over-activation of of CGNPs. METHODS/RESULTS: We describe a 21 months-old male with DS, clinical stigmata of Gorlin syndrome, and DNMB. 450K methylation profiling classified the tumor in the Shh molecular subgroup. Genetic testing revealed a de novo heterozygous germ line mutation in the PTCH1 gene encoding a tumor suppressor protein in the Shh pathway. CONCLUSIONS: The reduced presence of CGNPs in DS patients offers a plausible explanation for the rarity of medulloblastoma in this population. Conversely, patients with PTCH1 germline mutations experience Shh pathway overstimulation resulting in Gorlin Syndrome and an increased incidence of malignant transformation of CGNPs leading to medulloblastoma formation. This represents the first documented report of an individual with DS simultaneously carrying a PTCH1 mutation. Thus, we observe a highly unusual circumstance in which the PTCH1 mutation appears to ‘trump' the effects of trisomy 21 in causation of Shh-activated medulloblastoma.