PERINATOLOGY • Vol 24 • No. 1 • May–Aug 2023 • 65 Case Report Mistri J, et al. Respiratory Failure Due To a Novel Compound Heterozygous ABCA3 Mutation satisfactory history or laboratory findings, but the neonate may show the signs of diffuse lung disease. Some case reports have discussed about older children with ABCA3 gene mutation who presented with ILD. In neonates with NRF caused by surfactant deficiency, histopathologic examination findings show interstitial thickening, hyperplasia of type 2 pneumocytes, and airspaces with noticeable foamy macrophages (often lodged in variable amounts of proteinaceous material). Although these signs are also observed in patients with an inborn error of surfactant metabolism, they are not specific to SP-B, SP-C, and ABCA3 mutations. Hence, a molecular diagnosis can be considered to evaluate the specific mutation in each case.7,8 Although more than 200 mutations in the ABCA3 gene have been noticed among infants and children from various locations and ethnic origins, most of them are rare.5 In this case, a heterozygous two-base deletion in exon 15 of the ABCA3 gene with premature truncation of the protein 11 amino acids downstream to codon 632 (p.Gln632Alafs*11) was detected. In addition, a heterozygous 9-base in-frame deletion in exon 7 of the ABCA3 gene (c.558_566delGCTTTTCCC) that results in the deletion of 3 amino acid residues starting at codon 187 (p.Leu187_Pro189del) was also detected. This variant is not in a repeat region and results in the deletion of bases that are predicted to be highly conserved by GERP++ and PhyloP. This variant lies in the ABC2_membrane_3 domain of the ABCA3 protein. This mutation is novel. Existing genetic databases do not report this mutation. In many patients, there is a significant heterogeneity, and we are finding a number of novel mutations in the ABCA3 gene. This indicates that many more mutations are yet to be discovered, similar to genetic conditions like cystic fibrosis. Hence, the prognosis of neonates with ABCA3 mutations also varies.8 Conclusion In conclusion, differential diagnosis of ABCA3 mutations should be considered in neonates with unexplained RDS and in young children with chronic ILD, in whom the cause is not clear. An inborn error in surfactant metabolism should be suspected when the high-resolution computed tomography shows a widespread ground- glass opacification, septal thickening, and parenchymal cysts in the lungs. For a definitive diagnosis, it is nece- ssary to do DNA analysis for mutations in the ABCA3 gene. Mutations in SP-B and SP-C genes must also be considered because clinical, radiological, and pathological features of these conditions are similar. Lung biopsy is not required when genetic testing results confirm the mutation. However, when genetic test results are not clear or do not confirm the mutation, a lung biopsy should be done to identify similar histopathology patterns. Electron microscopy helps identify characteristic lamellar dense bodies.8 There is no specific treatment for these disorders currently, and supportive management has been the mainstay of treatment. Besides, none of the therapies can slow the progression of the severe neonatal illness. Although systemic steroids have been used in the treatment of infants and children with diffuse parenchymal lung disease, their efficacy is restricted. Lung transplantation has been a promising option in infants with SP-B, SP-C, and ABCA3 mutations, and this option provides a 5-year survival rate in approximately 50% of these patients.9 The prognosis of patients with ABCA3 mutations varies from severe irreversible respiratory failure in early infancy to progressive ILD. Without lung transplantation, many patients have survived into their second decade of life.8 The outcomes in this case did not change though the condition was diagnosed. Generally, the condition is diagnosed after the death of the patient. Hence, the parents and family members must be appropriately counseled about the mutation. They should also be warned about the risk of recurrence of similar mutations in future pregnancies. References 1. Batenburg JJ. Surfactant phospholipids: synthesis and storage. Am J Physiol. 1992;262(4 Pt 1):L367–L385. 2. Thomas AQ, et al. Heterozygosity for a surfactant protein C gene mutation associated with usual interstitial pneumonitis
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