Fibrous Dysplasia

Author: Daniel Hatch

Topic updated on 03/09/13 4:55pm


Introduction
A developmental abnormality caused by failure of the production of normal lamellar bone areas of the skeleton remain poorly mineralized trabeculae Epidemiology demographics male:female ratio females > males age bracket found in any and all ages onset for 75% of patients at <30 years of age location any bone can be involved the proximal femur is most common site, followed by rib, maxilla, and tibia Genetics GS alpha protein (chromosome 20q13) activating mutation (affects cAMP signaling pathway leading to increased production of cAMP) not inherited high production of FGF-23 which may lead to hypophosphatemia Associated conditions orthopedic manifestations McCune Albright syndrome condition defined by the presence of skin abnormalities (cafe au lait spots in coast of Maine pattern) endocrine abnormalities (precocious puberty)\ renal phosphate wasing due to FGF-23 (oncogenic osteomalacia) unilateral polyostotic fibrous dysplasia Mazabraud syndrome polyostotic fibrous dysplasia soft-tissue intramuscular myxomas Osteofibrous dysplasia rare form that primarily affects the tibia and is confined to the cortices nonorthopedic manifestations severe cranial deformities with blindness Prognosis 1% risk of malignant transformation to osteosarcoma, fibrosarcoma, or malignant fibrous histiocytoma poor prognosis

Presentation

Symptoms
- usually asymptomatic and discovered as an incidental finding
- may have swelling or deformity
- bone lesions may be monostotic (80%) or polystotic (20%)
- pain from stress fractures
Physical exam
- inspection
  - cafe au lait spots
    - larger and more irregular borders than neurofibromatosis
    - may or may not be present with fibrous dysplasia
    - by definition present with McCune-Albright syndrome
  - swelling around lesion

Imaging

Radiographs
- central lytic lesions in medullary canal (diaphysis or metaphysis)
  - may have cortical thinning with expansile lesion
- highly lytic lesions or a ground glass appearance
- "punched-out" lesion with well defined margin of sclerotic bone is common
- modest expansion of bone
- Shepherd's crook deformity
- vertebral collapse and kyphoscoliosis
Bone scan
- usually warm

Studies

Gross - yellow-white gritty tissue
Histology
- characteristic look of "alphabet soup" or "chinese letters"
- fibroblast proliferation surrounding islands of woven bone
  - woven bone lacks osteoblastic rimming (osteofibrous dysplasia has osteoblastic rimming)
- trabeculae of osteoid and bone in fibrous stroma with metaplastic cartilage or areas of cyst degeneration
- mitotic figures are common

Treatment

Nonoperative
- observation
  - indications
    - asymptomatic patients
- Diphosphonate therapy
  - indications
    - symptomatic polyostotic fibrous dysplasia
  - effective in decreaseing pain and reducing bone turnover
Operative
- internal fixation and bone grafting
  - indications
    - symptomatic lesions
    - impending/actual fractures through lesions in areas of high stress (femoral neck)
    - severe deformity
    - neurologic compromise in the spine
  - technique
    - never use autogenous cancellous bone, as the transplanted bone will quickly turn into fibrous dysplastic woven bone
    - use cortical or cancellous allografts
    - intramedullary device more effective than a plate in the lower extremity
- osteotomies
  - indications
    - deformity

Differentials & Groups

	Multiple lesions in young patients (1)	Treatment is Observation alone (2)	Benefits from Bisphonate therapy
Fibrous dysplasia	•	•	•
Eosinophilic granuloma	•	•
Lymphoma	•
Leukemia	•
Enchondroma / Olliers / Marfucci's	•	•
Osteochondroma / MHE	•	•
NOF / Jaffe-Campanacci syndrome	•	•
Hemangioendothelioma	•
Paget's		•	•
Metastatic Disease			•
Myeloma			•
ASSUMPTIONS: (1) Younger patient is > 40 yrs; (2) assuming aymptomatic and no impending fracture

IBank

	Location	Age	Xray	Xray	CT	B. Scan	MRI	MRI	Histo(1)
Case A	fibula	10 yrs.
Case A	spine
Case B	radius
Case C	humerus
Case D	skull

(1) - histology does not always correspond to clinical case

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Qbank (5 Questions)

TAG

(OBQ09.21) All of the following are characteristic of McCune-Albright syndrome EXCEPT? Topic

Review Topic

1. Caused by a mutation in G(s)alpha subunit
2. Cafe-au-lait spots
3. Polyostotic fibrous dysplasia
4. Multiple neurofibromas
5. Precocious puberty

PREFERRED RESPONSE ▶

DISCUSSION: Neurofibromas are seen in neurofibromatosis and are not associated with McCune-Albright syndrome.

McCune-Albright syndrome is a condition characterized by: 1) precocious puberty (endocrine abnormalities), 2) cafe-au-lait spots, 3) and polyostotic fibrous dysplasia. Fibrous dysplasia is caused by a mutation in the alpha subunit of stimulatory G protein and leads to activation of c-fos and other proto-oncogenes.

DiCaprio et al review the pathophysiology, evaluation, and treatment of fibrous dysplasia. As mentioned, fibrous dysplasia is caused by an activating mutation of the G(s) alpha gene. While most lesions are asymptomatic and found incidentally, symptomatic lesions are best initially managed with medical therapy like bisphosphonates. Patients who fail medical management may require surgical intervention with the use of cortical grafts to augment the structural properties of the involved bone.

Parekh et al review the molecular biology, presentation, and treatment of patients with fibrous dysplasia. As discussed, the G(s) alpha mutation causes activation of multiple oncogenes, causing a neoplastic proliferation of fibrous tissue in the bone. The overall prognosis of patients with fibrous dysplasia, even symptomatic lesions, is excellent as medical management successfully treats most symptomatic lesions. As the risk of malignant transformation is low, even symptomatic lesions can be treated conservatively.

Illustration A and B show radiographic findings of polyostotic fibrous dysplasia typical of McCune-Albright syndrome.

Illustrations: A

REFERENCES:

1. DiCaprio MR, Enneking WF: Fibrous dysplasia: Pathophysiology, evaluation, and treatment. J Bone Joint Surg Am 2005;87:1848-1864 PMID:16085630 (Link to Abstract)

2. Parekh SG, Donthineni-Rao R, Ricchetti E, Lackman RD. Fibrous dysplasia. J Am Acad Orthop Surg. 2004 Sep-Oct;12(5):305-13. Review. PMID:15469225 (Link to Abstract)

Question Authors:

Patrick O'Donnell MD/PhD, Patrick McCulloch MD, John Badylak MD, Ginger Holt,

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TAG

(OBQ09.74) A mutation in a G(s) alpha protein (activating G protein that increases cAMP) results in which of the following diseases? Topic

Review Topic

1. Fibrous dysplasia
2. Diastrophic dysplasia
3. Cleidocranial dysostosis
4. Osteogenesis imperfecta
5. Achondroplasia

PREFERRED RESPONSE ▶

DISCUSSION: Fibrous dysplasia is caused by a mutation in the GS alpha protein, which increases cAMP.

Weinstein discusses how fibrous dysplasia and MAS result from somatic mutations occurring during early development, resulting in a widespread mosaic of normal and mutant-bearing cells, which predicts that the clinical presentation of each patient is determined by the extent and distribution of abnormal cells. These mutations encode constitutively active forms of G(s)alpha, the ubiquitously expressed G protein alpha-subunit that couples hormone receptors to intracellular cAMP generation. These mutations lead to substitution of amino acid residues that are critical for the intrinsic GTPase activity that is normally required to deactivate the G protein.

Incorrect Answers:
Answer 2: Diastrophic dysplasia is caused by mutation in the DTD gene which leads to a defect in the sulfate transport protein.
Answer 3: Cleidocranial Dysostosis is caused by a mutation CBFA1 gene, which leads to a defect in intramembranous ossification.
Answer 4: Osteogenesis imperfecta is caused by a mutation in COL1A1 and COL1A2, which leads to a defect in Type I collagen.
Answer 5: Achondroplasia is caused by a mutation in the FGFR3 gene, that leads to abnormal chondroid production by chondroblasts.

REFERENCES:

1. Einhorn TA, O’Keefe RJ, Buckwalter JA (eds): Orthopaedic Basic Science: Foundations of Clinical Practice, ed 3. Rosemont, IL, American Academy of Orthopaedic Surgeons, 2007, pp 25-47

2. Weinstein LS. G(s)alpha mutations in fibrous dysplasia and McCune-Albright syndrome. J Bone Miner Res. 2006 Dec;21 Suppl 2:P120-4. PMID:17229000 (Link to Abstract)

Question Authors:

Derek Moore, Patrick McCulloch MD, John Badylak MD,

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(OBQ07.26) The G-protein coupled family of receptors play a crucial role in transmembrane cytokine signaling. Point mutation in the Gs-alpha subunit of this receptor is responsible for a specific bone/soft tissue disease. Which of the following radiographs corresponds to this disease? Topic

Review Topic

FIGURES: A

1. Figure A
2. Figure B
3. Figure C
4. Figure D
5. Figure E

PREFERRED RESPONSE ▶

DISCUSSION: Activating missense mutations in the GNAS1 gene encoding the Gs-alpha subunit of the G-protein family of receptors is associated with polyostotic fibrous dysplasia. This is shown by the proximal femur/acetabular "ground glass" lesions in Figure E.

Leet et al evaluated the functional and diagnostic features of these children and found that loss of femoral neck-shaft angle and involvement of the lower extremities had the greatest impact on function.

Bianco et al discuss the other implications of G-protein coupled receptor mutations outside of their effect on skeletal development.

Incorrect Answers:
Figure A represents an adamantinoma of the tibia.
Figure B shows the spickeled calcification of an enchondroma.
Figure C shows a destructive giant cell tumor of bone.
Figure D shows the "flowing wax" of melorheostosis.

REFERENCES:

1. Leet AI, Wientroub S, Kushner H, Brillante B, Kelly MH, Robey PG, Collins MT. The correlation of specific with functional outcome scores in children. J Bone Joint Surg Am. 2006 orthopaedic features of polyostotic fibrous dysplasia. Apr;88(4):818-23. PMID:16595472 (Link to Abstract)

2. Bianco P, Riminucci M, Majolagbe A, Kuznetsov SA, Collins MT, Mankani MH, Corsi A, Bone HG, Wientroub S, Spiegel AM, Fisher LW, Robey PG. Mutations of the GNAS1 gene, stromal cell dysfunction, and osteomalacic changes in non-McCune-Albright fibrous dysplasia of bone. J Bone Miner Res. 2000 Jan;15(1):120-8. PMID:10646121 (Link to Abstract)

Question Authors:

Patrick O'Donnell MD/PhD, John Badylak MD, Michael Hughes MD,

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TAG

(OBQ07.231) A 17-year-old high-school track athlete complains of vague pain along his anterior tibia. He denies any specific trauma to this area. Radiographs are seen in Figures A and B. A biopsy specimen in low and high power is seen in Figure C and D, respectively. What is the most likely diagnosis? Topic

Review Topic

FIGURES: A

1. Adamantinoma
2. Osteomyelitis
3. Fibrous dysplasia
4. Osteosarcoma
5. Stress fracture

PREFERRED RESPONSE ▶

DISCUSSION: The radiographs and histology are consistent with fibrous dysplasia.

Fibrous dysplasia is a developmental bone abnormality that results from a defect in the gene coding for alpha subunit of Gs, the G protein that stimulates cAMP formation (overproduction of cAMP, causes overexpression of c-fos, which regulates proliferation and differentiation of osteoblasts and osteoclasts). More commonly lesions are found in the medullary cavity.

Leet et al performed a retrospective study on polyostotic fibrous dysplasia and found that the disease had a very a wide clinical spectrum among the patients. The greatest amount of functional limitations were seen in children with a loss of the normal femoral neck-shaft angle and a high disease burden in the lower extremities.

Figures A and B are radiographs that show an eccentric lesion with a scalloped border and a ground glass appearance consistent with fibrous dysplasia. Figures C and D demonstrate fibrous stroma in a storiform pattern surrounding the immature lamellar bone consistent with fibrous dysplasia.

Incorrect Answers:
1. Adamantinoma: low-grade malignant tumor of unknown etiology that is almost always located in the mid-tibia. Histology shows characteristic fibrous and epithelial tissue in gland like pattern without immature lamellar bone
2. Osteomyelitis: there is no history of trauma or systemic signs of infection. Histology does not show any inflammatory cells.
4. Osteosarcoma: radiographs can usually show blastic and destructive features. Histology will show tumor cells with significant atypia, that produce "lacey" osteoid. Furthermore, stroma cells show malignant characteristics with atypia, high nuclear to cytoplasmic ratio, and abnormal mitotic figures.
5. Stress fracture: lateral xray may show "dreaded black line" and often patient will have vague symptoms that often subside with cessation of activity.

REFERENCES:

1. Leet AI, Wientroub S, Kushner H, Brillante B, Kelly MH, Robey PG, Collins MT. The correlation of specific orthopaedic features of polyostotic fibrous dysplasia with functional outcome scores in children. J Bone Joint Surg Am 2006;88:818-823. PMID:16595472 (Link to Abstract)

Question Authors:

Jan Szatkowski MD, Michael Hughes MD, Ben Taylor MD,

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TAG

(OBQ06.240) A genetic abnormality in the cyclic AMP signaling pathway is involved in which of the following conditions? Topic

Review Topic

1. achondroplasia
2. hypochondroplasia
3. multiple hereditary exostosis
4. fibrous dysplasia
5. neurofibromatosis type I

PREFERRED RESPONSE ▶

DISCUSSION: The genetic defect in fibrous dysplasia involves a G protein that affects the cAMP signaling pathway. The first references by Lietman et al mentions a novel technique using a polymerase chain reaction to detect mutations in genomic DNA from peripheral blood cells in patients with fibrous dysplasia. The second reference by DiCaprio et al is a review article describing the pathophysiology, evaluation, and treatment of fibrous dysplasia. Achondroplasia and hypochondroplasia are caused by a mutation in the FGF-3 gene. Multiple hereditary exostosis is caused by a mutation in the EXT1 gene. Neurofibromatosis involves a mutation in the NF1 gene that codes for neurofibromin.

REFERENCES:

1. Lietman SA, Ding C, Levine MA: A highly sensitive polymerase chain reaction method detects activating mutations of the GNAS gene in peripheral blood cells in McCune-Albright syndrome or isolated fibrous dysplasia. J Bone Joint Surg Am 2005;87:1289-2494 PMID:16264125 (Link to Abstract)

2. DiCaprio MR, Enneking WF: Fibrous dysplasia: Pathophysiology, evaluastion, and treatment. J Bone Joint Surg Am, 2005;87:1848-1864. PMID:16085630 (Link to Abstract)

Question Authors:

Greg Galano MD,

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Cases

http://upload.orthobullets.com/cases/1318/fib dysplasia hasib.jpg

http://upload.orthobullets.com/cases/1318/hasib fib dyspalsia.jpg

fibrous dysplasia (C1318)

General - Treatment Consult - Fibrous Dysplasia

HPI - pain in the rt hip thigh since 6 mths pain increases on long walking.

prophlactic nailing or prophlactic nailing with curettage of lesion

11/10/2012

13 responses

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Groups

ABOS II: Fibrous Dysplasia

General - Oral Boards Review

7/29/2011

0 responses

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Evidence & References Show References

Level of Evidence 5 and Other Journal Articles (includes Case Reports, Expert Opinions, Personal Observations, and Biomechanic Studies)

Leet AI, Wientroub S, Kushner H, Brillante B, Kelly MH, Robey PG, Collins MT. The correlation of specific orthopaedic features of polyostotic fibrous dysplasia with functional outcome scores in children. J Bone Joint Surg Am 2006;88:818-823. PMID:16595472 (Link to Abstract)
Parekh SG, Donthineni-Rao R, Ricchetti E, Lackman RD. Fibrous dysplasia. J Am Acad Orthop Surg. 2004 Sep-Oct;12(5):305-13. Review. PMID:15469225 (Link to Abstract)

Textbooks

Review of Orthopaedics, 6th Edition, Mark D. Miller MD, Stephen R. Thompson MBBS MEd FRCSC, Jennifer Hart MPAS PA-C ATC, an imprint of Elsevier, Philadelphia, Copyright 2012
AAOS Comprehensive Orthopaedic Review, Jay R. Leiberman. Published by American Academy of Orthopaedic Surgeons, Rosemont IL. Copyright 2009
Orthopaedic Knowledge Update 10, John M Flyn. Published by American Academy of Orthopaedic Surgeons, Rosemont IL. Copyright 2011
Hoppenfeld SP. Surgical Exposures in Orthopaedics: The Anatomic Approach. Lipponcott, Williams, and Wilkins, Philadelphia, PA, Copyright 2009
Orthopaedic In-training Examination (OITE) Questions 2004-2012, American Academy of Orthopaedic Surgeons, Rosemont IL. Copyright 2004-2012
Self-Assessment Examination (SAE) Questions 2004-2012, American Academy of Orthopaedic Surgeons, Rosemont IL. Copyright 2004-2012

Undefined

Bianco P, Riminucci M, Majolagbe A, Kuznetsov SA, Collins MT, Mankani MH, Corsi A, Bone HG, Wientroub S, Spiegel AM, Fisher LW, Robey PG. Mutations of the GNAS1 gene, stromal cell dysfunction, and osteomalacic changes in non-McCune-Albright fibrous dysplasia of bone. J Bone Miner Res. 2000 Jan;15(1):120-8. PMID:10646121 (Link to Abstract)
DiCaprio MR, Enneking WF: Fibrous dysplasia: Pathophysiology, evaluastion, and treatment. J Bone Joint Surg Am, 2005;87:1848-1864. PMID:16085630 (Link to Abstract)
DiCaprio MR, Enneking WF: Fibrous dysplasia: Pathophysiology, evaluation, and treatment. J Bone Joint Surg Am 2005;87:1848-1864 PMID:16085630 (Link to Abstract)
Einhorn TA, O’Keefe RJ, Buckwalter JA (eds): Orthopaedic Basic Science: Foundations of Clinical Practice, ed 3. Rosemont, IL, American Academy of Orthopaedic Surgeons, 2007, pp 25-47
Leet AI, Wientroub S, Kushner H, Brillante B, Kelly MH, Robey PG, Collins MT. The correlation of specific with functional outcome scores in children. J Bone Joint Surg Am. 2006 orthopaedic features of polyostotic fibrous dysplasia. Apr;88(4):818-23. PMID:16595472 (Link to Abstract)
Lietman SA, Ding C, Levine MA: A highly sensitive polymerase chain reaction method detects activating mutations of the GNAS gene in peripheral blood cells in McCune-Albright syndrome or isolated fibrous dysplasia. J Bone Joint Surg Am 2005;87:1289-2494 PMID:16264125 (Link to Abstract)
Weinstein LS. G(s)alpha mutations in fibrous dysplasia and McCune-Albright syndrome. J Bone Miner Res. 2006 Dec;21 Suppl 2:P120-4. PMID:17229000 (Link to Abstract)

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Fibrous Dysplasia

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