Inherited Disorders of Surfactant Metabolism

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Chapter 399 Inherited Disorders of Surfactant Metabolism

Pulmonary surfactant is a mixture of phospholipids and proteins synthesized, packaged, and secreted by type II pneumocytes that line the distal air spaces. This mixture forms a monolayer at the air-liquid interface that lowers surface tension at end-expiration of the respiratory cycle and thereby prevents atelectasis and ventilation-perfusion mismatch. Four surfactant-associated proteins have been described: surfactant proteins A and D (SP-A, SP-D) participate in host defense in the lung, whereas surfactant proteins B and C (SP-B, SP-C) contribute to the surface tension–lowering activity of the pulmonary surfactant. The ATP (adenosine triphosphate) binding cassette protein member A3, ABCA3, is a transporter located on the limiting membrane of lamellar bodies, the storage organelle for surfactant within alveolar type II cells, and has an essential role in surfactant phospholipids metabolism. Two genes for SP-A [SFTPA1, SFTPA2] and one gene for SP-D [SFTPD] are located on human chromosome 10, whereas single genes encode SP-B [SFTPB] and SP-C [SFTPC] and ABCA3 [ABCA3], which are located on human chromosomes 2, 8, and 16, respectively. Genetically engineered mice deficient in SP-A or SP-D are susceptible to viral and bacterial infections, and lineages deficient in SP-D accumulate lipids and foamy macrophages in their lungs and demonstrate emphysema as they age. Although inherited deficiencies of SP-D have not been identified in humans, mutations in the gene encoding SP-A2 may result in pulmonary fibrosis and lung cancer, although the disease did not manifest until adulthood in these cases. Inherited disorders of SP-B, SP-C, and ABCA3 have been identified in humans (see Table 399-1 on the Nelson Textbook of Pediatrics website at www.expertconsult.com).

Deficiency of Surfactant Protein B (Surfactant Metabolism Dysfunction, Pulmonary, 1; SMDP1; OMIM #265120)

Clinical Manifestations

Infants with an inherited deficiency of SP-B present in the immediate neonatal period with respiratory failure. This autosomal recessive disorder is clinically and radiographically similar to the respiratory distress syndrome (RDS) of premature infants (Chapter 95.3) but typically affects full-term infants. The initial degree of respiratory distress is variable, but the disease is progressive and is refractory to mechanical ventilation, surfactant replacement therapy, glucocorticoid administration, and extracorporeal membrane oxygenation. SP-B deficiency has been recognized in diverse racial and ethnic groups. Almost all affected patients have died without lung transplantation, but prolonged survival is possible in cases of partial deficiency of SP-B. Although murine lineages heterozygous for SP-B deficiency are susceptible to oxidant injury and pulmonary infection, humans heterozygous for loss-of-function mutations in SFTPB are clinically normal as adults and have normal pulmonary function.