A gene mutation passes down generations

Yale surgeon Julie Ann Sosa has performed thyroid surgeries on five members of the same family.

Horizontal scars across their throats, although now fading, remind members of the Block family of what they have been through in the past year. Last summer, doctors at Yale found that this family of cattle farmers from Monroe, Conn., has been passing more than hair and eye color between generations; the family’s 10th chromosome harbors a mutation that causes a rare and severe form of thyroid cancer.

Since this discovery, 13 members of the extended family have been diagnosed with the mutation and 10 have had their thyroids removed. Five of the surgeries took place at Yale-New Haven Hospital (YNHH) under the supervision of Julie Ann Sosa, M.D., assistant professor of surgery.

Sosa, who specializes in thyroid cancer, said that the mutation that the Blocks carry, called MEN2A, is extremely rare and that most families in this country with the condition have been known to researchers for years. Sosa herself follows five such families. “Many endocrinologists go their whole lives without seeing any cases of this mutation,” she said.

But last June, Beverly Block Lewis, 51, learned that she had medullary thyroid cancer. In a very few instances this rare cancer is inherited. “The genetic study we ran came back positive,” said Sosa.

Beverly already had hypothyroidism, a deficiency of thyroid hormone, which she inherited from her mother’s side of the family. The condition was the reason for her routine endocrinology appointments. The family assumed the thyroid cancer would also come from the maternal side.

But testing showed that Beverly inherited her mutation from her father, Burton Block, who was then found to have asymptomatic thyroid cancer. Two of Beverly’s siblings, her son and two nephews were also diagnosed with the mutation. All but 4-year-old nephew Jake already had cancer.

“Every diagnosis was a new blow,” said Alyce Block, Beverly’s mother. “Every time was as hard as the first.”

For Beverly’s recently married son, Aaron Lewis, 28, one of the biggest challenges was thinking about future generations. “Kids that aren’t even born yet are going to be affected,” he said.

Over the next several months, YNHH became like a second home for the family members, who were constantly in and out of the hospital with each successive surgery.

But every operation went well and the family pulled through. After his thyroid surgery, 83-year-old Burton also survived a near-fatal car accident that landed him back at YNHH, just doors away from where his son Dan was recovering from a pulmonary embolism following thyroid surgery.

In August, more than a year after the family’s medical saga began, Burton passed away due to inoperable pancreatic cancer unrelated to the thyroid cancer. “He’s really taught us a tremendous amount about strength and patience,” said Beverly, standing at Burton’s bedside a month before his death. “And the importance of a close-knit family bonding together,” added Alyce.

—Sarah C.P. Williams

Blood vessels made from scaffolds and stem cells soon to be in clinical trials

Two Yale physician-scientists are creating a living organ from scratch, coaxing cells to form artificial tissue that can be used to repair or replace faulty blood vessels. Christopher K. Breuer, M.D., assistant professor of surgery and pediatrics, and Toshiharu Shinoka, M.D., Ph.D., associate professor and director of pediatric cardiovascular surgery at Yale-New Haven Children’s Hospital, believe their tissue engineering project could lead to the building of more complex organs.

“We figure if you start with blood vessels, that’s going to be the first step in making just about anything,” said Breuer. “Plus, there’s an immediate need for vessels in vascular and cardiovascular surgery.”

Because the blood vessels Breuer and Shinoka have created rely on stem cells from a patient’s own bone marrow, they are not prone to the inflammation or rejection that affects transplanted tissue. And they are living organs that can grow as a child grows.

When a child is born with such defects as a heart with only a single ventricle, doctors first try to form the child’s own tissue into new vessels that can be used as grafts. “But the problem is these children usually require multiple grafts and you never have enough tissue,” said Breuer. Such alternatives as synthetic Gore-Tex grafts may lead to infections and blood clotting, while biological grafts from animals tend to calcify and need replacement.

Breuer and his colleagues designed a scaffold in the shape of a vein with materials used to make absorbable sutures. They then coat the scaffold with bone marrow stem cells. As blood flows through the vein, the stem cells attract cells from elsewhere in the body to form a blood vessel around the scaffolding. As the vessel forms the original matrix dissolves. The resulting vessel can grow over time, and its elasticity matches that of the body’s own blood vessels.

Over the past six years, Shinoka has used the process successfully in 47 children in Japan. The technique works well and the grafts have an excellent safety profile, he said, and no patients have needed replacement of tube grafts. Shinoka and Breuer expect to hear soon about their application to the U.S. Food and Drug Administration to conduct clinical trials of their grafts at Yale, but they also continue to pursue improvements in their techniques.

Breuer said that his next goal is to figure out which chemical in bone marrow is attracting cells to the scaffolding. He hopes to isolate that compound and build it into the matrix to eliminate the intermediate step of drawing bone marrow from each patient. “We would have immediate off-the-shelf availability when a patient needed a graft,” he said.

—S.C.P.W.

et cetera

Yale joins hypertension network

Two School of Medicine scientists will join colleagues in Switzerland, France and Mexico in a collaboration to pinpoint the role of the kidney in high blood pressure. The Transatlantic Network on Hypertension—Renal Salt Handling in the Control of Blood Pressure has received a five-year, $6 million grant from the Leducq Foundation, a Paris-based organization that supports international research collaborations in cardiovascular disease.

The exact causes of hypertension, one of the most important risk factors for such cardiovascular diseases as stroke and heart attack, remain unknown. The kidney’s management of salt levels, however, plays a major role.

Leading the Yale team are Steven C. Hebert, M.D., the C.N.H. Long Professor and chair of cellular and molecular physiology, and Richard P. Lifton, M.D., Ph.D., Sterling Professor and chair of genetics.

“The Leducq program,” Lifton said, “allows us to bring together a ‘dream team’ of investigators from around the world with diverse expertise in physiology, genetics and clinical investigation to combine forces to tackle this important medical problem.”

—John Curtis

Residents fall short on stats

Most medical residents don’t understand statistics in medical literature, calling into question their ability to interpret research data, according to a survey by Yale researchers published in the September 5 issue of JAMA: The Journal of the American Medical Association. In a survey of 277 internal medicine residents in 11 programs, residents scored an average of 41 percent. Senior residents performed worse than junior residents, suggesting that, with the passage of time, knowledge was lost or not reinforced.

“Most residents in this study lack the knowledge in biostatistics needed to interpret many of the results in published clinical research,” said corresponding author Donna M. Windish, M.D., M.P.H., assistant professor of medicine. “Residency programs should include more effective biostatistics training in their curricula to successfully prepare residents for this important lifelong learning skill.

—J.C.


			Originally published in Yale Medicine, Winter 2008. Copyright © 2008 Yale University School of Medicine. All rights reserved.