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, G_sα), is characterized by involvement of the skin, skeleton, and certain endocrine organs. However, because G_sα 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.

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.

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.

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

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.

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 4). (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) G_sα 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).

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, G_sα. Affected tissues can include those derived from ectoderm, mesoderm, and endoderm, and commonly include skin, skeleton, and certain endocrine organs. However, because G_sα 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 G_sα 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 (CT) (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 (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 2012].
  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].
• 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 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).
• 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].
• 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

• Hepatitis and neonatal cholestasis may be pronounced in infants, and generally wane with age to a mild persistent form [Silva et al 2000, Ikawa et al 2016].
• Hepatic adenomas with an identifiable GNAS activating pathogenic variant have also been reported [Gaujoux et al 2014].
• Liver failure in adults with FD/MAS has not been described.

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 for 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.

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 following studies, if they have not already been completed.

Skeleton

• Total body bone scintigraphy to identify and determine the extent of FD [Collins et al 2005]. The majority of clinically significant skeletal lesions are apparent on bone scan by age five years.
• Imaging of areas of identified areas of FD with radiographs (axial and appendicular FD) and/or computed tomography (craniofacial FD) to more clearly evaluate the extent and anatomy of the lesions
• Baseline ophthalmologic, otolaryngologic, and audiologic evaluations in persons with craniofacial FD
• Skeletal evaluation (See Figure 3.)

Endocrine. A thorough history and physical examination and review of a growth chart (if available) are recommended to evaluate for clinical signs of endocrinopathies:

• Biochemical screening for hyperthyroidism, growth hormone excess (IGF-1 level), and FGF23-mediated hypophosphatemia (See Figure 3, Figure 6, and Figure 7.)
• In individuals with clinical signs or a previous history of precocious puberty: biochemical screening, pelvic ultrasound examination (females), and bone age examination (See Figure 5 and Figure 6.)
• Ultrasound examination of the thyroid gland and testes (in all males) to evaluate for subclinical disease (See Figure 7 and Figure 8.)
• Testing for hypercortisolism in infants with clinical evidence of Cushing syndrome (hypertension, facial plethora, abdominal obesity, developmental delay, failure to thrive, small for gestational age) (See Figure 9.)

Less common manifestations. Consideration should be given to the less common manifestations cited in Clinical Description with appropriate clinical evaluations and imaging/biochemical studies performed as indicated (see Figure 10 for gastrointestinal evaluation).

Figure 5.

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

Figure 6.

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

Figure 7.

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

Figure 8.

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

Figure 9.

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

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.

Fibrous Dysplasia

There are no available medical therapies capable of altering the disease course in fibrous dysplasia. Current management is focused on optimizing function and minimizing morbidity related to fractures and deformity. The primary elements of management include the following (see also Figure 11):

• Orthopedic surgery to repair fractures and to prevent and correct deformities. A surgeon experienced in FD should be consulted, as approaches previously considered standard (e.g., curettage, grafting, external fixation) are frequently ineffective [Stanton et al 2012, Leet et al 2016].
• Diagnosis and treatment of scoliosis is of particular importance, as it may be rapidly progressive and in rare cases may lead to fatal respiratory compromise. For this reason, all individuals with spinal FD should be monitored closely by an orthopedic surgeon or physiatrist for possible progression. Surgical fusion has been shown to be effective at stabilizing the spine [Leet et al 2004b, Mancini et al 2009].
• Aneurysmal bone cysts, best detected by MRI, are rapidly expanding fluid-filled lesions that form within preexisting areas of FD. 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 and should be evaluated urgently by a surgeon [Lee et al 2012, Manjila et al 2013].
• 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].
• Physical therapy to optimize function and attenuate loss of mobility is appropriate. Affected individuals with lower-extremity FD in particular may benefit from therapies to address hip girdle weakness, range of motion, and leg length discrepancies [Paul et al 2014].
• Intravenous bisphosphonates such as zoledronic acid and pamidronate are usually effective at relieving bone pain. Dosing should be based on symptoms, not on a fixed interval or bone turnover markers. The oral bisphosphonate alendronate has been shown to be ineffective for treatment of bone pain [Boyce et al 2014].
• Denosumab, a human monoclonal antibody to RANKL, has been used in several cases of FD, with an apparent significant reduction in pain, bone turnover markers, and tumor growth rate. However, it has also 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]. For this reason, we only recommend the use of denosumab in centers with large experience in the treatment of individuals with FD, ideally in the context of a clinical study.
• Malignancy should remain a consideration for individuals with acute or rapidly expanding FD lesions, or with atypical radiographic features such as compromise of the bony cortex with an associated soft tissue mass.

Figure 11.

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

Endocrinopathies

Precocious puberty. Treatment of precocious puberty is important to prevent bone age advancement and compromise of adult height.

• Females (see Figure 12). The aromatase inhibitor letrozole is an effective treatment for females [Feuillan et al 2007]. In a recently published study with the longest follow up to date, letrozole treatment resulted in sustained beneficial effects on skeletal maturation, growth velocity, and predicted adult height [Estrada et al 2016]. Most females also have a decrease in the number of menstrual bleeding episodes while on treatment. Prophylactic surgical intervention for large and persistent ovarian cysts should be undertaken with extreme caution due to the known risk for cyst recurrence and the potential for decreased ovarian reserve in affected women.
• Males (see Figure 13). Given the rarity of precocious puberty in males, treatment options are less well established. One strategy includes the combination of an androgen receptor blocker (e.g., spironolactone or bicalutamide) and an inhibitor of sex steroid synthesis (e.g., letrozole) [Boyce et al 2012a].

Children of both sexes frequently enter central precocious puberty due to premature sex steroid exposure (see Clinical Description). This typically presents with reappearance of the signs of puberty in a child with previously well-controlled peripheral precocious puberty. Leuprolide therapy in combination with the above medications is an effective therapeutic strategy in most.

Figure 12.

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

Figure 13.

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

Thyroid disease. Methimazole is effective for medical management of hyperthyroidism [Tessaris et al 2012] and is the first line of treatment. Propilthiouracil has been associated with an unacceptable risk of hepatotoxicity in children and therefore is no longer recommended [Ross et al 2016]. 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. Selection of an experienced high-volume endocrine surgeon is critical to minimize complications and optimize outcomes. Affected individuals should be monitored post-surgically with yearly ultrasound examination to evaluate for tissue regrowth. See Figure 14.

Radioablation is 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. Additionally, GNAS pathogenic variants are associated with a slight increased risk of malignant transformation in both thyroid and non-thyroidal tissues; the risk is potentially enhanced by radiation exposure.

Figure 14.

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

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 [Boyce et al 2013, Salenave et al 2014] (see Figure 15).

• In growing children, the therapeutic goal is to maintain the IGF-1 level in the middle of the normal range with an IGF-1 Z-score below 0.
• In skeletally mature individuals, the goal is to decrease the IGF-1 level to as low as possible.

Medical therapy is typically continued indefinitely, as options for definitive treatment are associated with significant morbidity. 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]. 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].

The hyperprolactinemia that frequently accompanies growth hormone excess is generally responsive to treatment with dopamine agonists, including cabergoline and bromocriptine. This class of drugs could also have an effect on growth hormone excess treatment in those with modest elevations of GH and IGF-1 levels, with or without concomitant hyperprolactinemia [Katznelson et al 2014].

Figure 15.

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

FGF23-mediated phosphate wasting. Treatment of frank hypophosphatemia is the same as in other disorders of FGF23 excess, and includes oral phosphorus and calcitriol. Important therapeutic endpoints include growth velocity and radiographic evidence of epiphyseal healing. Unlike other disorders of FGF23 excess, bone turnover markers in FD/MAS (e.g., alkaline phosphatase) may be constitutively elevated and are not a useful indicator of skeletal response to treatment.

Hypercortisolism. Treatment guidelines for hypercortisolism are difficult to establish given the rarity of neonatal Cushing syndrome. Additionally, affected individuals may be critically ill at presentation, which significantly affects treatment options.

• 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.

Spontaneous 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. 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. See Figure 16.

Figure 16.

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

Pancreatic involvement. Natural history and specific risk of malignancy in FD/MAS-associated intraductal papillary mucinous neoplasms (IPMNs) have not been defined. Until that information becomes available, the authors recommend following guidelines for the evaluation of IPMNs in the general population [Tanaka et al 2012] (see Figure 17).

Figure 17.

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

Surveillance

Due to the mosaic nature of this condition, the clinical findings in any given affected individual can vary significantly, with some individuals having involvement of only one organ system and others having more widespread involvement. Additionally, some features are age dependent and are either not likely to develop after a certain age or are more likely to affect an older individual as opposed to a child. The following information on surveillance applies to individuals who have already been evaluated for signs and symptoms of the condition and in whom the extent of disease has been assessed; surveillance will need to be tailored to the individual's age and known affected organ systems (see Table 3).

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 EU Clinical Trials Register 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.

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. Because it is likely that testing methodology and our understanding of genes, pathogenic mechanisms, and diseases will improve in the future, consideration should be given to banking DNA from probands in whom a molecular diagnosis has not been confirmed (i.e., the causative pathogenic mechanism is unknown). For more information, see Huang et al [2022].

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.

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.

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

• 27 June 2019 (ma) Revision: Management section
• 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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