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Clinical Aspects of SDHA-Related Pheochromocytoma and Paraganglioma

Journal Contribution - Journal Article

Subtitle:A Nationwide Study

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.

Journal: J Clin Endocrinol Metab
ISSN: 0021-972X
Issue: 2
Volume: 103
Pages: 438-445
Publication year:2018
Keywords:Adolescent, Adrenal Gland Neoplasms/epidemiology, Adult, Aged, Aged, 80 and over, Child, DNA Mutational Analysis, Electron Transport Complex II/genetics, Female, Genetic Predisposition to Disease, Germ-Line Mutation, Humans, Male, Middle Aged, Netherlands/epidemiology, Paraganglioma/epidemiology, Penetrance, Pheochromocytoma/epidemiology, Retrospective Studies, Young Adult