No abstract

Background Pulmonary arterial hypertension (PAH) is a rare disease characterized by pulmonary arteriole remodeling, elevated arterial pressure and resistance, and subsequent heart failure. Compared to adult-onset disease, pediatric-onset PAH is more heterogeneous and often associated with worse prognosis. While BMPR2 mutations underlie ~70% of adult familial PAH (FPAH) cases, the genetic basis of PAH in children is less understood. Methods and Results We performed genetic analysis of 155 pediatric- and 257 adult-onset PAH patients, including both FPAH and sporadic, idiopathic PAH (IPAH). Following screening for two common PAH risk genes, mutation-negative FPAH and all IPAH cases were evaluated by exome sequencing. We observed similar frequencies of rare, deleterious BMPR2 mutations in pediatric- and adult-onset patients: ~55% in FPAH and 10% in IPAH patients in both age groups. However, there was significant enrichment of TBX4 mutations in pediatric-compared to adult-onset patients (IPAH: 10/130 pediatric- vs 0/178 adult-onset), and TBX4 carriers had younger mean age-of-onset compared to BMPR2 carriers. Mutations in other known PAH risk genes were infrequent in both age groups. Notably, among pediatric IPAH patients without mutations in known risk genes, exome sequencing revealed a 2-fold enrichment of de novo likely gene damaging (LGD) and predicted deleterious missense variants. Conclusions Mutations in known PAH risk genes accounted for ~70–80% of FPAH in both age groups, 21% of pediatric-onset IPAH, and 11% of adult-onset IPAH. Rare, predicted deleterious variants in TBX4 are enriched in pediatric patients and de novo variants in novel genes may explain ~19% of pediatric-onset IPAH cases.

Objective To identify clinical factors associated with pulmonary hypertension and mortality in patients with congenital diaphragmatic hernia (CDH). Study design A prospective cohort of neonates with a diaphragm defect identified at one of seven collaborating medical centers was studied. Echocardiograms were performed at one month and three months of age and analyzed at a central core by two cardiologists independently. Degree of pulmonary hypertension and survival were tested for association with clinical variables using Fischers exact test, chi-square and regression analysis. Results 220 patients met inclusion criteria. Worse pulmonary hypertension measured at one month of life was associated with higher mortality. Other factors associated with mortality were need for extracorporeal membrane oxygenation (ECMO), patients inborn at the treating center and patients with a prenatal diagnosis of CDH. Interestingly, patients with right sided CDH did not have worse outcomes. Conclusions Severity of pulmonary hypertension is associated with mortality in CDH. Other factors associated with mortality were birth weight, gestational age at birth, inborn status and need for ECMO.

BackgroundPulmonary arterial hypertension (PAH) is a rare disease characterized by distinctive changes in pulmonary arterioles that lead to progressive pulmonary arterial pressures, right-sided heart failure, and a high mortality rate. Up to 30% of adult and 75% of pediatric PAH cases are associated with congenital heart disease (PAH-CHD), and the underlying etiology is largely unknown. There are no known major risk genes for PAH-CHD.MethodsTo identify novel genetic causes of PAH-CHD, we performed whole exome sequencing in 256 PAH-CHD patients. We performed a case-control gene-based association test of rare deleterious variants using 7509 gnomAD whole genome sequencing population controls. We then screened a separate cohort of 413 idiopathic and familial PAH patients without CHD for rare deleterious variants in the top association gene.ResultsWe identified SOX17 as a novel candidate risk gene (p = 5.5e−7). SOX17 is highly constrained and encodes a transcription factor involved in Wnt/β-catenin and Notch signaling during development. We estimate that rare deleterious variants contribute to approximately 3.2% of PAH-CHD cases. The coding variants identified include likely gene-disrupting (LGD) and deleterious missense, with most of the missense variants occurring in a highly conserved HMG-box protein domain. We further observed an enrichment of rare deleterious variants in putative targets of SOX17, many of which are highly expressed in developing heart and pulmonary vasculature. In the cohort of PAH without CHD, rare deleterious variants of SOX17 were observed in 0.7% of cases.ConclusionsThese data strongly implicate SOX17 as a new risk gene contributing to PAH-CHD as well as idiopathic/familial PAH. Replication in other PAH cohorts and further characterization of the clinical phenotype will be important to confirm the precise role of SOX17 and better estimate the contribution of genes regulated by SOX17.Electronic supplementary materialThe online version of this article (10.1186/s13073-018-0566-x) contains supplementary material, which is available to authorized users.

Background: In pulmonary arterial hypertension (PAH), pathological changes in pulmonary arterioles progressively raise pulmonary artery pressure and increase pulmonary vascular resistance, leading to right heart failure and high mortality rates. Recently, the first potassium channelopathy in PAH, due to mutations in KCNK3, was identified as a genetic cause and pharmacological target. Methods: Exome sequencing was performed to identify novel genes in a cohort of 99 pediatric and 134 adult onset group I pulmonary arterial hypertension patients. Novel rare variants in the gene identified were independently identified in a cohort of 680 adult onset patients. Variants were expressed in COS cells and function assessed by patch-clamp and rubidium flux analysis. Results: We identified a de novo novel heterozygous predicted deleterious missense variant c.G2873A (p.R958H) in ABCC8 (ATP-binding cassette, subfamily C, member 8) in a child with idiopathic PAH. We then evaluated all individuals in the original and a second cohort for rare or novel variants in ABCC8 and identified 11 additional heterozygous predicted damaging ABCC8 variants. ABCC8 encodes sulfonylurea receptor 1 (SUR1), a regulatory subunit of the ATP-sensitive potassium channel (KATP). We observed loss of KATP function for all ABCC8 variants evaluated, and pharmacological rescue of all channel currents in vitro by the SUR1 activator, diazoxide. Conclusions: Novel and rare missense variants in ABCC8 are associated with pulmonary arterial hypertension. Identified ABCC8 mutations decreased KATP channel function, which was pharmacologically recovered.

BACKGROUND In spring 2020, a novel hyperinflammatory process associated with severe acute respiratory syndrome coronavirus 2 multisystem inflammatory syndrome in children (MIS-C) was described. The long-term impact remains unknown. We report longitudinal outcomes from a New York interdisciplinary follow-up program. METHODS All children <21 years of age, admitted to NewYork-Presbyterian with MIS-C in 2020, were included. Children were followed at 1 to 4 weeks, 1 to 4 months, and 4 to 9 months postdischarge. RESULTS In total, 45 children were admitted with MIS-C. The median time to last follow-up was 5.8 months (interquartile range 1.3–6.7). Of those admitted, 76% required intensive care and 64% required vasopressors and/or inotropes. On admission, patients exhibited significant nonspecific inflammation, generalized lymphopenia, and thrombocytopenia. Soluble interleukin (IL) IL-2R, IL-6, IL-10, IL-17, IL-18, and C-X-C Motif Chemokine Ligand 9 were elevated. A total of 80% (n = 36) had at least mild and 44% (n = 20) had moderate-severe echocardiographic abnormalities including coronary abnormalities (9% had a z score of 2–2.5; 7% had a z score > 2.5). Whereas most inflammatory markers normalized by 1 to 4 weeks, 32% (n = 11 of 34) exhibited persistent lymphocytosis, with increased double-negative T cells in 96% of assessed patients (n = 23 of 24). By 1 to 4 weeks, only 18% (n = 7 of 39) had mild echocardiographic findings; all had normal coronaries. At 1 to 4 months, the proportion of double-negative T cells remained elevated in 92% (median 9%). At 4 to 9 months, only 1 child had persistent mild dysfunction. One had mild mitral and/or tricuspid regurgitation. CONCLUSIONS Although the majority of children with MIS-C present critically ill, most inflammatory and cardiac manifestations in our cohort resolved rapidly.

Background We sought to assess the impact and predictors of Coronavirus Disease 2019 (COVID‐19) infection and severity in a cohort of congenital heart disease (CHD) patients at a large CHD center in New York City. Methods and Results We performed a retrospective review of all individuals with CHD followed at Columbia University Irving Medical Center who were diagnosed with COVID‐19 between 3/1/2020 and 7/1/2020. The primary endpoint was moderate/severe response to COVID‐19 infection defined as a) death during COVID‐19 infection; or 2) need for hospitalization and/or respiratory support secondary to COVID‐19 infection. Among 53 COVID‐19 positive patients with CHD, 10 (19%) were <18 years old (median age 34 years). 31 (58%) had complex congenital anatomy including 10 (19%) with a Fontan repair. Eight (15%) had a genetic syndrome, six (11%) had pulmonary hypertension (PH), and nine (17%) were obese. Among adults, 18 (41%) were physiologic class C or D. For the entire cohort, nine (17%) had a moderate/severe infection, including three deaths (6%). After correcting for multiple comparisons, the presence of a genetic syndrome (OR=35.82: p=0.0002), and in adults, physiological Stage C or D (OR=19.38: p=0.002) were significantly associated with moderate/severe infection. Conclusions At our CHD center, the number of symptomatic COVID‐19 patients was relatively low. CHD patients with a genetic syndrome and adults at advanced physiological stage were at highest risk for moderate/severe infection.

Pulmonary arterial hypertension (PAH) contributes to disability and death in children with diverse cardiac, pulmonary, or systemic diseases, and therapeutic options are currently limited. Data from adult studies provide the basis for most PAH-specific therapies; however, many of these medications are commonly used in children on an off-label basis due to the life-threatening nature of PAH. Although currently approved for use in adult PAH, sildenafil is used extensively off-label for the treatment of neonates, infants, and children with PAH. Past studies have generally suggested favorable effects and outcomes in infants and young children with PAH, but these reports are generally uncontrolled observations, except for one single-center trial for persistent pulmonary hypertension of the newborn. Despite extensive clinical experience with sildenafil therapy in children and approval by the European Medicines Agency for its pediatric use in Europe, the U.S. Food and Drug Administration recently issued a warning against the use of sildenafil for pediatric PAH between 1 and 17 years of age due to an apparent increase in mortality during long-term therapy. Although these data are extremely limited, this U.S. Food and Drug Administration review challenges the pediatric PAH community to further assess the efficacy and safety of sildenafil, especially with chronic treatment. Although low doses of sildenafil are likely safe in pediatric PAH, further studies should carefully examine its role in the long-term therapy of children, especially with diverse causes of PAH. Pediatric patients with PAH require close surveillance and frequent monitoring, and persistent sildenafil monotherapy is likely insufficient with disease progression.