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.