Surfactant Metabolism Dysfunction, Pulmonary, 4

A number sign (#) is used with this entry because of evidence that pulmonary surfactant metabolism dysfunction-4 (SMDP4) is caused by mutation in the CSF2RA gene (306250) on chromosome Xp22.

Description

Pulmonary alveolar proteinosis (PAP) is a rare lung disorder in which surfactant-derived lipoproteins accumulate excessively within pulmonary alveoli, causing severe respiratory distress. Three forms of PAP have been described: hereditary (usually congenital), secondary, and acquired. Hereditary PAP is associated with mutations in the CSF2RA gene or in genes encoding surfactant proteins. Secondary PAP develops in conditions in which there are reduced numbers or functional impairment of alveolar macrophages and is associated with inhalation of inorganic dust (silica) or toxic fumes, hematologic malignancies, pharmacologic immunosuppression, infections, and impaired CSF2RB (138960) expression. Acquired PAP (610910), the most common form, usually occurs in adults and is caused by neutralizing autoantibodies to CSF2 (138960) (Martinez-Moczygemba et al., 2008).

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

Clinical Features

Martinez-Moczygemba et al. (2008) reported a 4-year-old female with symptoms associated with Turner syndrome and respiratory insufficiency who had been diagnosed with PAP at age 3 years. She had exhibited respiratory failure caused by respiratory syncytial virus pneumonia in the first month of life, with a diagnosis of reactive airways disease. The patient presented with respiratory distress and hypoxemia, with a 'crazy paving' pattern on chest imaging. Open lung biopsy revealed alveolar proteinaceous material without alveolar epithelial hyperplasia or chronic interstitial changes, and bronchoalveolar lavage revealed proteinaceous material and foamy macrophages. ELISA showed no anti-CSF2 antibodies and elevated baseline CSF2 serum levels. Exogenous CSF2 administration, which may be efficacious in some patients with acquired PAP, resulted in no clinical improvement.

Suzuki et al. (2008) reported 2 sisters with PAP. The index patient presented at age 6 years with a 2-year history of progressive tachypnea and failure to thrive. Both parents were well developed and healthy with no history of lung disease. Examination of the patient revealed moderate tachypnea, mild tachycardia, and inspiratory crackles. Pulmonary function testing showed severe restrictive impairment. Oxygen saturation was 88% while breathing room air and decreased while talking or walking a short distance. PAP diagnosis was suspected based on chest radiography and confirmed by histopathologic examination of lung tissue. CSF2 autoantibodies were absent. Serum SPD (SFTPD; 178635) was increased in the patient compared with her parents and controls. The patient's 8-year-old sister, who was thought to be healthy, also had increased serum SPD. Subsequent clinical evaluation revealed that the sister had poor growth, a diffusion capacity for carbon dioxide of 57% that predicted, and mild patchy ground glass opacities throughout both lungs, consistent with a diagnosis of PAP.

Molecular Genetics

Using flow cytometry, Martinez-Moczygemba et al. (2008) found that CSF2RA was absent on monocytes from the patient they reported with PAP. The patient's mother expressed CSF2RA on all monocytes, whereas the patient's father and sister expressed CSF2RA only on a subpopulation of monocytes. Stimulation of granulocytes with CSF2 induced upregulation of CD11B (ITGAM; 120980) in the mother, but not the patient. Karyotypic analysis showed that the patient had 1 X chromosome of apparently normal length and 1 X chromosome with a truncated Xp arm that did not hybridize with a PAR1 probe. RT-PCR analysis detected expression of CSF2RA and IL3RA (308385), which are located in PAR1, in leukocytes from the patient's family members, but not in those from the patient. PCR analysis of the 11 coding exons of the CSF2RA gene detected a deletion of exons 5 through 13 (306250.0001), providing a genetic basis for the absence of CSF2RA mRNA and protein. The authors noted that the deletion affecting CSF2RA likely extends to IL3RA, but that impaired IL3 (147740) responses do not result in PAP in mice and have not been associated with PAP in humans.

Using flow cytometry, Suzuki et al. (2008) found that both CSF2RA and CSF2RB were present on leukocytes from the 2 sisters they reported with PAP, as well as all family members tested. However, Western blot analysis showed that the affected sisters expressed only a truncated form of CSF2RA, whereas their father was heterozygous for the normal and truncated forms, and their mother expressed only normal CSF2RA. CSF2 binding and CSF2-dependent signaling were severely reduced, but not abolished, in the sisters, and their CD11B stimulation test was abnormal. Suzuki et al. (2008) identified a mutation in the CSF2RA gene in the affected sisters that resulted in a gly174-to-arg (G174R; 306250.0002) substitution that altered 1 of 11 predicted N-glycosylation sites. The father was heterozygous for the G174R mutation, but the mother had only wildtype CSF2RA, suggesting a deletion of 1 maternal CSF2RA allele. PCR analysis showed that CSF2RA copy number was reduced in the sisters and their mother, but not in the father. FISH analysis demonstrated a 1.6-Mb deletion of PAR1, including the CSF2RA gene, in 1 X chromosome of the sisters and mother. Transfection of CSF2RA with the G174R mutation into 293 cells faithfully reproduced the CSF2 signaling defect at physiologic CSF2 concentrations. At high CSF2 concentrations, similar to those observed in the index patient, signaling was partially rescued, thereby providing a molecular explanation for the slow disease progression in the 2 sisters. Suzuki et al. (2008) concluded that PAP may be caused by compound heterozygous abnormalities affecting the CSF2RA gene, and that CSF2 signaling is critical for surfactant homeostasis in humans.

Clinical Management

Martinez-Moczygemba et al. (2008) noted that diagnosing PAP due to CSF2RA deficiency has important therapeutic implications, since bone marrow transplantation from a healthy donor should result in CSF2RA expression on leukocytes and thereby cure the impaired surfactant homeostasis that underlies PAP. The patient they reported with PAP due to CSF2RA deficiency underwent bone marrow transplantation, but she died of an infectious respiratory complication 4 weeks after transplantation, before the establishment of immune competency.

Animal Model

Using Csf2rb (138981)-null mice, which develop a myeloid cell disorder identical to hereditary pulmonary alveolar proteinosis (HPAP) in children with CSF2RA or CSF2RB mutations, Suzuki et al. (2014) showed that pulmonary macrophage transplantation (PMT) of either wildtype or Csf2rb gene-corrected macrophages without myeloablation was safe and well tolerated. One administration corrected lung disease and secondary systemic manifestations, normalized disease-related biomarkers, and prevented disease-specific mortality. PMT-derived alveolar macrophages persisted for at least 1 year, as did therapeutic effects. Suzuki et al. (2014) concluded that their findings identified mechanisms regulating alveolar macrophage population size in health and disease, indicated that GMCSF (138960) is required for phenotypic determination of alveolar macrophages, and supported translation of PMT as the first specific therapy for children with hereditary pulmonary alveolar proteinosis.