Lessons From Pediatric MDS: Approaches to Germline Predisposition to Hematologic Malignancies

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 suspected germline predisposition informs therapeutic considerations, guides monitoring pre- and post-treatment, and allows for family counseling. Presentation of MDS due to germline predisposition is not limited to children and spans a wide age range. In fact, the risk of MDS may increase with age in many germline predisposition conditions and can present in adults who lack classical stigmata in their childhood. Furthermore, germline predisposition associated with DDX41 mutations presents with older adult-onset MDS. Although a higher proportion of pediatric patients with MDS will have a germline predisposition, the greater number of MDS diagnoses in adult patients may result in a larger overall number of those with an underlying germline predisposition. In this review, we present a framework for the evaluation of germline predisposition to MDS across all ages. We discuss characteristics of personal and family history, clinical exam and laboratory findings, and integration of genetic sequencing results to assist in the diagnostic evaluation. We address the implications of a diagnosis of germline predisposition for the individual, for their care after MDS therapy, and for family members. Studies on MDS with germline predisposition have provided unique insights into the pathogenesis of hematologic malignancies and mechanisms of somatic genetic rescue vs. disease progression. Increasing recognition in adult patients will inform medical management and may provide potential opportunities for the prevention or interception of malignancy.

Pediatric Hematopathology in the Era of Advanced Molecular Diagnostics: What We Know and How We Can Apply the Updated Classifications

“…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.…”

Optimizing Diagnostic Methods and Stem Cell Transplantation Outcomes in Pediatric Bone Marrow Failure: A 50-Year Single Center Experience

“…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].…”

A Novel Constitutional t(3;8)(p26;q21) and ANKRD26 and SRP72 Variants in a Child with Myelodysplastic Neoplasm: Clinical Implications

“…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].…”

“…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.…”