PC1201: A Case of Nevoid Basal Cell Carcinoma Syndrome: Molecular Pathogenesis and Importance of Genetic Screening

Introduction: Nevoid Basal Cell Carcinoma Syndrome (NBCCS) is a rare genetic disorder caused by mutations in the PTCH1 or SUFU genes. It is characterized by the variable development of odontogenic jaw keratocysts, skeletal abnormalities, cardiac fibromas, basal cell carcinoma, and childhood medulloblastomas. Interestingly, 33% of patients with NBCCS who possess a SUFU mutation develop medulloblastomas compared to only 2% of those with a PTCH1 mutation. This case will discuss the molecular pathogenesis of SUFU in early medulloblastoma development and importance of genetic testing for early identification.

Case Description: An eight month old male presented to the pediatric neurosurgery clinic after MRI demonstrated a multinodular focus in the cerebellar vermis measuring 13mm in width. At age two, his older sister was diagnosed with medulloblastoma and upon genetic workup was found to have a SUFU mutation consistent with NBCCS. After birth, the infant was found to have the same SUFU mutation and underwent screening MRI. Upon presentation, he was almost entirely asymptomatic, with only slight gross motor delay. No other NBCCS manifestations were present. Due to family history and genetic predisposition to medulloblastomas, resection of the cerebellar mass was recommended. Parents were amenable and he underwent an uncomplicated suboccipital craniotomy and resection. Surgical pathology was consistent with WHO grade IV medulloblastoma and genetrails confirmed SUFU mutation.

Discussion: The sonic hedgehog (SHH) pathway is heavily involved in normal embryonic development. Purkinje cells of the cerebellum release large amounts of SHH protein during development, leading to mass proliferation of granule neuron progenitor cells. After birth, SHH signals are normally downregulated. In this process, SUFU is a crucial negative regulator, binding directly to a downstream transcriptional activator, GliA, and preventing its translocation to the nucleus. In addition, ubiquitination of the SUFU-Gli complex allows for cleavage of GliA into GliR, the repressor form, which directly inhibits SHH target gene transcription. However, when SuFu is inactivated, this downregulation is impaired and medulloblastomas can form. The proposed inactivating mutations to SuFu are nonsense mutations that lead to either a truncation of the SuFu protein that cannot bind Gli or a lack of lysine 457 required for SUFU-Gli ubiquitination.
Medulloblastoma is the most common malignant brain tumor in children. Up to 25% of cases are due to disruptions in the SHH pathway, with 1 in 5 of those being due to a germline mutation. However, less than half of patients are identified based on family history.

Conclusion: In patients with NBCCS secondary to SUFU mutation, a precarious molecular environment is created that genetically predisposes for early medulloblastoma formation. Early genetic diagnosis and appropriate cancer screening were critical to this patient's favorable outcome.