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

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

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

Abstract

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.

PMID:
20622029
[PubMed - indexed for MEDLINE]
PMCID:
PMC3001266
Free PMC Article
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