Diagnostic Value of a Protocolized In-Depth Evaluation of Pediatric Bone Marrow Failure: A Multi-Center Prospective
Khaled Atmar1, Claudia A L Ruivenkamp2, Louise Hooimeijer3
1Department of Pediatric Hematology and Stem Cell Transplantation, Willem-Alexander Children's Hospital, Leiden University Medical Center, Leiden, Netherlands.
Insights
A comprehensive diagnostic protocol identified causes in 40% of pediatric bone marrow failure (BMF) patients, highlighting the importance of genetic analysis for accurate diagnosis and treatment. This approach improves identification rates for heterogeneous BMF cases.
Area of Science:
- Pediatric Hematology
- Genetics
- Bone Marrow Failure Syndromes
Background:
- Severe multilineage cytopenia in children, often due to bone marrow failure (BMF), poses significant risks for infections and bleeding.
- Previous studies indicate a low rate of identifiable causes for pediatric BMF, frequently leading to a descriptive diagnosis like aplastic anemia (AA).
Purpose of the Study:
- To implement and evaluate an extensive diagnostic approach for pediatric patients with suspected bone marrow failure (BMF).
- To determine the frequency of identifiable causes in pediatric BMF using a multi-center prospective cohort study.
Main Methods:
- A multi-center prospective cohort study involving 50 pediatric patients with suspected BMF.
- Diagnostic evaluation included bone marrow analysis, whole exome sequencing (WES) with CNV/SNP analysis, and functional/immunological assessments.
- Malignant and transient causes were excluded prior to comprehensive evaluation.
Main Results:
- A causative diagnosis was established in 20 patients (40%), with 18 cases identified through genetic analysis (mutations or chromosomal deletions) and 2 with short telomeres.
- Severe aplastic anemia (SAA) was diagnosed in 21 patients (42%), and 9 (18%) had unexplained cytopenia without bone marrow hypoplasia.
- Hematopoietic stem cell transplantation (HSCT) was performed in 28 patients, 22 with unknown and 6 with identified causes of BMF.
Conclusions:
- A standardized, in-depth diagnostic protocol significantly increases the identification of causes in heterogeneous pediatric BMF.
- Full genetic analysis, including genome-wide approaches, is crucial as genetic causes are not limited to syndromic presentations.
- Identifying the causal abnormality guides treatment choices and can help prevent unnecessary invasive therapies.
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.
More Related Videos
12:05Database-guided Flow-cytometry for Evaluation of Bone Marrow Myeloid Cell Maturation
Published on: November 3, 2018
11:59Detection of Residual Donor Erythroid Progenitor Cells after Hematopoietic Stem Cell Transplantation for Patients with Hemoglobinopathies
Published on: September 6, 2017
