Diagnostic Value of a Protocolized In-Depth Evaluation of Pediatric Bone Marrow Failure: A Multi-Center Prospective Cohort Study
BackgroundSevere multilineage cytopenia in childhood caused by bone marrow failure (BMF) often represents a serious condition requiring specific management. Patients are at risk for invasive infections and bleeding complications. Previous studies report low rates of identifiable causes of pediatric...
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| Format: | Article |
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Frontiers Media S.A.
2022-04-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2022.883826/full |
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| author | Khaled Atmar Claudia A. L. Ruivenkamp Louise Hooimeijer Esther A. R. Nibbeling Corien L. Eckhardt Elise J. Huisman Arjan C. Lankester Marije Bartels Gijs W. E. Santen Frans J. Smiers Mirjam van der Burg Alexander B. Mohseny |
| author_facet | Khaled Atmar Claudia A. L. Ruivenkamp Louise Hooimeijer Esther A. R. Nibbeling Corien L. Eckhardt Elise J. Huisman Arjan C. Lankester Marije Bartels Gijs W. E. Santen Frans J. Smiers Mirjam van der Burg Alexander B. Mohseny |
| author_sort | Khaled Atmar |
| collection | DOAJ |
| description | BackgroundSevere multilineage cytopenia in childhood caused by bone marrow failure (BMF) often represents a serious condition requiring specific management. Patients are at risk for invasive infections and bleeding complications. Previous studies report low rates of identifiable causes of pediatric BMF, rendering most patients with a descriptive diagnosis such as aplastic anemia (AA).MethodsWe conducted a multi-center prospective cohort study in which an extensive diagnostic approach for pediatric patients with suspected BMF was implemented. After exclusion of malignant and transient causes of BMF, patients entered thorough diagnostic evaluation including bone marrow analysis, whole exome sequencing (WES) including copy number variation (CNV) analysis and/or single nucleotide polymorphisms (SNP) array analysis. In addition, functional and immunological evaluation were performed. Here we report the outcomes of the first 50 patients (2017-2021) evaluated by this approach.ResultsIn 20 patients (40%) a causative diagnosis was made. In this group, 18 diagnoses were established by genetic analysis, including 14 mutations and 4 chromosomal deletions. The 2 remaining patients had short telomeres while no causative genetic defect was found. Of the remaining 30 patients (60%), 21 were diagnosed with severe aplastic anemia (SAA) based on peripheral multi-lineage cytopenia and hypoplastic bone marrow, and 9 were classified as unexplained cytopenia without bone marrow hypoplasia. In total 28 patients had undergone hematopoietic stem cell transplantation (HSCT) of which 22 patients with an unknown cause and 6 patients with an identified cause for BMF.ConclusionWe conclude that a standardized in-depth diagnostic protocol as presented here, can increase the frequency of identifiable causes within the heterogeneous group of pediatric BMF. We underline the importance of full genetic analysis complemented by functional tests of all patients as genetic causes are not limited to patients with typical (syndromal) clinical characteristics beyond cytopenia. In addition, it is of importance to apply genome wide genetic analysis, since defects in novel genes are frequently discovered in this group. Identification of a causal abnormality consequently has implications for the choice of treatment and in some cases prevention of invasive therapies. |
| first_indexed | 2024-04-14T00:56:54Z |
| format | Article |
| id | doaj.art-021d8bd9944845ca8c30ccf0647fa945 |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-04-14T00:56:54Z |
| publishDate | 2022-04-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj.art-021d8bd9944845ca8c30ccf0647fa9452022-12-22T02:21:34ZengFrontiers Media S.A.Frontiers in Immunology1664-32242022-04-011310.3389/fimmu.2022.883826883826Diagnostic Value of a Protocolized In-Depth Evaluation of Pediatric Bone Marrow Failure: A Multi-Center Prospective Cohort StudyKhaled Atmar0Claudia A. L. Ruivenkamp1Louise Hooimeijer2Esther A. R. Nibbeling3Corien L. Eckhardt4Elise J. Huisman5Arjan C. Lankester6Marije Bartels7Gijs W. E. Santen8Frans J. Smiers9Mirjam van der Burg10Alexander B. Mohseny11Department of Pediatric Hematology and Stem Cell Transplantation, Willem-Alexander Children’s Hospital, Leiden University Medical Center, Leiden, NetherlandsDepartment of Clinical Genetics, Leiden University Medical Center, Leiden, NetherlandsDepartment of Pediatric Hematology, Beatrix Children’s Hospital, University Medical Center Groningen, Groningen, NetherlandsDepartment of Clinical Genetics, Leiden University Medical Center, Leiden, NetherlandsDepartment of Pediatric Hematology, Amsterdam University Medical Center, Amsterdam, NetherlandsDepartment of Pediatric Hematology, Erasmus Medical Center, Sophia Children’s Hospital, Rotterdam, NetherlandsDepartment of Pediatric Hematology and Stem Cell Transplantation, Willem-Alexander Children’s Hospital, Leiden University Medical Center, Leiden, NetherlandsDepartment of Pediatric Hematology, Wilhelmina Children’s Hospital, University Medical Center Utrecht, Utrecht, NetherlandsDepartment of Clinical Genetics, Leiden University Medical Center, Leiden, NetherlandsDepartment of Pediatric Hematology and Stem Cell Transplantation, Willem-Alexander Children’s Hospital, Leiden University Medical Center, Leiden, NetherlandsDepartment of Pediatric Hematology and Stem Cell Transplantation, Willem-Alexander Children’s Hospital, Leiden University Medical Center, Leiden, NetherlandsDepartment of Pediatric Hematology and Stem Cell Transplantation, Willem-Alexander Children’s Hospital, Leiden University Medical Center, Leiden, NetherlandsBackgroundSevere multilineage cytopenia in childhood caused by bone marrow failure (BMF) often represents a serious condition requiring specific management. Patients are at risk for invasive infections and bleeding complications. Previous studies report low rates of identifiable causes of pediatric BMF, rendering most patients with a descriptive diagnosis such as aplastic anemia (AA).MethodsWe conducted a multi-center prospective cohort study in which an extensive diagnostic approach for pediatric patients with suspected BMF was implemented. After exclusion of malignant and transient causes of BMF, patients entered thorough diagnostic evaluation including bone marrow analysis, whole exome sequencing (WES) including copy number variation (CNV) analysis and/or single nucleotide polymorphisms (SNP) array analysis. In addition, functional and immunological evaluation were performed. Here we report the outcomes of the first 50 patients (2017-2021) evaluated by this approach.ResultsIn 20 patients (40%) a causative diagnosis was made. In this group, 18 diagnoses were established by genetic analysis, including 14 mutations and 4 chromosomal deletions. The 2 remaining patients had short telomeres while no causative genetic defect was found. Of the remaining 30 patients (60%), 21 were diagnosed with severe aplastic anemia (SAA) based on peripheral multi-lineage cytopenia and hypoplastic bone marrow, and 9 were classified as unexplained cytopenia without bone marrow hypoplasia. In total 28 patients had undergone hematopoietic stem cell transplantation (HSCT) of which 22 patients with an unknown cause and 6 patients with an identified cause for BMF.ConclusionWe conclude that a standardized in-depth diagnostic protocol as presented here, can increase the frequency of identifiable causes within the heterogeneous group of pediatric BMF. We underline the importance of full genetic analysis complemented by functional tests of all patients as genetic causes are not limited to patients with typical (syndromal) clinical characteristics beyond cytopenia. In addition, it is of importance to apply genome wide genetic analysis, since defects in novel genes are frequently discovered in this group. Identification of a causal abnormality consequently has implications for the choice of treatment and in some cases prevention of invasive therapies.https://www.frontiersin.org/articles/10.3389/fimmu.2022.883826/fullbone marrow failureBMFaplastic anemiaAAcytopenianext-generation sequencing |
| spellingShingle | Khaled Atmar Claudia A. L. Ruivenkamp Louise Hooimeijer Esther A. R. Nibbeling Corien L. Eckhardt Elise J. Huisman Arjan C. Lankester Marije Bartels Gijs W. E. Santen Frans J. Smiers Mirjam van der Burg Alexander B. Mohseny Diagnostic Value of a Protocolized In-Depth Evaluation of Pediatric Bone Marrow Failure: A Multi-Center Prospective Cohort Study Frontiers in Immunology bone marrow failure BMF aplastic anemia AA cytopenia next-generation sequencing |
| title | Diagnostic Value of a Protocolized In-Depth Evaluation of Pediatric Bone Marrow Failure: A Multi-Center Prospective Cohort Study |
| title_full | Diagnostic Value of a Protocolized In-Depth Evaluation of Pediatric Bone Marrow Failure: A Multi-Center Prospective Cohort Study |
| title_fullStr | Diagnostic Value of a Protocolized In-Depth Evaluation of Pediatric Bone Marrow Failure: A Multi-Center Prospective Cohort Study |
| title_full_unstemmed | Diagnostic Value of a Protocolized In-Depth Evaluation of Pediatric Bone Marrow Failure: A Multi-Center Prospective Cohort Study |
| title_short | Diagnostic Value of a Protocolized In-Depth Evaluation of Pediatric Bone Marrow Failure: A Multi-Center Prospective Cohort Study |
| title_sort | diagnostic value of a protocolized in depth evaluation of pediatric bone marrow failure a multi center prospective cohort study |
| topic | bone marrow failure BMF aplastic anemia AA cytopenia next-generation sequencing |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2022.883826/full |
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