Genetic Analysis of Birt Hogg-Dube Syndrome and Characterization of Predisposition to Kidney Cancer

Birt-Hogg-Dub(SqrRoot)(Copyright) Syndrome: Characterization of the FLCN Disease Gene and Predisposition to Renal Cancer, Cutaneous Fibrofolliculoma and Pulmonary Cysts

This study will investigate the genetic cause of Birt Hogg-Dube (BHD) syndrome and the relationship of this disorder to kidney cancer. BHD is a rare inherited condition characterized by papules, or bumps-benign tumors involving hair follicles-on the head and neck. People with BHD are at increased risk of developing kidney cancer. Scientists have identified the chromosome (strand of genetic material in the cell nucleus) that contains the BHD gene and the region of the gene on the chromosome. This study will try to learn more about:

• The characteristics and type of kidney tumors associated with BHD
• The risk of kidney cancer in people with BHD
• Whether more than one gene causes BHD
• The genetic mutations (changes) responsible for BHD

Individuals with known or suspected Birt Hogg-Dube syndrome, and their family members, may be eligible for this study. Candidates will be screened with a family history and review of medical records, including pathology reports for tumors, and films of computed tomography (CT) and magnetic resonance imaging (MRI) scans.

Participants may undergo various tests and procedures, including the following:

• Physical examination
• Review of personal and family history with a cancer doctor, cancer nurses, kidney surgeon, and genetic counselor
• Chest and other x-rays
• Ultrasound (imaging study using sound waves)
• MRI (imaging study using radiowaves and a magnetic field)
• CT scans of the chest and abdomen (imaging studies using radiation)
• Blood tests for blood chemistries and genetic testing
• Skin evaluation, including a skin biopsy (surgical removal of a small skin tissue sample for microscopic evaluation)
• Cheek swab or mouthwash to collect cells for genetic analysis
• Lung function studies
• Medical photography of skin lesions

These tests will be done on an outpatient basis in either one day or over 3 to 4 days. When the studies are complete, participants will receive counseling about the findings and recommendations. Individuals with kidney lesions may be asked to return periodically, such as every 3 to 36 months, based on their individual condition, to document the rate of progression of the lesions.

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Study Overview

• Status: Recruiting
• Conditions: Kidney Cancer; Kidney Neoplasms; Pneumothorax; FLCN Protein, Human

Detailed Description

Background:

• Birt-Hogg-Dube (BHD) is a rare, autosomal dominantly inherited disorder which confers susceptibility to develop multifocal, bilateral renal cancer, spontaneous pneumothorax and fibrofolliculomas.
• BHD is caused by mutations in the FLCN gene located on Chromosome17p11.2
• Defining the genetic and biochemical pathways leading to renal tumorigenesis in BHD may lead to the development of new molecularly targeted drugs.

Objectives:

• To define the types and characteristics (including patterns of growth) of renal cancer associated with BHD
• To determine the risk of renal cancer, lung cysts and fibrofolliculomas in individuals with BHD
• To define the natural history of BHD related renal tumors
• To determine if other genes contribute to BHD
• Identify genotype/phenotype correlations

Eligibility:

-Individuals that meet one or more of the following criteria:

--Suspected or known to have phenotype or genotype suggestive of Birt-Hogg-Dube (BHD), such as:

• Individuals with histologically confirmed fibrofolliculomas
• Individuals with clinical evidence of multiple skin papules consistent with fibrofolliculomas, and/or a family history of spontaneous pneumothorax or kidney cancer
• Individuals with a known germline FLCN mutation

or

--Renal tumor histology consistent with BHD, including, but not limited to those suggestive of chromophobe, hybrid oncocytic neoplasm or oncocytoma

or

--Are a relative (related by blood) of an individual with a confirmed or suspected diagnosis of BHD

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 the BHD gene and to assess 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): 950

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 Office of Patient Recruitment (OPR); Phone Number: TTY dial 711 800-411-1222; Email: ccopr@nih.gov

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 histologically confirmed fibrofolliculomas, individuals with clinical evidence of multiple skin papules consistent with fibrofolliculomas, and/or a family history of spontaneous pneumothorax or kidney cancer, a biological relative of an individual with a confirmed diagnosis of BHD. Individuals with a known germline FLCN mutation

Description

• INCLUSION CRITERIA:

Individuals that meet one or more of the following criteria:

-Suspected or known to have phenotype or genotype suggestive of Birt-Hogg-Dube (BHD), such as:

--Individuals with at least one histologically confirmed fibrofolliculomas;

or

--Individuals with clinical evidence of multiple skin papules (without fibrofolliculoma biopsy confirmation) and a personal or family history of spontaneous pneumothorax/or kidney cancer;

or

--Individuals with spontaneous pneumothorax and skin papules or kidney cancer and a positive family history of spontaneous pneumothorax, skin papules or kidney cancer;

or

--Individuals with a known germline FLCN gene mutation

OR

-Renal tumor histology consistent with BHD, including, but not limited to those suggestive of chromophobe, hybrid oncocytic neoplasm or oncocytoma.

OR

• Are a relative (related by blood) of an individual with a confirmed or suspected diagnosis of BHD.

  -Participants must be >= 2 years of age.

• For children less than 18 years of age, parental permission or legal guardian consent will be obtained.

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
Family Members; A relative of an individual with a confirmed or suspected diagnosis of BHD (related by blood)
Individuals; Individuals with phenotype or genotype suggestive of Birt Hogg Dub(SqrRoot)(Copyright) and/or Renal tumor histology consistent with BHD
Non-Biologic Family Members; Spouses enrolled primarily for linkage analysis (Spouses have been removed from the inclusion criteria for this study. This closed cohort has been created for spouses previously enrolled on study.)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Identify genotype / phenotype correlations.	Collection of blood, saliva, tissue & urine for Identification of the Disease Gene, and Characterization of the disposition to Renal Cancer	on-going
Determine risk of renal cancer, lung cysts and fibrofollicullomas in patients with BHD.	Collection of blood, saliva, tissue & urine for Identification of the Disease Gene, and Characterization of the disposition to Renal Cancer	on-going
Determine if other genes contribute to BHD.	Collection of blood, saliva, tissue & urine for Identification of the Disease Gene, and Characterization of the disposition to Renal Cancer	on-going
Define types and characteristics (including patterns of growth) of renal cancer associated with BHD.	Collection of blood, saliva, tissue & urine for Identification of the Disease Gene, and Characterization of the disposition to Renal Cancer	on-going
Define the natural history of BHD related renal tumors.	Collection of blood, saliva, tissue & urine for Identification of the Disease Gene, and Characterization of the disposition to Renal Cancer	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): May 13, 2002

Study Registration Dates

• First Submitted: April 5, 2002
• First Submitted That Met QC Criteria: April 5, 2002
• First Posted (Estimated): April 8, 2002

Study Record Updates

• Last Update Posted (Actual): September 16, 2026
• Last Update Submitted That Met QC Criteria: September 15, 2026
• Last Verified: August 14, 2026

More Information

Terms related to this study

• Keywords: Neoplasms; Natural History; Kidney; Pneumothorax; Fibrofolliculoma; BHD
• Additional Relevant MeSH Terms: Urogenital Diseases; Urogenital Neoplasms; Neoplasms by Site; Male Urogenital Diseases; Kidney Diseases; Urologic Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Respiratory Tract Diseases; Urologic Neoplasms; Pleural Diseases; Neoplasms; Kidney Neoplasms; Pneumothorax
• Other Study ID Numbers: 020159; 02-C-0159

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