Skeletal Manifestations of the Holt-Oram Syndrome

Poznanski, Andrew K.; Gall, John C.; Stern, Aaron

doi:10.1148/10.1148/94.1.45

Cited by 89 publications

(37 citation statements)

References 21 publications

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“…This striking increase in metacarpal and proximal phalange length of digit I occurred in 100% of adult Tbx5 ϩ/⌬ mice (n ϭ 452) ( Fig. 2F) and corresponded to the "finger-like thumb" observed in Holt-Oram patients (37). We suspect that the higher level of expression of Tbx5 in digit I versus digits II to V in wild-type animals (assessed by whole-mount in situ hybridization [data not shown]) contributed to the uniform and marked elongation of digit I in Tbx5 ϩ/⌬ mice.…”

Section: Shared Skeletal Malformations In Tbx5mentioning

confidence: 58%

“…While structural heart malformations occur in approximately 85% of Holt-Oram patients, wrist and digit malformations are universally found, and are required for a clinical diagnosis (7,8,23,37). Some skeletal manifestations of HOS are visible on inspection, including a finger-like or absent thumb, foreshortened arms, and sloping shoulders that poorly abduct or adduct.…”

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confidence: 99%

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Connexin 40, a Target of Transcription Factor Tbx5, Patterns Wrist, Digits, and Sternum

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Burgon

Paul

et al. 2005

Molecular and Cellular Biology

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Haploinsufficiency of T-box transcription factor 5 (TBX5) causes human Holt-Oram syndrome (HOS),؉/⌬ mice. Although no role in skeleton patterning has been described for gap junctions, we demonstrate here that Cx40 is involved in formation of specific joints, as well as bone shape. Even a 50% reduction in either Tbx5 or Cx40 produces bone abnormalities, demonstrating their crucial control over skeletal development. Further, we demonstrate that Tbx5 exerts in part its key regulatory role in bone growth and maturation by controlling via Cx40 the expression of Sox9 (a transcription factor essential for chondrogenesis and skeleton growth). Our study strongly suggests that Cx40 deficiency accounts for many skeletal malformations in HOS and that Tbx5 regulation of Cx40 plays a critical role in the exquisite developmental patterning of the forelimbs and sternum.

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Section: Shared Skeletal Malformations In Tbx5mentioning

confidence: 58%

mentioning

confidence: 99%

Connexin 40, a Target of Transcription Factor Tbx5, Patterns Wrist, Digits, and Sternum

Pizard

Burgon

Paul

et al. 2005

Molecular and Cellular Biology

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“…Such limb deformity, for example, altered structure of a single carpal bone, may be quite subtle and only detectable radiographically, but individuals without such radial ray defects do not have Holt-Oram syndrome. 124,137 Other limb malformations (eg, syndactyly of digits other than the thumb, polydactyly, or lower-limb defects), craniofacial abnormalities, and/or evidence of noncardiac visceral organ abnormalities (including heterotaxy) make Holt-Oram syndrome unlikely. 124,125,131,138 Most Holt-Oram structural cardiac defects are either ostium secundum atrial septal defects or muscular VSDs.…”

Section: Noonan Syndromementioning

confidence: 99%

Genetic Basis for Congenital Heart Defects: Current Knowledge

Pierpont¹,

Basson²,

Benson³

et al. 2007

Circulation

729

377

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Abstract-The intent of this review is to provide the clinician with a summary of what is currently known about the contribution of genetics to the origin of congenital heart disease. Techniques are discussed to evaluate children with heart disease for genetic alterations. Many of these techniques are now available on a clinical basis. Information on the genetic and clinical evaluation of children with cardiac disease is presented, and several tables have been constructed to aid the clinician in the assessment of children with different types of heart disease. Genetic algorithms for cardiac defects have been constructed and are available in an appendix. It is anticipated that this summary will update a wide range of medical personnel, including pediatric cardiologists and pediatricians, adult cardiologists, internists, obstetricians, nurses, and thoracic surgeons, about the genetic aspects of congenital heart disease and will encourage an interdisciplinary approach to the child and adult with congenital heart disease. (Circulation. 2007;115:3015-3038.)

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“…[1][2][3][4][5] The gene for Holt-Oram syndrome has been identified as TBX5 on chromosome 12q24. [6][7][8][9][10][11] TBX5 encodes a protein of 518 amino acids that belongs to the family of the T box transcriptional factors, 10 11 and is expressed in embryonic heart and limb tissues, consistent with its involvement in development of the heart and skeletal structures.…”

mentioning

confidence: 99%