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


OBJECTIVE
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.


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.
Suzuki
Takuji
T
Cincinnati Children's Hospital Medical Center, OH 45229-3039, USA.
Sakagami
Takuro
T
Young
Lisa R
LR
Carey
Brenna C
BC
Wood
Robert E
RE
Luisetti
Maurizio
M
Wert
Susan E
SE
Rubin
Bruce K
BK
Kevill
Katharine
K
Chalk
Claudia
C
Whitsett
Jeffrey A
JA
Stevens
Carrie
C
Nogee
Lawrence M
LM
Campo
Ilaria
I
Trapnell
Bruce C
BC
D017668:Age of Onset; D001323:Autoantibodies / Q000502:physiology; D002648:Child; D002675:Child, Preschool; D018450:Disease Progression; D004417:Dyspnea / Q000209:etiology; D005260:Female; D030342:Genetic Diseases, Inborn / Q000175:diagnosis / Q000209:etiology* / Q000235:genetics / Q000628:therapy; D005819:Genetic Markers / Q000235:genetics; D005838:Genotype; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000097:blood; D006801:Humans; D007223:Infant; D008168:Lung / Q000473:pathology; D008297:Male; D009154:Mutation; D010375:Pedigree; D011649:Pulmonary Alveolar Proteinosis / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology / Q000628:therapy; D016188:Receptors, Granulocyte Colony-Stimulating Factor / Q000097:blood / Q000235:genetics / Q000502:physiology; D016187:Receptors, Granulocyte-Macrophage Colony-Stimulating Factor / Q000235:genetics / Q000502:physiology
D001323:Autoantibodies; C521678:CSF2RA protein, human; D005819:Genetic Markers; D016188:Receptors, Granulocyte Colony-Stimulating Factor; D016187:Receptors, Granulocyte-Macrophage Colony-Stimulating Factor; D016178:Granulocyte-Macrophage Colony-Stimulating Factor