Poster Presentation 5th International Symposium on Phaeochromocytoma and Paraganglioma 2017

Genetic Aetiology of Paediatric Phaeochromocytoma and Paraganglioma: Experience of a Tertiary Centre and Review of Literature (#67)

Anand Vasudevan 1 , Katherine Tucker 1 , Roderick Clifton-Blight 2 3 , Diana Benn 2 3
  1. Prince of Wales Hospital, Randwick, NSW, Australia
  2. Cancer Genetics, Kolling Institute, Royal North Hospital, Sydney, NSW, Australia
  3. University of Sydney, Sydney, NSW

Phaeochromocytomas (PC) and paragangliomas (PGL) occurring in the paediatric age group are highly likely to be associated with genetic predisposition. Common genes associated with paediatric PC/PGLs are VHL (in Von-Hippel-Lindau syndrome), SDHx (hereditary paraganglioma syndromes 1-5), RET (Multiple endocrine neoplasia-2) and NF1.

A clinical audit of 13 paediatric PC/PGL patients (11 unrelated and two siblings who presented independently) seen through our clinic between 1993 and 2017 was performed. Genetic testing was performed according to a clinical algorithm (1): Iterative testing of VHL, RET, SDHB, SDHD, SDHC and SDHA by Sanger sequencing (and MLPA in selected cases) was performed according to a clinical algorithm (1); MAX and TMEM127 were sequenced in two cases. A germline molecular cause was identified in nine (69%): six had pathogenic variants in SDHB and the three had pathogenic variants in VHL . Five of six patients with an SDHB mutation presented with extra-adrenal tumours. All VHL carriers and one SDHB carrier presented with PC.

In four patients without a pathogenic germline variant, none had phenotypic features to suggest neurofibromatosis-1 or somatic EPAS1 mutation. Strikingly, one case demonstrated loss of SDHB IHC despite absence of SDHx pathogenic variants, including assessment for large deletions by MLPA. It is possible that this represents another case of somatic epigenetic inactivation of SDHC (2), and confirmatory methylation studies are pending. Next-generation panel sequencing of all four cases is also pending.  

In conclusion, paediatric PPGLs are highly likely to be associated with pathogenic germline variants in VHL or SDHx (particularly SDHB). This high a priori likelihood of PC/PGL genetic predisposition has two important corollaries: paediatric PPGLs should routinely have comprehensive genetic testing for all predisposition genes (including somatic testing for EPAS1); and new modes of genetic predisposition are more likely to be discovered in “negative” cases with younger onset of disease.

  1. Benn, Diana E., et al. "Clinical presentation and penetrance of pheochromocytoma/paraganglioma syndromes." The Journal of Clinical Endocrinology & Metabolism 91.3 (2006): 827-836.
  2. Richter, Susan, et al. "Epigenetic mutation of the succinate dehydrogenase C promoter in a patient with two paragangliomas." The Journal of Clinical Endocrinology & Metabolism 101.2 (2015): 359-363.