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(Circulation Research. 2008;103:e96.)
© 2008 American Heart Association, Inc.

Letter to the Editor

Atrial Fibrillation and Other Clinical Manifestations of Altered TBX5 Dosage in Typical Holt–Oram Syndrome

Deborah A. McDermott, Cathy J. Hatcher, Craig T. Basson

Center for Molecular Cardiology, Greenberg Division of Cardiology, Weill Medical College of Cornell University, New York, NY, E-mail ctbasson@med.cornell.edu

An extract of the first 250 words of the full text is provided, because this article has no abstract.

To the editor:

We were pleased to read the recent study in Circulation Research by Postma et al¹ that describes an activation mutation in TBX5 that causes Holt–Oram syndrome. These exciting findings validate prior studies (reviewed elsewhere²) showing that cytogenetic abnormalities that produce TBX5 duplication (and presumed TBX5 overexpression) result in phenotypes that include Holt–Oram syndrome associated abnormalities. Moreover, we^3,4 and others⁵ have previously demonstrated in experimental models that cell biological consequences of diminished and augmented Tbx5 expression are similar. In aggregate, these prior findings and the current data support a model⁶ in which Tbx5 dosage must be finely controlled to avoid cardiovascular pathology. The findings of Postma et al provide an important platform to dissect the mechanisms underlying such regulation.

However, we would like to provide clarity for clinicians evaluating patients with potential Holt–Oram diagnoses. We note potential misinterpretation of our prior reports that may have contributed to the conclusion by Postma et al that their family has "atypical" Holt–Oram syndrome. Classically, Holt–Oram syndrome findings do include grossly obvious absent or triphalangeal thumb. In fact, though, mild hypoplasia of the thenar bones or eminence or of any structure within the radial ray is more commonly the only evidence of Holt–Oram syndrome.^7–10 In some cases of typical Holt–Oram syndrome, delayed bone age by carpal bone assessment may be the only evidence of disease.⁷ Unfortunately, these subtle abnormalities are often initially overlooked, as in the initial clinical report of the family in the study by Postma et al. The relative . . . [Full Text of this Article]