Perinatal/Neonatal Case Presentation

Respiratory failure in a term newborn due to compound heterozygous ABCA3 mutation: the case report of another lethal variant


Inherited disorders of surfactant metabolism are manifested in neonatal period as a severe respiratory failure not responding to exogenous surfactant administration. We illustrate the case of a term newborn with respiratory failure because of compound heterozygous mutation in adenosine triphosphate-binding cassette transporter A3 (ABCA3)—in exon 24 M1227R and in exon 29 Ins1510fs/ter1519. These mutations of ABCA3 have not been described yet and expand the group of lethal ABCA3 variants.


The pulmonary surfactant is a unique phospholipid and protein complex synthesized, stored and secreted by alveolar type II cells. Phospholipids (mainly phosphatidylcholine) make up nearly 90% of the pulmonary surfactant weight. The remaining 10% is formed by protein components, such as proteins A, B, C and D (SP-A, SP-B, SP-C, SP-D), which participate in the decreasing of the surface tension in the alveoli (SP-B, SP-C), and the lung host defence (SP-A, SP-D). SP-A also takes part in surfactant recycling and catabolism. The ATP-binding cassette member A3 (ABCA3) is a large protein responsible for transport of phospholipids into lamellar bodies where the final processing of the surfactant components occurs before the secretion. Mutations in SFTPB, SFTPC and ABCA3 may lead to surfactant quantitative or qualitative deficiency. It is possible to distinguish two clinical courses of the disease—severe respiratory failure in the neonatal period (usually SFTPB or ABCA3 mutations) or chronic respiratory insufficiency of varying course and severity that develops during infancy or early childhood (usually SFTPC or ABCA3 mutations).1,2


The term male newborn was born in a district hospital as the first child of non-consanguineous healthy parents. The pregnancy and delivery passed without complications. Birth weight and length was 3670 g and 51 cm, Apgar score were 5-10-10 points. Signs of respiratory distress developed 30 min after birth and the boy was transferred to the tertiary care centre. Chest X-ray after admission (5 h of life) showed age (postnatal and gestational)—appropriate translucency of both lungs, with slightly increased interstitial markings and unremarkable heart silhouette. Echocardiography excluded congenital heart defect and persistent pulmonary hypertension. The patient’s status worsened progressively despite support with CPAP (continuous positive airway pressure) and mechanical ventilation started at the age of 14 h. Chest X-ray was compatible with respiratory distress syndrome (decreased translucency, diffuse reticular granularity, air bronchogram) at this time. Exogenous surfactant (Curosurf, Chiesi Farmaceutici, Parma, Italy) administration led to immediate but only 2 h lasting improvement of oxygenation. High-frequency oscillatory ventilation was initiated at the age of 23 h (A-a gradient 600 mm Hg) and lead to stabilization of ventilation and normalization of blood gases. Laboratory markers ruled out early-onset infection; all microbiological tests were negative including PCR from tracheal aspirate. The clinical condition of the patient was unchanged during the 2nd week of life, the boy was dependent on high-frequency oscillatory ventilation with FiO2 0.40 to 0.60 (Figure 1). A bronchoscopy was performed on day 9. Bronchial tree and mucosa seemed normal and a sample of bronchoalveolar lavage fluid (BALF) was taken. Numerous macrophages with foamy cytoplasm and rare pigment were found in cytological examination of BALF. This finding was suggestive of desquamative interstitial pneumonia (DIP) and enhanced our suspicion of surfactant metabolism disorder. Genomic DNA isolated from the patient’s and the parent’s blood was analyzed by Gene Analysis Service, Berlin, Germany, after obtaining parents’ consent.

Figure 1

Chest X-ray: day 12 of life, high-frequency oscillatory ventilation.

Sequence analysis of the most frequently mutated coding exons 4, 5 and 7 of SFTPB and the protein-coding exons 4 to 33 and flanking intron sequences of ABCA3 was performed. Two novel compound heterozygous mutations in ABCA3 were found: M1227R (ATG>AGG, NM_001089.2: c.3680T>G) in exon 24 and Ins1510fs/ter1519 (NM_001089.2: c4289_4290insA) in exon 29. Parental studies identified the father as carrier of the M1227R mutation, and the mother as carrier of the Ins1510fs/ter1519 mutation. The non-conservative M1227R mutation substitutes a hydrophobic, nonpolar methionine for a hydrophilic, charged arginine in the 11th transmembrane segment of ABCA3, disturbing this conserved domain. The Ins1510fs/ter1519 mutation is likely to lead to ABCA3 deficiency by deleting the 2nd nucleotide binding domain containing the Walker B sequence.

The clinical condition of the patient did not change during DNA analysis; the boy was dependent on high-frequency oscillatory ventilation with FiO2 0.4 to 0.6 with normal values of blood gases. Attempts to influence the course of the disease with dexamethasone administration were unsuccessful, as well as macrolides application. The resuscitation care was terminated on day 33 after repeated discussions with the parents, who completely accepted this approach. The main goal of the therapy resided in providing comfort care to the patient. The boy died on the 33rd day of life in his mother’s arms.


ABCA3 is one of the ATP-binding cassette proteins that actively transport many of substances across cellular membranes. It is a large integral membrane protein, which is highly expressed mainly in the lungs and is a part of lamellar bodies of alveolar type II cells. ABCA3 is located on chromosome 16 (16p13.3) and contains 30 exons. ABCA3 mediates phosphatidylcholine and phosphatidylglycerol transport into lamellar bodies and is critical for the proper surfactant function.1,3,4 ABCA3 deficiency is also associated with abnormal and variable expression of SP-B and SP-C.5 Until 2010 over 180 mutations in ABCA3 have been identified in association with lethal RDS in newborns or with chronic respiratory insufficiency in children.1,4 With the exception of E292V that was found recurrently associated with interstitial lung disease,6 most ABCA3 mutations are individual familial mutations. The incidence of diseases due to recessive mutations in ABCA3 is not known, but according to published data single ABCA3 mutations are very common in the European and African-descent general population.7 Currently there is no screening test available for ABCA3 deficiency.

Lung histology is helpful in diagnostics, as inherited disorders of surfactant metabolism are associated with three microscopic patterns. The most common is pulmonary alveolar proteinosis when alveoli are completely filled with homogenous amorphous material. This finding is often observed in infants with mutations of SFTPB; it can be found in ABCA3 mutations less frequently. Chronic pneumonitis of infancy, affecting predominantly infants and young children, represent histological findings connected with mutations in SFTPC. DIP is the last type of histological pattern associated with surfactant metabolism disorders. The alveoli are filled with macrophages with pigment that react only weakly with iron-specific staining. Unfortunately, DIP is not a specific finding and together with ABCA3 defects can be also found in cases of severe viral infection, aspiration or toxic reaction.2,8 Bronchoalveolar lavage is less invasive procedure than lung biopsy and may be used as a supportive method in the diagnostics of the surfactant metabolism disorders, especially when SFTPB or ABCA3 mutations are suspected. We are unaware of any specific finding in BALF cytology for chronic pneumonitis of infancy, but the typical alveolar filing may be seen in BALF in the other morphological patterns. For instance pulmonary alveolar proteinosis is associated with the finding of proteinous material and DIP is associated with pigmented macrophages.8 The finding of DIP in BALF with the clear case history enhanced our suspicion of ABCA3 defect, and is why we consider BALF analysis as helpful in the illustrated case, especially in the decision, to start costly genetic testing.

The proof of inherited surfactant deficiencies is with certainty made by sequence analysis of genomic DNA. Two heterozygous mutations in trans were discovered in the reported case. Both mutations were not identified as variants in the NHLBI Exome Sequencing Project ( or reported as single-nucleotide polymorphism ( and are novel mutations. In silico prediction of the pathogenic state of M1227R classified it as probably benign (score 0.019) by PolyPhen29 but as not tolerated by SIFT.10 The position of M1227R in TM11 of ABCA3 is conserved through evolution as well as within the human ABCA subfamily.3 Two similar mutations were functionally analyzed in a cell culture system by Matsumura et al.:3 the missense mutation G1221S4 in TM11 impaired the ATP hydrolysis activity of ABCA3 (type II category deficiency mutation). The insertion mutation Ins1518fs/ter15194 lead to a mutant protein lacking the Walker B sequence of NBD-2, which was defective in the intracellular sorting of ABCA3 (type I category mutation). Position and nature of the two in trans mutations found in our patient suggest a type I/type II compound heterozygous genotype. With reference to literature,3,4 the ABCA3 mutations of our patient were found ominous considering their localization in the gene and clinical course of the disease.

No specific treatment exists for any of these disorders currently; moreover, no therapies have been shown to slow the progression of the severe neonatal illness. Systemic steroids are regarded the main treatment option in infants and children with diffuse parenchymal lung disease, however of limited efficacy. Recently, Thouvenin et al.11 described the positive therapeutic influence of azithromycine in a child with ABCA3 deficiency. The mechanism(s) of macrolides action in the treatment of these diseases remains unexplained, but may occur due to their anti-inflammatory or immunomodulatory effect.11,12 Unfortunately, we did not observe any improvement in our neonatal case. Long-term hydroxychloroquine therapy represents another option used for the treatment of ABCA3 deficiencies in infants and children and despite doubts of its safety Williamson and Wallis13 as well as Kitazawa et al.14 published promising information of years-lasting therapy.

Lung transplantation provides an option to prolong survival and is possible in infants with SP-B, SP-C and ABCA3 deficiency with 5-year survival rates of approximately 50%. Indication of lung transplantation is influenced by many factors and requires evaluation of the clinical course of the disease, functions of the other organ systems, availability of a pediatric lung transplantation centre and also, the parents’ wishes.1


Inherited surfactant metabolism deficiencies are rare diseases, but it is necessary to think of them in the context with etiologically unclear respiratory failure, especially in full-term newborns and also in infants and young children. DNA analysis with proof of specific protein gene mutations represents an explicit investigation leading to diagnosis. As in this case, thanks to DNA testing, other genetic variants of this life-threatening illness may be detected.


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We thank Professor Lawrence Nogee from Division of Neonatology, Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD, USA, for the help in interpreting the results of DNA analysis. This study was supported by PRVOUK programme P37/12.

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Malý, J., Navrátilová, M., Hornychová, H. et al. Respiratory failure in a term newborn due to compound heterozygous ABCA3 mutation: the case report of another lethal variant. J Perinatol 34, 951–953 (2014).

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