Characterization of CSF2RA mutation related juvenile pulmonary alveolar proteinosis
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RESEARCH
Open Access
Characterization of CSF2RA mutation related juvenile pulmonary alveolar proteinosis Jenna Hildebrandt1, Ebru Yalcin2, Hans-Georg Bresser3, Guzin Cinel2, Monika Gappa4, Alireza Haghighi5, Nural Kiper2, Soheila Khalilzadeh6, Karl Reiter1, John Sayer7, Nicolaus Schwerk8, Anke Sibbersen1, Sabine Van Daele9, Georg Nübling10, Peter Lohse11 and Matthias Griese1*
Abstract Background: Juvenile pulmonary alveolar proteinosis (PAP) due to CSF2RA mutations is a rare disorder with only a few cases described worldwide. Methods: We identified nine children with severe diffuse interstitial lung disease due to CSF2RA mutations. Clinical course, diagnostic findings and treatment were evaluated and correlated to the genotype. Functional impairment of the intracellular JAK/pStat5 signaling pathway was assessed using flow-cytometry of peripheral mononuclear cells (PBMC) and granulocytes. Results: We identified six individuals with homozygous missense/nonsense/frameshift mutations and three individuals homozygous for a deletion of the complete CSF2RA gene locus. Overall, four novel mutations (c.1125 + 1G > A, duplication exon 8, deletion exons 2–13, Xp22.3/Yp11.3) were found. Reduced STAT5 phosphorylation in PBMC and granulocytes was seen in all cases examined (n = 6). Pulmonary symptoms varied from respiratory distress to clinically silent. Early disease onset was associated with a more severe clinical phenotype (p = 0.0092). No association was seen between severity of phenotype at presentation and future clinical course or extent of genetic damage. The clinical course was favorable in all subjects undergoing whole lung lavage (WLL) treatment. Conclusions: Our cohort broadens the spectrum of knowledge about the clinical variability and genotype-phenotype correlations of juvenile PAP, and illustrates the favorable outcome of WLL treatment in severely affected patients.
Background Among the interstitial lung diseases [1], pulmonary alveolar proteinosis (PAP) represents a group of disorders defined by extensive alveolar deposition of lipoproteinaceous material [2]. Several causes of PAP have been identified [3-5]. In late adolescence and adulthood, the vast majority of cases are caused by autoantibodies directed against granulocytemacrophage colony-stimulating factor (GM-CSF). Secondary PAP develops due to impaired macrophage function from hematologic malignancies, toxic dust inhalations, and immunosuppression. In contrast, most pediatric cases of histologically diagnosed PAP can be attributed to defects in a variety of genes involved in surfactant metabolism. Mutations in the genes for surfactant protein-B (SFTPB), * Correspondence: [email protected] 1 Department of Pediatric Pneumology, Hauner Children’s Hospital, Ludwig-Maximilians-University, Member of the German Center for Lung Research (DZL), Munich, Germany Full list of author information is available at the end of the article
surfactant protein-C (SFTPC), member A3 of the ATPbinding cassette family of transporters (ABCA3) [6], and someti
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