eMedicine Specialties > Pediatrics: General Medicine > Endocrinology

McCune-Albright Syndrome

Author: Bruce A Boston, MD, Chief, Division of Pediatric Endocrinology, Director, Pediatric Endocrine Training Program, Associate Professor, Department of Pediatrics, Division of Pediatric Endocrinology, Oregon Health Sciences University and Doernbecher Children's Hospital
Coauthor(s): Marcie K Drury Brown, MD, Fellow in Pediatric Endocrinology, Department of Pediatrics, Oregon Health and Science University
Contributor Information and Disclosures

Updated: Feb 20, 2009

Introduction

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.^1,2 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 may also 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.

McCune-Albright syndrome is the result of a postzygotic somatic mutation in the gene that codes 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 has frequently 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 it 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 Gsa mutations can occur in individuals at any age.

Clinical

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 is noted. 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 alpha subunit of the stimulatory G protein (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 an activating Gsa mutation can be isolated in only one tissue type, confirmation requires 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 Media file 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, growth hormone (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 excess may also have hypertension and mild decreases in muscle tone.

Causes

The specific mutations that cause McCune-Albright syndrome occur at a site in the protein that mediates the inactivation of the Gsa subunit (see Media file 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) is normally 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.

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

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