Fibrous dysplasia

Fibrous dysplasia [FD] is a disorder of bones which may occur with or without endocrinological and skin disorders. It may cause bony pain, deformity, fracture and / or entrapment of nerves, It is basically the acquired mis-sense mutation of gene coding for the α-subunit of the stimulatory G-protein, Gs, in the guanine nucleotide binding, alpha stimulating (GNAS) complex locus in chromosome 20q13. It leads to immature or poor differentiation of body tissue at the time of ossification and replacement of bone by fibrous tissue. Diagnosis depends on radiology and biopsic specimen.

• Fibrous dysplasia was first observed in bone radiography by Von Recklinghausen in 1891.^[1]
• It was then entitled as separate entity by american pathologist Dr. Louis Lichtenstein in 1938 as fibrous dysplasia polyostotic.
• In 1942, Dr Lichtenstein and Dr. Jaffe together labeled syndrome named McCune-Albright syndrome (fibrous dysplasia-café au lait spots-endocrine dysfunction) or Mazabraud syndrome (fibrous dysplasia-myxomas). 

• Fibrous dysplasia may be classified according to number of bony sites involved into two groups:

• One bone: monostotic fibrous dysplasia
• Multiple bones: polyostotic fibrous dysplasia

• Other variants of FD include:^[2][3]
  • McCune-Albright syndrome
  • Mazabraud syndrome

The pathophysiology of fibrous dysplasia is based on mechanism of G protein mutation.^[4][5][6][7]

Genetics

• The somatic mutation in GNAS1 gene located on the long arm (q) of chromosome 20 (20q13.2) has been associated with the development of FD, involving the gain-of-function mutation pathway.
• Mutation of GNAS1 gene is a somatic mutation and it is not heritable.
• The exact reason for post fertilization mutation remains unknown.
• Mutation of GNAS1 gene results in the overproduction of this G-protein, which in turn increases cyclic adenosine monophosphate (cAMP).
• Cyclic adenosine monophosphate (cAMP) is important regulatory molecule of differentiation modulating osteoblasts and osteoclasts while ossification and remodeling of bones.
• Improper differentiation of osteoblasts due to mutation of the GNAS1 gene considered as a cause of FD.
• Osteoclasts removes ossified bones and creates space for immature osteoblasts to produce fibrous tissue and occupy space which may entrap nerves causing pain or neurological deficit depending on the site involved.

Gross pathology

• Following are characteristic gross pathology findings of fibrous dysplasia:
  • Well circumscribed, intramedullary lesion
  • Tan-white-yellow, gritty, large lesions that distort bone
  • Thin and expanded cortical bone

Microscopic histopathological analysis

• Following are characteristic microscopic histopathological findings of fibrous dysplasia:
  • Curvilinear trabeculae (Chinese letters) of metaplastic woven bone
  • Hypocellular and fibroblastic stroma
  • No osteoblastic rimming (due to maturation arrest)
  • Cartilaginous nodules (in 20% of cases particularly in femoral neck region)
  • Myxoid areas consist of rapidly growing secondary aneurysmal bone cysts, hemorrhage, foamy macrophages, calcified spherules, and focal hyaline cartilage
  • Abrupt transition of normal to abnormal bone
  • No/rare mitotic figures
  • No atypia (rarely is degenerative)
  • Resembling endochondral ossification in skull

• Fibrous dysplasia must be differentiated from other diseases that cause bone pain, deformity, and extra-skeletal involvement, such as:

• The prevalence and incidence of fibrous dysplasia is not known exactly.^[8][9]

• FD is more commonly found in age group from 3 -15 years of life.
• Polyostotic does not become symptomatic before age 10 years.
• Monostotic is asymptomatic until age of 20-30 years of life.

• FD affects men and women equally.

• There is no racial predilection for FD.

• Common risk factor in the development of fibrous dysplasia is gain-of-function mutation.

• The majority of patients with FD remain asymptomatic for the first decade of life.
• Early clinical features include bone pain, bony deformity, fever, and pathological fractures.
• Patients with fibrous dysplasia might develop skin/endocrine/malignancies depending on the variant.
• Common complications of FD include neurological deficit, endocrine abnormality, and in rare cases soft tissue tumors.
• Prognosis is generally good, and the patients with polyostotic form may have frequent fractures.

• The diagnosis of FD is made on the basis of clinical manifestations, radiology findings, and genetic testing to verify presence of GNAS mutation.^{[10][11][12][13][14][8][9]}

• FD is usually asymptomatic.
• Symptoms of FD may include:
  • Fever
  • Bone pain
  • Bony deformity
  • Pathological fractures

• Patients with FD usually appear normal unless there is any bony deformity or skin involvement
• Physical examination may be remarkable according to the classification of disease:

Monostotic

• Single bone involved.
• Mostly affects rib, femur, and tibia.
• Craniofacial bone and humerus bone
• Fracture at age of 10 years
• Less severe bone deformity
• Painless swelling of jaw
• Swelling of buccal and labial plate
• Protuberance of inferior border of mandible

Polyostotic

• Multiple bones involved
• Involve rib, femur, clavicle, lumbar spine, and tibia.
• Asymmetrical involvement
• Mainly misalignment of bones
• Tenderness over involved bone
• Bowing of weight bearing bone and increasing curvature of femur and tibia

Craniofacial

• Involvement of maxillofacial bones
• Maladjustment
• Tappering
• Displacement
• Intact over lesion
• Maxillary sinus and Zygomatic bone involved mostly
• Floor of orbit may extend to skull
• No extracranial involvement
• Hypertelorism, facial asymmetry, visual impairment, exophthalmos and blindness
• Vestibular dysfuntion, hearing loss and tinnitus.

McCune-Albright syndrome

• May involve all the bones
• Cafe au lait spots
• Endocrine abnormality of parathyroid hormone, gonadotropins Mazabraud syndrome
• Involve variable number of bones

• There are no specific laboratory findings associated with FD. However, we may find normal PTH, Ca levels, and increased level of alkaline phosphatase due to increased bone turnover and increased basal metabolic rate.

• Radiology is the imaging modality of choice for FD.
• On x-ray, FD is characterized by:
  • Network of fine bone trabeculae
  • Increased trabeculation
  • Opaque trabeculation forming ground glass appearance
  • Cortical thinning
  • Separated root of teeth

• MRI and CT scan may be helpful in diagnosis of fibrous dysplasia.
• Bone biopsy will reveal the histological findings such as:
  • Curvilinear trabeculae (Chinese letters) of metaplastic woven bone
  • Hypocellular and fibroblastic stroma
  • No osteoblastic rimming (due to maturation arrest)
  • Cartilaginous nodules (in 20% of cases particularly in femoral neck region)
  • Myxoid areas consist of rapidly growing secondary aneurysmal bone cysts, hemorrhage, foamy macrophages, calcified spherules, and focal hyaline cartilage

Treatment of FD is mostly symptomatic and it can be either medical or surgical depending on severity and presentation of disease.^{[15][16][17][18][19]}

• The mainstay of therapy for FD is bisphosphonates, which help in improving pain, slow down process of bone turnover, and also lower the fracture risk factor.
• Bisphosphonates acts by inhibiting osteoclasts.
• In the absence of a fracture or symptoms, the follow-up for a child with FD consists of twice yearly clinical evaluations with special attention to limited range of motion, obvious angular deformity, and limb length discrepancy.

• Conventional surgical procedures can only be performed for patients with symptomatic FD patients in conjugation of over all evaluation of disease and the age of child.
• Adult monostotic lesion may be observed with subsequent radiography if it is not symptomatic. surgical removal and grafting the defect is considered for patients who have symptoms or excessively growing deformity or when disease produces deficit.
• Child age group may have skin lesions and endocrinopathies which needs prompt attention and surgery will be delayed until bones are mature and in case of neurological defect or significant deformity surgery is advised immediately.

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