Pediatric Myelodysplastic Syndrome: Updated Classifications and Current Diagnosis and Treatment Challenges Open Access

Although diagnostic criteria for MDS were released in the early 1980s, the first diagnostic criteria for pediatric MDS were published in 2003,⁵  which divided pediatric MDS into 3 main categories: refractory anemia (later changed to refractory cytopenia), refractory anemia with excess blasts, and refractory anemia with excess blasts in transformation.^5,6 

The World Health Organization (WHO) 4th (2008) classification edition of MDS mostly adopted the 2003 classification system with modifications; most notable was the addition of a provisional entity about childhood MDS: refractory cytopenia of childhood (RCC), which is defined as (1) dysplasia in one or more hematopoietic lineages or at least 10% of cells in one cell line and (2) less than 5% blasts on bone marrow (BM) evaluation.⁷  The WHO 4th revised edition⁸  (2016) modified the terms and diagnostic criteria of MDS by incorporating new clinical, prognostic, morphologic, immunophenotypic, and genetic data since its 2008 classification publication—despite no addition of novel MDS categories. For instance, the categories of MDS with excess blasts remained unchanged and RCC continued as a provisional entity within childhood MDS. Importantly, in the WHO 4th revised edition, the denominator to calculate blast percentage was total nucleated cells.⁹ 

Advancements in molecular markers in pediatric MDS have shown associations with variable clinical behavior and patient outcomes. Therefore, the updated classifications of hematopoietic diseases from the WHO 5th edition (2022)³  and the International Consensus Classification (ICC)⁴  have recently been released. Both ICC and WHO 5th edition classifications recognize the different pathogenesis of MDS between the pediatric and adult populations.^3,4 

Both ICC and WHO 5th edition classify pediatric MDS into several broad categories, which can also be used to categorize de novo MDS, therapy-related MDS (t-MDS), and MDS secondary to germline predisposition. In the WHO 5th edition, the entity childhood MDS with low blasts replaces the category RCC.³  In contrast, the ICC classification keeps the term RCC.⁴  The detailed criteria and classifications are listed in the Table. Notably, ICC recognizes that some cases of RCC with the updated diagnostic criteria are de novo MDS and may lack evidence of clonality (somatic mutations or cytogenetic abnormalities).^4,10  In some cases, a germline predisposition may precede the development of RCC, where RCC represents disease progression to BM failure (BMF) or MDS.⁴  Therefore, ICC lists an additional category of MDS, not otherwise specified, for cases that do not meet the criteria of other categories.

Both ICC and WHO 5th edition recognize genetic abnormalities for categorizing MDS.^3,4  However, their labels for specific MDS subtypes, diagnostic criteria, and distinctions between MDS and AML differ considerably. For example, myelodysplastic neoplasms with defining genetic abnormalities are grouped in WHO 5th edition and include MDS with low blasts and isolated 5q deletion, MDS with low blasts and splicing factor 3b subunit 1 (SF3B1) mutation, and MDS with biallelic tumor protein p53 (TP53) inactivation. The latter supersedes MDS with low blasts and isolated 5q deletion and MDS with low blasts and SF3B1 mutation.³  The rationale to classify MDS based on these genetic abnormalities is based mostly on adult data. Although these genetic abnormalities have rarely been reported in pediatric MDS cases, they are more commonly seen in MDS progression in patients with germline predispositions,⁴  which would be better classified as MDS associated with germline predisposition. Future studies classifying MDS based on genetic mutations are needed in pediatric patients.

Both ICC and the WHO 5th edition acknowledge the role of genetics and prior exposure to cytotoxic therapy in determining the biology of myeloid malignancies.^3,4  Although therapy-related myeloid neoplasm (t-MN) is an entity in the WHO 4th edition and has been widely used in literature,⁷  t-MN is not a separate entity in the recently updated ICC and WHO classifications.^3,4  In the WHO 5th edition, myeloid neoplasms that arise secondary to exposure to cytotoxic therapy or germline predisposition are classified into the major category of secondary myeloid neoplasms with 3 subcategories: myeloid neoplasm post–cytotoxic therapy (MN-pCT), myeloid neoplasms with associated germline predisposition, and myeloid proliferation associated with Down syndrome (DS).³  However, the ICC classification system lists history of chemo/radiation therapy and germline predisposition as a descriptive condition in the diagnosis but not as a classification criterion. Moreover, in the new ICC classification, myeloid proliferation associated with DS has been expanded to myeloid or lymphoid neoplasm associated with DS.⁴ 

Evaluation and recognition of a possible germline predisposition is critical for the diagnosis and treatment of pediatric MDS.¹¹  Most known germline MDS predisposition genes have been recognized in patients with clinical syndromic phenotype(s) or family history. However, some patients, particularly those with a de novo germline mutation or subtle clinical findings, may lack a positive family history.¹²  Moreover, adult MDS can also have underlying germline predispositions (eg, DEAD-box helicase 41 [DDX41]).¹³  Below are summaries of currently well-recognized predisposition genes,¹⁴  including the categories of germline predisposition with or without preexisting platelet disorder or other organ dysfunction as described by the WHO.^3,4  Importantly, conventional next-generation sequencing (NGS) myeloid panels may not comprehensively contain all the germline predisposition genes, such as sterile alpha motif domain containing 9 (SAMD9/SAMD9L).¹⁵ 

RUNX family transcription factor 1 (RUNX1, formerly known as AML1) is a transcription factor critical for lineage differentiation of hematopoietic stem cells. Loss-of-function RUNX1 germline variants are associated with autosomal dominantly inherited familial platelet disorder (RUNX1-FPD), which has a broad spectrum of clinical phenotypes and a predisposition to hematologic malignancies, including MDS. BM hematopathologic features associated with a germline RUNX1 mutation include variable cellularity and atypical megakaryocytes, predominantly characterized by small forms with hypolobated and eccentric nuclei, as well as forms with high nuclear to cytoplasmic ratios (Figure 1, A through E).¹⁶  Another study of 11 patients from 7 pedigrees revealed that patients who did not develop hematologic malignancies showed baseline BM abnormalities including hypocellularity, dysmegakaryopoiesis, megakaryocytic hypoplasia/hyperplasia, and eosinophilia, whereas patients who developed hematologic malignancies showed additional cytopenia, BM hypercellularity, dysplasia in 2 or more lineages including megakaryocytes, and acquired clonal genetic aberrations.¹⁷  Somatically acquired secondary variants in genes such as RUNX1, tet methylcytosine dioxygenase 2 (TET2), ASXL transcriptional regulator 1 (ASXL1), BCL6 corepressor (BCOR), PHD finger protein 6 (PHF6), serine and arginine rich splicing factor 2 (SRSF2), NRAS proto-oncogene, GTPase (NRAS), and DNA methyltransferase 3 alpha (DNMT3A) contribute to the development and progression of RUNX1-FPD–associated MDS.^18–21 

ETS variant transcription factor 6 (ETV6) encodes a hematopoietic transcription factor whose mutations are associated with an autosomal dominant inherited familial platelet disorder, similar to RUNX1-FPD.^12,22  Patients often present with mild to moderate thrombocytopenia with variable predisposition to hematopoietic neoplasms.^22–24 

Ankyrin repeat domain containing 26 (ANKRD26)–related thrombocytopenia is another inherited thrombocytopenia disorder with a predisposition to hematopoietic malignancies and a low bleeding risk.²²  The germline mutations of ANKRD26 putatively cause dysregulation of apoptosis different from the pathogenetic mechanisms of RUNX1 and ETV6 mutations.^25,26 

GATA binding protein 2 (GATA2) encodes a zinc finger transcription factor regulating blood cell differentiation, which is critical for hematopoiesis, lymphatic, and other organ development. Germline GATA2 variants have variable inheritance patterns and a range of clinical presentations, including infection, immunodeficiency, and hematopoietic malignancies.^27,28  GATA2 deficiency is accompanied by a severe reduction in monocytes, natural killer cells, and dendritic cells and profound B-cell lymphopenia, including its progenitors in blood and BM.^29,30  The BM biopsy is characterized by hypocellularity with varying degrees of dysplasia. One study reports increased megakaryocytes with atypical/dysplastic features (eg, micromegakaryocytes, nuclear hypolobation, and large megakaryocytes with separated and peripheralized nuclear lobes), erythroid dysplasia (nuclear budding, binucleation, and prominent megaloblastoid change), myelodysplasia (maturation asynchrony, hypogranularity), and reticulin fibrosis (≥2 of 4).³¹ 

Recent studies identified germline GATA2 variants leading to haploinsufficiency in approximately 7% of primary pediatric MDSs, often with monosomy 7 and additional somatic mutations.¹  Moreover, MDS in patients with GATA2 pathogenic variants have the risk of more advanced disease.³²  The increased histone trimethylation and deregulated apoptosis might contribute to malignant transformation in patients with GATA2 deficiency.³³ 

SAMD9 and/or SAMD9L germline mutations have been reported in up to 17% of pediatric MDSs, as well as other phenotypes, such as ataxia-pancytopenia syndrome or MIRAGE syndrome (myelodysplasia, infection, restriction of growth, adrenal hypoplasia, genital phenotypes, and enteropathy).^15,34,35 SAMD9/SAMD9L encodes proteins that regulate cell proliferation and apoptosis. SAMD9/SAMD9L deficiency causes pancytopenia and organ hypoplasia in nonhematopoietic tissues. A study of 10 individuals with heterozygous SAMD9L mutations showed myeloid, B-, and natural killer cell deficiency as well as MDS development.³⁶  Monosomy 7 is commonly acquired in MDS with SAMD9/SAMD9L mutations. Interestingly, SAMD9/SAMD9L mutant allele can be lost because of copy-neutral loss of heterozygosity of 7q. Although the exact functional consequences of SAMD9/SAMD9L mutations are unclear, they may function as tumor suppressors and facilitate endosomal fusion. Samd9l-mutant mouse model resembles human disease in many ways, including BMF and the nonrandom loss of the mutant allele.³⁷ 

Children with DS have a high risk of developing hematopoietic neoplasms. DS-associated AML and DS-associated MDS have similar event-free and overall survival; they are now classified under myeloid leukemia associated with DS (ML-DS).³⁸  Differentiating ML-DS from an unrelated de novo myeloid neoplasm in a patient with DS is important as the prognosis and treatment plan vastly differ; the latter can be distinguished from ML-DS by the presence of typical translocations or inversions seen in AML and/or occurrence in children older than 4 years of age. Dysplasia of ML-DS is usually limited to megakaryocytic and erythroid lineages and is absent in myeloid lineages.³⁸  The BM morphology of ML-DS is characterized by clustered hyperplastic megakaryocytes with a peripheral ring of nuclei and smaller megakaryocytes with signet ring forms.^38,39  GATA binding protein 1 (GATA1) mutations are often present in ML-DS preleukemic conditions, such as transient abnormal myelopoiesis (TAM), and secondary mutations in cohesion genes, epigenetic regulators, and the Ras signaling pathway contribute to subsequent progression to ML-DS. Of note, TAM can be diagnosed in approximately 10% to 30% of infants with DS, which spontaneously regresses.⁴⁰  Usually, TAM does not have dyserythropoiesis or structural cytogenetic abnormalities aside from the constitutional trisomy 21.³⁹  Although primary ML-DS is associated with favorable outcomes, patients with refractory/relapsed ML-DS or patients with cyclin dependent kinase inhibitor 2A (CDKN2A) deletions or TP53 mutations may have poor outcomes. Novel genomic aberrations such as partial tandem duplications of RUNX1 may provide potential targets for ML-DS treatment with bromodomain-containing protein 4 inhibitors in the future.⁴¹ 

Few patients with suspected Noonan syndrome and de novo germline gain of function KRAS proto-oncogene, GTPase (KRAS) variants develop MDS. Patients with germline mutations in Ras signaling pathway genes present with diverse symptoms and predisposition to tumorigenesis.^42,43  Additional studies are needed to further understand the underlying pathobiology. Other cancer predisposition syndromes include Bloom syndrome (BLM RecQ like helicase [BLM] mutation), Li-Fraumeni syndrome (TP53 mutation), neurofibromatosis (neurofibromin 1 [NF1] mutation), and others with variable risks of MDS/AML.^3,44 

The use of NGS assays has allowed the identification of de novo predisposition genes in patients presenting with MDS in adulthood. Examples include germline mutations in DDX41 in older adults who present with myeloid malignancies,^13,45,46  and mutations in CCAAT enhancer binding protein alpha (CEBPA), which have also been identified in pediatric myeloid neoplasms.^47,48  Shortly, we would expect more pediatric MDS associated with novel germline predispositions.

Inherited BMF syndromes (IBMFSs) are hematopoietic progenitor cell defects owing to various germline mutations. Patients present with peripheral blood (PB) cytopenia, variable nonhematopoietic manifestations, and predisposition to MDS or AML.⁴⁹  Occasionally, MDS can be the initial clinical presentation of IBMFSs. IBMFSs are subclassified based on the underlying genetic mutation and are briefly reviewed below.^50,51 

Fanconi anemia (FA), caused by germline mutations in any of 23 FA genes (FA complementation group A [FANCA]–FANCW) that function in DNA repair, is characterized by genomic instability, hypersensitivity to DNA cross-linking agents, and predisposition to marrow failure, hematologic malignancies, and solid tumors.⁵²  Hematologic findings include cytopenia, red cell macrocytosis, and hypocellular marrow with mild dysplasia. Clonal chromosome abnormalities (eg, 1q and 3q) are common in FA and may represent a preleukemic condition but are insufficient for a diagnosis of MDS.⁵³  However, monosomy 7 or 7q− is considered diagnostic evidence of MDS in patients with FA.⁵⁴  The cumulative incidence for MDS/AML is approximately 40% by the age of 40 to 50 years.⁵⁵ 

Schwachman-Diamond syndrome (SDS), caused by autosomal recessive mutations in the SBDS ribosome maturation factor (SBDS) gene encoding for ribosome maturation factor, is characterized by exocrine pancreatic dysfunction, BMF, and additional physical findings. Germline variants in other genes have also been identified. Mild dysgranulopoiesis can be seen on BM evaluation. Somatic TP53 mutations are frequently detected at the early onset of clonal hematopoiesis and before a diagnosis of MDS. Surveillance of TP53 mutations in SDS patients may help screen those susceptible to MDS. Moreover, TP53 mutations may cause complex karyotypes during the progression to MDS/AML.⁵⁶  The cumulative incidence of MDS/AML is about 36% by the age of 40.^55,57 

Diamond-Blackfan anemia, caused by autosomal dominant mutations of ribosomal protein genes (most commonly ribosomal protein S19 [RPS19]), is characterized by macrocytic anemia and reticulocytopenia in early life. BM histopathology typically shows red cell aplasia in an otherwise normocellular marrow. The cumulative incidence of MDS/AML is approximately 2%.⁵⁵ 

Dyskeratosis congenita or telomere biology disorders encompass genetically heterogeneous disorders related to impaired telomere maintenance, caused by mutations in dyskerin pseudouridine synthase 1 (DKC1), protection of telomeres 1 (POT1), replication protein A1 (RPA1), regulator of telomere elongation helicase 1 (RTEL1), STN1 subunit of CST complex (STN1), telomerase RNA component (TERC), telomerase reverse transcriptase (TERT), and others.⁵⁸  Patients with dyskeratosis congenita/telomere biology disorders present with a triad of dysplastic nails, lacy reticular pigmentation of the upper chest and/or neck, and oral leukoplakia, as well as other variable nonhematologic complications (pulmonary fibrosis, hepatic abnormalities, and vascular anomalies). The cumulative incidence of MDS/AML is around 11%.⁵⁵ 

In both de novo pediatric MDS and MDS associated with germline predispositions, secondary genetic abnormalities contribute to neoplastic transformation. Genes known to be frequently mutated in adult MDS (eg, SF3B1, TET2, DNMT3A, TP53, and the spliceosome complex) are not frequently involved in pediatric MDS.^59,60  Instead, somatic mutations in SET binding protein 1 (SETBP1), ASXL1, RUNX1, and RAS oncogenes have been identified in pediatric MDS.⁵⁹  Sequencing of 32 pediatric MDS cases found Ras/MAPK pathway mutations in 45% whereas RNA splicing gene mutations were rare at 2%.¹  Genetic changes of Ras/MAPK signaling pathway are also seen in pediatric MDS post–cytotoxic therapy.⁶¹ 

Chromosomal number abnormalities, including chromosome 7 deletions (41% of primary pediatric MDS), trisomy 8 and 21, and chromosome 17 deletions or loss of heterozygosity, have also been reported.¹ 

The BM microenvironment regulates physiologic hematopoiesis and plays an important role in the pathogenesis of MDS.⁶²  Chronic inflammation, cytokines, and toll-like receptor ligands stress local hematopoietic progenitor cells, leading to cell damage that results in BMF or progression to MDS/leukemia.⁶³  BM microenvironment has been extensively studied in adult and elderly patients with MDS.⁶⁴  The mechanistic role of aberrant innate immune activation in pediatric MDS is limited. Raaijmakers et al⁶⁵  showed that deletion of Dicer1 or Sbds in mouse osteoprogenitors induced BM dysfunction with myelodysplastic changes, indicating primary stromal dysfunction, and can result in secondary neoplastic disease.

In children, MDS may develop months to years following exposure to cytotoxic therapies. Therapy-related AML and t-MDS have similar event-free and overall survival and are classified together as t-MN. The cumulative incidence of t-MN ranges from 5% to 11% in children treated for solid tumors and from less than 1% to 5% for patients treated for acute leukemia (Figure 2, A through F).^66,67  Recurrent abnormalities in chromosomes 5 and/or 7 have been associated with alkylating agents, whereas 11q23 abnormalities have been seen with topoisomerase II inhibitors.^66,68 

A recent study evaluating a large cohort of pediatric t-MDS found significant differences from that in adults; specifically, preexisting minor clones were rare in pediatric t-MDS, as most arose from unrelated clones following cytotoxic therapies.⁶¹  Mutations in Ras/MAPK signaling pathway, alterations in RUNX1 or TP53, and lysine methyltransferase 2A (KMT2A) rearrangements were common somatic drivers in pediatric t-MDS.⁶¹  Additionally, germline mutations that predispose to malignancy (eg, TP53) are known to further contribute to the development of t-MN.^68,69 

The diagnosis of pediatric MDS, like that in adults, requires the integration of laboratory values, histology, genetics, and clinical presentation, as well as the exclusion of other secondary causes (summarized in Supplemental Table 1; see supplemental digital content at https://meridian.allenpress.com/aplm in the July 2025 table of contents, containing 3 tables).

A patient’s complete blood cell count with a review of peripheral smear is critical to evaluate for MDS. Single-lineage or multilineage cytopenia is required for the diagnosis of MDS, and children often show a different pattern than that of adults. An elevated mean corpuscular volume, hypolobulated and/or hypogranular neutrophils, and the presence of circulating blasts are additional features seen in pediatric MDS. It is important to note that normal ranges of complete blood cell count values differ by age and sex.

Pediatric MDS is often hypocellular, which makes evaluation of the BM aspirate alone inadequate. Therefore, an optimal core biopsy is essential to evaluate BM cellularity, reticulin fibrosis, dysplastic megakaryocytes (eg, micromegakaryocytes), and atypical lymphoid infiltrates.³¹  In one large cohort study comparing the histomorphology between severe aplastic anemia (AA) and RCC, a typical, but not necessarily specific, finding on core biopsy of pediatric MDS is a hypocellular marrow with patchy erythroid islands with maturation arrests (Figure 3, A through C).³¹  However, in the European Association of Haematopathology 2020 virtual workshop, where 16 pediatric MDS cases were submitted, the majority were not diagnosed as RCC. One case was diagnosed as hypocellular RCC, which might have represented AA, partly because of its clinical picture with rapid onset cytopenia and absence of cytogenetic aberrations.^70,71  Interestingly, 5 of the 16 childhood MDS cases showed variable marrow fibrosis and chromosomal aberrations, including trisomy 8 (2 cases), trisomy 15 (1 case), monosomy 7 (1 case), and 11q aberration (1 case).⁷⁰ 

Flow cytometry (FCM) assesses for aberrant immunophenotype of hematopoietic cells and blast percentage of PB or BM aspirate.⁷²  Data on FCM use in pediatric MDS are scarce. Nevertheless, FCM can help identify some features, such as reduced/absent hematogones or percentage of paroxysmal nocturnal hemoglobinuria (PNH) clones. A low percentage of PNH clones can be seen in pediatric MDS and severe AA; clinical correlation with thrombosis and hemolysis should increase suspicion of PNH.^73,74 

Conventional cytogenetics and fluorescence in situ hybridization studies are routinely performed in the MDS workup. Pediatric MDS has a high frequency of abnormalities in chromosomes 7, 8 and/or 20, but rarely abnormalities of chromosome 5. Few cytogenetic or chromosomal abnormalities have been integrated into the WHO criteria as “MDS defining,” including loss of chromosome 7 and 7q del, among others.^3,4 

NGS should be included in MDS workup to identify genetic mutations. Panel-based NGS and/or whole-exome sequencing have identified somatic mutations seen in pediatric MDS, such as SET binding protein 1 (SETBP1), ASXL1, RUNX1, and RAS oncogenes.^59,61  Somatic mutations of TP53 occur in 5% to 10% of pediatric MDS and are often associated with a complex karyotype and poor prognosis.⁶⁹  If mutations in predisposition genes or a congenital syndrome are identified in a PB or BM sample, a genetic consult and comprehensive germline sequencing are important in optimizing diagnosis and treatment. The germline sequencing is usually tested on cultured skin fibroblasts or other tissue sources (ie, mucosa). Of note, different testing platforms may have variable sensitivity to detect different types of germline variants (ie, large gene deletions, copy number variations, or intronic variants).

Pediatric MDS, especially low-grade disease with a small blast percentage, subtle cytopenia, and subtle morphology dysplasia, creates a challenge in both pathology and clinical practice.⁷³  Adult MDS with 10% to 19% blasts may represent a spectrum of AML (defined as ≥20% blasts), and has been classified as a separate category of MDS/AML, according to the newly released ICC classification system. In contrast, pediatric MDS with excess blasts in the ICC continues to be defined as MDS with 5% to 19% blasts in the BM or 2% to 19% in the PB.⁷⁵  The recently released WHO 5th edition classification keeps the same blast cutoff value unchanged for pediatric and adult cases.^3,4 

Patients with predisposition gene mutations show highly variable phenotypes and clinical presentations. For instance, patients with GATA2 germline mutations can present with bacterial, fungal, or viral infections; lymphedema; pulmonary alveolar proteinosis; immunodeficiency; cytopenia; and a high frequency of MDS and/or AML. MDS/AML can be the initial presentation or occur at any time during the disease course of these patients. Common secondary genetic changes include monosomy 7, trisomy 8, and acquired mutations in ASXL1 or STAG2 cohesin complex component (STAG2).^28,32,76  Similarly, patients with germline RUNX1 mutations show variable clinical phenotypes and predisposition to myeloid and lymphoid malignancies.^20,22,77 

Comparably, patients with IBMFSs, such as FA, DC, SDS, congenital dyserythropoietic anemias, severe congenital neutropenia, and congenital amegakaryocytic thrombocytopenia, can present with features resembling the clinical and histologic features of pediatric MDS.^78–87  Subtle morphologic dysplasia and occasional chromosomal alterations and/or genetic mutations can occur in IBMFSs, creating significant challenges in differentiating them from MDS. The clinical presentation of progressive cytopenia, multilineage morphologic dysplasia, increase in blasts, and enlarging chromosomal and mutational numbers and/or allele frequencies indicate a transformation to MDS.⁴⁹ 

An inborn error of immunity (IEI) should be ruled out if pediatric MDS is suspected. MDS/AML progression has been occasionally reported in common variable immunodeficiency, an IEI caused by impaired B-cell function and antibody production.⁸⁸  Novel germline mutations associated with IEIs and/or autoinflammatory disorders have recently been identified; deficiency of adenosine deaminase type 2, characterized by immunologic, hematologic, and neurologic features, can resemble MDS.⁸⁹  Of note, many of these children with IEI show BM fibrosis, which can be challenging to differentiate from pediatric MDS with fibrosis. In a cohort of 19 children with primary BM fibrosis, none developed malignant transformation and 5 had spontaneous resolution of disease.⁹⁰  Actually, dysplastic megakaryocytes are commonly seen in the BM of patients with myelofibrosis, in both children and adults. Nonetheless, there are no specific molecular markers or clinical presentations to distinguish MDS with fibrosis from other causes of myelofibrosis.⁹¹ 

Acquired AA should be carefully differentiated from pediatric MDS in the presence of cytopenia and BM hypocellularity.^73,92,93  The presence of typical MDS morphology (eg, patchy erythropoiesis with defective maturation; Figure 3) is a helpful distinguishing factor, which, however, may not be entirely specific.⁷¹  Even with the guidelines, it can be challenging to differentiate AA from RCC or hypoplastic MDS in daily practice, especially with morphologic dysplasia. The latter can be seen in various reactive scenarios. Additionally, acquired PNH clones and/or genetic abnormalities do not necessarily define a diagnosis of MDS.^73,74,93 

Prognostic scoring systems have been developed for adult MDS to guide clinical management decisions.^94,95  The International Prognostic Scoring System (IPSS), created to evaluate risk factors for MDS relapse, integrates both clinical and molecular features and stratifies MDS into 3 prognostic categories (good, intermediate, and poor). The IPSS was revised in 2012 (R-IPSS) to include 5 cytogenetic risk categories (very good, good, intermediate, poor, and very poor), as cytogenetic abnormalities were found to be highly predictive of outcomes following allogeneic hematopoietic cell transplant (allo-HCT) (Supplemental Table 2).^96–98  However, given the differences between pediatric and adult MDS, the applicability of the IPSS or R-IPSS to pediatric MDS is largely unknown, and it is not used routinely in clinical practice. An additional limitation of R-IPSS is that it does not incorporate molecular genetic information.⁷⁵  In pediatric MDS, a complex karyotype (≥3 cytogenetic aberrations) is a major poor prognostic factor.^3,4,99 

A recent multispecialty MDS survey highlighted the variability in the initial management approaches of pediatric MDS as well as within management choices.^100–102  The mainstay curative option for most forms of pediatric MDS is allo-HCT; the role of chemotherapy or immunosuppressive therapy is controversial.

Conventional chemotherapy in pediatric MDS has traditionally been with AML-type induction therapy (cytarabine with daunorubicin and/or idarubicin). Despite its use, the outcomes of pediatric MDS treated with conventional chemotherapy without allo-HCT are dismal, with reports of overall survival of less than 30% and complete remission rates of less than 60%. The role of pre–allo-HCT AML-type induction chemotherapy in patients with advanced MDS to reduce relapse following HCT and improve disease-free survival remains a controversial issue.^102,103 

Allo-HCT is the only curative therapy for pediatric patients with most forms of MDS, including advanced MDS, t-MN/MN-pCT, MDS in IBMFSs, and MDS associated with germline predisposition or complex cytogenetics. Cure rates of allo-HCT in pediatric MDS not associated with IBMFSs, germline predisposition, or MN-pCT are 50% to 60%, with the remainder associated with worse outcomes.¹⁰³  Pediatric MDS HCT studies (excluding IBMFSs and genetic predisposition syndromes), conditioning regimens, and their outcomes are summarized in Supplemental Table 3.

Pediatric MDS is a rare and heterogeneous clonal, hematologic neoplasm with significant differences from MDS in adults. Underlying genetic predisposition syndromes comprise a portion of pediatric MDS, but primary MDS also exists. The diagnosis of pediatric MDS remains difficult in the setting of overlapping and similar histopathology as well as clinical presentation among various pediatric BMF pathologies. There is a variability in the diagnostic and treatment approaches of pediatric MDS. Nonetheless, allo-HCT is curative in the various forms of MDS, including transformed MDS/AML in IBMFSs and MN-pCT, but the prognosis following disease progression and/or post-HCT relapse remains grave.