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Letters to the Editor
Figure 1. Consensus on diagnostics in neonates with myeloblasts based on available literature and newly added cases 1In case of doubt always refer to a clin- ical geneticist. 2If these are not identified, deep sequencing techniques (SNP-array, RNA-seq, WGS) should be considered. Sporadic identified aberrations are listed in the text. 3Can be both transient and aggressive leukemia. 4Only if clinical presentation allows, with close monitoring of clinical symptoms and regular blood counts. 5In case of doubt, consider consulting international study groups (International Berlin-Frankfurt-Münster AML Study Group, European Working Groups of Myelodysplastic syndromes). References on individual IMD-related aberrations can be found in Table 2. 2-4, 10-12 AML: acute myeloid leukemia; BM: bone marrow; CT: chemotherapy; FISH: fluorescence in situ hybridization; HbF: fetal hemoglobin; HSCT: hematopoietic stem cell transplantation; IMD: infantile myeloproliferative disease (unrelated to Down syndrome); JMML: juvenile myelomonocytic leukemia; NS: Noonan syndrome; PB: peripheral blood; SNP: single nucleotide polymorphism; T21: trisomy 21; TAM: transient abnormal myelopoiesis related to Down syndrome; WGS: whole genome sequencing
ment has high success rates.8
In megakaryoblastic cases without germline (mosaic)
T21 and a GATA1 mutation, a bone marrow puncture can be considered. Furthermore, additional mutational analyses for recurrent germline or somatic IMD-related aberrations (such as somatic T21), as well as analyses for recurrent infant AML translocations, are advised (Figure 1; discussed below).
In neonatal non-M7/M0 hyperproliferation, first, dis- crimination between JMML and AML, and in rare cases, a non-M7 IMD, is important. Bone marrow investigation can be considered for immunophenotyping, karyotyping, fluo- rescenceinsituhybridization(FISH)andtargetedmutation- al analyses. Collection of germline material for sequencing discrimination purposes is advisable.
count.3 JMML is in 90% of the cases characterized by mutations in PTPN11, NRAS, KRAS, NF1 or CBL.3 Germline CBL, KRAS, NRAS, PTPN11 or RIT1 mutations indicate an RAS pathway driven JMML, in which sponta- neous remission often occurs and a ‘watch and wait’ policy may be considered if clinically feasible.3 In contrast, patients with a somatic RAS driver mutation commonly have aggressive disease requiring allogeneic hematopoietic stem cell transplantation in most cases.3
When the clinical picture of a non-megakaryoblastic leukemia is not consistent with JMML, IMD and AML may be seriously considered. Such cases mainly consist of monoblastic AML (FAB M5; immunophenotype CD4+CD11b+CD64+), characteristically present with leukemia cutis, hepatosplenomegaly, hyperleukocytosis andKMT2Afusions,andrequireAML-directedchemother- apy.2,5,6,10 A diagnostic bone marrow puncture is advised for molecular blast cell characterization. Recurrent transloca- tions, characteristic for infant AML, are t(1;22)(p13.3;q13.1)/RBM15-MKL1, 11q23.3/KMT2A translocation and t(8;16) (p11.2; p13.3)/KAT6A-CREBBP.
In monocytic proliferation, JMML diagnostics are
advised and morphology of the peripheral blood smear,
which shows (meta)myelocytes and nucleated red cells
combinedwiththeclinicalphenotype,isofutmostimpor-
tance.3Itisimportanttoidentifydysmorphicfeaturesof
RAS pathway related syndromes.3 Other JMML character- isticsaresplenomegaly,anelevatedfetalhemoglobinvalueFurther, t(8;21)(q22;q22)/RUNX1-RUNX1T1, and a normal or moderately increased bone marrow blast t(8;1)(p11;q22), t(5;6)(q31;q21), t(6;17)(q23;q11.2) and
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haematologica | 2022; 107(3)