VHL – Pheochromocytoma

Autosomal dominant mutations in the VHL tumor suppressor gene predispose to pheochromocytoma through dysregulated hypoxia signaling. A three-generation family with seven affected relatives demonstrated perfect co-segregation of a novel VHL variant and pheochromocytoma (PMID:8550742). In an unrelated cohort of 271 patients with apparently sporadic pheochromocytoma, 30 (11%) harbored germline VHL mutations, many of which were private missense or truncating alleles, revealing occult hereditary cases (PMID:12000816).

Genetic evidence supports autosomal dominant inheritance with high penetrance. Over 100 distinct pathogenic VHL variants have been reported in pheochromocytoma cases, including recurrent missense changes and exon deletions. A representative pathogenic allele is c.244C>G (p.Arg82Gly), identified in a de novo childhood pheochromocytoma (PMID:28781534). While most VHL alleles confer tumor risk, rare variants such as c.256C>T (p.Pro86Ser) occur at ~0.5% in the general population and do not cause disease, illustrating allele-specific pathogenicity (PMID:11257211).

Functional studies establish loss of pVHL E3 ubiquitin ligase activity as the mechanism of tumorigenesis. Wild-type pVHL binds elongin B/C and Cullin-2 to target hydroxylated HIF-α for proteasomal degradation; VHL mutants fail to promote HIF-1α ubiquitination in vitro (PMID:10973499) and display aberrant VEGF overexpression in renal cell models (PMID:9346879). Mouse conditional Vhl knockouts develop vascular tumors and adrenal lesions, recapitulating human phenotypes and confirming tumor suppressor function.

No significant conflicting evidence has been reported aside from the benign P25L variant, which affects only the longer pVHL isoform and lacks disease association. No bona fide refuting studies have emerged, supporting a definitive clinical validity for VHL–pheochromocytoma.

Integration of extensive genetic and mechanistic data confirms a definitive VHL–pheochromocytoma association. Germline screening for VHL mutations is indicated in all patients with bilateral, early-onset, or recurrent pheochromocytoma. Functional assays of pVHL–HIF interactions provide actionable biomarkers for variant interpretation and potential therapeutic targeting.

Key Take-home: Germline VHL testing informs diagnosis, guides surveillance for multisystem tumors, and supports genotype-directed management in pheochromocytoma.

References

• The Journal of clinical endocrinology and metabolism | 1996 | Familial pheochromocytoma associated with a novel mutation in the von Hippel-Lindau gene. PMID:8550742
• The New England journal of medicine | 2002 | Germ-line mutations in nonsyndromic pheochromocytoma. PMID:12000816
• Cancer research | 1997 | The von Hippel-Lindau gene product inhibits vascular permeability factor/vascular endothelial growth factor expression in renal cell carcinoma by blocking protein kinase C pathways. PMID:9346879
• Proceedings of the National Academy of Sciences of the United States of America | 2000 | Activation of HIF1alpha ubiquitination by a reconstituted von Hippel-Lindau (VHL) tumor suppressor complex. PMID:10973499
• Molecular diagnosis : a journal devoted to the understanding of human disease through the clinical application of molecular biology | 2001 | Is the P25L a "real" VHL mutation? PMID:11257211

Evidence Based Scoring (AI generated)