August 24, 2001

Researchers link pulmonary hypertension to family history

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Joel Lee answers one of the many questions posed by the Nash Trash ladies last week at the annual kick-off. “Cleopatra” Lee Limbird ponders a question in the background. (photo by Anne Rayner)

Researchers link pulmonary hypertension to family history

Not having a solid knowledge of one’s family medical history can be fatal for a group of patients with a rare lung disorder – primary pulmonary hypertension.

Once believed to be mostly a sporadic disease, researchers at Vanderbilt University Medical Center have recently discovered the reverse to be true.

In a study conducted over a 20-year period, the researchers developed a registry of 67 families affected with familial primary pulmonary hypertension (PPH) or high blood pressure in the lungs, a condition that is caused by scarred and obstructed arteries in the lungs.

The group linked five separately identified subfamilies that included 394 known members spanning seven generations. The cases were traced back to a Grundy County couple in the 1830s.

The study was released in the August issue of the New England Journal of Medicine. The team included: Dr. John H. Newman, Elsa S. Hanigan Chair in Pulmonary Medicine, professor of Medicine and author of the paper; Lisa Wheeler, PPH registry manager; Dr. James Loyd, professor of Medicine and co-investigator for the study; Kirk Lane, Ph.D., research assistant professor of Medicine; Emily Loyd; Radhika Gaddipati; and Dr. John A. Phillips, III, David T. Karzon Professor of Pediatrics.

“We had a female patient with PPH in 1980 who had multiple women in her family who died of unusual deaths,” said Newman. “By going through the records we saw that probably six women in this family died of PPH, and only one had an accurate premortem diagnosis. This is what stimulated our extensive search.

“This disease skips generations, which is odd because diseases that are inherited in a genetic fashion usually affect someone in every generation. We still don’t understand the reduced expression of disease in familial PPH.”

“Because people move frequently and lose contact with family members, people don’t know their family history very well. Not every family remains connected and there is no way to have a solid database for medical history,” Newman said.

A typical scenario of diagnosis: a person gets PPH and they are not aware that there is anyone else in their family with the disease. Without knowledge of previous medical history of the presence of PPH, the person is often misdiagnosed as having a sporadic form of the disease when they are actually familial.

This information is important for the descendants of those linked to PPH because of an increased risk of developing the disease, but most specifically for having the mutated gene BMPR2, which was recently found to cause familial PPH. BMPR2 causes cells to grow and block the inside of blood vessels in the lungs.

Researchers say that knowledge of family links is useful to people with hereditary PPH, a silent disease that eventually leads to shortness of breath. By the time most people see a specialist, three-fourths of their arteries are blocked.

“What we can do now is provide awareness for early screening,” Newman said. “If we can do a better job of finding the disease in earlier stages, then we have a greater chance of better treatment outcomes and survival rates.”

Current treatments for patients with PPH include calcium blockers, Flolan and transplant. There are several therapies currently under development as well.

Wheeler, a medical technologist who created the registry, said the number of familial PPH cases is higher than originally detected in national studies. She identified 102 families in the U.S. with PPH and 67 families are participating in the ongoing registry.

“Although familial PPH is a rare disease, it is more prevalent than we thought,” Wheeler said. “We know that many more people have inherited PPH than originally believed.

“This registry has been a big stepping stone to helping us find the answers and connections,” she said. “Family history has become an important tool for identifying those at-risk for developing the disease.”

Now that the mutation is a documented cause of this disease, Newman said the goals of the team are to perform biological studies to see how the mutation causes disease and create drugs to prevent it. Also with a growing registry, it will be possible to identify people who should be surveyed for possible early therapy.

“The overall hope would be to develop a marker for the disease for a blood test to show the mutation,” Newman said. “Now we can move forward in studying that aspect.

“Understanding the gene leads to a broader understanding of the disease and we can discover how to treat it,” he said. “Now we have the tools to find the answers.”