Pediatric MDS in GATA2 deficiency, narrowing the scope

TO THE EDITOR :

We read with interest the recently-published article by Kotmayer et al. [1]. studying phenotypic and molecular evolution of pediatric myelodysplastic syndrome (MDS) arising from GATA2 deficiency. This effort is to be applauded and commended since it required massive coordination of multiple medical centers and groups spanning several countries. We have the following observations on this excellent work:

• The title suggests that the purpose of the manuscript is to study the evolution of pediatric MDS in patients with GATA2 deficiency. However, most patients (187 of 218, 86%) are enrolled after they have already been diagnosed with MDS, meaning that the basis for patient selection is MDS diagnosis and not GATA2 deficiency.

• One of the goals of this study is to elucidate insights into the natural history and progression patterns of GATA2-MDS. However, there is no longitudinal study of individual patients overtime in order to reach a meaningful conclusion. It seems that all conclusions are based on one time encounter with each patient. In that regard, some statements are difficult to understand. These statements in the Result Section and the legend of Figure 1 include “.by the age of 6 years, only 7.2% of the affected cohort developed MDS”. The wording of the statement implies that the patients were followed up for a period of time and they “developed” MDS at a certain time period.

• The diagnosis of “early-stage MDS” in the pediatric population was based on the criteria for refractory cytopenia of childhood (RCC) provided by the International Consensus Classification (ICC) [2]. However, since the inclusion of this category in 2008 WHO Classification, then 2017 WHO Classification and the 2022 ICC, these criteria have been applied mostly for the diagnosis of de-novo pediatric MDS. The situation is different when MDS develops in patients with known hematologic neoplasms associated with germline predisposition syndromes (GPS), such as those with GATA2 deficiency. To the extent that both the ICC [2, 3] and the updated 5^th edition of the WHO Classification (HEME5) [4] have separate criteria for the diagnosis of MDS in patients with these disorders. Other independent recommendations highlighting more strict criteria have also been published [5]. It is surprising that the authors decided to use the ICC criteria for RCC rather than the ICC criteria for MDS evolving from GPS. RCC diagnosis requires less strict morphologic criteria, including dysplastic features in 10% or more in only one cell line and any degree of dysplasia in 2 or more cell lines without a defined threshold. Bone marrows in many inherited bone marrow failure syndromes (IBMFS) and GPS may satisfy the less strict criteria for RCC without actually having MDS [5]. GATA2 deficiency is no exception. Significant megakaryocytic dysplasia, mild dysgranulopoiesis, and mild dyserythropoiesis are common in a high percentage of patients with GATA2 deficiency without MDS [6, 7]. Flow cytometry studies on bone marrow aspirates often show hypogranular granulocytes [8]. In fact, the original description of the MonoMac syndrome by Calvo et al. [9]. reported all 18 patients to have a hematologic neoplasm with 72% classified as refractory cytopenia with multilineage dysplasia (RCMD) using the 2008 WHO Classification. In a follow-up study, 42 of 50 patients (84%) had hematologic malignancy with the majority being classified as RCMD. The same study didn’t report any cases with MDS with single lineage dysplasia but labeled them as megakaryocytic dysplasia without MDS [6]. In a study comparing GATA2-deficient marrows to acquired aplastic anemia, all 28 GATA2-deficient patients were reported as having MDS with 3 having MDS with single lineage dysplasia [10]. Based on these discrepancies, we thought that the group would apply more strict criteria as previously recommended [3–5] and revisit their classification and categorization of cases. It is to be noted that the term “RCMD” is no longer a standardized MDS terminology. It has been replaced by MDS with multilineage dysplasia in the 2017 WHO Classification and MDS, NOS with multilineage dysplasia in the 2022 ICC. It is worth stating that the adult “RCMD” has much stricter diagnostic criteria than RCC. It requires dysplastic features of ≥10% in at least 2 cell lines, which is consistent with the ICC recommendations for the diagnosis of MDS in individuals with GPS [3].

• As mentioned above, the authors have established MDS classification criteria by which they have categorized all patients in the Material and Methods Section. However, the authors also mention near the end of the manuscript “Cases with early-stage MDS and cytopenia without clear MDS diagnosis demonstrate phenotypic similarities, however, the inherent limitations of our study-including variations in the diagnostic criteria across submitting countries and potentially insufficient granular data-prevent confidently grouping these two diagnostic categories together”. This statement suggests that the MDS criteria used in the study may not be strict enough and/or not homogeneously applied by all participating members of the international group.

It seems obvious that more strict morphologic criteria for the diagnosis of MDS in the setting of IBMFS/GPS, including GATA2 deficiency, need to be applied in order to further our understanding of these disorders. Without standardization, the disease process, complications, and patient management may not be optimal.

In the end, we look forward to more international collaborations in these rare disorders in order to improve understanding of the disease mechanism and improve patient outcome.

Author contributions

This is the work of a single author.

Competing interests

The author declare no competing interests.