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\begin{document}

\title{Sever Graves' disease-associated orbitopathy: a rare case of a frontal
bone hemangioma.}



\author[1]{Ahmad Alamri}%
\author[1]{Daphné Pauchet}%
\author[1]{André Balaton}%
\author[1]{Constance Oriez}%
\author[1]{Olivier Dupuy}%
\author[2]{Adrien Ben Hamou}%
\affil[1]{Paris Saint Joseph Hospital Group}%
\affil[2]{Affiliation not available}%


\vspace{-1em}



  
  \date{May 08, 2024}


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\selectlanguage{english}
\begin{abstract}
Bone hemangiomas are extremely rare benign tumors. We hereby present a
case of 41-year old woman, that had a sever thyrotoxicosis, associated
with severe GO which has necessitated glucocorticoid treatment. A link
between hemangioma and sever thyrotoxicosis and/or IV GC might have
resulted in endothelial alterations, and/or bone loss.%
\end{abstract}%



\sloppy


\textbf{Introduction}

Graves' disease (GD) is the most common cause of hyperthyroidism,
affecting 1.5\% of the population. It is more prevalent in women than in
men (F/M 7:1)\textsuperscript{1}. The most frequent extra-thyroidal
manifestation is Graves' disease-associated orbitopathy (GO) affecting
more females than males with an annual incidence of 0.016\% and 0.003\%
respectively. This manifestation might lead to ocular adverse events as
a corneal breakdown or an optic neuropathy in 3 to 5\% of such patients.
The European guidelines of Graves' disease-associated orbitopathy was
commissioned by The European Thyroid Association to provide guidelines
for the management of GO. They recommend a high-dose intravenous
glucocorticoids (IV GC) be considered as a first-line treatment for
moderate-to-severe and active GO\textsuperscript{2}.

Skeletal hemangiomas are rare benign tumors of blood vessels which occur
most commonly in the vertebral bodies followed by the skull. These
tumors account for 0.7\% of bone neoplasma\textsuperscript{3}.

We hereby report a case of a severe GO treated by IV GC who developed a
frontal bone hemangioma four months after the treatment.

\textbf{Case Report}

A 41 year-old Ivoirian woman, non-smoker, who has a history of a
non-complicated type one diabetes, presented with GD, diagnosed in May
2018, with a clinical picture of weight loss and trembling. The initial
biological tests showed an undetectable thyroid stimulating hormone
(TSH) level, with high free thyroxine level (fT4) (31 pmol/L, N:
9.0-19.0 pmol/L), high free triiodothyronine (fT3) (11.8 pmol/L, N:
2.9-4.9 pmol/L), anti-thyrotropin receptor antibodies (TRAb) were
positive at 54 IU/l (N: \textless{}1.74 IU/L), anti-thyroglobulin
antibodies, and anti-thyroperoxidase antibodies were both negative.
Alkaline phosphatase and bone turn-over markers were in the normal range
excluding Paget's disease. Ultrasound showed a homogeneous hyper
vascularized goiter with a peak systolic velocity estimated at 78 cm/s
(N: 15-30 cm/s) with no other significant anomalies. A treatment with
carbimazole was introduced. In December, during follow-up, the patient
presented with GO that has developed over few months with conjunctival
redness, chemosis, tearing, bilateral eyelid swelling, right upper
eyelid retraction, blurry vision without diplopia, and ocular and retro
orbital pain. Clinical activity score (CAS) was 7/10 for both eyes.
There was no optic nerve involvement. Due to the severity of her GO, she
received a 10-week-course of high-dose IV GC pulses (six pulses of 750
mg in 30 days, followed by 7 pulses of 430 mg in about 45 days) to
improve the GO, and to normalize her thyroid function test that remained
uncontrolled despite high-doses of carbimazole. After the IV GC,
clinical reassessment showed a mild to moderate improvement of the CAS
of 4/10 in both eyes. TSH level remained undetectable, however fT4 and
fT3 were normalized (10.4 and 4.6 pmol/l respectively). One month later,
a total thyroidectomy was performed by the ENT team in May 2019, with no
postoperative outcomes.

During the follow-up, the patient has signaled (August 2019) a frontal
bone depression without any other symptoms or history of recent trauma.
The frontal depression was left-sided, with no pain, tenderness, nor
frontal paresthesia. The CT scan performed in November 2019 has showed a
rounded lytic lesion of the frontal bone involving the walls of the
frontal sinus, measuring 25 x 25 mm. The patient was then addressed to
the ENT clinic, with a CT scan control after 3 months that showed an
increase of the size of the lesion measuring 35 x 42 mm. Magnetic
resonance imaging showed a single lytic lesion of the frontal bone
left-sided with no intracranial invasion (\textbf{Figure 1} ). This
lesion was weakly hyper metabolic on the positron emission tomography
(TEP) scan with a standardized uptake value (SUV\textsubscript{max}) of
4.8.

A frontal bone biopsy was performed under local anesthesia. Histological
examination showed remodeled bone trabeculae separated by a loose
fibrous tissue containing numerous capillary vessels (\textbf{Figure 2}
). Cytologic atypia, cell crowding, mitotic activity, and giant cells
were not present.~A diagnosis of intra-osseous hemangioma was
established.

\textbf{Discussion}

Frontal bone hemangiomas are very rare tumors for which the origin is
not yet clear. Some studies suggested a congenital origin -- which
remains doubtful since the mean age in most case reports was about 30
years -- while other studies reported a post-traumatic
development\textsuperscript{4}. However, no link between sever
thyrotoxicosis and bone hemangiomas have been reported yet.

Firstly, changes in the systemic circulation -- as may occur in venous
obstruction and in heart failure -- may result in changes in arterial
and/or venous pressures which might explain the development of a
vascular malformation. These changes might be the result of her sever
thyrotoxicosis which has persisted for more than a year.

Secondly, the possible link between the lesion and high-dose IV GC
administration in a short period (7.5 grams in 10 weeks). To our
knowledge, no cases of hemangiomas resulting from high-dose of GC
therapy have been described\textsuperscript{5}. We propose two
mechanisms: \emph{1/} circulatory changes resulting from high-dose IV
GC, which could be explained by the expression of both type 1 and type 2
11\selectlanguage{greek}β-\selectlanguage{english}hydroxysteroid dehydrogenase isozymes in the arterial wall; which
might have a direct impact on vascular physiology, \emph{2/} the
increased risk of bone loss associated with the IV GC therapy; as a
result of \emph{(i)} a decrease in bone formation, by directly
inhibiting osteoblastic proliferation and differentiation, and by
increasing the apoptosis of mature osteoblasts, \emph{(ii)} an increase
in bone resorption by stimulating osteoclastogenesis. According to the
literature, this bone loss caused by high-dose GC therapy is most
pronounced in the first months following a high-dose GC therapy, and the
fact that the lesion appeared four months after the IV GC might suggest
a physiopathological link.

In conclusion, frontal bone hemangiomas are rare lesions, for which the
etiology is not clear. To our knowledge, there are no studies which have
described the occurrence of bone hemangiomas in patients having severe
GO, or in patients treated with high-dose IV GC. We suggest a possible
link between IV GC which might have resulted in endothelial alterations,
and/or bone loss. Severe thyrotoxicosis might have contributed due to
possible circulatory alterations. Finally, the role of carbimazole
cannot be excluded despite the lack of evidence.

\textbf{References}

1. Smith TJ, Heged\selectlanguage{ngerman}üs L. Graves' Disease. \emph{N Engl J Med} .
2016;375(16):1552-1565.

2. Bartalena L, Baldeschi L, Boboridis K, et al. The 2016 European
Thyroid Association/European Group on Graves' Orbitopathy Guidelines for
the Management of Graves' Orbitopathy. \emph{Eur Thyroid J} .
2016;5(1):9-26.

3. Seo BF, Kang KJ, Jung S-N, Byeon JH. Skeletal cavernous hemangiomas
of the frontal bone with orbital roof and rim involvement. \emph{Arch
Craniofac Surg} . 2018;19(3):214-217.

4. Cheng N-C, Lai D-M, Hsie M-H, Liao S-L, Chen Y-BT. Intraosseous
hemangiomas of the facial bone. \emph{Plast Reconstr Surg} .
2006;117(7):2366-2372.

5. Ueda-Sakane Y, Kanamoto N, Fushimi Y, et al. Overall safety and
efficacy of high-dose and low-dose intravenous glucocorticoid therapy in
patients with moderate-to-severe active Graves'
ophthalmopathy.\emph{Endocr J} . 2016;63(8):703-714.

\textbf{Legends}

\textbf{Figure 1.} The lytic bone lesion on computed tomography scan
(CT) and magnetic resonance imaging (MRI).

\begin{enumerate}
\tightlist
\item
  CT scan showing a rounded lytic lesion of the frontal bone,
  left-sided, involving the walls of the frontal sinus, measuring 35 x
  42 mm in diameter.
\item
  Magnetic resonance imaging showing the frontal bone lesion,
  lateralized to the left, with hyposignal in T1-weighted sequences,
  enhanced after injection with gadolinium.
\end{enumerate}

\textbf{Figure 2.} Numerous capillary vessels containing erythrocytes,
in between pre-existing bone trabeculae (Haematoxylin-eosin; original
magnification, X 250).

\textbf{Hosted file}

\verb`FIGURE_1.docx`  available at \url{https://authorea.com/users/338463/articles/464464-sever-graves-disease-associated-orbitopathy-a-rare-case-of-a-frontal-bone-hemangioma}

\textbf{Hosted file}

\verb`FIGURE_2.docx`  available at \url{https://authorea.com/users/338463/articles/464464-sever-graves-disease-associated-orbitopathy-a-rare-case-of-a-frontal-bone-hemangioma}

\selectlanguage{english}
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\end{document}

