CSIG-05. IS THERE ANY BRAIN TUMOR PREDISPOSITION IN RELATED PALLISTER-HALL SYNDROMES AT THE NEW GENOMICS ERA

Abstract Pallister-Hall Syndrome (PHS) and its related syndromes are a spectrum of congenital malformations. They are associated to GLI3 mutations and specific brain tumors. Considered as lethal, it is now well established that this disease may be miss-diagnosed with the report of adult cases. Here, we discuss the management of the genetic counselling and the risk of neurologic tumor predisposition in GLI3-related PHS. We comprehensively reviewed the scientific literature using various databases to explore the risk of neurologic tumors and evolving practice of neuro-cancer genetic counseling in GLI3-related PHS. The review of literature showed that GLI3 is involved in tissue development as well as in cancer. GLI3 was identified as either a pro or anti-cancerous protein. In fact, GLI3 is described as upregulated in multiple cancers and is found to positively regulate malignant behavior. In neuro-oncology GLI gene was first identified as a highly expressed gene in human glioma and then as having an anti-cancerous role in medulloblastoma where GLI3 seems act as a tumor suppressor. In mutational studies, GLI3-germinal mutations are characterized by a high recurrence of hypothalamic hamartoma in syndromic patients. GLI3-somatic alterations have been also demonstrated in cell samples of patients with non-syndromic hypothalamic hamartoma. In addition, while inactivation of GLI3 is suggested to be associated with medulloblastoma, mutations are not common in sporadic medulloblastoma. The association of germinal GLI3 variants in syndromic patients with medulloblastoma has been identified in only one patient harboring GLI3 H302X variant. Our review permitted us to conclude that germline GLI3 mutations may predispose to a specific non-severe form of delayed hypothalamic hamartoma, which can be revealed in pauci or asymptomatic and unrecognized mutated individuals. The likelihood of having a neuro-cancer predisposition in GLI3 mutated families seems to be insignificant.