Pulmonary vein stenosis in patients with Smith-Lemli-Opitz syndrome

Abstract

Objective To describe a group of children with co-incident pulmonary vein stenosis and Smith-Lemli-Opitz syndrome and to generate hypotheses as to the shared pathogenesis of these disorders. Design Retrospective case series Patients Five subjects in a pulmonary vein stenosis cohort of 170 subjects were diagnosed with Smith-Lemli-Opitz syndrome soon after birth. Results All five cases were diagnosed with Smith-Lemli-Opitz syndrome within six weeks of life, with no prior family history of either disorder. All cases had pathologically elevated 7-dehydrocholesterol levels and two of the five cases had previously reported pathogenic 7-dehydrocholesterol reductase mutations. Smith-Lemli-Opitz syndrome severity scores ranged from mild to classical (2–7). Gestational age at birth ranged from 35 to 39 weeks. Four of the cases were male by karyotype. Pulmonary vein stenosis was diagnosed in all cases within two months of life, earlier than most published cohorts. All cases progressed to bilateral disease and three cases developed atresia of at least one vein. Despite catheter and surgical interventions, all subjects’ pulmonary vein stenosis rapidly recurred and progressed. Three of the subjects died, at 2 months, 3 months, and 11 months. Survival at 16 months after diagnosis was 43%. Conclusions Patients with pulmonary vein stenosis who have a suggestive syndromic presentation should be screened for Smith-Lemli-Opitz syndrome with easily obtainable serum sterol tests. Echocardiograms should be obtained in all newly diagnosed patients with Smith-Lemli-Opitz syndrome, with a low threshold for repeating the study if new respiratory symptoms of uncertain etiology arise. Further studies into the pathophysiology of pulmonary vein stenosis should consider the role of cholesterol-based signaling pathways in the promotion of intimal proliferation.

Clinical Syndromic Phenotypes and the Potential Role of Genetics in Pulmonary Vein Stenosis

“…Overall, in this large cohort of PVS patients, a large proportion ( n = 23) were found to have syndromes which are generally known to have a genetic basis. Thirteen patients had T21, and five patients had SLOS which had been previously reported by Prosnitz [ 7 ], and another five had other pathogenic variants including 22q11 deletions or duplications.…”

“…The most common genetic syndrome found in children with PVS was T21 which was seen in 13 patients. The second most common genetic syndrome was SLO, which was seen in five patients as previously reported by our institution [ 7 ]. Other syndromes seen in our patients include DiGeorge syndrome (OMIM# 188400), Cat-eye syndrome (OMIM# 115470), mosaic Turner syndrome, and Adams–Oliver syndrome-5 (OMIM# 616028) confirmed by a pathogenic variant in NOTCH1 .…”

“…However, to our knowledge, only a few studies have explored the possibility of a genetic component in PVS development, with detailed accompanying clinical characterization of patients. A previous retrospective case series from our institution demonstrated an association between PVS and Smith–Lemli–Opitz syndrome (SLO; OMIM# 270400), raising the possibility of a link between genetic disease and PVS [ 7 ]. Small case reports have also suggested an association of PVS with Trisomy 21 (T21) in a few patients [ 4 , 8 ].…”

Pulmonary Vein Stenosis: Incremental Knowledge Gains to Improve Outcomes

“…Children with PVS may also have concomitant congenital heart disease (simple or complex) or chronic lung disease due to prematurity, all of which will affect clinical decision making. In addition, as many as 30% have some identifiable genetic syndrome (trisomy 21, CHARGE, Smith-Lemli-Opitz), which may have additional cardiac and extracardiac abnormalities [6,9,10]. Treatment of PVS must incorporate patient specific comorbidities to help improve outcomes.…”

Longer Exposure to Left-to-Right Shunts Is a Risk Factor for Pulmonary Vein Stenosis in Patients with Trisomy 21

“…The pathophysiology of PVS is unknown, but both genetic and clinical factors are likely to contribute to PVS [5]. PVS has been identified in patients with genetic syndromes such as Smith-Lemli-Opitz syndrome and Trisomy 21 [6,7]. However, a specific gene or molecular pathway has not been identified.…”