Abstract
Disclosure: R. Halperin: None. G. Reznick-Levi: None. A. Khalaileh: None. R. Svirsky-Frayden: None. O. Reish: None. K. Weiss: None. A. Tirosh: None.
Approximately 30% of patients with pheochromocytoma and paraganglioma (PPGLs) have a genetic predisposition due to a germline pathogenic variant (PV) in a susceptibility gene. We aimed to assess the prevalence of PPGL-related hereditary syndromes based on a multi-center national-level study, and to identify risk factors for hereditary PPGL based on clinical and biochemical data. Methods This is a retrospective study of patients with a personal history of PPGL. All patients underwent germline DNA sequencing (whole exome or panel sequencing). Demographic, clinical, biochemical, and genetic data were gathered. Results Of a total of 225 patients, 90 were evaluated for personal history of PPGL and 135 for family history. Overall, 76 patients (33.8%) carried a likely\PV in a PPGL-related gene, including 43 of the 135 patients with family history (31.8%); 30 with SDHB (three different PVs), eight with SDHD (two variants) and five with VHL (three variants). We found higher risk for positive genetic testing in patients with family history of PPGL among patients of Arab ancestry: 46 patients (60.5%) from 6 kindreds, carried SDHB PV (n=38), VHL PV (n=7) and SDHC (n=1), compared with 22.4% (n=17) among Jewish patients and 17.1% (n=13) among patients of Druze ancestry. Ninety patients with personal history of PPGL underwent genetic evaluation (median age at diagnosis 47 [7-73], 35.6% males), of them 29 (33.7%) had a family history of PPGL. Forty-one patients had pheochromocytoma, 45 had paraganglioma, and four had both. Thirty-four patients (37.8%) carried a PPGL susceptibility gene PV, most often in SHDB (14 patients, 41.1%), followed by SDHD (n=9, 25.7%), VHL (n=6, 17.6%), NF1 (n=2, 5.9%), SDHC, SDHAF2, and RET (one patient each, 2.9%). Age at diagnosis was significantly younger in the PV-carriers vs. non-carriers (31.63±2.71 vs. 50.48±2.41, p < 0.00001). All 17 carriers with elevated plasma/urine catecholamines had purely elevated normetanephrine (NMN) levels (52.2% vs 10.0% pure normetanephrine secretion in hereditary vs. sporadic PPGL, respectively, p=0.002). NMN-only secretion was associated with a younger age at diagnosis vs. other secretion profiles (36.1±3.7 vs. 48.85±3.1 years, p=0.0006). Twelve patients (13.3%) had aggressive tumor behavior (recurrence\metastases), with a significantly higher rate of PV compared with patients with the non-aggressive disease (n=8 [66.7%] vs. n=10 [27.0%], respectively, p = 0.01). Discussion Among patients with family history of PPGL, those from Arab ancestry had higher risk for positive testing for hereditary syndrome.
Presentation: Sunday, July 13, 2025