ID #130 First Report of SHH-Activated Medulloblastoma in a Child With RRAS2-Related Noonan Syndrome
Richard Suarez, Somak Roy, Sara Knapke, Abigail Riddle, Scott RaskinAbstract
Introduction
Medulloblastoma is the most common malignant brain tumor in children and is associated with several hereditary syndromes; however, it is not traditionally linked to RASopathies. Noonan syndrome (NS) is an autosomal dominant RASopathy with a prevalence of 1 in 1,000-2,500 live births. NS is often associated with hematologic malignancies and some solid tumors but rarely linked with medulloblastoma. Germline RRAS2 pathogenic variants are a rare cause of NS with only 17 reported cases and, to our knowledge, have not previously been reported in association with medulloblastoma. The only published NS-associated medulloblastoma case involved PTPN11.
Case Presentation
A 19-month-old male with suspected NS was evaluated for ventriculomegaly leading to a diagnosis of SHH-activated medulloblastoma. Tumor sequencing identified an activating SMO p.L412F mutation and an inactivating KMT2C splice-site variant. Germline testing from 2023 previously identified a RRAS2 Variant of Uncertain Significance that was reclassified as likely pathogenic during his medulloblastoma evaluation. This autosomal dominant RRAS2 c.70G>T, p.G24C missense mutation is consistent with NS. RRAS2 was not included in the tumor NGS panel (CinCSeq). Sanger sequencing targeting the RRAS2 variant confirmed its presence in the tumor DNA, consistent with the patient’s germline variant.
Discussion
The interplay between these mutations has not been previously described. The RRAS2 germline variant is responsible for the patient’s Noonan syndrome and potentially predisposed him to medulloblastoma. The somatic SMO mutation represents the likely activating driver mutation, as SMO activation is a canonical initiating event in SHH-activated medulloblastoma. The KMT2C splice-site variant likely contributes to epigenetic dysregulation supporting tumor progression but does not represent the primary driving mutation.
Conclusion
We report the first case of SHH-activated medulloblastoma in a child with RRAS2-related NS. In addition, this is the first report of the specific variant RRAS2 c.70G>T, p.G24C in NS. This expands the tumor spectrum of RASopathies.