Genetics of Phaeochromocytomas and Paragangliomas



Seven genes in which mutations may cause paragangliomas have been identified:

Paragangliomas are also seen in the Carney triad (not to be confused with the Carney complex).



Frequencies of genetic mutations in phaeochromocytomas and non-secretory paragangliomas

All (familial and non-familial, secreting and non-secreting, adrenal, extra-adrenal and head & neck) Overall mutation frequency 24-32% (Neumann, Mannelli, Amar).
From Mannelli:
  • VHL 9.6%, SDHD 9.3%, RET 5.4%, SDHB 4.8%, NF1 2.2%, SDHC 0.8%
  • Mutation frequency 95% in familial or syndromic tumours
  • Mutation frequency 39% in recurrent or multiple tumours without familial or syndromic presentation
  • Mutation frequency 11% in non-familial non-syndromic solitary tumours
Familial non-secretory head & neck paragangliomas SDH mutations account for most cases (~90%)
  • SDHB 6-20%, SDHC 0-10%, SDHD 50-90%
  • About 1% due to RET and VHL mutations (Boedeker)
Non-familial non-secretory head & neck paragangliomas Mutations less common, reported frequencies vary widely
  • 11-29% SDH mutations, of which 20%, 2%, 80% are SDHB, SDHC and SDHD respectively
Phaeochromocytomas and secretory paragangliomas Overall mutation frequency: 24-32% (Neumann, Mannelli, Amar)
  From Amar et al 2005 (n=314) From Neumann et al 2002 (n=271)
Gene All patients (%) Familial or syndromic cases (%) Apparently sporadic cases (%) Age at diagnosis All patients (%) Age at diagnosis
VHL 8.0 28.6 3.5 24 11.1 18.3
RET 5.1 26.8 0.4 30 4.8 36.4
SDHB 6.7 5.4 7.0 34 4.4 25.6
SDHD 3.5 16.1 0.8 31 4.1 28.7
SDHC 0 0 0
NF1 4.1 23.2 0 40
Total 27.4 100 11.6 24.4 24.9
None 72.6 0 88.4 46 75.6 43.9

Succinate dehydrogenase mutations

Gene Inheritance Phenotype Other features
SDHA Autosomal recessive Leigh synd (juvenile encephalopathy)  
SDHB Autosomal dominant Phaeo and HNPGL
  • extra-adrenal and malignant phaeo more common
  • 90% of SDHB-related phaeos secrete noradrenaline or dopamine
SDHC Autosomal dominant HNPGL, incomplete penetrance
SDHD Autosomal dominant with parent-of-origin effect HNPGL and phaeo
  • extra-adrenal phaeo more common
  • requires paternal transmission - presumably due to maternal imprinting