Etiology, Diagnosis and Management of Persistent Pulmonary Hypertension of the Newborn in Resource-limited Settings.

Persistent Pulmonary Hypertension of the Newborn (PPHN) is more common in Low and middle income countries (LMICs) due to high incidence of sepsis, perinatal asphyxia and meconium aspiration syndrome. Presence of hypoxic respiratory faillure and greater than 5% difference in preductal and post ductal saturation increases clinical sucipision for PPHN. The availability of Inhaled nitric oxide and extracorporaeal membrane oxygenation is limited but pulmonary vasodilators such as sildenafil are readily available in most LMICs.

Twins with alveolar capillary dysplasia with misalignment of pulmonary veins: Strategies for diagnosis and management.

We present a case of dichorionic-diamniotic twin females who developed hypoxemic respiratory failure. They were ultimately diagnosed by lung biopsy with alveolar capillary dysplasia with misalignment of pulmonary veins. This case highlights a practical approach to reaching a diagnosis in infants with suspected developmental lung disease.

Rapid genome diagnosis of alveolar capillary dysplasia leading to treatment in a child with respiratory and cardiac failure.

Alveolar capillary dysplasia (ACD) is a fatal disorder that typically presents in the neonatal period with refractory hypoxemia and pulmonary hypertension. Lung biopsy is traditionally required to establish the diagnosis. We report a 22-mo-old male who presented with anemia, severe pulmonary hypertension, and right heart failure. He had a complicated hospital course resulting in cardiac arrest and requirement for extracorporeal membrane oxygenation. Computed tomography of the chest showed a heterogenous pattern of interlobular septal thickening and pulmonary edema. The etiology of his condition was unknown, lung biopsy was contraindicated because of his medical fragility, and discussions were held to move to palliative care. Rapid whole-genome sequencing (rWGS) was performed. In 2 d it resulted, revealing a novel FOXF1 gene pathogenic variant that led to the presumptive diagnosis of atypical ACD. Cases of atypical ACD have been reported with survival in patients using medical therapy or lung transplantation. Based on the rWGS diagnosis and more favorable potential of atypical ACD, aggressive medical treatment was pursued. The patient was discharged home after 67 d in the hospital; he is currently doing well more than 30 mo after his initial presentation with only one subsequent hospitalization and no requirement for lung transplantation. Our case reveals the potential for use of rWGS in a critically ill child in which the diagnosis is unknown. rWGS and other advanced genetic tests can guide clinical management and expand our understanding of atypical ACD and other conditions.

[Diagnosis and treatment of a child with alveolar capillary dysplasia with misalignment of pulmonary veins due to variant of FOXF1 gene].

OBJECTIVE: To explore the diagnosis, treatment and genetic characteristics of a neonate with severe pulmonary hypertension and respiratory failure. METHODS: Perinatal history, clinical manifestations, laboratory finding and diagnosis and treatment data of the child were collected. Whole exome sequencing was carried out for the child, and Sanger sequencing was used to verify the candidate variants. RESULTS: The female neonate has developed progressive respiratory failure and refractory pulmonary hypertension shortly after birth. Conventional treatment such as mechanical ventilation, vasoactive drugs, and inhaled nitric oxide were ineffective. She has developed sustained pulmonary hypertension after weaning from extracorporeal membrane oxygenation therapy, and had died after the treatment had ceased. Whole exome sequencing revealed that she has harbored a heterozygous de novo variant of c.682_683insGCGGCGGC (p.G234Rfs*148) of the FOXF1 gene, which was predicted as pathogenic based on guidelines from the American College of Medical Genetics and Genomics (ACMG), with evidence items of PVS1_Strong+PM2_Supporting+PS2. Based on her clinical manifestations and result of genetic testing, the child was diagnosed with alveolar capillary dysplasia with misalignment of the pulmonary veins (ACD/MPV). CONCLUSION: Discovery of the c.682_683insGCGGCGGC (p.G234 Rfs*148) variant of the FOXF1 gene has expanded the mutational spectrum of the FOXF1 gene, which has facilitated implementation of specific treatment and provided a basis for clinical diagnosis and genetic counseling.

Clinical Relevance of Rapid FOXF1-Targeted Sequencing in Patients Suspected of Alveolar Capillary Dysplasia With Misalignment of Pulmonary Veins.

Alveolar capillary dysplasia with misalignment of pulmonary veins (ACDMPV) is a lethal congenital lung disorder that presents shortly after birth with respiratory failure and therapy-resistant pulmonary hypertension. It is associated with heterozygous point mutations and genomic deletions that involve the FOXF1 gene or its upstream regulatory region. Patients are unresponsive to the intensive treatment regimens and suffer unnecessarily because ACDMPV is not always timely recognized and histologic diagnosis is invasive and time consuming. Here, we demonstrate the usefulness of a noninvasive, fast genetic test for FOXF1 variants that we previously developed to rapidly diagnose ACDMPV and reduce the time of hospitalization.

Histologic features and decreased lung FOXF1 gene expression in severe bronchopulmonary dysplasia without a genetic diagnosis of alveolar capillary dysplasia.

We report the case of a preterm infant who died at 10 months of age with severe bronchopulmonary dysplasia (sBPD) with refractory pulmonary hypertension and respiratory failure who had striking histologic features compatible with the diagnosis of alveolar capillary dysplasia with misalignment of pulmonary veins (ACDMPV) but without genetic confirmation of the diagnosis. We further demonstrate dramatic reductions in lung FOXF1 and TMEM100 content in sBPD, suggesting common mechanistic links between ACDMPV and sBPD with impaired FOXF1 signaling.

Neonatal Diagnosis of Alveolar Capillary Dysplasia via Rapid Genomic Sequencing: A New Gold Standard?

Classic alveolar capillary dysplasia with misalignment of pulmonary veins (ACDMPV) is a rare congenital lung disorder presenting in the early neonatal period with refractory hypoxemic respiratory failure and pulmonary hypertension. No curative treatment is currently available. Although definitive diagnosis is obtained by histology, lung biopsy is often challenging in unstable, critically ill neonates. Molecular diagnosis has been achieved with chromosomal microarray and targeted gene sequencing; however, each of these modalities can be limited by turnaround time, coverage of the genome, and inability to detect all pathogenic variant types for ACDMPV. We present a case of ACDMPV diagnosed via rapid genome sequencing and posit that rapid genomic sequencing, including both rapid exome and genome sequencing, has an expanding role in severe neonatal respiratory failure as a comprehensive and noninvasive approach to timely diagnosis.

Evidence-Based Guidelines for Acute Stabilization and Management of Neonates with Persistent Pulmonary Hypertension of the Newborn.

Persistent pulmonary hypertension of the newborn, or PPHN, represents a challenging condition associated with high morbidity and mortality. Management is complicated by complex pathophysiology and limited neonatal specific evidence-based literature, leading to a lack of universal contemporary clinical guidelines for the care of these patients. To address this need and to provide consistent high-quality clinical care for this challenging population in our neonatal intensive care unit, we sought to develop a comprehensive clinical guideline for the acute stabilization and management of neonates with PPHN. Utilizing cross-disciplinary expertise and incorporating an extensive literature search to guide best practice, we present an approachable, pragmatic, and clinically relevant guide for the bedside management of acute PPHN. KEY POINTS: · PPHN is associated with several unique diagnoses; the associated pathophysiology is different for each unique diagnosis.. · PPHN is a challenging, dynamic, and labile process for which optimal care requires frequent reassessment.. · Key management goals are adequate tissue oxygen delivery, avoiding harm..

Milrinone Versus Sildenafil in Treatment of Neonatal Persistent Pulmonary Hypertension: A Randomized Control Trial.

ABSTRACT: Persistent pulmonary hypertension of the newborn (PPHN) is a condition caused by failure of pulmonary vascular adaptation at birth, resulting in severe hypoxia. Several therapeutic modalities are being tried in developing countries where established therapies (inhaled nitric oxide and extracorporeal membrane oxygenation) are widely unavailable. This study aimed to assess the efficacy of milrinone versus sildenafil as available alternative therapeutics in treating PPHN. Forty neonates (>34 weeks) admitted to neonatal intensive care units with evidence of PPHN were randomly allocated to receive either oral sildenafil (0.5-2 mg/kg/6 hours) or intravenous milrinone (0.25-0.75 mic/kg/min). Primary outcomes included improvements in systolic pulmonary artery pressure and oxygen saturation index (OSI) at 24 and 48 hours after treatment. Secondary outcomes included the duration of hospitalization and mechanical ventilation. The ClinicalTrials identifier is NCT04391478. Both groups showed significant improvement in the post-treatment hemodynamic variables compared with pretreatment levels ( P < 0.05 for all parameters). Systolic pulmonary artery pressure and OSI values significantly improved in both study groups compared with baseline ( P < 0.001). The 24-hour and 48-hour post-treatment OSI values were much lower in the milrinone group than those in the sildenafil group ( P < 0.05). The length of hospital stay was significantly shorter in the milrinone group than that in the sildenafil group ( P < 0.05). There were no significant differences in the duration of mechanical ventilation, incidence of intracranial hemorrhage and pulmonary hemorrhage, or mortality between the 2 groups ( P > 0.05). In conclusion, milrinone and sildenafil are effective and well-tolerated in neonates with PPHN, particularly when inhaled nitric oxide and extracorporeal membrane oxygenation are not available. Milrinone is superior to sildenafil in improving oxygenation without lowering blood pressure parameters.

Persistent pulmonary hypertension of the newborn: Historical perspectives.

For many decades, persistent pulmonary hypertension of the newborn (PPHN) remained a baffling disorder, often confused with cyanotic congenital heart disease, with a very high mortality. Originally described as a condition characterized by clear lung fields and profound hypoxemia, modern diagnostic techniques and novel therapeutics have improved the outcomes of affected newborns. This paper will review the historical aspects of PPHN and enable the reader to see how far we have come but also how far we have to go in conquering this unique disorder.

Possible association between a polymorphism of EPAS1 gene and persistent pulmonary hypertension of the newborn: a case-control study.

OBJECTIVE: To explore possible genes related to the development of persistent pulmonary hypertension of the newborn (PPHN). METHODS: The authors identified 285 single nucleotide polymorphisms (SNPs) of 11 candidate genes (BMPR2, EPAS1, PDE3A, VEGFA, ENG, NOTCH3, SOD3, CPS1, ABCA3, ACVRL1, and SMAD9), using an Illumina Asian Screening Array-24 v1.0 BeadChip Array. The FastLmmC and R package was used for statistical analyses. The chi-square test and Cochrane-Armitage trend test were used to compare the allele and genotype frequencies between the groups and to test the genetic models, respectively. RESULTS: A total of 45 PPHN infants and 294 control subjects were analyzed. The most common cause of PPHN was meconium aspiration syndrome. Among the 285 SNPs, 17 SNPs from 6 candidate genes (BMPR2, EPAS1, PDE3A, VEGFA, ENG, and NOTCH3) were significantly associated with PPHN (P < 0.05). After using the Bonferroni correction (P < 0.00018), only the rs17034984 SNP located in intron 1 of the EPAS1 gene remained significantly different between the PPHN and control subjects (P = 0.00014). The frequency of the TC/TT genotype of rs17034984 in the gene with the dominant model was significant in the patients with PPHN (OR = 5.38, 95% CI: 2.15-13.49). The T allele frequency of rs17034984 in the gene showed a significant difference compared with the control subjects (OR = 4.89, 95% CI: 2.03-11.82). CONCLUSIONS: The present study suggests that the rs17034984 variant of EPAS1 gene is associated with PPHN.

Pulmonary alveolar capillary dysplasia in infants: A rare and deadly missed diagnosis.

The pulmonary alveolocapillary dysplasia (ACD) with pulmonary vein misalignment (PVM) is a rare condition characterized by a congenital anomaly of the development of the pulmonary parenchyma. We present a case of an 8-month-old infant who died quickly from acute respiratory failure complicating an unknown ACD. We also describe its epidemiological characteristics in infants and we discuss the diagnosis's difficulties. In this case, a pulmonary arterial hypertension was decompensated by an infection. A medico-legal autopsy was performed. As for the Histological examination, it showed the features of ACD/PVM.

De Novo mutation of FOXF1 causes alveolar capillary dysplasia with misalignment of pulmonary veins: A case report.

RATIONALE: Alveolar capillary dysplasia with misalignment of the pulmonary veins (ACD/MPV) is a rare congenital malformation in neonates that results in severe respiratory distress and pulmonary hypertension. ACD/MPV is caused by mutations in the FOXF1 gene. Herein, a new case of a girl with ACD/MPV carrying a novel pathogenic variant of FOXF1 was reported. PATIENT CONCERNS: A 3-month-old Chinese girl was admitted to the hospital presenting a complaint of cyanosis for 10 days and respiratory distress for 2 days. The history of foreign body inhalation was denied. DIAGNOSES: Blood routine, liver and kidney function, electrolytes, type B natriuretic peptide, electrocardiogram, cardiac computed tomography (CT), and echocardiography were done after admission. Dysplasia of the alveolar and the left upper pulmonary vein was displayed through cardiac CT. Echocardiography showed atrial septal defect, tricuspid valve malformation, and pulmonary hypertension. Sequence analysis of FOXF1 from genomic deoxyribonucleic acid (DNA) revealed that the patient was heterozygous for a novel missense variant (c.418 C>T, p.Pro140Gly). Furthermore, genetic analysis of both parents confirmed the de novo occurrence of the variant. Conservation analysis showed that the locus was highly conserved across species. Then, ACD/MPV was a clinical diagnosis. INTERVENTIONS: After admission, nasal catheter oxygen inhalation, cefazoxime sodium, furosemide diuretic, milrinone lactate, and Bosentan were given to the patient. OUTCOMES: After 6 days of hospitalization, the patient's condition did not improved, the parents gave up treatment and discharged. The patient died half a month after discharge. LESSONS: ACD/MPV is a rare congenital malformation with a poor prognosis. A new de novo mutation of FOXF1 was found in our case. Non-invasive methods such as DNA sequencing and FOXF1 analysis are helpful in the clinical diagnosis of ACD/MPV especially in early infants with respiratory distress and pulmonary hypertension.

Two cases of different genetic variants of alveolar capillary dysplasia associated with left-sided obstructive CHDs.

Alveolar capillary dysplasia with misalignment of the pulmonary veins is an uncommon disorder that affects the lung vasculature development in the neonatal period and leads to pulmonary hypertension. We describe two patients with alveolar capillary dysplasia associated with left-sided obstructive heart defects with two different genetic variants. Our cases highlight the importance of early recognition of this disease in the setting of persistent and supra-systemic pulmonary hypertension despite surgical correction of the associated lesions. Identification of these cases will facilitate the development of a multidisciplinary approach and provide guidance to the affected families.

Early prenatal diagnosis of alveolar capillary dysplasia with misalignment of pulmonary veins due to a 16q24.1 deletion.

First trimester ultrasound screening is an essential fetal examination performed generally at 11-13 weeks of gestation (WG). However, it does not allow for an accurate description of all fetal organs, partly due to their development in progress. Meanwhile, increased nuchal translucency (INT) is a widely used marker known to be associated with chromosomal deleterious rearrangements. We report on a 14 WG fetus with an association of INT and univentricular congenital heart malformation (CHM) leading to chorionic villous sampling (CVS). Cytogenetic investigations performed using array-Comparative Genomic Hybridization (CGH) and fluorescence in situ hybridization (FISH) demonstrated a 1.17 Mb deletion in 16q24.1 encompassing FOXF1 arisen de novo on maternal inherited chromosome. Fetopathological study confirmed CHM with hypoplastic left heart syndrome (HLHS) associating aortic atresia, mitral stenosis, and left ventricular hypoplasia and revealed in addition specific lung lesions corresponding to alveolar capillary dysplasia with misalignment of pulmonary veins (ACDMPV). This is so far the first case of first trimester prenatal diagnosis of ACDMPV due to the deletion of FOXF1 gene. An interpretation of the complex genomic data generated by ultrasound markers is facilitated considerably by the genotype-phenotype correlations on fetopathological examination.

Surfactant dysfunction disorder masquerading as meconium aspiration syndrome and persistent pulmonary hypertension of the newborn.

About 10% of term neonates present with respiratory distress at birth. The most common aetiologies include transient tachypnoea of the newborn, pneumonia and meconium aspiration syndrome (MAS). Hyaline membrane disease (HMD) in a term infant occurs either as primary HMD, secondary surfactant deficiency or congenital surfactant dysfunction. A detailed history supported with appropriate radiological and laboratory investigations can help a clinician reach a diagnosis. We report a case of surfactant dysfunction disorder which presented as severe MAS and persistent pulmonary hypertension of the newborn. In the infant described, the significant history of a sibling death with severe neonatal respiratory disease led us to think of diffuse developmental lung diseases especially surfactant dysfunction syndromes. Exome sequencing detected a heterozygous missense variation in exon 21 of the ATP binding cassette protein member 3 (ABCA3) gene. Based on the clinical picture supported with the exome sequencing, a diagnosis of surfactant dysfunction disorder (ABCA3 deficiency) was confirmed.

Widefield Fluorescein Angiography in the Fellow Eyes of Patients with Presumed Unilateral Persistent Fetal Vasculature.

PURPOSE: To examine the retinal vascular findings on widefield fluorescein angiography (FA) in the fellow eyes of patients with unilateral persistent fetal vasculature (PFV). DESIGN: Retrospective case series. PARTICIPANTS: Consecutive patients with unilateral PFV evaluated by a single physician at an academic medical center from February 1, 2011, to November 30, 2018. METHODS: Clinical and demographic information, including age, gender, race, ethnicity, affected eye, subtype, stalk origin, complications on presentation, length of follow-up, and examination findings, was reviewed using the electronic medical record. Fluorescein angiograms of the affected and fellow eyes were reviewed by 2 authors for characteristic retinal vascular abnormalities. Agreement between the authors' scores was analyzed using Cohen's Kappa. MAIN OUTCOME MEASURES: Fluorescein angiography abnormalities, including peripheral vessel avascularity, aberrant circumferential vessels, terminal supernumerary branching, regional capillary dropout, terminal bulbing, abnormal choroidal flush, abnormal vessel straightening, and peripheral vessel leakage or dilation. RESULTS: Inclusion criteria were met by 41 patients. The average age at initial visit was 10.0 months. The average length of follow-up was 36.4 months. Abnormalities on FA were seen in 31 (75.6%) fellow eyes: peripheral vessel avascularity in 27.5 (67.1%), aberrant circumferential vessels in 20 (48.8%), terminal supernumerary branching in 17 (41.5%), regional capillary dropout in 9 (22.0%), terminal bulbing in 6 (14.6%), abnormal choroidal flush in 3.5 (8.5%), and abnormal vessel straightening and peripheral vessel leakage in 2.5 (6.1%). Statistical analysis disclosed an overall observed agreement of 93.4% among the raters (κ = 0.84, P < 0.0001). CONCLUSIONS: Retinal vascular abnormalities seen in patients with unilateral PFV were present in the majority of fellow eyes. This suggests that unilateral PFV may in fact be a bilateral, asymmetric process, but the clinical significance of these subtle findings is not known.

Peripheral Vascular Abnormalities Detected by Fluorescein Angiography in Contralateral Eyes of Patients With Persistent Fetal Vasculature.

BACKGROUND AND OBJECTIVE: To describe peripheral retinal vascular abnormalities in the contralateral eyes of patients with unilateral persistent fetal vasculature (PFV). PATIENTS AND METHODS: Retrospective medical record review of fluorescein angiography (FA) findings of patients with unilateral PFV. Width of the temporal peripheral avascular retina in contralateral eyes was measured in disc diameters (DD). Vascular abnormalities were described. RESULTS: In 45 included patients, mean width of temporal peripheral avascular areas in contralateral eyes was 1.87 ± 0.71 DD. Forty-three patients (95.6%) had temporal peripheral avascular areas of 1 DD or greater in contralateral eyes, with 16 having temporal peripheral avascular areas of 2 DD or greater. Vessel shunts, vascular tortuosity and dilatation, circumferential vessels, and abnormal capillary beds in the peripheral retina were observed in 23 (51.1%) contralateral eyes of patients with unilateral PFV. CONCLUSION: PFV patients should undergo careful evaluations of both eyes, preferably with FA, to identify vascular changes that are not visible clinically. [Ophthalmic Surg Lasers Imaging Retina. 2020;51:506-511.].