BackgroundThe molecular genetic basis of pulmonary arterial hypertension (PAH) is heterogeneous, with at least 26 genes displaying putative evidence for disease causality. Heterozygous variants in the ATP13A3 gene were recently identified as a new cause of adult-onset PAH. However, the contribution of ATP13A3 risk alleles to child-onset PAH remains largely unexplored.Methods and resultsWe report three families with a novel, autosomal recessive form of childhood-onset PAH due to biallelic ATP13A3 variants. Disease onset ranged from birth to 2.5 years and was characterised by high mortality. Using genome sequencing of parent–offspring trios, we identified a homozygous missense variant in one case, which was subsequently confirmed to cosegregate with disease in an affected sibling. Independently, compound heterozygous variants in ATP13A3 were identified in two affected siblings and in an unrelated third family. The variants included three loss of function variants (two frameshift, one nonsense) and two highly conserved missense substitutions located in the catalytic phosphorylation domain. The children were largely refractory to treatment and four died in early childhood. All parents were heterozygous for the variants and asymptomatic.ConclusionOur findings support biallelic predicted deleterious ATP13A3 variants in autosomal recessive, childhood-onset PAH, indicating likely semidominant dose-dependent inheritance for this gene.
Background/Aims: To review the pathological distribution of pediatric primary skull tumors, and to determine the diagnostic value of lesion location, patient age and lesion size. Methods: A retrospective chart review identified 51 consecutive pediatric patients with 54 primary skull tumors, treated between 2005 and 2010. Results: The most common diagnoses were dermoid cysts (n = 34) and fibrous dysplasia (n = 5). While dermoid tumors could reside anywhere (sensitivity = 0.41), a midline lesion had a specificity of 0.9 and a positive predictive value of 0.88. All of the fibrous dysplasia lesions were laterally placed, with a negative predictive value (NPV) of 1. Patient age < or >5 years had a high sensitivity and NPV for dermoid cysts and fibrous dysplasia, respectively. Size appeared to be sensitive (0.91, 0.8), but not specific (0.6, 0.78), with good NPV (0.8, 0.97) when considering dermoid cysts (≤2 cm) or fibrous dysplasia (>2 cm), respectively.Conclusion:Dermoid cysts followed by fibrous dysplasia are the most common primary skull tumors. Lesion location, patient age and lesion size give important clues as to the diagnosis. For the majority of cases, a clinical diagnosis based on CT is sufficient for presurgical evaluation.
Rationale Pulmonary hypertension (PH) is relatively common in infants with severe bronchopulmonary dysplasia (BPD), however, hemodynamic data and factors associated with mortality in this patient group are sparsely described in the literature. Objectives To characterize the hemodynamics of former preterm infants with BPD and PH, as measured at cardiac catheterization, and to identify respiratory and cardiovascular predictors of mortality. Methods Single‐center, retrospective cohort study, including, 30 patients born at less than 32‐week gestational age (GA), who had an oxygen requirement at 36 weeks postmenstrual age and underwent cardiac catheterization between July 2014 and December 2017. Results Median GA at birth was 25 5/7 weeks (interquartile range [IQR], 24 4/7‐26 6/7 weeks). Median birth weight was 620 g (IQR, 530‐700 g). With a median of 23 months of follow up (IQR, 11‐39 months), mortality as of July 2018 was 27% (8 of 30). The alveolar‐arterial oxygen gradient as a measure of lung disease did not correlate with mortality (log‐rank test P = 0.28). However, indexed pulmonary vascular resistance (PVR) of greater than 3 Woods units × m 2 showed a trend toward increased mortality (log‐rank test P = 0.12). Pulmonary vein stenosis was the only predictor significantly associated with mortality (log‐rank test P = 0.005). Conclusions In this cohort, the severity of lung disease as assessed by impaired oxygenation at cardiac catheterization did not correlate with mortality. The only factor significantly associated with mortality was the presence of pulmonary vein stenosis on cardiac catheterization, although PVR may also be an important factor.
Pulmonary arterial hypertension (PAH) is a frequent complication of congenital heart disease as a consequence of altered pulmonary hemodynamics with increased pulmonary blood flow and pressure. The development of pulmonary vascular disease (PVD) in this patient population is an important concern in determining operative strategy. Early, definitive surgical repair, when possible, is the best therapy to prevent and treat PVD. However, this is not possible in some patients because they either presented late, after the development of PVD, or they have complex lesions not amenable to one-step surgical correction, including patients with single ventricle physiology, who have a continuing risk of developing PVD. These patients represent an important, high-risk subgroup and many have been considered inoperable. We present a case series of two patients with complex congenital heart disease and advanced PVD who successfully underwent a treat and repair strategy with aggressive PAH therapies before surgical correction. Both patients had normalization of pulmonary vascular resistance prior to surgical correction. Caution is warranted in applying this strategy broadly and long-term follow-up for these patients is crucial. However, this treat and repair strategy may allow for favorable outcomes among some patients who previously had no therapeutic options.
There is limited published experience with transitioning pediatric patients from parenteral treprostinil to oral selexipag therapy. In addition, published transitions have typically been protracted, taking several weeks to complete. We present a case series of 3 adolescent patients who were transitioned from parenteral treprostinil to oral selexipag over a 5- to 7-day period. Their clinical courses leading up to the transitions are summarized and their outcomes are described. The 3 patients were successfully rapidly transitioned during an inpatient hospitalization without any observed adverse events or prostacyclin-related side effects. We conclude that when indicated rapid transition of parenteral to oral prostacyclin therapy may be performed safely in adolescents in an inpatient setting.
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