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McCune-Albright syndrome (MAS)

Rare congenital sporadic disorder defined by the triad of polyostotic fibrous dysplasia of bone (FD), café au lait skin pigmentation, and peripheral precocious puberty (PP).

Rare congenital sporadic disorder defined by the triad of polyostotic fibrous dysplasia of bone (FD), café au lait skin pigmentation, and peripheral precocious puberty (PP).


Etiopathogenesis

G protein/cAMP/adenylate cyclase signaling pathway:

The disease results from postzygotic somatic mutations of the GNAS gene, specifically mutations in the cAMP regulating protein, Gs alpha.
  • Postzygotic mutations (lack of vertical transmission of the disease): Cases are somatic mosaics (skin & bone lesions tend to respect the midline and be on one or the other side of the body)
Molecular and developmental defect in McCune-Albright syndrome (MAS)
Molecular and developmental defect in McCune-Albright syndrome (MAS): A sporadic mutation occurs in a single cell (bright spot) at some point early in development. If this occurs at the inner call mass stage (embryonic stem cell stage), tissues from all 3 germ layers will be affected. As the cells derived from this mutated clone are dispersed throughout the organism, the final phenotype emerges, MAS. | Dumitrescu, C. E., & Collins, M. T. (2008). McCune-Albright syndrome. Orphanet journal of rare diseases, 3, 12. https://doi.org/10.1186/1750-1172-3-12

Presentation

Clinical triad:

Typically, the signs and symptoms of either PP or FD usually account for the initial presentation. In girls with PP, it is usually vaginal bleeding or spotting, accompanied by development of breast tissue, usually without the development of pubic hair. In boys, it can be bilateral (or unilateral) testicular enlargement with penile enlargement, scrotal rugae, body odor, pubic and axillary hair, and precocious sexual behavior. In retrospect, café-au-lait spots which are usually present at birth or shortly thereafter, are the most common but unappreciated “presenting” sign.
  • Fibrous dysplasia of bone (FD)
  • Café-au-lait skin spots
  • Precocious puberty (PP)
Café-au-lait skin pigmentation
Café-au-lait skin pigmentation: A) A typical lesion on the face, chest, and arm of a 5-year-old girl with McCune-Albright syndrome which demonstrates jagged “coast of Maine” borders, and the tendency for the lesions to both respect the midline and follow the developmental lines of Blashko. B) Typical lesions that are often found on the nape of the neck and crease of the buttocks are shown (arrows). | Dumitrescu, C. E., & Collins, M. T. (2008). McCune-Albright syndrome. Orphanet journal of rare diseases, 3, 12. https://doi.org/10.1186/1750-1172-3-12

Precocious puberty (PP):

M/C endocrine manifestation of MAS, and it is much more frequently found in girls than in boys due to the autonomous activation of ovarian tissue.
  • Girls: Vaginal bleeding/spotting accompanied by development of breast tissue, usually without the development of pubic hair.
  • Boys: Bilateral (or unilateral) testicular enlargement with penile enlargement, scrotal rugae, body odor, pubic and axillary hair, and precocious sexual behavior.

Fibrous dysplasia (FD):

Can involve any part and combination of the craniofacial, axial, and/or appendicular skeleton, can range from an isolated, asymptomatic monostotic lesion discovered incidentally to severe disabling polyostotic disease involving practically the entire skeleton and leading to progressive scoliosis, facial deformity, and loss of mobility, vision, and/or hearing.
  • Appendicular FD: Limp and/or pain (sometimes reported by children as being “tired”), but occasionally a pathologic fracture may be the presenting sign
  • Axial FD: Scoliosis
  • Craniofacial FD: Painless “lump” or facial asymmetry, M/C involved areas: Proximal femora and skull base

Other hyperfunctioning endocrinopathies:

  • Hyperthyroidism
  • Growth hormone excess
  • Cushing syndrome
  • Renal phosphate wasting with/without rickets/osteomalacia (50% cases)
Appearance of Cushing in a neonate
Appearance of Cushing in a neonate: Rounded (moon) facies with plethora and facial hirsutism are present. This is usually accompanied by the presence of typical café-au-lait spots elsewhere on the examination. | Dumitrescu, C. E., & Collins, M. T. (2008). McCune-Albright syndrome. Orphanet journal of rare diseases, 3, 12. https://doi.org/10.1186/1750-1172-3-12

Case study:

McCune Albright Syndrome explained by parents. Interview presented by The MAGIC Foundation for Children’s Growth.

Diagnosis

Diagnosis of MAS is usually established on clinical grounds. The evaluation of patients with MAS should be guided by knowledge of the spectrum of tissues that may be involved, with specific testing for each.

Diagnostic imaging:

Plain radiographs are often sufficient to make the diagnosis of FD. Isotopic bone scans (eg. 99Tc-MDP bone scan) are the most sensitive tool for detecting the presence of FD lesions, and are often useful, especially at the initial evaluation, for determining the extent of the disease and predicting functional outcome.
  • Appendicular FD:
    • Ground glass appearance: Typical expansile lesions with endosteal scalloping and thinning of the cortex with the matrix of the intramedullary tissue
    • Long bone lesions: “Lytic” appearance
    • Classic “shepherd’s crook” deformity of proximal femur: Undermineralized soft bones, prone to deformation
  • Craniofacial FD:
    • Sclerotic appearance: Due to relatively greater degree of mineralization of FD tissue in craniofacial bones
    • Ground glass appearance: On CT scanning
Radiographic appearance of fibrous dysplasia (FD)
Radiographic appearance of fibrous dysplasia (FD): A) A proximal femur with typical ground glass appearance and shepherd’s crook deformity in a 10-year-old child is shown. B) The appearance of FD in the femur of an untreated 40-year-old man demonstrates the tendency for FD to appear more sclerotic with time C) The typical ground glass appearance of FD in the craniofacial region on a CT image of a 10-year-old child is shown. The white arrows indicate the optic nerves, which are typically encased with FD. D) A CT image in a 40-year-old woman demonstrates the typical appearance of craniofacial FD in an older person, with mixed solid and “cystic” lesions. The Hounsfield Unit measurements of “cystic” lesions are quite useful in distinguishing soft tissue “cystic” lesions from true fluid-filled cysts, which are much more uncommon and tend to behave aggressively with rapid expansion and compression of vital structures. E-G) Bone Scintigraphy in FD. Representative 99Tc-MDP bone scans which show tracer uptake at affected skeletal sites, and the associated skeletal disease burden score (see ref. Collins, 2005) are shown. E) A 50-year-old woman with monostotic FD confined to a single focus involving contiguous bones in the craniofacial region. F) A 42-year-old man with polyostotic FD shows the tendency for FD to be predominantly (but not exclusively) unilateral, and to involve the skull base and proximal femur. G) A 16-year-old boy with McCune-Albright syndrome and involvement of virtually all skeletal sites (panostotic) is shown | Leslie WD, Reinhold C, Rosenthall L, Tau C, Glorieux FH. Panostotic fibrous dysplasia. A new craniotubular dysplasia. Clinical nuclear medicine. 1992;17:556–560. doi: 10.1097/00003072-199207000-00005.

Ultrasonography (USG):

  • Testicular lesions: Leydig and/or Sertoli cell hyperplasia with characteristic USG features (discrete hyper- and hypoechoic lesions and microlithiasis) with/without associated gonadotropin-independent precocious puberty
  • Thyroid lesions: Characteristic USG features (mixed cystic and solid lesions interspersed with areas of normal-appearing tissue), with/without non-autoimmune hyperthyroidism
A. Pelvic ultrasound in a girl age seven years, showing a complex unilateral ovarian cyst (defined by cross-hatches). The uterus is prepubertal in size (arrow). | B. Testicular ultrasound in an adult showing a heterogeneous lesion with mixed solid and cystic elements C&D: Typical thyroid ultrasound findings, including heterogeneity and a cystic (“Swiss cheese”) appearance | Boyce AM, Florenzano P, de Castro LF, et al. Fibrous Dysplasia/McCune-Albright Syndrome. 2015 Feb 26 [Updated 2019 Jun 27]. In: Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2020. Available from: https://www.ncbi.nlm.nih.gov/books/NBK274564/

Bone biopsy:

Biopsy of FD lesions can confirm the diagnosis if doubt remains after review of the radiographs.
  • Lamellation pattern lost (seen in normal bone under polarized light): Matrix produced in lesions is of woven type
  • Chinese writing pattern: Histopathological description of FD
  • Extensive unmineralized osteoid
Representative histological images of FD
Representative histological images of FD: A) Calvarial FD lesions are characterized by uninterrupted networks of bone trabeculae (b) embedded in the fibrous tissue (ft). B) In FD lesions from gnathic bones, newly formed bone trabeculae (b) are deposited within the fibrous tissue (ft) in a typical discontinuous and parallel pattern. C) Collagen fibers perpendicularly oriented to forming bone surfaces (Sharpey fibers, arrows) represent a recurrent histological feature of FD at all skeletal sites. D-E) Osteomalacic changes and FGF23 production in FD. D) In many cases of FD, processing for undecalcified embedding reveals excess osteoid (asterisks) and severe undermineralization of the fibrous dysplastic bone. E) The mineralization defect of the FD tissue is related to elevated levels of FGF23 produced by activated FD osteogenic cells (arrows), as shown by in situ hybridization. | Dumitrescu, C. E., & Collins, M. T. (2008). McCune-Albright syndrome. Orphanet journal of rare diseases, 3, 12. https://doi.org/10.1186/1750-1172-3-12

Differential diagnoses:

MAS is most commonly confused with neurofibromatosis (NF), usually when a child presents with a large café-au-lait spot. The location and shape of the spots usually can help to distinguish between the MAS and NF. The spots in MAS have jagged borders (coast of Maine), whereas those in NF are smooth (coast of California). Although the spots can cross the midline, more often, they demonstrate a “respect” of the midline. Frequent locations are the nape of the neck and the crease at the apex of the buttocks (Fig. ​(Fig.1).1). In MAS, the skeletal disease (PFD) almost always involves one or both proximal femurs and/or the skull base, as well as other locations. Skeletal involvement in NF is uncommon and usually involves the diaphyses of the long bones, especially the tibiae, often leading to pseudoarthrosis [38,39].
  • Café-au-lait spot:
    • Neurofibromatosis (NF): Location and shape of spots distinguish between MAS and NF
      • MAS: Jagged borders (coast of Maine) for spots, don’t cross midline, skeletal involvement common
      • NF: Smooth borders (coast of California) for spots, cross midline, skeletal involvement uncommon
  • Precocious puberty:
    • Idiopathic central precocious puberty
    • Ovarian neoplasm
  • Isolated skeletal lesions in the absence of skin or endocrine findings represent FD (MFD or PFD).
    • Osteofibrous dysplasia “Campanacci’s lesion”: Ossifying fibroma of long bones; histologically distinct from FD
    • Non-ossifying fibromas (NOF): Lack of multiple skeletal foci and absence of extraskeletal findings distinguish FD from NOF
    • Cemento ossifying fibromas: Histologically similar to FD in jaw but tend to behave more aggressively

Management

Treatment is dictated by the tissues affected, and the extent to which they are affected.

Fibrous dysplasia (FD):

Current management is focused on optimizing function and minimizing morbidity related to fractures and deformity. Generally, some form of surgical intervention is recommended. Bisphosphonates are frequently used in the treatment of FD. Strengthening exercises are recommended to help maintaining the musculature around the FD bone and minimize the risk for fracture. Treatment of all endocrinopathies is required.
Recommended management for fibrous dysplasia in individuals with fibrous dysplasia/McCune-Albright syndrome
Recommended management for fibrous dysplasia in individuals with fibrous dysplasia/McCune-Albright syndrome | Boyce AM, Florenzano P, de Castro LF, et al. Fibrous Dysplasia/McCune-Albright Syndrome. 2015 Feb 26 [Updated 2019 Jun 27]. In: Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2020. Available from: https://www.ncbi.nlm.nih.gov/books/NBK274564/

Precocious puberty (PP):

Current treatment of peripheral PP in girls with MAS revolves around the use of anti-estrogens, including aromatase inhibitors (AIs) and estrogen receptor modulators.

Hyperthyroidism:

Methimazole is effective for medical management of hyperthyroidism and is the first line of treatment. Because FD/MAS-associated hyperthyroidism is persistent, most affected individuals ultimately elect for definitive treatment. Thyroidectomy is the preferred definitive treatment in most affected individuals. Total gland resection is generally recommended due to the potential for thyroid tissue regrowth.
Recommended management for hyperthyroidism in individuals with fibrous dysplasia/McCune-Albright syndrome
Recommended management for hyperthyroidism in individuals with fibrous dysplasia/McCune-Albright syndrome | Boyce AM, Florenzano P, de Castro LF, et al. Fibrous Dysplasia/McCune-Albright Syndrome. 2015 Feb 26 [Updated 2019 Jun 27]. In: Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2020. Available from: https://www.ncbi.nlm.nih.gov/books/NBK274564/

Growth hormone (GH) excess:

Medical therapy is the preferred first-line treatment. Options include (alone or in combination) somatostatin analogs and the growth hormone receptor antagonist pegvisomant
Recommended management for growth hormone excess in individuals with fibrous dysplasia/McCune-Albright syndrome
Recommended management for growth hormone excess in individuals with fibrous dysplasia/McCune-Albright syndrome | Boyce AM, Florenzano P, de Castro LF, et al. Fibrous Dysplasia/McCune-Albright Syndrome. 2015 Feb 26 [Updated 2019 Jun 27]. In: Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2020. Available from: https://www.ncbi.nlm.nih.gov/books/NBK274564/

Neonatal Cushing syndrome (hypercortisolism):

Definitive treatment includes surgical removal of the diseased adrenal glands. For medical treatment metyrapone is frequently effective, and is preferred over ketoconazole in children with liver abnormalities.
Recommended management for hypercortisolism in individuals with fibrous dysplasia/McCune-Albright syndrome
Recommended management for hypercortisolism in individuals with fibrous dysplasia/McCune-Albright syndrome | Boyce AM, Florenzano P, de Castro LF, et al. Fibrous Dysplasia/McCune-Albright Syndrome. 2015 Feb 26 [Updated 2019 Jun 27]. In: Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2020. Available from: https://www.ncbi.nlm.nih.gov/books/NBK274564/

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