Endocrine Abstracts

Introduction: Pheochromocytomas(PC)are rare catecholamine-producing neuroendocrine tumors. Germline variants of the MYC-associated factor (MAX) gene have been associated with familial PC and paragangliomas (PGL) with an autosomal dominant pattern of inheritance and an overall frequency estimated at 1.9%. Other endocrine and non endocrine tumors can be associated to germline MAX mutations.

Case presentation: We report a case of a 37 years old male patient, with no particular personal or family history, who presented with a bilateral PC diagnosed following severe hypertension with paroxysmal Menard’s triad, high urinary normetanephrine=32.26 μmol/24h (> 10x normal value, confirmed the diagnosis of PC). Abdominal CT scan showed 3 bilateral adrenal nodules. MIBG scintigraphy showed no suprarenal or extra suprarenal fixation. Patient underwent a bilateral adrenalectomy and histologic study confirmed the diagnosis of PC(PASS <3). A truncating heterozygous germline MAX variant located on exon 4(c.223 C>T(p.Arg75*)was identified. Reassessment at 3 years after surgery showed no signs of recurrence (no hypertension and negative urinary metanephrins). Moreover, our patient’s lab findings were compatible with an asymptomatic hypercalcemic primary hyperparathyroidism(PHPT), a superior parathyroid nodule was found on cervical ultrasound with a significant in-situ PTH level (5059pg/ml). Patient was referred to surgery for parathyroidectomy.

Discussion: The MAX gene is the tenth PCC/PGL susceptibility gene described, it encodes a transcription factor involved in cell proliferation, differentiation and apoptosis. This mutation is responsible for multiple and/or bilateral PCs and PGL. The biological pattern of catecholamine secretion with a predominance of normetanephrines described in this mutation and explained by a low expression of the PNMT enzyme was found in our patient. Hypercalcemia has been reported in 4 other individuals with germline MAX mutations and PC, one of them reported as PHPT with germline MAX pathologic variant(PV):c.223C >T(p.Arg75*)which is similar to the variant of our patient suggesting that this variant may be associated with PHPT with parathyroid adenoma. Other endocrine and non-endocrine tumors that have been occasionally reported in this syndrome are absent in our patient.

Conclusion: Germline MAX mutations are associated with PCs, PGLs, parathyroid adenomas, other endocrine and non endocrine tumors suggesting that MAX is a novel multiple endocrine neoplasia gene. Screening of PHPT should be considered in the individuals carrying the PV c.223C>T (p.Arg75*). First-degree relatives of an individual with a known MAX pathogen variant should be offered molecular genetic testing.