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Background: Pheochromocytomas (PHEOs) and paragangliomas (PGLs) (PPGLs) are rare tumors with a high heritability. The prevalence of germline mutations in sporadic PPGLs varies depending of series. Objective: To determine the prevalence and spectrum of germline mutations in our cohort of patients with apparently sporadic PPGLs. Method: We retrospectively reviewed the charts of patients with sporadic pathology-confirmed PPGLs who underwent genetic testing after genetic counselling at our Quaternary center from 2005–2019. Genetic analysis included sequential gene sequencing by Sanger method from 2005–2014 (n = 89) and a multigene sequencing by NGS with a panel (14 susceptibility genes for PPGLs) from 2015–2019 (n = 34). Some patients underwent both (n = 12). Results: Among 230 patients that were treated for PPGLs from 2005- 2019, 135 patients underwent genetic testing (77 females; 58 males and 77.8% French Canadians). There were 60 PGLs (29 head and neck, 21 abdominal and 10 thoracic) and 75 PHEOs, 4 being bilateral. The prevalence of pathogenic germline mutations was 27.4% (37/135). Patients carrying a germline mutation were younger than patients with no mutations (40.7 yo (20 - 67) vs. 49.6 yo (11 - 80)) and had a higher prevalence of metastatic tumors (26.6% vs. 20.4%). The prevalence of germline mutations was 43.3% (26/60) in PGLs and 14.7% (11/75) in PHEOs. In the 26 mutated PGLs, there were 13 SDHC (50.0%), 6 SDHB (23.1%), 4 SDHD (15.4%), 2 SDHA (7.7%) and 1 FH (3.8%) mutations. The recurrent pathogenic SDHC c.397C&amp;gt;T (p.Arg133*) mutation was found in 12 out of the 13 SDHC mutations reflecting the presence of a funder effect in the French Canadian population. In the 11 mutated PHEOs, there were 3 MAX (27.3%), 3 VHL (27.3%), 2 RET (18.2%), 1 SDHB (9.1%), 1 NF1 (9.1%), 1 FH (9.1%) mutations. From 2015- 2019, we proposed NGS assay with the multigene panel to 12 patients (9 PHEOS and 3 PGLs) for whom the initial genetic test was negative. Novel germline mutations were found in 4 (33.3%) of these patients, representing 10.8% (4/37) of the mutation-carriers. Mutations were found in 2/9 PHEOs; a 28 yo female with bilateral PHEOs (MAX (deletion exon 1 and 2)) and a 33 yo male with malignant PHEO (MAX (c.3G&amp;gt;A)), and in 2/3 PGLs; a 31 yo woman with metastatic abdominal PGL (SDHA (c.985C&amp;gt;T) and a 59 yo woman with a thoracic PGL (SDHA (c.1432_1432 + 1del). Variants of uncertain significance (VUS) were identified in 7/60 PGLs (11.6%) and 5/75 PHEOs (6.7%) but the significance of these variants remains to be determined. Conclusion: In our cohort, the prevalence of germline mutations was of 44.3% in apparently sporadic PGLs and 14.7% in PHEOs. Genetic re-evaluation overtime using multigene sequencing by NGS assay in a subgroup of patients led to an increase of mutation rate in PHEOs and PGLs with the identification of germline MAX and SDHA mutations.

journal of the endocrine society

MON-212 Genetic Spectrum Of A Canadian Cohort Of Sporadic Pheochromocytomas And Paragangliomas: Higher Prevalence Of Germline Mutations In PGL And NGS Assay With A Multigene Panel Increases The Mutation Rate