Search

Over the past decade recognition of the profound impact of the T-box 4 (TBX4) gene, which encodes a member of the evolutionarily conserved family of T-box-containing transcription factors, upon respiratory diseases has emerged. The developmental importance of TBX4 is emphasized by the association of TBX4 variants with congenital disorders involving respiratory and skeletal structures; however, the exact role of TBX4 in human development remains incompletely understood. Here, we discuss the developmental, tissue-specific, and pathological TBX4 functions identified through human and animal studies and review the published TBX4 variants resulting in variable disease phenotypes. We also outline future research directions to fill the gaps in our understanding of TBX4 function and of how TBX4 disruption impacts development.

Alveolar capillary dysplasia with misalignment of pulmonary veins (ACDMPV) results from haploinsufficiency of the mesenchymal transcription factor FOXF1 gene. To date, only one case of an ACDMPV-causative CNV deletion inherited from a very-low level somatic mosaic mother has been reported.Clinical, histopathological, and molecular studies, including whole genome sequencing, chromosomal microarray analysis, qPCR, and Sanger sequencing, followed by in vitro fertilization (IVF) with preimplantation genetic testing (PGT) were used to study a family with a deceased neonate with ACDMPV.A pathogenic CNV deletion of the lung-specific FOXF1 enhancer in the proband was found to be inherited from an unaffected mother, 36% mosaic for this deletion in her peripheral blood cells. The qPCR analyses of saliva, buccal cells, urine, nail, and hair samples revealed 19%, 18%, 15%, 19%, and 27% variant allele fraction, respectively, indicating a high recurrence risk. Grandparental studies revealed that the deletion arose on the mother's paternal chromosome 16. PGT studies revealed 44% embryos with the deletion, reflecting high-level germline mosaicism.Our data further demonstrate the importance of parental testing in ACDMPV families and reproductive usefulness of IVF with PGT in families with high-level parental gonosomal mosaicism.

Cardiac tumors remain rare in children with benign pathologies predominating. Indications for surgical management often result from compromised ventricular chamber size, biventricular outflow tract obstruction, impaired ventricular function, or the presence of medically refractory dysrhythmias. We present a case of a six-month-old infant with two intracardiac fibromas originating in the interventricular septum. The fibromas were causing significant biventricular outflow obstruction. The patient successfully underwent tumor resection on cardiopulmonary bypass The literature on pediatric cardiac tumors is reviewed. Multi-disciplinary medical planning is necessary for successful anesthetic and surgical treatment of this high-risk patient population.

INTRODUCTION Therapeutics exist to treat fibrotic lung disease in adults, but these have not been investigated in children. Defining biomarkers for pediatric fibrotic lung disease in children is crucial for clinical trials. Children with surfactant protein C (SFTPC) dysfunction mutations develop fibrotic lung disease over time. We evaluated chest computed tomography (CT) changes over time in children with SFTPC dysfunction mutations. METHODS We performed an institutional review board-approved retrospective review of children with SFTPC dysfunction mutations. We collected demographic and clinical information. Chest CT scans were evaluated using visual and computerized scores. Chest CT scores and pulmonary function tests were reviewed. RESULTS Eleven children were included. All children presented in infancy and four children suffered from respiratory failure requiring mechanical ventilation. Those who performed pulmonary function tests had stable forced vital capacities over time by percent predicted, but increased forced vital capacity in liters. CT findings evolved over time in most patients with earlier CT scans demonstrating ground glass opacities and later CT scans with more fibrotic features. In a pilot analysis, data-driven textural analysis software identified fibrotic features in children with SFTPC dysfunction that increased over time and correlated with visual CT scores. DISCUSSION We describe 11 children with SFTPC dysfunction mutations. Increases in forced vital capacity over time suggest that these children experience lung growth and that therapeutic intervention may maximize lung growth. Ground glass opacities are the primary early imaging findings while fibrotic features dominate later. CT findings suggest the development of and increases in fibrotic features that may serve as potential biomarkers for antifibrotic therapeutic trials.

Cardiac angiosarcoma (AS) is an extremely rare, malignant vascular tumor with

Minimally invasive core needle biopsies for medical diagnoses have become increasingly common for many diseases. Although tissue cores can yield more diagnostic information than fine needle biopsies and cytologic evaluations, there is no rapid assessment at the point-of-care for intact tissue cores that is low-cost and non-destructive to the biopsy. We have developed a proof-of-concept 3D printed millifluidic histopathology lab-on-a-chip device to automatically handle, process, and image fresh core needle biopsies. This device, named CoreView, includes modules for biopsy removal from the acquisition tool, transport, staining and rinsing, imaging, segmentation, and multiplexed storage. Reliable removal from side-cutting needles and bidirectional fluid transport of core needle biopsies of five tissue types has been demonstrated with 0.5 mm positioning accuracy. Automation is aided by a MATLAB-based biopsy tracking algorithm that can detect the location of tissue and air bubbles in the channels of the millifluidic chip. With current and emerging optical imaging technologies, CoreView can be used for a rapid adequacy test at the point-of-care for tissue identification as well as glomeruli counting in renal core needle biopsies.

A newborn infant patient presented with persistent pulmonary hypertension. For right ventricular decompression, the ductus arteriosus was kept open by prostaglandin E1 infusion and was stented at the age of 4 weeks during heart catheterization. The child was weaned from mechanical ventilation, since pulmonary functions were adequate. A small atrial septal defect was identified and closed in cardiac catheterization laboratory to decrease preductal hypoxemia. Diagnostic workup led to the diagnosis of alveolar capillary dysplasia with misalignment of the pulmonary veins. Suprasystemic pulmonary arterial hypertension with persisting nitric oxide dependency remained the leading symptoms. The child underwent bilateral lung transplantation at the age of 28 months. He is well at the age of 44 months.

Individuals with Down syndrome (DS) have an increased risk of developing pulmonary hypertension (PH). In this review, we explore the epidemiology and clinical characteristics of PH in the population with DS and examine genetic, molecular and clinical contributions to the condition. The presence of an additional copy of chromosome 21 (trisomy 21) increases the risk of developing PH in children with DS through many mechanisms, including increased hemodynamic stress in those with congenital heart disease, hypoxemia through impaired ventilation to perfusion matching secondary to developmental lung abnormalities, pulmonary hypoplasia from pulmonary vascular endothelial dysfunction, and an increase in pulmonary vascular resistance often related to pulmonary comorbidities. We review recent studies looking at novel biomarkers that may help diagnose, predict or monitor PH in the population with DS and examine current cardiopulmonary guidelines for monitoring children with DS. Finally, we review therapeutic interventions specific to PH in individuals with DS. Contemporary work has identified exciting mechanistic pathways including the upregulation of antiangiogenic factors and interferon activity, which may lead to additional biomarkers or therapeutic opportunities. Throughout the manuscript, we identify gaps in our knowledge of the condition as it relates to the population with DS and offer suggestions for future clinical, translational, and basic science research.

This study aimed to explore the value of synchrotron-based phase-contrast microcomputed tomography (micro-CT) in pulmonary vascular pathobiology. The microanatomy of the lung is complex with intricate branching patterns. Tissue sections are therefore difficult to interpret. Recruited intrapulmonary bronchopulmonary anastomoses (IBAs) have been described in several forms of pulmonary hypertension, including alveolar capillary dysplasia with misaligned pulmonary veins (ACD/MPV). Here, we examine paraffin-embedded tissue using this nondestructive method for high-resolution three-dimensional imaging. Blocks of healthy and ACD/MPV lung tissue were used. Pulmonary and bronchial arteries in the ACD/MPV block had been preinjected with dye. One section per block was stained, and areas of interest were marked to allow precise beam-alignment during image acquisition at the X02DA TOMCAT beamline (Swiss Light Source). A ×4 magnifying objective coupled to a 20-µm thick scintillating material and a sCMOS detector yielded the best trade-off between spatial resolution and field-of-view. A phase retrieval algorithm was applied and virtual tomographic slices and video clips of the imaged volumes were produced. Dye injections generated a distinct attenuation difference between vessels and surrounding tissue, facilitating segmentation and three-dimensional rendering. Histology and immunohistochemistry post-imaging offered complementary information. IBAs were confirmed in ACD/MPV, and the MPVs were positioned like bronchial veins/venules. We demonstrate the advantages of using synchrotron-based phase-contrast micro-CT for three-dimensional characterization of pulmonary microvascular anatomy in paraffin-embedded tissue. Vascular dye injections add additional value. We confirm intrapulmonary shunting in ACD/MPV and provide support for the hypothesis that MPVs are dilated bronchial veins/venules.

Germline mutation in bone morphogenetic protein type II (BMPR2) is the most common cause of idiopathic/heritable pulmonary hypertension in pediatric patients. Despite the discovery of this gene there are no known descriptions of the CT or CT angiography findings in these children.To correlate the clinical presentation, pathology and chest CT findings in pediatric patients with pulmonary hypertension caused by mutations in the BMPR2 gene.We performed a search to identify pediatric patients with a BMPR2 mutation and CT or CT angiography with the clinical history of pulmonary hypertension. Three pediatric radiologists reviewed the children's CT imaging findings and ranked the dominant findings in order of prevalence via consensus.We identified three children with pulmonary hypertension and confirmed germline BMPR2 mutations, two of whom had undergone lung biopsy. We then correlated the imaging findings with histopathology and clinical course.All of our patients with BMPR2 mutations demonstrated a distinct CT pattern of ground-glass nodules with a prominent central enhancing vessel/nodule. These findings correlated well with the pathological findings of plexogenic arteriopathy.

Background Respiratory conditions are the leading cause of hospitalization and death in children with Trisomy 21 (T21). Diffuse alveolar hemorrhage (DAH) occurs at higher frequency in children with T21; yet, it is not widely studied nor is there a standardized approach to diagnosis or management. The objective of this study was to identify children with T21 and DAH in order to understand contributing factors and identify opportunities to improve outcomes. We identified 5 children with T21 at a single institution with histology-proven DAH over 10 years and discuss their presentation, evaluation, management, and outcomes. We also reviewed the cases in the literature. Case presentation Patient 1 died at age seven due to secondary hemophagocytic lymphohistiocytosis. DAH was seen on autopsy. Patient 2 was a three-year-old with systemic-onset juvenile idiopathic arthritis diagnosed with DAH after presenting for hypoxia. Patient 3 was diagnosed with DAH at age nine after presenting with recurrent suspected pneumonia and aspiration. Patient 4 was diagnosed with DAH at age eight after presenting with pallor and fatigue. She had additional ICU admissions for DAH with infections. Patient 5 developed hemoptysis at age three and had recurrent DAH for 10 years. Four patients responded positively to immune-modulation such as intravenous immunoglobulin, glucocorticoids, and rituximab. Of the 19 patients identified in the literature, only one was from the United States. The majority had anemia, respiratory distress, autoantibodies, and recurrences. Very few patients had hemoptysis. Idiopathic pulmonary hemosiderosis was the most common diagnosis. Almost all received glucocorticoids with or without additional immunosuppression. The majority of our patients and those in the literature had positive auto-antibodies such as anti-neutrophil cytoplasmic antibodies and anti-nuclear antigen antibodies. Diagnostic clues included respiratory distress, hypoxia, anemia, recurrent pneumonia, and/or ground glass opacities on imaging. We identified four contributors to DAH: structural lung abnormalities, pulmonary arterial hypertension, infection/aspiration, and autoimmune disease/immune dysregulation. Conclusion These cases demonstrate the need for an increased index of suspicion for DAH in children with T21, particularly given the low frequency of hemoptysis at presentation, enrich the understanding of risk factors, and highlight the favorable response to immunosuppressive therapies in this vulnerable population.

Minimally invasive core needle biopsies for medical diagnoses have become increasingly common for many diseases. Although tissue cores can yield more diagnostic information than fine needle biopsies and cytologic evaluation, there is no rapid evaluation at the point-of-care for intact tissue cores that is low-cost and non-destructive to the biopsy. We have developed a proof-of-concept 3D printed millifluidic histopathology lab-on-a-chip device to automatically handle, process, and image fresh core needle biopsies. This device, named CoreView, includes modules for biopsy removal from the acquisition tool, transport, staining and rinsing, imaging, segmentation, and multiplexed storage. Reliable removal from side-cutting needles and bidirectional fluid transport of core needle biopsies from five tissue types has been demonstrated with 0.5-mm positioning accuracy. Automation is aided by a MATLAB-based biopsy tracking algorithm that can detect the location of tissue and air bubbles in the channels of the millifluidic chip. With current and emerging optical imaging technologies, CoreView can be used for a rapid adequacy test at the point-of-care for tissue identification and glomeruli counting from renal core needle biopsies, and has the potential to be used for breast cancer diagnosis, phenotyping, and mapping of enriched tumorous regions for downstream analyses in global health applications.

A foregut duplication cyst occurring together with both a congenital cystic pulmonary airway malformation and extralobar pulmonary sequestration is an unusual combination. Prenatal ultrasound, MRI, and postnatal CT are helpful for operative planning. Surgical resection is the definitive management for all three anomalies.

Past studies have shown that lung angiogenic signaling may be abnormal in children with Down syndrome, but whether differences in circulating angiogenic proteins can identify pulmonary hypertension in children with Down syndrome is unknown. A prospective study of 78 children from birth to 21 years of age was conducted to evaluate clinical data, echocardiograms, and cardiac catheterizations. Four patient populations were enrolled, including children with Down syndrome who have pulmonary hypertension (Down syndrome + pulmonary hypertension, n = 12); control children without Down syndrome who have pulmonary hypertension (C + pulmonary hypertension, n = 15); children with Down syndrome without a known diagnosis of pulmonary hypertension (Down syndrome − pulmonary hypertension, n = 26); and children without Down syndrome or a known diagnosis of pulmonary hypertension (C − pulmonary hypertension, n = 25). Blood samples were collected at enrollment and concentrations for 11 proteins were evaluated. A classification tree was created to identify angiogenic peptide signals that may be associated with pulmonary hypertension in children with Down syndrome compared with controls. Findings identified elevated endostatin levels (>4.98 log10 pg/ml) were associated with Down syndrome. Platelet-derived growth factor AA levels (>2.51 log10 pg/ml) were higher in non-Down syndrome patients with pulmonary hypertension (C + pulmonary hypertension), whereas lower angiogenin (3.59 log10 pg/ml) distinguished pulmonary hypertension in those with Down syndrome from the other groups. This study suggests that children with Down syndrome have high endostatin levels, but low levels of angiogenin levels in children with Down syndrome more often identified pulmonary hypertension than Down syndrome subjects without pulmonary hypertension or non-Down syndrome children. We speculate that these changes in circulating peptides support the concept of dysregulated angiogenesis in children with Down syndrome and pulmonary hypertension, which may further support potential utility as biomarkers for identifying subjects with Down syndrome at risk for pulmonary hypertension in this population.

The pleiotropic actions of interleukin-2 (IL-2) are essential for regulation of immune responses and maintenance of immune tolerance. The IL-2 receptor (IL-2R) is composed of IL-2Rα, IL-2Rβ, and IL-2Rγ subunits, with defects in IL-2Rα and IL-2Rγ and their downstream signaling effectors resulting in known primary immunodeficiency disorders. Here, we report the first human defect in IL-2Rβ, occurring in two infant siblings with a homozygous IL2RB mutation in the WSXWS motif, manifesting as multisystem autoimmunity and susceptibility to CMV infection. The hypomorphic mutation results in diminished IL-2Rβ surface expression and dysregulated IL-2/15 signaling, with an anticipated reduction in regulatory T cells. However, in contrast to the IL-2Rβ−/− animal model, which lacks NK cells, these siblings demonstrate an expansion of NK cells, particularly the CD56bright subset, and a lack of terminally differentiated NK cells. Thus, the early-onset autoimmunity and immunodeficiency are linked to functional deficits arising from altered IL-2Rβ expression and signaling in T and NK cells.

The expression of the NKX2–1 gene and its encoded protein, thyroid transcription factor 1 (TTF-1), plays a role in pulmonary surfactant homeostasis and lung development. NKX2–1 mutations have been associated with neonatal respiratory distress, hypotonia, choreoathetosis and congenital hypothyroidism. These clinical findings have been coined brain–lung–thyroid syndrome, although not all three organs are always involved. While many of these children develop interstitial lung disease, no systematic review of chest high-resolution CT (HRCT) findings has been reported. To summarize the clinical presentations, pathology and HRCT imaging findings of children with NKX2–1 mutations. We identified six children with NKX2–1 mutations, deletions or duplications confirmed via genetic testing at our institution. Three pediatric radiologists reviewed the children’s HRCT imaging findings and ranked the dominant findings in order of prevalence via consensus. We then correlated the imaging findings with histopathology and clinical course. All children in the study were heterozygous for NKX2–1 mutations, deletions or duplications. Ground-glass opacities were the most common imaging feature, present in all but one child. Consolidation was also a prevalent finding in 4/6 of the children. Architectural distortion was less common. HRCT findings of TTF-1 deficiency are heterogeneous and evolve over time. There is significant overlap between the HRCT findings of TTF-1 deficiency, other surfactant dysfunction mutations, and pulmonary interstitial glycogenosis. TTF-1 deficiency should be considered in term infants presenting with interstitial lung disease, especially if hypotonia or hypothyroidism is present.

Primary Sjögren syndrome is an autoimmune disease characterized by inflammation of the salivary and lacrimal exocrine glands but can also present with systemic extraglandular manifestations, including pulmonary disease. Commonly described pulmonary manifestations of Sjögren syndrome include airway disease, interstitial lung disease, pulmonary arterial hypertension, and lymphoproliferative disorders. However, diffuse alveolar hemorrhage as a sequela of Sjögren syndrome has rarely been described in the adult literature and has never been described in a child. Here we report the case of an 11-year-old girl who presented with diffuse alveolar hemorrhage and was diagnosed with childhood-onset Sjögren syndrome who otherwise lacked typical clinical features, such as sicca symptoms, at the time of presentation. She was successfully treated with corticosteroids and rituximab, with sustained pulmonary remission 1 year post diagnosis. Our case highlights the heterogenous presentation of Sjögren syndrome in the pediatric population and the need for increased awareness among pediatric providers to recognize potential systemic manifestations of this disease to avoid delayed diagnosis.

In pulmonary arterial hypertension, plexiform lesions are associated with severe arterial obstruction and right ventricular failure. Exploring their structure and position is crucial for understanding the interplay between hemodynamics and vascular remodeling. The aim of this research was to use synchrotron-based phase-contrast micro-CT to study the three-dimensional structure of plexiform lesions. Archived paraffin-embedded tissue samples from 14 patients with pulmonary arterial hypertension (13 idiopathic, 1 with known BMPR2-mutation) were imaged. Clinical data showed high-median PVR (12.5 WU) and mPAP (68 mmHg). Vascular lesions with more than 1 lumen were defined as plexiform. Prior radiopaque dye injection in some samples facilitated 3-D rendering. Four distinct types of plexiform lesions were identified: 1) localized within or derived from monopodial branches (supernumerary arteries), often with a connection to the vasa vasorum; 2) localized between pulmonary arteries and larger airways as a tortuous transformation of intrapulmonary bronchopulmonary anastomoses; 3) as spherical structures at unexpected abrupt ends of distal pulmonary arteries; and 4) as occluded pulmonary arteries with recanalization. By appearance and localization, types 1–2 potentially relieve pressure via the bronchial circulation, as pulmonary arteries in these patients were almost invariably occluded distally. In addition, types 1–3 were often surrounded by dilated thin-walled vessels, often connected to pulmonary veins, peribronchial vessels, or the vasa vasorum. Collaterals, bypassing completely occluded pulmonary arteries, were also observed to originate within plexiform lesions. In conclusion, synchrotron-based imaging revealed significant plexiform lesion heterogeneity, resulting in a novel classification. The four types likely have different effects on hemodynamics and disease progression.

The spread of severe acute respiratory syndrome caused by coronavirus 2 (SARS-CoV-2) has led to a devastating and world-wide pandemic disease known as the coronavirus disease (COVID-19). COVID-19 causes acute hypoxic respiratory failure (COVID-ARF), a major cause of mortality and morbidity, with an incompletely understood pathophysiologic mechanism. Gattinoni and colleagues noted that patients with COVID-ARF patients have lung disease that is often characterised by a remarkable dissociation between relatively well-preserved lung mechanics, including lung compliance, and severe hypoxemia [1]. The authors would like to acknowledge support from Fumiko Dekio, MD, and Rachel Brody, MD, PhD, from the Department of Pathology at the Icahn School of Medicine at Mount Sinai.

OBJECTIVE To determine the consequences of an early catheter-based intervention on pulmonary artery (PA) growth and right ventricular (RV) myocardial function in an animal model of branch PA stenosis. BACKGROUND Acute results and safety profiles of deliberate stent fracture within the pulmonary vasculature have been demonstrated. The long-term impact of early stent intervention and deliberate stent fracture on PA growth and myocardial function is not understood. METHODS Implantation of small diameter stents was performed in a pig model of left PA stenosis at 6 weeks (10 kg) followed by dilations at 10 (35 kg) and 18 weeks (65 kg) with intent to fracture and implant large diameter stents. Hemodynamics, RV contractility, and 2D/3D angiography were performed with each intervention. The heart and pulmonary vasculature were histologically assessed. RESULTS Stent fracture occurred in 9/12 and implantation of large diameter stents was successful in 10/12 animals with no PA aneurysms or dissections. The final stented PA segment and distal left PA branch origins equaled the corresponding PA diameters of sham controls. Growth of left PA immediately beyond the stent was limited and there was diffuse fibro-intimal proliferation within the distal left and right PA. RV contractility was diminished in the intervention group and the response to dobutamine occurred uniquely via increases in heart rate. CONCLUSIONS Early stent intervention in this surgically created PA stenosis model was associated with improved growth of the distal PA vasculature but additional investigation of PA vessel physiology and impact on the developing heart are needed.

Background Although fibrosis seems to be prognostic for adverse outcomes in adults with idiopathic dilated cardiomyopathy (IDC), little is known about the prevalence and development of fibrosis in pediatric IDC hearts. We hypothesized that there is less activation of fibrosis at a molecular level in pediatric IDC hearts than in failing adult hearts. Methods and Results Pediatric hearts were analyzed histologically to determine the prevalence of fibrosis. Left ventricular tissue from adult and pediatric IDC hearts and adult and pediatric nonfailing (NF) hearts were subjected to quantitative reverse-transcription polymerase chain reaction to study the expression of important mRNAs that affect fibrosis. We found age-specific differences between IDC and NF hearts in the regulation of noncoding galectin-3, Corin, matrix metalloproteinase (MMP) 2, MMP-9, tissue inhibitor of metalloproteinase (TIMP) 2, and TIMP-3. We also found markers that were similarly altered in both adult and pediatric IDC hearts (interleukin-1 receptor–like 1 receptor, TIMP-1, and TIMP-4). Finally, microRNAs 29a–c were significantly decreased in the pediatric IDC patients. Conclusions Pediatric IDC patients demonstrate age-specific differences in the molecular pathways implicated in fibrosis in the adult heart. At the ultrastructural level the unique gene expression pattern appears to limit fibrosis in the failing pediatric heart.

Introduction.Failure of the vascular pulmonary remodeling at birth often manifests as pulmonary hypertension (PHT) and is associated with a variety of neonatal lung disorders including a uniformly fatal developmental disorder known as alveolar capillary dysplasia with misalignment of pulmonary veins (ACD/MPV). Serum serotonin regulation has been linked to pulmonary vascular function and disease, and serotonin transporter (SERT) is thought to be one of the key regulators in these processes. We sought to find evidence of a role that SERT plays in the neonatal respiratory adaptation process and in the pathomechanism of ACD/MPV.Methods.We used histology and immunohistochemistry to determine the timetable of SERT protein expression in normal human fetal and postnatal lungs and in cases of newborn and childhood PHT of varied etiology. In addition, we tested for a SERT gene promoter defect in ACD/MPV patients.Results.We found that SERT protein expression begins at 30 weeks of gestation, increases to term, and stays high postnatally. ACD/MPV patients had diminished SERT expression without SERT promoter alteration.Conclusion.We concluded that SERT/serotonin pathway is crucial in the process of pulmonary vascular remodeling/adaptation at birth and plays a key role in the pathobiology of ACD/MPV.

Pulmonary hypertension (pHTN) is a severe, life-threatening disease, which can be idiopathic or associated with an underlying syndrome or genetic diagnosis. Here we discuss a patient who presented with severe pHTN and was later found to be compound heterozygous for pathogenic variants in the NFU1 gene causing multiple mitochondrial dysfunctions syndrome 1 (MMDS1). Review of autopsy slides from an older sibling revealed the same diagnosis along with pulmonary findings consistent with a developmental lung disorder. In particular, these postmortem, autopsy findings have not been described previously in humans with this mitochondrial syndrome and suggest a possible developmental basis for the severe pHTN seen in this disease. Given the rarity of patients reported with MMDS1, we review the current state of knowledge of this disease and our novel management strategies for pHTN and MMDS1-associated complications in this population.

A novel homozygous mutation in human IL2RB results in decreased IL-2Rβ protein expression and dysregulated IL-2/15 signaling. This hypomorphic mutation leads to decreased regulatory T cell frequency and an abnormal NK cell compartment, with clinical manifestations of autoimmunity and susceptibility to CMV., The pleiotropic actions of interleukin-2 (IL-2) are essential for regulation of immune responses and maintenance of immune tolerance. The IL-2 receptor (IL-2R) is composed of IL-2Rα, IL-2Rβ, and IL-2Rγ subunits, with defects in IL-2Rα and IL-2Rγ and their downstream signaling effectors resulting in known primary immunodeficiency disorders. Here, we report the first human defect in IL-2Rβ, occurring in two infant siblings with a homozygous IL2RB mutation in the WSXWS motif, manifesting as multisystem autoimmunity and susceptibility to CMV infection. The hypomorphic mutation results in diminished IL-2Rβ surface expression and dysregulated IL-2/15 signaling, with an anticipated reduction in regulatory T cells. However, in contrast to the IL-2Rβ−/− animal model, which lacks NK cells, these siblings demonstrate an expansion of NK cells, particularly the CD56bright subset, and a lack of terminally differentiated NK cells. Thus, the early-onset autoimmunity and immunodeficiency are linked to functional deficits arising from altered IL-2Rβ expression and signaling in T and NK cells., Graphical Abstract