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Orphanet J Rare Dis. 2014 Nov 26;9:171. doi: 10.1186/s13023-014-0171-z.

Characterization of CSF2RA mutation related juvenile pulmonary alveolar proteinosis.

Author information

1
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.
2
Department of Pediatrics, Hacettepe Üniversitesi Çocuk Göğüs Hastalıkları, Ankara, Turkey. ebruy@hacettepe.edu.tr.
3
Department of Paediatrics, Evangelisches Krankenhaus Bielefeld, Bielefeld, Germany. hans-georg.bresser@evkb.de.
4
Department of Pediatrics, Hacettepe Üniversitesi Çocuk Göğüs Hastalıkları, Ankara, Turkey. guzincinel@yahoo.com.
5
Children's Hospital, Marien Hospital Wesel, Wesel, Germany. Monika.Gappa@marien-hospital-wesel.de.
6
Department of Genetics, Harvard Medical School, Boston, MA, USA. haghighimd@yahoo.com.
7
Department of Pediatrics, Hacettepe Üniversitesi Çocuk Göğüs Hastalıkları, Ankara, Turkey. nkiper@hacettepe.edu.tr.
8
Pediatric Respiratory Disease Research Center, NRITLD, Shahid Beheshti University of Medical Sciences, Teheran, Iran. drkhalilzadeh@gmail.com.
9
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.
10
Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, UK. john.sayer@newcastle.ac.uk.
11
Clinic for Paediatric Pneumonology and Neonatology, Hannover Medical School, Hannover, Germany. Schwerk.Nicolaus@mh-hannover.de.
12
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.
13
Department of Pediatric Pulmonology, Ghent University Hospital, Ghent, Belgium. sabine.vandaele@uzgent.be.
14
Departments of Neurology and Palliative Care, Klinikum der Universität München, Munich, Germany. georg.nuebling@med.uni-muenchen.de.
15
Molecular Genetics Laboratory, Institute of Laboratory Medicine and Human Genetics, Singen, Germany. peter.lohse@labor-blessing.de.
16
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.

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.

PMID:
25425184
PMCID:
PMC4254258
DOI:
10.1186/s13023-014-0171-z
[Indexed for MEDLINE]
Free PMC Article

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