Characterization of CSF2RA mutation related juvenile pulmonary alveolar proteinosis
Jenna Hildebrandt, Ebru Yalcin, Hans-Georg Bresser, Guzin Cinel, Monika Gappa, Alireza Haghighi, Nural Kiper, Soheila Khalilzadeh, Karl Reiter, John Sayer, Nicolaus Schwerk8, Anke Sibbersen, Sabine Van Daele, Georg Nübling, Peter Lohse and Matthias Griese
Pediatric Respiratory Diseases Research Centre, NRITLD, Masih Daneshvari Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran
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.
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Orphanet Journal of Rare Diseases 2014, 9:171 |