Craniofacial Fibrous Dysplasia
Michael Groves, M.D.
July 10, 2008
Disclaimer: The information contained within the Grand Rounds Archive is intended for use by physicians and other health care professionals. These documents were prepared by resident physicians for presentation and discussion at a conference held at Baylor College of Medicine in Houston, Texas. No warranties, either express or implied, are made with respect to accuracy, completeness or timeliness of this material. This material does not necessarily reflect the current or past opinions of the faculty of Baylor College of Medicine and should not be used as a basis for diagnosis or treatment, and is not a substitute for professional consultation and/or peer-reviewed medical literature.
Fibrous dysplasia is a non-neoplastic, non-familial developmental abnormality of bone-forming mesenchyme causing progressive replacement of normal bone with a fibrous stroma containing randomly distributed osseous elements. It is a member of a family of benign fibro-osseous pathologies including dysplastic/reactive lesions such as osseous dysplasia (nonhereditary and hereditary); fibro-osseous neoplasms such as ossifying fibroma; and developmental/hamartomatous lesions such as fibrous dysplasia, which has many subtypes. The differential diagnosis includes Paget’s disease of bone, hyperostotic meningiomas, ossifying fibroma, giant cell tumor, aneurysmal bone cyst, fibrosarcoma and malignant fibrohistiocytosis. The subtypes of fibrous dysplasia include monostotic, polyostotic, McCune–Albright Syndrome, craniofacial and cherubism. The monostotic form represents 70-85% of cases and occurs almost equally in males and females. Most monostotic lesions involve the femur, tibia, ribs or skull. The polyostotic form represents 15-30% of cases and has a greater female predilection. About 50% of cases of polyostotic fibrous dysplasia involve bones in the head and neck. In 1937, Albright described a syndrome consisting of multiple bony lesions, café au lait spots, endocrine dysfunction and precocious puberty. It is seen predominantly in females and it is quite rare in males. This has now become known as McCune-Albright syndrome and is responsible for about 3% of cases of fibrous dysplasia. Craniofacial lesions most commonly arise in the maxilla, followed by the mandible, but the ethmoid, lacrimal, and temporal bones may also be involved. There is also a familial form of dysplasia of the mandible and the maxilla, which is called cherubism. This name comes from the chubby cheeked appearance of young children with this disease. This was thought to resemble the winged, angelic baby figures often seen in Renaissance art and referred to as cherubs in common parlance. This is a misnomer however, because cherubs are actually fierce four-winged “adult” angels of a high angelic order, and the flying babies are actually called Putti.
Fibrous dysplasia is a non-neoplastic, non-familial developmental abnormality of bone-forming mesenchyme causing progressive replacement of normal bone with a fibrous stroma containing randomly distributed osseous elements. It is a member of a family of benign fibro-osseous pathologies including dysplastic/reactive lesions such as osseous dysplasia (nonhereditary and hereditary); fibro-osseous neoplasms such as ossifying fibroma; and developmental/hamartomatous lesions such as fibrous dysplasia, which has many subtypes. The differential diagnosis includes Paget’s disease of bone, hyperostotic meningiomas, ossifying fibroma, giant cell tumor, aneurysmal bone cyst, fibrosarcoma and malignant fibrohistiocytosis.
The subtypes of fibrous dysplasia include monostotic, polyostotic, McCune–Albright Syndrome, craniofacial and cherubism. The monostotic form represents 70-85% of cases and occurs almost equally in males and females. Most monostotic lesions involve the femur, tibia, ribs or skull. The polyostotic form represents 15-30% of cases and has a greater female predilection. About 50% of cases of polyostotic fibrous dysplasia involve bones in the head and neck. In 1937, Albright described a syndrome consisting of multiple bony lesions, café au lait spots, endocrine dysfunction and precocious puberty. It is seen predominantly in females and it is quite rare in males. This has now become known as McCune-Albright syndrome and is responsible for about 3% of cases of fibrous dysplasia. Craniofacial lesions most commonly arise in the maxilla, followed by the mandible, but the ethmoid, lacrimal, and temporal bones may also be involved. There is also a familial form of dysplasia of the mandible and the maxilla, which is called cherubism. This name comes from the chubby cheeked appearance of young children with this disease. This was thought to resemble the winged, angelic baby figures often seen in Renaissance art and referred to as cherubs in common parlance. This is a misnomer however, because cherubs are actually fierce four-winged “adult” angels of a high angelic order, and the flying babies are actually called Putti.
To understand the pathogenesis of fibrous dysplasia, it helps to know a little bit about normal bone formation. There are two types of osteogenesis--endochondral and intramembranous. The long bones form via endochondral osteogenesis. This begins with a cartilage anlage, around which a bony collar forms. Next vessels penetrate into center of the bone and there is resorption of the central cartilage and formation of the marrow space. Finally, the bones begin a longitudinal growth phase. On the other hand, the flat bones of the face and skull form via intramembranous osteogenesis. This process begins with condensation of mesenchymal cells within a fibrous stroma and differentiation into osteoblasts. These cells then lay down an immature extracellular matrix, which mineralizes to form early bony trabeculae. These trabeculae then expand and are remodeled to form mature bone.
It is posited that in fibrous dysplasia there is a post-zygotic activating mutation in GNAS1, a membrane-bound G-protein coupled receptor. This produces a constitutively active Gs alpha subunit and intracellular overproduction of c-AMP. This in turn leads to abnormal osteoblast differentiation. These altered osteoblasts produce abnormal bone, unable to properly mature. There is also an increase in IL-6-induced osteoclastic bone resorption. Therefore, the lesion expands as more and more abnormal bone is produced in areas of active bone resorption. On histology, there are irregular-shaped woven-bone trabeculae residing in a fibrous stroma with minimal to no osteoblastic rimming. On radiology, there are three classic appearances described in the literature. One is the sclerotic appearance which is homogenously dense and blends imperceptibly with surrounding normal bone. The osteolytic/ cystic lesions have a radiolucent center with more dense borders, which is rare in the facial bones and typically seen in the extremities. Finally, a pagetoid appearance is more common and is simply a combination of sclerotic and osteolytic lesions. On CT fibrous dysplasia often appears as a heterogeneous mass frequently having cortical thickening, hazy borders, and intralesional calcifications. With regard to MRI, the lesions are hypointense on T1, have variable intensity on T2, and have heterogeneous post-gadolinium enhancement.
Symptoms include pain and headache; cosmetic defects, such as frontal bossing and orbital dystopia/hypertelorism; nasal obstruction; epiphora; sinusitis; visual impairment and hearing loss. Other cranial nerve deficits are more rare. Hearing impairment can be conductive, caused by narrowing of the external auditory canal and obstruction of the middle ear structures as well as impingement on the otic capsule or internal auditory canal, producing sensorineural hearing loss.
The natural history of the disease is typically one of child onset, with progression through adolescence and arrest of the disease process once the patient reaches skeletal maturity. Again, the process of bony enlargement is painless, but it can result in pain due to obstruction of the sinus outflow tracts or impingement on normal structures. Some patients continue to have progression of the disease into adulthood. The likelihood of this occurring increases with the number of bones involved. So monostotic disease is less likely to continue progression in adulthood than polyostotic or craniofacial lesions, which are in turn less likely to continue progression than patients with McCune-Albright syndrome.
It is also possible for lesions of fibrous dysplasia to degenerate into malignancy. The risk of transformation into a malignancy is 400 times greater in fibrous dysplasia than in normal bone. However, the chance of developing de novo carcinoma of bone is about 0.001 percent, whereas the chance of developing malignant degeneration of fibrous dysplasia is only 0.4 percent. Therefore, although the relative risk is significantly higher, the absolute risk remains quite low. The most common malignancy identified in fibrous dysplasia lesions is osteosarcoma and it is most often found in the facial bones. There is an association between malignant transformation and previous radiation exposure, so radiation is contraindicated in the treatment of fibrous dysplasia. Ominous clinical signs that a malignant transformation may have occurred include pain, rapid enlargement of a previous fibrous dysplasia lesion, and an elevated alkaline phosphatase.
Historically, fibrous dysplasia lesions are managed with an attitude of watchful waiting. Surgical intervention is reserved for patients who develop severe cosmetic deformity, continue to progress beyond adolescence, or develop symptoms related to compression of cranial nerves or obstruction of sinus outflow tracts. The most conservative surgical approach possible is often advocated, but there is a high (25-50%) recurrence rate for subtotal resection/contouring procedures. There is often a misconception that this type of shaving procedure can lead to a more rapid progression of the disease, however, this is not supported by any solid evidence. Occasionally, the cosmetic defect is so severe that more radical procedures are necessary with immediate reconstruction using bone grafts. There are also many instances of craniofacial fibrous dysplasia in which endoscopic techniques may be used with image guidance in order to relieve obstructions and impingement of cranial nerves.
In 1990, Chen and Noordhoff proposed a system classifying the location of craniofacial lesions and advocating a specific surgical strategy for each region. They described Zone 1, which includes the skeleton of the midface and frontal bone, where adequate reconstruction with bone grafts is feasible without tremendous cosmetic or functional disturbance and radical resection with immediate reconstruction is advocated. Zone 2 includes the hair-bearing cranium where cosmetic appearance is not as important. In Zone 2, shaving/contouring is easier, faster and achieves adequate cosmesis. Zone 3 includes the skull base, petrous mastoid, and pterygoid region, with cranial nerves and large vessels at risk. For this zone, surgery is recommended only in very symptomatic patients. This is the region where endoscopic approaches are favorable. Finally, Zone 4 includes the tooth-bearing bone of the maxilla and the mandible. Here the authors recommended conservative contouring/shaving.
There is some controversy as to the utility of optic nerve decompression in fibrous dysplasia. The optic nerve is a direct extension of the central nervous system and therefore is incapable of regeneration. The nerve is completely encircled by bone as it travels through the optic canal. Some believe that narrowing of this canal will lead to increased pressure on the nerve, with impaired venous outflow through the central vein and ultimately damage to the retina with vision loss. Whether this truly occurs, however, is not entirely agreed upon. Lee et al., in 2002, described 38 patients who had fibrous dysplasia with radiologic evidence of canal narrowing. Of these, 36 still had normal vision. Michael et al., in 2000, described 20 patients with visual loss and fibrous dysplasia, but noted that 16 of those patients had other reasons that could also explain the vision loss, such as hemorrhage, mucocele or aneurismal bone cyst.
In 2007, Tan et al. described their experience in performing optic nerve decompression in patients with canal narrowing due to fibrous dysplasia. With regard to their long-term results, 2/6 patients who started with normal vision (therefore undergoing prophylactic decompression) ended with abnormal vision. Of the 11 patients who started with abnormal vision, 1 ended with abnormal vision, 1 with “poor” vision, and 4 were completely blind. There was no speculation by the authors as to whether the progression of fibrous dysplasia or surgical complications caused the further visual deterioration in these patients. But they did suggest some guidelines for the use of optic nerve decompression based on their results. They stated that prophylactic decompression is ill advised as a stand-alone procedure, but could be considered in patients who were undergoing resection for some other symptomatic lesion. They also emphasized the importance of having an experienced neurosurgeon to perform the procedure.
Some studies also support the use of bisphosphonates for the treatment of fibrous dysplasia. These compounds rapidly bind to bone minerals, especially calcium. They are then taken up by osteoclasts as they resorb bone. Thus the drugs become concentrated in these cells, and their toxic effects lead to impaired osteoclast function and apoptosis. As stated above, an increase in osteoclastic bone resorption is thought to play a part in the progression of fibrous dysplasia, thus it makes intuitive sense that treatment with bisphosphonates may help arrest the disease process. Kos et al., in 2004, published a small prospective study on the treatment of craniofacial fibrous dysplasia with IV pamidronate infusions. Patients were given slow infusions over multiple days 2-3 times over the course of the study. In terms of results, all patients had stabilization or some decrease in size of the dysplastic lesions. This is admittedly a very small study and further investigation is necessary.
One of the reasons that treatment of fibrous dysplasia with bisphosphonates may have trouble gaining traction is a purported link between use of high doses of these medicines and osteonecrosis of the mandible. It is theorized that bisphosphonates inhibit osteoclast function, leading to an imbalance between osteoclastic and osteoblastic activity. This produces impaired bone remodeling. This is particularly detrimental in the bone of the mandible, which undergoes very high stresses associated with the act of mastication. Failure of the bone’s ability to appropriately remodel will lead to microfractures. This combined with other issues such as dental disease, local trauma, and infection can lead to exposed bone and localized osteonecrosis. It is important to remember, however, that this relationship is theoretical and a direct causal relationship between bisphosphonate use and osteonecrosis of the jaw is not well established. There are several case reports of patients who were also being treated for cancer and it is thought that the chemotherapy they received also played a role in the development of the mandibular osteonecrosis. Nonetheless, it is recommended that all patients receiving high dose bisphosphonate therapy receive careful pre-treatment dental assessment and observe excellent oral hygiene.
There is also some concern about use of bisphosphonates in women of child-bearing age. As stated before, these drugs tend to bind to the bone and can persist in the bone long after IV administration. Several small case reports have not shown any persistent ill effects on fetal development, but caution is still advised.
In review, fibrous dysplasia is a non-neoplastic, non-heritable replacement of bone with fibrous stroma and immature bone. It is the result of a somatic gene mutation which causes abnormal osteoblastic activity in a mosaic pattern. There are multiple subtypes of this disease, including monostotic, polyostotic, craniofacial and McCune-Albright syndrome. Treatment has traditionally been surgical, although the bisphosphonates may become a more widely accepted therapy in the future.
MP is a previously healthy 28 year old female who presented to otolaryngology clinic with a several month history of progressively worsening right-sided headaches and visual impairment. She had a history of nasal congestion symptoms and occasional sinus headaches, but these had become much more severe and persistent in the last several months. She denied any fevers, chills, neck stiffness, or photophobia. The vision in her right eye had also slowly deteriorated, but the left seemed to be unchanged.
On examination she was found to have subtle cosmetic deformities of her face including a right supraorbital prominence and displacement of the right globe laterally and inferiorly. External nose appeared normal. Nasal endoscopy revealed a large right nasal mass, which was quite firm on palpation. Basic vision screening revealed only light perception in right eye with essentially normal vision in the left. There was no major restriction of extraocular muscle movements. The remainder of the exam was essentially normal.
The patient was started on an oral steroid taper and a biopsy and imaging were obtained. Magnetic resonance imaging and computed tomography both showed signs of bony overgrowth and fibrotic changes consistent with fibrous dysplasia of the sphenoid, ethmoid, and frontal bones as well as the middle turbinate. She was also found to have a large mucocele from the right sphenoid sinus extending posterosuperiorly and slightly displacing the right temporal lobe and compressing the optic nerve. This was thought to be caused by blockage of the sinus by the fibrous dysplasia, which was confirmed by the biopsy.
The patient was taken to operating room for combined resection with neurosurgery and otolaryngology. Neurosurgery performed a left middle skull base craniectomy with resection of right lesser sphenoid wing, right orbital roof, decompression of optic nerve, fenestration of sphenoid wing and resection of the large mucocele. Otolaryngology performed a right medial maxillectomy, radical ethmoidectomy, resection of fibro-osseous lesion of right ethmoid, partial sphenoidectomy with sphenoidotomy and re-establishment of drainage to nasal cavity via a midface degloving approach. The right maxillary sinus and nasal cavity were then packed with bacitracin coated nu-gauze. Patient was admitted to NICU with a lumbar drain post-operatively and was found to have improved vision and no new deficits. After 5 days, the drain was removed and the nasal packing was pulled over the course of a couple of days. She was discharged on post-op day #7 in good condition. She continues to do well with stable vision and resolution of headaches.
Albright F, Butler AM, Hampton AO. Syndrome characterized by osteitis fibrosa disseminata, areas of pigmentation and endocrine dysfunction with precocious puberty in females. NEJM 1937;216:727-746.
Brannon RB, Fowler CB. Benign fibro-osseous lesions: a review of current concepts. Advances in Anatomic Pathology 2001;8:126-143.
Brodish BN, Morgan CE, Sillers MJ. Endoscopic resection of fibro-osseous lesions of the paranasal sinuses. Am J Rhinol 1999;13:11-16.
Chan B, Zacharin M. Maternal and infant outcome after pamidronate treatment of polyostotic fibrous dysplasia and osteogenesis imperfecta before conception: a report of four cases. J Clin Endocrinol Metab 2006;91:2017-20.
Chen YR, Noordhoff MS. Treatment of craniomaxillofacial fibrous dysplasia: How early and how extensive? Plastic Reconstr Surg 1990;86:835-842.
Cohen MM, Howell RE. Etiology of fibrous dysplasia and McCune-Albright syndrome. Int J Oral Maxillofacial Surg 1999;28:366-71.
Connor SEJ, Hussain, S, Woo EKF. Sinonasal imaging. Imaging 2007;19:39-54.
DiCaprio MR, Enneking WF. Fibrous dysplasia. Pathophysiology, evaluation, and treatment. J Bone Joint Surg 2005;87:1848-64.
Edgerton MT, Persing JA, Jane JA. The surgical treatment of fibrous dysplasia with emphasis on recent contributions from cranio-maxillo-facial surgery. Ann Surg 1985;202:459-478.
Feldman MD, Rao VM, Lowry LD, Kelly M. Fibrous dysplasia of the paranasal sinuses. Otolaryngol Head Neck Surg 1986;95:222-225.
Fries JW. The roentgen features of fibrous dysplasia of the skull and facial bones: a critical analysis of thirty-nine pathologically proved cases. Am J Roentgenol 1957;77:71-88.
Kos M, Luczak K, Godzinski J, Klempous J. Treatment of monostotic fibrous dysplasia with pamidronate. Journal of Cranio-Maxillofacial Surgery 2004;32:10-15.
Lee JS, Fitzgibbon E, Butman JA. Normal vision despite narrowing of the optic canal in fibrous dysplasia. NEJM 2002;347:1670-77.
Maher CO, Friedman JA, Meyer FB, Lynch JJ, Unni K, Raffel C. Surgical treatment of fibrous dysplasia of the skull in children. Pediatr Neurosurg 2002;37:87-92.
Makitie AA, Tornwall J, Makitie O. Bisphosphonate treatment in craniofacial fibrous dysplasia – a case report and review of the literature. Clin Rheumatol 2008;27:809-812.
McCune D, Bruch H. Osteodystrophia fibrosa: report of a case in which the condition was combined with precocious puberty, pathologic pigmentation of the skin and hyperthyroidism, with review of the literature. Am J Disease Child 1937;54: 806-848.
Michael CB, Lee AG, Patrinely JR. Visual loss associated with fibrous dysplasia of the anterior skull base: case report and review of the literature. J Neurosurg 2000;92:350-54.
Munro IR, Chen YR. Radical treatment of fronto-orbital fibrous dysplasia: The Chain-link fence. Plastic Reconstr Surg 1981;67:719-729.
Ozek C, Gundogan H, Bilkay U, Tokat C, Gurler T, Songur E. Craniomaxillofacial fibrous dysplasia. J Craniofacial Surg 2002;13:3.
Panda NK, Parida PK, Sharma R, Jain A, Bapuraj JR. A clinicoradiologic analysis of symptomatic craniofacial fibro-osseous lesions. Otolaryngol Head Neck Surg 2007;136:928-933.
Rogers MJ, Gordon S, Benford HL, Coxon FP, Luckman SP, Monkkonen J, Frith JC. Cellular and molecular mechanisms of action of bisphosphonates. Cancer 2000;88:2961-78.
Samaha M, Metson R. Image-guided resection of fibro-osseous lesions of the skull base. Am J Rhinol 2003;17:115-118.
Sharma RR, Mahapatra AK, Pawar SJ, Lad SD, Athale SD, Musa MM. Symptomatic cranial fibrous dysplasias: clinico-radiological analysis in a series of eight operative cases with follow-up results. J Clin Neuroscience 2002;9:381-390.
Slootweg PJ. Maxillofacial fibro-osseous lesions: classification and differential diagnosis. Seminars in Diagnostic Pathology 1996;13:102-12.
Tan YC, Yu CC, Chang CN, Ma L, Chen YR. Optic nerve compression in craniofacial fibrous dysplasia: the role and indications for decompression. Plast Reconstr Surg 2007;120:1957-62.
Toyosawa S, Yuki M, Kishino M, Ogawa Y, Ueda T, Murakami S, Konishi E, Iida S, Kogo M, Komori T, Tomita Y. Ossifying fibroma vs. fibrous dysplasia of the jaw: molecular and immunological characterization. Modern Pathology 2007;20:389-396.
Tricker N, Dixon R, Garetto L. Cortical bone turnover and mineral apposition in dentate bone mandible. In Garetto L, Turner C, Duncan R, Burr D, eds. Bridging the gap between dental and orthopaedic implants. Indianapolis, IN: Indiana University School of Dentistry; 2002. 226-7.
Updated recommendations for the prevention, diagnosis and treatment of osteonecrosis of the jaw in cancer patients. Professional Education Material 2006 East Hanover, NJ: Novartis.
Van den Wyngaert T, Huizing MT, Vermorken JB. Osteonecrosis of the jaw related to the use of bisphosphonates. Curr Opin Oncol 2007;19:315-22.
Waldron CA. Fibro-osseous lesion s of the jaws. J Oral Maxillo-Facial Surg 1993;51:828-35.
Yabut SM Jr, Kenan S, Sissons HA, Lewis MM. Malignant transformation of fibrous dysplasia. A case report and review of the literature. Clinical Orthopaedics & Related Research 1988;228:281-9.
Yetiser S, Gonul E, Tosun F, Tasar M, Hidir Y. Monostotitc craniofacial fibrous dysplasia: The Turkish experience. J Craniofacial Surg 2006;17:62-67.