Discussion
The treatment outcome of JMML is discouraging. HSCT was the only known
curative option, but merely about half of the patients achieved
long-term survival even if they received the
transplantation2,12. However, Niemeyer et
al4. found some patients with germlineCBL- mutated JMML often experienced spontaneous regression. An
international survey also found HSCT did not improve the outcome ofCBL -mutated JMML, thus active surveillance rather than immediate
HSCT was suggested for patients initially diagnosed withCBL -mutated JMML5. Nevertheless, individuals
harboring germline heterozygous CBL mutations had a higher risk
of growth retardation, development delay, cardiovascular disease, optic
or auditory problems, and autoimmune-related
diseases4,13,14 in addition to hematopoietic
disorders. Hence, the treatment principles of CBL -driven JMML are
distinct from other subtypes of JMML.
The CBL mutation, p.Tyr371His, found in our case, was confirmed
as pathogenic and highly recurrent in JMML15. However,
the myeloid NGS panel also disclosed a VUS of NF1 in this case
and put us into a difficult spot: should we initiate the HSCT plan for
our patient? For CBL- mutant JMML was often self-resolving, butNF1- driven JMML needed intensive therapies and bridged to
transplantation5. We did NF1 sequencing for
both this case’s parents and recognized this variant was inherited from
his mother. The maternal family members were withoutNF1 -associated hematological or dermatological diseases after the
survey. For these reasons, we speculated that the CBL mutation
was the driver mutation of his JMML, and observation with close
monitoring of the signs of disease progressing was suggested. In the
following year, no evidence of disease deterioration was noted, which
was supporting our speculation.
With the wide application of high throughput screening techniques,
comprehensive genetic testing would become commonplace for the
management of rare diseases and neoplastic malignancies. The detection
of VUS is not uncommon. More than 30% of patients with breast cancer
were found with at least one VUS by a 25 gene panel for cancer
susceptibility16. Defining the implication of a VUS is
an arduous task, and while a variant is suspected pathogenic,
re-evaluation with orthogonal methods is suggested8.
Designing computational prediction models or functional studies of the
gene is also helpful yet usually infeasible in clinical
setting8. Clinical evaluation is therefore an
indispensable part. In this case, we performed serial physical exams for
phenotype assessment, took family history to analyze the pattern of
inheritance, validated the NGS result with Sanger sequencing, and most
importantly, monitored the response after management. Combining
laboratory findings and bedside information, we could tailor a
personalized treatment strategy for patients with a rare disease and
genetic alterations with unknown effects.
In summary, we presented how we approached a rare case diagnosed withCBL -mutated JMML with concurrent germline NF1 VUS. Because
lacking information about the penetrance of these variants in
adolescence and adulthood, long term follow-up is warranted.