Periorbital inflammation associated with craniofacial fibrous dysplasia: report of three cases and review of the literature

Abstract

Fibrous dysplasia (FD) is a mosaic skeletal disorder in which the craniofacial bones are commonly affected. Normal structures are replaced by expansile, highly vascular, fibro-osseous tissue. The typical clinical course is a gradual, asymptomatic expansion of the osseous structures. However, in the periorbital region, even minor structural changes may cause functional impairment, such as diplopia and hyposmia. Furthermore, rapidly evolving secondary lesions, such as fluid-filled cysts, can sometimes develop. In the midface and periorbital regions, such acute change may be associated with severe pain, vision loss, and, signs of inflammation. Here we describe three patients with craniofacial FD who presented with recurrent episodes of periorbital inflammation mimicking orbital cellulitis. All presented with pain, edema, erythema, and warmth, with varying degrees of functional impairment. On imaging, all had cystic changes in the FD lesion, including two with aneurysmal bone cysts (ABCs). Two were initially diagnosed with periorbital cellulitis and treated with antibiotics; in two, the radiographic findings were misdiagnosed as osteomyelitis. Recurrent episodes were recognized as not infectious and effectively managed with corticosteroids. Given the vascular nature of FD and the association of ABCs, it is likely the findings in these patients represent inflammation associated with vascular leak in the relatively confined space of the tissues overlying the periorbital bones. Recognition of this entity can lead to more rapid and appropriate treatment.

INTRODUCTION

Fibrous dysplasia (FD) is a rare, mosaic skeletal disorder characterized by replacement of normal bone by expansile, fibro-osseous lesions. It arises from post-zygotic, activating mutations in GNAS, which encodes the stimulatory G-protein α-subunit (G_sα). In cells of the skeletal lineage, constitutive G_sα activity impairs differentiation and results in fibroblast-like cells that make immature woven bone within a highly vascular stroma. FD may occur in isolation or in combination with skin hyperpigmentation (formerly called café-au-lait spots) and hyperfunctioning endocrinopathies, termed McCune-Albright syndrome (MAS) [1–4].

Clinically, the mosaic nature of FD is reflected in its variable presentation, both in terms of location and severity that commonly involves the craniofacial bones [5]. Typically, FD lesions follow a predictable clinical course characterized by slow, painless expansion during childhood and adolescence. However, in the craniofacial region this structural change may be associated with significant morbidity in pronounced cases. In some patients, even gradual expansion may result in facial asymmetry, foramina narrowing, and cranial settling leading to functional impairments such as malocclusion, diplopia, chronic headaches, and others [5–7]. In rare cases, craniofacial FD may present with atypical signs and symptoms, such as severe pain, aggressive bony expansion, and rapid functional decline, which may suggest malignant transformation or development of secondary lesions, such as an aneurysmal bone cysts (ABCs). [8–10].

Another atypical presentation of FD is acute inflammation, characterized by five cardinal signs: erythema, warmth, edema, pain, and loss of function. In the craniofacial region, few cases of local inflammation have been reported; specifically, orbital inflammation has been described, arising secondary to FD obstruction of the paranasal sinuses, mucocele formation, and infection [9, 11–14]. Although infection is the most common cause of orbital inflammation in general, non-infectious etiologies are important to recognize to initiate appropriate treatment. Here, we describe three patients with craniofacial FD, two children and one adult woman, who presented with recurrent periorbital inflammation that mimicked infectious preseptal cellulitis. In these individuals with FD lesions involving the orbital bones, the pathogenesis of acute inflammation was associated with hemorrhagic-cystic changes, including ABC formation. The purpose of this article is to describe orbital inflammation as a presentation of craniofacial FD, review the varied causes, and discuss management strategies.

METHODS

Patients 1 and 3 were evaluated at the National Institutes of Health (NIH), Bethesda, Maryland, USA as a part of a natural history study of FD which started in 1999 and is ongoing. Patient 2 was evaluated by the pediatric department at Bnai Zion Medical Center in Haifa, Israel and provided verbal consent and assent to participate in this series. The natural history study was approved by the National Institute of Dental and Craniofacial Research Institutional Review Board. Patients 1 and 3 and or parents gave their written consent/assent to participate in the study. Clinical information and data were obtained from their evaluations at NIH as well as from outside hospitals and direct patient testimonials. Patient 1 is now 22 years old and has been followed for 15 years. Patient 3 is now 34 years old and has been followed for 3 years.

PATIENT 1

Patient 1 presented to his local primary care provider at 8 years of age with the chief complaint of pain and swelling above his right eye that had worsened over several days. Prior to onset, he experienced mild upper respiratory symptoms, including congestion and rhinorrhea. The patient denied recent head trauma. Physical exam was notable for significant periorbital soft tissue edema, erythema, and warmth without changes in vision. A CT scan of the head was obtained that demonstrated ground glass, osseous lesions of the anterior cranial base and facial bones, as well as findings suggestive of osteomyelitis. The patient was afebrile without leukocytosis but presented with an elevated erythrocyte sedimentation rate (ESR) of 47 mm/hr; he was admitted to the hospital and started on intravenous (IV) antibiotics. After 24 hours of antibiotic therapy, symptoms improved, and he was discharged on oral antibiotics. Due to concern for an underlying bone disorder, the patient was referred to a tertiary care center where he was diagnosed with fibrous dysplasia/McCune-Albright Syndrome (MAS) based on the finding of polyostotic FD involving the craniofacial and axial skeleton, mild growth hormone excess, and mild hyperprolactinemia. His craniofacial FD involved the right frontal bone, squamous portion of the right temporal bone, central mandible and superior alveolar ridge, as well as bilateral sphenoid, zygomatic and pterygoid bones. In addition, nearly all the paranasal sinuses were involved; near complete obliteration of the right frontal, right maxillary, and bilateral sphenoid sinuses were described, as well as partial obliteration of the ethmoid air cells.

Approximately one year later, the patient experienced a second, more severe, episode of periorbital inflammation with erythema and soft tissue swelling extending beyond the immediate periorbital region, involving the forehead (Fig 1; Table 2, episode A). He lacked additional local or systemic signs of infection such as fever, leukocytosis, purulent drainage, or an elevated erythrocyte sedimentation rate. CT scan of the head showed numerous lucencies within the right frontal bone, which were well corticated and serpiginous in configuration, as well as a sequestrum of high-density bone measuring 2.5 cm surrounded by a 2–3 mm margin of lucency, which appeared to communicate to the cortical bone of the right supraorbital ridge. There was evidence of increased vascularity within the bone without an overt vascular structure (Fig 2, Fig 4A).

Figure 1.

Photograph of patient 1 during an episode of periorbital inflammation, demonstrating erythema, swelling, and proptosis.

Table 2.

Selected episodes of orbital inflammation

Pt no.	Episode	History & Physical	Imaging during flare?	Presence of ABC, and/or lacrimal gland enlargement?	Laboratory values	Management	Admitted?
1	A	9y4m: pain, erythema, swelling over R forehead and R periorbital region. No fever. Pt’s worst episode and lasted 4–5 days.	CT Head	Unknown	WBC normal ESR (46 mm/hr)	IV antibiotics, opioid pain management	No
	B	11y4m: month-long episode that started with R forehead pain and swelling.	CT Head, MRI Brain	No ABC, enlarged but stabilized R lacrimal gland	WBC, CRP at beginning of episode were normal	Failed oral antibiotics before use of oral corticosteroids	No
	C	15y: last flare; pain woke Pt from sleep, erythema, swelling over R forehead/periorbital region. No allergy symptoms.	No	Unknown	No	Oral corticosteroids (prednisone 10 mg)	No
2	D	10y8m: presented with erythema, pain, swelling over R eye and forehead. Diagnosed with periorbital cellulitis and osteomyelitis of frontal bone.	MRI Brain	ABC of R frontal bone seen on imaging. No biopsy pursued. Edema and fluid of R frontal bone, with obliteration of the R frontal sinus, the process continuing to the dura mater in some regions.	WBC elevated (14,000/mm3) CRP elevated (21 mg/dL) Debrided discharge (-) for bacteria on culture/PCR	Debridement, 6 weeks of IV antibiotics (metronidazole and ceftriaxone)	Yes
	E	13y11m: pain and swelling of R eyelid, no fever, post trauma history.	CT Head, MRI Brain	ABC of right orbit secondary to FD, which was confirmed with biopsy.	WBC elevated (16,000/mm3) with 79% neutrophils CRP within normal limits	IV followed by oral corticosteroids, (high-dose solumedrol, prednisone) IV antibiotics (cefuroxime)	Yes
3	F	34y: brow pain, swelling, left temporofrontal headache lasting 4–5 days.	MRI Brain	left orbitofrontal bone expansion obliterating the frontal sinus, and signal abnormality with enhancement consistent with FD history. left lacrimal gland enlarged compared to MRI from 5 years prior.	WBC, ESR, CRP all within normal limits	Acetaminophen, NSAIDs	No

Pt = patient; no. = number; ABC = aneurysmal bone cyst; WBC = white blood count; IV = intravenous; ABC = aneurysmal bone cyst; CRP = C-reactive protein; ESR = erythrocyte sedimentation rate; NSAIDs = non-steroidal anti-inflammatory drugs

Figure 2.

Head CT of patient 1 during episode A in the (A) coronal, (B) axial, and (C) sagittal views with arrows highlighting well-corticated, serpiginous-like lucencies within the FD of the frontal bone, suggestive of increased vascularity without an overt vascular structure.

Figure 4.

T2-weighted axial MRI during episodes. White arrows highlight fluid enhancement and cystic changes in affected bone of (A) patient 1, episode B. Red triangles emphasize the fluid-fluid lines of ABCs in (B) patient 2, episode. White arrows highlight cystic change in (C) patient 3, episode F.

Combined with the significant edema in overlying bone, which was appreciated clinically and radiographically, these findings were interpreted as evidence of preseptal cellulitis (inflammation/infection of tissues anterior to the orbital septum, a fibrous extension of the frontal bone periosteum) and possible osteomyelitis of the frontal bone, for which he was treated with a 10-day course of IV antibiotics.

Over the following two years, he experienced multiple similar episodes of focal tenderness, localized soft-tissue edema, and erythema over the right periorbital region. These episodes were less severe and self-limiting, managed only with nonsteroidal anti-inflammatory drugs (NSAIDs); no biopsies nor aspirations were performed. care. His FD had significantly expanded during this period, resulting in facial asymmetry and proptosis of the right eye. Serial imaging during these flares and every 6 months throughout this two-year period documented a marked evolution in the lytic/sclerotic matrix of the right frontal bone and periorbital region with enhancement and evidence of increased vascularity (Fig 3).

Figure 3.

Serial imaging of patient 1 before and after episodes, with arrows demonstrating cystic change in FD following episodes: (A) 10 days prior to episode A, (B) 9 months post-episode A, (C) 1 month prior to episode B, and (D) 10 months post-episode B.

His fifth documented episode at age 11 had persisting symptoms over the course of one month (Table 2, episode B). He was empirically given oral antibiotics; however worsening symptoms prompted use of broad-spectrum IV antibiotics. Nearly a month later, the symptoms failed to resolve. Follow-up MRI continued to show fluid enhancement within the affected bone. Therefore, a trial of oral prednisone 10 mg was recommended, after which symptoms resolved after three days of this regimen. Since the initial use of corticosteroids, recurrent episodes have been successfully managed with short courses of prednisone (Table 2, episode C). These episodes typically start with pain and progress to erythema and swelling, occurring 1–2 times a year. There have not been any identifiable triggers, although it was initially thought to be related to seasonal allergies, as mild upper respiratory symptoms (rhinorrhea, congestion) tended to precede these episodes. The patient underwent allergen testing and is presently on allergen immunotherapy. The patient is now 22 years old. From his FD diagnosis at age 8 to his last episode to date at age 15, patient 1 had 11 documented episodes of orbital inflammation, of which, the last 7 were successfully managed at home with corticosteroids.

PATIENT 2

Patient 2 presented at 10 years of age with pain and swelling of the right eyelid without fever. His parents recalled that he collided with another child, sustaining a hard blow to the right frontal bone 3 months previously but appeared to recover. He was diagnosed with FD clinically at age six years when he was noted to have subtle proptosis of the right eye and on CT imaging found to have FD in the bilateral frontal bones, right sphenoid and lower mandible. At that time, there was radiographic evidence of narrowing of the optic canals bilaterally without clinical evidence of compression of the optic nerves on ophthalmologic evaluation. An endocrine evaluation was negative, but he was found to have an area of hyperpigmentation on his right neck measuring 2–3 cm with irregular borders. Based on the skin findings and the FD, a diagnosis of McCune-Albright syndrome was established. Since diagnosis, his FD was relatively radiographically stable until the episode described below.

During this acute phase of orbital inflammation, the patient was afebrile but with leukocytosis (14,000 WBC/mm³) and an elevated CRP of 21 mg/dL. CT and MRI imaging identified enhancement in the right frontal bone with well-septated loculations and visible fluid-fluid lines, dural enhancement, and obliteration of the right frontal sinus. This was interpreted as osteomyelitis with a large subperiosteal abscess. Due to involvement of dura, debridement was performed through the right supraorbital ridge. The discharge was tested for bacteria and returned negative on both culture and polymerase-chain reaction (PCR). Despite the negative work-up for infection, he was diagnosed with periorbital cellulitis and osteomyelitis of the frontal bone. After a 10-day hospitalization, the patient 2 completed six weeks of intravenous antibiotics (ceftriaxone and metronidazole) with clinical improvement and normalizing WBC count and CRP. This was the first episode of what was labeled as “orbital cellulitis” and summarized in Table 2, episode D.

At age 12, two years and three months after the first episode, patient 2 presented with pain and swelling of the conjunctiva and eyelids. CT of the skull showed progression of underlying FD, and a large hypodense lesion measuring 30 × 31 × 50 mm consisting of numerous small adjacent cysts with obvious fluid-fluid lines in the right frontal bone (Fig 4B). There were two posterior-medial loculations protruding on the orbital space, destroying the upper cortex of the orbital bone, as well as radiographic evidence of pressure on the optic nerve and the optic muscles. His CT and MRI imaging were interpreted as an ABC of the orbit secondary to FD, which was confirmed with biopsy (Fig 4B).

Again, there was marked leukocytosis (16,000 WBC/mm³) however, CRP was within normal limits. Apart from the biopsy, the patient did not undergo any additional surgical procedures. Medically, he was managed with high-dose solumedrol followed by prednisone and cefuroxime. Within a few days, the orbital pain and edema improved, and laboratory markers returned to baseline. After 9 days in the hospital, he was discharged solely with prednisone with recommendations for a slow taper (Table 2, episode E)

An MRI of the head performed 1 year after the ABC episode confirmed resolution of fluid-fluid lesions that were replaced by homogeneous content with slight expansion of FD in the frontal bone. As of this writing, his FD is slowly progressing; the most recent MRI obtained 3 years after the ABC diagnosis documented about 5 mm of FD progression in each direction compared to imaging six months prior. The patient has not experienced additional episodes of orbital inflammation since.

CASE 3

Patient 3 is a 32-year old woman with craniofacial FD who presented with pain and swelling of the left brow bone and periorbital region. Since the age of 24, she had experienced recurrent episodes of left brow pain with swelling and occasional light sensitivity without visual changes. The presentations varied; no consistent identifiable triggers were identified. These episodes occasionally overlapped with the beginning or end of her menstrual cycle; other times the pain followed a mild respiratory illness or allergy symptoms. Dependent positional changes have also triggered episodes. Episodes typically lasted 10–14 days, occurred 1–2 times a year, and were managed with acetaminophen or NSAIDs at home; she was never hospitalized for periorbital inflammation.

FD was diagnosed clinically at the age of 12, after an MRI was obtained as part of an evaluation for headaches. The lesion was monitored for several years without any changes. At age 24, she experienced left frontal headache with light sensitivity for 3–4 weeks. There was no change in overall size nor contour of FD in the left frontal region. Imaging found an aneurysmal bone cyst at the posterior aspect of the FD lesion, that perforated the inner table and impinged on the dura. A biopsy was performed, and pathology returned with benign cystic degeneration without evidence of malignancy. She underwent craniectomy of the ABC with reconstruction. Since then, she has had recurrent episodes of orbito-frontal pain and swelling of the periorbital region that resolves with over-the-counter anti-inflammatory medications.

During an episode at age 32, an MRI demonstrated left orbitofrontal bone expansion that obliterated the left frontal sinus, consistent with a history of FD. Enhancement indicating increased vascularity, cystic change, and a subtle fluid-fluid level suggesting a resolving ABC (Fig 4C; Table 2, episode F). There was no significant change seen from an MRI 5 years prior. Given the normal WBC count, ESR, and CRP, the pain and swelling was ultimately assessed to be an acute FD-related inflammation rather than an infectious process and she was managed conservatively with surveillance, and over the counter NSAIDs, and acetaminophen, after which her symptoms resolved.

DISCUSSION

This series describes three patients with craniofacial FD, all of whom experienced recurrent episodes of orbital inflammation. All three had FD in the frontal bone. In two patients, the initial episodes were misdiagnosed as osteomyelitis and infectious orbital cellulitis, resulting in hospitalization and use of intravenous antibiotics. All patients were found to have varying degrees of cystic change, including evidence of ABCs in two. Patient 2’s initial “cellulitis” episode was likely an ABC, however, given the inflammatory markers, a diagnosis of osteomyelitis with subperiosteal abscess was favored. The cystic change and ABC seen in Patient 1 and 2 were managed conservatively with corticosteroids and resolved symptoms. This discussion aims to explore FD as a noninfectious cause of orbital inflammation, describe underlying pathophysiological drivers of inflammation and discuss management strategies in symptomatic craniofacial FD involving the orbital bones.

ORBITAL INFLAMMATION IN THE SETTING OF FD

The term “orbital inflammation” is used in this series to describe inflammation occurring in the orbit, orbital cone, or immediately adjacent to the orbital cone. The causes of orbital inflammation can be broadly classified into infectious and non-infectious etiologies. Infectious orbital inflammation is the more common of the two in the general population and can be further subdivided into “preseptal” (or “periorbital”) and “postseptal” (or “orbital”) cellulitis, using the orbital septum as an anatomical landmark. The orbital septum is a fibrous membrane that extends from the periosteum of the orbital rim and defines the anterior boundary of the orbit. The most common cause of infectious postseptal cellulitis is contiguous spread of infection from the paranasal sinuses, particularly the ethmoid sinus. However, postseptal cellulitis may arise from preseptal cellulitis, with inciting causes such as recent surgery, trauma, dacryoadenitis, periodontal disease, and systemic infection [15]. The differential diagnosis of non-infectious causes of orbital inflammation are broad and include systemic inflammatory/autoimmune disease, neoplastic causes, and vascular malformations [15].

This paradigm translates well in classifying causes of orbital inflammation in the setting of FD. Although all three patients of the present series were considered to have non-infectious causes of orbital cellulitis, infectious causes should be considered in the differential diagnosis. Given the bony disfigurement in FD and the delicate spaces of the craniofacial skeleton, infectious causes of orbital inflammation in FD may be due to structural changes that predispose towards infection, such as an subperiosteal orbital abscess due to FD blocking the middle nasal meatus, a drainage point for the ethmoid sinus. [16]. Although rare, osteomyelitis can be a complication of sinus disease, known as Pott’s Puffy tumor, and may present with signs of orbital inflammation necessitating urgent treatment to avoid intracranial sequelae [17]. However, establishing a definitive osteomyelitis diagnosis in the setting of FD can be difficult as reactive osteomyelitis shares a similar presentation, imaging, and to some extent even a similar histological appearance to that of FD, and vice versa [13–16]. Some subtypes of osteomyelitis (diffuse sclerosing type) have a striking resemblance to FD even on histology [14] and radiographs alone are not able to reliably distinguish between osteomyelitis and FD [16]. As cultures are often negative, an accurate and timely diagnosis is challenging, as evidenced by our two FD patients whose episodes of non-infectious orbital inflammation were misdiagnosed and managed as osteomyelitis. Although CT scans are paramount in the diagnosis of infectious periorbital cellulitis, they are inadequate in evaluating FD patients with similar symptoms, demonstrating the need for physician awareness of this uncommon FD presentation.

Noninfectious causes of orbital inflammation in FD include structural changes, such as an invading frontal sinus mucocele [11, 12], lacrimal gland compression leading to dacroadenitis [13], and cystic change [9]. Inflammation, although understood to be an inherent pathophysiologic component of FD, has not been well described beyond anecdotal evidence of occasional erythema, pain, and swelling appreciated over sites of FD lesion. It is likely that the inflammatory nature of FD is particularly evident when occurring in the craniofacial skeleton since specifics of craniofacial anatomy— layers of thick connective tissue separating vital structures in delicate spaces— are generally not present in other locations.

Interleukin-6 (IL-6), a known mediator of inflammation, has been shown to be elevated in FD. In cultures of FD cells isolated from osteoclast-rich areas, increased intracellular cAMP was associated with increased IL-6 production; inhibition of cAMP with Rp-8 Br-cAMPxYZ, a PKA inhibitor significantly decreased IL-6 production, suggesting IL-6 is a downstream effector of elevated intracellular cAMP [18]. Riminucci and colleagues were able to further directly demonstrate increased IL-6 signaling in FD bone marrow stromal cells of osteoblastic lineage, promoting osteoclastogenesis [19]. Clinically, the soluble IL-6 inhibitor tocilizumab has been used to treat a 35-year-old FD patient, with subsequent improvements in bone turnover markers, imaging, scintigraphy, and pain [20]. Tocilizumab is approved for the treatment of rheumatoid arthritis and accompanied with a decrease in previously elevated bone-turnover markers [21]. These observations suggest the potential role of tocilizumab in mitigating bone turnover. In the present series, the improvement after steroid use in patients 1 and 2 emphasizes the critical role of inflammation in FD; we hypothesize that this intrinsic inflammatory nature of FD in the frontal bone may have promoted cystic change and could be responsible for the acute and recurrent orbital inflammation observed.

CYSTIC CHANGE & ANEURYSMAL BONE CYSTS IN FD

Patient 1 had marked recurrence of symptoms and clearly evolving FD captured on head imaging. Although he did not undergo biopsy of his craniofacial FD, cystic change and increased vascularity is readily observed on CT of the head (Fig 2; Fig 3B & 3D). The cystic change described here is a radiographic finding and known to occur in FD. As FD lesions mature, the classic radiographic “ground-glass” appearance gives way to a heterogenous ill-defined appearance, termed “cystic change” or “cystic degeneration”. Typically, this transformation occurs well after puberty and over the course of years [22]. This change seen in patient 1 is unusual considering his young age (9-years-old) and the short time interval in which it occurred (2 years). It is important to note that what is typically considered “cystic” radiographically is not a fluid-filled cyst. Hounsfield density measurement of these lesions indicates they are composed of soft tissue, not fluid, and clinically they develop over months-years.

Acute cystic change usually presents with pain, erythema, inflammation overlying the FD region, and/or rapidly enlarging mass as reported by others and seen in the present cases [9, 23, 24]. Diah and colleagues examined the histology tissue from nine patients with CFD and cystic change seen on imaging; the clinical presentation of frontal bone pain, periorbital swelling, and erythema of the selected cases were similar to that of our patients; the 12-year-old from Diah et al had a similar presentation to patients 1 and 2 described in this series and the 22-year-old woman from Diah et al had a similar presentation to patient 3 in this series.

PATHOGENESIS OF CYSTIC CHANGE & ABCs

Jaffe’s first report of FD included descriptions of cystic degeneration as a secondary feature. Microscopically, focal degeneration with hemorrhage in the FD led to the formation of secondary cysts with multinuclear giant cells and occasional foam cells [25]. Radiographically, cystic lesions have a radiolucent, multi-loculated appearance. While 11–31% of FD lesions are classified as “cystic-type” lesions (21%), only Martinez et al histologically evaluated the lesions and determined true fluid-filled cysts [26–28]. The pathogenesis of simple bone cysts is not yet proven; however, there is a growing acceptance that simple and aneurysmal bone cysts are distinct histologic expressions of a related process [29]. It is proposed that cystic lesions arise from an intraosseous vascular disruption (e.g. AVM), resulting in intramedullary hemorrhage. Complete venous obstruction of blood supply may lead to simple bone cyst formation, while a direct circulatory connection with the hematoma leads to ABC formation [30]. Previous histological studies on nonspecific cystic degeneration in FD described said entities as non-epithelialized blood-filled cavities in bone lined by fibrous tissue [9, 31, 32]. Although patient 1 and patient 3 did not have biopsies performed, the enhanced contrast and the vascular recruitment within the cystic lesions support the theory of vascular disruption contributing to cystic change and ABC formation.

CHARCATERISTICS of ABCs

At the end of this spectrum, two of our FD patients experienced an ABC, with patient 2 experiencing two distinct episodes of an ABC. ABC are benign, lytic, and hemorrhagic bone lesions that are diagnosed radiographically by their characteristic multiloculated “soap-bubble” appearance and the presence of fluid-fluid lines. The natural history of an ABC has four radiologic stages: initial, active, stabilization, and healing. The initial phase has a well-defined area of osteolysis with discrete elevation in the periosteum. The active phase is a period of rapid growth of the lesion with aggressive destruction of bone; this the characteristic “blown-out” appearance seen radiographically. After rapid growth, stabilization occurs with maturation of the bony shell. It is during this period that an ABC is classically recognized for its “soap-bubble” appearance (as seen in patient 2, Fig 4B). Resolution of the ABC finally occurs with progressive calcification and ossification, transforming the lesion into a bony mass [33, 34]. Whether or not this clearly defined natural history applies to FD or not, is not clear.

Although uncommon, ABCs in the setting of FD are a well-established entity [5, 36] with a prevalence of up to 5% in craniofacial FD [38]. Additionally, FD lesions are known to be hypervascular, with changes observed at a systemic and microscopic level. McIntosh and colleagues evaluated cardiac parameters in 6 FD patients and found that a majority of patients had an elevated resting cardiac index (5/6), cardiomegaly (3/6), and a narrow arteriovenous (AV) oxygen gradient with sampling, suggest that FD lesions contain functional AV fistulas and are capable of increasing regional blood flow [39]. These hypervascular changes are seen on microscopic evaluation of FD lesions, where Ippolito and colleagues found a high frequency of hemorrhagic changes in FD lesions. Histopathological exam of FD lesions demonstrated dilated and engorged vascular channels with foci of interstitial and peritrabecular hemorrhage reflect observations of the hemorrhagic tendencies of FD tissue [40]. Increased vascularity is clinically evidenced in extreme cases by the presence of AV fistulas [41, 42] and AVMs in the setting of FD [43, 44]. Given the unusually rich vascularity of FD and pathophysiology of ABCs, ABCs are an unsurprising sequela likely due to the arteriovenous shunting in FD lesions [37, 45]

MANAGEMENT

All three of our patients were eventually managed conservatively. Patient 1 received short courses of oral corticosteroids to resolves symptoms and prevented hospitalizations. Patient 2 was treated with corticosteroids and antibiotics with resolution seen on imaging, thus avoiding extensive surgery in a delicate region. Patient 3 had symptoms that subsided with NSAIDs after an evaluation did not reveal an acute infectious process.

Symptomatic improvements and diminishing recurrence in patients 2 and 3 may be due to the natural progression and healing of ABCs independent of corticosteroids as outlined by Dabska and Kransdorf [33, 34]. Additionally, the resolution in patient 2 after both ABC events may be due to a “curopsy” effect, a phenomenon whereby biopsied ABCs appear to resolve spontaneously after a biopsy procedure with low rates of recurrence [46]. It has been observed that ABCs tend to heal spontaneously after a biopsy or a fracture, and Marcove et al hypothesized that arresting the hemodynamic disturbances responsible for ABC formation induces healing and prevents recurrence [47]. Lastly, improvement of symptoms in Patient 1 and 2 may also be attributed directly to steroid action mitigating inflammation in FD tissue.

Definitive treatment for ABCs in FD is excision, as patients heal with low rates of recurrence [38]. Although intralesional corticosteroids have been used to treat ABCs outside of FD [48–50], perhaps ours is the first report of successful ABC management in FD with intravenous and oral corticosteroids.

None of our patients experienced visual changes with recurrent flares of orbital inflammation and none required surgery. However, cystic change in FD is unstable and aggressive change has been reported to cause acute blindness. A review of vision loss in FD point towards cystic change, ABCs, and hemorrhagic FD as most common causes for acute blindness [8]. In a separate study of optic nerve decompression in FD patients, seven patients experienced visual changes with two patients having acute visual changes complicated by cystic change and an aneurysmal bone cyst [51]. The presence of cystic change with FD in an orbital bone is concerning for acute blindness, warrants a low threshold for suspicion by providers, and may require surgical intervention in unstable cases. Although official guidelines are yet to be established, the patient may benefit from close imaging follow-up and referral to a rare bone disease specialist.

In general, when a patient with known FD presents with periorbital inflammation, as described in these three patients, we recommend that clinical assessment include an effort to exclude infection (temperature, white blood cell count with differential, and non-contrast CT). If infection is not likely and findings are consistent with cystic FD changes, we recommend treatment with non-steroidal anti-inflammatory medications, or a glucocorticoid, as indicated consistent with symptoms. Additionally, during acute episodes, avoidance of aspirin and other anticoagulation may be best, as these have the potential to exacerbate vascular leak.

Limitations of this case series are inherent to the retrospective studies and the study of a rare bone disease with extensive phenotypic heterogeneity. The lack of histopathological evaluation in our patients prevents definitive diagnosis of cystic change (patient 1) and ABC (patient 3).

Nevertheless, this series contributes to the literature in describing periorbital changes that may strongly resemble cellulitis and/or osteomyelitis as a complication or even initial presentation of FD. Given the vascular nature of FD, the association of ABC-like lesions, it is likely the findings in these patients represent inflammation associated with vascular leak in the relatively confined space of the tissues overlying the periorbital bones. Recognizing this entity leads to a more rapid and appropriate treatment. Notably, the clinical improvement, prevention of hospitalization, and an alternative to surgery present corticosteroids as a possible option for FD patients with similar symptoms. Further studies are warranted to study the vascular and inflammatory changes seen in FD.

Table 1.

Patients, demographics, & background

Patient Number	Demographics	Type of FD	Craniofacial involvement	McCune-Albright syndrome?	Complications	Number of documented episodes
1	22-year-old Caucasian man	Craniofacial, ribs	Right frontal bone and temporal bone, bilateral sphenoid bones, ethmoid bones, zygomas, maxilla, and pterygoid bones Obliteration of nearly all paranasal sinuses	Yes; growth hormone excess, hyperprolactinemia, bilateral testicular microlithiasis, hyperpigmented (café-au-lait) macules	Recurrent episodes of right forehead pain, occasionally with orbital inflammation Mild right-sided conductive hearing loss, right frontal lobe mass effect, transient Horner’s syndrome right eye	11
2	16-year-old Caucasian young man	Craniofacial only	Bilateral frontal bones, occipital bones, sphenoid bones, and mandible Bilateral obliteration of frontal, sphenoid, ethmoid sinuses, middle nasal conchae and nasal cavity	Yes; hyperpigmented macule	2 episodes of orbital inflammation, both with presence of aneurysmal bone cysts (ABCs)	2
3	34-year-old Caucasian woman	Craniofacial only	Left frontal bone with obliteration of the left frontal sinus	No	Aneurysmal bone cyst in left frontal bone, requiring craniectomy and mesh cranioplasty at the age of 24	2

Highlights.

• Recurrent periorbital inflammation is an atypical presentation of craniofacial fibrous dysplasia

• Periorbital inflammation likely arises due to vascular changes induced by dysplastic FD cells, promoting cystic change and potential ABC formation.

• Use of corticosteroids has been shown to mitigate and resolve episodes of non-infectious periorbital inflammation in the setting of FD

• When a patient with known FD presents with periorbital inflammation, it is recommended that clinical assessment clinical assessment include an effort to exclude infection; if infection is not likely and findings are consistent with cystic FD changes, non-steroidal anti-inflammatory medications and/ or a glucocorticoid may be of benefit