HIGH PREVALENCE OF GERMLINE PREDISPOSITION IN PAEDIATRIC MYELODYSPLASTIC SYNDROME: A SINGLE-CENTRE RETROSPECTIVE ANALYSIS

Introduction: Gain-of-function mutations in the SAMD9/ SAMD9L genes, together with GATA2 deficiency, are the main constitutional causes of myelodysplastic syndrome (MDS) in pediatric patients.Both have been included in the WHO and ICC classifications of myeloid neoplasms with germline predisposition.About 2/3 of these patients present somatic genetic rescue (SGR) events through acquired cytogenetic or molecular alterations (monosomy 7 (-7), uniparental disomy 7q or SAMD9 compensatory mutations), which can attenuate hematological phenotype or promote neoplastic progression.Materials and Methods: Clinical and genetic description of cases with SAMD9 syndrome by reviewing the national pediatric MDS registry-database.Results: Of the 101 cases of MDS in the Spanish registry, 4 cases with pathogenic germline variants in SAMD9 were identified.All patients, two males and two females, were diagnosed with hematological manifestations: thrombocytopenia (3/4) and severe neutropenia (1/4).The mean age at onset of hematological symptoms was 1.7 years (0.7-3.7).Three of them were diagnosed with refractory cytopenia and one with MDS with excess blasts (EB).-7 was detected in the patient with neutropenia and in the patient with MDS-EB, while another presented a second variant in SAMD9, confirmed as somatic.All patients displayed various nonhematopoietic manifestations: growth retardation (4/4), neurological alterations (2/4), facial dysmorphia (1/4), enteropathy (1/4) and bronchiectasis (1/4).The median follow-up is 8 years (3.9-14.8).Patients with -7 are in complete remission after undergoing hematopoietic stem cell transplantation, while the other two patients remain under follow-up with spontaneous hematological improvement.Conclusions: In our series, SGR events were demonstrated in 3/4 patients; two of them with -7 were considered as a high risk of MDS/ leukemia progression, while the other two had a spontaneous favorable outcome, one of them presented a somatic mutation in SAMD9 (adaptive SGR).The identification of somatic variants in hematological neoplasms with germline predisposition syndromes is essential.A better understanding of these features will facilitate more personalized follow-up and therapeutic decision-making