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

Abstract

BackgroundThe 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.MethodsOf 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.ResultsAge 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.ConclusionsIn 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.

Human genetics of life-threatening influenza pneumonitis

“…Second, type II IFN (IFN-γ)mediated hypercytokinemia during infection was observed in two patients who died from IAV infections, suggesting that immune dysregulation may also contribute to the severity of pneumonitis (Sologuren et al 2018). Third, severe pulmonary alveolar proteinosis and diffuse parenchymal lung disease have been reported in some GATA2-deficient patients (Donadieu et al 2018;Griese et al 2015;Svobodova et al 2015). None of the four lethal cases were associated with detectable abnormalities in the lung itself, but further studies are required to determine whether these and perhaps other features of GATA2 deficiency also contribute to the severity of influenza infections.…”

Children’s Interstitial and Diffuse Lung Disease. Progress and Future Horizons

“…As the human genome has become more accessible to discovery, new clinically relevant chILD gene abnormalities have been reported to include FLNA (filamin A, alpha) mutations that lead to lethal cystic lung disease (34,35), MARS (Methionyl-tRNA synthetase) mutations that cause severe pediatric PAP (36), COPA (Coatomer subunit alpha) mutations resulting in a syndrome of autoimmunity with arthritis, vasculitis and chILD (37), GATA-2 transcription factor mutations resulting in immunodeficiencies with monocytopenia, infections, lymphatic abnormalities, chILD and PAP (38)(39)(40) and LRBA (lipopolysaccharide-responsive and beige-like anchor protein) mutations causing immune mediated lung disease (41). This trend will only accelerate with more advanced genetic testing including whole exome sequencing in chILD syndrome.…”

Pulmonary Alveolar Proteinosis Syndrome

“…Myelodysplastic syndromes and chronic myeloid leukemia are the most commonly reported hematological disorders associated with PAP syndrome. 2,[45][46][47][48][49][50][51][52][53][54] Although the pathogenic mechanisms underlying secondary PAP are not well understood, it is apparent that most predisposing conditions associated with secondary PAP result in reduced macrophage numbers or function, hence it is likely that the ability of alveolar macrophages to clear surfactant is compromised.…”