Case Report: Pheochromocytoma and Synchronous Neuroblastoma in a Family With Hereditary Pheochromocytoma Associated With a MAX Deleterious Variant

Abstract

IntroductionPheochromocytomas are rare catecholamine-producing neuroendocrine tumours arising from chromaffin cells of the adrenal medulla or extra-adrenal sympathetic paraganglia. Recent studies have indicated that up to 40% of pheochromocytomas could be attributable to an inherited germline variant in an increasing list of susceptibility genes. Germline variants of the MYC-associated factor (MAX) gene have been associated with familial pheochromocytomas and paragangliomas with an autosomal dominant pattern of inheritance, a median age at onset of 33 years and an overall frequency estimated at 1.9%. We describe a deleterious MAX variant associated with hereditary pheochromocytoma in a family with four affected individuals.Case presentationThe first patient presented with bilateral pheochromocytoma in 1995; genetic testing was proposed to his oldest son, when he was diagnosed with a bilateral pheochromocytoma with a synchronous neuroblastoma. Upon the identification of the MAX variant c.97C>T, p.(Arg33Ter), in the latter individual, his two siblings and their father were tested and the same variant was identified in all of them. Both siblings were subsequently diagnosed with pheochromocytoma (one of them bilateral) and choose to remain on active surveillance before they were submitted to adrenalectomy. All the tumours secreted predominantly norepinephrine, accordingly to the typical biochemical phenotype ascribed to variants in the MAX gene.ConclusionThis case series is, to our knowledge, the one with the largest number of individuals with hereditary pheochromocytoma with a deleterious MAX variant in the same family. It is also the first case with a synchronous pheochromocytoma and neuroblastoma in carriers of a MAX deleterious variant. This report draws attention to some ill-defined features of pheochromocytoma and other malignancies associated with a MAX variant and highlights the importance of understanding the genotype-phenotype correlation in hereditary pheochromocytoma and the impact of oriented genetic testing to detect, survey and treat patients and kindreds at risk.

Bilateral Pheochromocytoma with Germline MAX Variant without Family History

“…Among 499 studies, 213 articles reported variants related to PPGLs and 16 papers reported MAX variants. We summarized the characteristics of the cases with PPGLs in MAX variants [ 5 , 15 , 16 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 ] ( Supplementary Table S1 ). Combining data from the 16 reports in MAX variants revealed that 42/71 cases (59.2%) had bilateral PCCs, 9/59 cases (8.5%) had PGLs, and 31/70 cases (44.3%) had an apparent family history of PPGLs.…”

HIF and MYC signaling in adrenal neoplasms of the neural crest: implications for pediatrics

“…Germline PVs in MAX are associated with bilateral and multifocal PPGLs (67%) ( 126 , 127 ) and the occurrence of both neuroblastomas and PPGLs ( 128 , 129 ), which highlights the importance of the MYC/MAX convergence point in these catecholamine-producing neoplasms. Furthermore, it suggests that the chromosomal second hit can occur early enough in embryogenesis to allow differentiation of the migrating neural crest cells into both, neuroblasts and chromaffin cells.…”

Biochemical Diagnosis of Catecholamine-Producing Tumors of Childhood: Neuroblastoma, Pheochromocytoma and Paraganglioma

“…Adding to the difficulties in differential diagnosis, cases have also been reported of composite neuroblastoma and pheochromocytoma ( 85 – 87 ). Furthermore, some gene mutations, such as those impacting the myc-associated factor X ( MAX ) gene, can predispose to both childhood neuroblastoma and pheochromocytoma ( 88 , 89 ).…”