Aneurysm Syndromes Caused by Mutations in the TGF- Receptor
Bart L. Loeys, M.D., Ph.D., Ulrike Schwarze, M.D., Tammy Holm, M.D., Bert L. Callewaert, M.D., George H. Thomas, Ph.D., Hariyadarshi Pannu, Ph.D., Julie F. De Backer, M.D., Gretchen L. Oswald, M.S., Sofie Symoens, B.S., Sylvie Manouvrier, M.D., Ph.D., Amy E. Roberts, M.D., Francesca Faravelli, M.D., M. Alba Greco, M.D., Reed E. Pyeritz, M.D., Ph.D., Dianna M. Milewicz, M.D., Ph.D., Paul J. Coucke, Ph.D., Duke E. Cameron, M.D., Alan C. Braverman, M.D., Peter H. Byers, M.D., Anne M. De Paepe, M.D., Ph.D., and Harry C. Dietz, M.D.
Background The Loeys–Dietz syndrome is a recently describedautosomal dominant aortic-aneurysm syndrome with widespreadsystemic involvement. The disease is characterized by the triadof arterial tortuosity and aneurysms, hypertelorism, and bifiduvula or cleft palate and is caused by heterozygous mutationsin the genes encoding transforming growth factor receptors1 and 2 (TGFBR1 and TGFBR2, respectively).
Methods We undertook the clinical and molecular characterizationof 52 affected families. Forty probands presented with typicalmanifestations of the Loeys–Dietz syndrome. In view ofthe phenotypic overlap between this syndrome and vascular Ehlers–Danlossyndrome, we screened an additional cohort of 40 patients whohad vascular Ehlers–Danlos syndrome without the characteristictype III collagen abnormalities or the craniofacial featuresof the Loeys–Dietz syndrome.
Results We found a mutation in TGFBR1 or TGFBR2 in all probandswith typical Loeys–Dietz syndrome (type I) and in 12 probandspresenting with vascular Ehlers–Danlos syndrome (Loeys–Dietzsyndrome type II). The natural history of both types was characterizedby aggressive arterial aneurysms (mean age at death, 26.0 years)and a high incidence of pregnancy-related complications (in6 of 12 women). Patients with Loeys–Dietz syndrome typeI, as compared with those with type II, underwent cardiovascularsurgery earlier (mean age, 16.9 years vs. 26.9 years) and diedearlier (22.6 years vs. 31.8 years). There were 59 vascularsurgeries in the cohort, with one death during the procedure.This low rate of intraoperative mortality distinguishes theLoeys–Dietz syndrome from vascular Ehlers–Danlossyndrome.
Conclusions Mutations in either TGFBR1 or TGFBR2 predisposepatients to aggressive and widespread vascular disease. Theseverity of the clinical presentation is predictive of the outcome.Genotyping of patients presenting with symptoms like those ofvascular Ehlers–Danlos syndrome may be used to guide therapy,including the use and timing of prophylactic vascular surgery.
Source Information
From the McKusick–Nathans Institute for Genetic Medicine (B.L.L., T.H., G.H.T., G.L.O., H.C.D.) and the Department of Surgery (D.E.C.), Johns Hopkins University School of Medicine, and the Kennedy Krieger Institute (G.H.T.) — both in Baltimore; the Departments of Pathology and Medicine, University of Washington, Seattle (U.S., P.H.B.); the Center for Medical Genetics, Ghent University Hospital, Ghent, Belgium (B.L.L., B.L.C., J.F.D.B., S.S., P.J.C., A.M.D.P.); the Department of Medicine, University of Texas, Houston (H.P., D.M.M.); the Department of Clinical Genetics, University Hospital, Lille, France (S.M.); the Department of Clinical Genetics, Harvard Medical School, Boston (A.E.R.); the Department of Human Genetics, Ospedale Galliera, Genoa, Italy (F.F.); the Department of Pathology, New York University School of Medicine, New York (M.A.G.); the Department of Medicine, University of Pennsylvania, Philadelphia (R.E.P.); the Department of Medicine, Washington University School of Medicine, St. Louis (A.C.B.); and Howard Hughes Medical Institute, Chevy Chase, Md. (H.C.D.).
Address reprint requests to Dr. Loeys at the Center for Medical Genetics, Ghent University Hospital, Bldg. 0K5, De Pintelaan 185, 9000 Ghent, Belgium, or at bart.loeys{at}ugent.be.
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Receptor
receptors 1 and 2 (TGFBR1 and TGFBR2, respectively). 
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