Rare inherited bone marrow failure syndromes with cancer predisposition associated with SRP72, SH2B3, MYSM1 and CBL variants: a literature review and case series

Abstract

Introduction. Inherited bone marrow failure syndromes (IBMFS) comprise a heterogeneous group of hereditary disorders characterized by impaired hematopoiesis and an increased risk of myelodysplastic syndrome, acute myeloid leukemia, and other malignancies. Rare forms of IBMFS present a particular clinical challenge because they may manifest as isolated cytopenia, a myeloproliferative phenotype, or a syndromic disorder with early clonal evolution. Materials and methods. We analyzed five male patients with rare inherited bone marrow failure syndromes. All the patients had undergone comprehensive molecular genetic testing. Clinical manifestations, molecular genetic and cytogenetic findings, indications for allogeneic hematopoietic stem cell transplantation (HSCT), and treatment outcomes were evaluated. Results. Variants in SRP72 were identified in 2 patients, SH2B3 in 1 patient, MYSM1 in 1 patient, and combined CBL and STAG2 alterations also in 1 patient. The age at disease onset ranged from the first months of life to 9 years (median – 61 months), whereas the median age at diagnosis verification was 10 years, indicating a substantial diagnostic delay. The most unfavorable disease course was observed in the patient with MYSM1 deficiency who had developed monosomy 7, del(5q) and myelodysplastic syndrome with subsequent transformation to acute myeloid leukemia, and ultimately died of disease progression. HSCT was performed in two patients with SRP72 variants, with one patient still alive and the other one deceased. Conclusion. Our findings highlight the importance of early molecular genetic testing in children with persistent hematopoietic abnormalities, along with regular cytogenetic surveillance and timely referral of high-risk patients for HSCT.