The genetic disorders of surfactant metabolism are a group of diseases caused by mutations in genes affecting surfactant protein production and transport. Clinical manifestations and severity are variable, with some children presenting in the first week of life with respiratory distress and rapidly progressive deterioration, and others surviving into adulthood with chronic interstitial lung disease. Remarkable advances in recent years have led to increased recognition and diagnosis of these rare diseases. Mutations in three genes are now known to cause lung disease due to abnormal surfactant metabolism, two resulting in deficiency of surfactant proteins (SFTPB, SFTPC) and one resulting in abnormal lamellar body structure (ABCA3). Although there is variation in severity and therefore variation in age at clinical presentation and biopsy, these disorders are generally unified histologically by a constellation of diagnostic clues: (i) alveolar proteinosis material and/or cholesterol clefts, (ii) alveolar epithelial hyperplasia, and (iii) evidence of chronicity with some degree of alveolar injury and remodeling. Specific histologic patterns associated with each are discussed below.

Mutations in SFTPB were recognized in 1993 to cause deficiency in surfactant protein B, resulting in neonatal respiratory distress and a histologic pattern of pulmonary alveolar proteinosis (PAP), also called congenital alveolar proteinosis or lipoproteinosis. Surfactant protein B deficiency has an autosomal recessive pattern of inheritance. The differential diagnosis of surfactant protein B deficiency includes acquired (secondary) forms of pulmonary alveolar proteinosis due to macrophage dyfunction, as is occasionally seen in immunocompromised or immunosuppressed individuals, or in patients with anti-GM CSF antibodies. These cases have more uniform finely granular proteinosis material, without evidence of striking alveolar epithelial hyperplasia or early lobular remodeling as in surfactant B deficiency.

Chronic pneumonitis of infancy (CPI) was described in 1995 by Katzenstein and colleagues as a novel form of interstitial lung disease affecting term or near-term infants. These infants were well for weeks to months before they developed cough, respiratory distress, and failure to thrive. Some remained symptomatic but stable, while others deteriorated and several died of respiratory disease. Since that time, a similar histologic picture has been associated with surfactant protein C abnormalities, particularly in biopsies from older infants. Compared to infants with surfactant protein B deficiency, these infants tend to have a greater component of lobular remodeling with foci of endogenous lipoid pneumonia and cholesterol clefts. In older children and adults, SFTPC mutations have been found to cause chronic lung disease with interstitial fibrosis and chronic lipoid/cholesterol pneumonias. Surfactant protein C mutations are inherited in an autsomal dominant fashion, and are a cause of familial chronic interstitial lung disease affecting multiple generations.

Most recently, in 2004, ABCA3 mutations were described as a cause of neonatal respiratory failure, and subsequently as a cause of chronic interstitial lung disease in older children, adolescents, and young adults. Mutations in the ABCA3 gene have now emerged as the most common of the three types of surfactant disorders and are inherited in an autosomal recessive fashion. ABCA3 encodes an ATP-binding cassette transporter, a family of proteins often affecting lipid transport. Like SPC deficiency, patients with ABCA3 mutations manifest with
a wider clinical spectrum than surfactant protein B (SPB) deficiency, and may either die in infancy or survive with chronic lung disease into adulthood. A wide variety of histologic patterns have also been reported in these patients and are described below.

Definitive diagnosis of the genetic surfactant disorders requires mutational analysis of these genes, all of which are clinically available. Recognition of the associated histologic patterns (PAP, CPI, pneumonia [DIP], nonspecific interstitial pneumonia [NSIP]) on a lung biopsy in an infant or child should prompt further investigation. In addition to molecular testing, electron microscopy is another important diagnostic tool that should be obtained routinely in diagnostic lung biopsies from infants and children. Multivesicular and abnormal lamellated structures are associated with SFTPB mutations, and small lamellar structures with distinct round dense bodies are associated with ABCA3 mutations. No specific abnormalities have been described in patients with SPC deficiency.