At least three severe, potentially fatal genetic diseases leave patients with aortas so flimsy that they can rupture in pregnancy and labor or even lesser activities, often without warning. Beta blockers, curbing exercise, proactive blood vessel surgery and other approaches can be helpful, but their usefulness varies according to which disease and when they’re offered.

Now a large follow-up study of more than 50 families by a multi-institutional team led by Johns Hopkins scientists should bring better guidelines for treating the disorders. The work, published August 24 in The New England Journal of Medicine, closely compares patients having one of two types of the lesser known Loeys-Dietz syndrome or Ehlers-Danlos syndrome with better-understood Marfan syndrome. It stresses the importance of comprehensive clinical evaluations when diagnosing the diseases.

People with Loeys-Dietz syndrome have wideset eyes, a cleft palate or split uvula (the tissue that hangs down in the back of the throat), and a convoluted arrangement of the body’s blood vessels, in addition to aggressive swelling of the aorta. In these patients, the aorta breaks at a much smaller size than it does in people with Marfan syndrome or most other causes of aortic aneurysm.

Marfan and Ehlers-Danlos syndromes both are similar heritable conditions with overlapping symptoms that affect the connective tissue, the tissue that holds the body together. Marfan syndrome can affect many body systems, including the skeleton, eyes, heart and blood vessels, nervous system, skin and lungs. The vascular variant of Ehlers-Danlos also affects skin, muscles and ligaments and causes hypermobility of joints and fragile blood vessels that tear easily.

“This study shows that both clinical and molecular analyses can distinguish patients with Loeys-Dietz syndrome from those with either Marfan syndrome or vascular Ehlers-Danlos syndrome,” says Harry Dietz, M.D., director of the William S. Smilow Center for Marfan Syndrome Research at Johns Hopkins, professor in the McKusick-Nathans Institute of Genetic Medicine, and a Howard Hughes Medical Institute investigator, “Distinguishing these conditions is essential in many ways. For example, when compared to Marfan syndrome, Loeys-Dietz patients are at high risk of rupturing their blood vessels at smaller dimensions, at a younger age, and in a wider distribution throughout the body. They are also at a much greater risk of tear or rupture of blood vessels or the uterus during pregnancy. When compared to people with vascular Ehlers-Danlos syndrome, patients with Loeys-Dietz syndrome do much better with cardiovascular surgery, highlighting the importance of aggressive surgical intervention for this disorder.”

“Because Loeys-Dietz shares so many symptoms with other conditions like Marfan or vascular Ehlers-Danlos, it’s critical that diagnostic distinctions are made accurately.”

The researchers gathered detailed information on patients’ physical characteristics, their symptoms, course of disease and timing and effect of treatments. They also used gene analysis of the DNA sequences that encode for two proteins, the transforming growth factor-beta protein receptors type 1 (TGF-betaR1) and type 2 (TGF-betaR2). All cases of Loeys-Dietz studied so far have mutations in either TGF-betaR1 or TGF-betaR2.

The two TGF-beta receptors act together to bind TGF-beta, a family of signaling molecules that controls cell growth, movement, activity and death by controlling whether certain genes are turned on or off. TGF-beta receptors normally are found on the cell’s surface, facing the outside of the cell, where TGF-beta can be found floating around.

The receptors contain specialized domains - dubbed kinase domains - that, when bound by TGF-beta, add a chemical phosphate group to molecules that set in motion a domino-like effect within the cell to activate other chemical reactions that eventually lead to changes in cellular growth or movement or activity.

Nearly all Loeys-Dietz patients studied thus far have mutations in or near the kinase domains in their TGF-beta receptors. The mutations are passed on through families; however, syndrome-causing mutations also have been found in patients whose parents were not affected.

“The bottom line here is that looking for TGF-beta receptor mutations will be most useful in patients who have features shared by multiple syndromes,” says Dietz.

A diagnostic test is available at Johns Hopkins’ DNA Diagnostic Laboratory.

The researchers were funded by the National Marfan Foundation, the William S. Smilow Center for Marfan Syndrome Research, the Howard Hughes Medical Institute, the Robert Wood Johnson Foundation, the Dana and Albert “Cubby” Broccoli Center for Aortic Diseases, the Bijzonder Onderzoeksfonds of Ghent University, the National Institutes of Health, the National Institute of Child Health and Human Development, and the Fund for Scientific Research-Flanders.

Authors on this paper are Bart Loeys, Tammy Holm, George Thomas, Gretchen Oswald, Duke Cameron and Dietz, all of Hopkins; Ulrike Schwarze and Peter Byers of the University of Washington, Seattle; Bert Callewaert, Julie De Backer, Sofie Symoens, Paul Coucke, Anne De Paepe, all of Ghent University Hospital, Belgium; Hariyadarshi Pannu and Dianna Milewicz of the University of Texas, Houston; Sylvie Manouvrier of University Hospital, Lille, France; Amy Roberts of Harvard Medical School; Francesca Faravelli of Ospedale Galliera, Genoa, Italy; M. Alba Greco of New York University School of Medicine; Reed Pyeritz of the University of Pennsylvania; and Alan Braverman of the Washington University School of Medicine.

Johns Hopkins Medical Institutions