Surfactant Metabolism Dysfunction, Pulmonary, 2

A number sign (#) is used with this entry because of evidence that pulmonary surfactant metabolism dysfunction-2 (SMDP2) is caused by heterozygous mutation in the gene encoding surfactant protein C (SFTPC; 178620) on chromosome 8p21.

Description

Surfactant protein C (SPC) deficiency is a rare autosomal dominant disease associated with progressive respiratory insufficiency and lung disease with a variable clinical course. The pathophysiology of the disorder is postulated to involve intracellular accumulation of a structurally defective SPC protein (Thomas et al., 2002).

For a general phenotypic description and a discussion of genetic heterogeneity of pulmonary surfactant metabolism dysfunction, see SMDP1 (265120).

Clinical Features

Nogee et al. (2001) reported a female infant who developed severe respiratory insufficiency at 6 weeks of age. She had cyanosis and tachypnea while breathing room air. Chest radiography showed hyperinflation with increased interstitial markings. Open-lung biopsy showed changes most consistent with cellular or nonspecific interstitial pneumonitis with hyperplasia of type II alveolar cells and interstitial infiltrate of mature lymphocytes and scattered myofibroblasts. Some non-inflated alveoli were filled with macrophages. Treatment with supplemental oxygen and corticosteroids resulted in some clinical improvement. The child's mother had infantile respiratory disease and received a pathologic diagnosis of desquamative interstitial pneumonitis (see DIP, 263000) at age 1 year. She was treated with glucocorticoids until age 15 years. She died after childbirth from respiratory failure. Lung tissue from the mother showed areas of fibrosis and honeycombing with patchy areas of mild interstitial lymphocytic infiltration, accumulations of alveolar macrophages, and areas of superimposed alveolar damage. Immunoblot analysis on lung tissue from both patients showed decreased surfactant C protein. Family history revealed that the mother's father died of life-long lung disease of unknown etiology. Autosomal dominant inheritance was suggested.

Amin et al. (2001) reported an 11-year-old girl, her 4-year-old half sister, and their mother with interstitial lung disease. The 11-year-old girl was diagnosed at age 7 years. She had no cough, chest pain, or recurrent infections, but reported tiring easily with exertion and required supplemental oxygen to maintain normal oxygen saturation. She had been born 5 weeks prematurely and required oxygen supplementation at that time. Lung biopsy showed interstitial inflammation, type II alveolar cell hyperplasia, and variable interstitial fibrosis. The patient's mother was diagnosed with interstitial lung disease at age 26 years. She had intermittent shortness of breath and pulmonary infiltrates. During her second pregnancy, she developed acute respiratory failure requiring mechanical ventilation. She was diagnosed with idiopathic pulmonary fibrosis (178500) based on CT scan; she refused lung biopsy. The 4-year-old half sister of the first child developed respiratory distress requiring mechanical ventilation at birth. At 3.5 weeks, she was diagnosed with lymphocytic interstitial pneumonitis secondary to Pneumocystis carinii infection. Lung biopsy showed dense interstitial infiltration of lymphocytes and active P. carinii infection. Both children responded well to hydroxychloroquine treatment. Chest CT scans showed hyperinflation in all 3 patients. The third patient had coarse linear densities and diffuse ground-glass opacities. Surfactant protein C (SPC) was undetectable in bronchoalveolar lavage fluid of all patients, whereas levels of surfactant A (SFTPA1; 178630) and B (SFTPB; 178640) were decreased. Immunostaining of lung biopsies showed markedly decreased proSPC in alveolar epithelial cells but strong staining for the other precursor surfactant proteins. Although DNA sequencing of the coding regions of SPB and SPC revealed no deviations from published sequences, Amin et al. (2001) suggested that the lung disease was due to protein C deficiency possibly resulting from mutations in the noncoding regions or of other processing defects of the SFTPC gene.

Thomas et al. (2002) reported a large family with variable phenotypic expressions of interstitial lung disease. Three members of this family had been previously described (Donohue et al., 1959; Young, 1966) as having 'fibrocystic pulmonary dysplasia,' which is a manifestation of pulmonary fibrosis. There were 14 affected members spanning 6 generations consistent with autosomal dominant inheritance. Respiratory viral infections were temporally related to disease onset in at least 3 affected family members. Six deceased family members diagnosed as adults before 1965 had dyspnea and cough, with or without clubbing. Pathologic and radiographic reports of these patients cited pulmonary fibrosis (4), fibrocystic pulmonary dysplasia (1), and usual interstitial pneumonitis (UIP) (1). Three adults diagnosed after 1986 had dyspnea and cough with pathologic reports of usual interstitial pneumonitis. Three infants were diagnosed with cellular nonspecific interstitial pneumonitis (NSIP). Chest radiographs of several patients showed various changes, including interstitial infiltrations, coarse reticulations, ground glass appearances, interstitial fibrosis, and interstitial opacities. Immunohistochemical analysis of 1 adult patient showed aberrant subcellular localization of the SPC precursor protein within abnormal, proliferating type II alveolar cells. Electron microscopy of 2 patients showed dense fibrosis and distorted cellular architecture with dysplastic type II cells containing abnormal-appearing lamellar bodies. Thomas et al. (2002) noted that cellular NSIP may be a precursor of UIP and ultimately fibrosis in this family. The presence of different pathologic findings in affected relatives sharing the same mutations suggested pleiotropic manifestations of the same central pathogenesis.

Tredano et al. (2004) and Brasch et al. (2004) reported a child with infantile onset of respiratory distress and surfactant protein C deficiency. After a full-term birth, he developed dyspnea and tachypnea at age 1 month. The disease was progressive, with recurrent bronchitis, failure to thrive, and worsening dyspnea requiring oxygen supplementation. Chest radiographs showed persistent diffuse bilateral pulmonary infiltrates. Open lung biopsy at age 13 months showed interstitial chronic inflammation, interstitial proliferation of mesenchymal cells, intraalveolar accumulation of granular PAS-positive material, and marked type II cell hyperplasia consistent with pulmonary alveolar proteinosis. Ultrastructural studies showed abnormal transport vesicles in type II pneumocytes and biochemical studies showed that expression of mutant proSPC resulted in abnormal proprotein trafficking and accumulation of aberrantly processed proSPC within alveoli. He was treated with repeated whole-lung lavage, systemic corticosteroids, and azathioprine. At 5-year follow-up, he showed normal psychomotor development. Genetic analysis identified a heterozygous de novo mutation in the SFTPC gene (178620.0002).

Clinical Management

Amin et al. (2001) reported the benefit of treatment with hydroxychloroquine for surfactant protein C deficiency.

Tredano et al. (2004) and Brasch et al. (2004) reported successful treatment with repeated whole-lung lavage, systemic corticosteroids, and azathioprine.

A patient reported by Rosen and Waltz (2005) was treated with oral hydroxychloroquine, which had been described as a therapy for pediatric interstitial lung disease (Dinwiddie et al., 2002). Rosen and Waltz (2005) suggested that the nonspecific antiinflammatory properties of the drug may have been effective, but also noted that hydroxychloroquine had been shown to cause inhibition of intracellular processing of the surfactant protein C precursor protein (Beers, 1996).

Molecular Genetics

In a mother and infant with respiratory insufficiency and interstitial pneumonitis due to surfactant protein C deficiency, Nogee et al. (2001) identified a heterozygous mutation in the SFTPC gene (178620.0001).

In affected members of a large kindred with variable phenotypic expression of interstitial lung disease due to surfactant protein C deficiency, Thomas et al. (2002) identified a heterozygous mutation in the SFTPC gene (178620.0004). Two unaffected obligate mutation carriers were also found to have the mutation, indicating reduced penetrance.

Nogee et al. (2002) identified mutations in the SFTPC gene in 11 of 34 infants with chronic interstitial lung disease of unknown etiology. Six patients had a family history of lung disease.

Stevens et al. (2005) identified a heterozygous mutation in the SFTPC gene (178620.0007) in a male infant with nonspecific interstitial pneumonitis and pulmonary alveolar proteinosis.

Among 121 children with diffuse lung disease and suspected surfactant deficiency, Guillot et al. (2009) identified 10 carrying a heterozygous I73T mutation (178620.0002) in the SFTPC gene. Seven novel SFTPC mutations (see, e.g., 178620.0008) were identified in 8 children, which included a dizygotic twin pair. Age of onset in patients with the I73T mutation was 5.9 months compared to 1.7 months for those with other mutations .