Aneurysm Syndromes and TGF- Receptor Mutations
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《新英格兰医药杂志》
To the Editor: Loeys et al. (Aug. 24 issue)1 describe the clinical and molecular characteristics of the Loeys–Dietz syndrome associated with mutations in the genes encoding transforming growth factor (TGF-) receptors 1 and 2 (TGFBR1 and TGFBR2, respectively).
We found mutations in TGFBR1 and TGFBR2 in 19 members of 11 unrelated families, including 1 healthy 12-year-old carrier. Eighteen had aortic aneurysm or dissection. Of the 19 patients with mutations in these genes, 11 had at least one of the traits of the Loeys–Dietz syndrome, and the characteristics of 3 adults met the Ghent criteria2 for Marfan's syndrome. Seven patients did not have bifid uvula, cleft palate, craniosynostosis, hypertelorism, or generalized arterial tortuosity. Of these patients, two met the Ghent criteria and five had aortic dissection, including two with maximal aortic dimensions of less than 5.0 cm.
Thus, we suggest that all patients with mutations of TGFBR1 and TGFBR2, regardless of their clinical presentation, have the Loeys–Dietz syndrome. For now, the use of this diagnosis should permit us to maintain the distinction between patients with classic Marfan's syndrome and those with the Loeys–Dietz syndrome. Larger prospective studies may clarify whether the ominous tendency toward early aortic rupture in patients with the Loeys–Dietz syndrome is related to TGFBR1 and TGFBR2 mutations alone or limited to patients with mutations who have at least one clinical sign of the Loeys–Dietz syndrome.
Eloisa Arbustini, M.D.
Nicola Marziliano, Ph.D.
Center for Inherited Cardiovascular Diseases
27100 Pavia, Italy
e.arbustini@smatteo.pv.it
Lorenzo Magrassi, M.D.
University of Pavia
27100 Pavia, Italy
References
Loeys BL, Schwarze U, Holm T, et al. Aneurysm syndromes caused by mutations in the TGF- receptor. N Engl J Med 2006;355:788-798.
De Paepe A, Devereux R, Dietz H, Hennekam RC, Pyeritz RE. Revised diagnostic criteria for the Marfan syndrome. Am J Med Genet 1996;62:417-426.
The authors reply: Like Arbustini et al., we have observed nonpenetrance, intrafamilial variability, an absence of craniofacial manifestations, and a substantial overlap with characteristics of Marfan's syndrome among patients with mutations in the TGF- receptor genes.1 In these patients, aortic dissection occurs with or without craniofacial manifestations at aortic dimensions that do not infer risk in patients with Marfan's syndrome caused by mutations in the fibrillin-1 gene. Individualized counseling and management are required because of the distinctions between these conditions. Given that a major function of diagnosis is to communicate information that will facilitate the management of these syndromes, we think that the proposal to use the designation "Loeys–Dietz syndrome" for all patients with TGF- receptor mutations is both reasonable and productive. It is no longer sufficient to identify features consistent with the diagnosis of Marfan's syndrome without considering manifestations that are not expected with this diagnosis. In addition to those mentioned by Arbustini and colleagues, findings that are specific to the Loeys–Dietz syndrome include blue sclerae, skin manifestations, localized tortuosity of neck vessels, instability of the cervical spine, visceral rupture, widespread aneurysms, congenital heart disease, and club feet.
Bart L. Loeys, M.D., Ph.D.
Ghent University Hospital
9000 Ghent, Belgium
bart.loeys@ugent.be
Harry C. Dietz, M.D.
Johns Hopkins University School of Medicine
Baltimore, MD 21205
References
Loeys BL, Chen J, Neptune ER, et al. A syndrome of altered cardiovascular, craniofacial, neurocognitive and skeletal development caused by mutations in TGFBR1 or TGFBR2. Nat Genet 2005;37:275-281.
We found mutations in TGFBR1 and TGFBR2 in 19 members of 11 unrelated families, including 1 healthy 12-year-old carrier. Eighteen had aortic aneurysm or dissection. Of the 19 patients with mutations in these genes, 11 had at least one of the traits of the Loeys–Dietz syndrome, and the characteristics of 3 adults met the Ghent criteria2 for Marfan's syndrome. Seven patients did not have bifid uvula, cleft palate, craniosynostosis, hypertelorism, or generalized arterial tortuosity. Of these patients, two met the Ghent criteria and five had aortic dissection, including two with maximal aortic dimensions of less than 5.0 cm.
Thus, we suggest that all patients with mutations of TGFBR1 and TGFBR2, regardless of their clinical presentation, have the Loeys–Dietz syndrome. For now, the use of this diagnosis should permit us to maintain the distinction between patients with classic Marfan's syndrome and those with the Loeys–Dietz syndrome. Larger prospective studies may clarify whether the ominous tendency toward early aortic rupture in patients with the Loeys–Dietz syndrome is related to TGFBR1 and TGFBR2 mutations alone or limited to patients with mutations who have at least one clinical sign of the Loeys–Dietz syndrome.
Eloisa Arbustini, M.D.
Nicola Marziliano, Ph.D.
Center for Inherited Cardiovascular Diseases
27100 Pavia, Italy
e.arbustini@smatteo.pv.it
Lorenzo Magrassi, M.D.
University of Pavia
27100 Pavia, Italy
References
Loeys BL, Schwarze U, Holm T, et al. Aneurysm syndromes caused by mutations in the TGF- receptor. N Engl J Med 2006;355:788-798.
De Paepe A, Devereux R, Dietz H, Hennekam RC, Pyeritz RE. Revised diagnostic criteria for the Marfan syndrome. Am J Med Genet 1996;62:417-426.
The authors reply: Like Arbustini et al., we have observed nonpenetrance, intrafamilial variability, an absence of craniofacial manifestations, and a substantial overlap with characteristics of Marfan's syndrome among patients with mutations in the TGF- receptor genes.1 In these patients, aortic dissection occurs with or without craniofacial manifestations at aortic dimensions that do not infer risk in patients with Marfan's syndrome caused by mutations in the fibrillin-1 gene. Individualized counseling and management are required because of the distinctions between these conditions. Given that a major function of diagnosis is to communicate information that will facilitate the management of these syndromes, we think that the proposal to use the designation "Loeys–Dietz syndrome" for all patients with TGF- receptor mutations is both reasonable and productive. It is no longer sufficient to identify features consistent with the diagnosis of Marfan's syndrome without considering manifestations that are not expected with this diagnosis. In addition to those mentioned by Arbustini and colleagues, findings that are specific to the Loeys–Dietz syndrome include blue sclerae, skin manifestations, localized tortuosity of neck vessels, instability of the cervical spine, visceral rupture, widespread aneurysms, congenital heart disease, and club feet.
Bart L. Loeys, M.D., Ph.D.
Ghent University Hospital
9000 Ghent, Belgium
bart.loeys@ugent.be
Harry C. Dietz, M.D.
Johns Hopkins University School of Medicine
Baltimore, MD 21205
References
Loeys BL, Chen J, Neptune ER, et al. A syndrome of altered cardiovascular, craniofacial, neurocognitive and skeletal development caused by mutations in TGFBR1 or TGFBR2. Nat Genet 2005;37:275-281.