A 16-Year-Old Boy with Facial Pain and Headache - Fibrous dysplasia

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 Fibrous dysplasia

1. Cause and Etiology

Fibrous dysplasia (FD) is a non-heritable, sporadic developmental bone disorder caused by a postzygotic activating mutation in the GNAS gene.

·         GNAS mutation: The mutation affects the GNAS1 gene located on chromosome 20q13.3, which encodes the α-subunit of the stimulatory G-protein (Gsα). This results in constitutive activation of adenylate cyclase, leading to increased cyclic AMP (cAMP) levels.

·         The mutation occurs postzygotically, meaning after fertilization. Therefore, the disease is not inherited but results from a somatic mutation.

·         This mutation leads to abnormal osteoblastic differentiation and proliferation, replacing normal bone and marrow with fibrous tissue and immature woven bone.

2. Pathophysiology

Fibrous dysplasia is characterized by the replacement of normal bone with fibrous connective tissue and irregular, immature woven bone.

·         Bone marrow stromal cells carrying the GNAS mutation proliferate abnormally.

·         These cells produce fibro-osseous tissue instead of normal lamellar bone and hematopoietic marrow.

·         The immature woven bone is laid down in a disorganized, "Chinese character" or "alphabet soup" pattern.

·         Lesions expand and weaken the bone, causing deformities, fractures, and pain.

·         Depending on the timing and location of the mutation, fibrous dysplasia may present as:

o    Monostotic (single bone) – ~70–80%

o    Polyostotic (multiple bones) – ~20–30%

o    McCune-Albright syndrome – when associated with endocrine dysfunction and café-au-lait skin pigmentation

o    Mazabraud syndrome – fibrous dysplasia with intramuscular myxomas

3. Epidemiology

·         Prevalence: Approximately 1 in 30,000 people.

·         Age of onset: Usually manifests in childhood or adolescence, often before age 30.

·         Sex: No strong sex predilection for monostotic or polyostotic forms; McCune-Albright syndrome is more common in females.

·         Distribution:

o    Monostotic FD: Common in ribs, femur, tibia, craniofacial bones

o    Polyostotic FD: Often involves pelvis, femur, tibia, ribs, craniofacial bones

4. Clinical Presentation

The presentation varies depending on the type (monostotic vs. polyostotic) and the site of involvement:

Monostotic FD

·         Often asymptomatic

·         May be discovered incidentally on imaging

·         Localized swelling, pain, or fracture

Polyostotic FD

·         More symptomatic and extensive

·         Limb length discrepancy, bone deformities, especially shepherd’s crook deformity of the femur

·         Pathologic fractures

·         Facial asymmetry if craniofacial bones are involved

McCune-Albright Syndrome (MAS)

·         Polyostotic FD plus:

o    Precocious puberty (especially in girls)

o    Café-au-lait spots with irregular borders ("coast of Maine" appearance)

o    Other endocrinopathies: hyperthyroidism, Cushing’s syndrome, acromegaly

Mazabraud Syndrome

·         Polyostotic FD + intramuscular myxomas

5. Imaging Features

Imaging is essential for diagnosis, monitoring, and surgical planning.

Plain Radiographs

·         Ground-glass appearance: classic feature due to the fine, hazy internal matrix

·         Expansile lesion with thinning of the cortex

·         Endosteal scalloping and no periosteal reaction

·         Shepherd’s crook deformity: varus deformity of the proximal femur

CT Scan

·         Better for craniofacial involvement

·         Shows ground-glass matrix, cortical thinning, and extent of bony expansion

MRI

·         Variable signal intensity

·         T1: low to intermediate

·         T2: variable, depending on fibrous content

·         Useful for evaluating adjacent soft tissue, myxomas, or optic canal compromise

Bone Scan (99mTc-MDP)

·         Shows increased uptake in active lesions

·         Helpful in assessing the full skeletal burden in polyostotic disease

6. Treatment

There is no cure for fibrous dysplasia, and management is largely symptomatic and supportive.

Medical Management

·         Bisphosphonates (e.g., pamidronate, zoledronic acid):

o    Reduce bone pain

o    May reduce bone turnover and lesion activity

·         Analgesics for pain control

Surgical Management

·         Fracture fixation

·         Deformity correction (e.g., osteotomy for shepherd’s crook)

·         Debulking or reconstructive surgery in craniofacial lesions

·         Bone grafting: often resorbed in fibrous dysplasia, so cortical grafts are preferred

Endocrine Therapy

·         In McCune-Albright syndrome, specific hormone-related treatment is needed:

o    Aromatase inhibitors for precocious puberty

o    Antithyroid drugs for hyperthyroidism

7. Prognosis

·         Monostotic FD: Usually has a good prognosis, often stabilizes after puberty.

·         Polyostotic FD: More complications, including deformity, fractures, and functional impairment.

·         Malignant transformation is rare (~0.5–4%) but can occur, especially in polyostotic FD and previously irradiated lesions.

o    Most common malignancies: osteosarcoma, fibrosarcoma, chondrosarcoma

Quality of Life

·         Many patients lead normal lives with monitoring.

·         Chronic pain or deformity may impact mobility or appearance in some cases.

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Case study: A 16-Year-Old Boy with Facial Pain and Headache
Fibrous Dysplasia

History and Imaging

  1. A 16-year-old boy presented with facial pain and headache.

  2. Physical examination revealed irregular hyperpigmented lesions on his back.

  3. A facial CT scan was performed.

Quiz 1

  1. There is an acute skull fracture.
    (1) True
    (2) False

    Explanation:
    CT imaging shows abnormal ground-glass bone matrix without any disruption of cortical bone or evidence of a fracture. The lesion causes bone expansion but preserves the cortex, typical of fibrous dysplasia, not an acute skull fracture.

  2. How can the main imaging finding best be characterized?
    (1) Ivory
    (2) Ground-glass
    (3) Crazy paving
    (4) Polka-dotted

    Explanation:
    The hallmark imaging feature of fibrous dysplasia on CT is a ground-glass appearance, reflecting the replacement of normal bone marrow with fibrous tissue and immature woven bone. This distinguishes it from patterns like "ivory" (osteoblastic metastasis), "crazy paving" (seen in alveolar diseases), or "polka-dotted" (vertebral hemangioma).

  3. Which syndrome is most commonly associated with this disease?
    (1) Marfan syndrome
    (2) McCune-Albright syndrome
    (3) Osler-Weber-Rendu syndrome

    Explanation:
    McCune-Albright syndrome is a well-known genetic disorder that includes polyostotic fibrous dysplasia, café-au-lait skin spots, and hyperfunctioning endocrinopathies (e.g., precocious puberty). It is directly linked to the same postzygotic GNAS mutation that causes fibrous dysplasia. Marfan syndrome and Osler-Weber-Rendu are unrelated conditions.

  4. MRI is generally required to diagnose this condition.
    (1) True
    (2) False 

    Explanation:
    CT is the imaging modality of choice for diagnosing fibrous dysplasia due to its superior ability to detect bone matrix changes, such as the ground-glass pattern. MRI is not routinely required and is usually reserved for evaluating potential soft tissue or neurovascular complications.

Findings and Diagnosis

Findings

CT: An abnormal bone lesion with ground-glass matrix was observed in the central portion of the left sphenoid sinus. It extended superiorly to the planum sphenoidale, inferiorly to the left clivus, and anteriorly to the left anterior clinoid process. The cortical bone was preserved, and there was no evidence of pathological fracture.

Differential Diagnosis

  • Fibrous dysplasia

  • Intraosseous meningioma

  • Paget disease

  • Sclerotic metastatic disease

Diagnosis: The final diagnosis is fibrous dysplasia. Based on the patient’s clinical history, McCune-Albright syndrome is also suspected.

McCune-Albright Syndrome (MAS) is a sporadic genetic mosaic disorder that is classically defined by the following triad of features:

  1. Fibrous Dysplasia
    • A condition in which normal bone is replaced by fibrous tissue, leading to structural weakness.
    • It often occurs on one side of the body (unilateral), causing pain or deformities in the face, arms, legs, or pelvis.
    • Recurrent bone fractures are common.

  2. Skin Pigmentation Abnormalities (Café-au-lait Spots)
    • Light brown, coffee-colored patches usually appear on one side of the body.
    • These spots are typically present at birth or appear in early childhood.
    • Unlike typical café-au-lait macules, the borders are irregular, often described as having a "Coast of Maine" appearance.

  3. Endocrine Abnormalities (e.g., Precocious Puberty)
    • Excess production of sex hormones can lead to early onset of puberty, particularly in girls (such as premature breast development or menstruation).
    • Other endocrine dysfunctions may include growth hormone excess, hyperthyroidism, or Cushing’s syndrome.

Discussion

Fibrous Dysplasia

Pathophysiology
Fibrous dysplasia is a congenital bone disorder in which normal bone marrow is replaced by abnormal fibrous tissue. It is caused by a postzygotic mutation in the GNAS gene, leading to the proliferation of undifferentiated skeletal precursor cells. Fibrous dysplasia can present in a monostotic form (involving a single bone) or a polyostotic form (involving multiple bones throughout the body).

Epidemiology

  • Estimated incidence: 1 in 5,000 to 10,000 people

  • Most patients are diagnosed before age 30

  • No gender predilection

  • Monostotic form is more common, accounting for approximately 75% of cases

  • Polyostotic fibrous dysplasia can occur in association with McCune-Albright syndrome (MAS)

McCune-Albright Syndrome (MAS) is a rare genetic mosaic disorder, classically characterized by the triad of:

  1. Fibrous Dysplasia

    • Abnormal development of bone replaced by fibrous tissue

    • Often unilateral, affecting face, limbs, or pelvis, with associated pain and deformity

    • Frequent pathological fractures

  2. Skin Pigmentation Abnormalities (Café-au-lait spots)

    • Light brown patches, often unilateral

    • Typically present from birth or early infancy

    • Characteristically have irregular borders (so-called “Coast of Maine” appearance)

  3. Endocrinopathies (e.g., Precocious Puberty)

    • Overproduction of sex hormones, particularly in girls, may lead to early breast development or menstruation

    • Can also be associated with hyperthyroidism, excess growth hormone, or Cushing’s syndrome

Etiology

  • Caused by somatic activating mutations in the GNAS gene

  • As the mutation occurs post-zygotically, the disorder manifests in mosaic form and is not inherited

Clinical Presentation

Most patients are asymptomatic, and fibrous dysplasia is often discovered incidentally. Symptomatic individuals may complain of bone pain or pathological fractures. Craniofacial involvement can cause symptoms due to compression of cranial nerves, such as vision loss. Patients with McCune-Albright syndrome classically present with polyostotic fibrous dysplasia, café-au-lait skin pigmentation, and hyperfunctional endocrinopathies.

Imaging Features

CT is the imaging modality of choice for evaluating fibrous dysplasia, as it effectively visualizes the morphologic changes of the bone. The classic radiographic appearance is a “ground-glass” matrix, representing fibrous replacement of normal marrow. Lesions typically show attenuation values between 60 and 140 HU. Fibrous dysplasia often causes expansion of the affected bone while preserving cortical integrity.

MRI is not required for the definitive diagnosis of fibrous dysplasia. Lesions are usually detected incidentally on MRI and further evaluated by CT. On MRI, lesions typically appear hypointense or mildly heterogeneous on T1-weighted images, heterogeneously hyperintense on T2-weighted images, and may enhance avidly post-contrast.

Bone scintigraphy using nuclear medicine techniques may be helpful to evaluate the extent of skeletal involvement.

Treatment

No treatment is necessary for asymptomatic patients, who are usually monitored with periodic imaging. Bisphosphonates may be prescribed to manage bone pain and osteoporosis associated with fibrous dysplasia. Surgical intervention may be required in cases of neurologic compression or pathological fractures.

Reference

  1. Boyce AM, Collins MT. Fibrous dysplasia/McCune-Albright syndrome. In: Adam MP, Mirzaa GM, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993–2024. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1239/
  2. Rosenberg AE. Bones, joints, and soft tissue tumors. In: Kumar V, Abbas AK, Aster JC, editors. Robbins and Cotran Pathologic Basis of Disease. 10th ed. Philadelphia, PA: Elsevier; 2020:1183–1185.
  3. DiCaprio MR, Enneking WF. Fibrous dysplasia: Pathophysiology, evaluation, and treatment. J Bone Joint Surg Am. 2005 Aug;87(8):1848–64. doi: 10.2106/JBJS.D.02942

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