• Germline gain-of-function mutations in STAT3 lead to lymphoproliferation and autoimmunity with prominent cytopenias.• Mutations in STAT3 cause altered regulatory T cells and cytokine signaling.Germline loss-of-function mutations in the transcription factor signal transducer and activator of transcription 3 (STAT3) cause immunodeficiency, whereas somatic gain-offunction mutations in STAT3 are associated with large granular lymphocytic leukemic, myelodysplastic syndrome, and aplastic anemia. Recently, germline mutations in STAT3 have also been associated with autoimmune disease. Here, we report on 13 individuals from 10 families with lymphoproliferation and early-onset solid-organ autoimmunity associated with 9 different germline heterozygous mutations in STAT3. Patients exhibited a variety of clinical features, with most having lymphadenopathy, autoimmune cytopenias, multiorgan autoimmunity (lung, gastrointestinal, hepatic, and/or endocrine dysfunction), infections, and short stature. Functional analyses demonstrate that these mutations confer a gain-of-function in STAT3 leading to secondary defects in STAT5 and STAT1 phosphorylation and the regulatory T-cell compartment. Treatment targeting a cytokine pathway that signals through STAT3 led to clinical improvement in 1 patient, suggesting a potential therapeutic option for such patients. These results suggest that there is a broad range of autoimmunity caused by germline STAT3 gain-of-function mutations, and that hematologic autoimmunity is a major component of this newly described disorder. Some patients for this study were enrolled in a trial registered at www.clinicaltrials.gov as #NCT00001350. (Blood. 2015;125(4):591-599)

BackgroundPulmonary arterial hypertension (PAH) is a rare, progressive, fatal vascular disorder. Genetic predisposition plays vital roles in the development of PAH, with most mutations being identified in genes involved in the transforming growth factor beta (TGF-β) signaling pathways. Defects in the BMP9 gene have been documented in hereditary hemorrhagic telangiectasia (HHT), the most common inherited vascular disorder, which is occasionally associated with PAH. Selective enhancement of endothelial BMPR2 with BMP9 reverses pulmonary arterial hypertension.Case presentationWe report the case of a 5-year-old Hispanic boy who was diagnosed with severe PAH and right heart failure at 3 years of age. During his stay in the pediatric intensive care unit, treatment was initiated with inhaled nitric oxide and intravenous epoprostenol; he subsequently was transitioned to treprostinil, sildenafil, and prophylactic enoxaparin. Now, two years later, the child is asymptomatic on sildenafil, bosentan, subcutaneous treprostinil, and warfarin. Genetic screening revealed a novel homozygous nonsense mutation in the BMP9 gene (c.76C > T; p.Gln26Ter). The child had no telangiectasias or arteriovenous malformations; family history also was negative. Subsequent parental testing showed both parents were heterozygous for the same mutation, indicating that the child inherited the BMP9 mutant allele from each parent.ConclusionTo our knowledge, this is the first report of a BMP9 mutation in a patient with PAH. The homozygous nonsense mutation may account for the early onset and severity of PAH in this patient and also fit the ‘two-hit’ model we proposed previously. The absence of clinical symptoms for PAH in the parents may be due to incomplete penetrance or various expressivities of the BMP9 mutations. Our study expands the spectrum of phenotypes related to BMP9 mutations.Electronic supplementary materialThe online version of this article (doi:10.1186/s12890-016-0183-7) contains supplementary material, which is available to authorized users.

Early pulmonary vascular disease (PVD) and established pulmonary hypertension (PH) are common associations of bronchopulmonary dysplasia (BPD). Diagnosis of PH is often made by echocardiography because of technical and logistic difficulties with the neonatal population. Optimization of respiratory support is the focus of treatment, however, medical therapies are being used with increased frequency. The prognosis for PH associated with BPD (PH-BPD) is tied to the child's respiratory status. PH is associated with increased risk of death in this population, so active screening and treatment is recommended to minimize morbidity and mortality. In this review, we discuss the pathophysiology of PH in infants with BPD, evaluate the current understanding of screening, diagnosis, and follow-up evaluation; describe comorbid conditions; and provide a framework for targeted physiology-based management strategies.

Bronchopulmonary dysplasia (BPD) following preterm birth and congenital diaphragmatic hernia (CDH) are both forms of developmental lung disease that may result in persistent pulmonary and pulmonary vascular morbidity in childhood. The pulmonary vascular disease (PVD) which accompanies BPD and CDH is due to developmental abnormalities and ongoing perinatal insults. This may be accompanied by evidence of elevated right heart pressures and pulmonary vascular resistance, leading to diagnosis of pulmonary hypertension (PH). The development of PH in these conditions is associated with increased morbidity and mortality in the vulnerable BPD and CDH populations. We present a review of PVD pathogenesis and evaluation in BPD and CDH and discuss management of related sequelae of PH co‐morbidity for affected infants.