Child's Nervous System

, Volume 32, Issue 12, pp 2439–2446 | Cite as

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

  • Ross MangumEmail author
  • 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
Case Report



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.


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.


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.


Down syndrome, Medulloblastoma, Gorlin syndrome, Sonic hedgehog signaling pathway, Molecular profiling 


Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.


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Copyright information

© Springer-Verlag Berlin Heidelberg 2016

Authors and Affiliations

  • Ross Mangum
    • 1
    Email author
  • Elizabeth Varga
    • 1
  • Daniel R. Boué
    • 1
  • David Capper
    • 2
    • 3
  • Martin Benesch
    • 4
  • Jeffrey Leonard
    • 1
  • Diana S. Osorio
    • 1
  • Christopher R. Pierson
    • 1
  • Nicholas Zumberge
    • 1
  • Felix Sahm
    • 2
    • 3
  • Daniel Schrimpf
    • 2
    • 3
  • Stefan M. Pfister
    • 2
    • 5
  • Jonathan L. Finlay
    • 1
  1. 1.The Divisions of Hematology/Oncology/BMT, Neurosurgery and Neuropathology, the Departments of Pediatrics, Surgery and PathologyNationwide Children’s Hospital and The Ohio State UniversityColumbusUSA
  2. 2.German Cancer Consortium (DKTK), Core Center HeidelbergHeidelbergGermany
  3. 3.Department of NeuropathologyUniversity Hospital HeidelbergHeidelbergGermany
  4. 4.Division of Pediatric Hematology/OncologyMedical University of GrazGrazAustria
  5. 5.Division of Pediatric NeurooncologyGerman Cancer Research Center (DKFZ)HeidelbergGermany

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