Hereditary kidney tumor syndromes: structured evaluation of a questionnaire-based approach

Abstract Background Up to 8% of renal tumors have a monogenic cause, yet hereditary renal cell carcinoma (hRCC) syndromes such as Von Hippel–Lindau (VHL), Tuberous Sclerosis Complex (TSC), Birt–Hogg–Dubé (BHD), and Hereditary Leiomyomatosis and RCC (HLRCC) remain underdiagnosed. Early diagnosis is critical for patient management, genetic counseling, and family screening. We developed and prospectively validated a structured risk assessment tool (hRCC score) for identifying patients at risk of hereditary renal tumors. Methods A prospective single-center study was conducted at the University Hospital Cologne (2020–2022) including 200 patients with histologically confirmed renal tumors. The hRCC score incorporated age at diagnosis, multifocal/bilateral disease, histology, extrarenal manifestations, and family history. Patients with a score ≥1.5 were referred for genetic testing using a multiplex MLPA-based panel including TSC, MET, VHL, FH, SDH-A-D, and FLCN. Results Of 195 eligible patients, 34.4% (n=67) had a high-risk (HR) hRCC score (≥1.5). Overall, 71 (36.4%) underwent genetic testing; a pathogenic or likely pathogenic variant was detected in 50.7% of tested patients, corresponding to 18.5% of the total cohort. The most common diagnoses were TSC (58.3%), VHL (16.7%), and BHD (11.1%). Confirmed hereditary cases had significantly higher mean hRCC scores (4.67 vs. 0.48, p0.0001). Extrarenal manifestations and bilateral or multifocal disease were the strongest predictors. The cutoff of 1.5 yielded 97.2% sensitivity and 79.8% specificity. Conclusions The hRCC score is an effective clinical screening tool for detecting patients at risk for hereditary renal tumors, demonstrating high diagnostic yield and supporting targeted referral for genetic evaluation.