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.

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.

• 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.