Ö. Baysal1, D.P.S. Samlal2, , A.R. Mensenkamp1, J.M. de Laat3, H.P.M. Kunst2, C.P.A. Delsing2, C.M. Kets1, H.J.L.M. Timmers3
Radboud University Medical Center, Departments of 1 Medical Genetics, 2 ENT Surgery, and 3 Internal Medicine, Nijmegen, The Netherlands
Background and aim: The clinical phenotype of patients with familial paraganglioma (PGL) syndrome due to germline pathogenic variants of the SDHA gene is dominated by head and neck and abdominal tumor locations, with a malignancy rate of 25%. In a previously reported study of SDHA pathogenic variant carriers in the Netherlands, including the c.91C>T, p.(Arg31*) Dutch founder mutation, the age related disease penetrance for non-index cases was estimated at 0% at age 25 y, 2% at age 50 y (95% CI 0-6%) and 10% at age 70 y (95% CI 0-21%), respectively (1). Based on Bayesian approach life time estimates, penetrance is suggested to be even much lower: 0.4%. The aim of the study was to assess the yield of standardized tumor surveillance in index and non-index SDHA pathogenic variant carriers.
Method: A total of 53 patients who were SDHA pathogenic variant carriers (19 index, 34 non-index) were evaluated at a single institution, undergoing periodic tumor screening through clinical, biochemical and imaging work-up according to international guidelines.
Results: In non-index cases, both at the initial evaluation and during a mean (IQR) follow-up of 3.1 (0.6-5.6) years, no PGLs, nor other SDHA-related tumors were diagnosed.
Conclusion: A (very) low disease penetrance of asymptomatic SDHA pathogenic variant carriers calls for rethinking the recommended ‘one size fits all’ protocols for tumor surveillance in SDHx carriers and rather consider a subunit-specific approach.
(1) Van der Tuin et al. J Clin Endocrinol Metab 2018. PMID: 29177515