Endocrine Abstracts

New possible pathogenic variants involved in pheochromocytomas and paragangliomas

Introduction: Pheochromocytomas and paragangliomas (PPGLs) are rare tumors of the chromaffin tissues that store and release catecholamines in excess. Most pheochromocytomas are sporadic, usually resulting in unilateral adrenal tumor, but 25–45% harbour a germline mutation.

Aim: To describe new possible pathogenic variants (VUS) involved in PPGLs.

Material and methods: From a cohort of 125 patients with PPGLs we prospectively performed genetic test of 80 patients. More than a half of those tested patients 59.4% (n=47) had a mutation (20 RET, 3 VHL, 1 SDHB, 1 NF1, 1 SDHD, 1 FANCA, 1 CASR, 19 VUS). From those 19 patients with VUS, 4 had less than 40 years old at the time of diagnosis. One patient (MSH 6 c.1474A>G) associated PHEO with pulmonary adenocarcinoma. One patient (BRIP 1 c.728T>C) had malignant PHEO, with an aggressive pattern and family history of colonic cancer. One patient had clinical phenotype of neurofibromatosis. She had 35 years at diagnosis, and her son has clinical features of neurofibromatosis. In her case, we identified somatic mutation of NF1 (c.7966del), and germline VUS of MSH2+ATM c.1134_1136delAGA+c.1444A>C. One patient (MEN1 c.526G>T) associated PHEO and familial hypocalciuric hypercalcemia, and 2 other had PHEO and idiopathic hypercalcemia (RB2 c.644C>T) respectively primary hyperparathyroidism (ATM c.5639C>T). Another patient, with PHEO, papillary thyroid carcinoma and colonic polyps, had a VUS of BARD1 (c.1333G>A).

Conclusion: In the presence of clear heritability and other syndromic tumors, we can suppose that a VUS is probably a pathogenic variant. Further clinical and molecular evaluation of VUS carriers should corroborate our results with others from the literature. When the clinical aspects and heritability are suggestive for a pathogenic variant, a functional assessment would help us to classify VUS as pathogenic variants related to PHEOs.