Case Presentation
A two-year-old boy was referred to our hospital for unexplained anemia and thrombocytopenia lasting for 6 months. His height was 81.8cm (3rd to 10th percentile; weight was 11.3kg (25th to 50th percentile). The development was normal without hearing or visual impairment. Physical examination findings were unremarkable except splenomegaly. There was no Café au lait spot nor hyperpigmentation on the skin. No low-set ears, webbed neck nor hypertelorism was noted. Echocardiogram revealed no cardiac structural anomaly. Splenic longitudinal length measured by sonography was 11.2cm (Suggested upper limit for 2 to 4 years old children was 9cm)9. Complete blood count showed monocytosis and the presence of myeloid and erythroid precursors. The fetal hemoglobin was 3.6% (reference range: less than 2%). Bone marrow studies revealed the blast cells were less than 20%. He had a normal karyotype (46; XY). The bone marrow mononuclear cells were identified to have a pathogenic CBL mutation (c.1111T>C; p.Tyr371His; variant allele frequency 97.3%) via NGS (Oncomine Myeloid Research Assay, Thermofisher). The diagnosis of JMML was established. Additionally, a single-nucleotide variant inNF1 (c.3352A>G; p.Ser1118Gly, variant allele frequency 49.62%) was also found. According to the classification in ClinVar, an openly accessible database for reports of interpreting the relationships between variants and medical conditions10, this was a VUS of NF1 .
For confirmation, we obtained his buccal swab and did Sanger sequencing for the CBL gene. The same variant was found on one allele, and the other remained wide type, confirming a germline heterozygous mutation. For inheritance investigation, we took blood samples for Sanger sequencing from both his parents. The result affirmed neither of them carried the mutation (Fig. 1). In a nutshell, this patient has ade novo CBL germline mutation. Given that JMML with germline heterozygous CBL mutation often experiences spontaneous regression4-7. We considered adopting observation for this patient. Yet, concerns regarding the NF1 variant raised, because HSCT is indicated for JMML patients with NF1mutations5. As a complementary diagnostic test, we draw his parents’ peripheral blood for NF1 Sanger sequencing. The result showed that the NF1 variant was inherited from his mother (Fig. 1). This patient’s mother was asymptomatic with a normal hemogram. There was no medical history of hematological malignancies or skin tumors among maternal relatives. We thus considered that this NF1variant was not the driver gene for the JMML in this case. Based on these findings, close observation with regular follow-up was suggested.
After the diagnosis, this boy was once hospitalized owing to left leg cellulitis and resolved after antibiotics. We re-evaluated this child one year after the diagnosis. His growth was fair with a height velocity of 8cm within the pasting year. Developmental milestones were in accordance with his age. There were no signs of autoimmune disorders, and the antinuclear antibody and anti-double stranded DNA antibodies were within the normal range. Hemogram of peripheral blood and bone marrow examination showed no signs of disease progressing according to the criteria for response evaluation of JMML11. The results of serial tests during the following up period were illustrated in Table 1.