Biallelic variants of ATP13A3 cause dose-dependent childhood-onset pulmonary arterial hypertension characterised by extreme morbidity and mortality.

BACKGROUND: The 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 RESULTS: We 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. CONCLUSION: Our findings support biallelic predicted deleterious ATP13A3 variants in autosomal recessive, childhood-onset PAH, indicating likely semidominant dose-dependent inheritance for this gene.

A single institution anesthetic experience with catheterization of pediatric pulmonary hypertension patients.

Cardiac catheterization remains the gold standard for the diagnosis and management of pediatric pulmonary hypertension (PH). There is lack of consensus regarding optimal anesthetic and airway regimen. This retrospective study describes the anesthetic/airway experience of our single center cohort of pediatric PH patients undergoing catheterization, in which obtaining hemodynamic data during spontaneous breathing is preferential. A total of 448 catheterizations were performed in 232 patients. Of the 379 cases that began with a natural airway, 274 (72%) completed the procedure without an invasive airway, 90 (24%) received a planned invasive airway, and 15 (4%) required an unplanned invasive airway. Median age was 3.4 years (interquartile range [IQR] 0.7-9.7); the majority were either Nice Classification Group 1 (48%) or Group 3 (42%). Vasoactive medications and cardiopulmonary resuscitation were required in 14 (3.7%) and eight (2.1%) cases, respectively; there was one death. Characteristics associated with use of an invasive airway included age <1 year, Group 3, congenital heart disease, trisomy 21, prematurity, bronchopulmonary dysplasia, WHO functional class III/IV, no PH therapy at time of case, preoperative respiratory support, and having had an intervention (p < 0.05). A composite predictor of age <1 year, Group 3, prematurity, and any preoperative respiratory support was significantly associated with unplanned airway escalation (26.7% vs. 6.9%, odds ratio: 4.9, confidence interval: 1.4-17.0). This approach appears safe, with serious adverse event rates similar to previous reports despite the predominant use of natural airways. However, research is needed to further investigate the optimal anesthetic regimen and respiratory support for pediatric PH patients undergoing cardiac catheterization.

Safety and tolerability of continuous inhaled iloprost in critically ill pediatric pulmonary hypertension patients: A retrospective case series.

Inhaled iloprost (iILO) has shown efficacy in treating patients with hypoxic lung disease and pulmonary hypertension, inducing selective pulmonary vasodilation and improvement in oxygenation. However, its short elimination half-life of 20-30 min necessitates frequent intermittent dosing (6-9 times per day). Thus, the administration of iILO via continuous nebulization represents an appealing method of drug delivery in the hospital setting. The objectives are: (1) describe our continuous iILO delivery methodology and safety profile in mechanically ventilated pediatric pulmonary hypertension patients; and (2) characterize the initial response of iILO in these pediatric patients currently receiving iNO. Continuous iILO was delivered and well tolerated (median 6 days; range 1-94) via tracheostomy or endotracheal tube using the Aerogen® mesh nebulizer system coupled with a Medfusion® 400 syringe pump. No adverse events or delivery malfunctions were reported. Initiation of iILO resulted in an increase in oxygen saturation from 81.4 ± 8.6 to 90.8 ± 4.1%, p < 0.05. Interestingly, prior iNO therapy for >1 day resulted in a higher response rate to iILO (as defined as a ≥ 4% increase in saturations) compared to those receiving iNO <1 day (85% vs. 50%, p = 0.06). When the use of iILO is considered, continuous delivery represents a safe, less laborious alternative and concurrent treatment with iNO should not be considered a contraindication. However, given the retrospective design and small sample size, this study does not allow the evaluation of the efficacy of continuous iILO on outcomes beyond the initial response. Thus, a prospective study designed to evaluate the efficacy of continuous iILO is necessary.

Failure to tolerate continuous subcutaneous treprostinil in pediatric pulmonary hypertension patients.

Continuous subcutaneous (SubQ) treprostinil is an effective therapy for pediatric patients diagnosed with pulmonary hypertension (PH). To date, the clinical characteristics and factors associated with failure to tolerate this therapy have not been described. The purpose was to describe patient-reported factors contributing to SubQ treprostinil intolerance in pediatric patients with PH. A retrospective descriptive study was performed at 11 participating sites in the United States and Canada for patients younger than 21 years of age diagnosed with PH who failed treatment to tolerate SubQ treprostinil between January 1, 2009, and December 31, 2019. All data were summarized using descriptive statistics. Forty-one patients met the inclusion criteria. The average age at SQ treprostinil initiation, and length of treatment, was 8.6 years and 22.6 months, respectively. The average maximum dose, concentration, and rate were 95.8 ng/kg/min, 6.06 mg/mL, and 0.040 mL/h, respectively. The reasons for failure to tolerate SubQ treprostinil included intractable site pain (73.2%), frequent site changes (56.1%), severe site reactions (53.7%), infections (26.8%), and noncompliance/depression/anxiety (17.1%). Thirty-nine (95.1%) patients transitioned to a prostacyclin therapy with 23 patients transitioning to intravenous prostacyclin, 5 to inhaled prostacyclin, 5 to oral prostacyclin, and 7 to a prostacyclin receptor agonist. A subset of pediatric PH patients failed to tolerate SubQ treprostinil infusions despite advances in SubQ site maintenance and pain management strategies. Intractable site pain, frequent SubQ site changes, and severe localized skin reactions were the most common reasons for failure.

Caveolin-1 associated with severe (pediatric-onset) presentation of pulmonary arterial hypertension.

There has been a growing interest in the role that genetic factors influence pediatric pulmonary vascular disease. In fact, data suggests that genetic factors contribute to ~42% of pediatric-onset pulmonary hypertension. Although animal and human studies suggest that aberrations in Caveolin1 (CAV1) signaling participate in the development of pulmonary vascular disorders, limited reports of CAV1-associated heritable pulmonary arterial hypertension (HPAH) exist. This is a case report of a 2-year-old female with late recognition of HPAH due to a CAV1 pathogenic variant: c.474del, (p.Leu159Serfs*22)(NM_001753.5). The pedigree demonstrates autosomal dominant transmission with reduced penetrance of PAH, suggestive that additional genetic or environmental factors modify PAH development. Genetic testing and the discovery of rare genetic alterations in PAH during infancy and childhood may aid in identifying disease etiologies, guide therapeutic decisions, and ultimately identify novel therapeutic targets. Moreover, CAV1 genetics implicate variable expressivity and incomplete penetrance for HPAH and underscores the utility of predictive genetic testing for unaffected family members no matter their age.

Hemodynamic assessment of transitioning from parenteral prostacyclin to selexipag in pediatric pulmonary hypertension.

Despite the increase in therapeutic options, parenteral prostacyclins remain the cornerstone in the medical management of pulmonary arterial hypertension (PAH). While the use of parenteral prostacyclins in pediatric patients is well documented, less is known about alternative drug delivery methods such as enteral administration. Given that parenteral routes of prostacyclin administration (IV or SC) are invariably accompanied by complicated logistics and lifestyle compromises, enteral prostacyclin administration represents an attractive treatment option. Selexipag (Uptravi®) was approved for adults PAH in 2015. There is limited data on the hemodynamic efficacy of transitioning from parenteral prostacyclins to selexipag, particularly in the pediatric population. We report 11 pediatric PAH patients who underwent this transition, in which 10 had complete cardiac catheterization data before and following the transition to selexipag. All patients/families reported an improvement in quality of life, and the transitions occurred without adverse effects. However, 3 of the 11 (27%) did not tolerate the transition; two for worsening hemodynamics, and one for acute right ventricular failure in the setting of an intercurrent illness. In addition, the transition to selexipag was associated with a modest increase in pulmonary vascular resistance index (6/10) and decrease in cardiac index (6/10) in some patients. Selexipag use in pediatric PAH represents a significant addition to our therapeutic arsenal, and its use provides a meaningful improvement in quality of life compared with other prostacyclin formulations. However, when goals of care include aggressive disease management, a decision between improved quality of life and possible adverse outcomes must be considered, and its substitution should include cautious, close, long-term follow-up.

Persistence of persistent pulmonary hypertension of the newborn: A case of de novo TBX4 variant.

We present a case of a late preterm infant placed on extracorporeal life support in the first day of life for persistent pulmonary hypertension of the newborn. Developmental arrest, pulmonary vascular hypertensive changes, and pulmonary interstitial glycogenosis were present on lung biopsy at 7 weeks of age. Pulmonary hypertension has persisted through childhood. Genetic testing at 8 years identified a novel mutation in TBX4.

Genetics dictating therapeutic decisions in pediatric pulmonary hypertension? A case report suggesting we are getting closer.

Despite therapeutic advances over the past decades, pulmonary arterial hypertension (PAH) and related pulmonary vascular diseases continue to cause significant morbidity and mortality in neonates, infants, and children. Unfortunately, an adequate understanding of underlying biology is lacking. There has been a growing interest in the role that genetic factors influence pulmonary vascular disease, with the hope that genetic information may aid in identifying disease etiologies, guide therapeutic decisions, and ultimately identify novel therapeutic targets. In fact, current data suggest that genetic factors contribute to ~42% of pediatric-onset PH compared to ~12.5% of adult-onset PAH. We report a case in which the knowledge that biallelic ATP13A3 mutations are associated with malignant progression of PAH in young childhood, led us to alter our traditional treatment plan for a 21-month-old PAH patient. In this case, we elected to perform a historically high-risk Potts shunt before expected rapid deterioration. Short-term follow-up is encouraging, and the patient remains the only known surviving pediatric PAH patient with an associated biallelic ATP13A3 mutation in the literature. We speculate that an increased use of comprehensive genetic testing can aid in identifying the underlying pathobiology and the expected natural history, and guide treatment plans among PAH patients.

Primary pediatric skull tumors.

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.

Safety and Tolerability of a Rapid Transition From Intravenous Treprostinil to Oral Selexipag in Three Adolescent Patients With Pulmonary Arterial Hypertension.

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.

Mortality in infants with bronchopulmonary dysplasia: Data from cardiac catheterization.

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.

Pushing the envelope: a treat and repair strategy for patients with advanced pulmonary hypertension associated with congenital heart disease.

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.