title: Pathological and Genetic Characterization of Bilateral Adrenomedullary Hyperplasia in a Patient with Germline MAX Mutation.
abstract: 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. Preoperative18F-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.
authors.affiliation: Laboratory of Molecular Biology, Aix Marseille University CNRS, CRN2M, Marseille, France & APHM Conception, 13385, Marseille, France.
authors.forename: Pauline
authors.initials: P
authors.lastname: Romanet
authors.affiliation: Department of Endocrine Surgery, Aix-Marseille University Marseille, France & APHM Conception, 13284, Marseille, France.
authors.forename: Carole
authors.initials: C
authors.lastname: Guerin
authors.affiliation: Laboratory of Molecular Biology, Aix Marseille University CNRS, CRN2M, Marseille, France & APHM Conception, 13385, Marseille, France.
authors.forename: Pascal
authors.initials: P
authors.lastname: Pedini
authors.affiliation: APHM Timone Department of Neuropathology, Marseille, France.
authors.forename: Wassim
authors.initials: W
authors.lastname: Essamet
authors.affiliation: Department of Endocrinology, Aix Marseille University, CNRS, CRN2M, Marseille, France & APHM Conception, Marseille, France.
authors.forename: Frédéric
authors.initials: F
authors.lastname: Castinetti
authors.affiliation: Department of Endocrine Surgery, Aix-Marseille University Marseille, France & APHM Conception, 13284, Marseille, France.
authors.forename: Fréderic
authors.initials: F
authors.lastname: Sebag
authors.affiliation: Integrative Structural & Chemical Biology (iSCB) & INT-3D Molecular Modeling Platform, Cancer Research Centre of Marseille, CNRS UMR7258; INSERM U1068; Institut Paoli Calmettes; Aix-Marseille University, UM105, Marseille, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Roche
authors.affiliation: Hereditary Endocrine Cancer Group, Spanish National Cancer Research Centre and Centro de Investigación Biomédica en Red de Enfermedades Raras, Madrid, Spain.
authors.forename: Alberto
authors.initials: A
authors.lastname: Cascon
authors.affiliation: Department of Pathology and Laboratory Medicine, Tufts Medical Center, Boston, MA, USA.
authors.forename: Arthur S
authors.initials: AS
authors.lastname: Tischler
authors.affiliation: Section on Medical Neuroendocrinology, Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD), National Institutes of Health, Bethesda, MD, 20892, USA.
authors.forename: Karel
authors.initials: K
authors.lastname: Pacak
authors.affiliation: Laboratory of Molecular Biology, Aix Marseille University CNRS, CRN2M, Marseille, France & APHM Conception, 13385, Marseille, France.
authors.forename: Anne
authors.initials: A
authors.lastname: Barlier
authors.affiliation: Department of Nuclear Medicine, La Timone University Hospital & CERIMED & Inserm UMR1068 Marseille Cancerology Research Center, Institut Paoli-Calmettes, Aix Marseille University, 264 Rue Saint-Pierre, 13385, Marseille, France. david.taieb@ap-hm.fr.
authors.forename: David
authors.initials: D
authors.lastname: Taïeb
mesh_terms: D000310:Adrenal Gland Neoplasms / Q000235:genetics* / Q000473:pathology; D000311:Adrenal Glands / Q000473:pathology*; D000328:Adult; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000235:genetics*; D018389:Codon, Nonsense; D020022:Genetic Predisposition to Disease / Q000235:genetics; D018095:Germ-Line Mutation; D006801:Humans; D006965:Hyperplasia / Q000235:genetics / Q000473:pathology; D008297:Male; D010673:Pheochromocytoma / Q000235:genetics* / Q000473:pathology
chemical_list: D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D018389:Codon, Nonsense; C499330:MAX protein, human
keywords: Adrenal medullary hyperplasia; MAX; MYC-associated factor X; Pheochromocytoma