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Optic disc edema in fibrous dysplasia/McCune-Albright

syndrome: prevalence, etiologies, and clinical implications

Layne N. Raborn, Kristen S. Pan, Edmond J. FitzGibbon, Michael

T. Collins, Alison M. Boyce

PII: S8756-3282(20)30441-5
DOI: https://doi.org/10.1016/j.bone.2020.115661
Reference: BON 115661

To appear in: Bone

Received date: 29 June 2020

Revised date: 11 September 2020
Accepted date: 20 September 2020

Please cite this article as: L.N. Raborn, K.S. Pan, E.J. FitzGibbon, et al., Optic disc edema
in fibrous dysplasia/McCune-Albright syndrome: prevalence, etiologies, and clinical
implications, Bone (2020), https://doi.org/10.1016/j.bone.2020.115661

This is a PDF file of an article that has undergone enhancements after acceptance, such
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© 2020 Published by Elsevier.

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Optic disc edema in fibrous dysplasia/McCune-Albright syndrome: prevalence, etiologies,

and clinical implications

Layne N. Raborn, B.S.,1 Kristen S. Pan, M.D.,1 Edmond J. FitzGibbon, M.D.,2 Michael T.

Collins, M.D.,1 Alison M. Boyce, M.D.1

1
Skeletal Disorders and Mineral Homeostasis Section, National Institute of Dental and

Craniofacial Research, National Institutes of Health, Bethesda, MD

2
Laboratory of Sensorimotor Research, National Eye Institute, National Institutes of Health,

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Bethesda, MD

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Correspondence to:

Alison M. Boyce, M.D.

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Skeletal Disorders and Mineral Homeostasis Section, NIDCR, NIH

30 Convent Drive
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Building 30, Room 228, MSC 4320

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Bethesda, MD 20892-4320

Tel: 301-827-4802
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Fax: 301-480-9962
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boyceam@mail.nih.gov

Abstract

Background: Fibrous dysplasia (FD) is a rare disorder of expansile fibro-osseous lesions that

may be associated with extraskeletal features as part of McCune-Albright syndrome (MAS).

Optic disc edema is a potentially serious ophthalmologic finding that has been rarely reported in
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patients with FD/MAS. The purpose of this study was to investigate the prevalence and potential

clinical associations of optic disc edema in a large cohort.

Methods: Clinical records were reviewed from subjects in an ongoing FD/MAS natural history

study. Computed Tomography scans were evaluated for the presence of structural craniofacial

abnormalities associated with optic disc edema, including Chiari I malformation and space-

occupying lesions. Craniomorphometric analyses were performed to determine optic canal

diameter and intracranial volume. Statistical analyses were performed to compare clinical and

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radiographic features between subjects with and without optic disc edema.

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Results: Optic disc edema was diagnosed in 7/187 subjects, for a prevalence of 3.7%. All

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subjects with optic disc edema were diagnosed before age 18 years and had mild, non-
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progressive disease. Radiographic structural abnormalities, including Chiari I malformation,

aneurysmal bone cysts, and arachnoid cysts, were associated with higher odds of optic disc
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edema (odds ratio [OR] 24.3; 95% confidence interval [CI], 4.2 to 121.4; p < 0.01)(OR 18.0;
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95% CI, 3.4 to 108.2; p <0.01). Treatment with leuprolide, a gonadotropin releasing hormone

analog, was also associated with optic disc edema (OR 26.0; 95% CI 3.3 to 177.5; p <0.05).
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There was no significant association of optic disc edema with other MAS endocrinopathies,
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medications, optic canal diameter, or intracranial volume.

Conclusion: Optic disc edema is an uncommon but potentially serious complication of

craniofacial FD, which may occur more frequently in pediatric patients and those with structural

craniofacial abnormalities. The potential association of leuprolide therapy with optic disc edema

in this population warrants further study.

Abbreviations
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FD = fibrous dysplasia; MAS = McCune-Albright Syndrome; ODE = optic disc edema; CM1 =

Chiari I malformation; CT = Computed Tomography; OCT = Optical Coherence Tomography;

RNFL = Retinal Nerve Fiber Layer; 3D multiplanar reconstruction = MPR; ROI = Region of

interest; OR = Odds ratio; CI = Confidence interval;

Keywords

Papilledema, Chiari I Malformation, Aneurysmal bone cysts, Arachnoid cysts, Optic neuropathy,

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Increased intracranial pressure

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1. Introduction
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Fibrous dysplasia (FD) is a mosaic skeletal disorder caused by somatic gain-of-function

mutations in GNAS [1]. Skeletal progenitor cell differentiation is disrupted, leading to

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replacement of normal bone and marrow with expansile fibro-osseous tissue [2]. FD can affect
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one or multiple bones and may occur in association with extraskeletal features, including café-

au-lait skin macules and hyperfunctioning endocrinopathies (precocious puberty,

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hyperthyroidism, growth hormone excess, neonatal Cushing syndrome, FGF23-mediated

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hypophosphatemia). The combination of FD and extraskeletal features is termed McCune-

Albright Syndrome (MAS) [3].

Craniofacial involvement in FD is common and potentially disabling [4]. FD expansion may

lead to facial asymmetry and functional deficits, including optic neuropathy due to optic nerve

compression or traction [5]. Optic disc edema (ODE) is a related but distinct ophthalmologic

finding which has been rarely reported in patients with craniofacial FD [6-9], and may serve as

an initial indicator of optic nerve damage. ODE may result from multiple disease processes, such
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as inflammation, infiltrative disorders, and intracranial compression, and may also arise as an

idiopathic process [10 11]. When ODE occurs in the setting of increased intracranial pressure, it

is termed papilledema. Potential etiologies of ODE in FD may include intracranial compression

and/or disruption of cerebrospinal fluid flow due to skull deformities and space-occupying

lesions [10 12], as well as risk factors for increased intracranial pressure such as MAS

endocrinopathies and medications [13-16]. However, the potential etiologies of ODE in

FD/MAS have not been systematically investigated, and the prevalence and clinical implications

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in this population are unknown.

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The purpose of this study was to: (i) determine the prevalence and clinical course of ODE in

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a large cohort of patients with craniofacial FD, (ii) identify risk factors and clinical correlations
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with ODE, and (iii) investigate potential mechanisms of ODE using computed tomography (CT)

craniomorphometric and volumetric analyses.

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2. Materials and Methods

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2.1 Subjects

Subjects were evaluated between 2000 and 2019 at the National Institutes of Health as
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part of an ongoing natural history study of FD/MAS (NCT00001727). The study was approved
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by the Institutional Review Board of the National Institute of Dental and Craniofacial Research,

and informed consent/assent was obtained from all subjects and/or guardians. Subjects were

diagnosed with FD/MAS according to previously published guidelines [3].

2.2 Neuro-ophthalmologic evaluation

All subjects were evaluated by a trained neuro-ophthalmologist at the NIH Clinical

Center. Subjects were diagnosed with ODE according to Modified Frisén scale criteria including

the appearance of disc elevation, blurring of surface vessels, disc margin blurring, or loss of
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physiologic cup upon fundoscopic exam [10 17]. Spectral-domain Optical Coherence

Tomography (OCT) was performed with the Cirrus-HD OCT (Carl Zeiss Meditec, Inc., Dublin,

CA). The Optic Disc Cube 200 x 200 protocol was used for acquisition and analysis of the

peripapillary retinal nerve fiber layer (RNFL) and optic nerve head. Standard neuro-

ophthalmologic assessment included: 1) best corrected visual acuity, using the Early Treatment

Diabetic Retinopathy Study scale (abnormal 20/40 or worse [18]); 2) visual fields, using

Humphrey Field Analyzer/Swedish Interactive Thresholding Algorithm Fast 30-2 automated

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perimetry testing; 3) color vision, using 16 Ishihara color plates (normal being at least 14 correct

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identifications); 4) contrast sensitivity, using Pelli-Robson contrast sensitivity chart (normal

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being equal or greater than 1.50 log units); and 5) fundoscopic exam.
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2.3 Clinical associations

Clinical records were reviewed to evaluate for established risk factors associated with
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ODE and increased intracranial pressure in the general population, including 1) medications:
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leuprolide [14 19-21], tetracyclines [13 14 22], fluoroquinolones [13 22-24], vitamin A

derivatives [13 14 22 25-29], levothyroxine [14 22 27], and/or growth hormone replacement [13
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14 22 27 29-31]; 2) endocrinopathies: growth hormone excess [15], growth hormone deficiency

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[32], hypoparathyroidism [13 14 33-36], hyperthyroidism [37], hypophosphatemia [38],

precocious puberty [21], and/or hypercortisolism [39]; and 3) other clinical variables: obesity [14

27 40], obstructive sleep apnea [14 40 41], and/or anemia [14 34]. Symptoms potentially

associated with increased intracranial pressure were reviewed, including headache, pulsatile

tinnitus, and transient visual obscurations [10].

2.4 CT evaluation
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CT studies performed within 1 year of neuro-ophthalmologic exams were systematically

reviewed to evaluate for structural abnormalities known to be associated with ODE, including 1)

Chiari 1 malformation [13 40], and 2) space-occupying lesions, such as aneurysmal bone cysts

[12 42], arachnoid cysts [43 44], and/or others [10].

Craniomorphometric analyses using OSIRIX imaging analysis software were performed

to investigate optic nerve compression and decreased intracranial volume as potential

mechanisms of ODE (Fig 1). CT scans measurements were collected via 3D multiplanar

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reconstruction (MPR) of ≤5 mm axial slices. To determine optic canal cross-sectional area, head

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orthogonal MPR planes were adjusted to align perpendicular to the optic canal, and the

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narrowest segment of the optic canal was outlined using digital calipers. To measure intracranial
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volume, the intracranial space was similarly outlined on several sagittal CT images to define the

ROI, and then a semiautomatic propagation function outlined the remaining CT slices to include
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the entire intracranial space. Intracranial volume was calculated from the outlined ROIs (ICV = Σ
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(A1, A2, . . ., Az) × CT slice thickness).

CT scans for all analyses were performed by a single trained reader (KSP).
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2.5 Statistical analysis

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Statistical analyses were performed using GraphPad Prism version 7.03 for Windows

(GraphPad Software, La Jolla, CA, USA; https://www.graphpad.com/). Fisher's exact test was

used to examine the significance of contingency between ODE and FD/MAS clinical

associations. Unpaired two-sided t-test and Mann-Whitney tests were used to evaluate

differences between groups as indicated depending on the normality of the distribution. Unpaired

two-sided t-test with age-matched controls was used to evaluate differences in the optic canal

area and intracranial volume of subjects with and without ODE. For optic canal measurements,
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one canal was randomly selected for statistical analysis from each control and ODE subject, with

exception of one subject with unilateral ODE.

3. Results

3.1 Subjects

The study population flowchart is included in Figure 2. Of the total FD/MAS cohort, 203

subjects had craniofacial disease, and 187 total subjects underwent neuro-ophthalmologic

evaluation that included examination of the optic disc. Idiopathic ODE was found in 7 subjects,

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for an overall prevalence of 3.7%. Of the 180 subjects without ODE, 48 were excluded from

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further analyses due to previous orbital surgery (n=5), unexplained vision changes (n=6), and/or

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other ophthalmologic diagnosis [total n=37: amblyopia (1), diabetic retinopathy (1),
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strabismus/exotropia (3), macular degeneration (1), confirmed or suspected optic neuropathy

(29), and uveitis (2)].

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General subject characteristics of the study cohort are described in Table 1. Subjects with
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ODE were younger, with a mean age of 12 years at diagnosis (range 5-17 years) vs 22.8 years (2-

80) in non-ODE subjects, however this did not meet statistical significance. As expected, RNFL
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thickness was greater in the subjects with ODE. Additional clinical characteristics and neuro-
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ophthalmologic exam findings for subjects with ODE are outlined in detail in Table 2. Six

subjects (Subjects 1, 2, 3, 4, 5, 6) were diagnosed with ODE on routine ophthalmologic

screening at NIH. Subject 7 had a previous diagnosis of ODE at an outside clinic and presented

to the NIH on acetazolamide therapy for ODE management.

3.2 Radiographic Associations with ODE

CT studies performed within 1 year of neuro-ophthalmologic exam were evaluated for the 7

subjects with ODE and 100 control FD subjects without ODE (Fig 2). Structural craniofacial
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abnormalities were identified in 4/7 (57%) of ODE subjects, including Chiari I malformations

(n=3) and space-occupying lesions: aneurysmal bone cyst (n=1) and arachnoid cysts (n=2) (Fig 3

D-E, Table 3). Structural abnormalities were identified 7/100 (7%) of control subjects, including

Chiari I malformations (n=3) and space-occupying lesions: arachnoid cysts (n=3) and

arteriovenous fistula (n=1). As expected, both Chiari I malformation and space occupying lesions

were associated with higher odds of ODE development (odds ratio 24.3; 95% confidence interval

[CI], 4.2 to 121.4; p < 0.01, and 18.0; 95% CI, 3.4 to 108.2; p <0.01, respectively).

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Craniomorphometric analyses were performed for the 7 ODE subjects and compared to

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controls. To account for age-related skull changes, only control subjects age <18 years (n=55)

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were included in these analyses (Fig 2). There was no association between ODE and
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craniomorphometric analyses, including optic canal diameter or intracranial volume

(Supplemental Table 1).

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Orbital FD involvement was similar between 2 groups, affecting 7/7 (100%) of ODE subjects
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and 93/100 (93%) of controls (p>1.0). Detailed information about the specific orbital bones

involved (optic canal, frontal, ethmoid, maxilla, zygoma, sphenoid, and lacrimal bones) is
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included in Supplemental Table 2. There were no significant differences in orbital bone

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involvement between the groups, with the exception of the lacrimal bone, which was more

frequently involved in ODE subjects [4/7 (57%) compared to 17/100 (17%) of controls, p=0.03].

3.4 Clinical Associations with ODE

Leuprolide use was associated with higher odds of ODE development (odds ratio 26.0; 95%

CI 3.3 to 177.5; p=0.01)(Table 3). There were no significant associations of ODE with MAS

endocrinopathies or other medications. The only symptom potentially associated with ODE in
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either cohort was headache, which was reported in 3/7 (43%) of ODE subjects and 34/132 (25%)

of controls; a difference that was not statistically significant (OR 2.2, CI 0.5—8.3; p=0.38).

3.5 ODE Clinical Course

Fundoscopic exams showed mild ODE for subjects 1-6. Subject 7 was previously diagnosed

with mild ODE by an outside neuro-ophthalmologist and was placed on acetazolamide, after

which she had a normal fundoscopic exam (Fig 3). All subjects had normal vision and neuro-

ophthalmologic exam; findings were otherwise unremarkable (Table 2).

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Subjects 1, 3 and 6 reported headaches; there were no other symptoms of ODE in other

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subjects. Only one subject (subject 1) underwent a lumbar puncture, which showed mildly

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increased opening pressure of 29cmH2O (nl <25cmH2O) [45]. Subjects were followed over a
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period from 0-11 years (median 1 year). Three subjects were treated with acetazolamide, which

was associated with resolution of ODE in two (subjects 4 and 7), and persistent but stable ODE
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in one (subject 1). Of note, subject 7 was on leuprolide therapy for 2.5 years at the time of ODE
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diagnosis; this medication was discontinued at the time acetazolamide was started. Of 3

untreated subjects with follow-up data available, ODE was persistent but stable in 2 (subjects 5
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and 6). Subject 3 developed mild intermittent ODE. It was first noted at age 10, one year after
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starting leuprolide treatment. ODE appeared to spontaneously resolve after 1 year but was again

noted at age 13, after which leuprolide was discontinued and ODE resolved. The patient was

followed with yearly exams with mild ODE noted persistently between ages 14-19, and again at

age 21. Subject 5 underwent posterior fossa decompression for treatment of Chiari I

malformation shortly after ODE was detected; she tolerated the procedure well but has not yet

undergone formal re-assessment of ODE.

4 Discussion
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Findings from this study demonstrate that patients with craniofacial FD are at risk for ODE,

with a prevalence of 3.7% in this large cohort. All cases in this study were mild, non-progressive,

and presented in pediatric patients <18 years of age. Associated risk factors included structural

craniofacial abnormalities (Chiari I malformation, aneurysmal bone cysts, and arachnoid cysts)

and leuprolide therapy. There was no association between ODE and craniomorphometric indices

or MAS endocrinopathies.

Craniofacial deformities are common in FD and include several types of structural

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abnormalities that may result in increased intracranial pressure. Chiari I malformation results

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from skull base deformity [46], and was strongly associated with ODE in this cohort. The

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mechanism of increased intracranial pressure in patients with Chiari I malformation has not been
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definitively established, but may be related to obstruction of cerebrospinal fluid flow at the

foramen magnum due to downward protrusion of the cerebellar tonsils [47]. Aneurysmal bone
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cysts are expansile, fluid-filled lesions that may arise as primary neoplasms in normal bone, or as
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secondary lesions within pathologic bone such as FD [12 48]. The prevalence of aneurysmal

bone cysts in patients with FD is approximately 5% [48]. When large or rapidly growing, these
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cysts can act as space-occupying lesions resulting in intracranial compression [49 50]. Arachnoid
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cysts are sacs of cerebrospinal fluid which typically develop on the arachnoid membrane, and

may rarely cause increased intracranial pressure through disruption of cerebrospinal fluid flow or

direct compression [43 44]. These cysts occur in 2.6% of children and 1.4% of adults, and are a

common incidental finding on neuroimaging studies [51]. In radiographic analysis of this cohort,

the prevalence of arachnoid cysts was slightly higher than would be expected in the general

population at 4.7% (5/107) overall, and 3% (3/100) in non-ODE subjects. Arachnoid cysts

typically do not involve bony structures, and there is no known association with metabolic bone
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diseases. However, we cannot exclude the possibility that patients with FD may be higher risk

for this deformity. In addition, it is possible that the structural compromise of FD bone may place

patients with arachnoid cysts at greater risk of developing secondary deformities that further

increase intracranial pressure, as was seen in subject 7 who developed both an arachnoid cyst and

Chiari I malformation.

Leuprolide is a synthetic gonadotrophin-releasing hormone analog used for treatment of

central precocious puberty in children, and for sex-steroid deprivation in adults with breast and

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prostate cancer [19]. Peripheral precocious puberty is a common feature of MAS, which may

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progress to central puberty requiring initiation of leuprolide therapy [1]. Similar to the findings

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in our cohort, there are rare reports of leuprolide use associated with increased intracranial
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pressure and papilledema in children and adults [19 20 52 53], however there is no clear

evidence to establish causation. In addition, unlike the associated structural abnormalities

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discussed above, there are no known pathogenic mechanisms that would explain a causative
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relationship between leuprolide use and increased intracranial pressure. The association between

leuprolide and ODE observed in this cohort supports the need for further investigation on this
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topic; however, given the small numbers of affected patients, it does not establish a definitive
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risk. Of note, there was no association between ODE and precocious puberty in this cohort,

suggesting that a causative relationship (if any) is more likely related to leuprolide treatment.

The decision whether to continue leuprolide in a patient with ODE must therefore be

individualized, taking into consideration the severity and progression of the ODE, as well as the

underlying disease being treated.

We speculate that increased intracranial pressure was the underlying mechanism for the

development of ODE in this cohort. Lumbar puncture with measurement of opening pressure is
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required to definitively diagnose increased intracranial pressure [45]; however, this test was

performed in only 1/7 subjects, largely due to the mild nature of ODE in this cohort. We are

therefore unable to say with certainty that ODE in patients with FD represents true papilledema,

although it is likely. Craniomorphometric analyses of optic canal area were performed to

investigate optic canal stenosis as a potential case of ODE, which could impact ocular venous

and/or lymphatic drainage [54 55]. However, no significant differences were detected between

subjects with and without ODE, suggesting this is a less likely cause of ODE in the FD

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population. The lack of association between ODE and GH excess lends further support to this

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concept, because GH excess likely increases the risk of optic neuropathy by driving craniofacial

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FD expansion [56]. Two subjects in this cohort (1 and 4) did not have clear clinical or structural
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etiologies for their ODE; it is therefore likely that subtle craniofacial differences or other

unknown factors contribute to disease development that were not identified in these analyses.
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Strengths of this study include the large number of subjects in this rare disease. This is the
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first study to systematically evaluate ODE in patients with FD/MAS, and these results provide

new insight into the prevalence and risk factors in this population. Limitations include the
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retrospective study design, the heterogeneity of the study population, and limited longitudinal
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data. The ODE cohort was composed of a small number of patients, and larger studies with more

thorough evaluations (including lumbar punctures with opening pressures) are needed to fully

characterize ODE in patients with FD. As a tertiary referral center, the cohort is likely biased

toward a more severe phenotype, and the prevalence of ODE in this cohort may be higher than in

the general FD/MAS population.

5. Conclusion
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ODE is an uncommon but potentially serious complication of craniofacial FD, which occurs

more frequently in pediatric patients with structural craniofacial abnormalities. The potential

association of leuprolide therapy with ODE warrants further study. While ODE may rarely lead

to disabling complications including vision loss, findings from this study suggest that ODE in

patients with FD/MAS is frequently mild and non-progressive. All patients with craniofacial FD

should have routine optic disc evaluation as part of a comprehensive neuro-ophthalmologic

exam. The finding of ODE in a patient with FD/MAS should prompt a thorough clinical

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evaluation, medication history, and imaging, with particular attention to structural abnormalities

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associated with craniofacial FD.

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Funding

This work was supported by the Intramural Research Programs of the National Institute of
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Dental and Craniofacial Research and National Eye Institute, National Institutes of Health. This
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research was made possible through the NIH Medical Research Scholars Program, a public-

private partnership supported jointly by the NIH and contributions to the Foundation for the NIH
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from the Doris Duke Charitable Foundation, Genentech, the American Association for Dental
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Research, the Colgate-Palmolive Company, and other private donors.

Author contributions

Conceptualization; LR, KP, AB, MC, EF, Data curation; LR, KP, Formal analysis; KP, Funding

acquisition: AB, MC, Methodology; LR, EF, KP, AB, MC, Project administration; LR, EF, AB,

MC, Resources; EF, MC, AB, Supervision; KP, MC, AB, EF, Writing original draft; LR, KP;

Writing review & editing; MC, AB, EF

Declaration of competing interest

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NIDCR receives funding from Amgen, Inc for an investigator sponsored study of denosumab in

fibrous dysplasia.

Acknowledgements

REDCap electronic data capture tools and Biomedical Translational Research Informatics

(BTRIS) electronic data system were used for data collection and management

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Figure 1. Craniomorphometric evaluation of the optic canal and intracranial volume using Osirix

imaging analysis software and 3D Multiplanar reconstruction (MPR). (A-C) Optic canal was

aligned perpendicularly to orthogonal MPR planes. (C) The narrowest segment of the optic canal

was outlined using digital calipers to define the region of interest (ROI) and calculate cross-

sectional area. (D-E) Intracranial volume was semi-automatically defined and calculated. (D)

The ROI of intracranial volume was manually defined for several sagittal CT images then semi-

automatically propagated for the remaining slices using Osirix. (E) The intracranial volume was

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generated through 3D reconstruction of ROIs.

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Figure 2. Study population flowchart. FD/MAS = fibrous dysplasia/McCune-Albright syndrome;
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craniofacial FD = craniofacial fibrous dysplasia; NEO = Neuro-ophthalmologic exam.
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Amblyopia (N=1), diabetic retinopathy (N=1), strabismus/exotropia (N=3), macular
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degeneration (N=1), optic neuropathy (N=29), Uveitis (N=2).

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Figure 3. Representative neuro-ophthalmologic exam and radiographic findings in subjects with

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optic disc edema (ODE) and craniofacial fibrous dysplasia (FD). (A&B) ODE visualized on
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fundoscopic exam exemplifying disc elevation, disc margin blurring, and small physiologic cup.

(C) Peripapillary Retinal Nerve Fiber Layer (RNFL) analysis report using Cirrus-HD OCT for a

subject with optic neuropathy (ON) in the right eye (OD) and ODE in the left eye (OS). We used

the average RNFL thickness for our calculations but note that the RNFL is also generated for

each quadrant of the nerve (N, NAS = nasal; T, TEMP = Temporal; S, SUP = Superior; I, INF =

Inferior). For subjects under the age of 18 years old, such as this subject, there is no normative

data stored by the manufacturer to generate an automatic comparison. (D) Computed

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tomography imaging of a subject with ODE. Note the presence of expansile FD lesions (white

asterisk). An arachnoid cyst is visible in the posterior fossa (white arrow) along with an

associated Chiari I malformation, manifesting with downward displacement of the cerebellar

tonsils (dashed line). (E) Magnetic resonance imaging in another subject with ODE reveals

extensive FD involvement (white asterisks), and an aneurysmal bone cyst in the posterior

calvarium (white arrow). This subject has also developed a Chiari I malformation (dashed line),

which is associated with a fluid filled cyst in the upper spinal cord, or syrix (double arrow).

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Author contribution statement

Layne Raborn: Conceptualization, Data curation, Formal analysis, Methodology, Project

administration, Writing original draft

Kristen Pan: Conceptualization, Data curation, Formal analysis, Methodology, Supervision,

Writing original draft

Edmond FitzGibbon: Conceptualization, Methodology, Project administration, Resources,

Supervision, Writing review & editing

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Michael Collins: Conceptualization, Funding acquisition, Methodology, Project administration,

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Resources, Supervision, Writing review & editing

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Alison Boyce: Conceptualization, Data curation, Formal analysis, Methodology, Project
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administration, Resources, Supervision, Writing original draft, Writing review & editing
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Table 1. Subject Characteristics

ODE Subjects Non-ODE Control Subjects p
Characteristic N=7 N=132
1
Age, mean (range) 12 (5-17) 23 (2-80) 0.10
2
Sex (M:F) 5:2 54:78 0.13
2
Extra-cranial FD 6 (85.7%) 116 (87.9%) >1.0
Craniofacial burden score3, mean (range) 4 (2-4) 3 (1-4) 0.071

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Neuro-ophthalmologic exam
Mean Visual Acuity (range) 20/24.7 (20/16-20/63) 20/21.7 (20/12-20/63)

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4 4 1
Mean Ishihara Score (range) 16 (16) 16 (14-16) 0.48
Mean Pelli-Robson Score (range)

Mean RNFL (range)

1.65 (1.65)

131 (96-198)
5.6

6,7
-p 1.68 (1.5-1.95)

98 (75-129)
7
5
0.38
1

<0.00018
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1 2
M=male, F=female, Retinal Nerve Fiber Layer = RNFL. Mann-Whitney test, significance p<0.05. Fisher’s
exact test, significance p<0.05. 3Ranges from 0 (no involvement) to 4 (>50% involvement), according to
previously published methodology (Collins MT et al. An instrument to measure skeletal burden and
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4
predict functional outcome in fibrous dysplasia of bone. J Bone Miner Res. 2005;20(2):219-226). There
were 107 controls who had no diagnosis of color blindness and had an Ishihara score, and 114 total
5 6
subjects. Pelli-Robson Score was available for only 104 controls, 111 total subjects. RNFL or Pelli-
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Robson Scores not included for the ODE subject’s eye with diagnosed optic neuropathy. RNFL was
available for 62 controls and 69 total subjects. 8Unpaired t-test, significance p<0.05.
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Table 2. Characteristics and initial neuro-ophthalmologic examPre-proof
findings in subjects with optic disc edema

Pelli-
Lengt Robso
h of Related Visu Ishihar n Outcome
Age MAS RNF Visual
Subje Ey Diagnos Follo Medications of Imaging 1 al a Contra Therapy over
ct e is
(years
w-up
Endocrinopath
symptom Consideration findings L Acuit
2 Field Color st Initiated follow-up
), sex ies (µm) y 3 4 5
(years s Test Score period
) (log
units)
O
ODE 154 20/16 wnl 16/16 1.65 Persistent
D Headach Acetazolami
1 17M 3 - es - - de
stable
OS ODE 198 20/16 wnl 16/16 1.65 ODE

O
ON Chiari I 67 20/20 onl 16/16 1.05
D Hyperthyroid -
2 15M n/a
> Hypothyroid
7 - Levothyroxine Malformati - n/a
OS ODE on 139 20/20 bl 16/16 1.65

O Leuprolide,
ODE Precocious 124 20/20 onl 16/16 1.65
D Levothyroxine

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puberty,
Tetracyclines,
Hyperthyroid - Headach Intermitte
3 10M 11 7 Fluoroquinolon - -
> Hypothyroid es nt ODE
OS ODE es, 96 20/20 bl 16/16 1.65
Cushing

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Vit A
syndrome
derivatives
O
ODE 118 20/16 bl 16/16 1.65
4
D

OS ODE
11M 1 - - -
-p -
158 20/20 wnl 16/16 1.65
Acetazolami
de
Resolved
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O Chiari I
ODE Precocious
D Malformati 125 20/20 wnl 16/16 1.65 Persistent
puberty,
5 16F 1
Hyperthyroid - - Levothyroxine on, - stable
Aneurysmal 113 20/20 wnl 16/16 1.65 ODE
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OS ODE > Hypothyroid

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Bone Cyst
O
ODE 139 20/20 nr 16/16 1.65 Persistent
D Headach Arachnoid
6 7M 1 Hyperthyroid
es - Cyst
- stable
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OS ODE 132 20/25 nr 16/16 1.65 ODE

O 6 Chiari I
D ODE Precocious Malformati 110 20/63 nr 16/16 1.65
Acetazolami
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7 4F 1 puberty, Leuprolide on, Resolved

6 de
OS ODE Hyperthyroid Arachnoid 101 20/50 nr 16/16 1.65
Cyst
1
OS=left, OD=right, ODE=optic disc edema, ON=optic neuropathy, M=male, F=female, RNFL=retinal nerve fiber layer. Cirrus HD OCT. Published
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pediatric normal ranges are limited but a normal range has been noted for global RNFL thickness between 82.4 µm – 109.23 µm (Pawar). In the
2
general population, ODE has been diagnosed with RNFL thickness of 102 µm – 426 µm (Saenz). Visual Acuity score 20/40 or worse considered
3
abnormal according to Early Treatment Diabetic Retinopathy Study Scale (Lee). Visual field test results: wnl = within normal limits; bl =
borderline normal; onl = outside normal limits according to Humphrey Visual Field/Swedish Interactive Thresholding Algorithm (SITA) 30-2
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computerized testing. nr = not recorded. 4Normal considered ≥ 14 correct plates identified. Normal ranges ≥ 1.50 log units for pediatric
6
population. Optic exam data was collected at the first visit to NIH. ODE was diagnosed at an outside provider prior to this visit and was
7
resolved, demonstrating normal RNFL, on Acetazolamide therapy at time of visit. Subject underwent total thyroidectomy for treatment of
MAS-associated hyperthyroidism, resulting in post-surgical hypothyroidism.
Table 3. Clinical and radiographic associations with optic disc edema
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Optic disc
Controls Odds 2
edema 95% CI p-value
(N=132) Ratio
(N=7)
1
Chiari I Malformation 3 (42.9%) 3 (3.0%) 24.3 4.2—121.4 0.003

Space-occupying 1,ⴕ
3 (42.9%)* 4 (4.0%) 18.0 3.4—108.2 0.006
lesion
Growth hormone
0 24 (18.2%) NE - -
excess
Precocious puberty 3 (42.9%) 70 (53.0%) 0.7 0.2—2.6 0.708

Hypophosphatemia 3 (42.9%) 41 (31.1%) 1.7 0.4—6.4 0.679

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Hyperthyroidism 5 (71.4%) 44 (33.3%) 5.0 1.0—25.6 0.096

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1 (14.3%) 9 (6.8%) 2.3 0.2—18.4 0.414
hypercortisolism
Hypothyroidism

Anemia
2 (28.6%)

0
-p
21 (15.9%)

12 (9.1%)
2.1

NE
0.4—11.1

-
0.327

-
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Obesity 0 23 (17.4%) NE - -
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Obstructive sleep
1 (14.3%) 2 (1.5%) 10.8 0.6—98.9 0.145
apnea
Leuprolide
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2 (28.6%) 2 (1.5%) 26.0 3.3—177.5 0.013

Levothyroxine 3 (42.9%) 21 (15.9) 4.0 0.9—15.4 0.099

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Vitamin A 1 (14.3%) 0 NE - -

Antibiotics
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(Tetracyclines and 1 (14.3%) 0 NE - -

Fluoroquinolones)
1
NE=not evaluable, CI=confidence interval. Radiographic analyses performed in 100 control subjects due
2
to available computed tomography scans within 12 months of neuro-ophthalmologic exam. Fisher’s
*
exact test, significance p<0.05 Aneurysmal bone cyst (n=1) and arachnoid cysts (n=2). ⴕArachnoid cysts
(n=3) and arteriovenous fistula (n=1).
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Highlights

 Optic disc edema is a potentially serious complication of fibrous dysplasia

 Chiari I malformation and aneurysmal bone cysts are risk factors
 Patients with skull fibrous dysplasia should have routine optic disc evaluation

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