Genes affected (with germline mutations): VHL, SDHB, SDHC, SDHD, TMEM127 and MAX
Additional genes that may be included: FH and SDHA (succinate dehydrogenase)
Clinical features:
(1) renal cell carcinoma (RCC)
(2) pheochromocytoma or paraganglioma
(3) without evidence of von Hippel Lindau (VHL)
(4) variable family history
Histologic correlations:
(1) VHL mutations are associated with clear cell renal cell carcinoma
(2) SDHB mutations are associated with renal cell carcinomas with solid growth, intracytoplasmic inclusions and mast cell infiltration.
Mutations in VHL may be associated with:
(1) central or retinal hemangioblastomas
(2) pancreatic cysts
(3) renal cysts
Flowchart for the genetic evaluation:
(1) test for VHL if there are clinical markers for VHL mutations
(2) if no evidence of VHL, then test for SDHB
(3) if there is loss of SDHB expression: look for SDHA, SDHB, SDHC, SDHD
(4) if there is preserved SDHB expression, then look for FH, MAX and TMEM127
(5) if step 3 is negative then test for genes in step 4; if step 4 is negative then test for the genes in step 3
