Diagnostic Value of a Protocolized In-Depth Evaluation of Pediatric Bone Marrow Failure: A Multi-Center Prospective Cohort Study.
AA
BMF
aplastic anemia
bone marrow failure
cytopenia
diagnostics
next-generation sequencing
Journal
Frontiers in immunology
ISSN: 1664-3224
Titre abrégé: Front Immunol
Pays: Switzerland
ID NLM: 101560960
Informations de publication
Date de publication:
2022
2022
Historique:
received:
25
02
2022
accepted:
29
03
2022
entrez:
16
5
2022
pubmed:
17
5
2022
medline:
20
5
2022
Statut:
epublish
Résumé
Severe 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). We 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. In 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. We 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.
Sections du résumé
Background
Severe 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).
Methods
We 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.
Results
In 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.
Conclusion
We 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.
Identifiants
pubmed: 35572556
doi: 10.3389/fimmu.2022.883826
pmc: PMC9094492
doi:
Types de publication
Journal Article
Multicenter Study
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
883826Informations de copyright
Copyright © 2022 Atmar, Ruivenkamp, Hooimeijer, Nibbeling, Eckhardt, Huisman, Lankester, Bartels, Santen, Smiers, van der Burg and Mohseny.
Déclaration de conflit d'intérêts
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Références
Haematologica. 2018 May;103(5):759-769
pubmed: 29419434
Hematology Am Soc Hematol Educ Program. 2016 Dec 2;2016(1):74-82
pubmed: 27913465
Blood Rev. 2010 May;24(3):101-22
pubmed: 20417588
Haematologica. 2010 Jul;95(7):1075-80
pubmed: 20595102
Histopathology. 2019 Jan;74(2):239-247
pubmed: 30062702
J Med Genet. 2015 Sep;52(9):575-84
pubmed: 26136524
Blood. 2016 Sep 1;128(9):1193-205
pubmed: 27281795
Thromb Haemost. 2022 Jan 20;:
pubmed: 35052006
Genet Med. 2010 Dec;12(12):753-64
pubmed: 21189492
Biol Chem. 2012 Aug;393(8):731-47
pubmed: 22944676
Blood. 2005 Dec 1;106(12):3699-709
pubmed: 16051736
Blood. 2015 Jan 1;125(1):56-70
pubmed: 25359990
Curr Opin Oncol. 2018 Nov;30(6):402-408
pubmed: 30222640
Pediatr Clin North Am. 2013 Dec;60(6):1311-36
pubmed: 24237973
J Clin Immunol. 2020 Jan;40(1):24-64
pubmed: 31953710
Haematologica. 2016 Nov;101(11):1343-1350
pubmed: 27418648
Appl Immunohistochem Mol Morphol. 2015 Feb;23(2):139-45
pubmed: 25032754
Leuk Lymphoma. 2013 Jan;54(1):28-35
pubmed: 22691122
Blood. 2016 Jul 21;128(3):337-47
pubmed: 27121470
Blood. 2021 Dec 30;138(26):2781-2798
pubmed: 34748628
Blood. 2014 Jan 2;123(1):26-34
pubmed: 24200684
Bone Marrow Transplant. 2008 Jan;41(2):127-32
pubmed: 18084332
Haematologica. 2015 Jan;100(1):42-8
pubmed: 25239263
Br J Haematol. 2017 May;177(4):526-542
pubmed: 28211564
Nat Genet. 2016 Jul;48(7):792-7
pubmed: 27182967
Blood. 2016 Mar 17;127(11):1387-97; quiz 1518
pubmed: 26702063
Sci Transl Med. 2016 Mar 2;8(328):328ra30
pubmed: 26936507
Leukemia. 2018 May;32(5):1106-1115
pubmed: 29535429
Ann N Y Acad Sci. 2020 Apr;1466(1):93-103
pubmed: 31647584
Blood. 2016 Jun 16;127(24):2971-9
pubmed: 27020090
N Engl J Med. 2015 Oct 22;373(17):1675-6
pubmed: 26488702
J Clin Immunol. 2018 Feb;38(2):166-173
pubmed: 29411230
Lancet. 1988 Feb 6;1(8580):303-4
pubmed: 2893118
Histopathology. 2012 Jul;61(1):10-7
pubmed: 22458667
Science. 2014 Sep 26;345(6204):1623-1627
pubmed: 25213377
PLoS One. 2016 Sep 09;11(9):e0162382
pubmed: 27611583
N Engl J Med. 2018 Oct 25;379(17):1643-1656
pubmed: 30354958
Immunol Invest. 2014;43(5):491-503
pubmed: 24661133
Blood. 2010 Nov 18;116(20):4175-84
pubmed: 20733158
Blood. 2015 Nov 19;126(21):2349-51
pubmed: 26585803
Blood. 2018 Feb 15;131(7):717-732
pubmed: 29146883
Hematology Am Soc Hematol Educ Program. 2011;2011:84-9
pubmed: 22160017
Indian J Hematol Blood Transfus. 2021 Jan;37(1):157-161
pubmed: 33707850
Hematology Am Soc Hematol Educ Program. 2016 Dec 2;2016(1):598-604
pubmed: 27913534
Blood. 2014 Oct 30;124(18):2775-83
pubmed: 25237198
Hematology Am Soc Hematol Educ Program. 2009;:329-37
pubmed: 20008218
J Pediatr Hematol Oncol. 2021 Oct 1;43(7):e1025-e1029
pubmed: 33273414
Genet Med. 2017 Jul;19(7):796-802
pubmed: 28102861
Blood. 2017 Apr 20;129(16):2266-2279
pubmed: 28202457
Br J Haematol. 2016 Jan;172(2):187-207
pubmed: 26568159
Semin Hematol. 2017 Apr;54(2):105-114
pubmed: 28637614
Zhonghua Yi Xue Za Zhi. 2011 Apr 26;91(16):1084-7
pubmed: 21609587
Neurotherapeutics. 2018 Oct;15(4):900-914
pubmed: 30338442
Am J Hum Genet. 2016 Jun 2;98(6):1146-1158
pubmed: 27259050
Nat Commun. 2018 Oct 12;9(1):4250
pubmed: 30315159
Blood. 2014 Dec 11;124(25):3699-708
pubmed: 25342713
Blood. 2017 Jun 22;129(25):3371-3378
pubmed: 28424163
Clin Invest Med. 1995 Oct;18(5):389-400
pubmed: 8529322
Leukemia. 2021 Nov;35(11):3223-3231
pubmed: 33664463