To the Editor
Juvenile xanthogranuloma (JXG) is a very rare benign tumor of
histiocytic origin. Being derived from CD14+ dermal dendrocytes, JXG
represents the most common type of non-Langerhans cell histiocytosis
(non-LCH) and typically affects young infants1,2.
Although it is usually confined to solitary, or rarely multiple,
yellow-reddish papulous lesions of the skin (monosystemic) that tend to
regress spontaneously over the course of a few years, JXG may also
extend to ocular, visceral, and central nervous system
(multisystem/systemic) disease2. Cutaneous lesions
generally heal without or sometimes with atrophic scarring, whereas
ocular or visceral involvement may result in severe, even
life-threatening morbidity and require systemic treatment, historically
consisting of agents used in the therapy of LCH (prednisolone, vinca
alkaloids, 6-mercaptopurine, cytarabine, cladribine; see alsoLCH-IV protocol of the Histiocyte Society at www.histiocytesociety.org,ClinicalTrials identifier: NCT02205762)2-5. In
analogy to LCH and other non-LCH diseases, recent studies have confirmed
the presence of activating mutations in the MAPK signaling pathways in
many cases of systemic JXG, or rarely, kinase fusions involving BRAF,
ALK, or NTRK in various non-LCH lesions6,7.
Vemurafenib has been shown to be effective in achieving clinical
remissions in refractory multisystem BRAF p.V600E-mutated
LCH8. Consequently, also patients with severe systemic
JXG may be offered an effective targeted therapy in the future.
We report on a female infant with multiple cutaneous lesions of JXG
affecting her face, upper trunk and proximal upper extremities. A
concurrence of a BRAF p.D594N and a KRAS p.G12V mutation
with identical allele frequencies of 12-13% was detected in these
lesions. The same constellation of both BRAF loss-of-function andKRAS gain-of-function mutations occurring simultaneously has been
experimentally explained by a mechanism of oncogenic RAS-dependent CRAF
binding of BRAF and paradoxical activation of the MAPK pathway via CRAF
in the presence of kinase-dead (class III) variants of BRAF or
pharmacological inhibition of BRAF in vitro and in
vivo9,10 . In line, patients treated with BRAF
inhibitors are at risk to develop RAS-mutated keratoacanthomas or
squamous cell carcinomas11, and class III BRAF
mutations were detected in melanoma, colorectal carcinoma, and non-small
cell lung cancer and are typically linked to oncogenic RAS mutations,
NF1 deletions, or increased receptor tyrosine kinase signaling
(reviewed in 12-15); whereby the exact sequence
of these events remains to be elucidated.
The child is clinically stable and neither eyes, nor visceral organs or
the CNS are affected as determined by imaging and ophthalmological
studies. To date, she is 30 months of age and has been observed without
therapy for one year with a mild “waxing and waning” course of the
skin lesions. In contrast, three other children diagnosed with unifocal
cutaneous JXG within the same year at our institution, did not show any
alteration of the genes analyzed (sequencing panel includes BRAF,
GNA11, GNAQ, HRAS, KRAS, RAC1, CDKN2A, KIT, MAP2K1, PIK3CA, PTEN ). This
finding and the presence of MAP2K1 besides BRAF p.V600E
mutations in a substantial proportion of current local LCH patients
analyzed with the same panel (MAP2K1 p.F53_Q58delinsL, n=2; BRAF V600E
n=4; total LCH patients analyzed n= 12) highlight the need for detailed
tumor genotyping and awareness of the affected stage within the altered
signaling pathway prior to initiation of kinase-directed treatment in
histiocytosis to identify the precise target and avoid unnecessary
adverse effects.