Clinical Manifestations and Molecular Bases of Heritable Urologic Malignant Disorders

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 acarcinoma (HLRCC) as
well as familial renal cancer.

- Studies have led to the identification and characterization of the VHL, HPRC, BHD 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 defect 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
von Hippel-Lindau (VHL) syndrome or hereditary papillary renal carcinoma (HPRC), Type I.

- 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 syndrome.

- 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 phenotype.

- INCLUSION CRITERIA - Subject Category A:

Category A will include patients, and biologic relatives, who may or may not be affected
who will be evaluated in the Warren G. Magnuson Clinical Center. Patients 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, microcystadenoma and/or cysts

- Pheochromocytoma

- Papillary cystadenoma of the epididymis or broad ligament

- Endolymphatic sac tumor

- Known or suspected cutaneous fibrofolliculomas or multiple skin-colored papules

- History of spontaneous pneumothorax

- Lung cysts

- Thyroid carcinoma

- Intestinal polyposis + / - colon cancer

- Cutaneous or Uterine leiomyoma or uterine leiomyosarcoma, sarcoma

INCLUSION CRITERIA - Subject Category B:

Category B will include patients, their at-risk biologic relatives and spouses 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.

INCLUSION CRITERIA - Subject Category C:

Category C will include biologic relatives and spouses 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:

Persons unable to give informed consent.