ODP051 Presymptomatic Genetic Screening Leading to the Diagnosis of Paraganglioma Associated with Duodenal and Pancreatic Neuroendocrine Tumours in a Carrier of a Pathogenic MAX Variant

MAXpathogenic variants have been found to predispose to pheochromocytomas and paragangliomas (PPGLs) and more recently to pituitary tumors 1.

A 30 yo man presented to the emergency department for diplopia and high blood pressure (200/100mmHg). His workup showed elevated plasmatic normetanephrines (9. 01nmol/L; N <0.92) and a 3.7cm right adrenal mass with a density of 30HU. The patient underwent right laparoscopic adrenalectomy and the pathologist reported a 4.5cm pheochromocytoma with a PASS score of 4 and a Ki-67 of 2-4%. The patient was screened with a panel of 14 susceptibility genes for PPGLs (INVITAE, CA, USA) that revealed a pathogenic germline nonsense heterozygous MAX mutation (c.223C>Tp. Arg75*). This mutation was previously described in a family where four members suffered from bilateral PHEOs at a young age (28-35 yo) 2 . Following the identification of the pathogenic variant of MAX gene, the patient's father (61 yo) underwent genetic counselling and was found to carry the same germline mutation. His past medical history included long-standing hypertension with hypertensive cardiomyopathy and diabetes. His blood work showed a mildly elevated plasmatic normetanephrine (1.41nmol/L; N <1.2) with normal metanephrine. An abdominal CT-scan showed a 1.5cm precaval nodularity. On a complementary 18 F-FDG PET/CT, the precaval mass had a 3.5 SUVMax and a second mass was identified in the duodenum (D3) with an uptake of 4.9 SUVMax. The 68 GaDOTATE PET/CT confirmed the precaval (SUVMax36.3) and duodenal (SUVMax51.6) lesion and in addition, revealed a pancreatic mass (SUVMax9.3). The patient underwent a distal pancreatic, duodenal and precaval node resection. The pathology report showed a 1.7cm G1 pancreatic neuroendocrine tumor (NET) (Ki-67 <3%) and a 2.3cmG1 duodenal NET (Ki-67 <3%). The precaval node was a paraganglioma (PGL) with a preserved SDHB staining, negative cytokeratine 8/18 and a Ki-67 of 1.65%. The son had normal imaging of his pancreas. To our knowledge we report the second case of association of MAXmutation with gastrointestinal TNE.

This case presents the rare association of a familial MAX mutation presenting with a pheochromocytoma in the index case and a presymptomatic discovery of a PGL and multiple NETs in the father. This supports the hypothesis that MAXmutations might be associated with multiendocrinetumors 3. References: 1. Daly AF, Castermans E, et al. Pheochromocytomas and pituitary adenomas in three patients with MAX exon deletions. Endocr Relat Cancer. May 2018;25(5): L37-l42. doi: 10.1530/erc-18-00652. Comino-Méndez I, Gracia-Aznárez FJ, et al. Exome sequencing identifies MAX mutations as a cause of hereditary pheochromocytoma. Nat Genet. Jun 19 2011;43(7): 663-7. doi: 10.1038/ng.8613. Petignot S, Daly AF, et al. Pancreatic Neuroendocrine Neoplasm Associated with a Familial MAX Deletion. Horm Metab Res. Nov 2020;52(11): 784-787. doi: 10.1055/a-1186-0790

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