Genetic Study of Patients and Families With Birt-Hogg-Dube Syndrome

OBJECTIVES:

- Define the types and characteristics (e.g., patterns of growth) of renal cancer
associated with patients and families with Birt Hogg Dube (BHD) syndrome.

- Define the risk of renal cancer and lung cysts in patients with BHD syndrome.

- Determine the incidence of germline BHD mutations in patients suspected to have this
syndrome.

- Determine whether there is a genotype/phenotype correlation in these patients.

- Determine whether there is genetic heterogeneity in BHD syndrome.

OUTLINE: Over a period of 1-4 days, patients provide a detailed family history and then
undergo a complete physical examination, blood collection (or buccal smears) for linkage or
DNA analysis, chest and other x-rays, abdominal ultrasound, cutaneous/dermatologic
assessment (photography of lesions and skin biopsy), pulmonary function tests, MRI, CT scans
of the abdomen and chest, and karyotypic analysis. Patients under age 15 do not undergo CT
scans (unless clinically indicated) or karyotypic analysis. Investigators also rule out VHL
and MET gene mutations for patients with papillary cell or clear cell histology.

Investigators may obtain pathologic material (e.g., fixed tissue blocks) from surgeries
performed at the National Institutes of Health (NIH) Clinical Center or outside institutions
or from autopsy materials. These samples undergo pathologic analysis to confirm diagnosis
and may be tested for genotype with polymorphic polymerase chain reaction-based markers for
linkage studies or direct mutation analysis. DNA and RNA may be prepared from appropriate
samples, including whole blood, skin fibroblasts, buccal scrapings containing epithelial
cells, or surgical tissue. Affected patients may be hospitalized for surgical excision of
tumors and procurement of tissue.

Relatives or spouses enrolled in this study primarily for linkage studies only undergo blood
draw for DNA analysis.

Affected and unaffected family members who choose not to travel to the NIH Clinical Center
but agree to a limited level of participation may undergo blood collection, skin biopsy,
photography of skin lesions, and/or local clinical evaluations. A team of National Cancer
Institute investigators may visit family members to conduct such evaluations. Medical
records may also be requested to document a family member's affected or unaffected status.
Pathology blocks/tissue slides also may be collected and analyzed to document tumor
histology.

After completion of all clinical studies, patients receive an explanation of study findings,
appropriate counseling about their own status, and recommendations.

A certificate of confidentiality protecting the identity of research participants in this
project has been issued by the National Cancer Institute.

Patients with known or suspected renal lesions may be followed every 3-36 months depending
on characteristics (e.g., size and/or growth rate) of the renal lesions for documentation of
the rate of progression of these lesions as part of the genotype/phenotype evaluation.
Patients whose clinical status is indeterminate may be followed subsequently to determine
their Birt Hogg Dube syndrome status.

PROJECTED ACCRUAL: A maximum of 600 patients will be accrued for this study within 3 years.