Laterality defects in the national birth defects prevention study (1998–2007): Birth prevalence and descriptive epidemiology

Abstract

Little is known epidemiologically about laterality defects. Using data from the National Birth Defects Prevention Study (NBDPS), a large multi-site case-control study of birth defects, we analyzed prevalence and selected characteristics in children born with laterality defects born from 1998 to 2007. We identified 517 nonsyndromic cases (378 heterotaxy, 73.1%; 139 situs inversus totalis [SIT], 26.9%) resulting in an estimated birth prevalence of 1.1 per 10,000 live births (95% confidence interval 1.0–1.2). Prevalence did not differ significantly across sites, over time, or by inclusion of pregnancy termination. Laterality defects were more common among preterm cases compared to term cases, and in children born to mothers who were non-white or younger than 20 years compared to white mothers or those age 25–29 years. The distribution of associated cardiac and extracardiac defects, excluding the expected heterotaxy anomalies, varied by type of laterality defect. Cases with heterotaxy were significantly more likely than those with SIT to have double outlet right ventricle, atrioventricular canal defects, pulmonary stenosis, non-tetralogy of Fallot pulmonary atresia with ventricular septal defect, totally and partially anomalous pulmonary venous return; also more likely to have orofacial clefts, esophageal atresia, bowel atresias, and omphalocele, though not reaching statistical significance. Relatively more common among cases with SIT were Dandy-Walker malformation, anotia/microtia, and limb deficiency. The similarity in the demographic characteristics of heterotaxy and SIT supports the hypothesis that they are part of a continuum of abnormal left-right axis patterning. These findings on laterality defects may help guide clinical care, future research, and prevention strategies.

Cilia and Ciliopathies in Congenital Heart Disease

“…Analysis of motile cilia mutant mice revealed CHD is typically observed in conjunction with heterotaxy, the randomization of left -right patterning (Tan et al 2007). This is consistent with the well-described clinical association of complex CHD with heterotaxy (Lin et al 2014). As the heart is the most left -right asymmetric organ, and this asymmetry is essential for efficient oxygenation of blood, it is perhaps not surprising that left -right patterning defects may play a major role in CHD pathogenesis.…”

Copy number variation as a genetic basis for heterotaxy and heterotaxy-spectrum congenital heart defects

“…In its classic form, heterotaxy is characterized by combined occurrence of visceral situs abnormalities (gut malrotation, stomach and liver situs anomalies, abnormalities of spleen positioning or number) and congenital heart defects (CHDs) of varying complexity, which account for the majority of associated morbidity and mortality. Over 96% of patients with heterotaxy exhibit some form of CHD [2], often requiring surgical intervention. Clinical outcomes are disproportionately poorer than in patients without heterotaxy who have similar CHDs and are typified by prolonged courses and significantly greater likelihood for post-surgical complications [3][4][5].…”

Dilated azygos arch mimicking an aortic arch anomaly during thoracic surgery

“…However, Mlczoch and Carvalho [14] debated that failure of IVC formation is not a situs abnormality in patients with omphalocele, despite frequently encountered in situs abnormalities. We support this theory, considering that our patients did not encompass at least three requested diagnostic categories for laterality defects [12]. Although low statistical power because of small study size, we think that the described association of rib anomalies, azygos continuation and EA arises from an early developmental disruption mechanism.…”

“…This asymptomatic developmental variation, secondary to interruption of at least the hepatic segment of the IVC, should be considered part of the clinical spectrum of the polymalformative complex EA with rib disorders. Although other AV anomalies have been reported in patients with EA [9,21,24], to best of our knowledge, there are only few reports of azygos continuation in infants with EA, all associated to left-isomerism [5,7,12].…”