Von Hippel-Lindau Syndrome is Associated with Family History of Renal Cell Carcinoma
Von Hippel-Lindau (VHL) syndrome is the correct answer (option A) for a syndrome associated with family history of renal cell carcinoma. Peutz-Jeghers syndrome (option B) is not primarily associated with renal cell carcinoma.
Rationale for VHL Syndrome
Von Hippel-Lindau disease is one of the most common hereditary renal cell carcinoma (RCC) syndromes identified in the NCCN Guidelines for Kidney Cancer 1. It is characterized by:
- Autosomal dominant inheritance pattern
- Germline mutations in the VHL tumor suppressor gene located on chromosome 3p25-26 2
- High risk of developing bilateral and multifocal clear cell renal cell carcinomas (ccRCC) 3
Clinical Features of VHL Syndrome
VHL syndrome presents with multiple manifestations beyond renal cell carcinoma:
- Renal manifestations: Bilateral and multifocal clear cell RCC, renal cysts
- Central nervous system: Hemangioblastomas of the brain and spinal cord
- Retinal: Retinal angiomas
- Pancreatic: Pancreatic cysts and neuroendocrine tumors
- Adrenal: Pheochromocytomas
- Other: Endolymphatic sac tumors, epididymal cystadenomas 4
Molecular Pathogenesis
The VHL gene functions as a tumor suppressor gene:
- VHL protein is part of an E3 ligase complex that regulates hypoxia-inducible factors (HIF-1α and HIF-2α)
- Loss of VHL function leads to aberrant accumulation of HIF proteins
- This results in uncontrolled activation of genes regulating angiogenesis, glycolysis, and apoptosis 1
- VHL inactivation is the earliest oncogenic driving event in clear cell RCC development 1
Diagnostic Approach
When a patient presents with a family history of renal cell carcinoma, genetic evaluation should be considered, especially with:
- RCC diagnosis at age ≤46 years
- Bilateral or multifocal tumors
- ≥1 known first- or second-degree relative with RCC 1
For patients with suspected VHL syndrome:
- Genetic testing for VHL gene mutations
- Comprehensive imaging with MRI (preferred) or CT for surgical planning 1
- Regular surveillance for development of new tumors
Management Considerations
For patients with confirmed VHL syndrome:
- Regular screening with MRI is recommended to detect early RCC
- Nephron-sparing surgery is preferred for renal tumors to preserve kidney function
- Systemic therapy options for advanced disease include VEGF pathway inhibitors, mTOR inhibitors, and immunotherapy 5
- Multidisciplinary management involving urology, oncology, neurology, ophthalmology, and genetics is essential 1
Important Distinctions
While VHL is the correct answer, it's important to note that other hereditary syndromes can also predispose to RCC, including:
- BAP1 tumor predisposition syndrome
- Birt-Hogg-Dubé syndrome
- Hereditary leiomyomatosis and renal cell cancer
- Hereditary papillary renal carcinoma
- Tuberous sclerosis complex 1
However, VHL syndrome has the strongest and most well-established association with clear cell renal cell carcinoma among the options presented.