McCune-Albright Syndrome 

Updated: Jan 17, 2019
Author: Gabriel I Uwaifo, MD; Chief Editor: George T Griffing, MD 

Overview

Practice Essentials

McCune-Albright syndrome (MAS) consists of at least two of the following three features: (1) polyostotic fibrous dysplasia (PFD), (2) café-au-lait skin pigmentation (see the image below), and (3) autonomous endocrine hyperfunction (eg, gonadotropin-independent precocious puberty). Other endocrine syndromes may be present, including hyperthyroidism, acromegaly, and Cushing syndrome. Mazabraud syndrome, which can also exist in association with MAS, involves the occurrence of myxomas and usually PFD.[1, 2, 3, 4]

Café-au-lait pigmentation in case of McCune-Albrig Café-au-lait pigmentation in case of McCune-Albright syndrome. Lesion does not cross midline, which is typical of pigmented lesions in this syndrome.

Signs and symptoms

The clinical presentation of MAS is highly variable, depending on which of the various potential components of the syndrome predominate. Major manifestations include the following:

  • Precocious puberty (typically gonadotropin-independent) - This includes breast development, genital maturation (with or without pubic hair growth), increased height velocity, and macroorchidism[5]

  • Café-au-lait pigmentation - This consists of spots ranging from light brown to dark brown in color, often displaying a segmental distribution, and frequently predominating on one side of the body without crossing the midline; these spots must be differentiated from those characteristic of neurofibromatosis (NF)

  • PFD - Multiple pathologic fractures may be prominent early in the history; in many cases, bony involvement is found to predominate clinically on 1 side; potential presenting features include gait anomalies, visible bony deformities (including abnormal bone growths of the skull), bone pain, and joint stiffness with pain

  • Hyperthyroidism (rare without several other features of MAS also being present) - Findings may include tachycardia, arrhythmias (mostly supraventricular), hypertension, hyperthermia, tremor, sleeplessness, weight loss, or (in infants) failure to thrive

Other possible manifestations include the following:

  • Cushing syndrome

  • Growth hormone (GH) excess (gigantism and acromegaly)

  • Acromegaly

  • Ovarian cysts

  • Pituitary tumors

  • Thyroid tumors

  • Hypophosphatemia (hypophosphatemic rickets)

  • Hypogonadotropic hypogonadism, particularly in the setting of hyperprolactinemia

See Clinical Presentation for more detail.

Diagnosis

Full endocrine studies should be performed. Testicular or ovarian hyperfunction is the most common abnormality. Laboratory studies that may be helpful include the following:

  • Gonadotropin (luteinizing hormone [LH], follicle-stimulating hormone [FSH]) and sex hormone levels

  • Blood and urinary chemistries

  • Thyroid testing (thyroid-stimulating hormone [TSH], thyroxine [T4], antithyroid antibodies)

  • Adrenocorticotropic hormone (ACTH) levels

  • Serum prolactin (PRL)

  • Dexamethasone suppression testing (standard or low-dose/high-dose)

  • Urine collection assayed for free cortisol (urinary free cortisol [UFC])

  • Growth hormone (GH) and insulinlike growth factor 1 (IGF-1) levels

  • Polymerase chain reaction (PCR) assay

Diagnostic imaging modalities that may be considered include the following:

  • Plain radiography (mainly skull and mandibles [craniofacial survey], pelvis, femurs; as clinically indicated)

  • Ultrasonography (neck and thyroid; ovarian and pelvic; as clinically indicated)

  • Computed tomography (CT); as clinically pertinent

  • Magnetic resonance imaging (MRI); as clinically pertinent

  • Radionuclide bone scanning

Other studies that may be considered include the following:

  • Arterial blood gas determination (for suspected acidosis)

  • Electrocardiography (ECG; (for suspected arrhythmia)

  • Gastrointestinal (GI) endoscopy can be performed to evaluate (for suspected polyposis)

  • Biopsy (bone, muscle, soft tissue, thyroid); as clinically pertinent

See Workup for more detail.

Management

There is no specific treatment for MAS per se. Pharmacologic agents that have been used to treat precocious puberty in MAS include the following:

  • Aromatase inhibitors

  • Gonadotropin-releasing hormone (GnRH) analogues (as adjuncts to aromatase inhibitors)

  • Ketoconazole[6]

  • Estrogen receptor agonists (eg, tamoxifen)

  • Spironolactone

  • Cyproterone acetate

  • Medroxyprogesterone acetate

Currently, no clinically proven medical therapies are available for PFD associated with MAS. Oral and intravenous (IV) bisphosphonates (eg, pamidronate, alendronate, zoledronate) may be beneficial to prevent disease progression, although data are conflicting. Important: bisphosphonates are very effective at relieving pain in the majority of cases.

Pharmacologic agents that have been used to treat hyperthyroidism in MAS include the following:

  • Thionamides (eg, propylthiouracil)

  • Methimazole

  • Radioiodine (for tissue ablation)

No long-term effective medical treatment for ACTH-independent Cushing syndrome is available.

Pharmacologic agents that have been used to treat GH excess in MAS include the following:

  • Octreotide

  • Dopamine agonists (eg, bromocriptine and cabergoline), typically in conjunction with octreotide

  • GH receptor antagonists (eg, pegvisomant), probably best not used as monotherapy in this setting

Pharmacologic treatment of other manifestations of MAS is as follows:

  • Hypogonadism - Appropriate hormone replacement therapy

  • Hypophosphatemia with hyperphosphaturia - Aggressive oral phosphorus replacement

  • Hypophosphatemic rickets - Appropriate calcitriol therapy with calcium and phosphate repletion

Surgical interventions that may be considered include the following:

  • Precocious puberty – Oophorectomy or ovarian cystectomy, when medical therapy fails

  • PFD – Traction or fixation for fractures; for most PFD lesions, routine removal is not warranted

  • Hyperthyroidism – Thyroidectomy (partial near-total, or total)

  • Infantile Cushing syndrome – Bilateral adrenalectomy

  • Gigantism or acromegaly – Surgical removal of the offending lesion (pituitary adenoma) is rarely curative and is considered only if the tumor is threatening vision (in consultation with an experienced base-of-skull neurosurgeon)

See Treatment and Medication for more detail.

Background

McCune-Albright syndrome (MAS) in its classic form consists of at least 2 of the following triad of features[7, 8, 9] :

  • Polyostotic fibrous dysplasia (PFD)

  • Café-au-lait skin pigmentation

  • Autonomous endocrine hyperfunction – The most common form of autonomous endocrine hyperfunction in this syndrome is precocious puberty, which is typically gonadotropin-independent[10, 11]

Other endocrine syndromes described in association with MAS include the following[12, 13] :

  • Hyperthyroidism

  • Acromegaly or gigantism (due to GH-producing pituitary adenoma)

  • Gonadotropinomas

  • Hyperprolactinemia

  • Cushing syndrome

  • Hyperparathyroidism

  • Gynecomastia

  • Hypophosphatemic rickets

Some severely affected patients may present with associated hepatic, cardiac, and gastrointestinal (GI) dysfunction (ie, elevated hepatic transaminases, GI polyposis, and cardiomyopathy).[14]

MAS has been shown to be due to a postzygotic activating mutation of the GNAS gene, coding for the G protein subunit Gs alpha in the affected tissues (see Pathophysiology and Etiology). For semantic reasons, it is important to differentiate MAS from Albright hereditary osteodystrophy (AHO). AHO, which also is caused by a GNAS1 gene defect,[15] results in pseudohypoparathyroidism or pseudopseudohypoparathyroidism.[16]

The clinical presentation of MAS is highly variable, depending on which of the various potential components of the syndrome predominate (see Presentation). Diagnosis of MAS depends on finding at least 2 of the phenotypic features associated with activating GNAS1 mutations.

Early recognition is vital. In typical cases, the diagnosis of MAS is not in doubt. However, in atypical cases, the combination of cutaneous pigmentation, bony lesions, and soft-tissue masses may suggest other conditions (eg, systemic mastocytosis and neurofibromatosis [NF]) (see DDx).

Full endocrine studies should be performed under the care of an endocrinologist. Testicular or ovarian hyperfunction is the most common abnormality. Diagnostic imaging modalities that may be considered include plain radiography, ultrasonography, computed tomography (CT), magnetic resonance imaging (MRI), and radionuclide bone scanning (as clinically indicated) (see Workup).

Because MAS is a multisystemic condition with a host of variable presentations, management often is challenging and requires a multidisciplinary approach. For most physicians who are not endocrinologists, the crucial points in management are recognition of MAS and referral of the patient to an endocrinologist who is experienced in its management. The endocrinologist, in turn, offers other referrals as indicated (eg, neurosurgeon) (see Treatment).

Pathophysiology

Most of the clinical features of MAS are caused by a noninherited postzygotic activating mutation of the GNAS1 gene that results in overproduction of a variety of protein products in a fashion independent from normal feedback control mechanisms (see Etiology).[8]

Precocious puberty, the most common endocrine feature of MAS, is a result of gonadotropin-independent autonomous ovarian or testicular function.[5] Precocious puberty caused by this condition is far more common in girls than in boys. In girls, it is the result of estrogen excess from ovarian follicular cysts.[17] Because the sexual precocity associated with MAS is gonadotropin-independent, it is more accurately described as pseudoprecocious puberty.

The café-au-lait spots in MAS are large melanotic macules, sometimes referred to as café-au-lait macules (CALMs). Except for hyperpigmentation of the basal layer, no abnormal pathology is seen.

Fewer than 10 cases of MAS associated with Cushing syndrome have been well documented. This syndrome is distinct, unlike all other endocrinopathies of MAS, which are slowly progressive and persistent without treatment. Several cases of Cushing syndrome in the context of MAS have regressed within the first few years following onset.

Cushing syndrome associated with MAS is predominantly due to adrenocortical hyperfunction. Most of these cases have been described in infants or children. The adrenal glands are bilaterally enlarged and contain multiple small nodules in the cortex. In some cases, Cushing syndrome is transitory. Pituitary-based (ACTH-dependent) Cushing disease in the setting of MAS is far less common.

Hyperthyroidism typically occurs later in childhood, though it can occur within the first year of life. Like Cushing syndrome and precocious puberty, hyperthyroidism associated with MAS is a result of 1 or more autonomous hyperfunctioning thyroid nodules.

Growth hormone (GH) excess from somatotroph adenomas in the pituitary can occur at any age, resulting in gigantism or acromegaly. The GH excess among patients with MAS has been noted to be as high as 21%. The basis of GH hypersecretion in MAS remains incompletely understood, but it appears to have a different basis from that of acromegaly or gigantism in non-MAS patients.[18]  A study by Yao et al suggested that growth hormone excess in MAS occurs more frequently in males than in females; the investigators determined that of 52 patients with MAS, 13 (25.0%) had growth hormone excess, including 10 males (76.9%). The study also found an association between growth hormone excess in MAS and greater severity of skeletal lesions, with more craniofacial bone involvement.[19]

Fibrous dysplasia (FD) in MAS can involve any bone but most commonly affects the long bones, ribs, and skull. It may range from small asymptomatic areas detectable only by bone scan to markedly disfiguring lesions that can result in frequent pathologic fractures and impingement on vital nerves.

Approximately 30 cases of FD associated with single or multiple intramuscular or juxtamuscular myxomas (Mazabraud syndrome) have been documented.[2, 3] This syndrome has been associated with precocious puberty and café-au-lait spots and occurs in association with MAS. The myxomas associated with this condition can occur in virtually any location in the muscular system. The exact etiopathogenesis of the syndrome is unclear, because no activating mutations of the GNAS1 gene have been demonstrated in this clinical variant.

Simple myxomas typically are benign and solitary, with peak incidence in the sixth and seventh decades. The age of peak incidence for this syndrome is young adulthood, and the tumors commonly are multiple. The main sites of involvement are the large muscles of the thighs, buttocks, and shoulders. They often are located close to FD lesions but typically remain separate from them. They commonly recur, even after attempts at surgical resection.

Hypophosphatemic rickets is a potential complication that may worsen the bone disease associated with PFD. It is due to a tubulopathy and characterized by hyperphosphaturia. In patients with MAS, hyperphosphaturia may be due to a phosphatonin similar to that seen in patients with tumor-induced osteomalacia, which appears to be fibroblast growth factor 23 (FGF-23). While MAS patients with hypophosphatemic rickets are typically managed with calcitriol and phosphorus supplements, they must be monitored closely for hypercalcemia, excessive hypercalciuria, nephrocalcinosis, and progressive loss of renal function, as well as the development of secondary hyperparathyroidism.

Hepatic abnormalities range from mild elevation of hepatic transaminases to severe neonatal jaundice and chronic cholestasis. Although some liver biopsies appear normal, others reveal mild biliary abnormalities or fatty liver. One case report described fatty liver in an infant with Cushing syndrome, suggesting that the fatty liver may have been secondary to glucocorticoid excess. Elevated transaminases in this infant, however, persisted long after the glucocorticoid excess had been corrected with adrenalectomy.

A study by Wood et al indicated that a wide range of gastrointestinal (GI) tract and pancreatic abnormalities occur in patients with MAS, with the investigators pointing out that GNAS mutations are not only responsible for MAS but are also found in association with several GI and pancreatic neoplasms. GI abnormalities in the study’s seven patients included gastric heterotopia/metaplasia, gastric hyperplastic polyps, fundic gland polyps, and a hamartomatous polyp, with endoscopic ultrasonographic findings in the pancreas suggesting the presence of intraductal papillary mucinous neoplasms (IPMNs).[20]

In a cross-sectional study of 54 patients with MAS, Robinson et al found radiographic GI abnormalities in 30 (56%) of them. IPMNs occurred in 25 (46%) patients, with 14 individuals having IPMNs alone and 11 also having abnormal hepatobiliary imaging. In addition, the investigators reported that, compared with the rest of the cohort, more fibrous dysplasia (as evaluated using skeletal burden scores), as well as a greater prevalence of acute pancreatitis and diabetes mellitus, was present in the patients with MAS-associated GI pathology.[21]

Many case reports describe sudden deaths, mostly occurring in patients with multiple endocrine and nonendocrine manifestations of MAS. Persistent tachycardia has been observed in addition to mild-to-moderate cardiomegaly, even in the absence of hyperthyroidism. Although the cause of death in these patients is unclear, it is presumed to be secondary to cardiac arrhythmia.

Only a few cases of malignant transformation of skeletal lesions have been described in the setting of MAS, most frequently in the setting of therapeutic irradiation. This occurs in probably less than 1% of MAS cases. The tendency for malignant transformation to occur may be greater in patients who have concomitant GH excess or those with Mazabraud syndrome. Observed malignancies include the following:

  • Osteosarcomas (most common)

  • Chondrosarcomas

  • Fibrosarcomas

  • Liposarcomas

Females appear to be at greater risk for breast cancer, probably as a consequence of prolonged exposure to elevated estrogen and/or GH levels. The underlying GNAS1 mutation also may play a role. For the same reasons, these patients also appear to be at increased risk for thyroid malignancies and testicular cancer (a novel finding by the National Institutes of Health [NIH]).

Etiology

MAS is caused by a sporadic, early postzygotic somatic mutation in the GNAS1 gene at locus 20q13.1-13.2, coding for the G protein subunit Gs alpha.[22] This genetic finding has been noted and confirmed in various tissue specimens from patients with MAS.[23] Researchers have isolated activating mutations of GNAS1 in pituitary adenomas, thyroid adenomas, ovarian cysts, monostotic bone dysplasia, and the adrenal glands.[24] GNAS1 gene abnormality in pseudohypoparathyroidism I-a has also been noted.[25]

G proteins couple cell surface receptors to intracellular proteins to activate or inactivate signaling cascades. The stimulatory G protein is normally activated when a hormone or other ligand binds to the cell surface receptor (see the image below). The activated Gs alpha disassociates from the receptor, binds to adenylyl cyclase, and stimulates an increase in intracellular cyclic adenosine monophosphate (cAMP) levels. Gs alpha then is inactivated, reassociates with the receptor, and is again available for hormone-mediated reactivation.

The G protein cycle begins with ligand binding to The G protein cycle begins with ligand binding to a 7-transmembrane domain G protein-coupled receptor (GPCR). Binding of the cognate ligand forms a ligand-receptor complex, which then stimulates an exchange of guanosine triphosphate (GTP) for guanosine diphosphate (GDP) on the alpha subunit of the stimulatory G protein (Gs alpha). This activates the alpha subunit, which subsequently stimulates adenylyl cyclase (AC) to increase production of cyclic adenosine monophosphate (cAMP). The alpha subunit contains intrinsic guanosine triphosphatase (GTPase) activity, which cleaves a phosphate group from GTP, converting it to GDP, and thus inactivates the alpha subunit. The inactivated alpha subunit is now ready to be reactivated by ligand-receptor binding, so that the next cycle of signal transduction can occur.

The mutations that cause MAS occur at a site in the protein that mediates inactivation of Gs alpha (see the image below). Once activated, the mutated Gs alpha subunit remains activated for a prolonged period despite the absence of hormone (GPCR ligand) stimulation. This results in constitutive activation of Gs alpha, constant stimulation of adenylyl cyclase, and persistently high levels of intracellular cAMP. Increased cAMP levels can mediate mitogenesis and increased cell function. The specific phenotype depends on the cell type containing the mutation.

Mutations in McCune-Albright syndrome inactivate i Mutations in McCune-Albright syndrome inactivate intrinsic guanosine triphosphatase (GTPase) activity, thus preventing inactivation of the "turned-on" Gs alpha subunit. Once activated, the mutated Gs alpha subunit is able to continuously stimulate adenylyl cyclase, even in absence of ligand binding to its cognate GPCR receptor. The result is elevation of intracellular cyclic adenosine monophosphate (cAMP) and continual stimulation of downstream cAMP signaling cascades.

The classic triad of features in MAS—PFD, autonomous endocrine hyperfunction, and café-au-lait skin pigmentation—can all be explained by activation of the Gs alpha subunit and increased intracellular cAMP levels.

Eumelanogenesis (formation of brown/black pigment) is normally stimulated by melanocyte-stimulating hormone (MSH) binding to the MSH receptor, a classic G protein receptor coupled to Gs alpha. Constitutive activation of the Gs alpha subunit in melanocytes results in the increase in brown pigmentation characteristic of the café-au-lait spots seen in the syndrome. Likewise, both the luteinizing hormone (LH) and the follicle-stimulating hormone (FSH) receptors are Gs alpha−coupled receptors.

Constitutive activation of the postreceptor cAMP signaling cascade in ovarian follicular cells results in cyst formation, estrogen production, and gonadotropin-independent precocious puberty. Similar mechanisms of increased intracellular cAMP likely explain essentially all of the other endocrine and nonendocrine features of MAS.

Because MAS results from a postzygotic somatic mutation, all the daughter cells of the embryonic cell in which the initial mutation occurred also contain the mutation. The earlier the mutation occurs in embryogenesis, the more widespread the tissue involvement.

Mutations late in embryogenesis are more focused and account for those mild cases in which only 2 or 3 of the classic phenotypic features of the syndrome are present. If the mutation occurs very late in tissue development after differentiation into a specific cell line, then a single adenoma may result. Gs alpha−activating mutations have been reported in isolated hyperfunctioning thyroid nodules and in somatotroph adenomas.

Although GNAS1 mutations could occur in germ cells (either oocytes or spermatocytes), the resulting zygote and all daughter cells then would contain the mutation. Activating GNAS1 mutations are likely lethal if they occur very early in embryogenesis. This accounts for the lack of autosomal dominant transmission of this syndrome.

Epidemiology

United States and international statistics

The exact incidence of MAS in the United States and internationally is unknown, but its prevalence is probably between 1 case in 100,000 population and 1 case in 1 million population, rendering it a very rare, sporadically occurring disorder.[8] In a review of radiographs from 82,000 patients, only 23 cases of PFD were found. Polyostotic variants of FD are uncommon, and MAS is even less common. The relative incidence of monostotic FD (MFD) is 70%, whereas that of PFD is 30% and that of MAS is less than 3%.

Age-, sex-, and race-related demographics

Severe cases of MAS involving multiple endocrine tissues may be recognized shortly after birth. Cases of infantile Cushing syndrome and hyperthyroidism have also been reported in the neonatal period. Additionally, FD, café-au-lait pigmentation, liver disease, and hypophosphatemia can initially be seen in infancy.

Less severe findings of MAS can occur at almost any time during childhood. Most commonly, the onset of MAS occurs in early childhood (mean age, 4.9 years; range, 0.3-9 years), typically earlier in girls than in boys. Precocious puberty in girls can be seen in infants as young as 4 months, though it more frequently occurs in girls older than 1 year. Café-au-lait pigmentation is more likely to become apparent later in the progression of the syndrome.

GH-producing pituitary tumors and functional-thyroid adenomas secondary to activating GNAS1 mutations can occur in individuals at any age. Disease with a later onset (ie, in the early to late teenage years) tends to be associated with clinically attenuated phenotypes.

Both sexes are affected by MAS, but the syndrome has been reported to be about twice as common in females as in males. That girls develop precocious puberty far more frequently than boys (9:1 female-to-male ratio) probably explains why this autosomal mutation is recognized more frequently in girls than in boys. Other manifestations of MAS probably occur with approximately equal frequency in females and males.

MAS has no ethnic predilection.

Prognosis

Apart from the small subgroup of patients with increased perioperative mortality and those patients who develop malignancies, MAS is not associated with a significantly increased mortality. In general, patients achieve a normal life span. Mortality and morbidity related to MAS result from the fractures, malignancies, endocrine disorders, and other conditions associated with this syndrome. The symptom and disability burden of MAS can be quite high, owing to the associated chronic pain and deformities, as well as the sequelae of chronic multihormonal endocrinopathies. Thus, the prognosis varies according to the manifestations of MAS.

With precocious puberty, the prognosis depends on the duration of premature estrogen exposure. Early puberty is not a life-threatening condition and does not seem to lead to problems after true, centrally mediated puberty begins at an appropriate age. Early breast development and vaginal bleeding can be accompanied by loss of adult height potential. Reduction of height potential depends on the degree of bone age advancement that occurs during the periods of early estrogen exposure.

A study of 16 girls and 10 boys with MAS found (1) that MAS occurs slightly more frequently in girls than in boys, (2) that peripheral precocious puberty (PPP) in MAS occurs significantly more frequently and at a younger age in girls than in boys, (3) that PPP in boys with MAS correlates with bilateral testicular enlargement, (4) that unilateral macroorchidism can occur, and (5) that testicular microlithiasis might function as another marker for MAS in males.[26]

Moreover, a literature review by Aversa et al indicated that at presentation, macroorchidism is the most common testicular abnormality related to MAS. In addition, the study found that in MAS, an association does not always exist between macroorchidism and clinical and biochemical evidence of peripheral precocious puberty.[27]

FD may have severe effects, including pathologic fractures, facial disfigurement, and vision and hearing problems. It is difficult to treat effectively. Current therapies focus on treating complications of FD, rather than on preventing it from developing. Current studies using bisphosphonates are promising, though it is unclear whether bisphosphonates significantly reduce the morbidity associated with these lesions.

Hyperthyroidism can cause severe failure to thrive in infants and young children, decreased attention span, and osteoporosis. Tachycardia resulting from severe hyperthyroidism may complicate or trigger a cardiac event. Radioiodine (131 I) ablation or thyroidectomy treats hyperthyroidism effectively. The long-term prognosis is excellent with adequate thyroid hormone replacement.

Infantile Cushing syndrome can cause severe growth failure, poor muscle tone, and hypertension. Permanent effect on growth potential is also possible. Comorbid heart and liver disease are poor prognostic markers and may indicate the need for prompt adrenalectomy.[28]

The long-term prognosis for infantile Cushing syndrome depends on adequate replacement of both mineralocorticoids and glucocorticoids. Individuals remain at risk for significant morbidity or mortality due to adrenal insufficiency during times of severe stress and should receive stress doses of hydrocortisone on an emergency basis.

Hypophosphatemia causes rickets and short stature; the pathophysiology of hypophosphatemic rickets, as well as the need for long-term therapy with calcitriol and phosphorus supplementation in these cases, increases the risk of nephrocalcinosis and loss of renal function over time.

Gigantism or acromegaly can occur, carrying a risk of glucose intolerance, hypertriglyceridemia, hypertension, and mild myopathy. GH secretion in MAS is difficult to treat effectively. Octreotide acetate or pegvisomant has proved effective in many cases, but not all. Furthermore, radiation treatment of the adenoma increases the risk of malignant change in areas of FD in the radiation field. The long-term prognosis in refractory cases of acromegaly is poor.

Although 2 long-term follow-up studies have shown no increased risk of premature death, several authors have noted unexplained sudden death in patients with a severe phenotype. Patients may have multiple endocrine, cardiac, GI, central nervous system (CNS), hematopoietic, and hepatic manifestations, all of which can contribute to significant morbidity. Although no arrhythmias have been detected in individuals with MAS, this is the presumed mechanism of sudden death.

Patient Education

Educational requirements depend on the phenotypic expression of MAS. Individuals with FD in critical weight-bearing areas should be instructed to avoid activities (eg, contact sports) that put the skeleton at risk for pathologic fracture.

Patients who have undergone bilateral adrenalectomy for Cushing syndrome should be given clear instructions on changing steroid dosing for febrile illnesses. Furthermore, these individuals need to wear medic alert identification bracelets or necklaces so that if severe illness or trauma occurs, medical personnel will be aware of the requirement for stress doses of hydrocortisone.

Patients should also be informed MAS is not hereditary and that offspring of affected patients are not at increased risk for the syndrome.

For patient education resources, see the Thyroid and Metabolism Center, as well as Thyroid Problems.

 

Presentation

History

A complete medical history is important in the evaluation of apparent endocrine hyperfunction such as that seen in McCune-Albright syndrome (MAS), though it is often more important for ruling out other causes of such hyperfunction than for diagnosing MAS itself. Patients generally do not have a family history of MAS. The clinical presentation of MAS is highly variable, depending on which of the various potential components of the syndrome predominate.

Precocious puberty

Precocious puberty can result from either central gonadotropin-dependent causes or peripheral gonadotropin-independent causes (see Etiology).[5] Symptoms of an intracranial process (eg, abrupt vision changes, nighttime headaches, or nighttime emesis) are suggestive of hypothalamic lesions that can lead to gonadotropin-dependent precocious puberty and are not consistent with MAS. Previous brain injury due to infection or trauma is also associated more often with central precocious puberty.

Although the following pattern is not universal, the [peripheral gonadotropin-independent puberty in MAS tends to be seen more frequently with vaginal bleeding or breast development unaccompanied by growth of pubic hair and tends to occur at an earlier age than central gonadotropin-dependent precocious puberty. Furthermore, vaginal bleeding often occurs before the onset of breast development and tends to be irregular. Bleeding episodes may be isolated or frequently recurrent, with very little pattern or predictability.

In patients with precocious vaginal bleeding or breast development, other possible causes of estrogen excess must be considered. Accidental ingestion of estrogen supplements can cause breast development, increased height velocity, and maturation of the endometrial lining. As estrogen levels decrease, withdrawal bleeding can occur. If vaginal bleeding occurs in the absence of other signs of estrogen excess (eg, breast development or increased height velocity), a careful history mindful of possible trauma or sexual abuse should be obtained.

Forms of sexual precocity are observed in more than 50% of women with MAS.[29] Sexual precocity also occurs in male patients but is less common. Some MAS patients may have normal onset of puberty at a normal age.

Café-au-lait pigmentation

Evaluation of café-au-lait pigmentation requires a detailed family history because neurofibromatosis (NF) also produces multiple café-au-lait spots. Unlike MAS, which occurs sporadically, NF is an autosomal dominant condition. A diagnosis of NF should be considered if a family history of café-au-lait pigmentation is noted, and the possibility should not be discounted even when precocious puberty occurs with café-au-lait spots. Hypothalamic optic gliomas with NF can lead to gonadotropin-dependent precocious puberty.

Polyostotic fibrous dysplasia

In cases where polyostotic fibrous dysplasia (PFD) is marked, multiple pathologic fractures are prominent early in the history (usually in childhood).[30] In many cases, bony involvement predominates clinically on 1 side.

The potential presenting features include gait anomalies (eg, a limp), visible bony deformities, bone pain, and joint stiffness with pain, most often the result of secondary osteoarthrosis. Symptoms begin during childhood, though in some cases, the disease is clinically silent and is discovered on routine radiographs obtained for an unrelated reason. In other cases, the phenotypic affectation is mild, and the onset of symptoms is considerably delayed; subtle findings can include mild facial asymmetry, dysmorphism, and a small difference in limb length.

Spontaneous improvement or resolution of the bony lesions does not occur. Existing bony lesions may slowly worsen or remain static, or new lesions may develop. Bony lesions have been noted to worsen during pregnancy and other settings of estrogen excess. This worsening may be due to the trophic effects of estrogen on fibrous dysplastic bone, which does possess estrogen receptors.

Patients with myxomas often present with a history of palpable masses in the limbs, anterior abdominal wall, or back. These often are otherwise asymptomatic and may be painful.

Other manifestations

Hyperthyroidism rarely occurs in MAS without several other features of the syndrome also being present. A family history of autoimmune thyroid disorders supports a diagnosis of Graves disease, though Graves disease can occur in the absence of a family history. If no other features of MAS are present, autoimmune thyroid disease is far more likely. In cases of unexplained hyperthyroidism, surreptitious administration of thyroid hormone should be considered; again, this explanation would be more likely in the absence of physical findings of MAS.

Infantile Cushing syndrome may initially be seen without other signs of MAS. Cortisol excess should be considered in any infant with profound failure to thrive, hypertension, muscle weakness, and easy bruising. Unlike older children with cortisol excess, infants may have decreased appetite and food intake.

In the absence of other signs of MAS, exogenously administered steroids should be considered before excess cortisol is attributed to an activating mutation of the alpha subunit of the stimulatory G protein (Gs alpha; GNAS1 gene). Injections of steroids can be long-lasting; triamcinolone acetonide has caused Cushing syndrome for well over 1 year after the final injection, presumably as a result of an inability to metabolize and excrete the steroid.

Growth hormone (GH) excess coexisting with MAS is uncommon and generally is not found until early adulthood or mid-adulthood. Patients with MAS and GH excess present with the same paradoxic responses as regular patients with acromegaly upon thyrotropin-releasing hormone stimulation and upon oral glucose tolerance tests.

Associated hypogonadotropic hypogonadism may be present, particularly in the setting of hyperprolactinemia. Hyperprolactinemia in the absence of acromegaly has not been described in patients with MAS.

Rarely, MAS has been associated with high-output congestive heart failure similar to that seen in Paget disease.

Physical Examination

Like the findings from the clinical history, the physical findings may vary, depending on the particular manifestations of MAS in a given patient. Diagnosis of MAS depends on finding at least 2 of the phenotypic features associated with activating GNAS1 mutations.

The presence of 2 distinct physical findings consistent with autonomous hyperfunction increases the likelihood that the single underlying cause is an activating GNAS1 mutation rather than activating mutations in genes (ie, receptors) specific to a tissue type. Although an activating GNAS1 mutation can be isolated in only 1 tissue type, confirmation requires molecular analysis of that specific tissue. Additionally, certain physical findings should lead away from the diagnosis of MAS.

Precocious puberty

Patients with precocious puberty invariably are taller as children. However, as a result of a combination of precocious puberty, recurrent fractures, and hypophosphatemic rickets, the majority of patients with MAS have a final height below that of their peers and below their projected midparental height. An important scenario in which a patient with MAS attains normal height is that in which there is a coexisting GH excess (a clinical pearl that aids in diagnosis in these particular cases).[5]

Precocious puberty in girls with MAS is indicated by the appearance of signs of excess estrogen for age, including breast development, genital maturation, and increased height velocity. Pubic hair growth may or may not be present. Both breast diameter and Tanner staging should be recorded at each clinic visit as a gauge of ongoing estrogen exposure.

If necessary, genital maturation can be determined by examining the vaginal mucosa. A pink mucosa with mucous covering is consistent with estrogen stimulation, whereas a glistening red appearance is indicative of a thin, non–estrogen-stimulated mucosa.

Examination of the vaginal mucosa should be performed with extreme care to avoid traumatizing the patient. Frequently, the introitus can be examined with the patient lying on her back with heels together and legs externally rotated. Very gentle traction of the labia majora may be necessary. Bimanual or speculum examinations should not be attempted. Only trained individuals should perform more detailed vaginal examinations with the patient under light general anesthesia.

Testicular enlargement (macroorchidism) occurs in males with MAS. Although it is usually bilateral and occurs against a context of sexual precocity, this is not always the case. A 4.6-year-old boy with unilateral macroorchidism without sexual precocity or other MAS pathology has been described.[31]

Café-au-lait pigmentation

Café-au-lait spots, ranging from light brown to dark brown in color, are the classic symptom of MAS. They may not be apparent in very young patients but may become more prominent with age. A Wood lamp can help detect subtle lesions. Pigmented areas are often few but can be quite large (see the first image below). These lesions often display a segmental distribution and frequently predominate on one side of the body (the side with more bony fractures and deformity). Individual lesions generally do not cross the midline (see the second image below).

Large café-au-lait patches around shoulder in chil Large café-au-lait patches around shoulder in child with McCune-Albright syndrome.
Café-au-lait pigmentation in case of McCune-Albrig Café-au-lait pigmentation in case of McCune-Albright syndrome. Lesion does not cross midline, which is typical of pigmented lesions in this syndrome.

If precocious puberty and café-au-lait pigmentation are the only features noted, NF cannot be ruled out. Generally, the café-au-lait spots in MAS are characterized by an irregular outline (“coast of Maine”; see the image below), whereas the spots in NF tend to be smaller and have a smooth outline (“coast of California”); however, this distinction may not hold true in all cases. The presence of axillary or inguinal freckling, pigmented iris hamartomas (Lisch nodules), or cutaneous neurofibromas is suggestive of NF.

Café au lait spot. This is a fairly large, irregul Café au lait spot. This is a fairly large, irregular-edged ("coast-of-Maine" variety) lesion. It presents as a brownish, otherwise-asymptomatic macule/patch. The degree of pigmentation is fairly uniform.

The lesions are arranged in a segmental fashion that coincides with the developmental lines of Blaschko. They are located most commonly on the buttocks and the lumbosacral back. Common areas to look for subtle café-au-lait spots include the nape of the neck and the nasal clefts. However, these pigmented lesions are absent in 10-20% of patients and can be detected (by a formal dermatologic assessment) in as many as 10% of healthy subjects; accordingly, their diagnostic utility is limited when they are not associated with other features of MAS. However, it was reported that irregular congenital café-au-lait macules in a blaschkoid pattern on a patient's back were used to diagnose MAS (later confirmed by genetic evaluation) even though other signs of the disorder were not present at the time.[32]

A few cases have been described in which MAS has been associated with either patchy or diffuse alopecia (first described by Shelley and Wood).

Polyostotic fibrous dysplasia

Fibrous dysplasia (FD) in MAS ranges from asymptomatic lesions to markedly disfiguring involvement of the skull, spine,[33] and long bones. Involvement of the skull can be particularly problematic, with lesions of the orbit resulting in visual loss or proptosis and lesions of the ear resulting in deafness and vertigo. Like the cutaneous lesions, the bony lesions are not uniformly distributed and tend to be unilateral.

Other manifestations

Hyperthyroidism is uncommon in MAS, commonly appearing as a hypermetabolic state. Findings may include tachycardia, supraventricular arrhythmias, hypertension, hyperthermia, tremor, sleeplessness, and involuntary weight loss. Infants with hyperthyroidism often exhibit failure to thrive. Hyperthyroidism does not always occur in infancy: There are case reports describing hyperthyroidism occurring abruptly in later childhood, including 1 report of thyroid storm after surgery for FD.

Cushing syndrome is also rare in MAS. Patients with Cushing syndrome have profound growth failure in infancy. Although both weight and length percentiles decrease, linear growth failure is more pronounced. Frequently, these infants have round cushingoid faces and may have markedly decreased muscle tone and soft doughy skin. Hypertension also may be present.

GH-producing somatotroph adenomas can occur in McCune-Albright syndrome. In children, GH excess results in a marked increase in linear growth velocity. If it goes untreated, features of acromegaly can develop later in life, including enlargement of the hands and feet and coarsening of the facial features. Individuals with GH excess may also have hypertension and mild decreases in muscle tone.

Rarely, severe hypophosphatemia can occur in MAS. If it is not treated, severe rickets and short stature can result. Typical findings in hypophosphatemic rickets include bowing of legs, widening of wrists, and thickening of the costochondral junction (rachitic rosary).

Infants with MAS may have persistent jaundice and mild hepatomegaly but generally lack other manifestation of liver failure.

Complications

Complications of MAS depend on the degree of involvement and tissue distribution of GNAS1 mutations.

In precocious puberty, increased estrogen secretion can result in an initial increase in height velocity (as well as early breast development and vaginal bleeding). Although early height percentiles are greater than expected, a rapid advancement of bone age results in an ultimate loss of adult height potential.

Early estrogen exposure may also mature the hypothalamic-pituitary-gonadal axis and result in earlier-than-expected central puberty. Furthermore, precocious puberty can have a profound psychological and social effect on a young patient experiencing puberty before she is intellectually ready.

Lesions in FD range from relatively benign and asymptomatic to serious and debilitating, depending on the location. Lesions in weight-bearing bones can cause pathologic fractures. Depending on the specific bone involved and the specific location, potential complications of fractures include secondary osteomyelitis, compressive neuropathy, Volkmann contractures, sympathetic algodystrophy (reflex sympathetic dystrophy), myositis, ligamentous ossifications, and pseudoarthrosis.

The most dreaded complication of PFD is osteosarcoma, which most often occurs in the setting of irradiation of PFD-affected bones.[34] It is very uncommon; the overall incidence of sarcomatous degeneration in the setting of PFD is less than 1%. Most frequently, it involves the bones of the face and femur.

FD in the skull can be quite disfiguring and may be associated with blindness as a consequence of optic nerve compression.[35] Deafness also can occur and is associated with vestibulocochlear nerve compression. Other potential complications can result from compressive neuropathies of the cranial nerves located at the base of the skull. Rarely, compression fractures in the spine with impingement on spinal nerves have been reported.

Hyperthyroidism in MAS can cause severe failure to thrive in infants and young children. Elevated thyroid levels result in a hypermetabolic state with possible weight loss, anxiety, tremor, tachycardia, and sleeplessness. A decreased attention span often results in poor school performance. Osteoporosis can also result from a prolonged hyperthyroid state.

Infantile Cushing syndrome is also associated with severe growth failure, though the weight-for-height percentile deviations are not as significant as those associated with hyperthyroidism in infancy. Infants with Cushing syndrome often have poor muscle tone and may have hypertension and bruise easily. Long-term untreated hypercortisolism also can result in death. Blood pressure, muscle tone, and growth should all improve with adrenalectomy, though some permanent effect on growth potential may occur.

GH excess associated with a somatotroph adenoma leads to gigantism or acromegaly, depending on the age of initial presentation. In addition to the characteristic tall stature and coarse facial features, individuals are at risk for glucose intolerance, hypertriglyceridemia, hypertension, and mild myopathy. The adenoma itself may interfere with the production of other pituitary hormones. Extension of the tumor above the sella can compromise the optic chiasm, resulting in visual field defects, most commonly bitemporal homonymous hemianopsia.

Hypophosphatemia as a result of increased urinary phosphate losses causes severe rickets and short stature. Although phosphate replacement and calcitriol treatment improve growth and heal the rickets, overall growth potential is reduced. Additionally, select patients may develop nephrocalcinosis and loss of renal function over time (iatrogenic sequelae).

More severe presentations of MAS are clearly associated with sudden death. Although no arrhythmias have been detected in individuals with MAS, this is the presumed mechanism of sudden death. The stimulatory G protein (see Pathophysiology) is one of the primary intracellular signal transducers of the beta-adrenergic receptor. Constitutive activation of adrenergic signaling could result in a refractory and pathologic arrhythmia.

Of particular concern is the possibility that the tachycardia resulting from severe hyperthyroidism may complicate or trigger a cardiac event. Hyperthyroidism could increase the risk of such events in susceptible individuals.

 

DDx

Diagnostic Considerations

Early recognition of McCune-Albright syndrome (MAS) is vital. The diagnostic possibility of MAS should be considered in all patients with recurrent fractures, particularly if the fractures occur in the setting of minimal trauma or without trauma. The common pitfall is to simply refer the patient for orthopedic procedures whenever a fracture occurs, without considering the underlying primary diagnosis. The physician should have a high index of suspicion for other endocrinopathies associated with the condition.

If multiple bony fractures and deformity predominate, MAS may be mistaken for a milder form of osteogenesis imperfecta. If precocious puberty predominates, the differential diagnosis becomes even wider and includes congenital adrenal hyperplasia. Vaginal bleeding in neonates and infants is one of the typical presentations of MAS. In this setting, rhabdomyosarcoma of the vaginal tract is an important differential. This typically appears as a “bunch of grapes” (hence the name sarcoma botryoides).

In a typical case, the diagnosis of MAS usually is not in doubt. However, in atypical cases, the combination of cutaneous pigmentation, bony lesions, and soft-tissue masses may suggest other conditions (eg, systemic mastocytosis and neurofibromatosis).

In addition to the conditions listed in the differential diagnosis, other problems to be considered include the following:

  • Central precocious puberty

  • Congenital adrenal hyperplasia

  • Exogenous estrogens, androgens, steroids, or thyroid hormone

  • Organic brain disease or tumors

  • Ovarian tumors

  • Ossifying fibromas of bone

  • Proteus syndrome

  • Russell-Silver syndrome

  • Stein-Leventhal syndrome

  • Thyrotoxicosis

  • Various congenital syndromes associated with hydrocephalus

Differential Diagnoses

 

Workup

Approach Considerations

Full endocrine studies should be performed. Testicular or ovarian hyperfunction is the most common abnormality. Testosterone or estradiol levels are elevated. Gonadotropin levels are usually reduced or normal. Hyperthyroidism is common (33%), with elevated thyroxine but low or normal thyrotropin levels. Growth hormone (GH), prolactin (PRL), and, rarely, luteinizing hormone (LH) or follicle-stimulating hormone (FSH) levels may be elevated. Elevated cortisol levels are not suppressed by dexamethasone. Hypophosphatemia with hyperphosphaturia is noted.

To surmount the variations in mutations of GNAS1 analysis for MAS, sensitive and specific molecular methods are needed and must be performed on affected tissues and from easily accessible tissues. This is particularly true for atypical and monosymptomatic forms of MAS.[36]

Diagnostic imaging modalities that may be considered include plain radiography, ultrasonography, computed tomography (CT), magnetic resonance imaging (MRI), and radionuclide bone scanning.

Laboratory Studies

Gonadotropin and sex hormone levels

In patients with sexual precocity, baseline gonadotropin (ie, LH and FSH) and gonadotropin levels stimulated by gonadotropin-releasing hormone (GnRH) are below normal limits. In females who are affected, estrogen levels are elevated above the age-adjusted expected level. Similarly, males who are affected have elevated serum free and total testosterone levels. Androgen levels in female patients remain within normal limits.

Precocious puberty in MAS is gonadotropin-independent. Therefore, the finding of elevated estradiol levels and suppressed or undetectable gonadotropin levels is diagnostic of gonadotropin-independent puberty. However, estrogen secretion is frequently episodic in MAS; thus, multiple assays over time may be necessary to demonstrate an elevation in estradiol levels.

Because secretion of LH and FSH is pulsatile, random gonadotropin levels in early puberty are often equal to prepubertal levels. Additionally, significant pulses may only occur at night in early puberty. An LH-releasing hormone (LH-RH) stimulation test (gonadorelin hydrochloride 100 mg intravenously [IV]) can help to differentiate between central gonadotropin-dependent and gonadotropin-independent precocious puberty.

In this test, serum is sampled for LH and FSH at 0 minutes, 15 minutes, 30 minutes, 45 minutes, and 60 minutes after administration of LH-RH. Suppressed or undetectable levels of LH and FSH after administration of LH-RH are consistent with MAS.

Blood and urinary chemistries

Individuals with MAS may have elevated liver enzymes or hyperbilirubinemia. Even after normalization of cortisol or thyroxine levels, these elevations can persist, suggesting the presence of G protein alpha subunit (Gs alpha)–activating (GNAS1) mutations in the liver. Furthermore, hypophosphatemia may result from increased urinary phosphate excretion. Therefore, a complete multichemistry panel should be performed that includes calcium, phosphorus, and liver function tests.

Blood and urinary chemistries show evidence of excessive bone turnover and elevated indicators for bone formation and resorption (eg, urinary N-telopeptide, pyridinolines, deoxypyridinolines). Serum alkaline phosphatase levels (total and bone-specific fractions), osteocalcin, and serum cyclic adenosine monophosphate (cAMP)[37] levels are elevated.

Urinary excretion of hydroxyproline, N-telopeptides, pyridinium X-links, and cAMP is elevated. Depending on the extent of coexisting osteomalacia, serum calcium may be normal or slightly reduced. Typically, the rickets or osteomalacia associated with MAS is hypophosphatemic and hyperphosphaturic.

Thyroid testing

Elevated thyroxine levels and suppressed thyroid-stimulating hormone (TSH) levels are consistent with hyperthyroidism. Because hyperthyroidism associated with MAS is not immune-mediated, levels of antithyroid antibodies, particularly thyroid-stimulating immunoglobulins (TSIs), are generally undetectable. Detection of these antibodies would be consistent with a diagnosis of Graves disease.

Adrenocorticotropic hormone levels

The glucocorticoid secretion in infantile Cushing syndrome is independent of adrenocorticotropic hormone (ACTH). Therefore, serum ACTH levels are generally suppressed despite elevated cortisol levels.

Dexamethasone suppression testing

Normally, cortisol levels are suppressed by overnight administration of dexamethasone (0.050 mg/kg; not to exceed 1 mg). Elevated cortisol levels at 8:00 AM suggest Cushing syndrome but do not distinguish between ACTH-dependent and ACTH-independent excess cortisol production.

Low-dose/high-dose dexamethasone suppression test

Low-dose (2 mg/1.7 m2/day)/high-dose (8 mg/1.7 m2/day) dexamethasone suppression testing can help distinguish ACTH-dependent Cushing syndrome from pituitary and ectopic sources and confirm the ACTH-independent nature of excessive cortisol secretion in MAS. Because the recommended treatment of ACTH-independent Cushing syndrome is bilateral adrenalectomy, such testing should be performed preoperatively.

Low-dose/high-dose dexamethasone suppression tests in infants are performed in a hospital setting. A Foley catheter is placed, and urine is collected in 24-hour increments for free cortisol determinations. ACTH and cortisol levels are obtained at 8:00 AM each day. After baseline measurements are collected, low-dose dexamethasone is administered for 2 days, followed by high dose dexamethasone for 2 days.

Lack of suppression of cortisol production with low-dose dexamethasone but suppression with high-dose dexamethasone suggests ACTH-dependent Cushing syndrome. Lack of suppression with high-dose dexamethasone suggests either ectopic ACTH production or ACTH-independent Cushing syndrome. Diagnosis of ACTH-independent Cushing syndrome consistent with MAS is confirmed in this situation if ACTH levels are also suppressed.

Urine collection assayed for free cortisol

A 24-hour urinary free cortisol (UFC) is the most sensitive measure of the cortisol production rate and is more accurate in determining Cushing syndrome than random cortisol levels are. Normal values for 24-hour urinary free cortisol vary with the size of the patient and should be adjusted for body surface area to allow comparison with published adult normal ranges (ie, 10-84 µg/1.7 m2/day). Elevated 24-hour urine free cortisol levels suggest Cushing syndrome but do not distinguish between ACTH-dependent and ACTH-independent excess cortisol production.

Serum growth hormone and insulinlike growth factor 1 levels

Individuals with somatotroph adenomas due to GNAS1 mutations have detectable elevations of GH, insulinlike growth factor 1 (IGF-1), or both in serum.

Polymerase chain reaction assay

A highly sensitive polymerase chain reaction (PCR) assay is capable of detecting activating mutations of the GNAS1 gene in peripheral blood cells of patients with MAS or isolated fibrous dysplasia (FD).[38] Using next-generation sequencing (NGS), millions of PCR amplicons can be analyzed in an independent fashion, and this can be expected to quantitatively detect low-abundance GNAS. NGS is able to detect somatic activating GNAS mutations sensitively and quantitatively and from peripheral blood. Now the peptide nucleic acid/NGS method appears most likely the most sensitive method to detect low-abundance mutated GNAS.[39]

Plain Radiography

In MAS, plain bone radiographs typically show multiple patchy areas of bony lysis (see the first image below) and sclerosis. The findings are consistent with bone dystrophy (ie, areas of hypertrophy and geodes bounded by fine sclerotic rims). Mixed radiopaque and radiolucent areas with thin or hypertrophic cortices are present (see the second image below).

Fibrous dysplasia of a long bone characterized by Fibrous dysplasia of a long bone characterized by focal bony expansion, patchy areas of sclerosis, and bony cyst formation in McCune-Albright syndrome.
Lucency characteristic of polyostotic fibrous dysp Lucency characteristic of polyostotic fibrous dysplasia in patient with McCune-Albright syndrome.

In general, monostotic FD (MFD) is more common than polyostotic FD (PFD); however, MFD is not associated with other findings that are typical of MAS. PFD can be detected by means of a skeletal survey. Total radiation exposure can be decreased if the skeletal survey is preceded by a bone scan. The laboratory can reduce the number of radiographs needed by focusing only on positive sites indicated by bone scanning.

Virtually any bone in the body may be affected. Commonly affected bones include the femur, tibia, ribs, and facial bones. Involvement of the small bones of the hands and feet accounts for 50% of cases. Long-bone lesions are more frequent in the metaphyseal and diaphyseal regions. The individual lesions may be trabeculated, with thin cortices and ground-glass appearance. Formal bone-age estimations may be higher in patients with sexual precocity.

Sclerosis of the basilar or temporal skull is seen (see the image below), with possible involvement of the ossicles or impingement on the temporal nerve. Evidence of past or current pathologic fractures is seen. Findings of hypophosphatemic rickets may be present. Osteosarcoma is rare (2%) and is found most often in patients who have received radiation treatment to affected bone lesions.

Plain skull radiograph in a typical McCune-Albrigh Plain skull radiograph in a typical McCune-Albright syndrome case shows marked macrocrania, frontal bossing, and markedly thickened bony table in patchy areas, particularly at base of skull and occiput. Skull also shows hair-on-end appearance, which needs to be differentiated from similar radiologic appearances in Paget disease or poorly controlled hemoglobinopathy (eg, beta-thalassemia, sickle cell disease).

Ultrasonography

Ultrasonography may be a useful diagnostic adjunct for evaluating patients with historical or physical evidence of soft-tissue swelling. Myxomas in the context of MS can be seen as sharply defined hypoechoic masses with a few central, fluid-filled cavities. However, an abdominal ultrasonogram that reveals multiple hypoechoic cystic lesions within the uterus and upper vaginal vault is characteristic of embryonal rhabdomyosarcoma.

Ultrasonographic examination of the pelvis is helpful in identifying ovarian cysts. Typically, ovarian size is not uniform in MAS: Cysts tend to be larger in one ovary. Often, cysts are unilateral, whereas cysts in central precocious puberty are small and bilateral. Furthermore, ultrasonography can help detect or rule out ovarian tumors or the presence of vaginal tumors or foreign bodies as a cause of isolated vaginal bleeding.

An uncomplicated ovarian cyst in a 3-year-old girl with MAS and precocious puberty mimicking an ectopic pregnancy is referred to as the daughter-cyst sign with ultrasound.[40]

CT and MRI

CT of the skull (see the image below) may show pituitary adenoma. Pathologic bone findings may be solitary (MFD) or multiple (PFD). The bones most frequently affected in MAS are the femur, tibia, ribs, and facial skeleton. A specific change involving the fibula is the presence of pseudocystic areas. This change is referred to as the shepherd’s crook deformation; it is due to the weight put on a less resistant bone, and the occurrence of many secondary cortical microfractures is not uncommon. Ground glass–like areas occur in the femur.

Base of the skull computed tomography scan showing Base of the skull computed tomography scan showing extensive fibrous dysplasia in McCune-Albright syndrome. Note the asymmetrical affectation, with near-total obliteration of various neural foramina at the base of the skull. This degree of fibrous dysplasia can result in multiple cranial nerve compression neuropathies, of which blindness and deafness (from involvement of cranial nerves II and VIII) are among the most disabling.

Abdominal CT can help evaluate infantile Cushing syndrome. Bilateral enlargement of the adrenal glands is consistent with the adrenal hyperplasia seen in infantile Cushing syndrome secondary to MAS. Unilateral enlargement is more consistent with an adrenal adenoma or adrenocortical carcinoma.

In the setting of myxomas, MRI identifies hypointense or isointense areas on T1-weighted imaging with gadolinium enhancement or on T2-weighted imaging. Like bone scanning, MRI may be useful for defining the extent of bony disease.[41]

Other Studies

Asymptomatic sites of FD can be detected with radionuclide (technetium-99m [99m Tc]–labeled methylene diphosphonate) bone scans. On bone scanning, PFD appears as areas of increased activity. This is helpful in defining the extent of disease activity after the diagnosis is made.[42, 43] Finding these sites when gonadotropin-independent precocious puberty is also present can confirm the diagnosis of MAS. The poor specificity of increased patchy bone activity on bone scans precludes their use for screening or exact diagnosis.

Arterial blood gas determination can be performed to evaluate for acidosis, if suspected. Electrocardiography (ECG) can be performed to evaluate for arrhythmia, if suspected. Endoscopy can be performed to evaluate for gastrointestinal (GI) polyposis, if suspected.

Biopsy

Bone biopsy may be necessary to rule out malignancy in a patient with a rapidly expanding lesion. It can be used clinically to aid in the diagnosis of osteomalacia and has been used for research purposes in an academic setting. Similarly, a rapidly expanding myxoma may call for muscle or soft-tissue biopsy. Enlarging thyroid nodules or hypofunctioning solitary thyroid nodules warrant a fine-needle aspiration (FNA) biopsy to establish a definitive diagnosis and—important—to exclude thyroid cancer.

Histologic Findings

The café-au-lait spots seen in MAS are large, melanotic macules (café-au-lait macules [CALMs]). Except for hyperpigmentation of the basal layer, no abnormal pathology is apparent. The melanocytes are normal in both number and size. Some specimens show giant melanosomes, but this finding is by no means diagnostic. Giant melanosomes can also be found in CALMs of patients with neurofibromatosis (NF) and in healthy patients.

That MAS is a disease of excess abnormal and imperfect bone formation helps elucidate its mechanisms.[44] The bone affected by PFD has areas of fibrous metaplasia within flat and tubular bones. The basic anomaly in FD lesions is a progressively expanding fibrous lesion of bone-forming mesenchyme. The lesions typically expand concentrically from the medullary cavity outwards (ie, toward the cortex). The bony lesions are well defined, though invariably, they are not encapsulated.

The bony lesions are rich in spindle-shaped fibroblasts, with a swirled appearance within the marrow space and erratically arranged “tongues” of woven bone. Islands of cartilaginous tissue also may be interspersed within the lesions. Some parts of the affected bones may have cystic lesions lined by multinucleated giant cells, akin to osteitis fibrosa cystica (of severe hyperparathyroidism) but with a paucity of osteoblasts.

Thyroid findings in individuals with hyperthyroidism secondary to MAS can range from a single adenoma to a goiter. The histologic appearance has been reported to range from multinodular hyperplasia to colloid goiter. Single nodules have the appearance of follicular adenomas.

Cushing syndrome in MAS is associated with bilateral nonpigmented adrenocortical hyperplasia with nodular elements (see the image below). Multiple micronodules can be found in the adrenal cortex surrounded by normal tissue. Only the nodules contain DNA coding for the activating Gs alpha mutation; the surrounding normal tissue does not contain the activating mutation, a finding that supports the mosaic nature of this genetic disorder.

Somatotroph adenomas take on the character of typical pituitary adenomas. Somatotroph tumors lack true capsules, with the margins of the adenoma containing normal cells interspersed with adenomatous cells. These adenomatous cells can be confirmed as somatotrophs by means of immunostaining. Although technically not malignant, somatotroph adenomas may be locally invasive into the surrounding bony architecture and vasculature.

Liver histology in individuals with elevated hepatic enzymes can range from the presence of normal hepatocytes with some fatty infiltration to focal nodular hyperplasia with bridging fibrosis and chronic cholestasis. Detailed study of liver biopsy specimens has detected mild biliary abnormalities in many of the specimens, with extramedullary hematopoiesis in a few.

Examination of the ovary in MAS generally reveals large unilateral ovarian cysts, which are follicular in nature.

 

Treatment

Approach Considerations

McCune-Albright syndrome (MAS) is a multisystemic condition with a host of variable presentations. Diagnosis and treatment of this syndrome require a high index of suspicion in any patient with characteristic café-au-lait spots and endocrine dysfunction or pathologic fractures. No measures are available to prevent MAS; however, appropriate care must be taken for fracture prevention in patients with severe polyostotic fibrous dysplasia (PFD).

For most physicians who are not endocrinologists, the crucial treatment aims are recognition of MAS and prompt referral of the patient to an endocrinologist who is experienced in its management. The endocrinologist, in turn, offers other referrals (eg, to an orthopedic surgeon or neurosurgeon) as indicated. An astute primary care physician (a pediatrician or an internist, depending on the age of the patient) who will coordinate the various aspects of the patient’s care is also necessary.

No specific medications are available to treat the bone manifestations of MAS. Antiresorptive agents (eg, alendronate and its congeners [bisphosphonates]) are being evaluated for this indication and have great palliative value owing to their pain-controlling attributes in this disease. Transsphenoidal surgery remains difficult secondary to massive thickening of the skull base. Irradiation of the bone should be avoided unless the treatment is absolutely necessary, because irradiation may increase the risk for sarcomatous degeneration.[18]

The precocious puberty of MAS generally does not respond to gonadotropin-releasing hormone (GnRH) agonists, and short-acting aromatase inhibitors have had limited effectiveness. Inconsistent results have been reported with bromocriptine, cabergoline, octreotide, or a combination of these. Pegvisomant, a growth hormone (GH) receptor antagonist, is a possibility, though it has not been specifically evaluated for treatment of MAS with GH pathology.[18]

Pharmacologic Therapy

Precocious puberty

Therapy for precocious puberty is available and should be tried; however, it is still largely experimental. Precocious puberty in MAS is gonadotropin-independent and therefore does not respond to the gonadotropin-releasing hormone (GnRH) agonist therapy that is so successful with gonadotropin-dependent central precocious puberty,[11] though one study did find GnRH analogue therapy for children to have some success in girls with MAS.[45]

For female patients, the central aim is to block estrogen effects. To this end, the aromatase inhibitors have been the mainstay of therapy in girls with persistent estradiol elevation.

Patients who respond to treatment should continue therapy until the age of normal puberty or until a bone age of 15-16 years.

A GnRH analogue may be added to aromatase inhibitors as an adjunct in the treatment of precocious puberty to suppress pituitary gonadotropin production. Depot leuprolide acetate at a dosage of 7.5 mg (300-500 µg/kg) every 28 days is a typical regimen; the dosage can be adjusted upward or downward on the basis of clinical and laboratory findings.

Preliminary trials of other aromatase inhibitors have been initiated with the aim of achieving better management of precocious puberty.[46] In 1 clinical trial, fadrozole, a more potent aromatase inhibitor, was ineffective in preventing progression of precocious puberty[47] ; however, anastrozole, a highly selective aromatase inhibitor, significantly slowed precocious puberty in 1 case and offered the added benefit of once-daily dosing.[48] The third-generation aromatase inhibitor letrozole has had some success.[49]

Ketoconazole was used in 1 study as an alternative therapy in 2 girls, who also showed significant improvement in signs of precocious puberty.[50] Unfortunately, ketoconazole’s dosing frequency is 3 times daily, which is a drawback in comparison with the once-daily dosing of anastrozole or tamoxifen.

Estrogen receptor antagonists, such as tamoxifen, may have a therapeutic role but have not yet been systematically investigated. Tamoxifen has shown some evidence of efficacy for treating precocious puberty in girls with MAS. In a multicenter study that used a regimen of 20 mg of tamoxifen once daily, the investigators reported significant improvement in growth velocity and rate of skeletal maturation.[51]

Other pilot clinical trials have been performed, in which the antiandrogen cyproterone acetate was used to block pubertal development in young female patients, while ketoconazole was used in males.

Adequate response to these therapies can be assessed by administering serial GnRH stimulation tests after 3-6 months of therapy.

Additional treatment options include medroxyprogesterone acetate, which is particularly useful for controlling menstrual bleeding. The preferred agent is Depo-Provera in intramuscular (IM) doses of 4-15 mg/kg monthly. No definitive clinical trials have determined the efficacy of this medication in the setting of MAS.

In males, adequate medical therapy for precocious puberty consists of the use of antiandrogen and antiestrogen preparations, typically a combination of spironolactone and aromatase inhibitors. Alternative antiandrogens (eg, ketoconazole) may also be used, in a dosage range of 600-800 mg/day. In one report, combined treatment with ketoconazole and cyproterone acetate was used in a boy with MAS and peripheral precocious puberty, with some positive effect.[52]

Polyostotic fibrous dysplasia

The bony disease associated with MAS (PFD) is very difficult to treat. Currently, no clinically proven medical therapies are available. Studies of oral and intravenous (IV) bisphosphonates (particularly pamidronate, alendronate, and zoledronate) suggest that these agents may have beneficial effects on the bony disease, with regard to reducing both bone pain and the frequency of pathologic fractures, as well as to slowing the evolution of the bony disease.[53, 8] However, data on the ability of bisphosphonates to heal fibrous dysplasia are conflicting.

One study found that long-term bisphosphonate treatment had beneficial effects on bone health in MAS; fracture rate and bone pain were reduced, and radiologic evidence of long-bone pathology resolution was observed.[54] Another suggested that bisphosphonate may be helpful.[55] A 2011 case report found continuous low-dose oral alendronate to be helpful in a 79-year-old woman with PFD.[56]

However, another study found that bisphosphonate treatment of PFD in children with MAS did not arrest progressive bone pathology.[57]  Similarly, a study by Florenzano et al reported that bisphosphonates did not affect disease burden progression in pediatric patients with FD. Moreover, although the investigators found that in adults with FD there was a decrease in bone-turnover markers and other disease-activity markers, these changes were determined to be age related and not significantly associated with bisphosphonate treatment.[58]

Tocilizumab, an interleukin-6 blocker used for rheumatoid arthritis, has been employed as a treatment for a polyostotic variant of bone fibrous dysplasia.[59]

Hyperthyroidism

As a rule, hyperthyroidism in the setting of MAS is treated with the same medication options as regular hyperthyroidism, including thionamides (eg, propylthiouracil) and methimazole.

Hyperthyroidism due to functional thyroid follicular adenomas can be treated medically. Antithyroid medications can be used to decrease thyroid hormone production. Unlike Graves disease, hyperthyroidism secondary to a GNAS1 mutation is unlikely to go into remission. Therefore, patients probably should use antithyroid drugs indefinitely. A more permanent treatment of the hyperthyroidism, including radioiodine therapy or thyroidectomy, should be considered if a diagnosis of MAS is confirmed.

Hyperthyroidism usually occurs in the context of toxic multinodular goiter. Notably, hyperthyroidism secondary to toxic multinodular goiter is the second most common endocrinopathy in MAS, after precocious puberty. Although radioiodine can be effective in controlling hyperthyroidism, it is a less popular option, because high doses or repeated administration may be necessary. Obvious issues arise with regard to the safety of radioiodine in children, especially in view of the potential for benign and malignant thyroid nodules to develop after radioiodine therapy.

Infantile Cushing syndrome

No effective medical treatment for adrenocorticotropic hormone (ACTH)-independent Cushing syndrome is available, and the currently recommended treatment is bilateral adrenalectomy.

During the procedure and afterwards, the patient needs replacement of both glucocorticoids and mineralocorticoids in appropriate amounts. Stress doses of glucocorticoid (approximately 10 times maintenance) should be administered perioperatively and slowly reduced to maintenance levels (eg, hydrocortisone 12-16 mg/m2/day in 3 divided doses). Mineralocorticoid replacement (eg, fludrocortisone 0.05-0.1 mg/day) should be started soon after surgery as the hydrocortisone dose is weaned toward maintenance levels.

Gigantism and acromegaly

Management of GH excess in the setting of MAS should be achieved by using pharmacotherapeutic agents because such excess is invariably the result of diffuse nodular pituitary hyperplasia rather than of a single definitive adenoma. Surgical removal of adenomas, even if they appear to be present on radiologic testing, may be complicated by coexisting fibrous dysplasia (FD) involving the skull bones that distorts anatomic planes and increases the potential for torrential intraoperative bleeding.

Irradiation of the pituitary is also not ideal, given the potential risk of inducing sarcomatous degeneration in bones affected by FD. No systemic investigation into the use of focused gamma knife–based pituitary irradiation has been done, because this condition is so uncommon.

Most patients with GH excess in MAS are treated with octreotide in dosages similar to those used in regular acromegaly, beginning at 50 µg subcutaneously (SC) every 8 hours and then titrated to response (on the basis of insulinlike growth factor 1 [IGF-1] and postinjection GH levels) to levels as high as 1500 µg/day. Octreotide successfully lowers GH levels in many cases but rarely normalizes GH secretion. Long-acting somatostatin analogues (eg, depot octreotide and lanreotide) have also been used on a case-by-case basis.[60]

The dopamine agonists bromocriptine and cabergoline have also been used to decrease GH secretion. (A third dopamine agonist, pergolide, was withdrawn from the US market in March 2007.) These agents appear to have particular utility in the setting of prolactin and growth hormone co-hypersecretory states suggestive of somatomammotropinomas.

Dopamine agonists have been used as monotherapy but are typically used in conjunction with octreotide. A study showed that cabergoline was able to decrease GH secretion but was unsuccessful in bringing GH secretion down to normal. Combined octreotide-cabergoline therapy has yielded additional improvement in GH secretion in comparison with monotherapy, but in general, it has not been successful in bringing levels down to normal.

No systemic data are presently available on the utility or place of GH receptor antagonists (eg, pegvisomant[61] ) in managing MAS-associated GH excess. Such therapy is not contraindicated; however, the inability of these agents to control GH levels would probably make their use as monotherapy in this setting inadvisable.

Other manifestations

In patients with MAS, other identified comorbidities that may be significantly affecting the bone density in a negative way must be identified and aggressively managed. Major morbidities and recommended treatments include the following:

  • Hypogonadism - Appropriate hormone replacement therapy

  • Hypophosphatemia with hyperphosphaturia - Aggressive oral phosphorus replacement

  • Hypophosphatemic rickets - Appropriate calcium supplementation, phosphate repletion, and calcitriol administration

  • Hyperparathyroidism (primary or secondary)

Surgical Interventions

Precocious puberty

The need for excision of hyperfunctioning endocrine tissue is directed by the severity of the patient’s endocrine imbalance and the efficacy of medical treatment. When medical therapy fails, oophorectomy or ovarian cystectomy has been used as a last resort for the control of precocious puberty. Despite this approach, most female patients with MAS who have had this surgery have retained normal fertility.

Historically, wedge resection of the ovary was performed if a single large follicular cyst was found. Unfortunately, this approach was often only temporarily successful in treating the estrogen hypersecretion, and other large follicular cysts subsequently formed. Accordingly, many advise against surgical treatment of precocious puberty in MAS.

Laparoscopy minimizes surgical aggression and allows the acquisition of tissue biopsy specimens for molecular analysis.[62] Additionally, hyperestrogenism can be arrested with the excision of hyperactive ovarian tissue. In girls younger than 3 years, laparoscopy can be performed by using the transumbilical laparoscopic ovarian cystectomy approach. In older females, traditional techniques are used.

Polyostotic fibrous dysplasia

Fracture is the primary indication for surgical treatment of dysplastic lesions. Most fractures are treated with traction. However, proximal fractures of the femur may have to be treated with surgically placed fixation devices.[63] Rarely, severe and progressive malformation of the femur can occur. These lesions are usually painful (because of the multiple small fractures associated with them) and may have to be removed surgically. For most PFD lesions, routine removal is not warranted; after removal, the lesion may recur at the same site.

En bloc resection and free metatarsal transfer have been used to treat FD of the fourth metacarpal associated with MAS.[64]

Hyperthyroidism

Ablative therapy (either radioiodine treatment or thyroidectomy) is warranted for the treatment of hyperthyroidism due to MAS. Any cells left behind that contain GNAS1 mutations may result in adenoma formation and recurrence of hyperthyroidism.

Thyroidectomy or hemithyroidectomy is the treatment of choice for hyperthyroidism associated with a goiter in patients with MAS. Partial or total/near-total thyroidectomy may be necessary for the control of thyrotoxicosis or the removal of multiple benign thyroid adenomas (even when they are not hyperfunctioning), progressively increasing goiter, and, of course, the very rare cases of coexisting thyroid carcinoma.

Other manifestations

The current recommendation for treatment of infantile Cushing syndrome in the context of MAS is bilateral adrenalectomy. Perioperative replacement of hormones is indicated (see Pharmacologic Therapy).

In MAS patients with gigantism or acromegaly, surgical removal should be considered only if the tumor is threatening vision; removal is rarely curative.

Diet and Activity

No specific dietary therapy is necessary for patients with MAS.

In general, patients should be encouraged to maintain a high degree of physical activity and a regular exercise program. Activity need not be limited unless the patient has PFD located at critical sites in the skeleton. Because this process can weaken bone, the presence of a lesion in a weight-bearing bone can increase the risk of a pathologic fracture and thus potentially warrant some restriction of activity. Patients may be advised, on an individual basis, to avoid certain contact sports, games, and pastimes associated with fracture risk.

Consultations

Consultation with an endocrinologist is indicated because patients may have multiple endocrine defects, which may necessitate careful orchestration of treatment. Consultation with an orthopedist is indicated for pathologic fractures.

In children with MAS, a pediatric endocrine consultation should be considered for aid in evaluating and managing the myriad potential endocrinopathies. Furthermore, new medical therapies to treat estrogen hypersecretion and PFD may be available through some pediatric endocrine programs. Before any major surgical procedure on dysplastic bone lesions, a pediatric orthopedic surgeon experienced in managing PFD should be consulted. These lesions can be difficult to treat because of the soft nature of the dysplastic bone.

Long-Term Monitoring

Endocrinology follow-up care for MAS patients is lifelong. Ablation of hyperfunctioning endocrine tissue should be arranged early. These patients have an increased incidence of breast cancer and osteosarcoma and thus require lifelong follow-up screening.

Precocious puberty

Routine monitoring of growth and development is important in the long-term management of individuals with gonadotropin-independent precocious puberty. Careful attention to growth velocity is warranted; early estrogen exposure can inappropriately advance skeletal maturity and decrease adult height potential.

In addition, early estrogen exposure can advance the maturity of the hypothalamic-pituitary-gonadal axis and result in precocious onset of gonadotropin-dependent puberty. Because adult height potential often is already diminished by premature estrogen exposure, consideration should be given to suppression of early onset of puberty to prevent further compromise of adult height.

Polyostotic fibrous dysplasia

Outpatient care of a child with PFD depends on the severity and location of the lesions. Vision and hearing should be closely monitored if lesions are located near the orbit or bones surrounding the middle and inner ear. Progressive deformities or increasing pain at other sites may indicate pathologic fractures and warrant evaluation by a pediatric orthopedist.

Hyperthyroidism

After treatment of hyperthyroidism with either thyroidectomy or radioactive iodine, close monitoring is warranted ensure appropriate replacement of thyroid hormone. In children younger than 3 years, thyroid hormone is very important for normal brain growth. Schedule office visits every 3 months with careful physical examination and thyroid function tests. In children older than 3 years, routine visits can be decreased to every 4-6 months.

Infantile Cushing syndrome

After treatment of infantile Cushing syndrome with bilateral adrenalectomy, monitoring is warranted to ensure adequate adrenal steroid replacement. Attention to growth rate is important: Both undertreatment with glucocorticoids and overtreatment can result in decreased growth velocity. Slight undertreatment (hydrocortisone 10-12 mg/m2/day) should provide adequate maintenance replacement without growth suppression.

Mineralocorticoid treatment should be carefully monitored; overtreatment with fludrocortisone can result in hypertension. Adequate mineralocorticoid replacement is confirmed by monitoring blood pressure and periodically assessing plasma renin activity.

Increased doses of steroids are required during times of stress. During febrile illnesses, both hydrocortisone and fludrocortisone doses should be doubled. During times of severe stress (eg, trauma or surgery), hydrocortisone doses should be administered at approximately 10 times maintenance levels.

Gigantism and acromegaly

Individuals with GH excess should be monitored for signs of increased tumor growth and subsequent effect on visual acuity. Repeat magnetic resonance imaging (MRI) of the pituitary should be obtained at intervals to ensure adequate suppression of adenoma growth. Medical therapy can be optimized by periodically measuring levels of GH, IGF-1, or both.

 

Medication

Medication Summary

At present, no therapy addresses the underlying molecular problem in McCune-Albright syndrome (MAS) (ie, inappropriate activation of the G protein subunit Gs alpha). Various medications may be administered to correct various endocrine and metabolic derangements, including aromatase inhibitors, hormones, steroids, somatostatin analogues, dopamine agonists, bisphosphonates, estrogen receptor antagonists, antithyroid agents, and metabolic agents.

In a 2014 study, alendronate therapy induced improvement in aBMD and decreased the level of the bone resorption marker NTX-telopeptides but did not effect pain or functional parameters or serum osteocalcin.[65]

Continuous positive effect with long-term safety data was found for zoledronic acid therapy for MAS with severe bone destruction.[66]

Combined therapy with cyproterone acetate, ketoconazole, and leuprolide depot in a boy with concomitant atypical MAS increased predicted adult height.[67]

Aromatase Inhibitors

Class Summary

Aromatase inhibitors are the mainstay of therapy in girls with persistent estradiol elevation. They have also been used in males. With adequate treatment response, serum estrone and estradiol levels are reduced. Patients who respond to treatment should continue therapy until the age of normal puberty or until a bone age of 15-16 years. Among the potential adverse effects associated with medication use are transient abdominal cramping, diarrhea, and mild hepatic inflammation.

Anastrozole (Arimidex)

Anastrozole is a highly selective aromatase inhibitor that significantly lowers serum estradiol concentrations by inhibiting the conversion of adrenally generated androstenedione to estrone. Daily dosing is convenient, and case reports have shown good response; however, larger studies are still needed.

Letrozole (Femara)

Letrozole is a competitive inhibitor of the aromatase enzyme system that leads to a reduction in plasma estrogen levels in postmenopausal women. Although this agent has been used extensively in breast cancer treatment, experience to date in MAS management is limited. Letrozole may decrease pain in patients whose conditions have previously failed other treatments.

Progestins

Class Summary

Hormones are given to correct endocrine disorders associated with sexual precocity manifestations (98% of cases), such as pubarche, menarche, and thelarche.

Medroxyprogesterone (Provera, Depo-Provera)

Progestins stop endometrial cell proliferation, allowing organized sloughing of cells after withdrawal. Medroxyprogesterone typically does not stop an acute bleeding episode but produces a normal bleeding episode after withdrawal.

Corticosteroids

Class Summary

Glucocorticoids are used for replacement therapy after adrenalectomy for infantile Cushing syndrome.

Mineralocorticoids are used for replacement therapy after adrenalectomy for infantile Cushing syndrome. They act on fluid and electrolyte balance and enhance sodium reabsorption in the kidney, resulting in expanded extracellular fluid volume. They increase renal excretion of potassium and hydrogen ions.

Hydrocortisone (Cortef, Solu-Cortef, A-Hydrocort)

Hydrocortisone is the drug of choice for glucocorticoid replacement because of its mineralocorticoid activity and glucocorticoid effects. A double or triple dose is required for febrile illnesses. Doses as high as 10 times the maintenance level may be needed in the context of severe stress (eg, from trauma, critical illness, or surgery).

Fludrocortisone

Fludrocortisone is used as partial replacement therapy for primary and secondary adrenocortical insufficiency.

Somatostatin Analogues

Class Summary

Somatostatin analogues inhibit growth hormone (GH) secretion and adenoma growth in somatotroph adenomas. They are used in treatment of patients with acromegaly and hormone-secreting tumors.

Octreotide (Sandostatin)

Octreotide is a potent, long-acting analogue of somatostatin. Like natural somatostatin, it inhibits GH secretion, insulin secretion and glucagon secretion. After intravenous (IV) administration, basal serum GH, insulin, and glucagon levels are lowered. Octreotide also inhibits prolactin secretion via vasoactive intestinal peptide (VIP)-mediated and thyrotropin-releasing hormone (TRH)-mediated secretion of prolactin.

Antiparkinson Agents, Dopamine Agonists

Class Summary

Dopamine receptor agonists have been used as adjuncts to octreotide for inhibiting GH release from somatotroph adenomas. Some of them have dopaminergic properties that inhibit prolactin secretion.

Bromocriptine (Parlodel)

Bromocriptine is a semisynthetic ergot alkaloid derivative that is a strong dopamine D2-receptor agonist and a partial dopamine D1-receptor agonist. It has been successful in further reducing GH levels in acromegalic patients treated with octreotide, though it is not generally a first-line therapy. It is indicated for amenorrhea or galactorrhea secondary to hyperprolactinemia in the absence of primary tumor.

Cabergoline

Cabergoline has been successful in further reducing GH levels in acromegalic patients treated with or without octreotide, though it is not generally a first-line therapy.

Bisphosphonates

Class Summary

Bisphosphonates are stable analogues of pyrophosphate and potent inhibitors of bone resorption and bone turnover. They are used to prevent the bone resorption and pain of polyostotic fibrous dysplasia (PFD).

Pamidronate (Aredia)

Pamidronate has been successful in treating the pain of PFD; it may have some benefit in increasing bone mineral density as well.

Alendronate (Fosamax, Binosto)

Alendronate has been successful in treating the pain of PFD; it may have some benefit in increasing bone mineral density as well. It offers the additional benefit of oral administration.

Ibandronate (Boniva)

Ibandronate increases BMD and reduces the incidence of vertebral fractures. Ibandronate increases BMD at the spine by 5.7-6.5% and the hip by 2.4-2.8%. It reduces vertebral fractures by 50% with intermittent (nondaily) dosing over 3 years; it has no effects on reduction of nonvertebral fractures. Ibandronate is approved for the treatment and prevention of postmenopausal osteoporosis. It is available as a 150-mg oral tablet and intravenous solution.

Risedronate (Actonel, Atelvia)

Risedronate is a potent antiresorptive agent that does not affect bone mineralization. The inclusion of an amino group within the heterocyclic ring makes risedronate one of the most potent antiresorptive bisphosphonates. As with other bisphosphonates, risedronate inhibits osteoclast formation and activity. Risedronate increases BMD at the spine by 5.4% and the hip by 1.6%. It reduces vertebral fractures by 41% and nonvertebral fractures by 39% over 3 years. It is approved for the treatment and prevention of postmenopausal osteoporosis, male osteoporosis, and glucocorticoid-induced osteoporosis.

Zoledronic acid (Reclast)

Zoledronic acid inhibits bone resorption by altering osteoclast activity and by inhibiting normal endogenous, as well as tumor-induced, mediators of bone degradation. Like other bisphosphonates, zoledronic acid binds to hydroxyapatite crystals in mineralized bone matrix. The binding to calcium phosphates slows the dissolution of hydroxyapatite crystals and inhibits the formation and aggregation of these crystals. It increases BMD at the spine by 4.3-5.1% and at the hip by 3.1-3.5%, as compared with placebo. It reduces the incidence of spine fractures by 70%, hip fractures by 41%, and nonvertebral fractures by 25% over 3 years.

Zoledronic acid is approved for the treatment and prevention of postmenopausal osteoporosis, glucocorticoid-induced osteoporosis, osteoporosis in men, and Paget disease of bone. It is contraindicated in patients with severe renal failure.

Estrogen Receptor Antagonists

Class Summary

Estrogen receptor antagonist therapy represents a newer approach to the treatment of persistent estradiol elevation in girls.

Raloxifene (Evista)

The biological actions of raloxifene are largely mediated through binding to estrogen receptors, which results in activation of estrogenic pathways in some tissues (agonism) and blockade of estrogenic pathways in others (antagonism). Raloxifene increases BMD at the spine and the hip. It reduces the incidence of spine fractures by 30-55% over 3 years. Raloxifene is approved for the prevention and treatment of postmenopausal osteoporosis in women. It is available as 60-mg tablets that are given orally daily. Adverse reactions commonly seen include hot flashes, leg cramps, peripheral edema, flu syndrome, arthralgia, and sweating.

Tamoxifen (Soltamox)

Tamoxifen competitively binds to estrogen receptors, producing a nuclear complex that decreases DNA synthesis and inhibits estrogen effects. It blocks the end-organ effects of abnormal estrogen exposure in prepubertal girls.

Antithyroid Agents

Class Summary

Antithyroid agents block production of thyroid hormone in functional thyroid nodules and are used in palliative treatment of hyperthyroidism.

Propylthiouracil (PTU)

Propylthiouracil is a derivative of thiourea that inhibits organification of iodine by the thyroid gland. It blocks oxidation of iodine in the thyroid gland, thereby inhibiting thyroid hormone synthesis; it also inhibits conversion of thyroxine to triiodothyronine (and thus possesses an advantage over other agents).

Methimazole (Tapazole)

Methimazole inhibits thyroid hormone by blocking oxidation of iodine in the thyroid gland. It is used to decrease the production of thyroid hormone in functional thyroid nodules associated with MAS. Hyperthyroidism in MAS, unlike autoimmune-mediated hyperthyroidism, is likely to require long-term treatment.

Vitamins, Fat-Soluble

Class Summary

Metabolic agents are indicated to correct deficiencies leading to hypoparathyroidism, as well as to treat hypercalcemia and prevent bone loss.

Ergocalciferol (Calciferol, Drisdol)

Ergocalciferol stimulates absorption of calcium and phosphate from the small intestine and promotes release of calcium from bone into blood.

 

Questions & Answers

Overview

What are features of McCune-Albright syndrome (MAS)?

What are the manifestations of McCune-Albright syndrome (MAS)?

Which lab tests are performed in the workup of McCune-Albright syndrome (MAS)?

Which imaging studies are performed in the workup of McCune-Albright syndrome (MAS)?

Which studies may be considered in the workup of McCune-Albright syndrome (MAS)?

How is precocious puberty treated in McCune-Albright syndrome (MAS)?

How is polyostotic fibrous dysplasia (PFD) treated in McCune-Albright syndrome (MAS)?

How is hyperthyroidism treated in McCune-Albright syndrome (MAS)?

How are endocrine abnormalities treated in McCune-Albright syndrome (MAS)?

What is the role of surgery in the treatment of McCune-Albright syndrome (MAS)?

What is McCune-Albright syndrome (MAS)?

Which endocrine syndromes are associated with McCune-Albright syndrome (MAS)?

What is the role of genetics in the etiology of McCune-Albright syndrome?

How is McCune-Albright syndrome diagnosed?

Which specialist consultation is beneficial to patients with McCune-Albright syndrome?

What is the pathophysiology of McCune-Albright syndrome (MAS)?

Which conditions are associated with McCune-Albright syndrome?

Which malignancies are associated with McCune-Albright syndrome?

What causes McCune-Albright syndrome (MAS)?

What causes the classic triad of features in McCune-Albright syndrome?

What is the prevalence of McCune-Albright syndrome (MAS)?

At what age is McCune-Albright syndrome (MAS) typically diagnosed?

At are the sexual and racial predilections of McCune-Albright syndrome (MAS)?

What is the prognosis of McCune-Albright syndrome (MAS)?

What is included in patient education about McCune-Albright syndrome (MAS)?

Presentation

Which clinical history findings are characteristic of café-au-lait pigmentation in McCune-Albright syndrome (MAS)?

What is the focus of clinical history in the evaluation of McCune-Albright syndrome (MAS)?

Which clinical history findings are characteristic of precocious puberty in McCune-Albright syndrome (MAS)?

Which clinical history findings are characteristic of polyostotic fibrous dysplasia (PFD) in McCune-Albright syndrome (MAS)?

Which clinical history findings are characteristic of McCune-Albright syndrome (MAS)?

Which physical findings are characteristic of café-au-lait pigmentation in McCune-Albright syndrome (MAS)?

Which physical findings are characteristic of McCune-Albright syndrome (MAS)?

Which physical findings are characteristic of precocious puberty in McCune-Albright syndrome (MAS)?

Which physical findings are characteristic of polyostotic fibrous dysplasia (PFD) in McCune-Albright syndrome (MAS)?

Which physical findings are characteristic of endocrine disorders in McCune-Albright syndrome (MAS)?

What are the possible complications of precocious puberty in McCune-Albright syndrome (MAS)?

What are the possible complications of polyostotic fibrous dysplasia (PFD) in McCune-Albright syndrome (MAS)?

What are the possible complications of endocrine disorders in McCune-Albright syndrome (MAS)?

What are the possible cardiac complications of McCune-Albright syndrome (MAS)?

DDX

Why should McCune-Albright syndrome (MAS) be considered in patients with recurrent fractures?

Which conditions are included in the differential diagnoses of McCune-Albright syndrome (MAS)?

What are the differential diagnoses for McCune-Albright Syndrome?

Workup

What are the initial studies in the workup of McCune-Albright syndrome (MAS)?

What is the role of hormone measurement in the diagnosis of McCune-Albright syndrome?

What is the role of blood and urinary chemistries in the diagnosis of McCune-Albright syndrome?

What is the role of thyroid testing in the diagnosis of McCune-Albright syndrome (MAS)?

What is the role of ACTH measurement in the diagnosis of McCune-Albright Syndrome?

What is the role of dexamethasone suppression testing in the diagnosis of McCune-Albright syndrome (MAS)?

What is the role of 24-hour urinary free cortisol (UFC) testing in the diagnosis of McCune-Albright syndrome (MAS)?

What is the role of serum growth hormone testing in the diagnosis of McCune-Albright syndrome (MAS)?

What is the role of polymerase chain reaction (PCR) assay in the diagnosis of McCune-Albright syndrome (MAS)?

What is the role of plain radiography in the diagnosis of McCune-Albright syndrome (MAS)?

What is the role of ultrasonography in the diagnosis of McCune-Albright syndrome (MAS)?

What is the role of CT scanning in the diagnosis of McCune-Albright syndrome (MAS)?

What is the role of MRI in the diagnosis of McCune-Albright syndrome (MAS)?

What is the role of bone scanning in the workup of McCune-Albright syndrome (MAS)?

What is the role of bone biopsy in the diagnosis of McCune-Albright syndrome (MAS)?

Which histologic findings are characteristic of McCune-Albright syndrome (MAS)?

Treatment

How is McCune-Albright syndrome (MAS) treated?

What is the role of pharmacologic therapy in the treatment of precocious puberty in McCune-Albright syndrome (MAS)?

What is the role of pharmacologic therapy in the treatment of polyostotic fibrous dysplasia (PFD) in McCune-Albright syndrome (MAS)?

What is the role of pharmacologic therapy in the treatment of hyperthyroidism in McCune-Albright syndrome (MAS)?

What is the role of pharmacologic therapy in the treatment of infantile Cushing syndrome in McCune-Albright syndrome (MAS)?

What is the role of pharmacologic therapy in the treatment of gigantism and acromegaly in McCune-Albright syndrome (MAS)?

What is the role of pharmacologic therapy in the treatment of the endocrine syndromes in McCune-Albright syndrome (MAS)?

What is the role of surgery in the treatment of precocious puberty in McCune-Albright syndrome (MAS)?

What is the role of surgery in the treatment of polyostotic fibrous dysplasia (PFD) in McCune-Albright syndrome (MAS)?

What is the role of surgery in the treatment of hyperthyroidism in McCune-Albright syndrome (MAS)?

What is the role of adrenalectomy in the treatment of other manifestations of McCune-Albright syndrome (MAS)?

Which dietary modifications are used in the treatment of McCune-Albright syndrome (MAS)?

Which specialist consultations are beneficial to patients with McCune-Albright syndrome (MAS)?

What is included in the long-term monitoring of patients with McCune-Albright syndrome (MAS)?

What is included in the long-term monitoring of precocious puberty in McCune-Albright syndrome (MAS)?

What is included in the long-term monitoring of polyostotic fibrous dysplasia (PFD) in McCune-Albright syndrome (MAS)?

What is included in the long-term monitoring of hyperthyroidism in McCune-Albright syndrome (MAS)?

What is included in the long-term monitoring of infantile Cushing syndrome in McCune-Albright syndrome (MAS)?

What is included in the long-term monitoring of growth hormones (GH) excess in McCune-Albright syndrome (MAS)?

Medications

What is the role of medications in the treatment of McCune-Albright syndrome (MAS)?

Which medications in the drug class Vitamins, Fat-Soluble are used in the treatment of McCune-Albright Syndrome?

Which medications in the drug class Antithyroid Agents are used in the treatment of McCune-Albright Syndrome?

Which medications in the drug class Estrogen Receptor Antagonists are used in the treatment of McCune-Albright Syndrome?

Which medications in the drug class Bisphosphonates are used in the treatment of McCune-Albright Syndrome?

Which medications in the drug class Antiparkinson Agents, Dopamine Agonists are used in the treatment of McCune-Albright Syndrome?

Which medications in the drug class Somatostatin Analogues are used in the treatment of McCune-Albright Syndrome?

Which medications in the drug class Corticosteroids are used in the treatment of McCune-Albright Syndrome?

Which medications in the drug class Progestins are used in the treatment of McCune-Albright Syndrome?

Which medications in the drug class Aromatase Inhibitors are used in the treatment of McCune-Albright Syndrome?