title: SHH desmoplastic/nodular medulloblastoma and Gorlin syndrome in the setting of Down syndrome: case report, molecular profiling, and review of the literature.
abstract: BACKGROUND
  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.
  
  
  METHODS
  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.
  
  
  CONCLUSIONS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: The Divisions of Hematology/Oncology/BMT, Neurosurgery and Neuropathology, the Departments of Pediatrics, Surgery and Pathology, Nationwide Children's Hospital and The Ohio State University, Columbus, OH, USA. ross.mangum@nationwidechildrens.org.
authors.forename: Ross
authors.initials: R
authors.lastname: Mangum
authors.affiliation: The Divisions of Hematology/Oncology/BMT, Neurosurgery and Neuropathology, the Departments of Pediatrics, Surgery and Pathology, Nationwide Children's Hospital and The Ohio State University, Columbus, OH, USA.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Varga
authors.affiliation: The Divisions of Hematology/Oncology/BMT, Neurosurgery and Neuropathology, the Departments of Pediatrics, Surgery and Pathology, Nationwide Children's Hospital and The Ohio State University, Columbus, OH, USA.
authors.forename: Daniel R
authors.initials: DR
authors.lastname: Boué
authors.affiliation: German Cancer Consortium (DKTK), Core Center Heidelberg, Heidelberg, Germany.|Department of Neuropathology, University Hospital Heidelberg, Heidelberg, Germany.
authors.forename: David
authors.initials: D
authors.lastname: Capper
authors.affiliation: Division of Pediatric Hematology/Oncology, Medical University of Graz, Graz, Austria.
authors.forename: Martin
authors.initials: M
authors.lastname: Benesch
authors.affiliation: The Divisions of Hematology/Oncology/BMT, Neurosurgery and Neuropathology, the Departments of Pediatrics, Surgery and Pathology, Nationwide Children's Hospital and The Ohio State University, Columbus, OH, USA.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Leonard
authors.affiliation: The Divisions of Hematology/Oncology/BMT, Neurosurgery and Neuropathology, the Departments of Pediatrics, Surgery and Pathology, Nationwide Children's Hospital and The Ohio State University, Columbus, OH, USA.
authors.forename: Diana S
authors.initials: DS
authors.lastname: Osorio
authors.affiliation: The Divisions of Hematology/Oncology/BMT, Neurosurgery and Neuropathology, the Departments of Pediatrics, Surgery and Pathology, Nationwide Children's Hospital and The Ohio State University, Columbus, OH, USA.
authors.forename: Christopher R
authors.initials: CR
authors.lastname: Pierson
authors.affiliation: The Divisions of Hematology/Oncology/BMT, Neurosurgery and Neuropathology, the Departments of Pediatrics, Surgery and Pathology, Nationwide Children's Hospital and The Ohio State University, Columbus, OH, USA.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Zumberge
authors.affiliation: German Cancer Consortium (DKTK), Core Center Heidelberg, Heidelberg, Germany.|Department of Neuropathology, University Hospital Heidelberg, Heidelberg, Germany.
authors.forename: Felix
authors.initials: F
authors.lastname: Sahm
authors.affiliation: German Cancer Consortium (DKTK), Core Center Heidelberg, Heidelberg, Germany.|Department of Neuropathology, University Hospital Heidelberg, Heidelberg, Germany.
authors.forename: Daniel
authors.initials: D
authors.lastname: Schrimpf
authors.affiliation: German Cancer Consortium (DKTK), Core Center Heidelberg, Heidelberg, Germany.|Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Stefan M
authors.initials: SM
authors.lastname: Pfister
authors.affiliation: The Divisions of Hematology/Oncology/BMT, Neurosurgery and Neuropathology, the Departments of Pediatrics, Surgery and Pathology, Nationwide Children's Hospital and The Ohio State University, Columbus, OH, USA.
authors.forename: Jonathan L
authors.initials: JL
authors.lastname: Finlay
mesh_terms: D001478:Basal Cell Nevus Syndrome / Q000150:complications / Q000235:genetics*; D002528:Cerebellar Neoplasms / Q000150:complications / Q000235:genetics*; D004314:Down Syndrome / Q000150:complications*; D018095:Germ-Line Mutation; D006801:Humans; D007223:Infant; D008297:Male; D008527:Medulloblastoma / Q000150:complications / Q000235:genetics*; D000072081:Patched-1 Receptor / Q000235:genetics*
chemical_list: C000606236:PTCH1 protein, human; D000072081:Patched-1 Receptor
keywords: Down syndrome, Medulloblastoma, Gorlin syndrome, Sonic hedgehog signaling pathway, Molecular profiling