Surfactant Metabolism Disorders, Including Surfactant Protein Deficiencies

Jennifer J Soares, MD, FAAP, and Eugene R. Soares, MD, PhD, FAAP

Introduction/Etiology/Epidemiology

•Pulmonary surfactant is a mixture of lipids and proteins (surfactant protein A, B, C, and D) produced by type II alveolar epithelial cells and packaged and stored in lamellar bodies until secreted into the alveoli.

•Once secreted, surfactant lines the alveoli, reducing the surface tension and preventing end-expiratory atelectasis, thus allowing for optimal gas exchange.

•Metabolism (production, function, degradation, and clearance) of surfactant depends on various proteins: thyroid transcription factor 1 (TTF-1), membrane transporter, member A3 of the adenosine triphosphate–binding cassette family (ABCA3), and granulocyte-macrophage (GM) colony-stimulating factor.

•Defects in the genes encoding the surfactant proteins or the proteins involved in their metabolism result in diffuse lung disease.

•Known surfactant metabolism defects include

—Surfactant protein B (SP-B) deficiency caused by mutations in SFTPB

—Loss of or reduced function of ABCA3 because of mutations in ABCA3

—Dysfunction of surfactant protein C (SP-C) because of mutations in SFTPC

—Haploinsufficiency of NKX2.1, the gene encoding TTF-1

—GM colony-stimulating factor receptor gene mutations or auto-antibody development

• These disorders are rare, cause substantial morbidity and mortality, and present a large cost burden for their evaluation and treatment.

—Signs include tachypnea, digital clubbing, pectus excavatum, crackles, wheeze, failure to thrive, cyanosis, and hypoxemia.

—Symptoms include increased work of breathing, cough, shortness of breath, and exercise intolerance.

•The severity of disease at presentation can be variable, depending on the etiologic origin and genotype.

Types of Surfactant Metabolism Disorders and Clinical Course

SP-B Deficiency

•Results in absent mature SP-B and secondary changes in surfactant

•Extremely rare (<1 in 1 million live births)

•At birth, the patient presents with severe atelectasis and poor lung compliance, leading to progressive, irreversible respiratory failure and death.

•Some rare SFTPB mutations causing only partial SP-B deficiency have been reported to result in milder disease.

ABCA3 Loss of Function or Reduced Function Defects

•Results in decreased surfactant lipids critical for surface tension reduction

•The most common cause of genetic surfactant dysfunction

•Can present at birth or later in childhood and, depending on genotype, may cause severe progressive respiratory failure, stabilize, or improve

NKX2.1 Haploinsufficiency

•Results in decreased amounts of TTF-1, leading to ineffective expression of 1 or all of the following:

—SP-B