Hereditary pulmonary alveolar proteinosis: Pathogenesis, presentation, diagnosis, and therapy

Takuji Suzuki, Takuro Sakagami, Lisa R. Young, Brenna C. Carey, Robert E. Wood, Maurizio Luisetti, Susan E. Wert, Bruce K. Rubin, Katharine Kevill, Claudia Chalk, Jeffrey A. Whitsett, Carrie Stevens, Lawrence M. Nogee, Ilaria Campo, Bruce C. Trapnell

Research output: Contribution to journalArticlepeer-review


Rationale: We identified a 6-year-old girl with pulmonary alveolar proteinosis (PAP), impaired granulocyte-macrophage colony-stimulating factor (GM-CSF) receptor function, and increased GM-CSF. Objectives: Increased serum GM-CSF may be useful to identify individuals with PAP caused by GM-CSF receptor dysfunction. Methods: We screened 187 patients referred to us for measurement of GM-CSF autoantibodies to diagnose autoimmune PAP. Five were children with PAP and increased serum GM-CSF but without GM-CSF autoantibodies or any disease causing secondary PAP; all were studied with family members, subsequently identified patients, and controls. Measurement and Main Results: Eight children (seven female, one male) were identified with PAP caused by recessive CSF2RA mutations. Six presented with progressive dyspnea of insidious onset at 4.8 ± 1.6 years and two were asymptomatic at ages 5 and 8 years. Radiologic and histopathologic manifestations were similar to those of autoimmune PAP. Molecular analysis demonstrated that GM-CSF signaling was absent in six and severely reduced in two patients. The GM-CSF receptor β chain was detected in all patients, whereas the α chain was absent in six and abnormal in two, paralleling the GM-CSF signaling defects. Genetic analysis revealed multiple distinct CSF2RA abnormalities, including missense, duplication, frameshift, and nonsense mutations; exon and gene deletion; and cryptic alternative splicing. All symptomatic patients responded well to whole-lung lavage therapy. Conclusions: CSF2RA mutations cause a genetic form of PAP presenting as insidious, progressive dyspnea in children that can be diagnosed by a combination of characteristic radiologic findings and blood tests and treated successfully by whole-lung lavage.

Original languageEnglish (US)
Pages (from-to)1292-1304
Number of pages13
JournalAmerican journal of respiratory and critical care medicine
Issue number10
StatePublished - Nov 15 2010


  • Alveolar macrophage
  • Genetic disease
  • Gm-csf receptor
  • Surfactant
  • Whole lung lavage

ASJC Scopus subject areas

  • Pulmonary and Respiratory Medicine
  • Critical Care and Intensive Care Medicine


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