AUTHOR AND EDITOR INFORMATION

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• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

INTRODUCTION

Section 2 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Background

McCune-Albright syndrome in its classic form consists of at least 2 features of the triad of polyostotic fibrous dysplasia, café au lait skin pigmentation, and autonomous endocrine hyperfunction. Reports of similar cases were published before McCune and Albright separately reported the most complete early descriptions of the syndrome in 1937. Later findings broadened the spectrum of the McCune-Albright syndrome. Although changes in ovary, bone, and skin tissue are most common, other endocrine and nonendocrine tissues also may be affected, including the adrenal, thyroid, pituitary, liver, and heart.

The most common form of autonomous endocrine hyperfunction in this syndrome is gonadotropin independent precocious puberty, but affected individuals also may have hyperthyroidism, hypercortisolism, pituitary gigantism, or acromegaly. Nonendocrine abnormalities in this disorder include hypophosphatemia, chronic liver disease, tachycardia, and, rarely, sudden death, possibly from cardiac arrhythmias.

Pathophysiology

Precocious puberty, the most common endocrine feature of McCune-Albright syndrome, is a result of gonadotropin independent autonomous ovarian or testicular function. Precocious puberty caused by this condition is far more common in girls than in boys. Girls as young as 4 months with McCune-Albright syndrome can have breast development or vaginal bleeding. A dominant ovarian cyst develops independent of stimulation by gonadotropins. This cyst secretes estradiol, which causes sexual precocity. In addition, excess estrogen exposure often stimulates increased growth velocity and can result in a marked advancement in skeletal maturity.

Adrenocorticotropic hormone (ACTH)–independent Cushing syndrome generally results in growth failure and hypertension in infancy. The adrenal glands are bilaterally enlarged and contain multiple small nodules in the cortex.

Hyperthyroidism typically occurs later in childhood, although it can occur within the first year of life. As in Cushing syndrome and precocious puberty, hyperthyroidism associated with McCune-Albright syndrome is a result of one or more autonomous hyperfunctioning nodules.

Growth hormone (GH) excess from somatotroph adenomas in the pituitary can occur at any age, resulting in gigantism and/or acromegaly.

Fibrous dysplasia in the McCune-Albright syndrome can involve any bone but most commonly affects the long bones, ribs, and skull. Fibrous dysplasia ranges 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.

Café au lait spots in McCune-Albright syndrome are large melanotic macules. Except for hyperpigmentation of the basal layer, no abnormal pathology is seen.

Hypophosphatemia is a result of decreased reabsorption of phosphate in the renal tubule, similar to the phosphaturia seen with hyperparathyroidism. Parathyroid hormone levels are not elevated, suggesting parathyroid hormone-independent stimulation of phosphaturia.

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. Therefore, the fatty liver may have been secondary to glucocorticoid excess. Elevated transaminases in this infant, however, persisted long past correction of the glucocorticoid excess with adrenalectomy.

Many case reports, including some originally reported by McCune and Albright, describe sudden death. Most of these episodes of sudden death have occurred in patients with multiple endocrine and nonendocrine manifestations of the syndrome. Persistent tachycardia has been observed in addition to mild-to-moderate cardiomegaly. Although the cause of death in these patients is unclear, it is presumed to be secondary to cardiac arrhythmia.

It was discovered only recently that McCune-Albright syndrome is the result of a postzygotic somatic mutation in the gene coding for the alpha subunit of the stimulatory G protein (Gsa). G proteins are involved in transmitting hormone signals intracellularly by coupling cell surface receptors to intracellular signaling cascades. The specific mutations that cause McCune-Albright syndrome cause constitutive activation of these intracellular signaling cascades in the absence of hormone stimulation. For further details of the molecular mechanisms behind stimulatory G protein function and McCune-Albright syndrome, see Causes.

Frequency

United States

McCune-Albright syndrome is a rare, sporadically occurring genetic disorder. The exact incidence is unknown.

Mortality/Morbidity

• In precocious puberty, early breast development and vaginal bleeding can be accompanied by loss of adult height potential.
• Some of the most severe effects of fibrous dysplasia are pathologic fractures, facial disfigurement, and vision and hearing problems.
• 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.
• Infantile Cushing syndrome can cause severe growth failure, poor muscle tone, and hypertension. Permanent effect on growth potential also is possible. Long-term untreated hypercortisolism can result in death.
• Gigantism or acromegaly can occur, with a risk of developing glucose intolerance, hypertriglyceridemia, hypertension, and mild myopathy.
• Hypophosphatemia causes rickets and short stature.
• Sudden death frequently has been associated with more severe disease. Although no arrhythmias have been detected in individuals with McCune-Albright syndrome, this is the presumed mechanism of sudden death.

Race

McCune-Albright syndrome occurs equally in all races.

Sex

Gonadotropin-independent precocious puberty is far more common in affected girls than in boys. Other manifestations of McCune-Albright syndrome probably occur equally in both sexes.

Age

• Severe cases involving multiple endocrine tissues may be recognized shortly after birth. Cases of infantile Cushing syndrome and hyperthyroidism also have been reported in the neonatal period. Additionally, fibrous dysplasia, café au lait pigmentation, liver disease, and hypophosphatemia initially can be seen in infancy.
• Less severe findings of McCune-Albright syndrome can occur at almost any time during childhood. Precocious puberty in girls can be seen in infants as young as 4 months, although frequently it 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 Gsa mutations can occur in individuals at any age.

CLINICAL

Section 3 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

History

A complete medical history is important in the evaluation of apparent endocrine hyperfunction such as that seen in McCune-Albright syndrome. A detailed history is often more important in ruling out other causes of endocrine hyperfunction than in diagnosing McCune-Albright syndrome.

• Precocious puberty can result from either central gonadotropin dependent or peripheral gonadotropin independent causes.
• • Symptoms of an intracranial process, such as 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 McCune-Albright syndrome. Previous brain injury due to infection or trauma also is associated more often with central precocious puberty.
  • Although the following pattern is not conclusive, puberty in McCune Albright syndrome is seen more frequently with vaginal bleeding and/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.
  • Consider other possible causes of estrogen excess with precocious vaginal bleeding and/or breast development. Accidental ingestion of estrogen supplements can cause some breast development, increase in height velocity, and maturation of the endometrial lining. As estrogen levels decrease, a withdrawal-bleeding episode can occur. If vaginal bleeding occurs in the absence of other signs of estrogen excess (eg, breast development, increased height velocity), a careful history mindful of possible trauma or sexual abuse should be obtained.
• Evaluation of café au lait pigmentation requires a detailed family history because neurofibromatosis also produces multiple café au lait spots. Unlike McCune-Albright syndrome, which occurs sporadically, neurofibromatosis is an autosomal dominant condition. Consider a diagnosis of neurofibromatosis if a family history of café au lait pigmentation exists. Do not discount the possibility of neurofibromatosis when precocious puberty occurs with café au lait spots. Hypothalamic optic gliomas with neurofibromatosis can lead to gonadotropin dependent precocious puberty.
• Hyperthyroidism in McCune-Albright syndrome rarely occurs without several other features of the syndrome. With hyperthyroidism, a family history of autoimmune thyroid disorders supports a diagnosis of Graves disease, although Graves disease can be seen without a family history. If no other features of McCune-Albright syndrome are present, autoimmune thyroid disease is far more likely. Also consider surreptitious administration of thyroid hormone in unexplained hyperthyroidism. Again, this explanation would be more likely in the absence of physical findings of McCune-Albright syndrome.
• Infantile Cushing syndrome may be seen initially without other signs of McCune-Albright syndrome. 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. Consider exogenously administered steroids in the absence of other signs of McCune-Albright syndrome before attributing excess cortisol to an activating Gsa mutation. Injections of steroids can be long lasting; there are case reports of triamcinolone acetonide causing Cushing syndrome for well over 1 year after the last injection, presumably from an inability to metabolize and excrete the steroid.

Physical

Diagnosis of McCune-Albright syndrome depends on finding at least 2 of the phenotypic features associated with activating Gsa mutations. The presence of 2 distinct physical findings consistent with autonomous function increases the likelihood that the single underlying cause is an activating Gsa mutation rather than activating mutations in genes (ie, receptors) specific to a tissue type. Although it is possible that an activating Gsa mutation can be isolated in only one tissue type, confirmation would require molecular analysis of that specific tissue. Additionally, certain physical findings should lead away from the diagnosis of McCune-Albright syndrome.

• Precocious puberty in girls with McCune-Albright syndrome is indicated by the appearance of signs of estrogen excess 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 examination of 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 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.
• If precocious puberty and café au lait pigmentation are the only features, neurofibromatosis cannot be ruled out. The café au lait spots in McCune-Albright syndrome are pigmented macules with irregular outlines (see Image 1). Color ranges from light brown to dark brown and may not be apparent in very young patients. A Wood lamp can help to detect subtle lesions. Pigmented areas often are few but can be quite large. These lesions often display a segmental distribution and frequently predominate on one side of the body.
• Individual lesions generally do not cross the midline. Café au lait spots in McCune-Albright syndrome are characterized by an irregular outline, described as coast of Maine, whereas spots in neurofibromatosis tend to be smaller and have a smooth outline, described as 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 are suggestive of neurofibromatosis.
• Fibrous dysplasia in McCune-Albright syndrome ranges from asymptomatic lesions to markedly disfiguring involvement of the skull, spine, and long bones. Involvement of the skull can be particularly problematic, with lesions of the orbit resulting in visual loss and/or proptosis, and lesions of the ear resulting in deafness and vertigo. As with the cutaneous lesions, the bony lesions are not uniformly distributed and tend to be unilateral.
• Hyperthyroidism in McCune-Albright syndrome is uncommon, appearing as a hypermetabolic state. Findings may include tachycardia, hypertension, hyperthermia, tremor, sleeplessness, and weight loss. Infants with hyperthyroidism often have failure to thrive. Hyperthyroidism does not always occur in infancy. Case reports describe hyperthyroidism occurring abruptly in later childhood, including one case of thyroid storm after surgery for fibrous dysplasia.
• Rarely, severe hypophosphatemia can occur in McCune-Albright syndrome. If untreated, 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).
• Cushing syndrome also occurs rarely in McCune-Albright syndrome. 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.
• Infants with McCune-Albright syndrome may have persistent jaundice and mild hepatomegaly but generally lack other symptoms of liver failure.
• Growth hormone producing somatotroph adenomas can occur in McCune-Albright syndrome. In children, GH excess results in a marked increase in linear growth velocity. If 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 also may have hypertension and mild decreases in muscle tone.

Causes

Recently, the discovery was made that McCune-Albright syndrome is the result of a postzygotic somatic mutation in the gene coding for the alpha subunit of the stimulatory G protein (Gsa). G proteins couple cell surface receptors to intracellular proteins to activate or inactivate signaling cascades (see Image 3). The stimulatory G protein is normally activated when a hormone or other ligand binds to the cell surface receptor. The activated Gsa subunit subsequently disassociates from the receptor, binds to adenylyl cyclase, and stimulates an increase in intracellular cyclic adenosine monophosphate (cAMP) levels. The Gsa subunit then is inactivated, reassociates with the receptor, and is again available for hormone-mediated reactivation.

• The specific mutations that cause McCune-Albright syndrome occur at a site in the protein that mediates the inactivation of the Gsa subunit (see Image 4). Once activated, the mutated Gs alpha subunit remains activated for a prolonged period despite the absence of hormone stimulation of the receptor. The result is constitutive activation of the Gsa subunit, constant stimulation of adenylyl cyclase, and persistently high levels of intracellular cAMP. In various tissues, increased cAMP levels can mediate mitogenesis and increased cell function. The specific phenotype depends on the cell type containing the mutation.
• The classic triad of features in McCune-Albright syndrome, polyostotic fibrous dysplasia, autonomous endocrine function, and café au lait skin pigmentation, can all be explained by activation of the Gsa subunit and increased intracellular cAMP.
• Eumelanogenesis (formation of brown/black pigment) normally is stimulated by melanocyte-stimulating hormone (MSH) binding to the MSH receptor, a classic G protein receptor coupled to Gsa. Constitutive activation of the Gsa 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 follicle-stimulating hormone (FSH) receptors are Gsa 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 McCune-Albright syndrome.
• Since McCune-Albright syndrome 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 the mild cases with only 2 or 3 of the classic phenotypic features of the syndrome. If the mutation occurs very late in tissue development after differentiation into a specific cell line, then a single adenoma may result. Gsa activating mutations have been reported in isolated hyperfunctioning thyroid nodules and in somatotroph adenomas.
• Although it is possible that Gsa mutations could occur in germ cells (either the oocyte or spermatocyte), the resulting zygote and all daughter cells then would contain the mutation. It is likely that activating Gsa mutations are lethal if they occur very early in embryogenesis. This would account for the lack of autosomal dominant transmission of this syndrome.

DIFFERENTIALS

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• Clinical
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Other Problems to be Considered

Central precocious puberty
Functional ovarian tumour
Exogenous steroid abuse
Exogenous thyroid hormone abuse

WORKUP

Section 5 of 11  

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• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
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Lab Studies

• Serum estradiol, FSH, LH levels: Precocious puberty in McCune-Albright syndrome is gonadotropin independent. Therefore, the finding of elevated estradiol levels and suppressed or undetectable gonadotropins is diagnostic of gonadotropin independent puberty. Frequently, however, estrogen secretion is episodic in McCune-Albright syndrome, so that multiple assays over time may be necessary to demonstrate an elevation in estradiol levels.
• Factrel stimulation testing: Random gonadotropin levels in early puberty often are equal to prepubertal levels as LH and FSH secretion is pulsatile. Additionally, significant pulses may only occur at night in early puberty. A luteinizing hormone-releasing hormone (LH-RH) stimulation test (Factrel 100 mg IV) can help to differentiate between central gonadotropin dependent and gonadotropin independent precocious puberty. Serum is sampled for LH and FSH at 0, 15, 30, 45, and 60 minutes after administration of LH-RH. Suppressed or undetectable levels of LH and FSH after administration of LH-RH are consistent with McCune-Albright syndrome.
• Multichemistry panel, including liver function tests: Individuals with McCune-Albright syndrome may have elevated liver enzymes or hyperbilirubinemia. Even after normalization of cortisol or thyroxine levels, these elevations can persist, suggesting the presence of Gsa activating mutations in the liver. Furthermore, hypophosphatemia may result from increased urinary phosphate excretion. Therefore, individuals with McCune-Albright syndrome should have a complete multichemistry panel performed that includes calcium, phosphorus, and liver function tests.
• Thyroid function testing: Elevated thyroxine levels and suppressed thyroid-stimulating hormone (TSH) levels are consistent with hyperthyroidism.
• Thyroid-stimulating antibodies: Since hyperthyroidism associated with McCune-Albright syndrome 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.
• Serum ACTH levels: The glucocorticoid secretion in infantile Cushing syndrome is ACTH independent. Therefore, ACTH levels generally are suppressed despite elevated cortisol levels.
• Dexamethasone suppression test: Cortisol levels normally are suppressed by overnight administration of dexamethasone (0.050 mg/kg; not to exceed 1 mg). Elevated 8:00 am cortisol levels are suggestive of Cushing syndrome but do not distinguish between ACTH-dependent and ACTH-independent excess cortisol production.
• Urine collection assayed for free cortisol: Twenty-four–hour urinary free cortisol is the most sensitive measure of cortisol production rate and is more accurate in determining Cushing syndrome than random cortisol levels. Normal values for 24-hour urine free cortisol vary with the size of the patient and should be adjusted for body surface area in order to compare to published adult normal ranges (ie, 10-84 mcg /1.7 m²/d). Elevated 24-hour urine free cortisol levels are suggestive of 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/d) and high-dose (8 mg/1.7 m²/d) dexamethasone suppression tests can help to distinguish ACTH-dependent Cushing syndrome from pituitary and ectopic sources and confirm the ACTH-independent nature of excessive cortisol secretion in McCune-Albright syndrome. Because recommended treatment of ACTH-independent Cushing syndrome is bilateral adrenalectomy, this test should be performed before surgery.

  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 collecting baseline measurements, 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 but suppression with high dose is suggestive of ACTH-dependent Cushing syndrome. Lack of suppression with high dose dexamethasone is suggestive of either ectopic ACTH production or ACTH-independent Cushing syndrome. Diagnosis of ACTH-independent Cushing syndrome consistent with McCune-Albright syndrome is confirmed in this situation if ACTH levels also are suppressed.

• Serum GH and insulinlike growth factor-1 (IGF-1) levels: Individuals with somatotroph adenomas due to Gsa activating mutations have detectable elevations of either GH and/or IGF-1 in the serum.

Imaging Studies

• Pelvic ultrasonography: Ultrasonographic examination of the pelvis is helpful in identifying ovarian cysts. Typically, ovarian size in McCune-Albright syndrome is not uniform. Cysts tend to be larger in one ovary. Often, cysts are unilateral, while cysts in central precocious puberty are small and bilateral. Furthermore, ultrasonography can help to detect or rule out ovarian tumors or the presence of vaginal tumors or foreign bodies as a cause of isolated vaginal bleeding.
• Bone scanning: Asymptomatic sites of fibrous dysplasia can be detected with bone scanning. Positive sites on bone can then be confirmed as fibrous dysplasia by means of radiography. Finding these sites when gonadotropin independent precocious puberty is also present can confirm the diagnosis of McCune-Albright syndrome.
• Skeletal survey: Polyostotic fibrous dysplasia 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 scan.
• Abdominal CT: 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 McCune-Albright syndrome. Unilateral enlargement is more consistent with an adrenal adenoma or adrenocorticocarcinoma.

Histologic Findings

Specific histologic findings include the following:

Ovary: Examination of the ovary in McCune-Albright syndrome generally reveals large unilateral ovarian cysts. These cysts are follicular in nature.

Café au lait spots: Café au lait spots in McCune-Albright syndrome are large, melanotic macules. Except for hyperpigmentation of the basal layer, no abnormal pathology is seen. Number and size of the melanocytes are normal.

Fibrous dysplasia: Examination of these lesions reveals an abundance of fibroblastlike cells with minimal extracellular matrix. Osteoblasts in the areas of fibrous dysplasia tend to lay down bone matrix rich in antiadhesion proteins, such as versican and osteonectin, rather than proadhesion molecules, such as osteopontin and bone sialoprotein. The lamellar trabeculae have been extensively resorbed and entrapped within dysplastic bone, giving the appearance of woven bone. Islands of cartilage may exist within the woven bone. The excess of preosteogenic cells is thought to be predominantly preosteoblasts that mature into abnormal osteoblasts.

Thyroid nodules: Findings in the thyroid gland in individuals with hyperthyroidism secondary to McCune-Albright syndrome can range from a single adenoma to a goiter. The histological appearance has been reported to range from multinodular hyperplasia to colloid goiter. Single nodules have the appearance of follicular adenomas.

Adrenal hyperplasia: Cushing syndrome in McCune-Albright syndrome is associated with bilateral nonpigmented adrenocortical hyperplasia with nodular elements (see Image 2). Multiple micronodules can be found in the adrenal cortex surrounded by normal tissue. Only the nodules contain DNA coding for the activating Gsa mutation. The surrounding normal tissue does not contain the activating mutation, thus supporting the mosaic nature of this genetic disorder.

Somatotroph adenoma: 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 immunostaining. Although they are technically not malignant, somatotroph adenomas may be locally invasive into the surrounding bony architecture and vasculature.

Liver: The histology of the liver in individuals with elevated liver enzymes can range from 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.

TREATMENT

Section 6 of 11  

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Medical Care

• Precocious puberty
  • Precocious puberty in McCune-Albright syndrome 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.
  • The aromatase inhibitor testolactone has been the mainstay of therapy in girls with persistent estradiol elevation. Aromatase inhibitors block the conversion of testosterone to estradiol, thus lowering circulating estrogen levels. Doses beginning at 20 mg/kg/d, divided in 3-4 doses, up to 40 mg/kg/d are used. Although fairly effective, the large amount of medication required and the frequency of dosing make compliance difficult.
  • Fadrozole, a more potent aromatase inhibitor, was shown in a clinical trial to be ineffective in preventing progression of precocious puberty. However, anastrozole, a highly selective aromatase inhibitor, was successful in significantly slowing precocious puberty in one case. It also had the added benefit of once daily dosage.
  • Tamoxifen, an antiestrogen that was initially developed for use in estrogen–sensitive breast cancer, has recently been shown to be effective in treating precocious puberty in girls with McCune-Albright syndrome. One multicenter study was performed using 20 mg of tamoxifen once a day. They found significant improvement in growth velocity and rate of skeletal maturation.
  • Ketoconazole was used in one study as an alternative therapy in 2 girls. They also showed significant improvement in signs of precocious puberty. Unfortunately, ketoconazole's dosing is 3 times daily, which is a drawback compared to the daily dosing of anastrozole or tamoxifen. Additional clinical studies of newer and more potent aromatase inhibitors, as well as antiestrogens and other therapies, continue to be pursued.
• Fibrous dysplasia: Symptomatic fibrous dysplasia is difficult to treat medically. Currently, no clinically proven medical therapies exist. Recent studies using both oral and intravenous bisphosphonates are encouraging. Conflicting data regarding the ability of bisphospanates to heal fibrous dysplasia have been reported. Some studies have shown no improvement in bone mineral density, whereas others have shown significant improvement in bone mineral density in the areas of fibrous dysplasia. However, bisphosphanates do make the lesions less painful.
• Hyperthyroidism: Hyperthyroidism due to functional thyroid follicular adenomas can be treated medically. Antithyroid medications, such as propylthiouracil and methimazole, can be used to decrease thyroid hormone production. Unlike Graves disease, hyperthyroidism secondary to an activating Gsa mutation is unlikely to go into remission. Therefore, patients probably should use antithyroid drugs indefinitely. Consider a more permanent treatment of the hyperthyroidism, including I131 therapy or thyroidectomy, if a diagnosis of McCune-Albright syndrome is confirmed.
• Hypophosphatemic rickets: The treatment for severe hypophosphatemia is similar to that used in X-linked dominant hypophosphatemic rickets. Phosphate supplementation (approximately 1.5-2.5 g/d divided in 5 doses) is given in addition to 1,25 dihydroxy vitamin D (calcitriol 0.25-0.5 mg/d).
• Infantile Cushing syndrome: No effective medical treatment for ACTH-independent Cushing syndrome exists, and the current recommendation for treatment is bilateral adrenalectomy. During the adrenalectomy and afterwards, the patient needs replacement of both glucocorticoid and mineralocorticoid in appropriate amounts. Stress doses of glucocorticoid (approximately 10 times maintenance) should be administered perioperatively and slowly reduced to maintenance replacement levels (hydrocortisone 12-16 mg/m²/d divided in 3 doses). Mineralocorticoid replacement (Florinef 0.05-0.1 mg/d) should be started soon after surgery as the hydrocortisone dose is weaned toward maintenance levels.
• Gigantism/acromegaly: Medical treatment is the most effective for GH-producing adenomas. Radiation therapy may cause sarcomatous changes in the surrounding dysplastic bone if fibrous dysplasia is present. Octreotide, the long-acting somatostatin analogue, has been used with variable success in decreasing GH secretion from these tumors. Octreotide has been successful in lowering GH levels in many cases but rarely has normalized GH secretion. Dopamine agonists, such as bromocriptine and cabergoline, have also been used to decrease GH secretion. They are typically used in conjunction with octreotide. A recent study showed that cabergoline was able to decrease GH secretion but it was unsuccessful in bringing GH secretion down to normal. Combination octreotide and cabergoline therapy has shown additional improvement in GH secretion compared with monotherapy but, in general, was not successful in bringing levels down to normal.

Surgical Care

• Precocious puberty: Historically, wedge resection of the ovary was performed if a single large follicular cyst was found. Unfortunately, this often only temporarily treated the estrogen hypersecretion and other large follicular cysts subsequently formed. Therefore, surgical treatment currently is not recommended to treat precocious puberty in McCune-Albright syndrome.
• 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 require surgically placed fixation devices. Rarely, severe and progressive malformation of the femur can occur. These lesions usually are painful because of the multiple small fractures associated with them and may need to be removed surgically. Routine removal of most polyostotic dysplastic lesions generally is not warranted and can result in the lesion recurring at the same site.
• Hyperthyroidism: Ablative therapy is warranted in treatment of hyperthyroidism due to McCune-Albright syndrome, either by radioactive iodine treatment or by thyroidectomy. A near total thyroidectomy should be considered, because any cells left behind containing activating Gsa mutations result in adenoma formation and recurrence of hyperthyroidism.
• Infantile Cushing syndrome: The current recommendation for treatment is bilateral adrenalectomy. See Medical Care for details on perioperative replacement of hormones.
• Gigantism/acromegaly: Consider surgical removal only if the tumor is threatening vision because removal is rarely curative.

Consultations

• Pediatric endocrine consultation should be considered in any child with McCune-Albright syndrome to evaluate for and manage the myriad potential endocrinopathies. Furthermore, new medical therapies to treat estrogen hypersecretion and fibrous dysplasia are being proposed in clinical studies that are available through some pediatric endocrine programs.
• Consider consultation with a pediatric orthopedic surgeon experienced in the management of polyostotic fibrous dysplasia prior to any major surgical procedure on dysplastic bone lesions. These lesions can be difficult to treat because of the soft nature of the dysplastic bone.

Diet

No special dietary considerations exist.

Activity

Activity is not limited unless the patient has fibrous dysplasia located at critical sites in the skeleton. Because fibrous dysplasia can weaken the bone, the presence of a lesion in a weight bearing bone can increase the risk of a pathologic fracture. Therefore, limiting activities (eg, contact sports) in these cases should be considered.

MEDICATION

Section 7 of 11  

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• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

The focus of therapy in McCune-Albright syndrome is to decrease secretion of the hormones in question. At present, no therapy addresses the underlying molecular problem (ie, the inappropriate activation of the Gsa subunit).

Drug Category: Aromatase inhibitors

Mainstay of therapy in girls with persistent estradiol elevation.

Drug Category: Glucocorticoids

These agents are used for replacement therapy postadrenalectomy in infantile Cushing syndrome.

Drug Category: Mineralocorticoids

These agents are used for replacement therapy postadrenalectomy in 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 ion.

Drug Category: Somatostatin analogues

These agents inhibit GH secretion and adenoma growth in somatotroph adenomas. Octreotide, like natural somatostatin, inhibits GH secretion, insulin secretion and glucagon secretion. Following IV administration, basal serum GH, insulin, and glucagon levels are lowered. It also inhibits prolactin secretion via vasoactive intestinal peptide-mediated and thyrotropin releasing hormone–mediated secretion of prolactin. They are used in treatment of patients with acromegaly and hormone-secreting tumors.

Drug Category: Dopamine receptor agonists

Bromocriptine and cabergoline have been used as adjunctive therapy to octreotide in the inhibition of GH release from somatotroph adenomas.

Drug Category: Bisphosphonates

These agents are stable analogs 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

Drug Category: Estrogen receptor antagonists

This is a new therapy for girls with persistent estradiol elevation.

Drug Category: Antithyroid agents

Blocks production of thyroid hormone in functional thyroid nodules.

FOLLOW-UP

Section 8 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Further Outpatient Care

• 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 as 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 the 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.
• Fibrous dysplasia: Outpatient care of the child with fibrous dysplasia depends on the severity and location of the lesions. Monitor vision and hearing closely 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: Closely monitor children treated with either thyroidectomy or radioactive iodine for hyperthyroidism to 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
• • Monitor children treated with bilateral adrenalectomy for infantile Cushing syndrome for adequate adrenal steroid replacement. Attention to growth rate is important as both undertreatment and overtreatment with glucocorticoids can result in decreased growth velocity. Slight undertreatment (hydrocortisone 10-12 mg/m²/d) should provide adequate maintenance replacement without growth suppression.
  • Carefully monitor mineralocorticoid treatment, as overtreatment with Florinef can result in hypertension. Confirm adequate mineralocorticoid replacement by monitoring blood pressure in addition to periodic assessment of plasma renin activity.
  • Increased doses of steroids are required during times of stress. During febrile illnesses, both hydrocortisone and Florinef doses should be doubled. During times of severe stress (eg, trauma, surgery), administer hydrocortisone doses at approximately 10 times maintenance levels.
• Gigantism/acromegaly: Monitor individuals with GH excess for signs of increased tumor growth and subsequent effect on visual acuity. Repeat imaging of the pituitary by MRI should be obtained at intervals to ensure adequate suppression of adenoma growth. In addition, medical therapy can be optimized by intermittent measurement of GH and/or IGF-1.

In/Out Patient Meds

• Testolactone: Consider aromatase inhibitors in cases of persistent estrogen secretion.
• Antithyroid agents: Tapazole or propylthiouracil can be used as temporizing therapy in severe hyperthyroidism associated with McCune-Albright syndrome.
• GH-suppressing agents: Sandostatin can decrease adenoma growth and GH secretion in somatotroph adenomas. Bromocriptine sometimes is added as adjunctive therapy.
• Hydrocortisone is used for glucocorticoid replacement perioperatively and postoperatively in infantile Cushing syndrome.
• Florinef is used postoperatively in infantile Cushing syndrome for mineralocorticoid replacement.

Complications

• The extent and severity of McCune-Albright syndrome depends on the degree of involvement and tissue distribution of the activating Gsa mutations.
• Precocious puberty: In addition to early breast development and vaginal bleeding, increased estrogen secretion in precocious puberty can result in an initial increase in height velocity. 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 also may 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.
• Fibrous dysplasia: Lesions in fibrous dysplasia range from relatively benign and asymptomatic to serious and debilitating, depending on the location. Lesions in weight bearing bones can cause pathologic fractures. Fibrous dysplasia in the skull can be quite disfiguring and impinge on optic and auditory nerves, thus affecting sight and hearing. Rarely, compression fractures in the spine with impingement on spinal nerves have been reported.
• Hyperthyroidism: Hyperthyroidism in McCune Albright syndrome 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. Decreased attention span often results in poor school performance. Osteoporosis also can result from a prolonged hyperthyroid state. Of particular concern, however, is the possibility that the tachycardia resulting from severe hyperthyroidism may complicate or trigger a cardiac event. Individuals with severe manifestations are at risk of sudden death from presumed cardiac involvement. Hyperthyroidism could increase the risk of these events in susceptible individuals.
• Infantile Cushing syndrome: Infantile Cushing syndrome also presents with severe growth failure, although the weight for height percentile deviations are not as significant as in 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, although some permanent effect on growth potential may occur.
• Gigantism/acromegaly: GH excess associated with a somatotroph adenoma leads to gigantism and/or acromegaly, depending on the age of initial presentation. In addition to the tall stature and coarse facial features associated with GH excess, individuals are at risk of developing 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: Hypophosphatemia as a result of increased urinary phosphate losses causes severe rickets and short stature. Although phosphate replacement and vitamin D treatment improve growth and heal the rickets, overall growth potential is reduced.
• Sudden death: More severe presentations of McCune-Albright syndrome are clearly associated with sudden death. Although no arrhythmias have been detected in individuals with McCune-Albright syndrome, this is the presumed mechanism of sudden death. The stimulatory G protein 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. Further study is needed to reach a conclusive understanding of sudden death in this syndrome.

Prognosis

• Precocious puberty: 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. Reduction of height potential depends on the degree of bone age advancement that occurs during the periods of early estrogen exposure.
• Fibrous dysplasia: Fibrous dysplasia is difficult to treat effectively. Current therapies focus on the treatment of complications of fibrous dysplasia (eg, pathologic fractures), rather than prevention. Current studies using bisphosphonates are promising, although it is unclear if bisphosphonates significantly reduce morbidity associated with these lesions.
• Hyperthyroidism: Radioiodine ablation or thyroidectomy treats hyperthyroidism effectively. Long-term prognosis is excellent with adequate thyroid hormone replacement.
• Infantile Cushing syndrome: Cushing syndrome is treated effectively with bilateral adrenalectomy. Long-term prognosis 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 emergently.
• Acromegaly/gigantism: GH secretion in McCune-Albright syndrome is difficult to treat effectively. Sandostatin has proven effective in many but not all cases. Furthermore, radiation treatment of the adenoma increases the risk of malignant change in areas of fibrous dysplasia in the radiation field. Long-term prognosis in refractory cases of acromegaly is poor, with an increased risk of diabetes and heart disease.

Patient Education

• Educational requirements depend on the phenotypic expression of McCune-Albright syndrome.
• • Instruct individuals with fibrous dysplasia in critical weight bearing areas to avoid activities (eg, contact sports) that put their skeleton at risk for pathologic fracture.
  • Patients that have undergone bilateral adrenalectomy for Cushing syndrome need clear instructions on changing steroid dosing for febrile illnesses. Furthermore, these individuals need to wear medic alert identification bracelets or necklaces in case of severe illness or trauma to inform medical personnel of the requirement for stress doses of hydrocortisone.
• For excellent patient education resources, visit eMedicine's Endocrine System Center. Also, see eMedicine's patient education article Thyroid Problems.

MISCELLANEOUS

Section 9 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Medical/Legal Pitfalls

• Determining the etiology of gonadotropin independent precocious puberty is important. If not associated with McCune-Albright syndrome, gonadotropin independent precocious puberty can indicate a benign or malignant tumor. If physical findings are consistent with McCune-Albright syndrome, then the likelihood of a malignant tumor is greatly reduced. Although autonomous ovarian cysts can cause precocious puberty, in the absence of other associated evidence for Gsa activating mutations, these cysts should be followed closely. If the radiographic character of the cyst is suggestive of malignancy, then biopsy should be considered.

MULTIMEDIA

Section 10 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Media file 1:  Café au lait pigmentation in a case of McCune-Albright syndrome. Lesion does not cross the midline, which is typical of the pigmented lesions in this syndrome.
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Media type:  Photo

Media file 2:  Adrenal hyperplasia with nodular elements in an adrenal gland isolated from an infant with infantile Cushing syndrome. DNA isolated from nodular tissue was determined to have the activating Gs alpha mutation, while DNA isolated from surrounding tissue did not contain the mutation.
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Media type:  Image

Media file 3:  The G protein cycle begins with ligand binding to a 7 transmembrane G protein coupled receptor. The ligand receptor complex stimulates an exchange of guanosine triphosphate (GTP) for guanosine diphosphate (GDP) on the alpha subunit of the stimulatory G protein. This activates the alpha subunit, which subsequently stimulates adenylyl cyclase to increase the production of cyclic adenosine monophosphate (cAMP). The alpha subunit contains intrinsic 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 the ligand receptor complex.
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Media type:  Graph

Media file 4:  Mutations in McCune-Albright syndrome inactivate the intrinsic GTPase activity, thus preventing the inactivation of the Gs alpha subunit. Once activated, the mutated Gs alpha subunit is able to continuously stimulate adenylyl cyclase, even in the absence of ligand binding to the receptor. The result is an elevation of intracellular cyclic adenosine monophosphate (cAMP) and continual stimulation of downstream cAMP signaling cascades.
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Media type:  Graph

REFERENCES

Section 11 of 11

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

• Akintoye SO, Chebli C, Booher S, et al. Characterization of gsp-mediated groth hormone excess in the context of McCune-Albright syndrome. J Clin Endocrinol Metab. 2002;87(11):5104-12. [Medline]. [Full Text].
• Albright F, Butler AM, Hampton AO. Syndrome characterized by osteitis fibrosa disseminata, areas of pigmentation and endocrine dysfunction, wit