Inherited Disorders of Surfactant Metabolism

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Chapter 399 Inherited Disorders of Surfactant Metabolism

Aaron Hamvas, Lawrence M. Nogee, F. Sessions Cole

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).

Table 399-1 COMPARISON OF SURFACTANT DEFICIENCY SYNDROMES

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

Genetics

More than 30 loss-of-function mutations in SFTPB have been identified. The most common is a net 2 base-pair insertion in codon 121 (termed 121ins2) that results in a frameshift, an unstable SP-B transcript, and absence of SP-B protein production. This mutation has accounted for 60-70% of the alleles found to date in patients identified with SP-B deficiency. Most other mutations have been family specific.

Pathology

Although SP-B deficiency was first described in a patient with newborn-onset alveolar proteinosis, this histology is neither specific for SP-B deficiency nor universally present in lungs of affected infants. The histologic characteristics seen in infants with SP-B deficiency are also present in children with mutations in other surfactant-associated genes and include alveolar type II cell hyperplasia, alveolar macrophage accumulation, interstitial thickening and inflammation, and alveolar proteinosis. This unique constellation of histologic features is specific for these disorders and is now classified as representing a disorder of surfactant metabolism, or surfactant dysfunction. Ultrastructural findings in SP-B deficiency include a lack of tubular myelin, disorganized lamellar bodies, and an accumulation of abnormal-appearing multivesicular bodies, suggesting abnormal lipid packaging and secretion.

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.