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.