Germline and somatic genetic landscape of pediatric myelodysplastic syndromes
Pediatric myelodysplastic syndromes (MDS) represent a rare group of clonal hematopoietic stem cell disorders accounting for ~5% of pediatric hematological malignancies. They are characterized by ineffective hematopoiesis, cytopenia, and dysplastic changes in the bone marrow with variable risk of pr...
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Ferrata Storti Foundation
2025-06-01
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| Series: | Haematologica |
| Online Access: | https://haematologica.org/article/view/12132 |
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| author | Lili Kotmayer Alyssa L. Kennedy Marcin W. Wlodarski |
| author_facet | Lili Kotmayer Alyssa L. Kennedy Marcin W. Wlodarski |
| author_sort | Lili Kotmayer |
| collection | DOAJ |
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Pediatric myelodysplastic syndromes (MDS) represent a rare group of clonal hematopoietic stem cell disorders accounting for ~5% of pediatric hematological 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%, 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 longterm 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.
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| format | Article |
| id | doaj-art-98d4d7c800074ca2be950be3526b6123 |
| institution | Kabale University |
| issn | 0390-6078 1592-8721 |
| language | English |
| publishDate | 2025-06-01 |
| publisher | Ferrata Storti Foundation |
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| series | Haematologica |
| spelling | doaj-art-98d4d7c800074ca2be950be3526b61232025-08-20T03:27:13ZengFerrata Storti FoundationHaematologica0390-60781592-87212025-06-01999110.3324/haematol.2024.285700Germline and somatic genetic landscape of pediatric myelodysplastic syndromesLili Kotmayer0Alyssa L. Kennedy1Marcin W. Wlodarski2Department of Hematology, St. Jude Children’s Research Hospital, MemphisDepartment of Hematology, St. Jude Children’s Research Hospital, MemphisDepartment of Hematology, St. Jude Children’s Research Hospital, Memphis Pediatric myelodysplastic syndromes (MDS) represent a rare group of clonal hematopoietic stem cell disorders accounting for ~5% of pediatric hematological 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%, 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 longterm 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. https://haematologica.org/article/view/12132 |
| spellingShingle | Lili Kotmayer Alyssa L. Kennedy Marcin W. Wlodarski Germline and somatic genetic landscape of pediatric myelodysplastic syndromes Haematologica |
| title | Germline and somatic genetic landscape of pediatric myelodysplastic syndromes |
| title_full | Germline and somatic genetic landscape of pediatric myelodysplastic syndromes |
| title_fullStr | Germline and somatic genetic landscape of pediatric myelodysplastic syndromes |
| title_full_unstemmed | Germline and somatic genetic landscape of pediatric myelodysplastic syndromes |
| title_short | Germline and somatic genetic landscape of pediatric myelodysplastic syndromes |
| title_sort | germline and somatic genetic landscape of pediatric myelodysplastic syndromes |
| url | https://haematologica.org/article/view/12132 |
| work_keys_str_mv | AT lilikotmayer germlineandsomaticgeneticlandscapeofpediatricmyelodysplasticsyndromes AT alyssalkennedy germlineandsomaticgeneticlandscapeofpediatricmyelodysplasticsyndromes AT marcinwwlodarski germlineandsomaticgeneticlandscapeofpediatricmyelodysplasticsyndromes |