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

Takuji Suzuki1, Takuro Sakagami, Lisa R Young

  • 1Cincinnati Children's Hospital Medical Center, OH 45229-3039, USA.

American Journal of Respiratory and Critical Care Medicine
|July 13, 2010
PubMed

Insights

Genetic mutations in CSF2RA cause a rare form of pulmonary alveolar proteinosis (PAP) in children. Early diagnosis through imaging and blood tests, followed by whole-lung lavage, leads to successful treatment.

Area of Science:

  • Pediatric Pulmonology
  • Genetic Medicine
  • Rare Diseases

Background:

  • Pulmonary alveolar proteinosis (PAP) is a rare lung disorder.
  • Impaired granulocyte-macrophage colony-stimulating factor (GM-CSF) receptor function and elevated GM-CSF levels are observed in some PAP cases.
  • Increased serum GM-CSF may indicate PAP due to GM-CSF receptor dysfunction.

Purpose of the Study:

  • To investigate the genetic basis of PAP in children with impaired GM-CSF receptor function.
  • To identify novel mutations causing PAP and assess their impact on GM-CSF signaling.
  • To evaluate diagnostic markers and treatment efficacy for this genetic form of PAP.

Main Methods:

  • Screened 187 patients for GM-CSF autoantibodies to identify autoimmune PAP.
  • Focused on pediatric PAP cases with elevated serum GM-CSF but no autoantibodies or secondary causes.
  • Conducted molecular analysis of CSF2RA gene and GM-CSF signaling pathways, alongside clinical and radiologic assessments.

Main Results:

  • Identified eight children (seven female, one male) with PAP caused by recessive CSF2RA mutations.
  • Clinical presentation included progressive dyspnea or asymptomatic disease; radiologic and histopathologic findings mimicked autoimmune PAP.
  • Molecular analysis confirmed absent or severely reduced GM-CSF signaling due to various CSF2RA mutations, including deletions and splicing defects.

Conclusions:

  • Recessive CSF2RA mutations cause a distinct genetic form of pediatric PAP.
  • This condition presents with insidious, progressive dyspnea and can be diagnosed via imaging and blood tests.
  • Whole-lung lavage is an effective treatment for symptomatic children with CSF2RA-associated PAP.
Abstract

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