Aneurysm syndromes caused by mutations in the TGF-β receptor

Bart L. Loeys, Ulrike Schwarze, Tammy Holm, Bert L. Callewaert, George H. Thomas, Hariyadarshi Pannu, Julie F. De Backer, Gretchen L. Oswald, Sofie Symoens, Sylvie Manouvrier, Amy E. Roberts, Francesca Faravelli, M. Alba Greco, Reed E. Pyeritz, Dianna M. Milewicz, Paul J. Coucke, Duke E. Cameron, Alan C. Braverman, Peter H. Byers, Anne M. De PaepeHarry C Dietz

Research output: Contribution to journalArticle

Abstract

BACKGROUND: The Loeys-Dietz syndrome is a recently described autosomal dominant aorticaneurysm 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 β 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.

Original languageEnglish (US)
Pages (from-to)788-798
Number of pages11
JournalNew England Journal of Medicine
Volume355
Issue number8
DOIs
StatePublished - Aug 24 2006

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Loeys-Dietz Syndrome
Ehlers-Danlos Syndrome
Aneurysm
Blood Vessels
Mutation
Craniofacial Abnormalities
Uvula
Hypertelorism
Collagen Type III
Growth Factor Receptors
Pregnancy Complications
Cleft Palate
Transforming Growth Factors
Natural History
Vascular Diseases

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Loeys, B. L., Schwarze, U., Holm, T., Callewaert, B. L., Thomas, G. H., Pannu, H., ... Dietz, H. C. (2006). Aneurysm syndromes caused by mutations in the TGF-β receptor. New England Journal of Medicine, 355(8), 788-798. https://doi.org/10.1056/NEJMoa055695

Aneurysm syndromes caused by mutations in the TGF-β receptor. / Loeys, Bart L.; Schwarze, Ulrike; Holm, Tammy; Callewaert, Bert L.; Thomas, George H.; Pannu, Hariyadarshi; De Backer, Julie F.; Oswald, Gretchen L.; Symoens, Sofie; Manouvrier, Sylvie; Roberts, Amy E.; Faravelli, Francesca; Alba Greco, M.; Pyeritz, Reed E.; Milewicz, Dianna M.; Coucke, Paul J.; Cameron, Duke E.; Braverman, Alan C.; Byers, Peter H.; De Paepe, Anne M.; Dietz, Harry C.

In: New England Journal of Medicine, Vol. 355, No. 8, 24.08.2006, p. 788-798.

Research output: Contribution to journalArticle

Loeys, BL, Schwarze, U, Holm, T, Callewaert, BL, Thomas, GH, Pannu, H, De Backer, JF, Oswald, GL, Symoens, S, Manouvrier, S, Roberts, AE, Faravelli, F, Alba Greco, M, Pyeritz, RE, Milewicz, DM, Coucke, PJ, Cameron, DE, Braverman, AC, Byers, PH, De Paepe, AM & Dietz, HC 2006, 'Aneurysm syndromes caused by mutations in the TGF-β receptor', New England Journal of Medicine, vol. 355, no. 8, pp. 788-798. https://doi.org/10.1056/NEJMoa055695
Loeys BL, Schwarze U, Holm T, Callewaert BL, Thomas GH, Pannu H et al. Aneurysm syndromes caused by mutations in the TGF-β receptor. New England Journal of Medicine. 2006 Aug 24;355(8):788-798. https://doi.org/10.1056/NEJMoa055695
Loeys, Bart L. ; Schwarze, Ulrike ; Holm, Tammy ; Callewaert, Bert L. ; Thomas, George H. ; Pannu, Hariyadarshi ; De Backer, Julie F. ; Oswald, Gretchen L. ; Symoens, Sofie ; Manouvrier, Sylvie ; Roberts, Amy E. ; Faravelli, Francesca ; Alba Greco, M. ; Pyeritz, Reed E. ; Milewicz, Dianna M. ; Coucke, Paul J. ; Cameron, Duke E. ; Braverman, Alan C. ; Byers, Peter H. ; De Paepe, Anne M. ; Dietz, Harry C. / Aneurysm syndromes caused by mutations in the TGF-β receptor. In: New England Journal of Medicine. 2006 ; Vol. 355, No. 8. pp. 788-798.
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abstract = "BACKGROUND: The Loeys-Dietz syndrome is a recently described autosomal dominant aorticaneurysm 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 β 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.",
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T1 - Aneurysm syndromes caused by mutations in the TGF-β receptor

AU - Loeys, Bart L.

AU - Schwarze, Ulrike

AU - Holm, Tammy

AU - Callewaert, Bert L.

AU - Thomas, George H.

AU - Pannu, Hariyadarshi

AU - De Backer, Julie F.

AU - Oswald, Gretchen L.

AU - Symoens, Sofie

AU - Manouvrier, Sylvie

AU - Roberts, Amy E.

AU - Faravelli, Francesca

AU - Alba Greco, M.

AU - Pyeritz, Reed E.

AU - Milewicz, Dianna M.

AU - Coucke, Paul J.

AU - Cameron, Duke E.

AU - Braverman, Alan C.

AU - Byers, Peter H.

AU - De Paepe, Anne M.

AU - Dietz, Harry C

PY - 2006/8/24

Y1 - 2006/8/24

N2 - BACKGROUND: The Loeys-Dietz syndrome is a recently described autosomal dominant aorticaneurysm 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 β 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.

AB - BACKGROUND: The Loeys-Dietz syndrome is a recently described autosomal dominant aorticaneurysm 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 β 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.

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