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Previous Volume 355:788-798 August 24, 2006 Number 8 Next

Aneurysm Syndromes Caused by Mutations in the TGF- Receptor

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ABSTRACT

Background The Loeys–Dietz syndrome is a recently described autosomal dominant aortic-aneurysm syndrome with widespread systemic involvement. The disease is characterized by the triad of arterial tortuosity and aneurysms, hypertelorism, and bifid uvula or cleft palate and is caused by heterozygous mutations in the genes encoding transforming growth factor receptors 1 and 2 (TGFBR1 and TGFBR2, respectively).

Methods We undertook the clinical and molecular characterization of 52 affected families. Forty probands presented with typical manifestations of the Loeys–Dietz syndrome. In view of the phenotypic overlap between this syndrome and vascular Ehlers–Danlos syndrome, we screened an additional cohort of 40 patients who had vascular Ehlers–Danlos syndrome without the characteristic type III collagen abnormalities or the craniofacial features of the Loeys–Dietz syndrome.

Results We found a mutation in TGFBR1 or TGFBR2 in all probands with typical Loeys–Dietz syndrome (type I) and in 12 probands presenting with vascular Ehlers–Danlos syndrome (Loeys–Dietz syndrome type II). The natural history of both types was characterized by aggressive arterial aneurysms (mean age at death, 26.0 years) and a high incidence of pregnancy-related complications (in 6 of 12 women). Patients with Loeys–Dietz syndrome type I, as compared with those with type II, underwent cardiovascular surgery earlier (mean age, 16.9 years vs. 26.9 years) and died earlier (22.6 years vs. 31.8 years). There were 59 vascular surgeries in the cohort, with one death during the procedure. This low rate of intraoperative mortality distinguishes the Loeys–Dietz syndrome from vascular Ehlers–Danlos syndrome.

Conclusions Mutations in either TGFBR1 or TGFBR2 predispose patients to aggressive and widespread vascular disease. The severity of the clinical presentation is predictive of the outcome. Genotyping of patients presenting with symptoms like those of vascular 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.

Full Text of this Article

Related Letters:

Aneurysm Syndromes and TGF- Receptor Mutations
Arbustini E., Marziliano N., Magrassi L., Loeys B. L., Dietz H. C.
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N Engl J Med 2006; 355:2155-2156, Nov 16, 2006. Correspondence

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