Prevalence, clinical characteristics, and prognosis of GATA2-related myelodysplastic syndromes in children and adolescents

Abstract

Key Points• Germline GATA2 mutations account for 15% of advanced and 7% of all primary pediatric MDS and do not influence overall survival. • The majority (72%) of adolescents with MDS and monosomy 7 carry an underlying GATA2 deficiency.Germline GATA2 mutations cause cellular deficiencies with high propensity for myeloid disease. We investigated 426 children and adolescents with primary myelodysplastic syndrome (MDS) and 82 cases with secondary MDS enrolled in 2 consecutive prospective studies of the European Working Group of MDS in Childhood (EWOG-MDS) conducted in Germany over a period of 15 years. Germline GATA2 mutations accounted for 15% of advanced and 7% of all primary MDS cases, but were absent in children with MDS secondary to therapy or acquired aplastic anemia. Mutation carriers were older at diagnosis and more likely to present with monosomy 7 and advanced disease compared with wild-type cases. For stratified analysis according to karyotype, 108 additional primary MDS patients registered with EWOG-MDS were studied. Overall, we identified 57 MDS patients with germline GATA2 mutations. GATA2 mutations were highly prevalent among patients with monosomy 7 (37%, all ages) reaching its peak in adolescence (72% of adolescents with monosomy 7). Unexpectedly, monocytosis was more frequent in GATA2-mutated patients. However, when adjusted for the selection bias from monosomy 7, mutational status had no effect on the hematologic phenotype. Finally, overall survival and outcome of hematopoietic stem cell transplantation (HSCT) were not influenced by mutational status. This study identifies GATA2 mutations as the most common germline defect predisposing to pediatric MDS with a very high prevalence in adolescents with monosomy 7. GATA2 mutations do not confer poor prognosis in childhood MDS. However, the high risk for progression to advanced disease must guide decision-making toward timely

Heterogeneity of GATA2-related myeloid neoplasms

“…GATA2 protein is expressed at high levels in endothelial cells and lymphatic vessel valves [26,27] and controls the expression of PROX1 and FOXC2 genes important for programming lymphatic valve development [28]. In one study, it has been suggested that N-terminal frameshift mutations or larger deletions of GATA2 are more likely to cause lymphedema [23]; however, this association could not be confirmed in other patient cohorts [6]. Congenital deafness is presumed to result from failure of generation of the perilymphatic space surrounding the semicircular ducts in inner ear [29].…”

“…Bold font denotes nonsense mutations, whereas bold italic font demonstrate splice site mutations unremarkable clinical history. However, preexisting immunodeficiency was shown to be retrospectively present in at least 50% of GATA2-carriers who developed MDS, pointing to the possibility of preexisting immuno-cytopenias might be present in more patients [6]. Depending on the studied patient cohort, the median age at diagnosis for roughly 380 cases in the literature was shown to be in range from 12 to 35 years (average 19.7 years), with 75% of carriers developing myeloid neoplasia [22].…”

“…This can continue for a few to tens of years and eventually, in the adulthood culminate in leukemic progress with the development of AML or other type of myeloid neoplasia. Notably, in children, the disease can take an "alternative" course where MDS can develop all of a sudden after Wlodarski et al [6]. Red-color circles represent affected amino acids.…”

“…Conversely, mutations were absent in the group with secondary MDS that was therapy related or occurred after aplastic anemia. We propose that GATA2 screening should be included in the workup of all children and young adults with monosomy 7, trisomy 8, or independent of karyotype if presenting with features suspicious for GATA2 deficiency [6,31]. Interestingly, in pediatric MDS cohorts, not monocytopenia but B-cell lymphopenia (including progenitors in bone marrow) was identified as the most consistent immunological feature [32,33].…”

“…Strikingly, at almost same time, germline GATA2 mutations were brought in association with other clinical entities, namely the autosomal dominant and sporadic monocytopenia and mycobacterial infection (Mono-MAC) syndrome [3], dendritic cell, monocyte, B and NK lymphoid (DCML) deficiency [4] and primary lymphedema associated with predisposition to acute myeloid leukemia (Emberger syndrome) [5]. Finally, GATA2 deficiency had been identified as the most common known genetic cause of primary childhood MDS, where the majority of affected cases had negative family history [6]. Today, it is well accepted that all these clinical manifestations belong to the broad spectrum of a single genetic disease.…”