GATA2 deficiency in children and adults with severe pulmonary alveolar proteinosis and hematologic disorders.
BACKGROUND
The majority of cases with severe pulmonary alveolar proteinosis (PAP) are caused by auto-antibodies against GM-CSF. A multitude of genetic and exogenous causes are responsible for few other cases. Goal of this study was to determine the prevalence of GATA2 deficiency in children and adults with PAP and hematologic disorders.


METHODS
Of 21 patients with GM-CSF-autoantibody negative PAP, 13 had no other organ involvement and 8 had some form of hematologic disorder. The latter were sequenced for GATA2.


RESULTS
Age at start of PAP ranged from 0.3 to 64 years, 4 patients were children. In half of the subjects GATA2-sequence variations were found, two of which were considered disease causing. Those two patients had the typical phenotype of GATA2 deficiency, one of whom additionally showed a previously undescribed feature - a cholesterol pneumonia. Hematologic disorders included chronic myeloic leukemia, juvenile myelo-monocytic leukemia, lymphoblastic leukemia, sideroblastic anemia and two cases of myelodysplastic syndrome (MDS). A 4 year old child with MDS and DiGeorge Syndrome Type 2 was rescued with repetitive whole lung lavages and her PAP was cured with heterologous stem cell transplant.


CONCLUSIONS
In children and adults with severe GM-CSF negative PAP a close cooperation between pneumologists and hemato-oncologists is needed to diagnose the underlying diseases, some of which are caused by mutations of transcription factor GATA2. Treatment with whole lung lavages as well as stem cell transplant may be successful.
Hauner Children's University Hospital, Ludwig-Maximilians University, Member of the German Center for Lung Research, Lindwurmstr. 4, 80337, Munich, Germany. matthias.griese@med.uni-muenchen.de.
Matthias
M
Griese
Hauner Children's University Hospital, Ludwig-Maximilians University, Member of the German Center for Lung Research, Lindwurmstr. 4, 80337, Munich, Germany. ralf.zarbock@med.uni-muenchen.de.
Ralf
R
Zarbock
Interstitial and Rare Lung Disease Unit, Ruhrland Hospital, University of Duisburg-Essen, Essen, Germany. ulrich.costabel@ruhrlandklinik.uk-essen.de.
Ulrich
U
Costabel
Hauner Children's University Hospital, Ludwig-Maximilians University, Member of the German Center for Lung Research, Lindwurmstr. 4, 80337, Munich, Germany. jenna.hildebrandt@med.uni-muenchen.de.
Jenna
J
Hildebrandt
Institute for Pathology and Neuropathology, University Hospital Essen, Essen, Germany. Dirk.Theegarten@uk-essen.de.
Dirk
D
Theegarten
Hauner Children's University Hospital, Ludwig-Maximilians University, Member of the German Center for Lung Research, Lindwurmstr. 4, 80337, Munich, Germany. michael.albert@med.uni-muenchen.de.
Michael
M
Albert
Hauner Children's University Hospital, Ludwig-Maximilians University, Member of the German Center for Lung Research, Lindwurmstr. 4, 80337, Munich, Germany. antonia.thiel@med.uni-muenchen.de.
Antonia
A
Thiel
Hauner Children's University Hospital, Ludwig-Maximilians University, Member of the German Center for Lung Research, Lindwurmstr. 4, 80337, Munich, Germany. andrea.schams@med.uni-muenchen.de.
Andrea
A
Schams
Department of Pediatric Pneumology and Allergy, University Hospital, University of Warsaw, Warsaw, Poland. joanna_lange@wp.pl.
Joanna
J
Lange
Department of Pediatric Pneumology and Allergy, University Hospital, University of Warsaw, Warsaw, Poland. katarzynakrenke@gmail.com.
Katazyrna
K
Krenke
Hauner Children's University Hospital, Ludwig-Maximilians University, Member of the German Center for Lung Research, Lindwurmstr. 4, 80337, Munich, Germany. traudl.wesselak@med.uni-muenchen.de.
Traudl
T
Wesselak
Hauner Children's University Hospital, Ludwig-Maximilians University, Member of the German Center for Lung Research, Lindwurmstr. 4, 80337, Munich, Germany. Carola.Schoen@med.uni-muenchen.de.
Carola
C
Schön
Hauner Children's University Hospital, Ludwig-Maximilians University, Member of the German Center for Lung Research, Lindwurmstr. 4, 80337, Munich, Germany. matthias.kappler@med.uni-muenchen.de.
Matthias
M
Kappler
LAFUGA Genomics, Gene center, Ludwig-Maximilians University Munich, Munich, Germany. blum@lmb.uni-muenchen.de.
Helmut
H
Blum
LAFUGA Genomics, Gene center, Ludwig-Maximilians University Munich, Munich, Germany. krebs-st@lmb.uni-muenchen.de.
Stefan
S
Krebs
Institute of Pathology, Ludwig-Maximilians University, Munich, Germany. andreas.jung@med.uni-muenchen.de.
Andreas
A
Jung
Hauner Children's University Hospital, Ludwig-Maximilians University, Member of the German Center for Lung Research, Lindwurmstr. 4, 80337, Munich, Germany. carolin.kroener@med.uni-muenchen.de.
Carolin
C
Kröner
Hauner Children's University Hospital, Ludwig-Maximilians University, Member of the German Center for Lung Research, Lindwurmstr. 4, 80337, Munich, Germany. christoph.klein@med.uni-muenchen.de.
Christoph
C
Klein
Department of Molecular Medicine, Pneumology Unit, IRCCS San Matteo Hospital Foundation, University of Pavia, Pavia, Italy. i.campo@smatteo.pv.it.
Ilaria
I
Campo
Department of Molecular Medicine, Pneumology Unit, IRCCS San Matteo Hospital Foundation, University of Pavia, Pavia, Italy. i.campo@smatteo.pv.it.
Maurizio
M
Luisetti
Interstitial and Rare Lung Disease Unit, Ruhrland Hospital, University of Duisburg-Essen, Essen, Germany. Francesco.Bonella@ruhrlandklinik.uk-essen.de.
Francesco
F
Bonella
D000293:Adolescent; D000328:Adult; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D002648:Child; D002675:Child, Preschool; D004247:DNA / Q000235:genetics*; D004252:DNA Mutational Analysis; D005260:Female; D050989:GATA2 Transcription Factor / Q000172:deficiency* / Q000235:genetics*; D005858:Germany / Q000453:epidemiology; D006402:Hematologic Diseases / Q000453:epidemiology / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D007223:Infant; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010641:Phenotype; D015995:Prevalence; D011649:Pulmonary Alveolar Proteinosis / Q000453:epidemiology / Q000235:genetics* / Q000378:metabolism; D055815:Young Adult
D050989:GATA2 Transcription Factor; C494711:GATA2 protein, human; D004247:DNA