Traditionally, establishing a diagnosis of JMML was challenging because its clinical and laboratory presenting features can also be associated with other disorders, including Wiskott-Aldrich syndrome,159 infantile osteopetrosis,160 infections (Epstein-Barr virus, cytomegalovirus, human herpesvirus 6, histoplasmosis, mycobacterium, and toxoplasmosis), class I Langerhans cell histiocytosis, hemophagocytic lymphohistiocytosis, FA, Kostmann syndrome, Shwachman syndrome, and Down syndrome. However, with a confirmed molecular mutation, patients who exhibit the category 1 features are now more easily diagnosed.
Recently, the term “Ras-associated lymphoproliferative disorder (RALD)” has been coined to describe patients with autoimmunity and lymphoid proliferation with activating RAS mutations in the blood. These mutations were initially thought to be in the germline, but later were established to be somatically acquired in the BM. These patients also exhibit splenomegaly and monocytosis, and they tend to meet clinical diagnostic criteria for JMML. At this time, there is no accepted method for distinguishing JMML from RALD, except to note that patients diagnosed with RALD have less fulminant myeloid disease and relatively more prominent immune dysregulation. Further study is needed to determine whether these diagnoses represent distinct clinicopathologic entities, or rather represent the spectrum of hematologic phenotypes specified by Ras pathway mutations. Along with reports of rare JMML patients who survive without chemotherapy despite persistent Ras pathway mutations, this idea has raised the controversial question as to whether or not select patients can be monitored without definitive therapy. However, given the difficulty of prospectively diagnosing RALD, its extremely low incidence, and the strong tendency of JMML to become more aggressive over time, most patients meeting JMML criteria should be treated as such.
