Discussion:
We report two pediatric cases of JMML with diagnostic challenges.5 The first patient had a KRAS mutation which is a diagnostic criterion for JMML, but was also found on genomic testing to have a translocation of NUP98::NSD1 , which makes this case qualify as an AML according to the recent 5th WHO and International Consensus Classification (ICC) classifications.4,10 Notably, a few JMML patients have been reported with structural rearrangements that are typically associated with AML (e.g. inversion 3 andNUP98::NSD1 ).6 NUP98::NSD1 translocations can be missed on routine karyotyping and are independently associated with very poor prognosis.11These patients, including our first patient, require aggressive treatment and in fact may respond well to JMML therapy.
The ICC classification includes a distinct entity of Noonan syndrome–associated myeloproliferative disorder (NS-MPD), to characterize patients with Noonan syndrome and germline mutations inPTPN11 , KRAS , NRAS or RIT1 experiencing a transient myeloproliferative disorder in the first year of life.12 These patients may be appropriately managed with close observation or mild chemotherapy.5,13 A recent study of a cohort of patients with NS-MPD further shows variable clinical outcomes.14 The disease onset within 1-year-old age and high VAF of PTPN11 mutation in our second patient raised a differential diagnosis of NS-MPD. However, this mutation was confirmed to be somatic in nature; and the blasts show aberrant immunophenotype.15 Hence, the findings fit JMML, and the patient received chemotherapy followed by BMT. Interestingly, Glu76 Lys of PTPN11 has been the most affected residue in JMML.16
In summary, our JMML cases demonstrate some common diagnostic pitfalls. It is important to recognize these unusual features of JMML and further risk stratify JMML, especially because rare JMML may self-resolve,14,17 and a significant percentage of JMML relapse after BMT.18