Germline and somatic genetic landscape of pediatric myelodysplastic syndromes

Abstract

Pediatric myelodysplastic syndromes (MDS) represent a rare group of clonal hematopoietic stem cell disorders accounting for approximately 5% of pediatric hematologic malignancies. They are characterized by ineffective hematopoiesis, cytopenia, and dysplastic changes in the bone marrow with variable risk of progression to acute myeloid leukemia. Unlike adult MDS, pediatric cases predominantly present with hypocellular bone marrow, with monosomy 7 and trisomy 8 as the most common cytogenetic aberrations. Pediatric MDS can manifest as primary disease or arise secondary to classical inherited bone marrow failure syndromes, prior cytotoxic therapy, or acquired aplastic anemia. In recent years, new germline syndromes have been identified in a substantial proportion of patients with "primary" MDS. The most common are GATA2 deficiency and SAMD9/SAMD9L syndromes, accounting for at least 7% and 8% of cases, respectively. The somatic mutational landscape is different from adult MDS, with recurrent mutations affecting SETBP1, ASXL1, RUNX1, and RAS pathway genes (PTPN11, NRAS, KRAS, CBL), while mutations in spliceosome components and epigenetic regulators, which are common in adults, are virtually absent in children. Monosomy 7 serves as a "central hub" in disease evolution, associating with somatic leukemia driver mutations. On the other hand, somatic UBTF-TD and NPM1 mutations define a subtype of MDS with excess blasts with predominantly normal karyotype without known germline predisposition. Hematopoietic stem cell transplantation is the only curative option for pediatric MDS. Understanding the unique genetic profile of pediatric MDS has implications for diagnosis, therapy, donor selection and long-term surveillance, particularly for patients with germline predisposition syndromes. This review discusses current classification systems (WHO and ICC), provides a detailed overview of the germline and somatic genetic landscape of pediatric MDS, and highlights clinical implications of these genetic alterations.

Figure 1.

Clinical and genetic characteristics of pediatric primary myelodysplastic syndromes.

Figure 2.

Classification of pediatric primary myelodysplastic syndromes. The relationship between pediatric myelodysplastic syndromes (MDS), aplastic anemia, and acute myeloid leukemia (AML). Dashed lines represent blast thresholds in bone marrow (BM) and peripheral blood (PB) defined by current classification systems: the 2022 International Consensus Classification (ICC) and the World Health Organization (WHO). WHO criteria permit AML diagnosis with <20% blasts when specific genetic alterations are detected (NPM1 mutations, KMT2A/MECOM/NUP98 rearrangements), while the ICC retains blast excess as a criterion for AML diagnosis but lowers the threshold to 10% in cases with AML-defining genetic abnormalities. Monosomy 7/del(7q) is MDS-defining even without dysplasia/ blast increase (classified as MDS, not otherwise specified [MDS-NOS]). Immune dysregulation is a major driver in aplastic anemia and some cases of pediatric MDS, while germline predisposition is exclusive to pediatric MDS. BM: bone marrow; MDS-EB/IB: MDS with excess blasts/increased blasts; MDS-LB: MDS with low blasts; PB: peripheral blood; RCC: refractory cytopenia of childhood.

Figure 3.

Inciting drivers and acquired somatic events across pediatric myelodysplastic syndrome spectrum. The chart illustrates the inciting events of pediatric myelodysplastic syndromes (MDS) (outside circle) along with associated somatic changes (inside circle). Blue wedges represent MDS caused by germline predisposition or by yet unknown causes (collectively termed “primary MDS”). Pink wedges correspond to MDS arising from pre-existing conditions (classically referred to as “secondary MDS”). CK: complex karyotype; IBMFS: inherited bone marrow failure syndromes.

Figure 4.

Risk for myelodysplastic syndrome development in common pediatric predisposition syndromes. Decreasing risk of myelodysplastic syndromes (MDS) over time in children with SAMD9/9L syndromes (blue) is depicted against the increasing risk seen in GATA2 deficiency (orange).

Figure 5.

Distribution of genetic changes across pediatric primary myelodysplastic syndromes. Prevalence of most common germline predisposition syndromes is shown across myelodysplastic syndrome (MDS) morphologic subtypes (MDS with or without blast increase) and major cytogenetic groups (monosomy 7 vs. normal karyotype). UBTF-TD and NPM1 mutations are found only in cases with blast increase and are mutually exclusive with germline predispositions. In contrast, common somatic mutations are found across all MDS subtypes/karyotypes and germline diseases (not shown here). Data used to generate prevalence estimates were aggregated from Sahoo et al., Schwartz et al., Erlacher et al., and Yoshimi et al. incl: including; MDS-EB/IB: MDS with excess blasts/increased blasts; MDS-LB: MDS with low blasts; RCC: refractory cytopenia of childhood; UBTF-TD: UBTF tandem duplication.