Pulmonary surfactant is a mixture of lipids and proteins lining the surface of the lungs that facilitates air exchange. Surfactant proteins are critical for pulmonary health as they manage infectious challenges and the biomechanical stresses of oxygen exchange on the lung tissue. Defects in production, processing, and transport of surfactant components have been associated with a wide range of diagnoses.^1,2 Genetic testing for defects in three genes (SFTPB, SFTPC, and ABCA3) is a useful and efficient diagnostic tool for the investigation of severe neonatal respiratory distress and interstitial lung diseases.

Surfactant Protein B (SP-B) has a critical role in stabilizing and enhancing rapid spreading of the surfactant phospholipid layer to reduce surface tension in the alveoli. Inherited Surfactant Protein B Deficiency is caused by autosomal recessive mutations of the SFTPB gene that result in atelectasis and respiratory failure in full-term infants. Rare cases of SP-B mutations resulting in severe disease with longer survival have been reported.³ Lung fluid and tissues of affected patients exhibit reduced or absent SP-B, accumulation of abnormal Surfactant Protein C precursor, and pulmonary alveolar proteinosis.

Surfactant Protein C (SP-C) has a similar role in reducing surface tension. Defects in SP-C’s SFTPC gene can manifest as one of many different diagnoses across a wide range of onset ages, even within the same family. SP-C related disease has presented as chronic or nonspecific interstitial pneumonitis in infancy and childhood, as the usual and desquamative types of interstitial pneumonitis in early through late adulthood, and as other types of interstitial lung disease (ILD).^4-6 Familial cases with dominant inheritance of mutations and sporadic cases with de novo mutations have been described.^5,6

ABCA3 protein is involved in the formation of lamellar bodies which transport surfactant phospholipids and proteins from their production site to the alveolar space.⁷ Clinical and histological presentation of ABCA3 gene mutations may be similar to that of either SP-B or SP-C deficiencies. Mutations are typically inherited in an autosomal recessive pattern and are a significant cause of both neonatal respiratory failure⁸ and pediatric ILD.⁹

Research on the interactions of these genes is unfolding.The co-occurrence of a heterozygous ABCA3 mutation and the SFTPC mutation 173T in three infantile-onset pediatric ILD patients whose asymptomatic parents each carried only one of the two mutations suggests ABCA3 mutations may modify the severity of the SFTPC mutation.¹