Abstract:Pediatric myelodysplastic syndromes (MDS) often raise concern for an underlying germline predisposition to hematologic malignancies, referred to as germline predisposition herein. With the availability of genetic testing, it is now clear that syndromic features may be lacking in patients with germline predisposition. Many genetic lesions underlying germline predisposition may also be mutated somatically in de novo MDS and leukemias, making it critical to distinguish their germline origin. The verification of a… Show more
“…To investigate for possible germline predisposition, experts suggest workup including evaluation of clinical presentation, personal history of cancer, growth and congenital anomalies, immunologic features, non-hematologic features, family history, physical examination, laboratory tests (including chromosomal breakage testing and telomere length testing), BM examinations, and genetic testing [93]. In bone marrow examination, hypocellularity and certain types of cytologic atypia can be seen in baseline bone marrows with germline predisposition.…”
Section: Germline Predisposition and Mdsmentioning
Pediatric hematologic malignancies often show genetic features distinct from their adult counterparts, which reflects the differences in their pathogenesis. Advances in the molecular diagnostics including the wide use of next-generation sequencing (NGS) technology have revolutionized the diagnostic workup for hematologic disorders and led to the identification of new disease subgroups as well as prognostic information that impacts the clinical treatment. The increasing recognition of the importance of germline predisposition in various hematologic malignancies also shapes the disease models and management. Although germline predisposition variants can occur in patients with myelodysplastic syndrome/neoplasm (MDS) of all ages, the frequency is highest in the pediatric patient population. Therefore, evaluation for germline predisposition in the pediatric group can have significant clinical impact. This review discusses the recent advances in juvenile myelomonocytic leukemia (JMML), pediatric acute myeloid leukemia (AML), B-lymphoblastic leukemia/lymphoma (B-ALL) and pediatric MDS. This review also includes a brief discussion of the updated classifications from the International Consensus Classification (ICC) and the 5th edition World Health Organization (WHO) classification regarding these disease entities.
“…To investigate for possible germline predisposition, experts suggest workup including evaluation of clinical presentation, personal history of cancer, growth and congenital anomalies, immunologic features, non-hematologic features, family history, physical examination, laboratory tests (including chromosomal breakage testing and telomere length testing), BM examinations, and genetic testing [93]. In bone marrow examination, hypocellularity and certain types of cytologic atypia can be seen in baseline bone marrows with germline predisposition.…”
Section: Germline Predisposition and Mdsmentioning
Pediatric hematologic malignancies often show genetic features distinct from their adult counterparts, which reflects the differences in their pathogenesis. Advances in the molecular diagnostics including the wide use of next-generation sequencing (NGS) technology have revolutionized the diagnostic workup for hematologic disorders and led to the identification of new disease subgroups as well as prognostic information that impacts the clinical treatment. The increasing recognition of the importance of germline predisposition in various hematologic malignancies also shapes the disease models and management. Although germline predisposition variants can occur in patients with myelodysplastic syndrome/neoplasm (MDS) of all ages, the frequency is highest in the pediatric patient population. Therefore, evaluation for germline predisposition in the pediatric group can have significant clinical impact. This review discusses the recent advances in juvenile myelomonocytic leukemia (JMML), pediatric acute myeloid leukemia (AML), B-lymphoblastic leukemia/lymphoma (B-ALL) and pediatric MDS. This review also includes a brief discussion of the updated classifications from the International Consensus Classification (ICC) and the 5th edition World Health Organization (WHO) classification regarding these disease entities.
“…Non-reversible bone marrow failure (BMF) in pediatric patients is caused by a broad spectrum of underlying diseases, including inherited bone marrow failure syndromes (IBMFS), (pre)malignant disease, and (idiopathic) aplastic anemia (AA) [1,2,3]. In up to 50% of these patients, a genetic defect can be identi ed [4,5,6].…”
Purpose: Peripheral cytopenia, a frequent presenting symptom in pediatric patients, can be caused by bone marrow failure (BMF). In most cases, reversible causes such as iron deficiency or viral infections underly transient BMF. However, timely identification of patients with non-reversible BMF is of crucial importance to reduce the risks of invasive infections and bleeding complications. In these patients, BMF can be caused by a wide spectrum of underlying diseases including (pre)malignant disease, inherited bone marrow failure syndromes (IBMFS) and (idiopathic) aplastic anemia (AA). Most pediatric patients with severe persistent cytopenia, independent of the underlying cause, are offered allogeneic hematopoietic stem cell transplantation (HSCT) as curative therapy. Here we report on our management guidelines and HSCT outcomes of pediatric BMF patients.
Methods: We formulated recommendations based on this 50 years’ experience, which were implemented at our center in 2017. By analysis of the HSCT cohort of 2017-2023, the 5-year outcome data is presented and compared to historical outcome data to pinpoint improvements and future challenges. In addition, outcomes of patients transplanted for an identified IBMFS is compared to AA outcomes to underline the often multiorgan disease in IBMFS with implications for long-term survival.
Results: Overall and event-free survival of pediatric patients with irreversible BMF has improved tremendously independent of the underlying cause for BMF. This improvement is mainly related to better survival in the first months after HSCT. The long-term survival after HSCT is lower in IBMFS patients as compared to AA patients.
Conclusions: Unbiased protocolized in-depth diagnostic strategies are crucial to increase the frequency of identifiable causes within the heterogeneous group of pediatric BMF. A comprehensive approach to identify the cause of BMF can prevent treatment delay and be useful to tailor treatment and follow-up protocols.
“…According to the 5th edition of the World Health Organization (WHO) classification, the myelodysplastic syndrome is now replaced by myelodysplastic neoplasm (MDS) [1]. Childhood myelodysplastic neoplasm (cMDS) is a rare disease, accounting for less than 5% of childhood hematologic malignancies, and it is associated with an elevated risk of evolution to acute myeloid leukemia (AML) [2,3].…”
Section: Introductionmentioning
confidence: 99%
“…The cMDS often raises concerns about germline predisposition, observed in 15% of MDS diagnoses [3]. Some family members with germline variants present a silent clinical picture and do not develop hematologic malignancy, while others develop after decades due to the acquisition of new alterations [3,4]. The penetrance of these germline alterations is heterogeneous.…”
Background: Childhood myelodysplastic neoplasm (cMDS) often raises concerns about an underlying germline predisposition, and its verification is necessary to guide therapeutic choice and allow family counseling. Here, we report a novel constitutional t(3;8)(p26;q21) in a child with MDS, inherited from the father, the ANKRD26 and SRP72 variants from the maternal origin, and the acquisition of molecular alterations during MDS evolution. Case presentation: A 4-year-old girl showed repeated infections and severe neutropenia. Bone marrow presented hypocellularity with dysplastic features. The patient had a t(3;8)(p26;q21)c identified by G-banding and FISH analysis. The family nucleus investigation identified the paternal origin of the chromosomal translocation. The NGS study identified ANKRD26 and SRP72 variants of maternal origin. CGH-array analysis detected alterations in PRSS3P2 and KANSL genes. Immunohistochemistry showed abnormal p53 expression during the MDS evolution. Conclusion: This study shows for the first time, cytogenetic and genomic abnormalities inherited from the father and mother, respectively, and their clinical implications. It also shows the importance of investigating patients with constitutional cytogenetic alterations and/or germline variants to provide information to their family nucleus for genetic counseling and understanding of the pathogenesis of childhood MDS.
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