Genetic landscape of Romanian PPGLs

Abstract

Pheochromocytomas and paragangliomas (PPGLs) are rare neuroendocrine tumours that originate from chromaffin cells and occur in the adrenal medulla and in the sympathetic or parasympathetic ganglia. Nearly 70% of PPGLs result from germline or somatic mutations in a single driver gene. The aim of this study was to characterize the genetic background and clinical characteristics related to genetic profile of patients with PPGLs from Romania. We retrospectively retrieved data of 125 patients consecutively registered, diagnosed with PPGLs in a tertiary referral center of endocrinology from Romania, between 1976 and 2022. We identified 88 (70.4%) women, and 37 (29.6%) men, with a mean age at diagnosis of 48.5 ± 15 years. From these 125 patients, 80 (64%) were submitted to the genomic study; 35% (n = 28) had a germline mutation (20 RET, 3 VHL, 1 SDHB, 1 NF1, 1 SDHD, 1 FANCA, 1 CASR) while 65% (n = 52) presented sporadic disease. Patients with hereditary disease had significantly lower age at diagnosis comparing to sporadic cases (37 ± 15 vs. 49.9 ± 12.2 years, p = 0.001). Bilateral tumors developed in twelve patients from the hereditary group. Metastatic disease was described in 4 out of 80 patients (2 of them with hereditary disease). Patients from sporadic group tended to have a right lateralisation of the tumour compared to hereditary cases, where the tumour was more often left sided. RET pathogenic variant (p.Cys634Trp) associated with MEN2A syndrome was the most prevalent in Romanian population with PPGLs and could be considered as a founder effect. Patients with hereditary disease are diagnosed at a younger age and develop bilateral tumors more frequently compared to sporadic cases.

Keywords: founder effect; genetics; hereditary; paraganglioma; pheochromocytoma; sporadic.