title: Characterization of CSF2RA mutation related juvenile pulmonary alveolar proteinosis.
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.
authors.affiliation: Department of Pediatric Pneumology, Hauner Children's Hospital, Ludwig-Maximilians-University, Member of the German Center for Lung Research (DZL), Munich, Germany. jenna.hildebrandt@med.uni-muenchen.de.
authors.forename: Jenna
authors.initials: J
authors.lastname: Hildebrandt
authors.affiliation: Department of Pediatrics, Hacettepe Üniversitesi Çocuk Göğüs Hastalıkları, Ankara, Turkey. ebruy@hacettepe.edu.tr.
authors.forename: Ebru
authors.initials: E
authors.lastname: Yalcin
authors.affiliation: Department of Paediatrics, Evangelisches Krankenhaus Bielefeld, Bielefeld, Germany. hans-georg.bresser@evkb.de.
authors.forename: Hans-Georg
authors.initials: HG
authors.lastname: Bresser
authors.affiliation: Department of Pediatrics, Hacettepe Üniversitesi Çocuk Göğüs Hastalıkları, Ankara, Turkey. guzincinel@yahoo.com.
authors.forename: Guzin
authors.initials: G
authors.lastname: Cinel
authors.affiliation: Children's Hospital, Marien Hospital Wesel, Wesel, Germany. Monika.Gappa@marien-hospital-wesel.de.
authors.forename: Monika
authors.initials: M
authors.lastname: Gappa
authors.affiliation: Department of Genetics, Harvard Medical School, Boston, MA, USA. haghighimd@yahoo.com.
authors.forename: Alireza
authors.initials: A
authors.lastname: Haghighi
authors.affiliation: Department of Pediatrics, Hacettepe Üniversitesi Çocuk Göğüs Hastalıkları, Ankara, Turkey. nkiper@hacettepe.edu.tr.
authors.forename: Nural
authors.initials: N
authors.lastname: Kiper
authors.affiliation: Pediatric Respiratory Disease Research Center, NRITLD, Shahid Beheshti University of Medical Sciences, Teheran, Iran. drkhalilzadeh@gmail.com.
authors.forename: Soheila
authors.initials: S
authors.lastname: Khalilzadeh
authors.affiliation: Department of Pediatric Pneumology, Hauner Children's Hospital, Ludwig-Maximilians-University, Member of the German Center for Lung Research (DZL), Munich, Germany. karl.reiter@med.uni-muenchen.de.
authors.forename: Karl
authors.initials: K
authors.lastname: Reiter
authors.affiliation: Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, UK. john.sayer@newcastle.ac.uk.
authors.forename: John
authors.initials: J
authors.lastname: Sayer
authors.affiliation: Clinic for Paediatric Pneumonology and Neonatology, Hannover Medical School, Hannover, Germany. Schwerk.Nicolaus@mh-hannover.de.
authors.forename: Nicolaus
authors.initials: N
authors.lastname: Schwerk
authors.affiliation: Department of Pediatric Pneumology, Hauner Children's Hospital, Ludwig-Maximilians-University, Member of the German Center for Lung Research (DZL), Munich, Germany. ankesibbersen@gmx.de.
authors.forename: Anke
authors.initials: A
authors.lastname: Sibbersen
authors.affiliation: Department of Pediatric Pulmonology, Ghent University Hospital, Ghent, Belgium. sabine.vandaele@uzgent.be.
authors.forename: Sabine
authors.initials: S
authors.lastname: Van Daele
authors.affiliation: Departments of Neurology and Palliative Care, Klinikum der Universität München, Munich, Germany. georg.nuebling@med.uni-muenchen.de.
authors.forename: Georg
authors.initials: G
authors.lastname: Nübling
authors.affiliation: Molecular Genetics Laboratory, Institute of Laboratory Medicine and Human Genetics, Singen, Germany. peter.lohse@labor-blessing.de.
authors.forename: Peter
authors.initials: P
authors.lastname: Lohse
authors.affiliation: Department of Pediatric Pneumology, Hauner Children's Hospital, Ludwig-Maximilians-University, Member of the German Center for Lung Research (DZL), Munich, Germany. matthias.griese@med.uni-muenchen.de.
authors.forename: Matthias
authors.initials: M
authors.lastname: Griese
mesh_terms: D000293:Adolescent; D002648:Child; D002675:Child, Preschool; D005260:Female; D005838:Genotype; D006801:Humans; D007223:Infant; D007963:Leukocytes, Mononuclear / Q000378:metabolism*; D008297:Male; D009154:Mutation; D011649:Pulmonary Alveolar Proteinosis / Q000235:genetics*; D016187:Receptors, Granulocyte-Macrophage Colony-Stimulating Factor / Q000235:genetics*; D055815:Young Adult
chemical_list: C521678:CSF2RA protein, human; D016187:Receptors, Granulocyte-Macrophage Colony-Stimulating Factor