Cardiovascular malformations in Smith‐Lemli‐Opitz syndrome

Abstract

We reviewed 215 patients (59 new, 156 from the literature) with Smith-Lemli-Opitz syndrome (SLOS), and found that 95 (44%) had a cardiovascular malformation (CVM). Classifying CVMs by disordered embryonic mechanisms, there were 5 (5.3%) class 1 (ectomesenchymal tissue migration abnormalities), 56 (58.9%) class II (abnormal intracardiac blood flow), 25 (26.3%) class IV (abnormal extracellular matrix), and 5 (5.3%) class V (abnormal targeted growth). Comparing the frequencies of individual CVMs in this series with a control group (the Baltimore-Washington Infant Study), there were 6 individual CVMs which showed a significant difference from expected values. When frequencies of CVMs in SLOS were analyzed by mechanistic class, classes IV and V were significantly more frequent, and class I significantly less frequent, than the control group. Although CVMs in SLOS display mechanistic heterogeneity, with an overall predominance of class II CVMs, the developmental error appears to favor alteration of the cardiovascular developmental mechanisms underlying atrioventricular canal and anomalous pulmonary venous return. This information should assist the clinical geneticist evaluating a patient with possible SLOS, and should suggest research direction for the mechanisms responsible for the SLOS phenotype.

The Smith-Lemli-Opitz syndrome

“…The cardiac anomalies of SLOS have been reviewed by Robinson et al ,7 Johnson,10and, most extensively, by Lin et al 92. Almost half of SLOS patients have a congenital heart defect, although if only biochemically confirmed patients are taken into consideration, this percentage is somewhat lower 23…”

“…Almost half of SLOS patients have a congenital heart defect, although if only biochemically confirmed patients are taken into consideration, this percentage is somewhat lower 2327 92 There is a strong predominance of endocardial cushion defects and the hypoplastic left heart sequence, whereas conotruncal defects are uncommon. Almost every known cardiac defect has been described at least once.…”

“…The five most prevalent defects found in a study of 95 biochemically confirmed cases of SLOS were atrioventricular canal (25%), primum atrial septal defect (20%), patent ductus arteriosus at term (18%), and membranous ventricular septal defect (10%) 92. Lin et al 92 hypothesised that the abnormal development of the extracellular matrix may be the cause of both the cardiac defects and the absence of ganglion cells in the bowel (Hirschsprung disease) because of altered cell membranes and cell to cell interactions. However, abnormal migration or proliferation of neural crest derived cells, which contributes substantially to the endocardial cushions, could also explain both the cardiac defects and abnormal intestinal ganglion cells.…”

Malformation syndromes caused by disorders of cholesterol synthesis

“…Although considered a normal variant, given the wide phenotypic spectrum for SLOS, syndactyly of the second and third toes in combination with other malformations, behavioral disturbances, or cognitive issues should prompt consideration of SLOS. Congenital heart defects, including atrioventricular canal, hypoplastic left heart sequence, and septal defects, are common in classical and severe cases ( 40 ), and hypertension can be a…”

Atrioventricular canal defect in Bardet-Biedl syndrome: Clinical evidence supporting the link between atrioventricular canal defect and polydactyly syndromes with ciliary dysfunction536

“…35 On the other hand, the association of AVCD and anomalous pulmonary venous return is specifically associated with Smith-LemliOpitz syndrome (Table 1). 36,40 Recent experimental evidences regarding BBS are intriguing in regard to CHD and situs abnormalities. In fact, a role for several BBS proteins in regulating ciliary function has been demonstrated.…”