Sirenomelia and VACTERL association in the offspring of a woman with diabetes

Abstract

Sirenomelia and VACTERL association are defects of blastogenesis of unknown cause. Although they appear clinically distinct, some epidemiological and experimental studies suggest a common pathogenetic mechanism. We report on the reproductive history of a 28-year-old obese, diabetic mother who had three pregnancies. The first resulted in the birth of a sirenomelic child, the second in a miscarriage, while the third was terminated for fetal malformations, diagnosed post-mortem as VACTERL association. This observation supports the relationship between sirenomelia and VACTERL, which probably represent the two ends of the same phenotypic spectrum. Their occurrence in the same sibship also indicates a possible common cause. The coexistence with maternal diabetes seems more than a chance occurrence and the constellation of malformations observed in the present family may be explained as the pleiotropic effect of the same teratogenic agent interacting with genetic predisposition to diabetes and/or obesity.

A Fetus with Hemifacial Microsomia and Sirenomelia. The Same Mesodermal Defect Spectrum?

“…There have been many studies describing the interrelationship between sirenomelia, VACTERL, caudal dysplasia, and hemifacial microsomia [7,18,19]. Recently, Thottungal et al [11] described four cases of CD that were classified as having VACTERL association and Castori et al [10] reported sirenomelia and VACTERL in the offspring of a woman with diabetes, reinforcing a common pathogenetic mechanism of mesodermal development. VACTERL, CD, and sirenomelia result from the pleiotropic effect of a single agent simultaneously affecting a variety of midline structures [10].…”

“…Similar defects are seen in axial mesodermal dysplasia, VACTERL (Vertebral anomalies, Anal atresia, Cardiac malformations, Tracheoesophageal fistula, Renal anomalies, Limb anomalies) association, and caudal dysgenesis (CD). Recent studies consider sirenomelia as the most severe form of CD or VACTERL although others still support the idea that sirenomelia is a different pathologic entity [3,[7][8][9][10][11].…”

Sirenomelia

“…The vascular steal theory would also not account for other abnormalities noted in sirenomelic foetuses. Hence, sirenomelia has again recently been postulated to be either at the severe end of the caudal dysgenesis (CD) spectrum (Rougemont et al, 2008;Thottungal et al, 2010) or a severe form of the VACTERL association (Castori et al, 2010).…”

“…Both CD and VACTERL association occur more often in babies born to diabetic mothers (Castori et al, 2010). Although there have also been reports of infants with sirenomelia born to diabetic mothers, the birth prevalence rates range from less than 4% (Duesterhoeft et al, 2007) to up to 20% (Al-Haggar et al, 2010.…”

Genetics of gastrointestinal atresias

“…Mothers with maternal diabetes may give birth to infants showing a phenotype similar to VATER/VACTERL. Interestingly it has been suggested that maternal diabetes could have a possible influence in the etiology of VATER/VACTERL (Castori et al, 2008(Castori et al, , 2010. To help understand the mechanisms behind these anomalies, several mouse models have been used.…”