Structural and numerical changes of chromosome X in patients with esophageal atresia

Abstract

Esophageal atresia with or without tracheoesophageal fistula (EA/TEF) is a relatively common birth defect often associated with additional congenital anomalies such as vertebral, anal, cardiovascular, renal and limb defects, the so-called VACTERL association. Yet, little is known about the causal genetic factors. Rare case reports of gastrointestinal anomalies in children with triple X syndrome prompted us to survey the incidence of structural and numerical changes of chromosome X in patients with EA/TEF. All available (n ¼ 269) karyotypes of our large (321) EA/TEF patient cohort were evaluated for X-chromosome anomalies. If sufficient DNA material was available, we determined genome-wide copy number profiles with SNP array and identified subtelomeric aberrations on the difficult to profile PAR1 region using telomere-multiplex ligation-dependent probe amplification. In addition, we investigated X-chromosome inactivation (XCI) patterns and mode of inheritance of detected aberrations in selected patients. Three EA/TEF patients had an additional maternally inherited X chromosome. These three female patients had normal random XCI patterns. Two male EA/TEF patients had small inherited duplications of the XY-linked SHOX (Short stature HOmeoboX-containing) locus. Patients were small for gestational age at birth (oP5) and had additional, mostly VACTERL associated, anomalies. Triple X syndrome is rarely described in patients with EA/TEF and no duplications of the SHOX gene were reported so far in these patients. As normal patterns of XCI were seen, overexpression of X-linked genes that escape XCI, such as the SHOX gene, could be pathogenic by disturbing developmental pathways.

Short Stature in Isodicentric Y Chromosome and Three Copies of the SHOX Gene: Clinical Report and Review of Literature

“…One girl with partial duplication of exons 2-6a was born small for gestational age [Benito-Sanz et al, 2011], which is a known cause of short stature [Rogol and Hayden, 2014]. Two additional small for gestational age babies with SHOX duplication and complex malformations resembling VACTERL association have been described, but their postnatal growth pattern was not shown [Brosens et al, 2014]. Phenotype may be LWD (47%), mainly in partial duplications, or isolated short stature (53%) in both complete and partial duplications, as in the present case ( table 2 ).…”

“…This finding is not always true in individuals with microduplications of PAR1 involving SHOX or its regulatory sequences. In fact, cases with tall, normal and short stature have been reported [Roos et al, 2009;Thomas et al, 2009;D'haene et al, 2010;Iughetti et al, 2010;Benito-Sanz et al, 2011;Brosens et al, 2014].…”

“…Patients with LWD phenotype or Madelung deformity without short stature, who have a 5 ′ SHOX duplication are also described [Thomas et al, 2009;BenitoSanz et al, 2011]. The causative role of SHOX duplication in other phenotypic or neurological abnormalities de- scribed in some patients with SHOX duplication [Roos et al, 2009;D'haene et al, 2010;Iughetti et al, 2010;Brosens et al, 2014] requires further investigations, assessing the possible extraskeletal effect of this gene. Indeed, a definite genotype/phenotype correlation is currently not possible, due to the limited number of patients and the difficulties in comparing the extent of duplicated regions.…”

Patterns of malformation associated with esophageal atresia/tracheoesophageal fistula: A retrospective single center study

“…EA/TEF can also be part of the VACTERL or VATER association, an acronym that refers to the nonrandom occurrence of V ertebral defects, A nal atresia, C ardiac , T racheo‐ E sophageal fistula, R enal and L imb defects (Nora & Nora, 1975; Solomon, 2011; Temtamy & Miller, 1974). The etiology of nonsyndromic EA/TEF is still unknown, a variety of genetic (Brosens, de Jong, et al, 2014; Shaw‐Smith, 2006) and environmental (Felix et al, 2008; Mc Laughlin, Hajduk, Murphy, & Puri, 2013) factors have been proposed. While familial isolated EA/TEF cases have been infrequently reported (Pletcher, Friedes, Breg, & Touloukian, 1991), large studies have shown a very low recurrence risk for isolated EA/TEF among first degree relatives (Bartels et al, 2012; Choinitzki et al, 2013).…”

Population‐based birth defects data in the United States, 2010–2014: A focus on gastrointestinal defects

“…Several previous reports also explored the co‐occurrence of chromosomal anomalies among children with gastrointestinal defects (Best et al, ; Brosens et al, ; Felix et al, ; Harris et al, ; Hemming & Rankin, ; Shaw‐Smith, ; Takahashi et al, ; Torfs et al, ). Table also includes the median of the state prevalence estimates of more common chromosomal anomalies (i.e., trisomies 13, 18, and 21, Turner syndrome, and 22q11.2 deletion syndrome) by gastrointestinal defect.…”