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Fibrous Dysplasia/McCune-Albright Syndrome

Synonym: FD/MAS

, MD, , MD, , PhD, and , MD.

Author Information

Initial Posting: ; Last Update: August 16, 2018.

Summary

Clinical characteristics.

Fibrous dysplasia/McCune-Albright syndrome (FD/MAS), the result of an early embryonic postzygotic somatic activating pathogenic variant in GNAS (encoding the cAMP pathway-associated G-protein, Gsα), is characterized by involvement of the skin, skeleton, and certain endocrine organs. However, because Gsα signaling is ubiquitous, additional tissues may be affected.

Café au lait skin macules are common and are usually the first manifestation of the disease, apparent at or shortly after birth. Fibrous dysplasia (FD), which 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. Endocrinopathies include:

  • Gonadotropin-independent precocious puberty resulting from recurrent ovarian cysts in girls and autonomous testosterone production in boys;
  • Testicular lesions with or without associated gonadotropin-independent precocious puberty;
  • Thyroid lesions with or without non-autoimmune hyperthyroidism;
  • Growth hormone excess;
  • FGF23-mediated phosphate wasting with or without hypophosphatemia in association with fibrous dysplasia; and
  • Neonatal hypercortisolism.

The prognosis for individuals with FD/MAS is based on disease location and severity.

Diagnosis/testing.

In most individuals, the diagnosis of FD/MAS is based on the finding of two or more typical clinical features. In individuals whose only clinical finding is monostotic fibrous dysplasia, identification of a somatic activating pathogenic variant in GNAS by molecular genetic testing is required to establish the diagnosis. Variant detection depends on the level of mosaicism in the tissue and the sensitivity of the technique.

Management.

Treatment of manifestations: Management is most effectively accomplished by a multidisciplinary team of specialists.

  • FD. Management focuses on optimizing function and minimizing morbidity related to fractures and deformity (including scoliosis).
  • Precocious puberty. Treatment prevents bone age advancement and compromise of adult height. For girls, the aromatase inhibitor letrozole is used; for boys, treatment options are less well established.
  • Thyroid disease. Methimazole effectively manages hyperthyroidism; however, because hyperthyroidism is persistent, thyroidectomy is common.
  • Growth hormone excess. Medical therapy is the preferred first-line treatment; options include (alone or in combination) octreotide and the growth hormone receptor antagonist pegvisomant.
  • Hypercortisolism. Treatment varies by the presentation of neonatal Cushing syndrome.

Surveillance:

FD/MAS. Monitor for the following:

  • Infants: clinical signs of hypercortisolism
  • All children: growth acceleration and other clinical signs of precocious puberty and/or growth hormone excess
  • Children:
    • Age <5 years: thyroid function abnormalities
    • With thyroid abnormalities on ultrasound examination but normal thyroid function: periodic monitoring of thyroid function
  • Males: testicular lesions (physical examination and testicular ultrasound)
  • Individuals on:
    • Pegvisomant: hepatotoxicity
    • Somatostatin analogs: signs and symptoms of gallbladder disease
  • Females: breast cancer (earlier than is recommended for the general population)

FD

  • Periodic radiographs to monitor existing FD and development of new lesions
  • Periodic serum phosphorus (for development of hypophosphatemia) and 25-hydroxyvitamin D levels
  • Craniofacial FD: yearly vision and hearing evaluations; periodic skull CT; routine serum IGF-1 levels through young adulthood
  • Spine FD: close monitoring for progressive scoliosis

Agents/circumstances to avoid: Contact sports and other high-risk activities (when skeletal involvement is significant); prophylactic optic nerve decompression (in individuals with craniofacial FD); surgical removal of ovarian cysts; radiation therapy for treatment of FD; risk factors for malignancy (e.g., radiation exposure).

Genetic counseling.

FD/MAS is not inherited. No parent of a child with FD/MAS has been demonstrated to have any significant, distinctive manifestations of the disorder. The risk to sibs is expected to be the same as in the general population. There are no verified instances of vertical transmission of FD/MAS.

Diagnosis

Fibrous dysplasia/McCune-Albright syndrome (FD/MAS) is usually diagnosed on clinical grounds, although formal diagnostic criteria have not been published.

Suggestive Findings

Fibrous dysplasia/McCune-Albright syndrome (FD/MAS) should be suspected in individuals with any of the following skin, skeletal, or endocrine features.

Skin. Individuals may have characteristic café au lait skin macules.

  • Borders are jagged and irregular, often referred to as resembling the "coast of Maine" (in contrast to the smooth-bordered "coast of California" lesions seen in neurofibromatosis type 1).
  • Distribution shows an association with ("respecting") the midline of the body and following the developmental lines of Blaschko, which reflect patterns of embryonic cell migration (see Figure 1).
Figure 1.

Figure 1.

Café au lait skin pigmentation A. Skin lesions in a newborn demonstrating the characteristic association with the midline of the body, and distribution reflecting patterns of embryonic cell migration (developmental lines of Blaschko)

Skeletal. Fibrous dysplasia (FD), a condition in which normal bone and bone marrow are replaced by fibroosseous tissue, results in an increased risk of fractures, deformity, functional impairment, and pain.

  • FD can be classified as monostotic (i.e., involvement of 1 bone) or polyostotic (i.e., involvement of >1 bone).
  • FD can involve any part and combination of the craniofacial, axial, and/or appendicular skeleton (see Figure 2).
  • The initial radiologic evaluation for FD should include a 99Tc-MDP bone scan.
    • Areas of skeletal involvement identified on scintigraphy should be further evaluated with radiographs and head computerized tomography (CT), depending on the location and extent of the disease.
    • See Figure 3 for the suggested evaluations used to diagnose FD.
Figure 2.

Figure 2.

Fibrous dysplasia (FD) A. Proximal femur FD demonstrating the typical ground-glass appearance with a coxa vara ("shepherd's crook") deformity

Figure 3. . Suggested evaluations to determine if fibrous dysplasia (FD) is present and the extent of disease if FD is present.

Figure 3.

Suggested evaluations to determine if fibrous dysplasia (FD) is present and the extent of disease if FD is present.

Endocrine. Findings may include the following:

  • Gonadotropin-independent precocious puberty
  • Testicular lesions including Leydig and/or Sertoli cell hyperplasia with characteristic ultrasonographic features, with or without associated gonadotropin-independent precocious puberty (see Figure 4B)
  • Thyroid lesions with characteristic ultrasonographic features, with or without non-autoimmune hyperthyroidism (see Figures 4C and 4D)
  • Growth hormone excess
  • Fibroblast growth factor 23 (FGF23)-mediated phosphate wasting with or without hypophosphatemia
  • Neonatal hypercortisolism
Figure 4.

Figure 4.

Ultrasonography 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).

Establishing the Diagnosis

The diagnosis of FD/MAS is established in individuals who have two or more typical clinical features of FD/MAS. In individuals whose only clinical finding is monostotic fibrous dysplasia, identification of a somatic activating GNAS pathogenic variant is required to confirm the diagnosis (see Table 1).

Molecular genetic testing approaches include targeted analysis of codons p.Arg201 and p.Gln227. Testing a sample of the lesional tissue, if possible, has the highest clinical sensitivity in PCR-sequencing-based diagnostic methods:

  • ~80% in lesional tissue
  • ~20%-30% in peripheral blood lymphocytes

Note: (1) Variant detection depends on the level of mosaicism in the tissue and the sensitivity of the technique. Detection frequency of a variant at p.Arg201 using standard PCR was highest in endocrine organs and lowest in affected skin specimens [Lumbroso et al 2004]. The ability to detect mosaicism affects the detection rate of the assay (see Table 1 and Table 8). (2) Targeted analysis may be performed by sequencing of GNAS exons 8 and 9. GNAS variants other than those previously reported to be associated with FD/MAS would likely be interpreted as variants of unknown significance. (3) Gsα is expressed in nearly all tissues from both maternal and paternal GNAS alleles. However, GNAS is a complex locus where alternative transcripts and additional phenotypes may result from GNAS imprinting (see Genetically Related Disorders and Molecular Genetics).

Table 1.

Molecular Genetic Testing Used in Fibrous Dysplasia/McCune-Albright Syndrome

Gene 1Test MethodVariants DetectedProportion of Probands with a Pathogenic Variant 2 Detectable by This Method
GNASTargeted analysis of lesion biopsy of exons 8 and 9 3, 4p.Arg201His, p.Arg201Cys 5, 68%-90% 7
75%-100% 8
p.Gln227Leu 65% 5
1.
2.

See Molecular Genetics for information on allelic variants detected in this gene.

3.

Targeted analysis may be performed by sequence analysis. Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

4.

Testing tissue from a lesion biopsy has a higher clinical yield than testing a blood sample. The detection rate for a blood sample is ~20%-30% [Lumbroso et al 2004, Kalfa et al 2006].

5.

Somatic GNAS missense variants in individuals with FD/MAS are known to occur at only one of two amino acid residues: p.Arg201 (>95% of pathogenic variants) [Lumbroso et al 2004] or p.Gln227 (<5%) [Idowu et al 2007].

6.

Rarely, other amino acid substitutions at p.Arg201 and at p.Gln227 have been detected (see Molecular Genetics).

7.

Variant detection depends on the level of mosaicism in the tissue and the sensitivity of the technique. Variant detected at p.Arg201 using standard PCR was highest in endocrine organs and lowest in affected skin specimens [Lumbroso et al 2004].

8.

When modified primers (peptide nucleic acid) [Bianco et al 2000] and next-generation sequencing [Narumi et al 2013] technologies are combined [Narumi et al 2013], a p.Arg201 variant can be detected in virtually all affected tissues and in leukocytes of up to 75% of individuals.

Clinical Characteristics

Clinical Description

Fibrous dysplasia/McCune-Albright syndrome (FD/MAS) results from mosaic somatic activating pathogenic variants in GNAS, which encodes the cAMP pathway-associated G-protein, Gsα. Affected tissues can include those derived from ectoderm, mesoderm, and endoderm, and commonly include skin, skeleton, and certain endocrine organs. However, because Gsα signaling is present in virtually every tissue, additional sites may be affected.

The phenotypic spectrum of FD/MAS ranges from asymptomatic incidental findings to neonatal lethality. There is a high degree of variability between individuals, both in the number of affected tissues and the degree to which they are affected. Disease manifestations depend on the time during embryogenesis that the somatic pathogenic variant occurred, the tissue involved, and the role of Gsα in the affected tissue. Pathogenic variants occurring early in development lead to widespread disease, while those occurring later in development lead to limited disease.

Pigmented macules. Café au lait skin macules are common and are usually the first manifestation of the disease, apparent at or shortly after birth. There is no correlation between the size of the skin lesions and the extent of disease, nor between the distribution of skin lesions and the location of fibrous dysplasia.

Fibrous dysplasia of bone. As with skin, fibrous dysplasia demonstrates a mosaic pattern: it can involve any part and combination of the craniofacial, axial, and/or appendicular skeleton. The bones most commonly involved are the skull base and proximal femurs [Kelly et al 2008]. While there is generally a central-to-peripheral gradient, any combination of involved bones is possible.

Fibrous dysplasia can manifest along a wide spectrum: from an isolated, asymptomatic monostotic lesion discovered incidentally to severe, disabling polyostotic disease involving practically the entire skeleton and leading to loss of vision, hearing, and/or mobility.

Individual bone lesions typically manifest during the first few years of life and expand during childhood. The vast majority of clinically significant bone lesions are detectable by age ten years, with few new and almost no clinically significant bone lesions appearing after age 15 years [Hart et al 2007]. In adulthood, fibrous dysplasia lesions typically become less active, likely related to apoptosis of pathogenic variant-bearing cells [Kuznetsov et al 2008].

The clinical presentation and course of fibrous dysplasia (FD) depends on the location and extent of the affected skeleton:

  • Appendicular skeleton
    • Children with fibrous dysplasia in the appendicular skeleton typically present with a limp, pain, and/or pathologic fractures.
    • Recurrent fractures and progressive deformity may lead to difficulties with ambulation and loss of mobility.
  • Craniofacial region
    • FD may present as a painless "lump" or facial asymmetry.
    • Expansion of craniofacial lesions may lead to progressive facial deformity (see Figure 2B), and in rare cases (usually in association with growth hormone excess) loss of vision and/or hearing due to compromise of the optic nerves and/or external auditory canals [Cutler et al 2006, Boyce et al 2018].
  • Vertebrae
    • FD involving the vertebrae is common, and may lead to scoliosis, which in rare instances may be severe, progressive, and even lethal [Leet et al 2004b].
    • Untreated, progressive scoliosis is one of the few features of FD that can lead to early morbidity.

Bone pain is a common complication of fibrous dysplasia. Although bone pain may present at any age, it is common for bone pain to be absent in childhood, occur in adolescence, and progress into adulthood [Kelly et al 2008].

Aneurysmal bone cysts are rapidly expanding fluid-filled lesions that form within preexisting areas of FD. Such lesions are best detected by MRI. Affected individuals experience acute onset of severe pain, rapidly expanding localized deformity, and rarely – when cysts compress the optic nerve – rapid loss of vision. Aneurysmal bone cysts thus carry a high risk of morbidity (see Management).

Malignant transformation of FD lesions is a rare complication. Many instances of malignant transformation were reported in association with previous radiation treatment [Ruggieri et al 1994]. Growth hormone excess may be a predisposing factor [Salenave et al 2014].

Radiographic appearance of fibrous dysplasia varies according to location:

  • Radiographs of the appendicular skeleton show expansive lesions with endosteal scalloping, thinning of the cortex, and a "ground glass" appearance (Figure 2A).
  • Fibrous dysplasia in the craniofacial skeleton is typically expansile and appears sclerotic on x-ray, but demonstrates a typical "ground glass" appearance on computed tomography (Figure 2C).
  • With aging, fibrous dysplasia lesions in the appendicular skeleton tend to become sclerotic on radiographs and craniofacial fibrous dysplasia lesions develop a "cystic" appearance (Figure 2D).

Endocrinopathies can include any of the following:

  • Precocious puberty. Precocious puberty is common in girls with FD/MAS (~85%), and is often the presenting feature. Recurrent ovarian cysts (Figure 4A) lead to intermittent estrogen production resulting in breast development, growth acceleration, and vaginal bleeding; during the intervals between cyst formation, breast tissue typically regresses and estrogen levels fall to prepubertal levels. Ovarian cysts typically continue into adulthood, leading to irregular menses. This has the potential to interrupt ovulatory cycles, which may increase the time to conception in adult women. Ovarian torsion has been seen rarely in girls and women with large and persistent cysts [Clark et al 2000].
    Precocious puberty is less common in boys with FD/MAS (~10-15%), and is due to autonomous testosterone production [Boyce et al 2012a], which leads to progressive pubertal development including growth acceleration, pubic and axillary hair, acne, and aggressive and/or inappropriately sexual behavior.
    In both girls and boys, prolonged autonomous sex steroid production typically leads to activation of the hypothalamic-pituitary axis and the development of central precocious puberty.
  • Fertility. The effects of autonomous sex steroid production on pituitary-gonadal function and fertility in adults are not well characterized. Women with FD/MAS may have recurrent cysts leading to irregular menses in adulthood [Lala et al 2007]. While many women in the NIH cohort have achieved successful pregnancies, it is possible that interruption of ovulatory cycles could decrease fertility and increase the time to conception [Authors, personal observation].
  • Testicular abnormalities. Testicular abnormalities are seen in the majority of boys and men with MAS (~85%), and typically manifest as unilateral or bilateral macroorchidism [Boyce et al 2012a]. Ultrasound examination demonstrates discrete hyper- and hypoechoic lesions and microlithiasis, corresponding to areas of Leydig and/or Sertoli cell hyperplasia (see Figure 4B).
    The potential for malignant transformation of testicular lesions is unknown, but appears to be low [Boyce et al 2012a].
  • Thyroid disease. Thyroid involvement in FD/MAS is common. Approximately half of individuals with FD/MAS have ultrasound findings consistent with thyroid involvement, including mixed cystic and solid lesions interspersed with areas of normal-appearing tissue (Figure 4C and 4D) [Celi et al 2008, Tessaris et al 2012a].
    Hyperthyroidism is present in 10% to 30% of individuals with FD/MAS, and results from both increased hormone production and increased conversion of thyroxine (T4) to triiodothyronine (T3) [Celi et al 2008].
    Hyperthyroidism is typically mild to moderate, but may be severe, and if undetected can lead to thyroid storm during anesthetic induction for surgery [Lawless et al 1992].
    Uncontrolled hyperthyroidism may lead to bone age advancement, elevated bone turnover, and fractures.
    Malignant transformation of affected thyroid tissue has rarely been reported [Collins et al 2003].
  • FGF23-mediated phosphate wasting. In the majority of individuals with FD, increased production of the phosphaturic hormone FGF23 in FD tissue results in a renal tubulopathy with some degree of phosphate wasting [Collins et al 2001]. However, frank hypophosphatemia in persons with FD is infrequent, in part due to alterations in FGF23 processing that takes place in FD tissue and results in increased cleavage of FGF23 to its inactive fragments [Bhattacharyya et al 2012]. The degree of FGF23 overproduction in FD correlates with disease severity and skeletal burden; thus, frank hypophosphatemia is only seen in individuals with a substantial FD burden [Riminucci et al 2003].
    In contrast to most other features of FD/MAS, hypophosphatemia may wax and wane over the course of a person's lifetime and become more severe during periods of rapid skeletal growth. Hypophosphatemia may resolve as persons with FD become older, likely reflecting the intrinsic changes in FD that occur with age [Kuznetsov et al 2008].
    Affected individuals with frank hypophosphatemia may develop rickets/osteomalacia, increased fractures, and bone pain [Leet et al 2004a].
  • Growth hormone excess. Approximately 15%-20% of individuals with FD/MAS harbor GNAS pathogenic variants in the anterior pituitary that can lead to autonomous growth hormone production; approximately 80% of affected individuals with autonomous growth hormone production will also have hyperprolactinemia [Salenave et al 2014].
    Affected individuals typically present with linear growth acceleration, and may develop features of acromegaly. Clinically, growth hormone excess must be distinguished from precocious puberty and hyperthyroidism, which also present with growth acceleration.
    Untreated growth hormone excess is associated with expansion of craniofacial fibrous dysplasia, leading to macrocephaly and increased risk of vision loss [Boyce et al 2013] (see Figure 2B).
  • Hypercortisolism. Infants with FD/MAS may rarely present with Cushing syndrome due to excess cortisol production from the fetal adrenal gland [Brown et al 2010, Carney et al 2011]. Clinical symptoms typically develop in the neonatal period, and may be severe, leading to critical illness and death. Spontaneous regression has been reported in approximately half of survivors, presumably related to fetal adrenal involution.

Liver

Gastrointestinal

  • Gastroesophageal reflux manifests in childhood and may be severe.
  • Upper gastrointestinal polyps have been recently described as a common finding in individuals with FD/MAS [Wood et al 2017].

Pancreas. Approximately 15% of individuals with FD/MAS have pancreatic complications:

  • Pancreatitis
  • Intraductal papillary mucinous neoplasms (IPMN), which may present with variable grades of dysplasia [Gaujoux et al 2014, Wood et al 2017]
    An individual with pancreatic carcinoma derived from an intestinal subtype of IPMN has been described [Parvanescu et al 2014].

Myxomas. Intramuscular myxomas are benign, usually asymptomatic, and often found incidentally.

Hematology

  • Bone and bone marrow are, to varying degrees, replaced by fibroosseous tissue typically devoid of hematopoietic marrow.
  • There have been reports of bone marrow failure with pancytopenia and extramedullary hematopoiesis requiring splenectomy in individuals with FD/MAS [Mahdi et al 2017, Robinson et al 2018].

Breast cancer. The risk of breast cancer in women with FD/MAS may be increased and it can occur at a younger age compared to the general population. However, pathogenic activating GNAS variants were identified in only half of the breast tumors from women with FD/MAS studied [Majoor et al 2018a].

Health-related quality of life. Several series have shown impaired physical functioning in individuals with FD/MAS, strongly correlated with disease severity. Nevertheless, individuals with this condition show preserved social and emotional functioning. This finding is important for prognosis and parental reassurance [Kelly et al 2005, Majoor et al 2018b].

Genotype-Phenotype Correlations

There are no known genotype-phenotype correlations.

To date, only activating GNAS somatic pathogenic variants at residues p.Arg201 and p.Gln227 have been identified in individuals with FD/MAS.

Disease severity is likely correlated with the degree of mosaicism and the tissues that are affected.

Nomenclature

The association of intramuscular myxomas with FD/MAS has been termed Mazabraud syndrome [Cox et al 2017].

Prevalence

FD/MAS is rare. While reliable data of prevalence are not available, estimates range between 1:100,000 and 1:1,000,000.

In contrast, fibrous dysplasia (particularly the monostotic form) is not rare, and has been estimated to account for as much as 7% of all benign bone tumors.

FD/MAS affects both sexes and shows no predilection for any particular populations.

Differential Diagnosis

Neurofibromatosis type 1 (NF1) and FD/MAS have several overlapping features, including café au lait macules and skeletal abnormalities. Skin findings in NF1 include six or more café au lait macules, which are generally smooth bordered ("coast of California," as opposed to the irregularly bordered "coast of Maine" lesions seen in FD/MAS). Skeletal features of NF1 include kyphoscoliosis, sphenoid dysplasia, cortical thinning of long bones, and bowing and dysplasia, particularly of the tibia, which may result in pseudarthroses. Distinct features of NF1 include tumors of the nervous system such as neurofibromas and optic gliomas, pigmented iris hamartomas, and axillary freckling. NF1 is caused by heterozygous pathogenic variants in NF1 and is inherited in an autosomal dominant manner.

Cutaneous-skeletal hypophosphatemia syndrome is a mosaic disorder resulting from somatic activating pathogenic variants in HRAS and NRAS [Lim et al 2014]. Affected individuals develop cutaneous lesions (epidermal and large congenital melanocytic nevi) following a mosaic distribution, a mosaic skeletal dysplasia, overproduction of FGF23 resulting in rickets/osteomalacia, and variable other associated anomalies of the eye, brain, and vasculature [Ovejero et al 2016].

Fibroosseous skeletal lesions may have radiologic and/or histologic features similar to fibrous dysplasia. These lesions are typically solitary, are not associated with extraskeletal features, and do not harbor pathogenic variants in GNAS.

  • Giant cell tumors of bone are acquired lesions with histopathologic features similar to fibrous dysplasia, including proliferation of bone marrow stromal cells and the presence of multiple multinucleated giant cells. Giant cell tumors are typically benign, but may result in localized bone destruction and (rarely) metastases.
  • Ossifying fibromas are benign lesions typically affecting the mandible and maxillae and presenting with local expansion of a firm, painless mass. Ossifying fibromas are generally more aggressive than craniofacial fibrous dysplasia lesions, and are treated with surgical excision.
  • Osteofibrous dysplasia lesions typically occur in children younger than age ten years, and most commonly affect the anterior tibia. Affected children present with painless localized swelling and, in rare cases, with fracture or progressive deformity. Radiographs show a well-circumscribed radiolucent lesion with a characteristic sclerotic rim along the intra-cortical surface.
  • Cherubism is characterized by progressive fibroosseous lesions of the mandible and maxilla primarily. It typically presents in early childhood with bilateral symmetric enlargement of the lower face leading to a characteristic "cherubic" appearance in which the eyes appear to gaze upward because of maxillary involvement. Facial deformity progresses during childhood and early puberty, after which it sometimes spontaneously regresses. In most cases, cherubism arises from heterozygous pathogenic variants in SH3BP2. Inheritance is autosomal dominant.

Management

Evaluations Following Initial Diagnosis

After the initial diagnosis, all individuals with fibrous dysplasia/McCune-Albright syndrome (FD/MAS) should be evaluated to determine the extent of disease. The presence of any features of FD/MAS should prompt more detailed clinical evaluation for additional manifestations. The authors recommend the studies detailed in Table 3 if they have not already been completed.

Table 3.

Recommended Evaluations Following Initial Diagnosis in Individuals with Fibrous Dysplasia/McCune Albright Syndrome

Organ SystemEvaluationComment
Constitutional (growth) (see Figure 5)Review growth 1For signs of poor growth, which could suggest hyperthyroidism
For signs of rapid growth, which could indicate growth hormone excess &/or precocious puberty
IGF-1, random growth hormone, prolactin levels
Bone ageAdvanced bone age may suggest the presence of precocious puberty.
Musculoskeletal 2Clinical evaluation for scoliosisFurther radiographic confirmation may be necessary.
Total body bone scintigraphy 3The majority of clinically significant skeletal lesions are apparent on bone scan by age 5 yrs.
Radiographs (axial & appendicular) &/or CT (craniofacial) of areas of FDTo more clearly evaluate extent & anatomy of lesions
EndocrinePuberty (females)Evaluation for signs & symptoms of precocious puberty (see Figure 6)
Puberty (males)Evaluation for signs & symptoms of precocious puberty (see Figure 7)
Serum LH, FSH, & testosterone levels
Testicular ultrasoundTo evaluate for discrete hyper- & hypoechoic lesions & microlithiasis
Thyroid (see Figure 8)Thyroid ultrasoundFor signs of mixed cystic & solid lesions (see Figures 4C, 4D)
T3, free T4, & TSH levelsThe primary biochemical abnormality is elevated T3 production, which may occur in the setting of normal T4 and free T4.
AdrenalAssessment for signs & symptoms of Cushing syndrome (see Figure 9)e.g., hypertension, facial plethora, abdominal obesity, developmental delay, failure to thrive
If no signs or symptoms of hypercortisolism after age 3 yrs, no further evaluation needed
RenalSerum phosphorus levelVerification by calculating tubular reabsorption of phosphorus
EyesEvaluation by neuroophthalmologistIn those w/craniofacial FD
ENTEvaluation by otolaryngologistIn those w/craniofacial FD
Evaluation by audiologist
GastrointestinalSerum amylase, lipase, AST, & ALTSee Figure 10
Screening for symptoms of GERD
OtherConsultation w/clinical geneticist &/or genetic counselor

CT = computed tomography

GERD = gastroesophageal reflux disease

1.

Including determining predicted adult height and mid-parental height

2.

See Figure 3 for recommended evaluations of the skeletal system after diagnosis.

3.
Figure 5.

Figure 5.

Recommended evaluations for growth hormone excess in individuals with fibrous dysplasia/McCune-Albright syndrome

Figure 6.

Figure 6.

Recommended evaluations for gonadal abnormalities in females with fibrous dysplasia/McCune-Albright syndrome

Figure 7.

Figure 7.

Recommended evaluations for gonadal abnormalities in males with fibrous dysplasia/McCune-Albright syndrome

Figure 8.

Figure 8.

Recommended evaluations for thyroid abnormalities in individuals with fibrous dysplasia/McCune-Albright syndrome

Figure 9.

Figure 9.

Recommended evaluations for adrenal gland dysfunction in individuals with fibrous dysplasia/McCune-Albright syndrome

Figure 10.

Figure 10.

Recommended evaluations for gastrointestinal issues in individuals with fibrous dysplasia/McCune-Albright syndrome

Treatment of Manifestations

Management is most effectively accomplished through the input of a multidisciplinary team of specialists including an endocrinologist, orthopedic surgeon, physiatrist, ophthalmologist, audiologist, endocrine surgeon, craniofacial surgeon, and clinical geneticist. No consensus management guidelines have been published.

Table 4.

Treatment of Fibrous Dysplasia in Individuals with Fibrous Dysplasia/McCune Albright Syndrome

ManifestationTreatmentConsiderations/Other
Fibrous dysplasia (see Figure 11)No available medical therapies alter disease course; management is focused on optimizing function & minimizing morbidity.
Fractures / bone deformityOrthopedic surgeryA surgeon experienced in FD should be consulted, as approaches previously considered "standard," (e.g., curettage, grafting, external fixation) are frequently ineffective. 1
ScoliosisSurgical fusion in those w/rapidly progressive scoliosis 2Rarely, rapidly progressive scoliosis can lead to fatal respiratory compromise.
Aneurysmal bone cystsUrgent evaluation by a surgeon 3Particularly for lesions affecting the face or eyes, which can lead to optic nerve compression 4
Limited function & mobilityPhysical therapyTherapies to address hip girdle weakness, range of motion, & leg length discrepancies in those w/lower-extremity FD 5
Bone painIntravenous bisphosphonates (e.g., zoledronic acid, pamidronate) 6, 7Dosing should be based on symptoms, not on a fixed interval or bone turnover markers.
Acute or rapidly expanding FD lesionsEvaluation for malignancy 8 & aneurysmal bone cyst
1.
2.
3.
4.

Prophylactic optic nerve decompression to reduce the risk of vision loss can in fact increase the risk of vision loss and is thus contraindicated [Lee et al 2002, Cutler et al 2006, Amit et al 2011].

5.
6.

The oral bisphosphonate alendronate has been shown to be ineffective for treatment of bone pain [Boyce et al 2014].

7.

Denosumab (a human monoclonal antibody to RANKL) may reduce pain, bone turnover markers, and tumor growth rate. However, Denosumab has been associated with clinically significant disturbances of mineral metabolism both while on treatment and after discontinuation [Boyce et al 2012b, Benhamou et al 2014, Ganda & Seibel 2014]; use should be limited to experienced centers only.

8.

Atypical radiographic features (e.g., compromise of the bony cortex with an associated soft tissue mass) should also prompt an evaluation for malignancy.

Figure 11.

Figure 11.

Recommended management for fibrous dysplasia in individuals with fibrous dysplasia/McCune-Albright syndrome

Table 5.

Treatment of Endocrinopathies in Individuals with Fibrous Dysplasia/McCune Albright Syndrome

ManifestationTreatmentConsiderations/Other
Precocious puberty (females) 1Letrozole (aromatase inhibitor) 2, 3Treatment prevents bone age advancement & compromise of adult height.
Precocious puberty (males) 4Combined androgen receptor blocker (e.g., spironolactone or bicalutamid) & an inhibitor of sex steroid synthesis (e.g., letrazole) 5Treatment options are less well established.
Central precocious puberty (females & males) 6Leuprolide combined w/medications listed above for precocious puberty
Persistent ovarian cystsProphylactic surgical intervention may be considered for large cysts.Caution is advised due to risk for recurrent cysts & potential for decreased ovarian reserve.
Hyperthyroidism 7Methimazole 8Propilthiouracil has been associated w/unacceptable risk for hepatotoxicity in children & thus is no longer recommended. 9
Thyroidectomy 10Total gland resection is generally recommended due to potential for thyroid tissue regrowth.
FGF23-mediated phosphate wastingStandard treatment w/oral phosphorus & calcitriolTherapeutic endpoints include normal growth velocity & radiographic evidence of epiphyseal healing. 11
Growth hormone (GH) excess (see Figure 15)Alone or in combination: somatostatin analogs & the GH receptor antagonist pegvisomant 12. 13In growing children, the therapeutic goal is to maintain IGF-1 level in the middle of normal range w/an IGF-1 Z-score <0.
In skeletally mature individuals, goal is to decrease the IGF-1 level to as low as possible.
Medical therapy is typically continued indefinitely, because options for definitive treatment are associated w/significant morbidity. 14
HyperprolactinemiaDopamine agonists, 15 including cabergoline & bromocriptine
Hypercortisolism 16Medical: Metyrapone 17Spontaneous remission has been clearly documented in some affected individuals [Brown et al 2010]; however, it is not possible to identify prospectively which individuals will undergo remission.
Surgical: Removal of the adrenal glands 18
Intraductal papillary mucinous neoplasms of the pancreasStandard treatment 19See Figure 17
1.

See Figure 12. Most girls will have a decrease in the number of menstrual bleeding episodes while on treatment.

2.
3.

Letrozole treatment resulted in sustained beneficial effects on skeletal maturation, growth velocity, and predicted adult height [Estrada et al 2016].

4.

See Figure 13. Precocious puberty is rare in affected males.

5.
6.

Due to premature sex steroid exposure (see Clinical Description), central precocious puberty presents with reappearance of signs of puberty in a child with previously well-controlled peripheral precocious puberty.

7.

See Figure 14. Radioabalation is avoided (see Agents/Circumstances to Avoid).

8.
9.
10.

Selection of an experienced high-volume endocrine surgeon is critical to minimize complications and optimize outcomes.

11.

Bone turnover markers (e.g., alkaline phosphatase) may be constitutively elevated and are not a useful indicator of skeletal response to treatment.

12.
13.

Radiation treatment may be effective in refractory cases, but has been associated with fatal malignant transformation of craniofacial FD [Hansen & Moffat 2003, Liu et al 2011].

14.

Surgery may be technically difficult or precluded due to craniofacial FD. Additionally, given the diffuse pituitary infiltration of GH-producing cells, affected individuals treated surgically require total hypophysectomy with resulting total hypopituitarism [Vortmeyer et al 2012].

15.

This class of drugs could also have an effect on growth hormone excess treatment, in affected individuals with modest elevations of GH and IGF-1 levels, with or without concomitant hyperprolactinemia [Katznelson et al 2014].

16.

See Figure 16; treatment guidelines are difficult to establish given the rarity of neonatal Cushing syndrome.

17.

Preferred over ketoconazole in children with liver abnormalities

18.

The decision to pursue or delay adrenalectomy must be made on an individual basis, taking into account the severity of illness, the ability of medications to control cortisol levels, and the potential effect of continued hypercortisolism on neurodevelopment.

19.
Figure 12.

Figure 12.

Recommended management for precocious puberty in girls with fibrous dysplasia/McCune-Albright syndrome

Figure 13.

Figure 13.

Recommended management for gonadal involvement in boys with fibrous dysplasia/McCune-Albright syndrome

Figure 14.

Figure 14.

Recommended management for hyperthyroidism in individuals with fibrous dysplasia/McCune-Albright syndrome

Figure 15.

Figure 15.

Recommended management for growth hormone excess in individuals with fibrous dysplasia/McCune-Albright syndrome

Figure 16.

Figure 16.

Recommended management for hypercortisolism in individuals with fibrous dysplasia/McCune-Albright syndrome

Figure 17.

Figure 17.

Recommended management for pancreatic involvement in individuals with fibrous dysplasia/McCune-Albright syndrome

Table 6.

Treatment of Other Manifestations in Individuals with Fibrous Dysplasia/McCune Albright Syndrome

ManifestationTreatmentConsiderations/Other
Optic nerve compressionStandard treatment
Hearing lossStandard treatmentSee Hereditary Hearing Loss and Deafness Overview
Gastroesophageal refluxStandard treatment
PancreatitisStandard treatment
Bone marrow failureStandard treatmentIn those w/pancytopenia & extramedullary hematopoiesis, consider splenectomy. 1
Breast cancerStandard treatmentConsider early routine mammography screening. 2

Surveillance

Table 7.

Recommended Surveillance for Individuals with Fibrous Dysplasia/McCune Albright Syndrome

Organ SystemEvaluationFrequency
Musculoskeletal 1Monitoring for progression of scoliosis & other skeletal findings by orthopedic surgeon or physiatristRoutinely
Computed tomography of the skullEvery 5 yrs or potentially sooner in younger individuals, those w/severe disease, or if vision or hearing deficits develop
Radiographs to evaluate new or worsening symptoms & to provide additional information about FD anatomy & bone qualityPeriodically
EndocrinePuberty (females)Evaluation for growth acceleration & other clinical signs of precocious puberty 2, 3At each visit
Bone age assessmentEvery 6 mos in those w/bone age advancement of ≥2 yrs
Puberty (males)Evaluation for growth acceleration & other clinical signs of precocious puberty 2, 3At each visit
Bone age assessmentEvery 6 mos in those w/bone age advancement of ≥2 yrs
Testicular physical examinationAt each visit
Testicular ultrasoundPeriodically
ThyroidThyroid function tests (TSH, free T4, T3)Routinely in all children age <5 yrs; every 4-6 mos in children <3 yrs & annually in children >3 yrs throughout childhood if ultrasound abnormalities are present 4
Physical examination of the thyroidPeriodically in those w/retained abnormal thyroid tissue following thyroidectomy 5
Thyroid ultrasoundPeriodically in those w/abnormalities on thyroid ultrasound or who have undergone thyroidectomy 5, 6
Adrenal 7Clinical signs of hypercortisolism 8In infants at each visit
Signs & symptoms of late-appearing adrenal insufficiency in those w/history of Cushing syndrome that has spontaneously resolved 9At each visit
Serum IGF-1 levelsRoutinely through young adulthood in those w/craniofacial FD
For signs & symptoms of gallbladder disease in those treated w/somatostatin analogsPeriodically
RenalSerum phosphorus & 25-hydroxyvitamin D levels 1, 10Periodically
EyesEvaluation by ophthalmologist (or neuroophthamologist)Annually in those w/craniofacial FD
ENTEvaluation by audiologistAnnually in those w/craniofacial FD
GastrointestinalEvidence of hepatotoxicity for those on pegvisomantPeriodically
OncologyConsider initiating breast cancer screening earlier than recommended for general population. 11Periodically
1.
2.
3.

Growth acceleration can also be a sign of growth hormone excess.

4.

Individuals with abnormalities on thyroid ultrasound examination but normal thyroid function tests are at risk for the development of frank hyperthyroidism.

5.
6.

Thyroid tissue can regrow after thyroidectomy.

7.
8.

Routine biochemical surveillance for hypercortisolism is not indicated.

9.
10.

To monitor for the development of FGF23-mediated hypophosphatemia and as part of routine bone health

11.

Agents/Circumstances to Avoid

Contact sports and other high-risk activities should be avoided in those with significant skeletal involvement.

Avoid prophylactic optic nerve decompression (see Treatment of Manifestations).

Surgical removal of ovarian cysts should be performed with caution and only in limited circumstances.

Radiation therapy is not indicated for treatment of FD, and radiation exposure to FD lesions should be limited due to potential risk for malignant transformation [Ruggieri et al 1994].

Radioablation for hyperthyroidism is also typically avoided due to potential preferential uptake by tissues bearing a somatic activating GNAS pathogenic variant, which may lead to increased risk of malignancy in the remaining unaffected gland.

Evaluation of Relatives at Risk

Because FD/MAS is not inherited, relatives are not at increased risk and do not require evaluation.

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Pregnancy Management

While the effects of pregnancy on bone and endocrine disease in women with FD/MAS are not well studied, in the authors' experience most affected women do not experience a worsening of disease during pregnancy.

Therapies Under Investigation

Search ClinicalTrials.gov in the US and www.ClinicalTrialsRegister.eu in Europe for information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

Fibrous dysplasia/McCune-Albright syndrome (FD/MAS) is not inherited.

  • Verified vertical transmission has never been observed.
  • Molecular data indicates that all affected individuals are mosaic for an activating GNAS pathogenic variant that arises sporadically early in embryonic development.

Risk to Family Members

Parents of a proband. No parent of a child with FD/MAS has been demonstrated to have any significant, distinctive manifestations of the disorder, nor would such a finding be expected given the somatic nature of the disease.

Sibs of a proband. Given the somatic mutational mechanism of FD/MAS, the risk for an affected sib would be expected to be the same as in the general population.

Offspring of a proband. There are no verified instances of vertical transmission of FD/MAS, potentially the result of embryonic lethality.

Other family members. The risk to other family members is the same as that in the general population.

Related Genetic Counseling Issues

Considerations in families with an apparent de novo mosaic pathogenic variant. Counseling for recurrence risks in FD/MAS should emphasize that, while no pregnancy is at zero risk, evidence suggests that the risk of recurrence for this disorder is not increased over that of the general population.

Family planning. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

As FD/MAS is the result of postzygotic somatic mutation of GNAS and is not inherited, prenatal testing for FD/MAS is not indicated.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A.

Fibrous Dysplasia/McCune-Albright Syndrome: Genes and Databases

Data are compiled from the following standard references: gene from HGNC; chromosome locus from OMIM; protein from UniProt. For a description of databases (Locus Specific, HGMD, ClinVar) to which links are provided, click here.

Table B.

OMIM Entries for Fibrous Dysplasia/McCune-Albright Syndrome (View All in OMIM)

139320GNAS COMPLEX LOCUS; GNAS
174800MCCUNE-ALBRIGHT SYNDROME; MAS

Gene structure. GNAS is a complex locus with an imprinted expression pattern. Multiple gene products, including maternally, paternally, and biallelically expressed transcripts, are derived from the use of four promoters and 5' exons that splice onto a common set of downstream exons [Weinstein et al 2004] (summarized in OMIM 139320). The major GNAS product is the ubiquitously expressed Gsα, which is generated by the most downstream promoter (exon 1). For a detailed summary of gene and protein information, see Table A, Gene.

Pathogenic variants. Somatic mosaicism for pathogenic missense variants at p.Arg201 has been identified in more than 95% of all published reports of FD/MAS. The most frequent missense pathogenic variants are p.Arg201His and p.Arg201Cys [Lumbroso et al 2004]. Very infrequently, arginine is replaced by serine, glycine, or leucine. Rarely, missense variants at p.Gln227 have been reported [Idowu et al 2007].

There are ongoing experimental approaches to develop methods with increased sensitivity [Bianco et al 2000, Narumi et al 2013, de Sanctis et al 2017] that in the future may enable the use of peripheral blood lymphocytes (PBL) for pathogenic variant detection and also allow the quantification of the mutated to wild type cell ratio within the sample (as opposed to presence-absence in PCR-RFLP techniques):

Table 8.

Techniques to Detect GNAS Somatic Variants

MethodDetection Rate
BloodLesional tissue
Variant-specific amplification by polymerase chain reaction (PCR) &/or restriction enzyme digestion (RFLP) followed by directed sequencing of the variant loci 1~20%-30%~80%
PCR with peptide-nucleic acid probes 2 combined w/next-generation sequencing (PNA-NGS3~75%~100%
Co-amplification at lower denaturation temperature and allele-specific PCR-based TaqMan genotyping (real-time COLD-MAMA-PCR4~75%~100%

Recent studies implicate alternate transcripts of GNAS in the pathogenesis of FD/MAS. A p.Arg543His variant, corresponding to position p.Arg201His in Gαs, on the large XLαs transcript of Gαs, was detected in individuals with a paternal pathogenic variant, whereas mutated neuroendocrine secretory protein 55 (NESP55) variant transcript was detected in those with a maternal pathogenic variant in the affected tissues. Functional in vitro assays of wild type XLαs showed strong induction of adenyl cyclase activity in transfected cells, suggesting that this GNAS variant could be playing a role in the pathogenesis of FD [Mariot et al 2011].

Table 9.

GNAS Somatic Variants Discussed in This GeneReview

DNA Nucleotide ChangePredicted Protein ChangeReference Sequences
c.601C>Tp.Arg201CysNM_000516​.4
NP_000507​.1
c.601C>Gp.Arg201Gly
c.601C>Ap.Arg201Ser
c.602G>Ap.Arg201His
c.602G>Tp.Arg201Leu
c.679C>Ap.Gln227Lys
c.680A>Tp.Gln227Leu
c.680A>Gp.Gln227Arg
c.681G>Tp.Gln227His

Note on variant classification: Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (varnomen​.hgvs.org). See Quick Reference for an explanation of nomenclature.

Normal gene product. GNAS encodes the cAMP pathway-associated G-protein, Gsα. Gsα is a key component of many hormonal and other signal transduction pathways. Its primary role is to couple G-coupled protein receptors to adenylyl cyclase, promoting receptor-stimulated production of intracellular cAMP. Gsα in its inactive state forms a heterotrimer with the Gsβ and Gsγ subunits, with GDP bound to its binding site. Ligand binding to the G-coupled protein receptor promotes release of GDP from the α-subunit and binding of GTP. The GTP-bound Gsα dissociates from the β-γ heterotrimer and translocates to interact with adenylyl cyclase to promote cAMP production. Intrinsic GTPase hydrolyzes the bound GTP to GDP, leading to cessation of cAMP generation and reassembly of the α-β-γ heterotrimer. Downstream, cAMP is metabolized to AMP by one of many tissue-dependent phosphodiesterases.

Abnormal gene product. The FD/MAS-associated GNAS variants at residues p.Arg201 and p.Gln227 disrupt the activity of intrinsic GTPase, causing constitutive activity and inappropriately increased cAMP signaling [Landis et al 1989].

The spectrum of FD/MAS ranges from asymptomatic incidental findings to neonatal lethality. The phenotype of FD/MAS is a reflection of the role of Gsα in that tissue and whether or not a given tissue harbors a pathogenic variant in GNAS. The distribution of affected tissues is a reflection of the timing of the occurrence of the sporadic pathogenic variant during development and the fate of the specific clone in which the pathogenic variant occurs. It is likely that the stem cells of certain tissues will not tolerate mutated Gsα and are eliminated during development. Therefore, some tissues in which there is significant Gsα signaling will not be affected. For example, Gsα signaling is important in growth plate development, yet the growth plate is virtually never affected.

Activating or gain-of-function GNAS pathogenic variants in individuals with FD/MAS are present in the mosaic state, resulting from postzygotic somatic pathogenic variants appearing early in the course of development, which yields a monoclonal population of mutated cells within variously affected tissues. The non-mosaic state for most activating pathogenic variants is presumably lethal to the embryo (modified from OMIM 174800).

Cancer and Benign Tumors

The FD/MAS-associated activating GNAS pathogenic variants at residues p.Arg201 and p.Gln227 (collectively referred to as the gsp oncogene) have been reported in nonsyndromic benign [Landis et al 1989] and malignant [Wood et al 2007] tumors. However, the presence of the GNAS pathogenic variant alone is insufficient for malignant transformation of the affected tissues, but more likely predisposes for additional genetic or epigenetic events.

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Chapter Notes

Author Notes

Alison M Boyce, MD is a pediatric endocrinologist who specializes in the evaluation and treatment of bone disorders in children and adolescents. She performs clinical research in FD/MAS and other pediatric skeletal diseases at the National Institutes of Health.

Pablo Florenzano, MD is an endocrinologist who specializes in the evaluation and treatment of bone disorders in adults. He performs clinical research at Pontificia Universidad Catolica de Chile, primarily in disorders of bone and mineral homeostasis.

Luis Fernandez de Castro Diaz, PhD is a staff scientist in the Skeletal Disorders and Mineral Homeostasis Section. He performs basic and translational research primarily in disorders of bone and mineral homeostasis.

Michael T Collins, MD is an endocrinologist who conducts translation research at the National Institutes of Health. He studies and treats primarily patients with rare disorders of bone and mineral homeostasis, including FD/MAS.

Acknowledgments

This research was supported by the Intramural Research Program of the NIH, NIDCR (AMB, MTC) and the Bone Health Program, Division of Orthopaedics and Sports Medicine, Children's National Health System (AMB). The authors are grateful to the patients and their families for participation in the research and the efforts of the trainees of the NIH Interinstitute Endocrine Training Program for the excellent care they provide to our research subjects at the NIH Mark O Hatfield Clinical Research Center.

Revision History

  • 16 August 2018 (ma) Comprehensive update posted live
  • 26 February 2015 (me) Review posted live
  • 17 October 2014 (amb) Original submission
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