A multi-disciplinary, comprehensive approach to management of children with heterotaxy

Abstract

Heterotaxy (HTX) is a rare condition of abnormal thoraco-abdominal organ arrangement across the left–right axis of the body. The pathogenesis of HTX includes a derangement of the complex signaling at the left–right organizer early in embryogenesis involving motile and non-motile cilia. It can be inherited as a single-gene disorder, a phenotypic feature of a known genetic syndrome or without any clear genetic etiology. Most patients with HTX have complex cardiovascular malformations requiring surgical intervention. Surgical risks are relatively high due to several serious comorbidities often seen in patients with HTX. Asplenia or functional hyposplenism significantly increase the risk for sepsis and therefore require antimicrobial prophylaxis and immediate medical attention with fever. Intestinal rotation abnormalities are common among patients with HTX, although volvulus is rare and surgical correction carries substantial risk. While routine screening for intestinal malrotation is not recommended, providers and families should promptly address symptoms concerning for volvulus and biliary atresia, another serious morbidity more common among patients with HTX. Many patients with HTX have chronic lung disease and should be screened for primary ciliary dyskinesia, a condition of respiratory cilia impairment leading to bronchiectasis. Mental health and neurodevelopmental conditions need to be carefully considered among this population of patients living with a substantial medical burden. Optimal care of children with HTX requires a cohesive team of primary care providers and experienced subspecialists collaborating to provide compassionate, standardized and evidence-based care. In this statement, subspecialty experts experienced in HTX care and research collaborated to provide expert- and evidence-based suggestions addressing the numerous medical issues affecting children living with HTX.

Understanding laterality disorders and the left-right organizer: Insights from zebrafish

“…The frequency of HTX is estimated to be ~1 in 10,000 births, and most patients (~90%) have a congenital heart defect (Lin et al, 2014;Eitler, Bibok, and Telkes 2022). The spectrum of congenital heart defects associated with HTX has been described in detail-including helpful diagrams and radiographs-in previous reviews (Ramsdell 2005;Maldjian and Saric 2007;Desgrange, Le Garrec, and Meilhac 2018;Agarwal et al, 2021;Saba et al, 2022). Here, we highlight cardiac and extracardiac birth defects found in HTX patients with classifications as right or left isomerism (Jacobs et al, 2007).…”

“…Heterotaxy syndrome (HTX) collectively refers to a broad spectrum of organ malformations that result from defects in establishing laterality during embryogenesis. HTX can be an isolated disorder or a feature of a genetic syndrome (Saba et al, 2022). The frequency of HTX is estimated to be ~1 in 10,000 births, and most patients (~90%) have a congenital heart defect (Lin et al, 2014;Eitler, Bibok, and Telkes 2022).…”

“…These patients often have bilaterally trilobed lungs, and the absence of a spleen (asplenia) that leaves them at risk for infections (Loomba et al, 2016a;Buca et al, 2018). Characteristic cardiac defects include atrioventricular canal defects, a single functional ventricle (or large ventricular septal defect), pulmonary valve stenosis or atresia, anomalous pulmonary venous return, and transposition of the great arteries (Saba et al, 2022;Yi et al, 2022). On the other hand, individuals with left isomerism will often have bilaterally bilobed lungs and multiple spleens (polyspenia).…”

“…It is important to note that organ arrangement in some HTX cases deviates from these descriptions of left or right isomerism (Yim et al, 2018). An extracardiac defect common in both types of isomerism is malrotation of the intestine (Ryerson et al, 2018;Saba et al, 2022). Failure of the intestine to complete an asymmetric 270 °rotation around the superior mesenteric artery during development can cause mispositioning and give rise to volvulus (Langer 2017), which can disrupt blood supply and cause obstruction.…”

“…Individuals with HTX typically require medical intervention (Saba et al, 2022). In an ideal situation, a prenatal diagnosis can be made with ultrasound and/or prenatal echocardiogram that can facilitate pre-planning for clinical care after delivery.…”