Endocrine Abstracts

JOINT78

Background: Data on pediatric/adolescent von Hippel-Lindau (VHL) disease is sparse, and comprehensive studies detailing the phenotype of all associated neoplasms are lacking. Their current surveillance/management recommendations rely on expert opinion or extrapolation from adults, not individualized to the mutation type.

Objectives: The study aimed to characterize the childhood/adolescent-onset VHL disease phenotype, compare it to adult-onset disease and identify genotype-phenotype correlations.

Methods: This was a retrospective review of children/adolescents (≤19 years) and adults (≥20 years) with VHL disease from a single endocrine center (2000-2024). The diagnosis was based on either clinical criteria (15%, per the guidelines) or genetic confirmation (85%: 66% missense, 19% truncating variants). Only neoplasms diagnosed until 19 years of age were included in the childhood/adolescent group and compared with the last follow-up of adults. The demographic, clinical, anatomical/functional imaging, operative details, histopathology (operated patients) for each VHL-associated neoplasm, and genetics were noted.

Results: Twenty-six children/adolescents (median age at diagnosis 15. 5 years) were identified. By age 19 years, 81% developed pheochromocytoma/paraganglioma (PPGL, of which 10% head and neck PGL), 42% central nervous system hemangioblastoma (CNS-HB), 31% each retinal RHB and pancreatic neuroendocrine tumor (PNET), while none had endolymphatic sac tumor/renal cell carcinoma. At diagnosis, all those with PPGLs were symptomatic (median size 4. 5 cm, 52 lesions). CNS-HBs showed female preponderance, with a high disease burden (60% symptomatic, 50% synchronous in ≥2/3 components of the neuroaxis) and surgical requirement by age 19. Two pediatric patients needed surgery for a symptomatic PNET before the recommended surveillance initiation age (15 years). Two children/adolescents developed polycythemia during follow-up. Compared to adults (n = 39), pediatric/adolescent PPGL patients had significantly higher plasma free-normetanephrine (median 1099. 5 vs 2513. 5 pg/mL), more bilateral (47% vs 76%) and extra-adrenal (19% vs 48%) disease by 19 years, and an 8. 3-fold higher operative-site recurrence over a similar follow-up duration (median 108 months: adults, 75 months: children/adolescents) independent of cortical-sparing surgery. Other neoplasms’ frequency and burden by 19 years resembled adults. Childhood/adolescent PPGLs occurred predominantly (16/17 cases) and PNETs exclusively, with missense variants. Codon 167 missense variants were associated with synchronous bilateral pheochromocytomas.

Conclusion: In pediatric/adolescent VHL disease, we report a severe phenotype, more extensive (PPGL) or comparable to adults. Our findings support head and neck PGL and earlier PNET surveillance in pediatric/adolescent protocols. The occurrence of childhood/adolescent PPGLs and PNETs almost exclusively with missense variants suggests the genotype may guide the pediatric surveillance strategy for these neoplasms.