Abstract
Medulloblastoma is the most common malignant brain tumor of childhood. It is a molecularly and clinically heterogeneous tumor. There are currently four recognized molecular subtypes of medulloblastoma, one of which is sonic hedgehog (SHH)-activated medulloblastoma. We discuss a case of an 18-month-old male with a desmoplastic SHH-activated TP53-wildtype medulloblastoma, failure to thrive, global developmental delay, and polydactyly found to have a novel de novo heterozygous c.565-568delGACT germline GNAS frameshift mutation on the paternal allele identified through peripheral blood trio clinical exome sequencing. Germline GNAS mutations are known to be associated with several diseases. However, to the authors knowledge, this is only the second report in the literature of a germline GNAS mutation in a patient with medulloblastoma. GNAS is a known tumor suppressor of the SHH pathway. A prior study has shown that low somatic GNAS expression characterizes a subset of patients with aggressive SHH-activated medulloblastoma. The normal function of GNAS encoded Gas is to stimulate adenylyl cyclase activity to produce intracellular cyclic adenosine monophosphate (cAMP), which activates the cAMP-dependent protein kinase A (PKA), and inhibits SHH signaling. Thus, low or loss of GNAS expression leads to aberrant SHH pathway activation. Upregulation of the SHH pathway results in increased granule cell progenitor proliferation and tumor formation. This provides insight into the mechanism by which our patients GNAS mutation may have fueled development of medulloblastoma. Germline GNAS mutation must be considered in patients with SHH-activated medulloblastoma and in particular, in patients with phenotypic similarities to our patient including developmental delay, small size for age, and polydactyly. Advancing our understanding of medulloblastoma development through the study of germline and tumor genomics including better understanding the role of GNAS, holds great promise for enabling improved treatments and patient outcomes.