Familial and early recurrent pheochromocytoma in a child with a novel in-frame duplication variant of VHL

抄録

Pheochromocytomas and paragangliomas (PPGLs) are rare neuroendocrine tumors often linked to underlying genetic variants. Genetic analysis can promote gene-adjusted, specific follow-up, and surveillance protocols for both patients and their families at risk. We report the case of a 7-yr-old boy with bilateral pheochromocytoma, which recurred a year after partial adrenalectomy. The patient’s father developed bilateral pheochromocytomas at 25 yr of age. Both individuals possessed a novel heterogeneous in-frame duplication germline variant of VHL, yet neither exhibited other clinical manifestations of von Hippel–Lindau disease (VHL). Traditionally, VHL missense mutations have been associated with a higher risk of PPGL development, whereas truncating mutations typically confer a lower risk. In-frame duplication variants are rarely observed in patients with VHL but may lead to changes in the three-dimensional structure of the translated protein, similar to truncating variants. Our analysis suggests that these in-frame duplications of amino acids in specific regions may cause pheochromocytomas in a manner similar to missense variants. Further accumulation of VHL cases with various genotypes and standardized open-access worldwide databases, including longitudinal and specific clinical data linked to genotypes, is required. It is crucial to consider genetic analyses for pediatricians who may diagnose childhood-onset PPGL.