Phenotype of a patient with contiguous deletion of TBX5 and TBX3: Expanding the disease spectrum

Abstract

The important roles that T-box genes play in the morphogenesis of the heart and its conduction system has long been established, and a number of disorders are linked to mutations in these T-box genes. Holt-Oram syndrome (HOS), the classic heart and hand syndrome, is clinically typified by radial ray upper limb abnormalities and cardiac malformations, and is caused by mutations involving TBX5. Another member of the T-box gene family, TBX3, is found in close proximity to TBX5 on chromosome 12q24. Mutations in TBX3 cause ulnar-mammary syndrome (UMS), which is distinguished by upper limb malformations affecting the ulnar ray, apocrine, and mammary gland hypoplasia, and genital defects. While disorders involving isolated mutations of TBX5 and TBX3 have been well described, contiguous deletions of these T-box genes remain exceptional. We report on a patient with features of both HOS and UMS consisting of bilateral symmetric limb malformations, congenital cardiac defects, and rapidly progressive cardiac conduction disease.

Novel copy number variants and major limb reduction malformation: Report of three cases

“…While the de novo deletion in Patient 2 is novel, dual deletion of TBX3 and TBX5 has been reported in three families with combined features of Holt–Oram and Ulnar–Mammary syndromes, caused by dominant mutations in TBX3 and TBX5 , respectively [Borozdin et al, ; Alby et al, ; Bogarapu et al, ]. It is likely that the severe upper limb malformation in Patient 2 is caused by the combined effect of TBX3 and TBX5 deletion on ulnar and radial rays, respectively.…”

Pulmonary Agenesis and Associated Pulmonary Hypertension: A Case Report and Review on Variability, Therapy, and Outcome

“…Mutations in the T-box genes can produce a combination of cardiopulmonary and extremity malformations (classically, for example, Holt–Oram syndrome), along with urogenital defects. 17 Cardiac and laterality defects including the oculofaciocardiodental syndrome, may be due to suppression of the PITX2 gene in the embryonic lateral plate mesoderm. 18 An interesting observation in this context is that in most cases of pulmonary agenesis, the associated malformations seem to be ipsilateral.…”

Inherited Conduction Disease and Atrial Fibrillation

“…Mutations in the TBX3 gene, which lies close to TBX5 on chromosome 12q24, result in ulnar-mammary syndrome. A case of contiguous deletions of both TBX5 and TBX3 displaying clinical features of both, had rapidly progressive cardiac conduction disease (69).…”