Search

Context: Paraganglioma (PGL) has the highest degree of heritability among human neoplasms. Current clinical understanding of germline SDHA mutation carriers is limited., Objective: To estimate the contribution of SDHA mutations in PGL and to assess clinical manifestations and age-related penetrance., Design: Nationwide retrospective cohort study., Setting: Tertiary referral centers in the Netherlands (multicenter)., Patients: Germline SDHA analysis was performed in 393 patients with genetically unexplained PGL. Subsequently, 30 index SDHA mutation carriers and 56 nonindex carriers were studied., Main Outcome Measures: SDHA mutation detection yield, clinical manifestations, and SDHA-related disease penetrance., Results: Pathogenic germline SDHA variants were identified in 30 of the 393 referred patients with PGL (7.6%), who had head and neck PGL (21 of 174 [12%]), pheochromocytoma (4 of 191 [2%]), or sympathetic PGL (5 of 28 [18%]). The median age at diagnosis was 43 years (range, 17 to 81 years) in index SDHA mutation carriers compared with 52 years (range, 7 to 90 years) in nonmutation carriers (P = 0.002). The estimated penetrance of any SDHA-related manifestation was 10% at age 70 years (95% confidence interval, 0% to 21%) in nonindex mutation carriers., Conclusion: Germline SDHA mutations are relatively common (7.6%) in patients with genetically unexplained PGL. Most index patients presented with apparently sporadic PGL. In this SDHA series, the largest assembled so far, we found the lowest penetrance of all major PGL predisposition genes. This suggests that recommendations for genetic counseling of at-risk relatives and stringency of surveillance for SDHA mutation carriers might need to be reassessed., (Copyright © 2017 Endocrine Society)

Germline mutations in succinate dehydrogenase B (SDHB) predispose to hereditary paraganglioma (PGL) syndrome type 4. The risk of developing PGL or pheochromocytoma (PHEO) in SDHB mutation carriers is subject of recent debate. In the present nationwide cohort study of SDHB mutation carriers identified by the clinical genetics centers of the Netherlands, we have calculated the penetrance of SDHB associated tumors using a novel maximum likelihood estimator. This estimator addresses ascertainment bias and missing data on pedigree size and structure. A total of 195 SDHB mutation carriers were included, carrying 27 different SDHB mutations. The 2 most prevalent SDHB mutations were Dutch founder mutations: a deletion in exon 3 (31% of mutation carriers) and the c.423+1G>A mutation (24% of mutation carriers). One hundred and twelve carriers (57%) displayed no physical, radiological or biochemical evidence of PGL or PHEO. Fifty-four patients had a head and neck PGL (28%), 4 patients had a PHEO (2%), 26 patients an extra-adrenal PGL (13%). The overall penetrance of SDHB mutations is estimated to be 21% at age 50 and 42% at age 70 when adequately corrected for ascertainment. These estimates are lower than previously reported penetrance estimates of SDHB-linked cohorts. Similar disease risks are found for different SDHB germline mutations as well as for male and female SDHB mutation carriers., (© 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Objective: Succinate dehydrogenase B subunit ( SDHB ) gene germline mutations predispose to pheochromocytomas, sympathetic paragangliomas, head and neck paragangliomas and non-paraganglionic tumors (e.g. renal cell carcinoma, gastrointestinal stromal tumor and pituitary neoplasia). The aim of this study was to determine phenotypical characteristics of a large Dutch cohort of SDHB germline mutation carriers and assess differences in clinical phenotypes related to specific SDHB mutations., Design: Retrospective descriptive study., Methods: Retrospective descriptive study in seven academic centers., Results: We included 194 SDHB mutation carriers consisting 65 (33.5%) index patients and 129 (66.5%) relatives. Mean age was 44.8 ± 16.0 years. Median duration of follow-up was 2.6 years (range: 0-36). Sixty persons (30.9%) carried the exon 3 deletion and 46 (23.7%) the c.423 + 1G > A mutation. Fifty-four mutation carriers (27.8%) had one or multiple head and neck paragangliomas, 4 (2.1%) had a pheochromocytoma and 26 (13.4%) had one or more sympathetic paragangliomas. Fifteen patients (7.7%) developed metastatic paraganglioma and 17 (8.8%) developed non-paraganglionic tumors. At study close, there were 111 (57.2%) unaffected mutation carriers. Statistical analyses showed no significant differences in the number and location of head and neck paragangliomas, sympathetic paragangliomas or pheochromocytomas, nor in the occurrence of metastatic disease or other tumors between carriers of the two founder SDHB mutations (exon 3 deletion vs c.423   + 1G > A)., Conclusions: In this nationwide study of disease-affected and unaffected SDHB mutation carriers, we observed a lower rate of metastatic disease and a relatively high number of head and neck paragangliomas compared with previously reported referral-based cohorts., (© 2017 European Society of Endocrinology.)