A male neonate born vaginally at 36 weeks (birth weight 2250 g) to 26-year-old mother, developed respiratory distress by six hours of age.

Bronchoalveolar lavage was done to test for SP-B and C, and blood sample was collected for DNA analysis. Infant’s condition deteriorated subsequently and he died on 39th day of life. Post-mortem lung biopsy was sent for histopathological study. Enzyme-linked immunosorbent assay (ELISA) using different monoclonal antibodies (done at John Hopkins laboratory, Baltimore, USA) showed adequate SP-A protein but SP-B protein was not detected. Immune staining for the surfactant proteins SP-B, ProSP-B, ProSP-C showed normal protein concentrations but there was absence of immunostaining of ABCA3 protein even at higher concentration of antibody. Lung biopsy revealed extremely thickened interstitium with histology of pseudoglandular lung.

Automated DNA sequencing was performed on both strands with the use of ABI Big Dye Terminator sequencing reagents and an ABI 3730 sequencer (Applied Biosystems). DNA sequencing was analyzed with the aid of Seq Man software (DNA Star) and Mutation Explorer software (Soft Genetics) which showed that infant was homozygous for a G to T transversion at the 1st base in intron 24 (immediately after exon 24).This could be referred as IVS 24+1 G> T or c3703+1 G>T, where 3703 refers to the numbering of the m RNA sequence and position 3703 corresponds to the last base in exon 24. No mutations were detected for SP-B or SP-C gene. Genetic counseling and tests were offered to both parents but was refused. Antenatal study in next pregnancy showed normal surfactant protein level by ELISA test and a term male infant was born who was asymptomatic till one year of follow-up.

ABCA3 deficiency is increasingly being recognized as a cause of respiratory distress syndrome (RDS) in term babies in whom congenital deficiencies of SP-B and SP-C have been excluded. ABCA3 gene is located on chromosome 16(16p13.3), spans more than 80kb bases, and contains 33 coding exons which encode a 1704 amino acid protein [2]. More than 180 distinct ABCA3 gene mutations including missense, nonsense, spice site, frame shift, insertions and deletions have been detected ‘private’ and unique to a given family [1,3]. Lung disease caused by ABCA3 mutation is inherited as an autosomal recessive disorder requiring mutations on both alleles. Depending on location of mutations in ABCA3 gene, lung disease may be caused by loss or decreased expression of abnormal intracellular trafficking of the protein to the lamellar body, abnormal folding, packaging or secretion of phospholipids. It may also secondarily affect SP-B and SP-C processing [4].

Neonates who have ABCA3 deficiency may present similarly as SP-B deficiency, with signs and symptoms of respiratory distress, pulmonary hypertension, diffuse infiltrates in X-ray, rapid progression to hypoxemic respiratory failure and death despite intensive medical therapy. The clinical course of babies with ABCA3 deficiency varies from presentation in neonatal period to that in childhood presenting as interstitial lung disease. A common mutation involving substitution of valine for glutamic acid in codon 292(E292V), of the ABCA3 protein, has been identified in older children with chronic interstitial lung disease [1].

Detailed evaluation with immune staining, lung histology and gene sequencing showed evidence of a novel ABCA3 gene mutation in this neonate whose clinical presentation was consistent with surfactant deficiency. Presence of this mutation in both allele could have accounted for the severity of disease in this neonate. Reduced amount of SP-B seen in our case could be explained by impaired processing of proSP-B to mature SP-B – that has been sometimes observed in association with ABCA3 deficiency.

Acknowledgments: Dr Suhas Kallapur, Director (Neonatology), Cincinati Children’s Hospital, US and Dr LM Nogee, Professors of Pediatrics, John Hopkins Hospital, Baltimore for DNA analysis and histology.

Contributors: NP was responsible for patient management and manuscript writing. PPK was responsible for drafting the paper; he will act as guarantor of the study. CDK helped in manuscript writing. The final manuscript was approved by all authors.

Funding: None; Competing interest: None stated.

1. Gower WA, Wert SE, Nogee LM. Inherited surfactant disorders. Neoreviews. 2008;9:e458-67.

2. Shulenin S, Nogee LM, Annilo T, Wert SE, Whitsett JA, Dean M. ABCA3 gene mutations in newborns with fatal surfactant deficiency. N Engl J Med. 2004;350:1296-303.

3. Hamvas A. Evaluation and management of inherited disorders of surfactant metabolism. Chin Med J. 2010;123:2943-7.