Pulmonary Hypoplasia Research Articles

De Novo Missense Mutation in FREM1 Identified in a Chinese Patient with Comorbid Congenital Microtia and Pulmonary Hypoplasia

Cases of microtia combined with pulmonary hypoplasia are occasionally in clinics, and its genetic etiology has so far proved inconclusive. Here, aiming to contribute to a better understanding of microtia-related comorbid respiratory anomalies, the authors provide a clinical and genetic description of a rare trio family of which the son suffers combined deformities of right microtia, left pulmonary hypoplasia, and dextrocardia using whole-genome sequence (WGS). A novel potential pathologic compound heterozygosity in the FREM1 gene was identified and validated by the trio and bioinformatics analysis. This case expands the FREM1 mutation genotype and phenotype spectrum, sheds light on the congenital deformities of microtia and pulmonary hypoplasia, and emphasizes the importance of the FREM1 gene in pulmonary and craniofacial development.

Multipotent mesenchymal stromal cell therapy for a neonate with congenital diaphragmatic hernia and adhesive small bowel obstruction

Background. In the last decade, therapy using multipotent mesenchymal stromal cells (MSCs) has offered hope for regenerating the lungs of preterm babies with chronic lung disease. Due to similar disease mechanisms, it is logical to explore the potential impact of MSC therapy on pulmonary hypoplasia in congenital diaphragmatic hernia. Furthermore, MSCs may also contribute to the regeneration of the intestines affected by adhesive small bowel obstruction in patients with congenital diaphragmatic hernia. Case presentation. A female newborn, delivered at 32 weeks and six days gestational age, was diagnosed with a left congenital diaphragmatic hernia. After surgical repair and respiratory/nutritional support for 39 days, she was still dependent on a ventilator and total parenteral nutrition. Two MSC treatments were given a week apart: 10 million cells/kg intratracheally and 5 million cells/kg intravenously. She was extubated, and her enteral nutrition improved after the treatment. No side effects were detected. We present the first documented case using MSCs derived from the umbilical cord to simultaneously treat pulmonary hypoplasia and adhesive small bowel obstruction of congenital diaphragmatic hernia. Conclusion. Although MSC treatment is very promising for pulmonary hypoplasia and adhesive small bowel disease of congenital diaphragmatic hernia, much more needs to be learned about potential side effects, appropriate dosage, and the optimal method of administration.

Effect of tadalafil on pulmonary hypoplasia in congenital diaphragmatic hernia of rat fetuses

Background. Pulmonary hypoplasia and persistent pulmonary hypertension in congenital diaphragmatic hernia are the cause of adverse perinatal outcomes. Dissatisfaction with the outcomes of intrauterine surgical correction of CDH determines the search for alternative non-surgical prenatal methods of treating pulmonary hypoplasia in CDH. Objective. To study the effect of a reversible selective inhibitor of specific phosphodiesterase type 5 (tadalafil) on the development of fetal lungs in rats in a model of congenital diaphragmatic hernia. Design and methods. An experimental study was conducted on the possibility of correcting fetal lung hypoplasia in rats when modeling a diaphragmatic hernia with nitrophen (100 mg orally, once on the 9th day of pregnancy). Results. Congenital diaphragmatic hernia was recorded in 12.5 % of offspring. Subcutaneous administration of tadalafil to pregnant rats (0,83 mg/kg, for 10 days, from the 9th day of pregnancy) in the lungs of fetuses increases the number of alveoli (by 22 % at p ≤ 0.05), the area of microvasculature vessels and the volume of lung parenchyma increases (by 1.25 % and 1.13 % more (at p ≤ 0.05)). Conclusion. The results obtained from the first experiment conducted in the Russian Federation to study the effect of tadalafil on the lungs in congenital diaphragmatic hernia of the fetus are comparable with the data of the authors who used sildenafil, however, the use of tadalafil seems more optimal due to the ease of its administration for potential practical use.

MicroRNAs in Congenital Diaphragmatic Hernia: Insights into Prenatal and Perinatal Biomarkers and Altered Molecular Pathways: microRNAs in Congenital Diaphragmatic Hernia for Pathway Analysis and Prognostic Biomarkers

Congenital diaphragmatic hernia (CDH) is characterized by a diaphragmatic defect, leading to herniation of abdominal organs into the chest, lung compression, and impaired lung development, often resulting in pulmonary hypertension and lung hypoplasia. Prenatal imaging techniques like ultrasound and MRI provide anatomical predictors of outcomes, but their limitations necessitate novel biomarkers for better prognostic accuracy. This study aims to identify unique circulating maternal, fetal, and neonatal microRNAs (miRNAs) that can distinguish CDH pregnancies from healthy controls and assess their potential as markers of disease severity. We conducted a prospective study involving third-trimester maternal blood, amniotic fluid, cord blood, and neonatal blood samples from pregnancies complicated by CDH and healthy controls. miRNA expression was analyzed using RNA-sequencing, and random forest analysis identified miRNAs distinguishing CDH survivors from non-survivors. Pathway enrichment analyses were performed to explore the biological relevance of differentially expressed miRNAs. Significant miRNA expression differences were observed between CDH and control samples across all sample types. In infant blood, 148 miRNAs were up-regulated, and 36 were down-regulated in CDH cases. Pathway analysis revealed that dysregulated miRNAs in CDH targeted pathways related to protein binding, transcription regulation, and signaling pathways implicated in pulmonary hypertension and lung hypoplasia. Random forest analysis identified miRNAs in maternal blood (miR-7850-5p_L-1R+2, miR-942-3p, and miR-197-3p) that distinguished CDH survivors from non-survivors, with an ROC area under the curve of 1.0. Circulating miRNAs in maternal blood offer promising biomarkers for predicting CDH outcomes. miRNAs from infant blood provide mechanistic insights and potential targets for therapeutic intervention in critical pathways of pulmonary hypertension and lung hypoplasia. Further studies with larger cohorts are needed to validate these findings and explore the clinical application of miRNA biomarkers in CDH management.

Severity of native pulmonary annular hypoplasia and late outcomes of tetralogy of Fallot: retrospective cohort study.

Pulmonary annular hypoplasia and valvar dysplasia are key morphological features affecting long-term outcomes of tetralogy of Fallot. This retrospective study aimed to analyse factors affecting contemporary long-term outcomes with a focus on pulmonary annular growth and function over time. 131 consecutive isolated tetralogy of Fallot repairs performed between 2004 and 2014 at University Children's Hospital Zurich were included. Median age and weight at the time of repair were 4.8 (interquartile range [IQR] 3.2-6.3) months and 6.1 (IQR 5.1-7) kg, respectively. Based on the severity of native pulmonary annular hypoplasia, the cohort was divided into group 1 (preoperative pulmonary annular Z score < -4; n = 20), group 2 (Z score -2 to -4; n = 56) and group 3 (Z score > -2; n = 54). A transannular patch was used in 88/131 (67.2%) patients: 80%, 67.9% and 61.1% in groups 1, 2 and 3, respectively. The primary outcome was defined as right ventricular outflow tract (RVOT) reoperation or pulmonary valve replacement. Secondary outcome was composite pulmonary valve dysfunction defined as peak gradient >40 mm Hg or severe pulmonary regurgitation at follow-up. A multiple Cox regression model was used to quantify the association of age at tetralogy of Fallot repair, preoperative pulmonary annular Z score and RVOT approach with primary and secondary outcome. Follow-up was 98.5% complete, with a median follow-up duration of 9.6 (95% confidence interval [CI] 9-10.4) years. All patients were alive at last follow-up resulting in 100% survival. 20/131 patients underwent pulmonary valve replacement (14 surgical and 6 catheter interventional) while 5/131 underwent RVOT reoperations other than valve replacement. The Kaplan-Meier 10-year freedom from primary outcome was 85% (95% CI 78-92%); 69% (46-100%), 91% (82-100%) and 84% (74-95%) for groups 1, 2 and 3, respectively (log rank p = 0.16). Composite dysfunction at follow-up was observed in 29.8% (overall): 45%, 28.6% and 25.9% for groups 1, 2 and 3, respectively (p = 0.12). The multiple Cox regression analysis for primary outcome indicated that the use of a transannular patch results in a Hazard Ratio (HR) of 3.3 (95% CI 0.7-14.7, p = 0.13). Additionally, the presence of composite dysfunction at discharge results in a HR of 2.1 (95% CI 0.8-5.4, p = 0.1). Age (in months) with a HR of 0.8 (95% CI 0.6-1, p = 0.06) and group 2 with a HR of 0.4 (95% CI 0.14-1.2, p = 0.11) showed a trend to being protective for the primary outcome. However, the 95% CI of all estimates included the HR of 1. Transannular patch use and composite dysfunction at discharge, although not statistically significant at 5% level, may be associated with pulmonary valve replacement and RVOT reoperation. Avoiding the use of a transannular patch or using reconstructive techniques to achieve a better composite dysfunction at discharge could reduce the primary outcome. Large multicentre studies are needed to demonstrate more precisely the impact of pulmonary annulus Z scores on outcome.

Sex-specific differences in the severity of pulmonary hypoplasia in experimental congenital diaphragmatic hernia and implications for extracellular vesicle-based therapy.

Amniotic fluid stem cell extracellular vesicles (AFSC-EVs) hold regenerative potential to treat hypoplastic lungs secondary to congenital diaphragmatic hernia (CDH). This study aims to investigate sex-specific differences in pulmonary hypoplasia severity and responses to AFSC-EV administration in an experimental CDH mouse model. C57BL/6J dams were fed with nitrofen + bisdiamine (left-sided CDH) or olive oil only (control) at embryonic day (E) 8.5. Lungs were dissected (E18.5), grown ex vivo and treated with medium ± AFSC-EVs that were collected via ultracentrifugation and characterized (nanoparticle tracking analysis, electron microscopy, Western blotting). Pulmonary hypoplasia was assessed via mean linear intercept (MLI). Gene and protein expression changes (Cd31, Enos, Il1b, TNFa) were measured via RT-qPCR and immunofluorescence. Pups were genotyped for Sry. Experimental CDH showed a male predominance without sex differences for pulmonary hypoplasia severity, fetal lung vascularization, and inflammation. AFSC-EV administration led to improved lung growth (decreased MLI), improved fetal lung vascularization (increased Cd31 and Enos), and decreased fetal lung inflammation (Il1b, TNFa). There was no sex-specific response to AFSC-EV administration. This study shows sex-independent impaired lung growth, vascularization and fetal lung inflammation in a CDH mouse model. Antenatal administration of AFSC-EVs reverses aspects of pulmonary hypoplasia secondary to CDH independent of the biological sex.

Toll-like receptors ligand immunomodulators for the treatment congenital diaphragmatic hernia

BackgroundCongenital diaphragmatic hernia (CDH) is a rare disease that affects the development of the diaphragm, leading to abnormal lung development. Unfortunately, there is no established therapy for CDH. Retinoic acid pathways are implicated in the ethology of CDH and macrophages are known to play a role in repairing organ damage.MethodsWe have analyzed the effect of several Toll like receptor (TLR) ligands in the nitrofen-induced CDH model in pregnant rats widely used to study this disease and in the G2-GATA4Cre;Wt1fl/fl CDH genetic mice model. Morphometric and histological studies were carried out. Immune cell infiltration was assayed by immunochemistry and immunofluorescence and retinoic pathway gene expression analyzed in vivo and in vitro in macrophages.ResultsWe found that administering a single dose of atypical TLR2/4 ligands (CS1 or CS2), 3 days after nitrofen, cured diaphragmatic hernia in 73% of the fetuses and repaired the lesion with complete diaphragm closure being on the other hand nontoxic for the mothers or pups. Moreover, these immunomodulators also improved pulmonary hypoplasia and alveolar maturation and vessel hypertrophy, enhancing pulmonary maturity of fetuses. We also found that CS1 treatment rescued the CDH phenotype in the G2-GATA4Cre;Wt1fl/fl CDH genetic mice model. Only 1 out of 11 mutant embryos showed CDH after CS1 administration, whereas CDH prevalence was 70% in untreated mutant embryos. Mechanistically, CS1 stimulated the infiltration of repairing M2 macrophages (CD206+ and Arg1+) into the damaged diaphragm and reduced T cell infiltration. Additionally, those TLR ligands induced retinol pathway genes, including RBP1, RALDH2, RARα, and RARβ, in the affected lungs and the diaphragm and in macrophages in vitro.ConclusionsOur research has shown that TLR ligand immunomodulators that influence anti-inflammatory macrophage activation can be effective in treating CDH, being nontoxic for the mothers or pups suggesting that those TLR ligands are a promising solution for CDH leading to orphan drug designation for CS1. The immune system of the fetus would be responsible for repairing the damage and closure of the hernia in the diaphragm and enhanced proper lung development after CS1 treatment.

Swyer – James – McLeod syndrome in an adult male

Swyer – James syndrome, also called Swyer – James – MacLeod syndrome (SJMS), is a rare acquired disorder characterized by pulmonary artery hypoplasia, unilateral hyperlucent lungs, and usually also bronchiectasis. Adults with SJMS are often diagnosed with and treated for chronic obstructive pulmonary disease (COPD), bronchial asthma, pneumothorax, or pulmonary embolism due to the similar clinical manifestations. Underestimation of an important radiological sign – unilateral “impoverishment” of the pulmonary pattern and hyperlucent lung – leads to erroneous diagnosis and inadequate treatment. Diagnosis of SJMS involves a computed tomography scan of the chest.The aim of this work was to familiarize readers with aspects of diagnosis and detail the clinical, radiological, and other characteristics of a patient with McLeod syndrome. The described adult man was diagnosed with SJMS at the age of 32. Some typical mistakes in examinations of such patients and the lack of vigilance of radiologists in case of unilateral hyperlucent lung are presented.Conclusion. Using the example of a rare clinical case of SJMS, we demonstrated the need to consider this syndrome when diagnosing adults with unjustified shortness of breath and a history of frequently recurrent pulmonary infections, with radiological signs of unilateral pulmonary emphysema and hyperlucent lung. According to the literature and our observations, computed tomography of the chest organs is a fast and reliable method for establishing the diagnosis of SJMS.

A Splice Site Variant in ADAMTS3 Is the Likely Causal Variant for Pulmonary Hypoplasia with Anasarca in Persian/Persian-Cross Sheep.

Pulmonary hypoplasia with anasarca, or hydrops fetalis, is characterized by stillbirth, diffuse oedema, and generalized lymph node hypoplasia. The enlarged fetus frequently causes dystocia. The disease has been reported in cattle and sheep as an inherited condition with a recessive mode of inheritance. This is the first report of the disease in Persian/Persian-cross sheep in Australia. Affected fetuses were reported from three flocks, and a total of eleven affected, eleven obligate carrier, and 188 related Persian/Persian-cross animals were available for analysis, as well as unrelated control animals. SNP genotyping revealed a region of homozygosity in affected animals on ovine chromosome six, which contained the functional candidate gene ADAMTS3. Whole genome sequencing of two affected fetuses and one obligate carrier ewe revealed a single nucleotide deletion, ENSOARG00000013204:g.87124344delC, located 3 bp downstream from a donor splice site region in the ADAMTS3 gene. Sanger sequencing of cDNA containing this variant further revealed that it is likely to introduce an early splice site in exon 14, resulting in a loss of 6 amino acids at the junction of exon 14 and intron 14/15. A genotyping assay was developed, and the ENSOARG00000013204:g.87124344delC segregated with disease in 209 animals, allowing for effective identification of carrier animals.

Unilateral pulmonary vein atresia: Difficulties of radiological diagnosis

Pulmonary vein atresia is a rare congenital abnormality that could manifest in isolation or in association with other congenital abnormalities in the cardiovascular system such as pulmonary vein hypoplasia. Pulmonary vein atresia leads to changes in cardiovascular functioning. This abnormality is often diagnosed in children with recurrent pneumonia and hemoptysis. In adulthood, pulmonary vein atresia is much less common, with clinical symptoms such as dyspnea during physical exercises and hemoptysis. However, some patients are asymptomatic. Owing to the nonspecific imaging findings, lung parenchymal changes are often misdiagnosed as another lung disease, including inflammatory genesis disease. In this article, a case of a young man with asymptomatic unilateral pulmonary vein atresia combined with pulmonary artery hypoplasia and interstitial lung changes in a lung with hypoplasia was presented. These pathologies were first identified in a 21-year-old patient by contrast-enhanced computed tomography.

Prenatal Prognosis of Omphalocele Using Magnetic Resonance Imaging Measurement of Fetal Lung Volumes

BackgroundOmphalocele is a congenital midline abdominal wall defect resulting in herniation of viscera into a membrane-covered sac. Pulmonary complications, including pulmonary hypoplasia, pulmonary hypertension, and prolonged respiratory support are a leading cause of neonatal morbidity and mortality. Objective(s)This study aimed to assess the role of fetal MRI-derived lung volumes and omphalocele defect size as clinical tools to prognosticate postnatal pulmonary morbidity and neonatal mortality in those with a prenatally diagnosed omphalocele (PDO). Study DesignThis was a retrospective cohort study of all pregnancies with PDO at our fetal center from 2007–2023. Pregnancies with aneuploidy or concurrent life-limiting fetal anomalies were excluded. Using fetal MRI, observed-to-expected total fetal lung volume (O/E TLV) ratios were determined by a previously published method. The transverse diameter of the abdominal defect was also measured. The O/E TLV ratios and abdominal defect measurements were compared with postnatal outcomes. The primary outcome was death at any time. Secondary outcomes included death in the first 30 days of life or before discharge from birth hospitalization, the requirement of respiratory support with intubation and mechanical ventilation, or development of pulmonary hypertension. ResultsOf 101 pregnancies with a PDO, 54 pregnancies (53.5%) with prenatally diagnosed omphalocele met inclusion criteria. There was a significant increase in the rate of death when compared between the three O/E TLV classifications: 1/36 (2.8%) in the O/E≥50% group, 3/14 (21.4%) in the O/E 25%–49.9% group, and 4/4 (100%) in the O/E<25% group (P<.001). The rate of intubation increased with the severity of O/E TLV classification, with 27.8% in the O/E≥50% group, 64.3% in the O/E 25%–49.9% group, and 100% in the O/E<25% group (P=.003). The rate of pulmonary hypertension was also higher in the O/E 25%–49.9% (50.0%) and the O/E<25% (50.0%) groups compared to the O/E≥50% group (8.3%, P=.002). There was no association between the transverse diameter of the abdominal wall defect and the primary outcome of death (OR=1.08 95% CI=[0.65–1.78], P=.77). ConclusionsIn our cohort of patients with PDO, O/E TLV<50% is associated with death, need for intubation, prolonged intubation, and pulmonary hypertension. In contrast, omphalocele size demonstrated no prognostic value for these outcomes. The strong association between low fetal lung volume on MRI and poor neonatal outcomes highlights the utility of fetal MRI for estimating postnatal prognosis. Clinicians can utilize fetal lung volumes to direct perinatal counseling and optimize the plan of care.

A case of late-presenting congenital diaphragmatic hernia diagnosed at 5 years with acute abdomen

BackgroundSome congenital diaphragmatic hernias are diagnosed beyond 1 month. A late-presenting congenital diaphragmatic hernia shows a variety of clinical manifestations, and the preoperative clinical course is variable. We herein report a pediatric case of late-presenting congenital diaphragmatic hernia diagnosed as acute abdomen.Case presentationA 5-year-old boy was brought to our hospital because of herniation of the intestine into the left thoracic cavity, which was observed on radiography performed for abdominal pain. Enhanced computed tomography showed herniation of the small intestine and colon into the left thoracic cavity. Emergency laparoscopic surgery was performed based on the diagnosis of left diaphragmatic hernia. The entire small intestine and part of the colon herniated from the posterolateral defect of the diaphragm. We were able to retract the herniated intestine back into the abdomen but confirmed that the diaphragmatic defect and closure of the defect seemed to be technically challenging via laparoscopy; therefore, we converted the procedure to open laparotomy. The diaphragmatic defect was directly closed with interrupted sutures, and the thoracic cavity was degassed. Postoperatively, the left lung was found to be poorly expanded, but pulmonary hypoplasia was not evident in this case.ConclusionsWe herein report a pediatric case of late-presenting congenital diaphragmatic hernia diagnosed as abdominal pain. Late-presenting congenital diaphragmatic hernias present with a wide variety of symptoms; therefore, it is important to be reminded of these conditions and check chest radiographs in children presenting with acute or chronic respiratory or gastrointestinal symptoms of unknown etiology.

Clinical and histopathological spectrum of congenital pulmonary airway malformations: A case series

BackgroundCongenital pulmonary airway malformations (CPAM) are a spectrum of cystic and non-cystic anomalies arising from abnormal airway development in utero, with an incidence of 1 in 25,000 to 35,000 births. CPAM can present prenatally or postnatally with respiratory distress, recurrent infections, or occasionally as an incidental finding. This case series aims to highlight the clinical, radiological, and histopathological characteristics of CPAM through three pediatric cases, which include types 1, 2, and 3 CPAM. Case presentationCase 1: A four-month-old male presented with cough, cold, and respiratory distress. Imaging revealed hypoattenuation and overinflation of the left upper lobe with mediastinal shift. Left upper lobectomy confirmed CPAM type 2.Case 2: A one-month-old female presented with recurrent respiratory distress and infections. Imaging showed a large cystic lesion in the right middle lobe. Right middle lobectomy confirmed CPAM type 3.Case 3: A two-month-old male presented with dyspnea. Imaging showed a large bullae in the right chest with mediastinal shift. Right upper lobectomy confirmed CPAM type 1. Clinical discussionCPAM is a rare congenital lung malformation characterized by abnormal bronchial development and localized glandular overgrowth. Management involves surgical resection, with the timing of surgery dependent on symptomatology. Early identification and intervention are crucial for preventing complications such as pulmonary hypoplasia and recurrent infections. Histopathological examination post-resection is essential for accurate classification and management of CPAM. ConclusionThis case series provides valuable insights into the clinical, radiological, and histopathological features of CPAM, including the types encountered in each case. It underscores the importance of early diagnosis and timely surgical intervention, advocating for routine prenatal and postnatal screenings to effectively identify and manage CPAM.

Comparative Transcriptome Analysis of Human and Mouse Canalicular Lungs in Fetal Diaphragmatic Hernia

BackgroundThe nitrofen model of congenital diaphragmatic hernia (CDH) is widely used in translational research. However, the molecular pathways associated with pulmonary hypoplasia in this model compared to the human CDH phenotype have not been well described. The aim of this study was to investigate differentially expressed genes (DEG) and signaling pathways in early stage fetal lungs in mouse and human CDH. MethodsCDH lung tissue was obtained from human fetuses (21–23 weeks gestation) and nitrofen mouse pups (E15.5). NovaSeq Flowcell RNA-seq was performed to evaluate differentially expressed transcriptional and molecular pathways (DEGs) in fetal mice with CDH, compared with age-matched normal mouse lungs and human CDH samples. ResultsThere were thirteen overlapping DEGs in human and mouse CDH lung samples compared to controls. These genes were involved in extracellular matrix, myogenesis, cilia, and immune modulation pathways. Human CDH was associated with an upregulation of collagen formation and extracellular matrix reorganization whereas mouse CDH was associated with an increase in muscular contraction. The most common cell types upregulated in human and mouse CDH samples were ciliated airway cells. ConclusionsThis study highlights the unique gene transcriptional patterns in early fetal mouse and human lungs with CDH. These data have implications when determining the translational potential of novel therapies in CDH using nitrofen-based animal models. Level of EvidenceLevel IV. Study TypeBasic science/case series.

Fetal hypoplastic lungs have multilineage inflammation that is reversed by amniotic fluid stem cell extracellular vesicle treatment.

Antenatal administration of extracellular vesicles from amniotic fluid stem cells (AFSC-EVs) reverses features of pulmonary hypoplasia in models of congenital diaphragmatic hernia (CDH). However, it remains unknown which lung cellular compartments and biological pathways are affected by AFSC-EV therapy. Herein, we conducted single-nucleus RNA sequencing (snRNA-seq) on rat fetal CDH lungs treated with vehicle or AFSC-EVs. We identified that intra-amniotically injected AFSC-EVs reach the fetal lung in rats with CDH, where they promote lung branching morphogenesis and epithelial cell differentiation. Moreover, snRNA-seq revealed that rat fetal CDH lungs have a multilineage inflammatory signature with macrophage enrichment, which is reversed by AFSC-EV treatment. Macrophage enrichment in CDH fetal rat lungs was confirmed by immunofluorescence, flow cytometry, and inhibition studies with GW2580. Moreover, we validated macrophage enrichment in human fetal CDH lung autopsy samples. Together, this study advances knowledge on the pathogenesis of pulmonary hypoplasia and further evidence on the value of an EV-based therapy for CDH fetuses.

Bilateral renal agenesis: fetal intervention and outcomes.

Bilateral renal agenesis (BRA) is a fetal anomaly which leads to anhydramnios and resultant pulmonary hypoplasia. Historically, this anomaly was universally fatal early in the neonatal period due to the severity of the associated lung disease. Over the last 30years, innovations in fetal therapies-specifically, serial amnioinfusions-have led to instances of infant pulmonary survival and initiation of postnatal dialysis, raising the possibility that early neonatal death may not be inevitable. Amnioinfusions are not without risk, and maternal complications can include prelabor rupture of membranes, preterm labor, infection, and bleeding. The data detailing neonatal outcomes are still limited and actively being collected. Two case series and one non-randomized clinical trial have supplied most of the known outcome data for infants with BRA after prenatal amnioinfusion. Although there are survivors reported in the literature, mortality remains high, with many deaths in infancy due to dialysis-associated sepsis. In addition, previously unknown morbidities have been documented in these infants, including neurologic injury. These challenges, in addition to the mechanical difficulties of providing dialysis to extremely small infants, can result in significant burdens for patients and their caregivers and moral distress for the health care team. The present review aims to explain the pathophysiology of BRA, detail the historical context and rationale for serial amnioinfusions to treat the pulmonary insufficiency associated with BRA, describe the available data regarding outcomes of infants born following prenatal amnioinfusions, discuss ethical issues surrounding this fetal intervention, and describe critical aspects of prenatal counseling for patients considering the intervention.

The ten-year evaluation of clinical characteristics in congenital lung anomaly in pediatrics; a retrospective study in North of Iran

IntroductionCongenital lung anomalies (CLA) are a group of anomalies, including congenital cystic adenomatoid malformation (CCAM), bronchopulmonary sequestrations (BPS), congenital lobar emphysema (CLE), and bronchogenic cysts (BC). The prevalence of these rare anomalies has risen in recent years, according to various population-based studies due to advances in fetal ultrasound technology.MethodThis retrospective study examines the diagnosis of CLA, and was conducted on 72 patients between March 2014 and March 2024 at Taleghani Pediatric Hospital in Gorgan, Iran.ResultThe average age was 18.8 ± 30.3 months, with the majority being boys (62.5%). Most participants had CCAM (41.7%), followed by CLE (18.1%), BPS (16.7%), pulmonary hypoplasia (9.7%), BC (8.3%), and hybrid lesion (5.6%). The majority of patients were Fars (62.5%), and the average hospitalization days was 9.4 ± 4.5 days. Cardiac anomalies were observed in 19.4% of the patients. 62 patients (86.1%) exhibited respiratory symptoms, and prenatal screening during pregnancy led to the diagnosis in 51 patients (70.8%). Most patients had left lung anomalies (43; 59.7%), and the majority (90.3%) survived. There is a statistically significant relation between needed for surgical treatment and patients’ type of pulmonary lesions (p-value: 0.02). In addition, there was a significant relation between the Fars ethnicity and the presence of cardiac anomalies (p-value: 0.04).ConclusionSome CLAs remain undiagnosed or untreated due to the rare nature of congenital lung anomalies. Nevertheless, improvements in ultrasound and other imaging methods will make diagnosing and managing these anomalies during the prenatal period more prevalent, resulting in enhanced understanding.

Genetic landscape and clinical outcomes of autosomal recessive polycystic kidney disease in Kuwait

BackgroundAutosomal recessive polycystic kidney disease (ARPKD), a rare genetic disorder characterized by kidney cysts, shows complex clinical and genetic heterogeneity. This study aimed to explore the genetic landscape of ARPKD in Kuwait and examine the intricate relationship between its genes and clinical presentation to enhance our understanding and contribute towards more efficient management strategies for ARPKD. MethodsThis study recruited 60 individuals with suspected ARPKD from 44 different families in Kuwait. The participants were of different ethnicities and aged 0–70 years. Additionally, 33 were male, 15 were female, and 12 had indeterminant sex due to congenital anomalies. Comprehensive clinical data were collected. Mutations were identified by next-generation whole exome sequencing and confirmed using Sanger sequencing. ResultsOf the 60 suspected ARPKD cases, 20 (33.3 %) died within hours of birth or by the end of the first month of life and one (1.7 %) within 12 months of birth. The remaining 39 (65.0 %) cases were alive, at the time of the study, and exhibited diverse clinical features related to ARPKD, including systematic hypertension (5.0 %), pulmonary hypoplasia (11.7 %), dysmorphic features (40.0 %), cardiac problems (8.3 %), cystic liver (5.0 %), Potter syndrome (13.3 %), developmental delay (8.3 %), and enlarged cystic kidneys (100 %). Twelve mutations, including novel truncating mutations, were identified in 31/60 cases (51.7 %) from 17/44 families (38.6 %). Additionally, 8/12 (66.7 %) mutations were in the PKHD1 gene, with the remaining four in different genes: NPHP3, VPS13P, CC2D2A, and ZNF423. ConclusionsThis study highlights the spectrum of clinical features and genetic mutations of patients with ARPKD in Kuwait. It highlights the necessity for personalized approaches to improve ARPKD diagnosis and treatment, offering crucial insights into managing ARPKD.

Bias in the prenatal lung measurements in fetal congenital diaphragmatic hernia with intrauterine growth restriction.

The failure of a fetus to develop to its full potential due to maternal or placental factors is known as intrauterine growth restriction (IUGR). Fetal head growth is usually preserved in that situation producing a potential discordance between head and body size. Our goal is to discover if IUGR has an impact on the prenatal ultrasound measurements taken to assess pulmonary development in congenital diaphragmatic hernia (CDH). A retrospective chart review (IRB#2017-6361) was performed on all prenatally diagnosed CDH patients from 2007 to 2016. Patient demographics, fetal and neonatal anthropometric measurements, and fetal lung parameters were the main subjects of the data that were gathered. Fetal growth was assessed by the curves based on US data by Olsen etal. and by Peleg etal. Of 147 CDH patients, 19 (12.9 %) patients were diagnosed with IUGR before the 30th gestational week while there were 20 (13.6 %) patients after the 30th gestational week. Patients with IUGR and the observed-to-expected lung-to-head ratio (O/E LHR) less than 25 % had better survival rates both to discharge and date compared to non IUGR group (p=0.226, OR 2.25 95 % CI 0.60-1.08 and p=0.175, OR 2.40 95 % CI 0.66-1.17, respectively). Moreover, the ECMO need of the patients who had IUGR and O/E LHR less than 25 % was significantly less than the patients without IUGR (38.5 vs. 80.0 %, p=0.005). This study confirms that the intrauterine measurements to predict pulmonary hypoplasia in CDH patients are misleading in the presence of IUGR and cause an overestimation.

The brain of fetuses with congenital diaphragmatic hernia shows signs of hypoxic injury with loss of progenitor cells, neurons, and oligodendrocytes

Congenital diaphragmatic hernia (CDH) is a birth defect characterized by incomplete closure of the diaphragm, herniation of abdominal organs into the chest, and compression of the lungs and the heart. Besides complications related to pulmonary hypoplasia, 1 in 4 survivors develop neurodevelopmental impairment, whose etiology remains unclear. Using a fetal rat model of CDH, we demonstrated that the compression exerted by herniated organs on the mediastinal structures results in decreased brain perfusion on ultrafast ultrasound, cerebral hypoxia with compensatory angiogenesis, mature neuron and oligodendrocyte loss, and activated microglia. In CDH fetuses, apoptosis was prominent in the subventricular and subgranular zones, areas that are key for neurogenesis. We validated these findings in the autopsy samples of four human fetuses with CDH compared to age- and sex-matched controls. This study reveals the molecular mechanisms and cellular changes that occur in the brain of fetuses with CDH and creates opportunities for therapeutic targets.