Josh Netherton''s life wasn''t only changed by heart surgery at Barnes-Jewish Hospital. A deadly family medical mystery was finally solved as well.

Josh Netherton, 23, of suburban Tulsa, OK, is one of many Netherton family members who thought for years they were affected with Marfan Syndrome. Marfan syndrome is a hereditary disorder of the connective tissue affecting about 1 in 5000 people. It can lead to abnormalities in multiple of organ systems, including the skeleton, eye and heart.

Most significantly, Marfan patients face a high risk of having the aorta, the largest blood vessel in the body, weaken and form an aneurysm (or bulge) that then can dissect or rupture. Because of this risk, Marfan patients are followed closely by a cardiologist. When a patient has an aortic aneurysm that reaches five centimeters – the point when dissection or rupture becomes a danger -- they must have surgery to repair the aorta.

"Many Marfan patients follow a fairly predictable course," says Alan Braverman, MD, cardiologist and Director of the Marfan Clinic at Barnes-Jewish Hospital and Washington University School of Medicine. "They are followed closely with serial evaluations and have preventive heart surgery when the aorta reaches about five centimeters in diameter."

However, in Josh Netherton''s family there was no predictable course. Several family members died of aortic dissection at variable aortic diameters.

"I''d estimate two-thirds of my family died from their heart bursting," says Steve Netherton, Josh''s father, who had his aorta repaired a few years ago. "My dad died when he was 37. I''ve lost brothers, uncles. It''s been crazy."

Steve Netherton is one of four children. Physically, his family displays many of the classic symptoms of Marfan – tall, lanky frames, exceptionally long fingers and toes and lantern jaws. For example, Abraham Lincoln is thought to have had Marfan.

There is no one test to diagnose Marfan syndrome. So, doctors use a combination of tests including an echocardiogram of the heart, eye exam to detect lens abnormalities and physical exam to make the diagnosis. Steve underwent evaluation in Oklahoma and his doctors determined he was among three of the four Netherton children of his generation who had Marfans. But why were family members dying before their time? It left one of Steve''s siblings looking for answers.

In August 2005, when Barnes-Jewish Hospital hosted the National Marfan Foundation conference, Carol Netherton Lambert – the lone child of four not to have inherited the condition – made the drive up I-44 from Oklahoma to find out what she could about Marfan and why her loved ones were dying premature deaths. In addition, her nephew, Josh, had an aneurysm of 4.7 centimeters and knowing how volatile this heart problem was in her family, she was desperate for more information.

"My family has lived life with daggers over their head wondering when they would drop," says Lambert.

It was at the conference she met Hal Dietz, MD, PhD, geneticist and Director of the William S. Smilow Center for Marfan Syndrome Research at Johns Hopkins University in Baltimore. Lambert brought a mountain of paperwork with her, including a family tree showing how the family was affected. Dr. Dietz offered to see her entire family, but in order to spare the family the long trip to Baltimore, he recommended she see Dr. Braverman here in St. Louis.

"When Josh came, he had the family history and a lot of the physical symptoms, but he had many features you don''t see with Marfan syndrome," says Dr. Braverman. "He was tall and had a sunken chest typical of Marfan. But, Josh had clubbed feet and no history of lens dislocation. His eyes were somewhat wide set. But most prominently, he had an abnormal uvula on his oral exam."

The uvula is the small piece of tissue projecting from the palate into the throat. A bifid uvula means the tissue is forked.

In 2005, Dr. Dietz and his colleague at Johns Hopkins, Bart Loeys, MD, discovered a new aortic aneurysm syndrome. While physical characteristics are similar to Marfan, patients diagnosed with this new discovery – Loeys-Dietz Aneurysm Syndrome -- were at risk of an aortic dissection before the typical five-centimeter mark. And the new syndrome''s most obvious external sign? A bifid uvula and wide set eyes.

"So when I was examining Josh, the room was filled with his whole family. I asked if anyone had a bifid uvula and they all pointed to Josh''s father," says Dr. Braverman. "His father Steve opened his mouth and it was the most prominent bifid uvula I have ever seen."

Dr. Braverman''s Marfan Clinic is one of the most respected in the country. He''s a member of the National Marfan Foundation''s Professional Advisory Board and is kept abreast by his colleagues around the country when new treatments or discoveries for Marfan are made. Drs. Loeys and Dietz presented information about the new aneurysm syndrome at a research conference Dr. Braverman attended at Johns Hopkins Medical Center.

"The very first person I saw after that conference was a new patient who had just turned 18 and previously was being treated at St. Louis Children''s Hospital," says Dr. Braverman. "She had multiple heart and aortic surgeries at a young age. The information I had just heard at that conference explained why she had such severe vascular abnormalities as opposed to the typical Marfan patient. She had this new syndrome."

Features of Loeys-Dietz aneurysm syndrome may include marked arterial tortuosity, bluish sclera, scoliosis, aortic root enlargement, wide set eyes, and cleft palate/or bifid uvula. This disorder is due to mutations in transforming growth factor beta receptor, type 1 and 2.

"It''s a terrific example of molecular genetic research being used to significantly alter clinical management," says Dr. Braverman. "I certainly had never looked in anyone''s mouth before when evaluating for the cause of aortic aneurysms." "When someone is diagnosed with this condition, prophylactic surgery is done when the aorta reaches only 4 cm."

So far, over 75 patients in 50 families have been diagnosed with Loeys-Dietz aneurysms syndrome, with eight of them discovered by Dr. Braverman and his colleagues from medical genetics. Josh Netherton is among those eight.

The Netherton family''s genetic test results were sent to Dr. Dietz at Johns Hopkins and Dr. Loeys at University of Ghent, Belgium, who determined Josh was indeed affected by Loeys-Dietz aneurysm syndrome. Surgery at Barnes-Jewish with Washington University cardiac surgeon Marc Moon, MD, was scheduled for March. However, another family member fell victim to an aortic dissection.

Steve''s brother, Ray, died suddenly at age 53. He previously had aortic root replacement surgery, but developed another aortic dissection. Because of this, Josh''s surgery was moved up to late January.

"This is a big relief," says Josh. "I hadn''t let this slow me down and I''m glad it''s over and done with."

Josh will be followed by Dr. Braverman in the Marfan Clinic for the rest of his life. While the rest of his family awaits results of genetic testing that will almost assuredly confirm they have Loeys-Dietz Syndrome as well, it is a nerve-wracking situation.

"It''s a little reassuring, but it''s unnerving as well," says Lambert. "More than anything, I think everyone is excited because this will help the up-and-comings in diapers."

For more information about the Marfan Clinic at Barnes-Jewish Hospital and Washington University School of Medicine, call 314-TOP-DOCS or 866-867-3627 or the National Marfan Foundation at 1-800-8-MARFAN.