JMML is a chronic myeloproliferative disorder that typically affects young children: more than 95% of cases are diagnosed before age 4

JMML arises from pluripotent hematopoietic stem cells (Cooper et al., 2000). Clonal proliferations of myeloid, monocyte-macrophages, erythroid, and sometimes lymphoid progenitor cells are seen.

The annual incidence of JMML is estimated to be roughly 0.67/million (Passmore et al, 2003). The median age is 1.1-1.8 years with a male to female ratio of 2-3:1. (Hasle et al., 1999; Niemeyer et al., 1997; Passmore et al., 2003). Those with neurofibromatosis type 1 (NF-1) have a 200-fold increased risk of JMML (Stiller et al., 1994)

Typical peripheral blood findings include leukocytosis (usually less than 100 x 10⁹/L) with variable degree of left shift, monocytosis, and thrombocytopenia. Nucleated red blood cells are often identified in the peripheral blood. Myeloblasts average about 1-5% of total nucleated cells, and by definition, blasts account for

Bone marrow findings are not specific. The marrow is usually hypercellular with a mildly increased M:E ratio (typically 3-5:1), dispersed erythroid elements, and decreased numbers of megakaryocytes. Dysplasia is usually not prominent. Blasts are required to be less than 20%; monocytes are less prominent in the marrow than in the peripheral blood, and are usually enumerated at 5-10% (Hess et al., 1996; Niemeyer et al., 1997).

Aberrant flow immunophenotype antigens can be seen in monocytes, neutrophils, and blasts in JMML. Monocytes can show decreased expression of CD4 and heterogeneous CD33. Maturing neutrophils may show decreased expression of CD10, CD64, CD13, and/or CD15. Myeloid blasts can express aberrant CD7. B cell precursors (hematogones) are often decreased (Maioli et al. 2016).

Curative therapy involves an allogeneic hematopoietic stem cell transplant (HSCT). Locatelli and Neimeyer (2015) recommend swift HSCT for those with germline NF1 mutations, somatic PTPN11 mutations, somatic KRAS mutations, and most children with somatic NRAS mutations. Most children with germline CBL mutations demonstrate spontaneous regression, though if there is disease progression, a HSCT should be considered. In children with Noonan syndrome (germline mutations of PTPN11, KRAS, and/or NRAS), the disease may be transient, and hence one can consider a watch and wait scenario, with mild cytoreductive therapy for symptoms, usually 6-mercaptopruine.
In the rare patients with tyrosine kinase fusions, ALK/ROS1 inhibitors, such as crizotinib, may be beneficial (Murakami et al., 2018).

As stated above, those with Noonan syndrome with germline mutations in PTPN11, KRAS, and/or NRAS as well as those with germline CBL mutations have disease that may spontaneously regress without therapy (Locatelli and Neimeyer, 2015). However, in other cases, in those who did not receive an allogeneic hematopoietic stem cell transplant (HSCT), the median survival after diagnosis is

High risk features include older age (>1.4-4 years), PTPN11 mutation, monosomy 7, HbF >40%, low platelets (20% bone marrow blasts (Dvorak and Loh, 2014; Locatelli et al., 2005; Niemeyer et al., 1997; Novitzky et al., 2000; Passmore et al., 2003). In genetic studies, patients with

Approximately 85-90% of children with JMML have identified mutations, either germline and/or somatic. Somatic, gain-of-function mutations occur in PTPN11, KRAS, and NRAS, in 35-38%, 18%, and 14% of cases respectively. NF1 germline mutations with acquired loss of the normal allele are seen in 5-15% of patients, and CBL germline mutations with acquired loss of the normal allele and duplication of the mutant allele (acquired uniparental disomy) are seen in 9-18% of patients. (Chan et al., 2009; Niemeyer and Flotho, 2019). Rare cases without any of the above mutations have been found to harbor RRAS or RRAS2 somatic mutations (Stieglitz et al., 2015).
Secondary mutations in SETBP1, JAK3, ASXL1, and SH2B3 are also identified and are often subclonal. Additional mutations in the RAS pathway genes are also sometimes detected, coined Ras double mutants (Caye et al., 2015; Stieglitz et al., 2015).
A recent study reported receptor tyrosine kinase fusions ( DCTN1 /ALK, RANBP2 /ALK, and TBL1XR1 / ROS1) in patients without identified RAS pathway mutations (Murakami et al., 2018).

This current topic of JMML does not include discussion on Ras-associated autoimmune leukoproliferative disorder (RALD), which is a nonmalignant disorder with myelomonocytic hyperplasia and somatic mutations in KRAS or NRAS, often showing clinical overlap with JMML (Calvo et al., 2015)