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\begin{document}

\title{Juvenile xanthogranuloma manifesting with LCH-associated
neurodegenerative disease-like radiological findings}



\author[1]{Katsutsugu Umeda}%
\author[2]{Tomoo Daifu}%
\author[1]{Atsushi Yokoyama}%
\author[1]{Takeshi Yoshida}%
\author[1]{Satoshi Saida}%
\author[1]{Itaru Kato}%
\author[1]{Hidefumi Hiramatsu}%
\author[3]{Ko Kudo}%
\author[2]{Yoshihisa Higuchi}%
\author[1]{Junko Takita}%
\affil[1]{Kyoto Daigaku Daigakuin Igaku Kenkyuka Igakubu Hattatsu Shoni Kagaku}%
\affil[2]{Otsu Sekijuji Byoin}%
\affil[3]{Hirosaki Daigaku Igakubu Daigakuin Igaku Kenkyuka}%


\vspace{-1em}



  
  \date{May 26, 2024}


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\selectlanguage{english}
\begin{abstract}
Here, we describe two patients with juvenile xanthogranuloma (JXG)
manifesting with Langerhans cell histiocytosis-associated
neurodegenerative disease (ND)-like radiological findings. One patient
showed typical radiological abnormalities at onset, which worsened with
progressing central nervous system symptoms 7 years after LCH-oriented
chemotherapy. Another showed spontaneous regression of clinical
symptoms, with a transient radiological change 1 year after salvage
chemotherapy for recurrence of JXG. These data regarding JXG-associated
ND will facilitate future investigation of the disease, as well as
development of therapeutic interventions.%
\end{abstract}%



\sloppy


\textbf{BRIEF REPORT}

\textbf{Juvenile xanthogranuloma manifesting with LCH-associated
neurodegenerative disease-like radiological findings}

Tomoo Daifu\textsuperscript{1}, Katsutsugu Umeda\textsuperscript{2},
Atsushi Yokoyama\textsuperscript{2}, Takeshi Yoshida\textsuperscript{2},
Satoshi Saida\textsuperscript{2}, Itaru Kato\textsuperscript{2},
Hidefumi Hiramatsu\textsuperscript{2}, Ko Kudo\textsuperscript{3},
Yoshihisa Higuchi\textsuperscript{1}, Junko Takita\textsuperscript{2}

\textsuperscript{1}Department of Pediatrics, Japanese Red Cross Otsu
Hospital, Otsu, Japan

\textsuperscript{2}Department of Pediatrics, Graduate School of
Medicine, Kyoto University, Kyoto, Japan

\textsuperscript{3}Department of Pediatrics, Hirosaki University
Graduate School of Medicine, Hirosaki, Japan

*Corresponding author: Katsutsugu Umeda

Department of Pediatrics, Graduate School of Medicine, Kyoto University,
54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto, 606-8507, Japan

Phone: +81-75-751-3290; Fax: +81-75-752-2361

Email address: umeume@kuhp.kyoto-u.ac.jp

\textbf{Text word count} : Abstract, 80 words, main text, 985 words

\textbf{Number of tables and figures} : 0 tables, 2 figures

\textbf{Running title} : JXG manifesting with LCH-ND-like radiological
findings

\textbf{Keywords} : Juvenile xanthogranuloma, neurodegenerative
diseases, histiocytic disorders

\textbf{Abbreviations} :\selectlanguage{english}
\begin{longtable}[]{@{}ll@{}}
\toprule
ECD & Erdheim--Chester disease\tabularnewline
FFPE & Formalin-fixed paraffin-embedded\tabularnewline
IVIG & Intravenous immunoglobulin\tabularnewline
JXG & Juvenile xanthogranuloma\tabularnewline
LCH & Langerhans cell histiocytosis\tabularnewline
MAPK & Mitogen-activated protein kinase\tabularnewline
MRI & Magnetic resonance imaging\tabularnewline
ND & Neurodegenerative disease\tabularnewline
\bottomrule
\end{longtable}

\textbf{ABSTRACT}

Here, we describe two patients with juvenile xanthogranuloma (JXG)
manifesting with Langerhans cell histiocytosis-associated
neurodegenerative disease (ND)-like radiological findings. One patient
showed typical radiological abnormalities at onset, which worsened with
progressing central nervous system symptoms 7 years after LCH-oriented
chemotherapy. Another showed spontaneous regression of clinical
symptoms, with a transient radiological change 1 year after salvage
chemotherapy for recurrence of JXG. These data regarding JXG-associated
ND will facilitate future investigation of the disease, as well as
development of therapeutic interventions.

\textbf{1 \textbar{} INTRODUCTION}

Juvenile xanthogranuloma (JXG), the most common form of non-Langerhans
cell histiocytosis (LCH), is thought to arise from dermal dendrocytes or
macrophages. The majority of patients with the disease present primarily
with skin lesions, which usually regress spontaneously. However, some
patients develop extracutaneous lesions, with or without cutaneous
lesions (i.e., systemic JXG); sometimes, these lesions can progress
rapidly and can reduce quality of life, or even become life-threatening,
despite aggressive LCH-oriented
chemotherapy.\textsuperscript{1,2}Similar to other histiocytic disorders
such as LCH and Erdheim--Chester disease (ECD), patients with systemic
JXG often harbor somatic mutations in the mitogen-activated protein
kinase (MAPK) pathway genes, most notably BRAF.\textsuperscript{3}

LCH affects the central nervous system, manifesting primarily as
diabetes insipidus, or more rarely as neurodegenerative disease (ND).
LCH-associated ND, characterized by progressive radiological
abnormalities of the cerebellum, basal ganglia, and pons, as well as
cerebellar dysfunction accompanied by cognitive impairment and
behavioral disturbance, can develop many years after treatment for
LCH.\textsuperscript{4} Involvement of multiple organ systems,
particularly the pituitary gland, skin, base skull, or orbit bone
involvement, and presence of the BRAF V600E mutation, are risk factors
for developing LCH-associated ND.\textsuperscript{5}

ND also occurs in patients with ECD;\textsuperscript{4} however, there
is no report about ND in patients with JXG. Here, we report two cases of
JXG who presented with radiological abnormalities similar to those
observed for LCH-associated ND.

\textbf{2 \textbar{} CASE REPORT}

\textbf{(Case 1)} A 7-year-old boy, who developed diffuse papules on his
trunk and extremities 1 year previously, was admitted to our hospital
due to polydipsia and polyuria. Cranial magnetic resonance imaging (MRI)
revealed swelling of the pituitary gland and multiple T2-hyperinFig.
1A). He had no long bone involvement or other classic radiographic
findings associated with ECD. Histopathological examination of a papule
resected from his waist revealed accumulation of skin dendrocyte-derived
histiocytes, which were positive for CD68 and FXIII, and negative for
S100, CD1a, CD207 (langerin), and BRAF V600E. Therefore, the patient was
diagnosed with systemic JXG.

Although a 1-year LCH-oriented chemotherapy resulted in long-term
stabilization of the disease,\textsuperscript{6} his gait was unstable,
and he developed ataxia and cognitive deterioration 7 years after
treatment. Cranial MRI revealed widespread T2-hyperintense lesions in
the bilateral cerebellar dentate nuclei, a finding similar to typical
MRI findings in cases of LCH-associated ND (Fig. 1B). Despite monthly
intravenous immunoglobulin (IVIG) therapy, his neurological symptoms
worsened gradually. No genomic data were derived from old formalin-fixed
paraffin-embedded (FFPE) samples due to the low amount of DNA that could
be extracted.

(Case 2) A 1-year-old boy presented with fever, papules on his face,
pancytopenia, and hepatosplenomegaly. He had no long bone involvement or
other classic radiographic associated with ECD. Cranial MRI revealed no
abnormal findings. Histopathological examination of a papule and liver
biopsy revealed proliferation of histiocytes, which were positive for
CD68 and FXIII, and negative for S100, CD1a, CD207, and BRAF-V600E. He
was diagnosed with systemic JXG.

The patient underwent a 1-year LCH-oriented chemotherapy, during which
he achieved complete remission. Although he experienced relapse of the
skin and bone marrow 1 year after the initial treatment, salvage
cladribine monotherapy led to second complete remission. year after the
salvage treatment, he complained of frequent falls, and fluid attenuated
inversion recovery cranial MRI revealed bilateral hyperintense lesions
in the cerebellar dentate nuclei (Fig. 2A). Both his neurological
symptoms and radiological findings improved spontaneously (Fig. 2B).
Droplet digital polymerase chain reaction and next generation sequence
analyses of FFPE samples\textsuperscript{7,8} failed to detect the
somatic mutations frequently found in histiocytic neoplasms, including
BRAF, MAP2K1, KRAS, NRAS, CSF1R, and ALK.

\textbf{3 \textbar{} DISCUSSION}

Despite recent advances in molecular diagnosis of histiocytic disorders,
some issues remain unresolved regarding their association with ND,
including pathophysiology and treatment. Although LCH, ECD, and systemic
JXG have distinct clinical and pathologic features, these histiocytic
disorders are categorized into the ``Langerhans (L)'' group, mainly
because they harbor somatic mutations in the MAPK pathway, and LCH/ECD
and LCH/JXG histological phenotypes can co-exist in a single
case.\textsuperscript{3,9-11} The present two cases raise the
possibility that patients with all disease types categorized in the L
group can develop ND.

In the present cases, multiple organ systems were initially affected,
which is considered to be a risk factor for developing LCH-associated
ND.\textsuperscript{5} In case 1, abnormal MRI findings in the
cerebellum, which were present already at onset, progressed gradually
after chemotherapy, followed by development of cerebellar dysfunction
and cognitive impairment. By contrast, the clinical symptoms and
abnormal MRI findings in case 2 disappeared spontaneously. Such
inter-patient heterogeneity has been reported for LCH-associated
ND.\textsuperscript{12} Nonetheless, careful screening and long-term
follow-up are required to detect development of ND in patients with
systemic JCG.

One of the greatest concerns is development of effective treatments for
JXG-associated ND. Monthly IVIG treatment may halt progression, but it
failed to improve the disease status of ND in case 1, as reported for
cases of LCH-associated ND. \textsuperscript{12,13} One possible
second-line therapy is cytarabine-containing chemotherapy, in
combination with vincristine, dexamethasone, or IVIG, which has been
effective for some patients with LCH-associated
ND.\textsuperscript{12,14,15} Because a BRAF inhibitor may be a
promising option for LCH-associated ND, \textsuperscript{16} discovery
of clinically meaningful therapeutic targets is mandatory.

In conclusion, additional studies are required to obtain more data
regarding JXG-associated ND, which will serve as a starting point for
further investigations and development of drugs to treat histiocytic
disorder-associated ND.

\textbf{ACKNOWLEDGMENTS}

We would like to thank Drs Sakamoto K, Shioda Y, and Morimoto A for
helpful discussion, and for comments regarding the manuscript.

\textbf{CONFLICTS OF INTEREST}

The authors declare no conflicts of interest associated with this
manuscript.

\textbf{FIGURE LEGENDS}

\textbf{Figure 1.} T2-weighted Magnetic resonance imaging (MRI) findings
in case 1 at onset (A) and at 7 years post-treatment (B). Arrows
indicate hyperintense lesions in the cerebellum.

\textbf{Figure 2.} Fluid attenuated inversion recovery MRI findings in
case 2 at 1 year (A) and 3 years post-treatment (B). Arrows indicate
hyperintense lesions in the cerebellum.

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