Medulloblastoma, macrocephaly, and a pathogenic germline PTEN variant: Cause or coincidence?

Jussi‐Pekka Tolonen,Riitta Niinimäki,Olli Tynninen,Anne Hekkala,Outi Kuismin,Hannu Tuominen,Maria Suo‐Palosaari

doi:10.1002/mgg3.1302

Jussi‐Pekka Tolonen, Riitta Niinimäki + Show 5 more

Open Access

https://doi.org/10.1002/mgg3.1302

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Abstract

BackgroundMedulloblastomas (MBs) are a heterogeneous group of childhood brain tumors with four consensus subgroups, namely MBSHH, MBWNT, MBGroup 3, and MBGroup 4, representing the second most common type of pediatric brain cancer after high‐grade gliomas. They suffer from a high prevalence of genetic predisposition with up to 20% of MBSHH caused by germline mutations in only six genes. However, the spectrum of germline mutations in MBSHH remains incomplete.MethodsComprehensive Next‐Generation Sequencing panels of both tumor and patient blood samples were performed as molecular genetic characterization. The panels cover genes that are known to predispose to cancer.ResultsHere, we report on a patient with a pathogenic germline PTEN variant resulting in an early stop codon p.(Glu7Argfs*4) (ClinVar ID: 480383). The patient developed macrocephaly and MBSHH, but reached remission with current treatment protocols.ConclusionsWe propose that pathogenic PTEN variants may predispose to medulloblastoma, and show that remission was reached with current treatment protocols. The PTEN gene should be included in the genetic testing provided to patients who develop medulloblastoma at an early age. We recommend brain magnetic resonance imaging upon an unexpected acceleration of growth of head circumference for pediatric patients harboring pathogenic germline PTEN variants.

Highlights

Medulloblastoma (MB), a heterogeneous solid tumor of the posterior fossa, is the second most common malignant pediatric brain tumor after high-grade gliomas (Millard &De Braganca, 2016; Ostrom et al, 2015)
We suggest that pathogenic germline PTEN variants may predispose patients to the early development of medulloblastoma and show that current treatment protocols may prove effective despite the PTEN status
We present the first known case report of a toddler carrying a pathogenic germline PTEN variant with macrocephaly and MBSHH

Summary

| INTRODUCTION

Medulloblastoma (MB), a heterogeneous solid tumor of the posterior fossa, is the second most common malignant pediatric brain tumor after high-grade gliomas MBs account for roughly 10% of central nervous system malignancies in children between 0 and 14 years of age with a worldwide age-adjusted incidence of 2.0–5.8 cases per 1,000,000 annually (Millard & De Braganca, 2016; Waszak et al, 2018). Extensive single-cell transcriptomics have revealed that MBs originate from irregularities in early brain development (Vladiou et al, 2019), which may explain why at least 70% of MBs occur in the pediatric population (Millard & De Braganca, 2016). We present the first known case report of cerebellar medulloblastoma with an inactivating germline variant in the tumor suppressor PTEN (OMIM *601728). We suggest that pathogenic germline PTEN variants may predispose patients to the early development of medulloblastoma and show that current treatment protocols may prove effective despite the PTEN status. We recommend brain magnetic resonance imaging (MRI) upon an unexpected acceleration of growth of head circumference for pediatric patients known to harbor such variants of the PTEN gene

| Methods

Findings

| DISCUSSION