Von Hippel-Lindau (VHL): Clinical Manifestations, Diagnosis, Management and Molecular Bases of Inherited Renal and Other Urologic Malignant Disorders

We will investigate the clinical manifestations and molecular genetic defects of heritable urologic malignant disorders. Families with urologic malignancy with known or suspected genetic basis will be enrolled. Affected individuals or individuals suspected of having a germline urologic malignant disorder will undergo periodic clinical assessment and genetic analyses for the purpose of: 1) definition and characterization of phenotype, 2) determination of the natural history of the disorder, and 3) genotype/phenotype correlation. Genetic linkage studies may be performed in situations in which the genetic basis of the disorder has not been elucidated.

Study Overview

• Status: Recruiting
• Conditions: Kidney Cancer; Renal Cell Carcinoma; Urologic Malignant Disorders; Familial Renal Cancer (FRC); Clear Cell Renal Cancer

Detailed Description

Background:

• Disorders under investigation are: Autosomal dominant inherited urologic malignant disorders including: von Hippel-Lindau (VHL), hereditary papillary renal cancer (HPRC), Birt Hogg Dube (BHD) and hereditary leiomyomatosis and renal cell carcinoma (HLRCC) as well as familial renal cancer.
• Studies have led to the identification and characterization of the VHL, HPRC, FLCN and HLRCC genes.
• The genetic etiology of the most common type of inherited kidney cancer, familial renal cancer (FRC), remains to be determined.

Objectives:

• To characterize the natural and clinical histories of inherited urologic malignant disorders.
• To determine the genetic etiology of hereditary urologic malignant disorders in which the gene variation is unknown, by linkage analysis, positional cloning and evaluation of candidate genes.
• To correlate specific mutations and their associated protein domains with disease phenotypic expression based on parameters including presenting age, clinical manifestations, histopathology and rate of recurrence.
• To identify and describe as yet unknown or uncharacterized inherited urologic malignant disorders.

Eligibility:

• Individuals and biologic family members with a suspected or an established diagnosis of an inherited urologic malignancy in which the disease gene is known, including von Hippel-Lindau (VHL) and hereditary papillary renal carcinoma (HPRC).
• Individuals and biologic family members with a suspected or an established diagnosis of an inherited urologic malignancy in which the disease gene is not yet known, specifically hereditary forms of Type II papillary renal cancer, clear cell renal carcinoma, renal oncocytoma, chromophobe renal carcinoma or Birt Hogg Dube.
• Individuals and biologic family members who have urologic malignant diseases of suspected, but not proven genetic etiology, including families with more than one individual affected by the same or related cancers.

Design:

• These rare families will be recruited to genetically confirm diagnosis, determine size and location of renal tumors, size at presentation, growth rate and metastatic potential of renal tumors.
• Genetic testing will be offered to gain appreciation of the effect of mutations on the relative activity of various germline and somatic mutations.
• We will determine if there is a relationship between mutation and disease manifestations and phenotype.

• Study Type: Observational
• Enrollment (Estimated): 5000

Contacts and Locations

• Study Contact: Name: Deborah A Nielsen, R.N.; Phone Number: (240) 760-6247; Email: deborah.nielsen@nih.gov
• Study Contact Backup: Name: W. Marston Linehan, M.D.; Phone Number: (240) 858-3700; Email: linehanm@mail.nih.gov

Study Locations

• United States
  • Maryland
    • Bethesda, Maryland, United States, 20892
      • Recruiting
      • National Institutes of Health Clinical Center
      • Contact: For more information at the NIH Clinical Center contact National Cancer Institute Referral Office; Phone Number: 888-624-1937

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 2 years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: Yes

• Sampling Method: Non-Probability Sample

Study Population

Individuals with known or suspected inherited urologic malignant disorders and their biologic family members with inherited urologic malignancies will be recruited primarily from the urology, oncology, and genetics communities worldwide

Description

• INCLUSION CRITERIA:

Participants must be greater than or equal to 2 years of age. All participants and guardians (for children younger than 18 years of age) must sign an informed consent document indicating their understanding of the investigational nature and the risks of this study before any protocol related studies are performed.

Criteria for Acceptance into this Study (i.e., Disease Categories):

Disease Category I

Individuals and biologic family members with a suspected or an established diagnosis of an inherited urologic malignancy in which the disease gene is known, including von Hippel-Lindau (VHL) and hereditary papillary renal carcinoma (HPRC).

Disease Category II

Individuals and biologic family members with a suspected or an established diagnosis of an inherited urologic malignancy in which the disease gene is not yet known, specifically hereditary forms of Type II papillary renal cancer, clear cell renal carcinoma, renal oncocytoma, chromophobe renal carcinoma or Birt Hogg Dube.

Disease Category III

Individuals and biologic family members who have urologic malignant diseases of suspected, but not proven genetic etiology, including families with more than one individual affected by the same or related cancers. A total of 5000 individuals will be enrolled during the study (i.e., that includes individuals registered since the beginning of the protocols in 1989 (89C0086) and 1999 (99C0101)).

Enrollment per Subject Category (to include both affected and unaffected biologic relatives)

Subject Category A:

Category A will include individuals, and biologic relatives, who may or may not be affected who will be evaluated in the Warren G. Magnuson Clinical Center. Individuals in this category will be eligible if they or their biologic family members manifest one or more of the following features in a pattern suggestive of a heritable urologic malignant disorder:

• One or more histologically proven or suspected renal carcinomas and/or cysts
• Cerebellar, spinal, medullary or cerebral hemangioblastomas
• Retinal angioma
• Pancreatic neuro-endocrine carcinoma,micro cystadenoma and/or cysts
• Pheochromocytoma
• Papillary cystadenoma of the epididymis or broad ligament
• Endolymphatic sac tumor
• Cutaneous fibrofolliculomas or multiple skin-colored papules
• History of spontaneous pneumothorax
• Lung cysts
• Thyroid carcinoma
• Intestinal polyposis plus/minus colon cancer
• Cutaneous or Uterine leiomyoma or uterine leiomyosarcoma, sarcoma

Subject Category B:

Category B will include individuals and the biologic relatives of patients with inherited urologic malignancies with the above listed clinical findings who live at a distance and who will not be evaluated at the Clinical Center. In some cases, local diagnostic testing may be necessary for these individuals in addition to collection of a blood sample for molecular analysis.

Subject Category C:

Category C will include biologic relatives who enroll in this study primarily for genetic linkage studies. These individuals will contribute a blood sample for DNA analysis only. No imaging diagnostic testing will be performed on individuals from this category.

EXCLUSION CRITERIA:

None

Study Plan

How is the study designed?

Design Details

• Observational Models: Cohort
• Time Perspectives: Prospective

Number of groups / cohorts

3

Cohorts and Interventions

Group / Cohort
Disease Category I; Individuals, biologic family members with a suspected or an established diagnosis of an inherited urologic malignancy in which the disease gene is known, including VHL and HPRC
Disease Category II; Individuals and biologic family members with a suspected or an established diagnosis of an inherited urologic malignancy in which the disease gene is not yet known
Disease Category III; Individuals and biologic family members with a urologic malignant disease of suspected, but not proven genetic etiology

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Identify and describe as yet unknown or uncharacterized inherited urologic malignant disorders.	Collection of blood, tissue & urine to address further scientific questions related to this protocol.	on-going
Determine the genetic etiology of hereditary urologic malignant disorders in which the gene variation is unknown, by linkage analysis, positional cloning and evaluation of candidate genes.	Collection of blood, tissue & urine to address further scientific questions related to this protocol.	on-going
Correlate specific mutations and their associated protein domains with disease phenotypic expression based on parameters including presenting age, clinical manifestations, histopathology and rate of recurrence.	Collection of blood, tissue & urine to address further scientific questions related to this protocol.	on-going
Characterize the natural and clinical histories of inherited urologic malignant disorders.	Collection of blood, tissue & urine to address further scientific questions related to this protocol.	on-going

Collaborators and Investigators

• Sponsor: National Cancer Institute (NCI)
• Investigators: Principal Investigator: W. Marston Linehan, M.D., National Cancer Institute (NCI)

Publications and helpful links

Helpful Links

• NIH Clinical Center Detailed Web Page

Study record dates

Study Major Dates

• Study Start (Actual): December 5, 1990
• Primary Completion: December 7, 2022
• Study Completion: December 7, 2022

Study Registration Dates

• First Submitted: November 3, 1999
• First Submitted That Met QC Criteria: November 3, 1999
• First Posted (Estimated): November 4, 1999

Study Record Updates

• Last Update Posted (Actual): August 24, 2026
• Last Update Submitted That Met QC Criteria: August 21, 2026
• Last Verified: March 11, 2026

More Information

Terms related to this study

• Keywords: Hereditary Papillary Renal Cancer (HPRC); Birt Hogg Dube (BHD); Hereditary Leiomyomatosis and Renal Cell Carcinoma (HLRCC); Pheochromocytoma; Von Hippel-Lindau (VHL)
• Additional Relevant MeSH Terms: Urogenital Diseases; Urogenital Neoplasms; Neoplasms by Site; Neoplasms; Male Urogenital Diseases; Kidney Diseases; Urologic Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Neoplasms by Histologic Type; Neoplasms, Glandular and Epithelial; Adenocarcinoma; Urologic Neoplasms; Carcinoma; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Paraganglioma; Neuroendocrine Tumors; Carcinoma, Renal Cell; Pheochromocytoma; Kidney Neoplasms; Hereditary leiomyomatosis and renal cell cancer
• Other Study ID Numbers: 890086; 89-C-0086

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: All IPD recorded in the medical record will be shared with intramural investigators upon request. @@@@@@In addition, all large scale genomic sequencing data will be shared with subscribers to dbGaP.
• IPD Sharing Time Frame: Clinical data available during the study and indefinitely.@@@@@@Genomic data are available once genomic data are uploaded per protocol GDS plan for as long as database is active.
• IPD Sharing Access Criteria: Clinical data will be made available via subscription to BTRIS and with the permission of the study PI.@@@@@@Genomic data are made available via dbGaP through requests to the data custodians.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No