Juvenile myelomonocytic leukemia: a case report

¹Laboratory of Hematology, Central Laboratory, Mohammed VI University Hospital Center of Oujda, Oujda, Morocco, ²Faculty of Medicine and Pharmacy of Oujda, Oujda, Morocco, ³Laboratory of Materno-Infenatile and Mental Health, Faculty of Medicine and Pharmacy of Oujda, Oujda, Morocco

^&Corresponding author
Chaimaa Boujloud, Laboratory of Hematology, Central laboratory, Mohammed VI University Hospital Center of Oujda, Oujda, Morocco

Introduction    

Juvenile myelomonocytic leukemia (JMML) is a rare pathology affecting the hematopoietic stem cell. Its pathophysiology is linked to deregulation of the RAS signal transduction pathway. It has long been considered a borderline myelodysplastic/myeloproliferative (MDS/SMP) syndrome. Moreover, this classification has undergone updates and now recognizes JMML as a myeloproliferative neoplasm [1]. We report the case of a male child, aged 3.5 years, who was hospitalized in January 2023 for prolonged fever associated with a tumor syndrome. The etiological investigation led to the diagnosis of JMML according to the 2016 WHO criteria. The interest of this observation is to report a rare case of JMML.

Patient and observation     

Patient information: this is a male child, aged 3 and a half, from a non-consanguineous marriage, with a pathological history of repeated hospitalizations for prolonged fever and a family history of neoplasia.

Clinical findings: clinical examination revealed a conscious child, hemodynamically and respiratorily stable, febrile at 39°C, with mucocutaneous pallor and a tumor syndrome consisting of hepatomegaly, splenomegaly, and adenopathy. Pulmonary examination revealed bilateral crepitus rales. The patient presented with anorexia, asthenia, and general ill health.

Timeline of the current episode: the history of the disease goes back two months with the onset of a fever unresponsive to treatment.

Diagnostic assessment: biological workup showed blood count: hyperleukocytosis at 51670/mm³, with monocytosis at 6200/mm³, regenerative microcytic hypochromic anemia at 6.5 g/dL and thrombocytopenia at 4000/mm³. A blood smear revealed blasts and myelimia. The medullogram showed a rich marrow. The cell diagram showed the following percentages: blasts 12%, granular neutrophils 49%, erythroblasts 30%, lymphocytes 06%, eosinophils 01%, and monocytes 02%. Signs of dysplasia were noted in the erythroblast lineage (binuclearity, interchromatin bridges) and in the neutrophil granulocyte lineage, with dyslobulation and dysgranulation (Figure 1). Tumour lysis and inflammatory tests were negative. Abdominal ultrasound revealed homogeneous hepatomegaly, heterogeneous splenomegaly and coeliomeningeal adenopathies. Serum protein electrophoresis showed polyclonal hypergammaglobulinemia. Hemoglobin F was increased on hemoglobin electrophoresis. The bone marrow karyotype was without abnormality. Breakpoint cluster region-Abelson murine leukemia (BCR-ABL) transcript was negative.

Diagnosis: the diagnosis of JMML was retained according to the diagnostic criteria established by the WHO in 2016.

Therapeutic interventions: the patient was put on hydrea 30 mg/kg/d for two weeks.

Follow-up and outcome of interventions: the evolution was marked by worsening respiratory signs due to abdominal distention. The patient died of respiratory distress.

Informed consent: parents have expressed their consent to the publication of this report.

Discussion     

Juvenile myelomonocytic leukemia (JMML) is a pathology of the hematopoietic stem cell, linked to hyperactivation of the RAS/MAP kinase signaling pathway following mutation of RAS (NRAS, KRAS) or a regulator of RAS (PTPN11, NF1, or CBL). This signaling pathway is involved in the transmission of signals for cell proliferation, differentiation, and survival, which are mediated by growth factors and certain cytokines. Consequently, hyperactivation of the RAS/MAPK pathway leads to hypersensitivity of myeloid progenitors to Granulocyte-macrophage colony-stimulating factor (GM-CSF). Juvenile myelomonocytic leukemia (JMML) can be observed in various syndromes called rasopathies, such as Noonan syndrome and neurofibromatosis type 1. The latter is also linked to deregulation of the RAS/MAP kinase signaling pathway. Juvenile myelomonocytic leukemia (JMML) was classified by the World Health Organization (WHO) in 2016 as a borderline myelodysplastic/myeloproliferative syndrome (MDS/SMP) [1]. In our case, the diagnosis of AMLJ was retained according to the diagnostic criteria established by WHO in 2016. However, this classification has been revised and recognized JMML as a myeloproliferative neoplasm. Updates to the diagnostic criteria include exclusion of Histone-lysine N-methyltransferase 2A (KMT2A) rearrangements, elimination of monosomy 7 as a cytogenetic criterion and highlighting the importance of diagnostic molecular studies, particularly those aimed at demonstrating activation of the reticular activating system (RAS) pathway [2]. Thus, the WHO tends to emphasize the importance of molecular biology studies and is now based on genetic investigation, encouraging hospital structures to incorporate molecular biology activities.

In children, JMML accounts for 3% of hematological malignancies and 18% of MDS. It generally occurs in young children before the age of three, with a clear male predominance [3]. In the Niemeyer et al. series, the median age was 1.8 years [3]. In our case, the onset of JMML was later (3.5 years). The clinical picture is heterogeneous, including signs of bone marrow failure and tumor syndrome. In the series by Niemeyer et al. the most frequent clinical signs were splenomegaly (97%), hepatomegaly (97%), adenopathy (76%), pallor (65%), fever (54%), and cutaneous haemorrhages (46%) [3]. Skin lesions may include xanthomas, eczema, and purpuric erythematous nodules [4]. Respiratory and digestive manifestations have also been reported in the literature [5]. Our patient presented with fever, tumor syndrome and respiratory signs. According to WHO 2016 criteria, the diagnosis of JMML is based on a cluster of clinical, cytological, and genetic arguments [1]. The blood count reveals hyperleukocytosis in excess of 10 G/L, which can sometimes exceed 100 G/L with monocytosis in excess of 1 G/L. Anemia and thrombocytopenia are frequently observed. In the study by Niemeyer et al. anemia was present in 83% of patients, 16% of whom had Hb<7g/dL, and severe thrombocytopenia was present in 17% of patients [3]. The blood smear revealed circulating blasts and myeloma, signs of dyserythropoiesis with erythroblastemia, dysgranulopoiesis and numerous dacryocytes [6]. The myelogram usually shows a rich marrow with granular hyperplasia and signs of dysmyelopoiesis. It is essential to assess the percentage of blasts, which by definition remains below 20% in JMML.

These haematological data are similar to those reported in our case. On the other hand, some authors have reported a hyperplasia of the erythroid lineage, which seems to be associated with monosomy 7 [3]. Elevated HbF levels are frequently reported in children with JMML [7]. However, a normal level can be observed in 1/3 of patients [3]. In our case, the HbF assay was increased. Hypergammaglobulinemia may also be present. In the retrospective study by Niemeyer et al. increased IgG, IgM, and IgA levels were observed in 65% of children [3]. The karyotype is usually without cytogenetic abnormalities, as was the case with our patient. Niemeyer et al. reported 64.3% of JMML cases with a normal karyotype [3]. Monosomy 7, no longer part of the diagnostic criteria, was described in 25.5%, and 24% in the Niemeyer series [3]. Other chromosomal aberrations reported in JMML include trisomy 8, trisomy 21, and 12p deletion [3]. Molecularly speaking, the BCR-ABL fusion gene has never been described in JMML. Indeed, the absence of BCR-ABL is one of the diagnostic criteria. Molecular studies have reported the presence of mutations including RAS/MAPK, PTPN11, KRAS, and NF1 in 80% of cases [8,9]. In our case, the molecular biology study was normal. Juvenile myelomonocytic leukemia (JMML) continues to have a poor prognosis and a high mortality rate. Unfortunately, it appears to be resistant to most of the therapeutic agents used in haematological malignancies. To date, the only known curative treatment is hematopoietic stem cell transplantation. Studies have reported an increased survival rate after allogeneic transplantation in JMML [10].

Conclusion     

Juvenile myelomonocytic leukemia (JMML) is a rare hematological malignancy. Our case illustrates the difficulty of diagnosing JMML, which is based on a combination of clinical, cytological and genetic arguments. Genetic studies are now required for all patients with JMML. The prognosis is often poor, and the mortality rate remains high. Current molecular studies are aimed at the use of targeted therapies aimed at deregulated signaling pathways.

Competing interests     

The authors declare no competing interests.

Authors' contributions     

All authors have read and approved the final version of this manuscript.

Figure     

Figure 1: juvenile myelomonocytic leukemia; A) medullary smear image showing erythroblastic binuclearity; B) medullary smear image showing hyposegmentation of neutrophils and degranulation of neutrophil precursors

References