Co-Occurrence of Achondroplasia and 16p11.2 Deletion Syndrome in a Child With Group 4 Medulloblastoma: Expanding the Spectrum of Dual Genetic Diagnoses.
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Achondroplasia (OMIM #100800), the most common skeletal dysplasia, results from the recurrent FGFR3 c.1138G > A (p.Gly380Arg) gain-of-function variant, which constitutively activates fibroblast growth factor receptor 3 signaling and impairs endochondral ossification. The 16p11.2 microdeletion (OMIM #611913) is a recurrent ~600 kb copy-number variant associated with developmental delay, autism spectrum disorder, epilepsy, and obesity, encompassing dosage-sensitive genes including MAPK3, KCTD13, and PRRT2. Recent genome-wide analyses have linked 16p11.2 deletion to a 13.9-fold increased risk of neuroblastoma, though no association with medulloblastoma has been documented. Medulloblastoma, the most common malignant pediatric brain tumor, is classified into molecularly defined subgroups-WNT-activated, SHH-activated, Group 3, and Group 4-each with distinct genetic drivers and clinical outcomes. We describe a 13-year-old male with achondroplasia confirmed by the pathogenic FGFR3 c.1138G > A variant and a de novo 16p11.2 microdeletion who developed metastatic non-WNT/non-SHH (Group 4) medulloblastoma with leptomeningeal dissemination (M3) at age 12. Despite multimodal therapy including resection, craniospinal irradiation, and combination chemotherapy, the tumor recurred and progressed. The patient died at age 13. To our knowledge, this is the first report of co-occurring achondroplasia and 16p11.2 deletion complicated by medulloblastoma. Although neither condition independently confers established risk for this tumor, both perturb MAPK/ERK signaling-a pathway implicated in Group 4 medulloblastoma biology. This case underscores the importance of recognizing multilocus pathogenic variation and supports further investigation of potential interactions between developmental and oncogenic signaling networks.