Correspondence

Aneurysm Syndromes and TGF-β Receptor Mutations

N Engl J Med 2006; 355:2155-2156November 16, 2006

Article

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 β (TGF-β) 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

2 References

1. 1

   Loeys BL, Schwarze U, Holm T, et al. Aneurysm syndromes caused by mutations in the TGF-β receptor. N Engl J Med 2006;355:788-798
   Full Text | Web of Science | Medline

2. 2

   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
   CrossRef | Web of Science | Medline

Author/Editor Response

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-β 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-β 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

1 References

1. 1

   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
   CrossRef | Web of Science | Medline

Citing Articles (2)

Citing Articles

1. 1

   Nicola Marziliano, Maurizia Grasso, Andrea Pilotto, Emanuele Porcu, Marilena Tagliani, Eliana Disabella, Marta Diegoli, Michele Pasotti, Valentina Favalli, Alessandra Serio, Fabiana Gambarin, Luigi Tavazzi, Catherine Klersy, Eloisa Arbustini. (2009) Transcriptomic and proteomic analysis in the cardiovascular setting: unravelling the disease?. Journal of Cardiovascular Medicine 10:5, 433-442
   CrossRef

2. 2

   M Attanasio, I Lapini, L Evangelisti, L Lucarini, B Giusti, MC Porciani, R Fattori, C Anichini, R Abbate, GF Gensini, G Pepe. (2008) FBN1 mutation screening of patients with Marfan syndrome and related disorders: detection of 46 novel FBN1 mutations. Clinical Genetics 74:1, 39-46
   CrossRef