NTRK1 Gene Fusions Are Frequent in Juvenile Xanthogranuloma

Juvenile Xanthogranuloma (JXG) is a rare form of non-Langerhans cell histiocytosis. The most common known gene mutations affect the mitogen-activated protein (MAP) kinase, phosphoinositide 3-kinase (PI3K), and Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling pathways. We present a case of congenital JXG in a premature newborn from a dicygotic twin pregnancy with subdermal infiltrates on the chest, hepatosplenomegaly, ascites, pancytopenia, and petechiae on the abdomen and extremities. Next-generation sequencing of tissue from a subdermal infiltrate revealed a tropomyosin 3::neurotrophic tyrosine kinase receptor (TPM3::NTRK1) gene fusion. Therefore, a retrospective analysis of 34 additional non-Langerhans cell histiocytoses (16 JXG, 3 adult xanthogranuloma and 1 benign cephalic histiocytosis, both clinical subtypes of JXG, as well as 13 Rosai-Dorfman and 1 Erdheim-Chester disease) for NTRK1, 2 and 3 aberrations was performed. This analysis revealed an NTRK1 gene fusion in 4 additional JXGs and 1 adult xanthogranuloma. In conclusion, NTRK1 gene fusions are moderately common in JXG (6/21; 28.6% in our series). This finding places JXG in the category of proliferative diseases with one of the highest frequencies of NTRK gene rearrangements. Therefore, NTRK gene fusions should be included in a gene panel test for difficult-to-treat JXG. Given the potential of NTRK gene fusions as a therapeutic target, NTRK inhibitors may represent a novel effective treatment for JXG with a challenging clinical course.