Oral Presentation 5th International Symposium on Phaeochromocytoma and Paraganglioma 2017

Phenotype and penetrance of germline SDHA mutations in 30 Dutch families (#54)

FJ Hes 1 , K van der Tuin 1 , AR Mensenkamp 2 , CMJ Tops 1 , HP Kunst 3 , JC Jansen 4 , EP van der Kleij-Corssmit 5 , H Morreau 6 , B Kusters 7 , MM de Jong 8 , AN van de Horst-Schrivers 9 , EM Leter 10 , L Spruijt 2 , BMP van Nesselrooij 11 , WN Dinjens 12 , RA Oldenburg 13 , HJ Timmers 14
  1. Genetics, LUMC, Leiden, ZUID-HOLLAND, Netherlands
  2. Genetics, Radboud University Medical Centre, Nijmegen, The Netherlands
  3. Otorhinolaryngology, Head and Neck Surgery, Radboud University Medical Centre, Nijmegene, The Netherlands
  4. Otorhinolaryngology, LUMC, Leiden, The Netherlands
  5. Endocrinology, LUMC, Leiden, The Netherlands
  6. Pathology, LUMC, Leiden, The Netherlands
  7. Pathology, Radboud University Medical Centre, Nijmegen, The Netherlands
  8. Genetics, UMCG, Groningen, The Netherlands
  9. Endocrinology, UMCG, Groningen, The Netherlands
  10. Genetics, MUMC, Maastricht, The Netherlands
  11. Genetics, UMCU, Utrecht, The Netherlands
  12. Pathology, Erasmus MC, Rotterdam, The Netherlands
  13. Genetics, Erasmus MC, Rotterdam, The Netherlands
  14. Endocrinology, Radboud University Medical Centre, Nijmegen, The Netherlands

Introduction: So far, clinical information of germline SDHA mutation carriers is limited to case reports and only one larger series.

Subjects and Methods: We studied 393 genetically unexplained pheochromocytoma and paraganglioma (PPGL)-patients referred for germline analysis in the Netherlands. Subsequently, clinical manifestations and disease penetrance were studied in 30 index SDHA mutation carriers and their 51 relatives whom were identified as carriers via cascade screening.

Results: Pathogenic germline SDHA variants were identified in 30 of the 393 referred PPGL-patients (7.6%). In subgroups we found mutations in: 22 of 175 patients with head and neck PGL (13%), 4 of 191 with pheochromocytoma (2%) and 4 of 27 with sympathetic PGL (15%). The mean age (± SD) at diagnosis in index SDHA mutation carriers was 43±16 years compared to 52±15 years in non-mutation carriers (p=0.002). The estimated penetrance of any SDHA-related disease was 12% at age 70 (95% CI 0-25%) in 51 non-index mutation carriers.

Conclusions: Pathogenic germline SDHA variants are frequently found in genetically unexplained PPGL patients. The majority of identified index-patients presented with an apparently sporadic PGL in head and neck. In the largest SDHA series assembled so far, we found the lowest penetrance of all major PPGL predisposition genes. This suggests that recommendations for genetic counselling of at risk relatives and stringency of surveillance for SDHA  mutation carriers might need to be reassessed.