Clinical course and long-term follow-up of a preterm infant with non-fatal respiratory distress syndrome due to heterozygous ABCA3 gene mutation: A case report and review of literature

Abstract

BACKGROUND:

Adenosine triphosphate-binding cassette transporter A3 (ABCA3) mutations are recognized as a congenital cause of surfactant deficiency. Clinical presentations of such mutations are largely variable. There are many mutations of the ABCA3 gene, of which, p.E292V is the most common. Despite being the most common ABCA3 gene mutation, there is limited literature on extra pulmonary and long-term outcomes of the affected infants.

CASE:

We present the case of a Caucasian male infant born at 32 weeks gestation that developed severe respiratory distress shortly after birth, and review published case reports and case series of infants affected with this gene mutation. He was found to have a heterozygous missense mutation p.E292V of ABCA3 resulting in a chronic lung disease. He required multiple courses of systemic and inhalational steroids. He developed supraventricular tachycardia (SVT), feeding problems and hypotonia during his prolonged hospital stay. He demonstrated mild neurodevelopmental delays on follow up at 18 months of age. The chronic lung disease improved over the first 2 years of life. He continued to have feeding difficulties and supraventricular tachycardia at nearly 2 years of age.

CONCLUSION:

The infant’s SVT may be associated with this ABCA3 variant. Further long-term follow-up studies are needed to better characterize extrapulmonary manifestations of this ABCA3 mutation.

Keywords

BSID III neurodevelopment p.E292V supra ventricular tachycardia

1 Introduction

Pulmonary surfactant, a phospholipid-protein complex produced by type II alveolar cells and assembled into lamellar bodies, has long been recognized for its crucial role in decreasing surface tension to prevent alveolar collapse on expiration [1]. While surfactant deficiency classically causes respiratory distress syndrome (RDS) in preterm infants due to deficient production, congenital abnormalities leading to surfactant deficiency can also present with RDS. Mutations in the ATP-binding cassette transporter 3 (ABCA3) gene are known to disrupt surfactant production [2].

The ABCA3 protein is a lamellar body transmembrane protein in type II alveolar cells. It functions as a transporter of the phospholipid components of pulmonary surfactant, and appears to be involved in the formation of normal lamellar bodies [1]. There are more than 400 mutations of the ABCA3 gene reported to date, and outcomes of patients with ABCA3 gene mutations is highly variable, ranging from fatal neonatal respiratory failure to childhood interstitial lung disease to diffuse parenchymal lung disease in adults [3]. Although the true incidence of surfactant deficiency due to ABCA3 mutation is unknown, a study by Wambach et al., estimates the frequency of ABCA3 deficiency may be as high as one in 3100 among European-descent individuals and one in 18000 among African-descent individuals [4]. The most common mutation is p.E292V (c.875 A > T), which is expected to result in the substitution of valine for glutamic acid in codon 292 of the ABCA3 gene [5].

We describe the clinical course, long term pulmonary and neurodevelopmental outcomes of a child with a heterozygous missense mutation (p.E292V) of the ABCA3 gene.

2 Case report

A Caucasian male infant was born at 32 weeks of gestation by emergency cesarean section due to fetal bradycardia. The pregnancy was complicated by gestational diabetes mellitus and Hemolysis, Elevated Liver enzymes, Low Platelet count (HELLP) syndrome. He was born with a birth weight of 2.38 kg (appropriate for gestational age) and Apgar scores of 7, 6, and 8 at 1, 5, and 10 minutes respectively. After stabilization from the delivery, the infant was transferred to the NICU for management of respiratory failure. Bubble Continuous Positive Airway Pressure (BCPAP) was used initially for the management of respiratory distress. However, because of worsening respiratory failure and oxygen requirements, he was intubated at 3 hours of life and was extubated again to BCPAP after administration of 1^st dose of exogenous surfactant (CUROSURF® (poractant alfa)) through the endotracheal route. There was some improvement in the oxygen requirement and work of breathing. However, he was again intubated at about 48 hours of life for worsening respiratory distress. He received 2nd dose of surfactant. Over next 4 days he was weaned on respiratory support and was extubated to BCPAP when the oxygen requirement was 30–35%. Multiple initial chest radiographs showed low lung volumes with diffuse interstitial and granular opacities (Fig. 1A).

Fig. 1

Chest radiographs taken A. at birth with low lung volumes, crowding of bronchovascular structures, diffuse interstitial and granular opacities with a few scattered patchy pulmonary opacities. B. at 36 weeks of corrected age with persisting coarse interstitial prominence with hyperinflation. C. at 22 months of corrected age with bilateral perihilar peribronchial thickening and opacities.

He was continued on BCPAP+ 6 cm H20 with oxygen requirements in the range of 30–35%. At four weeks of age, the respiratory support was changed to heated humidified High Flow Nasal Cannula (HHFNC) with maximum flow of eight liters per minute. As the infants was nearly 36 weeks corrected age and still was needing mild to moderate respiratory support, following were considered as differential diagnoses –surfactant protein deficiencies including ABCA3 mutation, NKX2.1/TTF-1, neuroendocrine cell hyperplasia of infancy, pulmonary interstitial glycogenosis, pulmonary alveolar proteinosis (CSF2RA and CSF2RB). Alveolar capillary dysplasia syndromes were less likely given the mild to moderate severity and that patient had already demonstrated some degree of ability to wean ventilatory support. He did not show symptoms of viral or bacterial infection. There was no history of pulmonary hemorrhage. A lung computed tomography (CT) done at a month of age showed diffuse ground glass opacities with septal thickening and small areas of irregular cystic type change in the left upper lobe and bilateral lobes (Fig. 2A). Following this, genetic analysis returned positive for the heterozygous pathogenic variant p.E292V of the ABCA3 gene and negative for mutations in NKX2-1.

Fig. 2

CT chest findings at A. one month of age with diffuse ground glass opacities with septal thickening, small areas of irregular cystic type changes in bilateral lower lobes. B. 13 months of age with overinflated lungs with areas of mosaic attenuation and very mild bronchiectasis without bronchial wall thickening.

Over the next five months, he continued to require non-invasive respiratory support. Multiple courses of steroids including dexamethasone (DART), methylprednisolone and inhaled steroids were used.

He was also diagnosed with severe gastroeso-phageal reflux disease (GERD) and was fed using a nasogastric (NG) tube throughout his stay in NICU. He developed significant oral aversion. Gastrostomy tube placement and Nissen fundoplication were performed at six months of life. Initial cranial ultrasound done at two months of age showed bilateral germinal matrix hemorrhage and borderline dilated ventricles.

His NICU course was also complicated by supra-ventricular tachycardia (SVT), starting at three weeks of age. Multiple brief episodes with heart rate up to 260 were noted with no hemodynamic instability. Electro cardiogram (EKG) monitoring suggested that the SVT episodes possibly resulted from atrioventricular reentrant tachycardia (AVRT). Vagal maneuvers or adenosine did not abort the episodes. Propranolol was started and weaned off after three weeks due to increasing but mild cough, which was thought to be from the medication. SVT recurred two days after stopping propranolol for which the same medication was restarted as he responded well previously to the same medication and it was unclear if cough was related to medication use. An echocardiogram revealed structurally normal heart.

He was discharged from the NICU after six months on low flow oxygen of 0.5 liters per minute, albuterol, steroids (oral and inhaled), propranolol and gastrostomy feeds. Physical exam on discharge was remarkable for moderate hypotonia.

Follow up ultrasound done at 12 months of age showed near complete resolution with residual nodularity of the caudothalamic groove and irregularity of the choroid plexi. Subsequent lung CT at 13 months of age showed overinflated lungs with areas of mosaic attenuation and very mild bronchiectasis without bronchial wall thickening, suggesting changes related to chronic lung disease of prematurity (Fig. 2B).

He was followed in the NICU neurodevelopmental follow up clinic. The Bayley Scales of Infant Development (BSID-III) was performed at 12 months of age, indicating a mild gross motor delay. He received physical, occupational and speech therapies from the time of discharge. Repeat BSID was performed at 18 months of age and showed mild delay in expressive communication, low normal cognitive and motor skills. The infant was screened for Autism using the Modified Checklist for Autism in Toddlers, Revised (M-CHAT-R) form and was not referred based on criteria.

He was weaned off propranolol at one year of age. Following this, he had two episodes of elevated heart rate on his pulse oximeter while sleeping that was suspicious for recurrence of SVT. He was not restarted on medication. However, at 22 months of age he again developed SVT during an acute respiratory illness. During that hospitalization, he was treated with digoxin and was continued after discharge.

At 28 months of age, he remains on 0.25 liters/min of supplemental oxygen at night and during naps. He is predominantly G-tube dependent for the feeds though takes small quantities of pureed foods and is working with a feeding clinic. All his growth parameters are in the normal range. His physical examination was non-focal. BSID-III testing demonstrated normal cognitive, motor and language scores. He continues to receive speech and physical therapies.

3 Discussion

Descriptions of the clinical spectrum of lung disease caused by variations in the ABCA3 gene are well documented in the literature; however, understanding of extra pulmonary manifestations and the long-term neurodevelopment in affected infants is limited in the current literature. We described the clinical course and neurodevelopmental outcomes of a child who is a carrier of the p.E292V. This particular mutation is associated with partially impaired ABCA3 function and with milder chronic lung disease in childhood. It is also known to have importance for the protein’s ATP hydrolysis activity [5]. Our patient presented at birth with symptoms of respiratory distress syndrome and subsequently developed chronic lung disease. The pathogenic p.E292v mutation in our patient led to a severe phenotype of severe bronchopulmonary dysplasia.

Given that p.E292V is the most common known mutation in ABCA3, several studies have reported clinical manifestations of the mutation. In a study that examined the DNA samples of 195 children with chronic lung disease of unknown etiology, authors identified 10 patients with the p.E292V mutation. Age of symptom onset ranged from at birth to 7 years of age. Clinical outcomes also varied from death at 6 months of age to lung transplant [6]. Similarly, another study that looked at genotype-phenotype correlations for children with ABCA3 deficiency, identified 16 subjects with the p.E292V mutation. One infant who was homozygous for p.E292V presented with respiratory failure at birth and died at one month of age. The remaining individuals were compound heterozygous for p.E292V and had various timing of symptom onset (at birth to seven years of age) and differing outcomes ranging from death shortly after birth to lung transplant as an adolescent to long-term survival [7]. This suggests that the phenotype in p.E292V carriers ranges from minimal changes on lung biopsy and no symptoms to severe fatal lung disease. A few other case reports have also described the clinical features observed in patients with this mutation (Table 1). Unlike our case, most of these cases demonstrated more than one mutation in the ABCA3 gene; however, there were some similarities among clinical presentation, including feeding issues and hypotonia.

Table 1

Overview of previously reported cases of heterozygous p.E292V mutation in neonates

Study	Case	Variants	Associated Conditions	Neurodevelopment	Miscellaneous
[8]	Male infant born at 25 weeks, immediate RDS	–p.E292V –p.R1081W	GERD with gastrostomy tube placement and Nissen fundoplication at 4.5 months of age, axial hypotonia, asymmetric chest wall with right prominence	Assessment at two years showed severe motor, language, and cognitive delays	Started on hydroxychlorquine at three months
[9]	Male infant born at 37 weeks, immediate RDS	–p.E292V –p.Met1647fs	Gastrostomy supplementation	Not available	Prescribed hydroxychloroquine daily starting at two months of life
[10]	Male born full term with no postnatal complications	–p.E292V –p.Arg288Lys	Subcutaneous emphysema in the setting of acute febrile respiratory infection at four years, diffuse pneumomediastinum	Not available
[11]	Neonatal pneumonia Neonatal respiratory failure	–p.E292V –p.T1114M –p.E292V) –c.4706delTCA (delta1569)	Tachypnea, crackles, clubbing, failure to thrive, hypoxemia at 10 years Tachypnea, clubbing, failure to thrive at six years	Not available Not available	Lung transplant at 12 years Alive at 18 years
[12]	Neonatal RDS	–p.E292V –p.Ser1028Valfs^*103	GERD, mild pectus excavatum, finger clubbing, bilateral basal crackles, pneumonia at 33 years Combined pulmonary fibrosis and emphysema at 41 years	Not available
[13]	Neonatal RDS, prolonged survival (> 5 years)	–p.E292V –p.E765X	Not available	Not available	Treated with hydroxychloro-quine
[14]	Brief oxygen requirement at birth Term RDS at birth	p.E292V c.1742-9 G.A Homozygote p.E292V	Chronic respiratory difficulties Intubation due to RDS at birth	Not available Not available	Diagnosed at 30 mo of age, died at age of 19 years
[15]	Term birth, onset at 4 months (recurrent LTRI) Term birth, immediate RDS Term birth, immediate RDS Term birth, immediate RDS	–p.E292V –p.Arg155Trp –p.Glu292Val –p.Pro248Leu Homozygote p.E292V –p.Glu292Val p.Arg998ProfsX1		Not available Not available Not available Not available	Age at diagnosis of eight years, alive at 11 years Managed with surfactant, vent, and hydroxychloroquine, alive at nine months Surfactant, vent, hydroxychloroquine and prednisolone, alive at two years O2 dependent at six months of age
Current case	Male infant 32 weeks, immediate RDS	p.E292V	SVT, GERD requiring Nissen’s fundoplication, gastrostomy tube, hypotonia	BSID III –mild gross motor and expressive language delays at 12 and 18 mo of age, normal at 28 mo of age	Multiple courses of steroids- systemic and inhalational

The developmental delay and hypotonia in this infant are likely related to his prolonged respiratory illness and need for multiple courses of steroids. Three infants with pathogenic variants in the ABCA3 gene, one of whom had the p.E292V variant, were also reported to have GERD and developmental delay in their clinical course [8]. Specifically, the infant with the p.E292V mutation had a developmental assessment at two years of age that revealed severe motor, language, and cognitive delays [8].

A salient finding in our case was the cardiac presentation of the neonate. To our knowledge, this is the first neonate with ABCA3 mutation presenting with SVT. As most cases of SVT do not have any genetic basis, it is unclear whether the SVT is primarily related to his prematurity or could be related to his p.E292V genotype. Several factors in this patient’s presentation point towards a possible association with the p.E292V genotype as opposed to competing causes. These include negative family history of arrhythmias, occurrence of SVT relatively later in life, absence of umbilical lines, and partial resistance to vagal maneuvers/propranolol. Given that the clinical spectrum of p.E292V mutation is so wide, larger case series are needed to examine for a possible association between this mutation and SVT. It is apparent that more long-term follow-up needs to be conducted for neonates with identified ABCA3 mutations to better characterize extrapulmonary manifestations and neurodevelopmental outcomes so that milder cases do not go unrecognized and underdiagnosed.

Disclosure statements

This study received no funding.

Conflict of interest

The authors declare that they have no conflict of interest.

References

Mulugeta

, Gray

, Notarfrancesco

, Gonzales

, Koval

, Feinstein

, et al. Identification of LBM180, a lamellar body limiting membrane protein of alveolar type II cells, as the ABC transporter protein ABCA3. J Biol Chem. 2002;277(25):22147–55.

Michael

. Beers and Surafel Mulugeta. The Biology of the ABCA3 Lipid Transporter in Lung Health and Disease. Cell Tissue Res. 2017;367(3):481–93.

Lawrence

, Nogee

. Genetic Causes of Surfactant Protein Abnormalities. Curr Opin Pediatr. 2019;31(3):330–9.

Wambach

, Casey

, Fishman

, Wegner

, Wert

, Sessions Cole

, et al. Genotype-phenotype correlations for infants and children with ABCA3 deficiency. Am J Respir Crit Care Med. 2014;189(12):1538–43.

Bækvad-Hansen

, Nordestgaard

, Dahl

. Heterozygosity for E292V in ABCA3, lung function and COPD in 64,000 individuals. Respir Res. 2012;13:1–9.

Bullard

, Wert

, Whitsett

, Dean

, Nogee

. ABCA3 mutations associated with pediatric interstitial lung disease. Am J Respir Crit Care Med. 2005;172(8):1026–31.

Wambach

, Wegner

, DePass

, Heins

, Druley

, Mitra

, et al. Single ABCA3 mutations increase risk for neonatal respiratory distress syndrome. Pediatrics. 2012;130(6).

, Steffes

, Schymick

, Hazard

, Tracy

, Cornfield

. Three Infants with Pathogenic Variants in the ABCA3 Gene: Presentation, Treatment, and Clinical Course. J Pediatr. 2021;231:278–283.e2.

Akil

, Fischer

. Surfactant deficiency syndrome in an infant with a C-terminal frame shift in ABCA A case report. Pediatr Pulmonol. 2018;53(5):E12–4.

10.

Copertino

, Barbi

, Poli

, Zennaro

, Ferrari

, Carrera

, et al. A Child With Severe Pneumomediastinum and ABCA3 Gene Mutation: A Puzzling Connection. Arch Bronconeumol. 2012;48(4):139–40.

11.

Doan

, Guillerman

, Dishop

, Nogee

, Langston

, Mallory

, et al. Clinical, radiological and pathological features of ABCA3 mutations in children. Thorax. 2008;63(4):366–73.

12.

El Boustany

, Epaud

, Grosse

, Barriere

, Grimont-Rolland

, Carsin

, et al. Unusual long survival despite severe lung disease of a child with biallelic loss of function mutations in ABCA-3. Respir Med Case Reports. 2018;23:173–5.

13.

Kröner

, Wittmann

, Reu

, Teusch

, Klemme

, Rauch

, et al. Lung disease caused by ABCA3 mutations. Thorax. 2017;72(3):213–20.

14.

Soares

, Deutsch

, Moore

, Fazili

, Austin

, Brown

, et al. Childhood interstitial lung diseases: An 18-year retrospective analysis. Pediatrics. 2013;132(4):684–91.

15.

Turcu

, Ashton

, Jenkins

, Gupta

, Mok

. Genetic testing in children with surfactant dysfunction. Arch Dis Child. 2013;98(7):490–6.