Bone
Fibrous and fibroosseous tumors of bone
McCune-Albright syndrome

Senior Author: Jessica L. Davis, M.D.
Editorial Board Member: Borislav Alexiev, M.D.
Editor-in-Chief: Debra Zynger, M.D.
Travis H. Johnson, D.O., M.S.
Jessica L. Davis, M.D.

Topic Completed: 9 October 2019

Revised: 5 November 2019

Copyright: 2003-2019, PathologyOutlines.com, Inc.

PubMed Search: McCune-Albright syndrome[TI] bone pathology

See Also: Fibrous dysplasia, Mazabraud syndrome

Travis H. Johnson, D.O., M.S.
Jessica L. Davis, M.D.
Page views in 2018: 472
Page views in 2019 to date: 673
Cite this page: Johnson TH, Davis JL. McCune-Albright syndrome. PathologyOutlines.com website. http://www.pathologyoutlines.com/topic/bonefibrousdysplasiamccunealbright.html. Accessed November 14th, 2019.
Definition / general
  • McCune-Albright syndrome (MAS) is a rare condition resulting from postzygotic activating somatic mutations in the GNAS gene
  • Exact presentation and severity depend on the extent of mosaicism and the involved tissues (Curr Osteoporos Rep 2015;13:146)
  • Most patients are diagnosed in childhood or adolescence
Essential features
  • Classically defined as the triad of
    • Polyostotic fibrous dysplasia of bone
    • Precocious puberty
    • 3+ café au lait macules
  • However, a more inclusive definition has been proposed, consisting of
    • Monostotic fibrous dysplasia of bone or polyostotic fibrous dysplasia of bone
    • Hyperfunctional endocrinopathy or café au lait macules (J Bone Miner Res 2006;21:P99)
Terminology
  • McCune-Albright syndrome (MAS) has no synonyms
ICD coding
  • ICD-10: Q78.1 - polyostotic fibrous dysplasia
  • ICD-11: FB80.0 - fibrous dysplasia of bone
Epidemiology
Sites
Pathophysiology
  • Constitutively active mutant GNAS results in increased cyclic adenosine monophosphate, which
    • Promotes proliferation and inhibits differentiation of fibroblasts, which replace normal bone, producing fibrous dysplasia lesions
    • Promotes proliferation and autonomous function of endocrine organs
  • Fibrous dysplasia elaborates fibroblast growth factor 23, which
    • Inhibits renal resorption of phosphate
    • Causes hypophosphatemia
    • Causes hyperphosphaturia
  • Examples:
Etiology
  • Results from de novo mutations in GNAS (Curr Osteoporos Rep 2015;13:146)
    • No inherited case has ever been reported
    • Germline GNAS mutation is presumed embryonic lethal
  • Has no risk factors
Clinical features
  • 2 most common presentations are fibrous dysplasia related pain and precocious puberty
  • Fibrous dysplasia
    • May be monostotic or polyostotic
    • When polyostotic, may be unilateral, in keeping with postzygotic mutation
  • Classical and most common endocrinopathy is precocious puberty; however, other endocrinopathies include
  • Café au lait macules typically
    • Are present at or shortly after birth
    • Are recognized after another feature of the disease has prompted a skin survey
    • Are near the midline
    • Respect the lines of Blaschko
    • Have jagged irregular borders, unlike the smooth borders that are characteristic of macules seen in neurofibromatosis
    • Are ipsilateral with fibrous dysplasia (Orphanet J Rare Dis 2008;3:12)
Diagnosis
  • Essentially a clinical diagnosis
  • Genetic testing:
    • Not routinely performed but available
    • False negatives are common due to mosaicism and sampling
    • Positive results merely confirm a clinical diagnosis
    • No genotype / phenotype correlation, therefore no prognostic value (Orphanet J Rare Dis 2008;3:12)
  • When there is clinical suspicion:
    • Skeletal survey to identify lesions suspicious for fibrous dysplasia
    • CT is more sensitive for craniofacial fibrous dysplasia
    • Biopsy can confirm fibrous dysplasia
    • Skin survey to identify café au lait macules
    • If not apparent at presentation, endocrinopathies may become apparent with laboratory studies and focused examinations
Laboratory
  • Some patients have multiple endocrinopathies; others have none
  • The following laboratory abnormalities may be present in any combination (Orphanet J Rare Dis 2008;3:12):
    • Depressed serum phosphate
    • Elevated urine phosphate
    • Elevated cortisol
    • Elevated sex steroid hormones
    • Elevated thyroid hormone
    • Depressed thyroid stimulating hormone
Radiology images

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Ulnar fracture

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Lucency in long bones

Prognostic factors
Case reports
Treatment
  • There is no specific therapy
  • Various endocrinopathies are treated just as their sporadic counterparts
  • Fibrous dysplasia is treated just as its sporadic counterpart (Holbrook: McCune Albright Syndrome, 2019)
Clinical images

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4 year old girl with mosaic skin and body cast due to fractures

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Café au lait spots

Gross images

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Ovarian abnormalities

Microscopic (histologic) description
  • Fibrous dysplasia lesions are histologically indistinguishable from nonsyndromic fibrous dysplasia, characterized by (Arch Pathol Lab Med 2013;137:134)
    • Woven bone with trabeculae that are thin, irregular and curvilinear
    • Fibrous stroma
    • Absence of osteoblastic rimming
Microscopic (histologic) images

Contributed by Jessica L. Davis, M.D.

Fibrous dysplasia

Molecular / cytogenetics description
  • Mutation specific restriction enzyme digest (MSRED) method may identify mutations in codon 201 or 227 of the GNAS1 gene (Histopathology 2007;50:691)
Sample pathology report
  • Bone, biopsy:
    • Fibrous dysplasia of bone (see comment)
    • Comment: Fibrous dysplasia is most commonly sporadic but is also a typical presenting feature of McCune-Albright syndrome and Mazabraud syndrome. Clinical correlation is advised.
Differential diagnosis
Additional references
Board review question #1
A 23 year old man diagnosed at age 8 with McCune-Albright syndrome is considering starting a family and seeks genetic counseling. Which of the following best describes his likelihood of having an affected child?



  1. 0% chance of having an affected child
  2. 25% chance of having an affected female child
  3. 25% chance of having an affected male child
  4. 50% chance of having an affected child
  5. 100% chance of having an affected child
Board review answer #1
A. 0% chance of having an affected child. McCune-Albright syndrome results from postzygotic mutations and an inherited case has never been reported. Germline mutation in GNAS is believed to be embryonic lethal. The likelihood the patient will have an affected child is effectively 0% (Curr Osteoporos Rep 2015;13:146).

Reference: McCune-Albright syndrome

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Board review question #2
A 6 year old girl is brought to her pediatrician by her father who is concerned about her early breast development. On exam, the patient's breasts are Tanner stage 3 and the clinician also notes a large, irregularly contoured pigmented macule on her left flank. In addition to starting letrozole, which of the following is an appropriate next step?

  1. Diagnose the patient with McCune-Albright syndrome and order a skeletal survey
  2. Perform a complete skin survey in clinic and order a skeletal survey
  3. Perform a punch biopsy at the edge of the macule
  4. Send a blood sample for sequencing of GNAS
  5. Send a tissue sample for sequencing of GNAS
Board review answer #2
B. Perform a complete skin survey in clinic and order a skeletal survey. A complete skin survey and skeletal survey would potentially reveal additional findings that would rule in or provisionally rule out McCune-Albright syndrome (MAS). As presented in the question, the patient has findings suggestive of but not diagnostic for MAS, making A wrong. A punch biopsy, as in C, would likely reveal melanocyte proliferation but would not aid in diagnosis or direct treatment. Sequencing studies, as in D and E, if negative, would not rule out MAS and if positive, would only confirm a clinical diagnosis; thus, neither is contributory (Curr Osteoporos Rep 2015;13:146).

Reference: McCune-Albright syndrome

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