Page 83 - Haematologica Vol. 107 - September 2022

ARTICLE - Inherited cytopenias in children
O. Gilad et al.
entity with immediate implications for follow-up and management programs of patients and their family members.3 The clinical presentation of syndromes predis- posing to leukemia is variable, and may include isolated thrombocytopenia, neutropenia, anemia or pancytopenia, with or without bone marrow failure. Diagnosing such syndromes before the emergence of leukemia is essential for proper treatment and cure.
Classical inherited bone marrow failure syndromes (IBMFS) are well recognized as predisposing to myeloid malignancies.4,5 Non-classical IBMFS with pathogenic vari- ants in an increasing number of genes has been profusely described.6 IBMFS differ in their extra-hematopoietic con- genital anomalies, the age of onset of BMF, and the risk and age of developing myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). Refractory cytopenia of childhood (RCC) is the most common form of MDS in children.7 In contrast to MDS in adults, pediatric MDS is more commonly associated with genetic predisposition.8 Genetic alterations in GATA2 and SAMD9L have emerged as the most common cause of inherited pediatric MDS.9 Familial platelet disorder, associated with MDS and leuke- mia, was first described in 1999, with the identification of deleterious heterozygous RUNX1 variants in families with inherited thrombocytopenia (IT) and AML.10 Later, addi- tional genes causing thrombocytopenia and a predisposi- tion to MDS/AML were described, for example, ETV6 and ANKRD26.11 RUNX1 and ETV6 variants also predispose to lymphocytic malignancies.12 The presentation of IT in in- dividuals with a predisposition to MDS may include iso- lated mild to moderate thrombocytopenia, and normal platelet size and morphology; and thus overlaps with classical IT.9,13
An accurate diagnosis of inherited syndromes with a pre- disposition to leukemia has major therapeutic implica- tions, including intensive follow-up of patients; this may entail an annual bone marrow examination.14 The diagnosis is also crucial for determining the management program, including decisions regarding hematopoietic stem cell transplantation (HSCT) prior to the development of acute leukemia, and for selecting the appropriate conditioning for transplant. In addition, accurate molecular diagnosis is essential for identifying asymptomatic family members who may be at risk for myeloid transformation, for pro- viding genetic counseling to affected patients and family members, and for selecting unaffected related donors for transplantation.
Genetic workup may be initiated with Sanger sequencing, when a single gene is the major cause of a particular dis- order. However, due to the non-specific clinical and lab- oratory presentation of syndromes causing cytopenias, an unbiased diagnosis, as offered by next-generation se- quencing (NGS) technologies, is usually essential.11,15,16 In- deed, several studies have demonstrated advantages of
NGS technologies for improving diagnosis,11,13,15-18 and re- ported genetic diagnostic rates of 13-54%. However, dif- ferences were evident in the patient populations (IBMFS only, MDS only, IT only or all these conditions), age (children, adults or both), sequencing method (NGS panel or whole exome sequencing [WES]), the type of variants detected (germline variants or both somatic and germline variants) and the types of sequence variants reported (pa- thogenic and likely pathogenic [P/LP]) only or also variants of unknown significance [VOUS]). Therefore, comparing the results of those studies is challenging.
We hypothesized that a substantial fraction of children with persistent cytopenias may have inherited syndromes predisposing to MDS/AML and should be identified prior to the development of leukemia. We hereby present the results of a comprehensive Israeli nationwide study of germline variants detected in children with prolonged cytopenias, referred to our laboratory during a 4-year period. Only P/LP sequence changes were reported. Our study revealed that almost one third of the children had identifiable inherited disorders, of whom 79.7% predis- posed to leukemia. Based on our findings, we suggest that children and young adults presenting with prolonged cytopenias should undergo genetic evaluation.
Methods
Patients
The study included children and adolescents (aged 0-20 years at presentation) with prolonged cytopenias, evalu- ated between January 2016 and December 2019. The pa- tients were classified into five subgroups according to referral diagnoses: (i) suspected IBMFS, based on the presence of extra-hematopoietic manifestations and early onset cytopenias; (ii) MDS with BM dysplasia and less than 20% blasts or BM cytogenetic abnormality;7,8,19 (iii) severe aplastic anemia (SAA), based on an abrupt onset of severe pancytopenia and marrow aplasia;20 (iv) a refractory single cytopenia including thrombocytopenia (platelet count <150X109/L) or neutropenia (absolute neutrophil count <1X109/L up to 1 year of age or <1.5X109/L in older children and adults).21 Exclusion criteria were hemolytic and micro- cytic anemias, overt leukemia, and a known pathogenic variant in the family.
Data extracted from medical charts included age at pres- entation, current age, ethnic origin, family history, extra- hematopoietic manifestations, and therapy. The laboratory data recorded comprised complete blood counts, hemo- globin electrophoresis, fluorescent in situ hybridization (FISH) telomere length, chromosomal breakage tests and BM morphology, cellularity (based on trephine biopsies in the majority of patients), cytogenetics and FISH-MDS pa- nels for detecting common chromosomal changes.22
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