Medulloblastoma Associated with Down Syndrome: From a Rare Event Leading to a Pathogenic Hypothesis

Abstract

Down syndrome (DS) is the most common chromosome abnormality with a unique cancer predisposition syndrome pattern: a higher risk to develop acute leukemia and a lower incidence of solid tumors. In particular, brain tumors are rarely reported in the DS population, and biological behavior and natural history are not well described and identified. We report a case of a 10-year-old child with DS who presented with a medulloblastoma (MB). Histological examination revealed a classic MB with focal anaplasia and the molecular profile showed the presence of a CTNNB1 variant associated with the wingless (WNT) molecular subgroup with a good prognosis in contrast to our case report that has shown an early metastatic relapse. The nearly seven-fold decreased risk of MB in children with DS suggests the presence of protective biological mechanisms. The cerebellum hypoplasia and the reduced volume of cerebellar granule neuron progenitor cells seem to be a possible favorable condition to prevent MB development via inhibition of neuroectodermal differentiation. Moreover, the NOTCH/WNT dysregulation in DS, which is probably associated with an increased risk of leukemia, suggests a pivotal role of this pathway alteration in the pathogenesis of MB; therefore, this condition should be further investigated in future studies by molecular characterizations.

Medulloblastoma and Down Syndrome: An Extremely Rare Association

“…Only 3 previous cases with this extremely rare association have been documented in the medical literature; these published cases belonged to Group 3, WNT, and SHH subgroups. [8][9][10] The latter occurred in a patient with Gorlin syndrome, a well-known predisposition syndrome for medulloblastoma, suggesting that the medulloblastoma pathogenesis was related to the PTCH1 variant rather than to DS. Characteristics of the reported cases with medulloblastoma and DS are described in Table 1.…”

“…We report the original description of the second case of SHH medulloblastoma and DS, providing other features leading to treatment as well as chemotherapy-related toxicities and long-term outcome. Only 3 previous cases with this extremely rare association have been documented in the medical literature; these published cases belonged to Group 3, WNT, and SHH subgroups 8–10. The latter occurred in a patient with Gorlin syndrome, a well-known predisposition syndrome for medulloblastoma, suggesting that the medulloblastoma pathogenesis was related to the PTCH1 variant rather than to DS.…”

“…This would be at the expense of a lower number of progenitor cells of cerebellar granular neurons in the outer layer of granular cells. 9 Another protective factor described is the endostatin, encoded by the COL18A1 gene at 21q22. It has recently been shown to be a potent angiogenic inhibitor for many different types of solid tissue tumors.…”

“…A research study in mice suggests that DS individuals exhibit an overall reduction in brain size with a disproportionately greater reduction in cerebellar volume due to reduction of both the internal granule layer and the molecular layer of the cerebellum. This would be at the expense of a lower number of progenitor cells of cerebellar granular neurons in the outer layer of granular cells 9. Another protective factor described is the endostatin, encoded by the COL18A1 gene at 21q22.…”

How Genetics and Genomics Advances Are Rewriting Pediatric Cancer Research and Clinical Care

“…Down syndrome (DS) is the most common cancer predisposition syndrome that has a higher risk of developing acute leukemia and a lower incidence of solid tumors. Boni et al [ 83 ] identified a variant in CTNNB1 that is associated with the WNT subgroup that is usually associated with a good prognosis in a patient with Down syndrome who presented with a medulloblastoma with focal aplasia and early metastatic recurrence [ 83 ]. In this study, Boni et al highlight that the NOTCH/WNT dysregulation in DS—which is likely to be associated with an increased risk of leukemia—suggests that it has a pivotal role in the pathogenesis of MB; therefore, this condition should be further investigated in future studies using molecular characterizations [ 83 ].…”