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

Am J Respir Crit Care Med. 2010 Nov 15;182(10):1292-304. doi: 10.1164/rccm.201002-0271OC. Epub 2010 Jul 9.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Age of Onset
  • Autoantibodies / physiology
  • Child
  • Child, Preschool
  • Disease Progression
  • Dyspnea / etiology
  • Female
  • Genetic Diseases, Inborn / diagnosis
  • Genetic Diseases, Inborn / etiology*
  • Genetic Diseases, Inborn / genetics
  • Genetic Diseases, Inborn / therapy
  • Genetic Markers / genetics
  • Genotype
  • Granulocyte-Macrophage Colony-Stimulating Factor / blood
  • Humans
  • Infant
  • Lung / pathology
  • Male
  • Mutation
  • Pedigree
  • Pulmonary Alveolar Proteinosis / diagnosis
  • Pulmonary Alveolar Proteinosis / genetics*
  • Pulmonary Alveolar Proteinosis / pathology
  • Pulmonary Alveolar Proteinosis / therapy
  • Receptors, Granulocyte Colony-Stimulating Factor / blood
  • Receptors, Granulocyte Colony-Stimulating Factor / genetics
  • Receptors, Granulocyte Colony-Stimulating Factor / physiology
  • Receptors, Granulocyte-Macrophage Colony-Stimulating Factor / genetics
  • Receptors, Granulocyte-Macrophage Colony-Stimulating Factor / physiology


  • Autoantibodies
  • CSF2RA protein, human
  • Genetic Markers
  • Receptors, Granulocyte Colony-Stimulating Factor
  • Receptors, Granulocyte-Macrophage Colony-Stimulating Factor
  • Granulocyte-Macrophage Colony-Stimulating Factor