SHH desmoplastic/nodular medulloblastoma and Gorlin syndrome in the setting of Down syndrome

• Verfasst von: Mangum, Ross Michael [VerfasserIn]
• Verfasst von: Capper, David [VerfasserIn]
• Verfasst von: Sahm, Felix [VerfasserIn]
• Verfasst von: Schrimpf, Daniel [VerfasserIn]
• Verfasst von: Pfister, Stefan [VerfasserIn]
• Titel: SHH desmoplastic/nodular medulloblastoma and Gorlin syndrome in the setting of Down syndrome
• Titelzusatz: case report, molecular profiling, and review of the literature
• Verf.angabe: Ross Mangum, Elizabeth Varga, Daniel R. Boué, David Capper, Martin Benesch, Jeffrey Leonard, Diana S. Osorio, Christopher R. Pierson, Nicholas Zumberge, Felix Sahm, Daniel Schrimpf, Stefan M. Pfister, Jonathan L. Finlay
• Umfang: 8 S.
• Fussnoten: Gesehen am 25.10.2017
• Titel Quelle: Enthalten in: Child's nervous system
• Jahr Quelle: 2016
• Band/Heft Quelle: 32(2016), 12, S. 2439-2446
• ISSN Quelle: 1433-0350
• DOI: doi:10.1007/s00381-016-3185-0
• Datenträger: Online-Ressource
• Sprache: eng
• K10plus-PPN: 1564783405

Abstract

IntroductionIndividuals with Down syndrome (DS) have an increased risk of acute leukemia compared to a markedly decreased incidence of solid tumors. Medulloblastoma, the most common malignant brain tumor of childhood, is particularly rare in the DS population, with only one published case. As demonstrated in a mouse model, DS is associated with cerebellar hypoplasia and a decreased number of cerebellar granule neuron progenitor cells (CGNPs) in the external granule cell layer (EGL). Treatment of these mice with sonic hedgehog signaling pathway (Shh) agonists promote normalization of CGNPs and improved cognitive functioning.Case reportWe describe a 21-month-old male with DS and concurrent desmoplastic/nodular medulloblastoma (DNMB)—a tumor derived from Shh dysregulation and over-activation of CGNPs. Molecular profiling further classified the tumor into the new consensus SHH molecular subgroup. Additional testing revealed a de novo heterozygous germ line mutation in the PTCH1gene encoding a tumor suppressor protein in the Shh pathway.DiscussionThe developmental failure 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 overstimulation resulting in Gorlin (Nevoid Basal Cell Carcinoma) 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 PTCH1 germline mutation.ConclusionWe have observed a highly unusual circumstance in which the PTCH1 mutation appears to “trump” the effects of DS in causation of Shh-activated medulloblastoma.