Evaluation and Management of Genetic Respiratory Disorders Presenting as Hypoxemic Respiratory Failure in the Newborn Infant

INTRODUCTION

From common to rare diagnoses, hypoxemic respiratory failure in term and late preterm infants is a frequently encountered clinical scenario in the neonatal intensive care unit (NICU). Many diverse etiologies can result in the common endpoint of hypoxemic neonatal respiratory failure. It is important for the neonatologist to distinguish among these etiologies as the treatments, prognoses, disease courses, outcomes, and recurrence risks vary substantially. Most of these diagnoses are not anticipated antenatally, and thus, families are often unexpectedly in the NICU with a critically ill infant. Here, we discuss both common causes of hypoxemic respiratory failure in term and late preterm (34–36 weeks’ estimated gestation) infants (Table 1) as well as rarer causes for neonatologists to consider (Table 2). Improvements in noninvasive and invasive respiratory support as well as the use of inhaled nitric oxide have reduced the use of extracorporeal membrane oxygenation (ECMO) for term infants with respiratory failure, especially those with meconium aspiration and persistent pulmonary hypertension (PH). Increased access to broad genetic testing has decreased the time to diagnoses for rare diseases, broadened the phenotypic spectrum of diseases not previously associated with neonatal respiratory failure, and identified novel genetic diagnoses of neonatal respiratory failure.^1-4 Many rare genetic disorders that result in hypoxemic respiratory failure are fatal within the first few months of life due to lack of specific therapies, although lung transplantation may be an option. Early recognition and diagnosis of these rare lung diseases are essential if discussions about and referral for lung transplantation are to occur (see later discussion). Awareness of both the common and rare causes of neonatal hypoxemic respiratory failure in term and late preterm infants is needed to optimize clinical care for affected infants, assess for comorbidities, and counsel families regarding prognosis and recurrence risk.

Table 1.

Relatively common causes of neonatal respiratory failure

Disorder	Clinical	Imaging	Pathophysiology	Comment
Transient Tachypnea of the Newborn (TTN)	Onset at birth Tachypnea Crackles on examination +/− retractions Hypoxemia is generally mild (need for supplemental Fio2 < 0.40) Usually improves within 12–24 h	Hyperexpansion Fluid in fissures ± pleural effusions Air leak uncommon	Delayed clearance of alveolar fluid, delayed activation of epithelial sodium channels	Common Increased risk in delivery without labor Antenatal steroids decrease risk
Neonatal Respiratory Distress Syndrome (RDS)	Onset at or within 4 h of birth Signs of respiratory distress (tachypnea, grunting, retractions, cyanosis) May improve rapidly with surfactant therapy Untreated natural history is usually worsening over 48–72 h, followed by plateau for 3–7 d, then improvement	Hypoinflation Diffuse ground glass opacities Air bronchograms Air leak	Developmental insufficiency of pulmonary surfactant production leading to diffuse atelectasis	Prematurity is most common risk factor, risk decreases inversely with advancing gestational age Antenatal steroids decrease risk Male gender, C-section delivery, maternal diabetes, European ancestry, second born of twins increase risk
Meconium Aspiration Syndrome (MAS)	Onset at birth Usually thick meconium-stained amniotic fluid and secretions at birth	Hyperexpansion Patchy alveolar and interstitial infiltrates Air leak	Meconium plugging of small airways leading to focal overexpansion and atelectasis Surfactant inactivation Pulmonary hypertension	Incidence decreasing
Sepsis	Prematurity, prolonged rupture of membranes, maternal infection risk factors, although ~50% without risk factors	Variable: may have diffuse infiltrates mimicking RDS in preterm infants or more patchy with effusions	Inflammatory infiltrates Surfactant inactivation Pulmonary hypertension	Incidence in term infants estimated at ~1 in 1000 live births GBS less common with intrapartum antibiotic prophylaxis
Pulmonary hypoplasia	Anhydramnios or severe oligohydramnios secondary to renal agenesis or anomalies or loss of amniotic fluid due to prolonged rupture of membranes Space occupying lesions in the chest	Small lungs and chest cavity Pneumothorax and pneumomediastinum common	Inadequate lung surface area for gas exchange and pulmonary hypertension	Renal agenesis estimated at ~1 in 5000 live births Prenatal serial amnioinfusions may rescue fatal pulmonary phenotype

Table 2.

Key features of rare, genetic causes of neonatal respiratory failure

Disorder	Gene(s)	Clinical	Imaging	Pathology	Comment
SP-B deficiency	SFTPB	Usually full-term Onset at or shortly after birth, respiratory distress	Diffuse ground glass opacities with alveolar and interstitial infiltrates Air leak	AEC2 hyperplasia Interstitial thickening with mesenchymal cells and fibrosis Alveolar filling with proteinaceous material,	Incidence ~1 in 1 million live births Founder effect variant (‘121ins2’, c.361delCinsGAA, p.P121Qfs*95) accounts for ~70% of pathogenic alleles Autosomal recessive inheritance
ABCA3 deficiency	ABCA3	Similar to SP-B deficiency with more variable severity		cholesterol clefts, and/or macrophages	Incidence estimated at ~1 in 50,000–90,000 live births Monoallelic variants may cause transient neonatal RDS in late preterm and term infants Autosomal recessive inheritance
Brain-thyroid-lung syndrome	NKX2-1				May not have pulmonary disease Hypothyroidism in ~ 80% with lung disease Neurologic symptoms early are nonspecific (hypotonia) and often attributed to severity of respiratory illness Familial (autosomal dominant) or sporadic due to de novo variants; genic or genomic deletions reported
SP-C dysfunction	SFTPC				Usually presents in infancy or older children, neonatal presentation is rare (<10%) Familial (autosomal dominant) or sporadic due to de novo variant
ACDMPV	FOXF1	Early-onset respiratory distress and hypoxemic respiratory failure, severe pulmonary hypertension	Hypoinflation Diffuse ground glass opacities	Paucity of septal capillaries Abnormal shunt vessels in same bronchovascular bundles as pulmonary arteries (“misaligned pulmonary veins”)	Usually sporadic due to de novo variants; rare familial cases reported Deletions in promoter region (5′ untranslated region) recognized Extrapulmonary manifestations common (>50%): cardiac, gastrointestinal, genitourinary Pulmonary lymphangiectasia in >30%
Acinar dysplasia/congenital alveolar dysplasia	TBX4 FGF10		Hypoinflation Diffuse infiltrates	Arrest of lung development at pseudoglandular or canalicular stages	Skeletal abnormalities Mainly sporadic due to de novo variants, although familial cases recognized Later-onset pulmonary hypertension observed
PCD	More than 50 genes recognized	Respiratory distress developing after birth, usually between 12 and 24 h	Focal infiltrates	TEM of nasal or tracheal brushings for ciliary defects—abnormalities or normal depending upon gene(s) involved Bronchiectasis later in life	>80% present in neonatal period Laterality defects in ~50% Chronic wet cough, otitis, and sinus infections in infancy Incidence ~1 in 10,000

Abbreviations: ABCA3, member A3 of the ATP-binding cassette family; AEC2, alveolar type 2 pneumocyte; SP-B, surfactant protein B; SP-C, surfactant protein C; TEM, transmission electron microscopy.

Transient Tachypnea of the Newborn

The most common cause of neonatal respiratory failure among late preterm and term infants is transient tachypnea of the newborn (TTN), also referred to as retained amniotic fluid or delayed transition. Risk factors for TTN include cesarean-section without labor, early term (37–38 weeks’ estimated gestation) or late preterm status, and male sex. Infants with TTN typically present with respiratory distress at or shortly after birth which, as its name implies, includes tachypnea as well as retractions, grunting, nasal flaring, and hypoxemia.

The pathophysiology of TTN is due to delayed clearance of amniotic fluid from the lungs after birth. The process of labor and the transition from fetal to neonatal life result in a surge of catecholamines and exposure to mechanical forces, which activate sodium channels in the pulmonary epithelium.⁵ These channels absorb lung fluid into the pulmonary circulation and lymphatics. For infants with TTN, this absorption process is impaired and results in residual fluid in the alveoli and interstitium (pulmonary edema) and decreased pulmonary compliance, which manifest as tachypnea, increased work of breathing, and hypoxemia.⁵ As the pulmonary fluid is absorbed, respiratory symptoms rapidly improve.

Term infants with TTN can usually be managed with continuous positive airway pressure (CPAP) and rarely require intubation and mechanical ventilation. Affected infants may require supplemental oxygen, but this is typically low with fraction of inspired oxygen (FiO2) less than 0.40. Blood gas monitoring may demonstrate respiratory acidosis, and chest radiograph often demonstrates increased opacities and fluid in the fissure between the right upper and middle lobes. Most infants with TTN improve rapidly within the first 12 hours after birth, and nearly all have improved by 24 to 48 hours. Severe or persistent respiratory distress, high need for supplemental oxygen, or prolonged need for respiratory support should prompt the clinician to consider other etiologies.

Respiratory Distress Syndrome

Respiratory distress syndrome (RDS) typically results from a developmental insufficiency of surfactant production by alveolar epithelial type 2 (AEC2) cells and is extremely common in preterm infants, affecting nearly all infants born prior to 29 weeks’ estimated gestation.⁶ However, RDS can also occur among term and late preterm infants, especially those with risk factors of male sex, European ancestry, maternal diabetes, induced vaginal delivery or Cesarean section without labor, and the second born of twins.^7,8 While the incidence of RDS decreases with advancing gestational age toward 40 weeks, RDS still occurs in 3.2% of late preterm and 0.12% of term infants.⁷ The incidence of RDS is lower among female infants and those of African, Asian, or Hispanic ancestry.⁷ Antenatal steroids provided to mothers at 34 to 36 weeks’ gestation decrease the incidence of RDS and NICU admission but are associated with an increased risk for neonatal hypoglycemia.⁹ The increased risk for RDS among male infants is attributed to differences in lung maturation driven by sex hormones.¹⁰ Estrogen accelerates and testosterone delays surfactant production and alveologenesis. Fetal surfactant production is also delayed in mothers with diabetes, especially those with poor glycemic control.¹¹

The clinical features of RDS and management of term and late preterm infants with RDS are similar to those for preterm infants. Respiratory symptoms are usually present at or shortly after birth and include tachypnea, retractions, grunting, and nasal flaring. Chest radiograph typically demonstrates diffuse ground glass opacities and air bronchograms. Term and late preterm infants are at an increased risk for developing air leak (pneumothorax, pneumomediastinum, pulmonary interstitial emphysema) related to RDS given their ability to generate substantial intrathoracic pressure with vigorous crying or significant work of breathing and from uneven expansion of distal airspaces due to surfactant insufficiency. Arterial blood gas measurement may demonstrate respiratory acidosis and hypoxemia. Clinical management includes positive pressure ventilation (CPAP or mechanical ventilation for severe cases), supplemental oxygen, and exogenous surfactant administration for persistent oxygen requirement and/or impaired ventilation. Untreated, respiratory symptoms of RDS typically worsen over the first 48 to 72 hours and may persist for 7 to 10 days. However, many term and late preterm infants demonstrate clinical improvement after 48 to 72 hours and may have marked improvement after exogenous surfactant administration.

Clinical suspicion for other underlying disorders (eg, congenital heart disease and genetic surfactant dysfunction disorders) should be considered for infants without traditional risk factors for RDS as well as those who have progressive chest radiograph findings (eg, total anomalous pulmonary venous return), require multiple doses of surfactant, have severe PH, or prolonged need for mechanical ventilation (>7 days). Given that RDS can be difficult to distinguish from sepsis, most infants are treated with empiric antibiotics. Twin studies of monozygotic and dizygotic twins support the observation that RDS among term and preterm infants is a heritable disorder, with genetic as well as environmental factors contributing to disease risk.⁸ Monoallelic variants in the gene that encodes the ATP-binding cassette transporter member A3 (ABCA3) have been associated with reversible RDS in term and late preterm infants.^12,13 ABCA3 deficiency is an autosomal recessive disorder, requiring pathogenic variants on both alleles (biallelic), and is frequently associated with progressive respiratory failure requiring lung transplantation for survival (see later discussion and Table 2). In contrast, infants with monoallelic (heterozygous) ABCA3 variants and neonatal RDS typically improve with supportive care in the NICU.^12,14 Studies on the long-term follow-up of infants with monoallelic ABCA3 variants and neonatal respiratory symptoms are needed.

Meconium Aspiration Syndrome

Meconium-stained amniotic fluid is present at the time of birth for up to 16% of term infants and 27% of post-term infants.¹⁵ Despite this, only 2-4% of infants born with meconium-stained amniotic fluid develop meconium aspiration syndrome (MAS).¹⁶ Infants with MAS often have a history of non-reassuring fetal status, prolonged rupture of membranes, chorioamnionitis, need for resuscitation at birth, and/or cord blood with lactic acidosis. These infants are at an increased risk for persistent pulmonary hypertension (PPHN) as well as neonatal encephalopathy, the treatment of which is therapeutic hypothermia, which may also exacerbate respiratory failure and PPHN.17

The pathogenic mechanisms of MAS include airway obstruction in which meconium can partially or completely occlude small airways, resulting in a ball-valve mechanism in which air enters during inhalation but is unable to completely exit during exhalation. Meconium also contains bile salts and pancreatic enzymes that can cause inflammation and pneumonitis, and meconium can inactivate surfactant. Chest radiograph findings typically include coarse patchy opacities, air trapping, and hyperinflation. Blood gases measurements frequently demonstrate respiratory acidosis and hypoxemia. Infants with MAS can develop severe PH, which may be especially difficult to manage when an infant is also undergoing therapeutic hypothermia for neonatal encephalopathy. Prior to the clinical application of inhaled nitric oxide, MAS was one of the most common indications for ECMO use in term infants.¹⁸ Given that MAS can be difficult to distinguish from sepsis, most infants are treated with empiric antibiotics. Administration of exogenous surfactant may improve oxygenation and ventilation in infants with MAS.

Sepsis

Infants with sepsis may present with respiratory symptoms at birth or in the hours or days following. Especially concerning for sepsis is the infant who was initially breathing comfortably on room air for several hours who then develops respiratory symptoms including tachypnea, hypoxemia, and/or retractions. The most common causes of early onset (<72 hours of life) neonatal sepsis are group B streptococcus (GBS), Escherichia coli, Listeria monocytogenes, and other gram-negative bacteria including Klebsiella, Haemophilus influenzae, and Enterobacter cloacae. Risk factors for sepsis include maternal fever or chorioamnionitis, prolonged rupture of membranes, and maternal GBS colonization with inadequate intrapartum antibiotic exposure. The Kaiser Permanente Early-Onset Sepsis Calculator, which includes both maternal and neonatal risk factors, is a useful tool for stratifying sepsis risk in term and late preterm neonates, reducing empiric antibiotic use in well-appearing infants, and maintaining high sensitivity to identify those infants with bacterial infections.¹⁹ Empiric antibiotics for neonatal sepsis typically consist of ampicillin and gentamicin, based on the most likely organisms and local microbiology sensitivity data. Antibiotic coverage should be narrowed for positive cultures once sensitivities are available. Chest radiograph findings from infants with sepsis can vary from unremarkable to diffuse ground glass opacities or focal opacity consistent with neonatal pneumonia. Blood cultures are the gold standard for diagnosis, with careful attention to adequate blood volume (≥1 mL per culture bottle, aerobic bottle prioritized over anaerobic) to maximize bacterial pathogen detection.

Secondary Causes of Neonatal Respiratory Failure in Term Infants

There are many secondary causes of neonatal respiratory failure in term and late preterm infants due underlying conditions including maternal exposures. Maternal magnesium exposure may cause decreased tone and insufficient respiratory effort, and maternal anesthesia may cause apnea and/or hypopnea. Maternal use of selective serotonin reuptake inhibitors has been associated with PPHN that generally improves with respiratory support.²⁰

Infants with trisomy 21 are at risk of neonatal respiratory failure due to multiple mechanisms including congenital heart disease, upper airway abnormalities, pulmonary growth disorders, and hypotonia.²¹ Infants with trisomy 21 are at an increased risk for PPHN and may have prolonged oxygen requirements, even after other respiratory symptoms have improved.²¹ Hypotonia may result in hypopnea or insufficient respiratory effort, which generally improves with supportive care, growth, and time.

Infants with neuromuscular disorders such as spinal muscle atrophy, congenital myopathies, and congenital myotonic dystrophies often present with profound hypotonia and insufficient respiratory effort. Their needs for respiratory support and prognosis vary depending on the underlying disorder, the majority of which are genetic in etiology. These disorders are often suspected based on physical examination with generalized hypotonia, weakness, and/or contractures.

Infants with congenital anomalies affecting pulmonary development can present with respiratory failure, most commonly congenital diaphragmatic hernia, congenital pulmonary airway malformation (CPAM), and bronchopulmonary sequestration. Infants with pulmonary hypoplasia secondary to renal anomalies or disrupted musculoskeletal development (eg, thanatophoric dysplasia and short-rib polydactyly syndromes) can also present with neonatal respiratory failure. The fatal pulmonary phenotype associated with renal agenesis or other renal anomalies resulting in anhydramnios may be rescued by prenatal serial intra-amniotic infusions of saline.²² However, such treated infants will still have renal failure requiring dialysis until they are large enough for a renal transplant. Surviving infants have also had a high incidence of adverse neurologic outcomes including strokes.²² Oligohydramnios that occurs late in gestation has a more variable, less predictable outcome, and infants may have initial severe disease but eventually improve with supportive therapy, including prolonged ventilation and pulmonary vasodilators.

Congenital heart malformations that can present as neonatal respiratory failure shortly after birth include total anomalous pulmonary venous return, hypoplastic left heart syndrome, left ventricular outflow obstruction, transposition of the great arteries, Ebstein’s anomaly, and severe pulmonary stenosis or atresia. Infants with in utero supraventricular tachycardia can develop cardiac failure that may also result in neonatal respiratory failure. Infants with critical coarctation of the aorta can develop respiratory failure in the first few days of life after the ductus arteriosus closes, and infants with truncus arteriosus, ventricular septal defects, and arteriovenous malformations (AVMs, most commonly cerebral or liver) can present with respiratory failure due to heart failure. Antenatal ultrasound may detect some but not all of these anomalies. The diagnostic approach for these disorders includes a thorough physical examination as well as ultrasound studies including echocardiogram, head, abdominal, and/or renal ultrasounds, or advanced imaging (eg, MRI for AVMs).

GENETIC CAUSES OF NEONATAL RESPIRATORY FAILURES IN TERM INFANTS

Surfactant Dysfunction Disorders (Surfactant Protein-B, Surfactant Protein-C, ATP-Binding Cassette Transporter Member A3, NKX2-1)

Term and late preterm infants with pathogenic variants in genes that encode proteins required for surfactant production or function frequently present with neonatal respiratory failure. Infants with biallelic loss-of-function variants in the genes encoding surfactant protein-B (SFTPB) or ATP-binding cassette transporter member A3 (ABCA3) present with severe, progressive neonatal respiratory failure that is usually fatal in the first months of life without lung transplant.^23-27 Chest radiograph findings are similar to those of extremely preterm infants with RDS with persistent diffuse ground glass opacities and air bronchograms. Arterial blood gas measurements typically demonstrate impaired oxygenation and ventilation. Air leaks are common in affected infants as high pressures with mechanical ventilation are often needed to inflate the poorly compliant, surfactant-deficient lungs. Diagnosis is made via genetic testing, and these disorders should be suspected in term and late preterm infants with respiratory failure who do not demonstrate clinical improvement by 7 days, particularly if there are no clinical risk factors for more common neonatal lung diseases. If genetic testing results are diagnostic, then lung biopsy is not necessarily required for confirmation. Lung histopathology features for SP-B and ABCA3 deficiencies differ from those of RDS, in which the principal lung pathology involves diffuse atelectasis and hyaline membrane formation.²⁸ In contrast, the lung histopathology for surfactant dysfunction disorders demonstrates characteristic findings including AEC2 hyperplasia, mesenchymal thickening with interstitial cells and fibrosis, and variable accumulations of proteinaceous material, alveolar macrophages, and cholesterol clefts filling distal airspaces.²⁹ While these findings are highly suggestive of surfactant dysfunction, they are not specific for a given gene.

Currently available therapies for SP-B and ABCA3 deficiencies remain limited and are largely supportive with optimization of mechanical ventilation and nutritional support. Affected infants may demonstrate improvement in oxygenation and ventilation with exogenous surfactant, but these effects are transient, lasting only several hours and often diminish with subsequent doses.³⁰ Empiric medications used to treat childhood interstitial lung disease (chILD) including azithromycin, hydroxychloroquine, and corticosteroids typically do not have a substantial or sustained clinical effect for infants with SP-B or ABCA3 deficiencies.^25,26,31 Currently, lung transplantation is the only definitive treatment option for affected infants.^31-33 Early consultation with one of the few centers in the United States who perform infant lung transplantation^32,33 is recommended to confirm the molecular diagnosis, preliminarily assess transplant candidacy, provide family education regarding lung transplantation, and coordinate transport, if desired. The 5 year survival for infant lung transplant is approximately 50-60%, and approximately half of counseled families decline to pursue lung transplantation.^32,33 The vast majority of pathogenic variants in SFTPB and ABCA3 are inherited from healthy/unaffected parents, and the recurrence risk is 25%, similar to other autosomal recessive disorders. Some families elect to pursue preimplantation genetic testing or prenatal testing with subsequent pregnancies.

In contrast to biallelic loss-of-function variants in SFTPB and ABCA3 that are associated with neonatal respiratory failure and death in the first few months of life without lung transplantation, the respiratory phenotypes of infants with missense variants in ABCA3 or less commonly in SFTPB that may permit some amount of protein function are more difficult to predict.^23,25,34 For example, the most common pathogenic variant in ABCA3, p.Glu292Val, is relatively frequent in the population (0.4% of individuals in the genome aggregation database, gnomAD³⁵ [accessed April 2026]), permits some amount of ABCA3 function,^23,25,34 and is most commonly associated with chILD phenotypes rather than progressive neonatal respiratory failure.^{23,25,34,36,37} The majority of ABCA3 variants are unique to individuals and families, and some missense variants also result in severe phenotypes. Some ABCA3 variants can also occur on the same allele (in cis) with only a single allele affected, thereby demonstrating the importance of trio testing (infant proband and parents) to phase variants.^23,38 Consultation with clinical geneticists and/or chILD experts is recommended for interpretation of genetic testing results.

In contrast to SP-B and ABCA3 deficiencies that are autosomal recessive disorders, pathogenic variants in the genes that encode surfactant protein-C (SFTPC) and thyroid transcription factor 1 (NK2 Homeobox 1 [NKX2-1]) can be inherited in an autosomal dominant manner or arise de novo and cause sporadic disease. The disease penetrance is highly variable, even in family members who share the same pathogenic variant.³⁹ A parent of an infant with respiratory failure and a SFTPC variant may carry the same variant, yet be completely asymptomatic, making interpretation of the significance of the variant challenging if it has not been previously recognized as pathogenic. In contrast, an apparent de novo variant identified in a symptomatic infant is more likely to be pathogenic, again emphasizing the importance of trio testing. Infants with pathogenic SFTPC variants can present with neonatal respiratory failure, but the more typical clinical presentation is that of chILD among older infants and children.⁴⁰ Clinical features of chILD include tachypnea, failure to gain weight, digital clubbing, and hypoxemia.⁴¹

Aside from its role in regulating lung development and surfactant expression, TTF-1 is also important in thyroid and brain development.⁴² Infants with pathogenic variants in NKX2-1 can present with neonatal respiratory failure, as well as chILD or recurrent pulmonary infections, and often have hypothyroidism or neurologic features including chorea, ataxia, hypotonia, and/or developmental delay. This constellation of findings is termed “brain-thyroid-lung” syndrome, and affected infants can have abnormalities in a single or multiple organ systems, which may be present at birth or develop over time (Figs. 1-3). Importantly, pathogenic variants in NKX2-1 include both single nucleotide variants (SNVs), small in-frame insertions or deletions (in/dels), or larger deletions encompassing NKX2-1 and contiguous genes, emphasizing the utility of genetic testing to assess copy number variants (CNVs), such as offered through genome sequencing (GS).^42-45 Deletions of noncoding regions adjacent to NKX2-1 important for its regulation have also been described as a cause of the disorder.⁴⁶

Fig. 1.

Overview of surfactant metabolism. Surfactant lipids and proteins are synthesized in alveolar epithelial type 2 cells (AEC2s), stored in organelles called lamellar bodies, secreted into the thin layer of liquid overlying the alveolar cells (hypophase), and spread to form a monolayer at the air–liquid interface. Surfactant components are recycled into the AEC2s and catabolized by alveolar macrophages. SP-B and SP-C are synthesized as proproteins in the endoplasmic reticulum, processed through the Golgi apparatus, and transported to the lamellar bodies. ABCA3 sits on the surface of lamellar bodies and imports key phospholipids (phosphatidylcholine and phosphatidylglycerol) into the lamellar bodies. Surfactant is secreted by exocytosis of the lamellar body into the hypophase forming a structure called tubular myelin, and SP-B and SP-C help facilitate the formation of the surfactant monolayer. TTF-1 is a transcription factor important for regulating the genes encoding ABCA3, SP-B, and SP-C and many others in the lung as well as in the brain and thyroid gland. ABCA3, Member A3 of the Adenosine Triphosphate Binding Cassette; PC, phosphatidylcholine; PG, phosphatidylglycerol; SP-B, surfactant protein B; SP-C, surfactant protein C; TTF-1, thyroid transcription factor 1. (Image courtesy of Dr Satyan Lakshminrusimha, MD, MBBS, FAAP.)

Fig. 3.

Alterations in lung development in acinar dysplasia and congenital alveolar dysplasia. The left side illustrates the interruptions in lung development in acinar dysplasia (at the pseudoglandular stage) and congenital alveolar dysplasia (at the canalicular and early saccular stages) resulting from pathogenic variants in either the genes encoding TBX4 or FGF10. Variable abnormalities in other organ systems are illustrated on the right. ASD, atrial septal defect; FGF10, fibroblast growth factor 10; PDA, patent ductus arteriosus; TBX4, T-box transcription factor 4 ; VSD, ventricular septal defect. (Image courtesy of Dr Satyan Lakshminrusimha, MD, MBBS, FAAP.)

The disease courses for individuals with lung disease due to pathogenic SFTPC and NKX2-1 variants are variable and can be difficult to predict. Even among individuals with the most frequently encountered pathogenic SFTPC variant, p.Ile73Thr, the disease course can vary from severe neonatal respiratory failure, chILD, adult pulmonary fibrosis, or remaining relatively asymptomatic for decades.^39,40 Treatments have included empiric medication use (eg, azithromycin, hydroxychloroquine, and corticosteroids), which may have more clinical benefit in SFTPC-related lung disease,^47,48 although evidence supporting the efficacy of these medications is limited. Infants with severe lung disease due to pathogenic SFTPC variants may have considerable improvement with supportive therapy including chronic oxygen, mechanical ventilation through tracheostomy or noninvasive support, and optimization of nutrition.^49,50 Individuals with pathogenic NKX2-1 variants should have thyroid function studies evaluated and receive thyroid replacement therapy if hypothyroid. Lung transplantation is an option for progressive respiratory failure. Children (>1 year of age) transplanted for SFTPC and NKX2-1 associated lung disease have a 5 year survival of approximately 80%, but bronchiolitis obliterans remains a major cause of chronic graft failure and mortality.^32,33 Recurrence risk for SFTPC and NKX2-1 is related to the underlying genetic mechanism identified in the family, whether inherited (50%) or de novo (~1%–5%). Due to possible germ-line mosaicism, recurrence risk is not 0 even with apparent de novo variants.⁵¹ Parents of infants identified with variants in surfactant-related genes should be referred for genetic counseling.

Monogenic lung diseases such as SP-B and ABCA3 deficiencies are compelling candidates for gene therapy.^52,53 Gene therapy with an adeno-associated virus (AAV) capsid 6 resulted in prolonged survival (>6 months) in a mouse model of SP-B deficiency.⁵⁴ This vector also transduces human lung tissue, demonstrating its potential for clinical translation to human infants.⁵⁴ To target SP-C dysfunction, a dual function AAV6 vector designed to express functional SP-C and suppress the Sftpc^I73T variant allele was developed, resulting in improved lung function and attenuated alveolar simplification in a mouse model.⁵⁵ Lentiviral-mediated gene therapy performed in cell lines that stably express ABCA3 variants that encode mistrafficking and phospholipid transport mutant proteins suggest that different gene complementation strategies may be required based on ABCA3 variant class.⁵⁶ While several hurdles need to be addressed before these therapies are available for human infants, these preclinical studies suggest hope for the development of future therapies for these often fatal disorders.

Pulmonary surfactant also contains two larger, hydrophilic proteins, surfactant proteins A (SP-A) and D. Pathogenic variants in the two genes for SP-A (SFTPA1 and SFTPA2) cause pulmonary fibrosis and lung cancer in adults but have not been observed as a cause of neonatal respiratory disease.⁵⁷ Disease related to pathogenic variants in SFTPD have not been reported.

Alveolar Capillary Dysplasia with Misalignment of the Pulmonary Veins (Forkhead box 1 Transcription Factor) and Other Developmental Lung Disorders (TBX4 and Fibroblast Growth Factor 10)

The classic or typical presentation of alveolar capillary dysplasia with misalignment of the pulmonary veins (ACDMPV) is that of severe neonatal respiratory failure and PH at or within hours of birth in term and late-preterm infants. ACDMPV is caused by pathogenic SNVs and deletions of the FOXF1 gene, which encodes a transcription factor important for lung as well as cardiac, gastrointestinal, genitourinary, and other organ system development. Affected infants may have congenital anomalies in other organ systems, most commonly intestinal malrotation and structural heart disease, some of which may be detected prenatally and prompt genetic testing. Some infants do not have anomalies outside the lung, and the diagnosis may not be suspected until several days of life, especially if other features such as meconium-stained amniotic fluid are present. Infants with ACDMPV often have progressive hypoxemia and refractory PH despite mechanical ventilation, FiO2 1.0, inhaled nitric oxide, and other pulmonary vasodilators and may be referred for and treated with ECMO. As the medical treatment of severe PH has improved over the past 30 years, genetic testing that includes assessment of CNVs (eg, GS) should be strongly considered in term infants who progress to requiring ECMO support, in the absence of another confirmed diagnosis (eg, several viral infection, congenital diaphragmatic hernia).

ACDMPV has historically been diagnosed with lung biopsy or on autopsy. Histopathologic features include reduced number of alveolar capillaries located within the interstitium, medial arterial hypertrophy, lobular maldevelopment, lymphangiectasia (~30%), and pulmonary veins abnormally located in the bronchovascular bundle— the “misaligned pulmonary veins.” These vessels are now recognized to be persistent shunt vessels present in the developing lung.⁵⁸ With the discovery of pathogenic FOXF1 variants as the primary cause of ACDMPV, diagnosis is currently often made via genetic testing, although lung biopsy may still be utilized if rapid genetic testing is not available. The majority of FOXF1 variants arise de novo on the maternal allele,⁵⁹ thus making recurrence risk low (1%–5%) but not 0 due to germline mosaicism.^51,60 Deletion of noncoding regulatory regions upstream of FOXF1 have been identified in affected infants, emphasizing the importance of broad genetic testing (eg, GS) that includes CNVs. Some families with more than one affected child have been reported, as well as FOXF1 variants present on the paternal allele and infants with histologic features of ACDMPV without FOXF1 variants identified.⁶¹ Exome sequencing (ES) has not identified a second gene consistently associated with ACDMPV.⁶² Given the complex gene regulation and imprinting of this genomic region,^61,63 genetic mechanisms resulting in ACDMPV may not be detected with current clinical technologies. Consultation with a clinical geneticist is recommended for interpretation of results and family counseling.

Aside from ACDMPV, other rare lung developmental disorders may have a genetic basis. Acinar dysplasia (AD) and congenital alveolar dysplasia (CAD) are disorders where lung development is arrested at the pseudoglandular and canalicular stages, respectively.⁶⁴ A genetic basis for AD had been postulated, and pathogenic variants in the genes that encode transcription factor TBX4 and one of its downstream targets, FGF10, have been identified as causes of AD and CAD.^65,66 These disorders may present with severe neonatal respiratory failure, but the phenotype can be variable with later onset lung disease or PH.^67,68 As TBX4 is expressed in other tissues, infants with TBX4 variants may have abnormalities in other organ systems, primarily skeletal.⁶⁹

Treatment options for lung developmental disorders remain very limited, with severe cases usually fatal within the first weeks of life. Lung transplant with long-term survival has not been reported for infants with the classic ACDMPV presentation, likely due to the severity of illness and median wait time of approximately 2 months for suitable organs.^32,33 Infants with less fulminant or delayed presentations of ACDMPV have been reported, with the oldest infant presentation reported at 7 months of age.^70,71 Several of these infants with “atypical presentations” have survived to lung transplant while receiving supplemental oxygen and pulmonary vasodilators, and at least one child stabilized with pulmonary vasodilator therapy to age 2.5 years without lung transplant after genetic testing in the neonatal period.⁷² Some promising therapies for ACDMPV have been reported in animal models, including nanoparticle delivery of Signal Transducer And Activator Of Transcription 3 (STAT3), a downstream target of FOXF1 as well as a compound that stabilizes the FOXF1 protein, transcellular activator of nuclear FOXF1 expression (TanFe).^73,74 While there are challenges to overcome before clinical application to patients, these advances provide some potential therapeutic strategies for this devastating disorder.

Primary Ciliary Dyskinesia

While the lung disease is generally not as severe as with surfactant or developmental disorders, primary ciliary dyskinesia (PCD) should be considered in the differential diagnosis of neonatal respiratory failure. Multiple studies have demonstrated that greater than 80% of affected infants are admitted to an NICU with neonatal respiratory distress.^75,76 However, the typical age of diagnosis is greater than 4 years, so an opportunity for early diagnosis is often missed.^75,76 The diagnosis may be suggested when laterality defects (situs inversus, heterotaxy) are present, but these occur in fewer than 50% of affected infants. The typical presentation generally occurs after birth (12–24 hours) with imaging showing more focal infiltrates, often interpreted as pneumonia.⁷⁵ PCD is genetically heterogenous as many (>50) genes encode proteins involved in ciliary assembly and function, but pathogenic variants can be detected by multiple available panels, ES, or GS. A history neonatal respiratory distress and chronic nasal congestion, chronic wet cough, and recurrent otitis after NICU discharge should prompt consideration of PCD.^75,76

Genetic Testing for Rare Lung Diseases

While examination of lung tissue was historically needed for diagnosis of many rare disorders, as most of these disorders have a genetic basis, rapid genetic testing has become the primary means for establishing a diagnosis. Genetic testing is noninvasive, can establish a specific diagnosis, and with advances in sequencing methodologies and analysis can provide results in a timely and cost-effective manner.^44,77 Rapid ES/genome sequencing (GS) is now widely available with preliminary results returned in 5 to 7 days, often sooner.^45,78 Disadvantages of genetic testing include cost, possible ambiguous results from variants of uncertain significance, variable turn-around times, and possible incidental findings, including pathogenic variants in other genes and discovery of nonpaternity or consanguinity. Sensitivity even for known disorders is also not 100%. Next-generation sequencing (NGS) panels of multiple targeted genes may not include a potential gene of interest, especially if recently recognized. Results reported from ES/GS depend on the phenotypic features communicated to the testing laboratory at the time the sample is sent, and potential pathogenic variants in genes interpreted as not related to the phenotype may not be reported. ES may need to be complemented with a method sensitive to detecting CNVs (in/dels). While NGS panels have an advantage with potential greater sensitivity due to a deeper depth of coverage (the average number of times a base is sequenced) and often lower cost, ES or GS can detect variants in genes that are ultra-rare causes of neonatal lung disease that are not initially clinically suspected and may otherwise be missed.⁷⁷ Turn-around-times for ES/GS are also often shorter than for panels.

SUMMARY

In summary, hypoxemic respiratory failure in term and late preterm infants is commonly encountered in the NICU. The majority of affected infants have self-limiting conditions that resolve with supportive therapies and time. However, some infants have rare genetic disorders that result in severe, progressive, and even fatal disease. Recognition of these common and rare disorders is needed to determine for whom and when to send genetic testing and to facilitate early discussion of lung transplantation. Increased use of broad genetic testing (eg, GS) will expand the phenotypic spectrum of rare diseases not previously associated with neonatal respiratory symptoms and identify novel genes associated with neonatal respiratory failure.

Fig. 2.

Alterations in lung development in alveolar capillary dysplasia with misalignment of the pulmonary veins (ACDMPV). A normally developed acinar unit is shown on the left, and the changes seen in ACDMPV are seen in the middle. Key changes include thickening of the media of the pulmonary arteries (contributing to severe pulmonary hypertension), dysplastic airspaces with a paucity of capillaries, dilated lymphatics, and the presence of persistent fetal shunt vessels in the same bronchovascular bundle as the pulmonary artery. ACDMPV results from pathogenic variants in the gene FOXF1, which is critical for vascular development in the lung and other organs. Consequences of FOXF1 variants in other organ systems are shown on the right, which occur in greater than 50% of affected infants. FOXF1, gene encoding Forkhead box 1 transcription factor; IBA, intermediate bronchial artery; PA, pulmonary artery; PV, pulmonary vein; SNV, single nucleotide variant. (Image courtesy of Dr Satyan Lakshminrusimha, MD, MBBS, FAAP.)

KEY POINTS.

• Respiratory failure in term and late preterm infants can result from diverse etiologies and is commonly encountered in the neonatal intensive care unit (NICU).

• Transient tachypnea of the newborn, respiratory distress syndrome, and meconium aspiration are the most common causes of neonatal respiratory failure in term and late preterm infants.

• Respiratory failure in term and late preterm infants can be secondary to multiple causes including maternal medications, neonatal encephalopathy, congenital anomalies, or neuromuscular disorders.

• Rare genetic diseases including surfactant dysfunction disorders and alveolar capillary dysplasia often present as persistent, progressive respiratory failure in term or late preterm infants.

• Broad, rapid genetic testing for rare diseases should be pursued for term or late preterm infants not improving by 7 days of life to inform prognosis and clinical decision-making, including lung transplantation or palliative care.

Best Practices.

• Transient tachypnea of the newborn, respiratory distress syndrome, and meconium aspiration syndrome are the most common causes of hypoxemic respiratory failure in term and late preterm infants and typically resolve with supportive care.

• Broad, rapid genetic testing for rare diseases should be pursued in term or late preterm infants with progressive or prolonged hypoxemic respiratory or severe pulmonary hypertension who do not demonstrate clinical improvement by 7 days.

• Identification of rare genetic etiologies of hypoxemic respiratory failure informs prognosis and guides clinical decision-making, including consideration of lung transplantation or palliative care.

Abbreviations

AAV

adeno-associated virus

ABCA3

ATP-binding cassette transporter member A3

ACDMPV

alveolar capillary dysplasia with misalignment of the pulmonary veins

AD

acinar dysplasia

AEC2

alveolar epithelial type 2

ASD

atrial septal defect

AVMs

arteriovenous malformations

CAD

congenital alveolar dysplasia

chILD

childhood interstitial lung disease

CNVs

copy number variants

CPAM

congenital pulmonary airway malformation

CPAP

continuous positive airway pressure

ECMO

extracorporeal membrane oxygenation

FGF10

fibroblast growth factor 10

FOXF1

gene encoding Forkhead box 1 transcription factor

GBS

group B streptococcus

GS

genome sequencing

IBA

intermediate bronchial artery

in/dels

insertions or deletions

MAS

meconium aspiration syndrome

NGS

next-generation sequencing

NICU

neonatal intensive care unit

PA

pulmonary artery

PC

Phosphatidylcholine

PCD

primary ciliary dyskinesia

PDA

patent ductus arteriosus

PG

phosphatidylglycerol

PH

pulmonary hypertension

PPHN

persistent pulmonary hypertension

PV

pulmonary vein

RDS

respiratory distress syndrome

SFTPA

surfactant protein-A

SFTPB

surfactant protein-B

SFTPC

surfactant protein-C

SNVs

single nucleotide variants

TBX4

gene encoding T-box transcription factor 4

TEM

transmission electron microscopy

TTF-1

thyroid transcription factor 1

TTN

transient tachypnea of the newborn

VSD

ventricular septal defect