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Published in: Child's Nervous System 12/2016

01-12-2016 | Case Report

SHH desmoplastic/nodular medulloblastoma and Gorlin syndrome in the setting of Down syndrome: case report, molecular profiling, and review of the literature

Authors: 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

Published in: Child's Nervous System | Issue 12/2016

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Abstract

Introduction

Individuals 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 report

We 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 PTCH1 gene encoding a tumor suppressor protein in the Shh pathway.

Discussion

The 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.

Conclusion

We have observed a highly unusual circumstance in which the PTCH1 mutation appears to “trump” the effects of DS in causation of Shh-activated medulloblastoma.
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Metadata
Title
SHH desmoplastic/nodular medulloblastoma and Gorlin syndrome in the setting of Down syndrome: case report, molecular profiling, and review of the literature
Authors
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
Publication date
01-12-2016
Publisher
Springer Berlin Heidelberg
Published in
Child's Nervous System / Issue 12/2016
Print ISSN: 0256-7040
Electronic ISSN: 1433-0350
DOI
https://doi.org/10.1007/s00381-016-3185-0

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