Diffuse parenchymal lung disease as first clinical manifestation of GATA-2 deficiency in childhood

GATA-2 deficiency is a protean disease with a broad spectrum of symptoms. Most of the patients present with hematological abnormalities (cytopenias, early-onset myeloid malignancies) and an increased susceptibility to opportunistic infections [1-9]. In the recently published cohort of 57 patients treated at the National Institute of Health (NIH, Bethesda, USA) [9] 70% of the patients had severe viral infections, particularly infection with HPV (63%) presenting with recalcitrant warts, condylomata, and/or dysplasia. Severe herpesvirus infections were present in 35% of patients: recurrent herpes stomatitis, esophagitis, genital infection, severe varicella in 11% of cases, and cytomegalovirus pneumonia or disseminated disease. Interestingly, in 11% of patients persistent EBV viremia similar to our patient was documented; in 2 patients EBV-positive skin tumors occurred. Infection with non-tuberculous mycobacteria was seen in 53%, severe bacterial infection was observed in 49% and severe invasive fungal infection in 16% of the patients. Eighteen percent of patients showed no increased susceptibility to infection. Additionally, vascular/lymphatic defects (venous thrombosis, lymphedema), sensorineural hearing loss, miscarriages and hypothyroidism were found [1-9].

Pulmonary involvement in GATA-2 deficiency is frequent, involving infections and PAP [1,3,8,9], particularly in more advanced stages of the disease. In the NIH cohort, 79% and 63% of the patients had diffusion and ventilatory defects, respectively. PAP was found in 18% and pulmonary arterial hypertension in 9% of patients. Structural abnormalities included nodules, reticular and ground glass opacities, subpleural blebbing, “crazy paving”, and paraseptal emphysema [9]. Similar picture could be seen in our patient. The surprisingly normal pulmonary function test results in our patient could possibly be explained by localized affliction of the pulmonary tissue. The infiltrated and fibrotic tissue decreased the elasticity of the lung parenchyma, however, there was still enough normal tissue that kept the static volumes and transfer factor normal (Table 1). Unfortunately, it is not possible to compare our findings with other pediatric patients as the data on pulmonary infliction in children are scarce. There were 24 children in the NIH cohort. Data on the pulmonary function tests were presented for only 6 of them (median age at testing 16 years, range 12–17 years; median time from disease manifestation 2.5 years, range 0–16 years). All those children suffered from myeloid malignancy, in four of them a chronic infection with herpesviruses or mycobacteria species was documented. Mild to severe diffusion defects were found in all tested patients, in two children a bronchial obstruction was seen. No information on structural lung changes in the affected children was provided [9].

The median age at initial presentation in the NIH cohort was 20 years but was highly variable (range 5 months – 78 years). Of note, four individuals (7%) had no apparent clinical manifestations as of the last follow-up (range 5–55 years). The proportion of patients without symptoms was 50% by age 20, 25% by age 30, and 16% by age 40 irrespective of the type of genetic change in GATA2. The phenotype varied within families significantly [9]. This fact strongly argues for a substantial impact of epigenetic, infectious and environmental factors on disease manifestation. Effects of germline or somatic mutations in other genes may play a role as well. This may explain the variability of symptoms in the three individuals carrying the same GATA2 mutation within our index family.

An intriguing issue is the etiology of the chronic diffuse parenchymal lung tissue changes in our patient in the absence of respiratory symptoms. The extensive investigations revealed only EBV presence in peripheral blood as well as in pulmonary tissue without specific tissue changes or clinically apparent EBV infection (e.g. mononucleosis-like symptoms, lymphoproliferation). As the patient presented with serological signs of acute EBV infection whereas the pulmonary changes were chronic, a decisive role of EBV in the pathogenesis of the pulmonary tissue changes in our patient was improbable. Possibly repeated mild infections in an environment of impaired regulation of the endothelial nitric oxide synthetase expression [13], defective phagocytosis and impaired GM-CSF signaling in pulmonary macrophages [14,15] played a role in the pathogenesis of the chronic pulmonary inflammatory changes.

Poor control of EBV replication resulting in persistent EBV viremia irrespective of lung involvement is a known phenomenon in GATA-2 deficient patients [1,7-9]. It has been shown that the inability to confine viral infections in patients with GATA-2 deficiency correlates well with the extent of cytopenias, namely with the lack of DC-, NK- and CD4^pos T-cells. Similarly, the defective antibody response at more advanced stages is associated with B cell lymphopenia [8,9]. However, with regards to the possible oligogenic etiology of immunodeficiency in GATA-2 deficiency, impact of other genes implicated in EBV control should be considered. We have excluded only the most common syndrome – X-linked lymphoproliferative disease type 1 caused by a defect in an adapter protein SAP, involved in signalling of cell-cell interactions. Other molecules implicated in EBV control encompass for example: the ubiquitously expressed XIAP with both antiapoptotic function and multiple signalling pathway connections; the surface molecule CD27, important for intercellular communication; the NK cell activating receptor for antibody-dependent cell cytotoxicity (CD16), and minichromosome maintenance 4 (MCM4) crucial for NK-cell function; or IL-2-inducible T-cell kinase (ITK), coronin1A, serine-threonine kinase (STK)4 and magnesium transporter, MAGT1, indispensable for T-cell receptor signalling and T-cell homeostasis [16].

The search for a GATA-2 defect in our patient was prompted by the abnormalities in the leukocyte and lymphocyte counts. Another serum marker useful in diagnostics as well as in monitoring of the disease progression (correlating with cytopenia) is the stem cell growth Fms-related tyrosine kinase 3 ligand (Flt3 ligand) [8]. We have shown that the newborn screening using KREC/TREC analysis [17] cannot be used to screen for GATA-2 deficiency.

The prognosis of individuals with GATA2 mutations is difficult to establish due to high clinical variability, incomplete penetrance and lack of close phenotype-genotype correlation data [8,9,18]. Antibiotics (e.g. azithromycin) and HPV vaccination are the recommended prophylactic measures [9]. Use of steroids or other immunosuppressive therapy is not indicated and exclusion of immunodeficiency in DPLD prior to use is warranted. A large proportion of patients will develop myeloid malignancy later in life [1,7-9]. The only curative therapy is allogeneic hematopoietic stem cell transplantation. Two patients with GATA-2 deficiency with pulmonary involvement transplanted for advanced MDS were reported to have profited significantly from this procedure [7].