Ulnar mammary syndrome and TBX3: Expanding the phenotype

Abstract

We present a patient with features of Ulnar Mammary syndrome (UMS) consisting of bilateral ulnar defects, inverted nipples, short stature with associated growth hormone deficiency, and cryptorchidism. Our patient also had a hypoplastic anterior pituitary and an ectopic posterior pituitary gland, ventricular septal defect (VSD), and cardiac conduction defects consistent with Wolff-Parkinson-White (WPW) syndrome. Although TBX3 is known to be expressed in both the developing heart and the pituitary gland, conduction defects and anatomical pituitary abnormalities have not been previously described in UMS. This may, in part, be due to the fact that these features are not actively sought in individuals with UMS. Because these new findings have important clinical implications, we suggest that clinicians caring for individuals with UMS offer brain imaging, growth hormone testing, and cardiac arrhythmia screening. The diagnosis of UMS was confirmed on mutation analysis of TBX3. The mother of the propositus was also found to carry the same mutation, although she did not show the classical features of UMS. Therefore, our report also supports the variable expressivity of UMS within the same family.

Lethal arrhythmias in Tbx3 -deficient mice reveal extreme dosage sensitivity of cardiac conduction system function and homeostasis

“…Multiple Tbx genes are expressed in the developing CCS in mice and mutations in TBX3 and TBX5 have been associated with human CCS dysfunction (1,6,7). Mutations in TBX3 cause human ulnar-mammary syndrome (UMS), characterized by limb malformations, apocrine and mammary gland hypoplasia, and dental and genital abnormalities (8).…”

“…Mutations in TBX3 cause human ulnar-mammary syndrome (UMS), characterized by limb malformations, apocrine and mammary gland hypoplasia, and dental and genital abnormalities (8). Cardiac structural defects have been reported in two patients with UMS, one with the Wolff-Parkinson-White syndrome conduction abnormality (7,9). TBX3 expression was decreased in the hearts of patients with right ventricular outflow tract tachycardia, and variability in the TBX5-TBX3 region correlates with PR interval duration (10,11).…”

T-Box Genes and Developmental Anomalies

“…The syndrome was named for two of the more common abnormalities that make up this disorder: defects in the posterior part of the hand and arm (particularly the ulna) and a deficiency of mammary gland development. Other features are variably present in UMS, including a lack of axillary apocrine glands, a lack of axial hair, delayed puberty in males, a variety of anomalies of the internal and external urogenital system, obesity, abnormalities of teeth and palate, laryngeal stenosis, ventricular septal defects, and foot defects (Washkowitz et al, 2012;Linden et al, 2009;Meneghini et al, 2006;Joss et al, 2011). The availability of large multigenerational kindreds with UMS allowed for the fine mapping of the disorder and the discovery of causative mutations in TBX3 (Bamshad et al, 1997).…”

The emerging genetic landscape underlying cardiac conduction system function

“…Tbx3 encodes a transcriptional repressor that is expressed throughout the developing conduction system and plays an essential role in the specification of the ventricular conduction (Bakker et al, 2008). In humans, mutations in Tbx3 are linked to Ulnar-Mammary syndrome (Bamshad et al, 1997), which classically includes ulnar defects, inverted nipples, and short stature, but which also may include conduction system defects (Linden et al, 2009). Tbx20 is necessary for heart tube looping and growth (Cai et al, 2005), and mutations in Tbx20 are linked to a range of congenital heart malformations in human including defects in septation, chamber growth, and valvulogenesis (Kirk et al, 2007).…”