Disordered expression of the cardiac genes, myl7, vmhc, myh6, bmp4, tbx2b and notch1b, as well as reduced number of myocardial cells and endocardial cells, indicated the collapsed development of ventricle and atrium and failed differentiation of atrioventricular canal (AVC).
During mammalian heart development, restricted myocardial Bmp2 expression is a key patterning signal for atrioventricular canal specification and the epithelial-mesenchyme transition that gives rise to the valves.
Expression of Pitx2 appears to be repressed in a large portion of the heart ventricle and atrioventricular canal of wild-type mice by a negative feedback mechanism at a time when the gene is still expressed in its other domains.
Finally, droplet digital PCR using a probe specific for this novel mutation detected the complex BRAF mutation in both the 2000 and 2008 lesions, indicating this case to be ECD with a novel underlying BRAFp.Thr599_Val600delinsArgGlu mutation.
Functional studies in the mouse have shown that a Hey-Bmp2 regulatory circuit restricts Bmp2 expression to presumptive valve myocardium (atrioventricular canal and outflow tract).
Further, binding of an agonistic antibody (MM12) specific to human TrkB-EJM activated the full-length TrkB and unexpectedly also truncated TrkB lacking ECD (TrkBdelECD365), suggesting that TrkB is activated by attenuating the inhibitory effect of EJM through MM12 binding-induced conformational changes.
Furthermore, Fc-CLEC2(ECD) treatment improves cytokine profiles and increases both the M2 macrophage population and the genes involved in the oxidation of lipid metabolism in the liver.
Furthermore, the osteopontin mRNA decreased following glucocorticoid therapy with xanthogranuloma regression, suggesting that the expression level of osteopontin could be a marker of the disease activity of ECD.
Here, we report a 2-year-old boy, the youngest patient in the literature so far, who was diagnosed with concomitant BRAF mutation-positive LCH and ECD.
Here, we retrospectively evaluated the clinical and pathologic characteristics, presence of the BRAFV600E mutation, treatment options, and outcomes of Chinese patients diagnosed with ECD at our center.
However, at least in the cases of LCH and ECD, there is a very high frequency of activating mutations in MAPK pathway genes, most notably BRAF-V600E, as well as MAP2K1, in LCH and NRAS in ECD.
However, at least in the cases of LCH and ECD, there is a very high frequency of activating mutations in MAPK pathway genes, most notably BRAF-V600E, as well as MAP2K1, in LCH and NRAS in ECD.
Identification of BRAF and other MAPK pathway mutations in biopsies improves ECD diagnosis, allows for development of targeted treatments, and demonstrates that ECD is a neoplastic disorder.
IMPLICATIONS FOR PRACTICE: Vemurafenib, an oral monotherapy targeting a mutation in BRAF, is the first U.S. Food and Drug Administration approval for the treatment of Erdheim-Chester disease (ECD).
Importantly, gastrointestinal ECD might exhibit poor response to steroid treatment and other potential treatments including chemotherapy, and biologic treatments targeting IL-1 and TNF-alpha signalling should be considered.