Patient case: 50-year-old male with prostate cancer; genetic feature: ATM deletion

Clinical trial: Pulmonary Hypertension--Mechanisms and Family Registry

Summary: To establish a registry of primary pulmonary hypertension (PPH), a lethal disease which causes progressive obstruction of small pulmonary arteries and to investigate basic mechanisms of the disease.

Detailed description: BACKGROUND:
  Primary pulmonary hypertension (PPH) is a serious disease of unknown cause in which small arteries in the lungs become obstructed. Mean survival is less than three years, and women develop PPH twice as commonly as men. It is familial (FPPH) in about 6 percent of cases. The National FPPH Registry was established in 1994 to collect and analyze family history and clinical data from PPH families to better characterize the disease phenotype as well as to identify the underlying genetic etiology. Through the collection of 72 families, FPPH has been shown to be inherited as an autosomal dominant disorder, with incomplete penetrance and genetic anticipation. Micro-satellite marker studies in six families have identified linkage to chromosome 2q31 without evidence of genetic heterogeneity.
  DESIGN NARRATIVE:
  The study established a national registry of familial PPH (FPPH). The primary goal of the family registry was to establish and expand the database of FPPH pedigrees to definitively establish the mode of inheritance of FPPH, which initial segregation analysis suggested was autosomal dominant. The FPPH family registry provided the framework for the linkage analysis of the molecular search for basic mechanisms of PPH. The investigators developed a tissue bank for specimens (DNA and transformed lymphocytes) from families and patients with pulmonary hypertension, both for their investigations and as a national resource for other interested investigators. Their search used three different approaches to investigate for a FPPH gene locus. First, they performed karyotyping and high resolution chromosome studies to search for a chromosomal translocation, interstitial deletion, or inversion, the finding of which would implicate a specific gene locus. Second, they pursued the proposed association of human leukocyte antigen (HLA) tissue type with familial PPH in a parallel attempt to identify a related locus about which to perform an intensified molecular search, using regional mapping studies of closely linked markers. Finally, they performed linkage analysis in selected PPH families which had the most informative inheritance patterns, using polymerase chain reaction (PCR) based microsatellite markers for selected candidate genes, including those for transforming growth factor beta, endothelin, beta globin, and HLA. An additional promising approach included a search for linkage of FPPH to genes with GC-rich trinucleotide repeats, as had been successful for other diseases with genetic anticipation, including Fragile X syndrome, myotonic dystrophy, and Huntington's disease.
  The study was renewed in 1999 through 2003 to expand the registry in order to obtain enough PPH families to localize and clone the PPH gene, and support the DNA bank for these and further studies. Other goals included prospective and biochemical mediator studies of obligate gene carriers, who did not have clinically evident PPH. This aim determined which mediators first became abnormal during developing PPH, and defined the natural history of pre-symptomatic diseases. In addition, the registry broadened its scope to include sporadic PPH patients, including those who had used appetite suppressant medications, who were screened for gene mutations.

Eligibility: No eligibility criteria

Relevance to patient case: not relevant