Pathological and Genetic Characterization of Bilateral Adrenomedullary Hyperplasia in a Patient with Germline MAX Mutation

• DOI: 10.1007/s12022-016-9460-5
• Publication Date: 2016-11-12T06:53:15Z
• Authors: Pauline Romanet; Carole Guerin; Pascal Pedini; Wassim Essamet; Frédéric Castinetti; Fréderic Sebag; Philippe Roche; Alberto Cascon; Arthur S. Tischler; Karel Pacak; Anne Barlier; David Taïeb
• Keywords: Adult; Male; 0301 basic medicine; Hyperplasia; Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; [SDV]Life Sciences [q-bio]; Adrenal Gland Neoplasms; Pheochromocytoma; Adrenal medullary hyperplasia; [SDV] Life Sciences [q-bio]; 03 medical and health sciences; Codon, Nonsense; Adrenal Glands; Humans; Genetic Predisposition to Disease; MYC-associated factor X; Germ-Line Mutation; MAX

In recent years, familial pheochromocytoma (PHEO) with germline mutations in the MAX (MYC associated factor X) gene has been reported in a few cases. Here, we investigated a 25-year-old patient with multiple PHEOs associated with a non-sense germline MAX mutation. Preoperative 18F-FDOPA PET/CT revealed bilateral adrenal involvement with multiple tumors. In addition, both adrenal glands were found to have diffuse or nodular adrenal medullary hyperplasia (AMH), a histopathological feature previously described as a precursor of MEN2- and SDHB-related PHEOs but not MAX. After bilateral adrenalectomy, different paraffin-embedded and frozen samples were analyzed for allelic imbalances of the MAX gene using allelic quantification by pyrosequencing. The expression of the protein MAX was studied by immunohistochemistry. All PHEOs but also nodular AMH exhibited a loss of the normal allele. By contrast, the diffuse AMH did not show loss-of-heterozygosity. Nevertheless, immunohistochemistry demonstrated loss of protein MAX expression in all samples including diffuse hyperplasia, suggesting a causative role of MAX mutation for both PHEOs and AMH. The present case shows that both nodular and diffuse AMH belongs to the spectrum of MAX-related disease. These data support the possible continuum between nodular AMH and PHEO, expanding the qualification of micro-PHEO to nodular AMH.