Fibrous dysplasia

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

Overview

Fibrous dysplasia 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.

Historical Perspective

• Fibrous dyspepsia was first observed in bone radiography by Von Recklinghausen in 1891.
• It was then entitled as separate entity by american pathologist Dr. Louis Lichtenstein in 1938 as fibrous dyspepsia 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). 

Classification

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

• Monoostiotic
• Polyostiotic

• Other variants of FD include McCune-Albright syndrome, and Mazabraud syndrome.

Pathophysiology

The pathophsiology of FD is based on mechanism mutation of Gs protein.

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.
• As it is somatic mutation that is why it is not heritable, post fertilization mutation occurring due to unknown reason.
• 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 is the 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 nurological deficit depending on the site involved.
• On gross pathology, Well circumscribed, intramedullary,Tan-white-yellow, gritty, Large lesions distort bone, Cortical bone often thin and expanded are characteristic findings of FD.
• On microscopic histopathological analysis :
  • Curvilinear trabeculae (Chinese letters) of metaplastic woven bone (never matures) in hypocellular,
  • fibroblastic stroma
  • No osteoblastic rimming (due to maturation arrest), 20% of cases have cartilaginous nodules (particularly in femoral neck region)
  • Also myxoid areas, rapidly growing secondary aneurysmal bone cysts, hemorrhage, foamy macrophages, calcified spherules (similar to cementifying fibromas), cellular areas, focal hyaline cartilage or cystic areas
  • Usually abrupt transition of normal to abnormal bone
  • No/rare mitotic figures, no atypia (rarely is degenerative)
  • Overall resembles endochondral ossification in skull are characteristic findings of FD.

Clinical Features

There are four varriets of FD and the clinical features are pertaining to that specific feature.

• Monoostiotic
• Polyostiotic
• McCune-Albright syndrome
• Mazabraud syndrome

Differentiating Fibrous dyspepsia from other Diseases

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

• [Differential dx1]
• [Differential dx2]
• [Differential dx3]

Epidemiology and Demographics

• The prevalence and incidence of FD is not known exactly.

Age

• FD is more commonly observed among children.

Gender

• FD affects men and women equally.

Race

• There is no racial predilection for FD.

Risk Factors

• Common risk factor in the development of PD is gain in function mutation.

Natural History, Complications and Prognosis

• The majority of patients with [disease name] remain asymptomatic for [duration/years].
• Early clinical features include [manifestation 1], [manifestation 2], and [manifestation 3].
• If left untreated, [#%] of patients with [disease name] may progress to develop [manifestation 1], [manifestation 2], and [manifestation 3].
• Common complications of [disease name] include [complication 1], [complication 2], and [complication 3].
• Prognosis is generally [excellent/good/poor], and the [1/5/10­year mortality/survival rate] of patients with [disease name] is approximately [#%].

Diagnosis

Diagnostic Criteria

• The diagnosis of [disease name] is made when at least [number] of the following [number] diagnostic criteria are met:

• [criterion 1]
• [criterion 2]
• [criterion 3]
• [criterion 4]

Symptoms

• [Disease name] is usually asymptomatic.
• Symptoms of [disease name] may include the following:

• [symptom 1]
• [symptom 2]
• [symptom 3]
• [symptom 4]
• [symptom 5]
• [symptom 6]

Physical Examination

• Patients with [disease name] usually appear [general appearance].
• Physical examination may be remarkable for:

• [finding 1]
• [finding 2]
• [finding 3]
• [finding 4]
• [finding 5]
• [finding 6]

Laboratory Findings

• There are no specific laboratory findings associated with [disease name].

• A [positive/negative] [test name] is diagnostic of [disease name].
• An [elevated/reduced] concentration of [serum/blood/urinary/CSF/other] [lab test] is diagnostic of [disease name].
• Other laboratory findings consistent with the diagnosis of [disease name] include [abnormal test 1], [abnormal test 2], and [abnormal test 3].

Imaging Findings

• There are no [imaging study] findings associated with [disease name].

• [Imaging study 1] is the imaging modality of choice for [disease name].
• On [imaging study 1], [disease name] is characterized by [finding 1], [finding 2], and [finding 3].
• [Imaging study 2] may demonstrate [finding 1], [finding 2], and [finding 3].

Other Diagnostic Studies

• [Disease name] may also be diagnosed using [diagnostic study name].
• Findings on [diagnostic study name] include [finding 1], [finding 2], and [finding 3].

Treatment

Medical Therapy

• There is no treatment for [disease name]; the mainstay of therapy is supportive care.

• The mainstay of therapy for [disease name] is [medical therapy 1] and [medical therapy 2].
• [Medical therapy 1] acts by [mechanism of action 1].
• Response to [medical therapy 1] can be monitored with [test/physical finding/imaging] every [frequency/duration].

Surgery

• Surgery is the mainstay of therapy for [disease name].
• [Surgical procedure] in conjunction with [chemotherapy/radiation] is the most common approach to the treatment of [disease name].
• [Surgical procedure] can only be performed for patients with [disease stage] [disease name].

Prevention

• There are no primary preventive measures available for [disease name].

• Effective measures for the primary prevention of [disease name] include [measure1], [measure2], and [measure3].

• Once diagnosed and successfully treated, patients with [disease name] are followed-up every [duration]. Follow-up testing includes [test 1], [test 2], and [test 3].