Difference between revisions of "HAEM5:Childhood myelodysplastic neoplasm with increased blasts"

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This page was converted to the new template on 2023-12-07. The original page can be found at HAEM4:Refractory Cytopenia of Childhood.

(General Instructions – The main focus of these pages is the clinically significant genetic alterations in each disease type. Use HUGO-approved gene names and symbols (italicized when appropriate), HGVS-based nomenclature for variants, as well as generic names of drugs and testing platforms or assays if applicable. Please complete tables whenever possible and do not delete them (add N/A if not applicable in the table and delete the examples). Please do not delete or alter the section headings. The use of bullet points alongside short blocks of text rather than only large paragraphs is encouraged. Additional instructions below in italicized blue text should not be included in the final page content. Please also see Author_Instructions and FAQs as well as contact your Associate Editor or Technical Support)

Primary Author(s)*

Xiaoli Du, Ph.D; Teresa A. Smolarek, Ph.D, FACMG

Division of Human Genetics, Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, OH, 45229, USA.

Cancer Category / Type

Myelodysplastic Syndrome

Cancer Sub-Classification / Subtype

Refractory Cytopenia of Childhood

Definition / Description of Disease

Refractory Cytopenia of Childhood (RCC) is a low-grade MDS most common in childhood, which is characterized by <2% blood blasts and <5% bone marrow blasts and persistent cytopenia^[1]. Since more than 80% RCC has a hypocellular bone marrow, it is important to distinguish RCC with aplastic anemia from other bone marrow failure disorders^[2]. Aplastic anemia is an autoimmune-mediated disorder, while RCC is caused by a clonal stem cell defect with the potential to progress to an advanced disease. The presence of micromegakaryocytes is a strong indicator of RCC. Hematopoietic stem cell transplantation (HSCT) is the only curative treatment^[3].

Synonyms / Terminology

Refractory Cytopenia of Childhood (RCC)

Epidemiology / Prevalence

RCC accounts for 50% of all cases of MDS^[3] ^[4]^[5].

Most common childhood MDS
No significant sex predilection

Clinical Features

Put your text here and fill in the table (Instruction: Can include references in the table)

Signs and Symptoms	EXAMPLE Asymptomatic (incidental finding on complete blood counts) EXAMPLE B-symptoms (weight loss, fever, night sweats) EXAMPLE Fatigue EXAMPLE Lymphadenopathy (uncommon)
Laboratory Findings	EXAMPLE Cytopenias EXAMPLE Lymphocytosis (low level)

editv4:Clinical Features

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The clinical symptoms are usually related to cytopenia such as anemia, bleeding tendency, and infection. However, approximately 20% of patients have no clinical symptoms or signs^[6].

Hemoglobin concentration: <10 g/dL AND

Platelet count: <150 x10⁹/L

Sites of Involvement

Peripheral blood and bone marrow

Morphologic Features

The main morphologic features of the peripheral blood smear and bone marrow are for the diagnosis of RCC^[3].


Categories	Morphologic Features
Peripheral blood	Anisopoikilocytosis and macrocytosis; neutropenia with pseudo-Pelger-Huet nulei, hypogranularity or agranularity,
Bone marrow aspirate/biopsy	Erythropoiesis: immature erythroid precursors, nuclear budding, multinuclearity, internuclear bridging; Graulopoiesis: pseudo-Pelger-Huet nulei, hypogranularity or agranularity, macrocytic bands; Megakaryopoiesis: absent or very few, however, micromegakaryocyte is crucial for the diagnosis.

Immunophenotype

Put your text here and fill in the table (Instruction: Can include references in the table)

Finding	Marker
Positive (universal)	EXAMPLE CD1
Positive (subset)	EXAMPLE CD2
Negative (universal)	EXAMPLE CD3
Negative (subset)	EXAMPLE CD4

editv4:Immunophenotype

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CD61, CD41, von Willebrand factor are useful to help detect the micromegakaryocyte. No increase of CD34 staining should be observed, which indicates the progression of high grade MDS^[3].

Chromosomal Rearrangements (Gene Fusions)

Put your text here and fill in the table

Chromosomal Rearrangement	Genes in Fusion (5’ or 3’ Segments)	Pathogenic Derivative	Prevalence	Diagnostic Significance (Yes, No or Unknown)	Prognostic Significance (Yes, No or Unknown)	Therapeutic Significance (Yes, No or Unknown)	Notes
EXAMPLE t(9;22)(q34;q11.2)	EXAMPLE 3'ABL1 / 5'BCR	EXAMPLE der(22)	EXAMPLE 20% (COSMIC) EXAMPLE 30% (add reference)	Yes	No	Yes	EXAMPLE The t(9;22) is diagnostic of CML in the appropriate morphology and clinical context (add reference). This fusion is responsive to targeted therapy such as Imatinib (Gleevec) (add reference).

editv4:Chromosomal Rearrangements (Gene Fusions)

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No

editv4:Clinical Significance (Diagnosis, Prognosis and Therapeutic Implications).

Please incorporate this section into the relevant tables found in:
Chromosomal Rearrangements (Gene Fusions)

Individual Region Genomic Gain/Loss/LOH

Characteristic Chromosomal Patterns

Gene Mutations (SNV/INDEL)

Diagnosis: <2% blood blasts and <5% bone marrow blasts and persistent cytopenia

Prognosis: In RCC, patients with monosomy 7 have a higher probability of progression^[7]^[8]^[9]. Patients with trisomy 8 or a normal karyotype are unlikely to progress to advanced MDS.

Therapeutic: Hematopoietic stem cell transplantation (HSCT) is the only curative therapy for RCC patients. This treatment is suitable for patients with monosomy 7 or a complex karyotype in the early stage of the process. Some of the RCC patients benefit from immunosuppressive therapy, although it is unclear whether the immunosuppressive therapy has the risk of relapse long-term^[10]^[11].

Individual Region Genomic Gain / Loss / LOH

Put your text here and fill in the table (Instructions: Includes aberrations not involving gene fusions. Can include references in the table. Can refer to CGC workgroup tables as linked on the homepage if applicable.)

Chr #	Gain / Loss / Amp / LOH	Minimal Region Genomic Coordinates [Genome Build]	Minimal Region Cytoband	Diagnostic Significance (Yes, No or Unknown)	Prognostic Significance (Yes, No or Unknown)	Therapeutic Significance (Yes, No or Unknown)	Notes
EXAMPLE 7	EXAMPLE Loss	EXAMPLE chr7:1- 159,335,973 [hg38]	EXAMPLE chr7	Yes	Yes	No	EXAMPLE Presence of monosomy 7 (or 7q deletion) is sufficient for a diagnosis of AML with MDS-related changes when there is ≥20% blasts and no prior therapy (add reference). Monosomy 7/7q deletion is associated with a poor prognosis in AML (add reference).
EXAMPLE 8	EXAMPLE Gain	EXAMPLE chr8:1-145,138,636 [hg38]	EXAMPLE chr8	No	No	No	EXAMPLE Common recurrent secondary finding for t(8;21) (add reference).

editv4:Genomic Gain/Loss/LOH

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Monosomy 7 is the most frequent cytogenetic abnormality of RCC patients, followed by trisomy 8 and other abnormalities, including complex karyotypes^[12]^[13]^[14].

Characteristic Chromosomal Patterns

Put your text here (EXAMPLE PATTERNS: hyperdiploid; gain of odd number chromosomes including typically chromosome 1, 3, 5, 7, 11, and 17; co-deletion of 1p and 19q; complex karyotypes without characteristic genetic findings; chromothripsis)

Chromosomal Pattern	Diagnostic Significance (Yes, No or Unknown)	Prognostic Significance (Yes, No or Unknown)	Therapeutic Significance (Yes, No or Unknown)	Notes
EXAMPLE Co-deletion of 1p and 18q	Yes	No	No	EXAMPLE: See chromosomal rearrangements table as this pattern is due to an unbalanced derivative translocation associated with oligodendroglioma (add reference).

editv4:Characteristic Chromosomal Aberrations / Patterns

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Monosomy 7 (CCHMC), trisomy 8 and other abnormalities, including complex karyotypes.
Pictures are needed to be upload!!

Gene Mutations (SNV / INDEL)

Put your text here and fill in the table (Instructions: This table is not meant to be an exhaustive list; please include only genes/alterations that are recurrent and common as well either disease defining and/or clinically significant. Can include references in the table. For clinical significance, denote associations with FDA-approved therapy (not an extensive list of applicable drugs) and NCCN or other national guidelines if applicable; Can also refer to CGC workgroup tables as linked on the homepage if applicable as well as any high impact papers or reviews of gene mutations in this entity.)

Gene; Genetic Alteration	Presumed Mechanism (Tumor Suppressor Gene [TSG] / Oncogene / Other)	Prevalence (COSMIC / TCGA / Other)	Concomitant Mutations	Mutually Exclusive Mutations	Diagnostic Significance (Yes, No or Unknown)	Prognostic Significance (Yes, No or Unknown)	Therapeutic Significance (Yes, No or Unknown)	Notes
EXAMPLE: TP53; Variable LOF mutations EXAMPLE: EGFR; Exon 20 mutations EXAMPLE: BRAF; Activating mutations	EXAMPLE: TSG	EXAMPLE: 20% (COSMIC) EXAMPLE: 30% (add Reference)	EXAMPLE: IDH1 R123H	EXAMPLE: EGFR amplification				EXAMPLE: Excludes hairy cell leukemia (HCL) (add reference).

Note: A more extensive list of mutations can be found in cBioportal (https://www.cbioportal.org/), COSMIC (https://cancer.sanger.ac.uk/cosmic), ICGC (https://dcc.icgc.org/) and/or other databases. When applicable, gene-specific pages within the CCGA site directly link to pertinent external content.

editv4:Gene Mutations (SNV/INDEL)

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Mutations are less common than in adult MDS with a different profile

Most frequent mutations: RAS/MAPK, SAMD9/SAMD9L, GATA2^[15]^[16].

Other Mutations

No

Epigenomic Alterations

No

Genes and Main Pathways Involved

Put your text here and fill in the table (Instructions: Can include references in the table.)

Gene; Genetic Alteration	Pathway	Pathophysiologic Outcome
EXAMPLE: BRAF and MAP2K1; Activating mutations	EXAMPLE: MAPK signaling	EXAMPLE: Increased cell growth and proliferation
EXAMPLE: CDKN2A; Inactivating mutations	EXAMPLE: Cell cycle regulation	EXAMPLE: Unregulated cell division
EXAMPLE: KMT2C and ARID1A; Inactivating mutations	EXAMPLE: Histone modification, chromatin remodeling	EXAMPLE: Abnormal gene expression program

editv4:Genes and Main Pathways Involved

The content below was from the old template. Please incorporate above.

RAS/MAPK: involved in MAPK tyrosine Kinase pathway

SAMD9/SAMD9L: involved in regulating the growth and proliferation and differentiation of cells

GATA2: involved in regulating transcription of genes related with the development and proliferation of hematopoietic and endocrine cell lineages

Genetic Diagnostic Testing Methods

Bone marrow minimal histological criteria for refractory cytopenia of childhood^[17]^[18]. Refractory cytopenia of childhood is defined as persistent cytopenia with <5% blasts in bone marrow and <2% blasts in peripheral blood. The criteria of dysplasia must be fulfilled in ≥2 cell lineages or ≥10% of cells within one cell lineage on bone marrow aspirate smears. See table:


Cellularity	Erythropoiesis	Granulopoiesis	Megakaryopoiesis
Variable	A few clusters of ≥20 erythroid precursors. Arrest in maturation, with increased number of proerythroblasts. Increased number of mitoses.	No minimal diagnostic criteria.	Unequivocal micromegakaryocytes; immunohistochemistry is obligatory (CD61, CD41, CD42b); other dysplastic changes in variable numbers.

In addition, RCC must be differentiated from aplastic anemia, bone marrow failure syndromes, infection, nutritional deficiencies, and metabolic diseases.

Familial Forms

Put your text here (Instructions: Include associated hereditary conditions/syndromes that cause this entity or are caused by this entity.)

Additional Information

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Links

Put your text placeholder here (or anywhere appropriate on the page) and use the "Link" icon at the top of the page (Instructions: Once you have a text placeholder entered to which you want to add a link, highlight that text, select the "Link" icon at the top of the page, and search the name of the internal page to which you want to link this text, or enter an external internet address including the "http://www." portion.)

References

(use the "Cite" icon at the top of the page) (Instructions: Add each reference into the text above by clicking on where you want to insert the reference, selecting the “Cite” icon at the top of the page, and using the “Automatic” tab option to search such as by PMID to select the reference to insert. The reference list in this section will be automatically generated and sorted. If a PMID is not available, such as for a book, please use the “Cite” icon, select “Manual” and then “Basic Form”, and include the entire reference.)

↑ Hasle, H.; et al. (2003-02). "A pediatric approach to the WHO classification of myelodysplastic and myeloproliferative diseases". Leukemia. 17 (2): 277–282. doi:10.1038/sj.leu.2402765. ISSN 0887-6924. PMID 12592323. Check date values in: |date= (help)
↑ Niemeyer, Charlotte M.; et al. (2011). "Classification of childhood aplastic anemia and myelodysplastic syndrome". Hematology. American Society of Hematology. Education Program. 2011: 84–89. doi:10.1182/asheducation-2011.1.84. ISSN 1520-4383. PMID 22160017.
↑ ^3.0 ^3.1 ^3.2 ^3.3 Arber DA, et al., (2016). WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues, revised 4^th edition. Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, Thiele J Editors. IARC Press: Lyon, France, p106-109.
↑ Passmore, S. Jane; et al. (2003-06). "Paediatric myelodysplastic syndromes and juvenile myelomonocytic leukaemia in the UK: a population-based study of incidence and survival". British Journal of Haematology. 121 (5): 758–767. doi:10.1046/j.1365-2141.2003.04361.x. ISSN 0007-1048. PMID 12780790. Check date values in: |date= (help)
↑ Germing, Ulrich; et al. (2012-06). "Evaluation of dysplasia through detailed cytomorphology in 3156 patients from the Düsseldorf Registry on myelodysplastic syndromes". Leukemia Research. 36 (6): 727–734. doi:10.1016/j.leukres.2012.02.014. ISSN 1873-5835. PMID 22421409. Check date values in: |date= (help)
↑ Kardos, Gabriela; et al. (2003-09-15). "Refractory anemia in childhood: a retrospective analysis of 67 patients with particular reference to monosomy 7". Blood. 102 (6): 1997–2003. doi:10.1182/blood-2002-11-3444. ISSN 0006-4971. PMID 12763938.
↑ Passmore, S. Jane; et al. (2003-06). "Paediatric myelodysplastic syndromes and juvenile myelomonocytic leukaemia in the UK: a population-based study of incidence and survival". British Journal of Haematology. 121 (5): 758–767. doi:10.1046/j.1365-2141.2003.04361.x. ISSN 0007-1048. PMID 12780790. Check date values in: |date= (help)
↑ Pui, Ching-Hon; et al. (2004). "Childhood and adolescent lymphoid and myeloid leukemia". Hematology. American Society of Hematology. Education Program: 118–145. doi:10.1182/asheducation-2004.1.118. ISSN 1520-4391. PMID 15561680.
↑ Kardos, Gabriela; et al. (2003-09-15). "Refractory anemia in childhood: a retrospective analysis of 67 patients with particular reference to monosomy 7". Blood. 102 (6): 1997–2003. doi:10.1182/blood-2002-11-3444. ISSN 0006-4971. PMID 12763938.
↑ Hasegawa, Daisuke; et al. (2009-12). "Treatment of children with refractory anemia: the Japanese Childhood MDS Study Group trial (MDS99)". Pediatric Blood & Cancer. 53 (6): 1011–1015. doi:10.1002/pbc.22121. ISSN 1545-5017. PMID 19499580. Check date values in: |date= (help)
↑ Yoshimi, Ayami; et al. (2014-04). "Comparison of horse and rabbit antithymocyte globulin in immunosuppressive therapy for refractory cytopenia of childhood". Haematologica. 99 (4): 656–663. doi:10.3324/haematol.2013.095786. ISSN 1592-8721. PMC 3971075. PMID 24162791. Check date values in: |date= (help)
↑ Kardos, Gabriela; et al. (2003-09-15). "Refractory anemia in childhood: a retrospective analysis of 67 patients with particular reference to monosomy 7". Blood. 102 (6): 1997–2003. doi:10.1182/blood-2002-11-3444. ISSN 0006-4971. PMID 12763938.
↑ Niemeyer, Charlotte M.; et al. (2011). "Classification of childhood aplastic anemia and myelodysplastic syndrome". Hematology. American Society of Hematology. Education Program. 2011: 84–89. doi:10.1182/asheducation-2011.1.84. ISSN 1520-4383. PMID 22160017.
↑ Gupta, Ruchi; et al. (2018-10). "Prevalence of Chromosome 7 Abnormalities in Myelodysplastic Syndrome and Acute Myeloid Leukemia: A Single Center Study and Brief Literature Review". Indian Journal of Hematology & Blood Transfusion: An Official Journal of Indian Society of Hematology and Blood Transfusion. 34 (4): 602–611. doi:10.1007/s12288-018-0941-1. ISSN 0971-4502. PMC 6186231. PMID 30369728. Check date values in: |date= (help)
↑ Schwartz, Jason R.; et al. (2017-11-16). "The genomic landscape of pediatric myelodysplastic syndromes". Nature Communications. 8 (1): 1557. doi:10.1038/s41467-017-01590-5. ISSN 2041-1723. PMC 5691144. PMID 29146900.
↑ Wlodarski, Marcin W.; et al. (2016-03-17). "Prevalence, clinical characteristics, and prognosis of GATA2-related myelodysplastic syndromes in children and adolescents". Blood. 127 (11): 1387–1397, quiz 1518. doi:10.1182/blood-2015-09-669937. ISSN 1528-0020. PMID 26702063.
↑ Arber DA, et al., (2016). WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues, revised 4^th edition. Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, Thiele J Editors. IARC Press: Lyon, France, p106-109.
↑ Iwafuchi, Hideto (2018). "The histopathology of bone marrow failure in children". Journal of clinical and experimental hematopathology: JCEH. 58 (2): 68–86. doi:10.3960/jslrt.18018. ISSN 1880-9952. PMC 6413145. PMID 29998978.

Notes

*Primary authors will typically be those that initially create and complete the content of a page. If a subsequent user modifies the content and feels the effort put forth is of high enough significance to warrant listing in the authorship section, please contact the CCGA coordinators (contact information provided on the homepage). Additional global feedback or concerns are also welcome. *Citation of this Page: “Childhood myelodysplastic neoplasm with increased blasts”. Compendium of Cancer Genome Aberrations (CCGA), Cancer Genomics Consortium (CGC), updated 09/3/2024, https://ccga.io/index.php/HAEM5:Childhood_myelodysplastic_neoplasm_with_increased_blasts.

[1] Hasle, H.; et al. (2003-02). "A pediatric approach to the WHO classification of myelodysplastic and myeloproliferative diseases". Leukemia. 17 (2): 277–282. doi:10.1038/sj.leu.2402765. ISSN 0887-6924. PMID 12592323. Check date values in: |date= (help)

[2] Niemeyer, Charlotte M.; et al. (2011). "Classification of childhood aplastic anemia and myelodysplastic syndrome". Hematology. American Society of Hematology. Education Program. 2011: 84–89. doi:10.1182/asheducation-2011.1.84. ISSN 1520-4383. PMID 22160017.

[:0-3] 3.0 ^3.1 ^3.2 ^3.3 Arber DA, et al., (2016). WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues, revised 4^th edition. Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, Thiele J Editors. IARC Press: Lyon, France, p106-109.

[4] Passmore, S. Jane; et al. (2003-06). "Paediatric myelodysplastic syndromes and juvenile myelomonocytic leukaemia in the UK: a population-based study of incidence and survival". British Journal of Haematology. 121 (5): 758–767. doi:10.1046/j.1365-2141.2003.04361.x. ISSN 0007-1048. PMID 12780790. Check date values in: |date= (help)

[5] Germing, Ulrich; et al. (2012-06). "Evaluation of dysplasia through detailed cytomorphology in 3156 patients from the Düsseldorf Registry on myelodysplastic syndromes". Leukemia Research. 36 (6): 727–734. doi:10.1016/j.leukres.2012.02.014. ISSN 1873-5835. PMID 22421409. Check date values in: |date= (help)

[6] Kardos, Gabriela; et al. (2003-09-15). "Refractory anemia in childhood: a retrospective analysis of 67 patients with particular reference to monosomy 7". Blood. 102 (6): 1997–2003. doi:10.1182/blood-2002-11-3444. ISSN 0006-4971. PMID 12763938.

[7] Passmore, S. Jane; et al. (2003-06). "Paediatric myelodysplastic syndromes and juvenile myelomonocytic leukaemia in the UK: a population-based study of incidence and survival". British Journal of Haematology. 121 (5): 758–767. doi:10.1046/j.1365-2141.2003.04361.x. ISSN 0007-1048. PMID 12780790. Check date values in: |date= (help)

[8] Pui, Ching-Hon; et al. (2004). "Childhood and adolescent lymphoid and myeloid leukemia". Hematology. American Society of Hematology. Education Program: 118–145. doi:10.1182/asheducation-2004.1.118. ISSN 1520-4391. PMID 15561680.

[9] Kardos, Gabriela; et al. (2003-09-15). "Refractory anemia in childhood: a retrospective analysis of 67 patients with particular reference to monosomy 7". Blood. 102 (6): 1997–2003. doi:10.1182/blood-2002-11-3444. ISSN 0006-4971. PMID 12763938.

[10] Hasegawa, Daisuke; et al. (2009-12). "Treatment of children with refractory anemia: the Japanese Childhood MDS Study Group trial (MDS99)". Pediatric Blood & Cancer. 53 (6): 1011–1015. doi:10.1002/pbc.22121. ISSN 1545-5017. PMID 19499580. Check date values in: |date= (help)

[11] Yoshimi, Ayami; et al. (2014-04). "Comparison of horse and rabbit antithymocyte globulin in immunosuppressive therapy for refractory cytopenia of childhood". Haematologica. 99 (4): 656–663. doi:10.3324/haematol.2013.095786. ISSN 1592-8721. PMC 3971075. PMID 24162791. Check date values in: |date= (help)

[12] Kardos, Gabriela; et al. (2003-09-15). "Refractory anemia in childhood: a retrospective analysis of 67 patients with particular reference to monosomy 7". Blood. 102 (6): 1997–2003. doi:10.1182/blood-2002-11-3444. ISSN 0006-4971. PMID 12763938.

[13] Niemeyer, Charlotte M.; et al. (2011). "Classification of childhood aplastic anemia and myelodysplastic syndrome". Hematology. American Society of Hematology. Education Program. 2011: 84–89. doi:10.1182/asheducation-2011.1.84. ISSN 1520-4383. PMID 22160017.

[14] Gupta, Ruchi; et al. (2018-10). "Prevalence of Chromosome 7 Abnormalities in Myelodysplastic Syndrome and Acute Myeloid Leukemia: A Single Center Study and Brief Literature Review". Indian Journal of Hematology & Blood Transfusion: An Official Journal of Indian Society of Hematology and Blood Transfusion. 34 (4): 602–611. doi:10.1007/s12288-018-0941-1. ISSN 0971-4502. PMC 6186231. PMID 30369728. Check date values in: |date= (help)

[15] Schwartz, Jason R.; et al. (2017-11-16). "The genomic landscape of pediatric myelodysplastic syndromes". Nature Communications. 8 (1): 1557. doi:10.1038/s41467-017-01590-5. ISSN 2041-1723. PMC 5691144. PMID 29146900.

[16] Wlodarski, Marcin W.; et al. (2016-03-17). "Prevalence, clinical characteristics, and prognosis of GATA2-related myelodysplastic syndromes in children and adolescents". Blood. 127 (11): 1387–1397, quiz 1518. doi:10.1182/blood-2015-09-669937. ISSN 1528-0020. PMID 26702063.

[17] Arber DA, et al., (2016). WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues, revised 4^th edition. Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, Thiele J Editors. IARC Press: Lyon, France, p106-109.

[18] Iwafuchi, Hideto (2018). "The histopathology of bone marrow failure in children". Journal of clinical and experimental hematopathology: JCEH. 58 (2): 68–86. doi:10.3960/jslrt.18018. ISSN 1880-9952. PMC 6413145. PMID 29998978.

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