GATA2 deficiency in children and adults with severe pulmonary alveolar proteinosis and hematologic disorders

TL;DR

This study shows that GATA2 deficiency can cause severe pulmonary alveolar proteinosis and hematologic disorders, especially in children and adults without GM-CSF auto-antibodies.

Contribution

The study identifies GATA2 mutations as a novel cause of PAP in patients with hematologic disorders and highlights the importance of interdisciplinary collaboration for diagnosis and treatment.

Findings

Half of the GM-CSF auto-antibody negative PAP patients had GATA2 sequence variations, two of which were disease-causing.

Two patients with GATA2 deficiency showed a typical phenotype, including a previously undescribed feature of cholesterol pneumonia.

Successful treatment of a child with MDS and PAP was achieved through whole lung lavages and stem cell transplant.

Abstract

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.

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.

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.

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.

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