Congenital heart disease in pregnancies complicated by maternal diabetes mellitus. An international clinical collaboration, literature review, and meta-analysis.

PURPOSE: Investigation of the incidence and distribution of congenital structural cardiac malformations among the offspring of mothers with diabetes type 1 and of the influence of periconceptional glycemic control. METHODS: Multicenter retrospective clinical study, literature review, and meta-analysis. The incidence and pattern of congenital heart disease in the own study population and in the literature on the offspring of type 1 diabetic mothers were compared with the incidence and spectrum of the various cardiovascular defects in the offspring of nondiabetic mothers as registered by EUROCAT Northern Netherlands. Medical records were, in addition, reviewed for HbA(1c) during the 1st trimester. RESULTS: The distribution of congenital heart anomalies in the own diabetic study population was in accordance with the distribution encountered in the literature. This distribution differed considerably from that in the nondiabetic population. Approximately half the cardiovascular defects were conotruncal anomalies. The authors' study demonstrated a remarkable increase in the likelihood of visceral heterotaxia and variants of single ventricle among these patients. As expected, elevated HbA(1c) values during the 1st trimester were associated with offspring fetal cardiovascular defects. CONCLUSION: This study shows an increased likelihood of specific heart anomalies, namely transposition of the great arteries, persistent truncus arteriosus, visceral heterotaxia and single ventricle, among offspring of diabetic mothers. This suggests a profound teratogenic effect at a very early stage in cardiogenesis. The study emphasizes the frequency with which the offspring of diabetes-complicated pregnancies suffer from complex forms of congenital heart disease. Pregnancies with poor 1st-trimester glycemic control are more prone to the presence of fetal heart disease.

Mirror extreme BMI phenotypes associated with gene dosage at the chromosome 16p11.2 locus.

Both obesity and being underweight have been associated with increased mortality. Underweight, defined as a body mass index (BMI) ≤ 18.5 kg per m(2) in adults and ≤ -2 standard deviations from the mean in children, is the main sign of a series of heterogeneous clinical conditions including failure to thrive, feeding and eating disorder and/or anorexia nervosa. In contrast to obesity, few genetic variants underlying these clinical conditions have been reported. We previously showed that hemizygosity of a ∼600-kilobase (kb) region on the short arm of chromosome 16 causes a highly penetrant form of obesity that is often associated with hyperphagia and intellectual disabilities. Here we show that the corresponding reciprocal duplication is associated with being underweight. We identified 138 duplication carriers (including 132 novel cases and 108 unrelated carriers) from individuals clinically referred for developmental or intellectual disabilities (DD/ID) or psychiatric disorders, or recruited from population-based cohorts. These carriers show significantly reduced postnatal weight and BMI. Half of the boys younger than five years are underweight with a probable diagnosis of failure to thrive, whereas adult duplication carriers have an 8.3-fold increased risk of being clinically underweight. We observe a trend towards increased severity in males, as well as a depletion of male carriers among non-medically ascertained cases. These features are associated with an unusually high frequency of selective and restrictive eating behaviours and a significant reduction in head circumference. Each of the observed phenotypes is the converse of one reported in carriers of deletions at this locus. The phenotypes correlate with changes in transcript levels for genes mapping within the duplication but not in flanking regions. The reciprocal impact of these 16p11.2 copy-number variants indicates that severe obesity and being underweight could have mirror aetiologies, possibly through contrasting effects on energy balance.