Abstract
Pulmonary fibrosis may be more prevalent in adults with GATA2 deficiency due to a longer duration of the disease http://ow.ly/WHnu30aCZ4S
From the authors:
Over the past few years, genetics has significantly improved the understanding of interstitial lung diseases (ILD). For example, in idiopathic pulmonary fibrosis, telomerase complex mutations have been shown to drive a specific phenotype including haematological, liver and cutaneous abnormalities [1]. Recently, GATA2 deficiency has been associated with a broad phenotype including haematological, vascular, infectious and pulmonary diseases [2–4]. GATA2 is a zinc finger transcription factor essential for differentiation of immature haematopoietic cells. Among many other functions, GATA2 regulates the phagocytosis of alveolar macrophages. Therefore, alveolar macrophage dysfunction is thought to be the pathophysiological basis for the occurrence of pulmonary alveolar proteinosis, the main lung condition in GATA2 deficiency [4]. However, pulmonary alveolar proteinosis associated with GATA2 deficiency does not share the same clinical, biological or radiological features as autoimmune pulmonary alveolar proteinosis. In all cases of GATA2 deficiency-associated pulmonary alveolar proteinosis reported in the literature, granulocyte–macrophage colony-stimulating factor (GM-CSF) antibodies were absent [2, 4]. Moreover, other pulmonary diseases such as fibrosis or pulmonary hypertension (PH) have been reported to occur in GATA2 deficiency [4], suggesting that the precise pathophysiological mechanisms are not fully understood.
S. Sanges and colleagues report the case of a 41-year-old patient with GATA2 deficiency, and histologically proven pulmonary alveolar proteinosis and pulmonary fibrosis, complicated with haemodynamically proven PH. As PH was considered secondary to the lung disease (World Health Organization group 3), specific pulmonary arterial hypertension therapies were not introduced [5]. As highlighted by S. Sanges and colleagues, physicians should be aware of the possible occurrence of PH in patients with GATA2 deficiency, as well as in every patient presenting with chronic fibrosing ILD.
What is striking in this adult case, as in our previous report [6], is the computed tomography (CT) appearance of ILD. Indeed, reticulations (i.e. pulmonary fibrosis) are the predominant pattern and there is no “crazy paving”. In both cases, chest CT was not suggestive of pulmonary alveolar proteinosis and the diagnosis was finally made by surgical lung biopsy.
Another recent case from Bordeaux Academic Hospital (Bordeaux, France) illustrates the same points (X. Demant and co-workers, unpublished observations): a 21-year-old patient with chest CT scan showing fibrosing ILD (subpleural and perihilar reticulations associated with some areas of ground-glass opacity without typical crazy paving) and a diagnosis of pulmonary alveolar proteinosis made on surgical lung biopsy. Associated severe monocytopenia and lymphopenia led to the diagnosis of GATA2 deficiency.
Traditionally, crazy paving, defined as the superimposition of reticular lines on ground-glass opacity, is considered the cardinal CT sign of pulmonary alveolar proteinosis, leading to bronchoalveolar lavage to confirm the diagnosis. Although crazy paving has been described in GATA2 deficiency-associated pulmonary alveolar proteinosis [2, 4], it appears less frequent and less typical than in autoimmune pulmonary alveolar proteinosis. Moreover, pulmonary complications such as end-stage fibrosis or PH are not uncommon in GATA2 deficiency, while they are quite rare in autoimmune pulmonary alveolar proteinosis.
Therefore, the spectrum of pulmonary CT findings in GATA2 deficiency appears to be more heterogeneous than in autoimmune pulmonary alveolar proteinosis, ranging from “pure” crazy paving to severe lung fibrosis, potentially complicated by PH. A fibrosis-predominant phenotype may be more prevalent in adults due to a longer duration of pulmonary alveolar proteinosis, as illustrated by the three cases presented herein. Furthermore, pulmonary fibrosis as final evolution of pulmonary alveolar proteinosis has been described, especially in old case reports [7, 8]. However, because most patients with GATA2 deficiency-associated pulmonary alveolar proteinosis exhibit a severe phenotype including myelodysplastic syndrome as well as immunodeficiency and recurrent infections [4], confounding factors might also account for the association between pulmonary alveolar proteinosis and fibrosis. The occurrence of PH seems to be less frequent than that of pulmonary alveolar proteinosis and fibrosis but might be underdiagnosed. Further research is necessary to investigate whether GATA2 deficiency might be an independent risk factor for PH.
Pulmonologists should be aware of the severe and heterogeneous clinical spectrum associated with GATA2 deficiency. As allogenic haematopoietic stem cell transplantation seems to be the only efficient treatment to improve the respiratory condition, it is crucial that patients with pulmonary alveolar proteinosis without GM-CSF antibodies are screened for GATA2 deficiency. Likewise, patients exhibiting fibrosing ILD, with or without PH, associated with haematological abnormalities need to benefit from early genetic diagnosis for appropriate therapeutic management as well as family screening.
Footnotes
Conflict of interest: None declared.
- Received February 25, 2017.
- Accepted March 5, 2017.
- Copyright ©ERS 2017