What is McCune Albright syndrome

McCune-Albright syndrome is a disorder that affects the skin, skeleton, and certain endocrine organs (hormone-producing tissues). Cafe-au-lait spots of the skin are common and are usually the first apparent sign of McCune-Albright syndrome. People with McCune-Albright syndrome develop areas of abnormal scar-like (fibrous) tissue in their bones, a condition called polyostotic fibrous dysplasia. Polyostotic means the abnormal areas (lesions) may occur in many bones; often they are confined to one side of the body ¹. Replacement of bone with fibrous tissue may lead to fractures, uneven growth, and deformity. When lesions occur in the bones of the skull and jaw it can result in uneven (asymmetric) growth of the face. Asymmetry may also occur in the long bones; uneven growth of leg bones may cause limping. Abnormal curvature of the spine (scoliosis) may also occur. Early skeletal symptoms may include limping, pain, or fracture ². Bone lesions may become cancerous, but this happens in fewer than 1 percent of people with McCune-Albright syndrome.

In addition to bone abnormalities, affected individuals usually have light brown patches of skin called café-au-lait spots, which may be present from birth. The irregular borders of the café-au-lait spots in McCune-Albright syndrome are often compared to a map of the coast of Maine. By contrast, café-au-lait spots in other disorders have smooth borders, which are compared to the coast of California. Like the bone lesions, the café-au-lait spots in McCune-Albright syndrome may appear on only one side of the body.

Endocrinous features may include precocious puberty especially in girls (resulting of estrogen excess from ovarian cysts), excess growth hormone; thyroid lesions with possible hyperthyroidism; renal phosphate wasting, and, rarely, Cushing syndrome caused by an excess of the hormone cortisol produced by the adrenal glands, which are small glands located on top of each kidney ¹. Girls with McCune-Albright syndrome may reach puberty early. These girls often have menstrual bleeding by age 2. This early onset of menstruation is believed to be caused by excess estrogen, a female sex hormone, produced by cysts that develop in one of the ovaries. Less commonly, boys with McCune-Albright syndrome may also experience early puberty.

The thyroid gland, a butterfly-shaped organ at the base of the neck, may become enlarged (a condition called a goiter) or develop masses called nodules. About 50 percent of affected individuals produce excessive amounts of thyroid hormone (hyperthyroidism), resulting in a fast heart rate, high blood pressure, weight loss, tremors, sweating, and other symptoms. The pituitary gland (a structure at the base of the brain that makes several hormones) may produce too much growth hormone. Excess growth hormone can result in acromegaly, a condition characterized by large hands and feet, arthritis, and distinctive facial features that are often described as “coarse.” Excess growth hormone secretion may also lead to increased expansion of the fibrous dysplasia in the bones, most visibly in the skull. Rarely, affected individuals develop Cushing syndrome, an excess of the hormone cortisol produced by the adrenal glands, which are small glands located on top of each kidney. Cushing syndrome causes weight gain in the face and upper body, slowed growth in children, fragile skin, fatigue, and other health problems. In people with McCune-Albright syndrome, Cushing syndrome occurs only before age 2.

Problems in other organs and systems, such as noncancerous (benign) gastrointestinal growths called polyps and other abnormalities, can also occur in McCune-Albright syndrome.

McCune-Albright syndrome is not inherited ¹. McCune-Albright syndrome is caused by a somatic mutation in a gene called GNAS, which is acquired after an egg is fertilized and only affects some of the body’s cells and tissues ³.

McCune-Albright syndrome occurs in 1 in 100,000 to 1 in 1,000,000 people worldwide. McCune-Albright syndrome affects males and females in equal numbers. Precocious puberty is more common in females. The disorder is estimated to affect 1 in 100,000 to 1 in 1,000,000 individuals in the general population. Because the disorder is difficult to diagnose, affected individuals may go undiagnosed or misdiagnosed, making it difficult to determine the true frequency of MAS in the general population.

McCune-Albright syndrome is usually a clinical diagnosis, which means that specific signs and symptoms must be present before the diagnosis can be made. If McCune Albright syndrome is suspected, various tests may be considered to look for the presence of additional signs and symptoms that may confirm the diagnosis. Tests that may be considered include:

• endocrine studies
• imaging studies including x-ray, ultrasound, CT scan, MRI, and/or radionuclide bone scanning
• blood and urine tests
• bone biopsy or soft-tissue biopsy ⁴

While genetic testing for McCune Albright syndrome is available, the ability to detect a mutation depends on the level of mosaicism in the tissue, and the sensitivity of the technique used. In the absence of the clinical criteria needed for a diagnosis, genetic testing may detect a mutation. However, because of the somatic mosaic nature of the disease (the mutation only being present in some cells and tissues), a negative result from readily available (but unaffected) tissue does not exclude the presence of the mutation elsewhere in the body ⁵.

Unfortunately, it is often not possible to determine how severely a person will be affected when a diagnosis is first suspected or confirmed. For this reason, it is important to be aware of the various tissues that can be (or become) involved, and then to screen for involvement ⁵.

Management of McCune-Albright syndrome is most effective with a multidisciplinary team of specialists including orthopedists and endocrinologists. Management depends on the symptoms in each person and may include optimizing function related to fractures and deformities; medications; and surgery ¹. Although there is no cure for McCune Albright syndrome, drug treatments or surgery may help some of the endocrine symptoms, and surgery may help to manage bone problems that cause visual disturbance, severe pain, or severe disfigurement ⁶. Generally, treatment depends on what tissues are affected as well as the severity ⁷.

Bisphosphonates are frequently used to treat fibrous dysplasia. Strengthening exercises are recommended to help maintain strength around the bones and minimize the risk of fractures ⁶.

Figure 1. McCune Albright syndrome café-au-lait skin pigmentation

Footnote: A) A typical lesion on the face, chest, and arm of a 5-year-old girl with McCune-Albright syndrome which demonstrates jagged “coast of Maine” borders, and the tendency for the lesions to both respect the midline and follow the developmental lines of Blashko. B) Typical lesions that are often found on the nape of the neck and crease of the buttocks are shown (arrows).

Is McCune-Albright syndrome inherited?

McCune-Albright syndrome is not inherited. Instead, it is caused by a random mutation in the GNAS gene that occurs very early in development. As a result, some of the body’s cells have a normal version of the GNAS gene, while other cells have the mutated version. This phenomenon is called mosaicism. The severity of this disorder and its specific features depend on the number and location of cells that have the mutated GNAS gene. Affected individuals may have reproductive cells (eggs or sperm) with the mutation. However, a resulting embryo would have the mutation in every cell, which is thought to be incompatible with life, so the condition is not passed to the next generation.

What are risks of pregnancy with McCune Albright syndrome?

Although a lot is known about McCune Albright syndrome in children, issues arising specifically during adulthood are less well understood. Precocious puberty can lead to abnormal gonad (ovary or testes) function and problems with fertility in adults ⁸. Women with McCune Albright syndrome are susceptible to developing large ovarian cysts and irregular vaginal bleeding. This can interfere with normal ovulation. Some affected women experience anovulation (when an egg is not released from the ovaries) ⁸. In most cases, adults with McCune Albright syndrome have been able to have children, even if it may take longer than normal to conceive ⁹. Endometrial function may be also affected due to elevated progesterone levels throughout the cycle, which may make implantation of an embryo difficult. In some cases, removal of the affected ovary (ovariectomy) may improve endocrine function and the function of the remaining ovary, thus improving fertility ¹⁰.

Reports have shown that during pregnancy in women with McCune Albright syndrome, the rate of bone turnover (when the body removes old bone that should then be replaced) is increased compared with unaffected pregnant women, suggesting that pregnancy could induce changes of bone metabolism. Some researchers have suggested there may be an increased risk of tumor development during pregnancy (i.e. an increased risk of fibrous dysplasia developing into osteosarcoma). However, further studies are needed to clarify the relationship between pregnancy and tumor development in women with McCune Albright syndrome ¹¹.

McCune Albright syndrome causes

McCune-Albright syndrome is caused by a mutation in the GNAS1 gene. The GNAS1 gene provides instructions (encodes) for making one part of a protein complex called a guanine nucleotide-binding protein, or a G protein. The GNAS1 gene is located on the long arm (q) of chromosome 20 (20q13.2). Each chromosome has a short arm designated “p” and a long arm designated “q”. Chromosomes are further sub-divided into many bands that are numbered. For example, “chromosome 20q13.2” refers to band 13.2 on the long arm of chromosome 20. The numbered bands specify the location of the thousands of genes that are present on each chromosome.

In a process called signal transduction, G proteins trigger a complex network of signaling pathways that ultimately influence many cell functions by regulating the activity of hormones. The protein produced from the GNAS1 gene helps stimulate the activity of an enzyme called adenylate cyclase. GNAS1 gene mutations that cause McCune-Albright syndrome result in continuous activation of this G-protein that causes the adenylate cyclase enzyme to be constantly turned on (constitutively activated). In turn, there is an overproduction of a molecule known as cyclic adenosine monophosphate (cAMP), which is involved in various chemical processes of the body.

Overproduction of cAMP contributes to the development of symptoms. For example, cAMP is involved in the change (differentiation) of osteoblasts in bone. Osteoblasts are immature bone-forming cells that form new bone. The human skeleton is living tissue that is constantly changing (remodeling). It is believed that McCune-Albright syndrome involves increased bone turnover. Bone turnover is a normal process in which bone gradually breaks down (bone resorption) and then reforms. Bone turnover involves osteoblasts and cells that control bone resorption (osteoclasts). The interaction between osteoclasts and osteoblasts determines how bone reforms. The interaction is a complex process that involves many factors. Improper differentiation of osteoblasts due to mutation of the GNAS1 gene is believed to contribute to the development of fibrous dysplasia in individuals with McCune-Albright syndrome.

When a GNAS1 mutation affects skin or endocrine cells, the additional characteristic symptoms of McCune-Albright syndrome can develop.

McCune Albright syndrome symptoms

McCune-Albright syndrome signs and symptoms is highly variable, depending on which of the various potential components of the syndrome predominate.

McCune-Albright syndrome symptoms can range from mild to severe ¹².

The main symptom of McCune-Albright syndrome is early puberty in girls. Menstrual periods may begin in early childhood, long before the breasts or pubic hair develop (which normally occur first). The average age that symptoms appear is 3 years old. However, puberty and menstrual bleeding have occurred as early as 4 to 6 months in girls.

Early sexual development may also occur in boys, but not as often as in girls.

Other symptoms include:

• Bone fractures
• Deformities of the bones in the face
• Gigantism
• Irregular, large patchy cafe-au-lait spots

Skeletal symptoms may include:

• Fibrous dysplasia – Normal bone is replaced by softer, fibrous tissue. This may lead to limping, pain, fractures, progressive scoliosis, uneven growth, facial deformity, and loss of mobility ¹.

Endocrine symptoms may include:

• Early puberty (also called precocious puberty) – Girls with McCune-Albright syndrome can have menstrual bleeding by age 2 (as early as 4-6 months in some), many years before breast enlargement and pubic hair growth begin ¹³. Early-onset menstruation is thought to be due to excess estrogen that may be produced by ovarian cysts ¹⁴. Precocious puberty in boys with McCune-Albright syndrome occurs less frequently and later in life when compared to girls, and presents with penile growth and testes enlargement ¹⁴.
• Thyroid disease – The thyroid gland may become enlarged (called a goiter) or develop masses called nodules. About half of people with McCune-Albright syndrome have hyperthyroidism ¹⁴.
• Increased production of growth hormone – The pituitary gland may produce too much growth hormone. This can result in acromegaly ¹⁴.
• Cushing’s syndrome – Rarely, people with McCune-Albright syndrome produce too much cortisol in the adrenal glands. This can cause weight gain in the face and upper body, slowed growth, fragile skin, fatigue, and other health problems ¹⁴.
• Testicular abnormalities in males – Testicular abnormalities are seen in the majority of males with McCune-Albright syndrome (~85%), and typically manifest as abnormally large testes (macro-orchidism) ¹.
• Phosphate wasting – Increased production of the hormone FGF23 can result in renal tubulopathy, impairing the kidneys’ ability to function properly.

Skin symptoms may include:

• Cafe-au-lait spots – People with McCune-Albright syndrome usually have light brown patches of skin. These spots often appear on one side of the body and may be present from birth ¹⁴.

Less common features of McCune-Albright syndrome may include hepatitis; gastroesophageal reflux or gastrointestinal polyps; pancreatic complications such as pancreatitis; intramuscular myxomas (benign tumors); and cancers. Cancers that have been associated with McCune-Albright syndrome include bone, thyroid, testicular, and breast. Precocious puberty and growth hormone excess may contribute to an increased risk of cancer ¹.

McCune Albright syndrome possible complications

McCune Albright syndrome complications may include:

• Blindness
• Cosmetic problems from bone abnormalities
• Deafness
• Osteitis fibrosa cystica
• Premature puberty
• Repeated broken bones
• Tumors of the bone (rare)

McCune Albright syndrome diagnosis

The diagnosis of McCune-Albright syndrome may be suspected at birth based upon identification of the characteristic skin pigmentations (cafe-au-lait spots). However, in many cases, the disorder may not be suspected until late infancy or childhood when precocious puberty develops or when bone deformities become obvious. A diagnosis may be confirmed based upon characteristic physical findings (i.e., association of characteristic skin, bone, and endocrine abnormalities), a detailed patient history, thorough clinical evaluation, and specialized tests including x-ray studies and blood tests.

The diagnosis of McCune-Albright syndrome can be made in people who have two or more of the following typical clinical features of McCune Albright syndrome ¹:

• Café-au-lait skin spots with characteristic features (jagged, irregular borders; distribution respecting the midline of the body; and following the developmental lines of Blaschko)
• Polyostotic fibrous dysplasia (involving more than one bone) or GNAS mutation-proven monostotic fibrous dysplasia (involving a single bone)
• Any of the following endocrine abnormalities (each with specific characteristics):
  • gonadotropin-independent precocious puberty
  • testicular lesions
  • thyroid lesions
  • growth hormone excess
  • phosphate wasting
  • neonatal hypercortisolism (Cushing’s syndrome)

McCune Albright syndrome may be suspected at birth based upon identifying the characteristic cafe-au-lait spots. However, in many cases, it may not be suspected until late infancy or childhood when precocious (very early) puberty develops or when bone deformities become obvious ¹⁵.

In cases when only one bone has fibrous dysplasia and there are not other symptoms genetic testing is needed to establish the diagnosis ¹.

Clinical Testing and Workup

A complete body survey should be performed for the characteristic cafe-au-lait spots, and x-ray studies should be combined with bone scans to evaluate the presence and extent of fibrous dysplasia. Blood tests may reveal elevated hormone levels (e.g., estrogen, testosterone, cortisol, thyroid hormone, growth hormone, prolactin, somatomedin C) and evidence of abnormally increased bone activity (elevated alkaline phosphatase).

Specialized imaging techniques may be used to evaluate bone. Such imaging techniques include computerized tomography (CT) scanning and magnetic resonance imaging (MRI). During CT scanning, a computer and x-rays are used to create a film showing cross-sectional images of certain tissue structures. An MRI uses a magnetic field and radio waves to produce cross-sectional images of particular organs and bodily tissues. The abnormal tissue in fibrous dysplasia resembles ground glass when seen on x-ray. These tests may be used to determine how extensively bones are affected.

A bone scan, also known as bone scintigraphy, is used to determine the extent of bone disease. During this test, a harmless radioactive dye is injected into the affected bone. A special camera that can track the dye as it travels through bone is used to create a picture of the skeleton and determine all affected areas. Bone biopsy is the surgical removal and microscopic examination of a small sample of affected tissue. A bone biopsy can reveal characteristic changes to bone that occur in individuals with fibrous dysplasia and may be necessary to distinguish a fibrous dysplasia lesion from other types of growths or tumors if it is unclear after an x-ray.

A highly sensitive, specific form of polymerase chain reaction (PCR) has been used to detect somatic mutations of the GNAS1 gene that characterize McCune-Albright syndrome. PCR is a laboratory test that has been described as a form of “photocopying.” It enables researchers to enlarge and repeatedly copy sequences of DNA. As a result, they are able to closely analyze DNA and more easily identify genes and genetic changes (mutations). In McCune-Albright syndrome, a specific form of PCR testing can detect activating mutations of GNAS1 in peripheral blood cells. However, because only some cells in the body are affected by the mutation, a normal test would not rule out McCune-Albright syndrome, and so this test is not frequently used in clinical diagnosis.

McCune Albright syndrome treatment

The treatment of McCune-Albright syndrome is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, orthopedists, orthopedic surgeons, endocrinologists, dermatologists, and other healthcare professionals may need to systematically and comprehensively plan an affected child’s treatment. Psychosocial support for the entire family is essential as well. Although McCune Albright syndrome is not inherited, genetic counseling may be of benefit for affected individuals and their families.

Specific therapeutic procedures and interventions may vary, depending upon numerous factors, such as extent of the disease; the presence or absence of certain symptoms; an individual’s age and general health; and/or other elements. Decisions concerning the use of particular drug regimens and/or other treatments should be made by physicians and other members of the health care team in careful consultation with the patient based upon the specifics of his or her case; a thorough discussion of the potential benefits and risks, including possible side effects and long-term effects; patient preference; and other appropriate factors.

Fibrous dysplasia associated with McCune Albright syndrome has been treated with drugs known as bisphosphonates such as pamidronate or alendronate. These drugs reduce bone turnover by inhibiting bone resorption. Calcium and vitamin D may be given along with the drug. Some affected individuals respond favorably to such therapy with the main benefit being decreased bone pain. Other affected individuals do not respond to therapy with bisphosphonates or relapse after an initial period of improvement. Relapse of bone pain is more common. Stronger bisphosphonate medications such as zoledronic acid may be used in such cases and may be most effective in improving bone pain.

Surgery is sometimes used to treat fibrous dysplasia, although most physicians recommend a conservative strategy. Surgery should be undertaken only for lesions that causing difficulty in some way. Surgery may be undertaken to correct disfigurement or deformity, to correct limb length discrepancy, to eradicate symptomatic lesions (e.g. those causing pain and/or compressing a nerve), to treat specific complications such as scoliosis, or to prevent fracture.

Exercises designed to strengthen the muscles surrounding fibrous dysplasia lesions may be recommended and may help to reduce the risk of fracture.

In mild cases, females experiencing precious puberty may not require treatment, but only observation. Drug therapy may be required if females experience progressive precious puberty. Such drugs include letrozole, which is an aromatase inhibitor and has a long history of safety for the treatment of precocious puberty in McCune Albright syndrome. These drugs block the conversion of androgens to estrogen. No drugs have been shown to be completely effective to-date. In some cases, males experiencing precious puberty may be treated with aromatase inhibitors. Additional drugs are being studied for the treatment of precious puberty in individuals with McCune Albright syndrome.

Precocious puberty in McCune Albright syndrome is known as gonadotropin-independent. Gonadotropins are hormones such as follicle stimulating hormone and luteinizing hormone that are produced by the pituitary gland during puberty and regulate various actions involved in puberty. Most cases of precocious puberty (e.g. those not associated with McCune Albright syndrome) are known as central precocious puberty or gonadotropin-dependent precious puberty and can be successfully treated with gonadotropin-releasing hormone, a hormone that, when used regularly, decreases the amount of these hormones released by the pituitary gland. This drug is not effective in most cases of McCune Albright syndrome. However, in some affected females, central precocious puberty can develop as a secondary condition and can be successfully treated by long-acting gonadotropin-releasing hormone analogues.

Hyperthyroidism may also be treated with drug therapy, specifically thionamides, which inhibit the production of thyroid hormones. Most individuals with McCune Albright syndrome respond favorably to this therapy. However, hyperthyroidism in McCune Albright syndrome is often persistent and some physicians recommend surgical removal of the thyroid (thyroidectomy) followed by radioactive iodine ablation. Iodine is a chemical element used by the thyroid to synthesize thyroid hormones. Nearly all of the iodine in a person’s blood is absorbed by thyroid tissue. Radioactive iodine therapy destroys any thyroid tissue that remains after a near-total thyroidectomy. After these procedures, individuals must take hormone replacement therapy for the remainder of their lives to replace the hormones normally produced by the thyroid.

Growth hormone excess may be treated by drugs known as long-acting somatostatin analogues such as octreotide or bromocriptine. This class of drugs inhibits the production of growth hormone. A growth hormone receptor antagonist, pegvisomant, has also been used to treat growth hormone excess, although somatostatins have generally proven more effective, particularly in children. If medication does not work, surgical removal of the pituitary gland and the destruction of pituitary tissue using radiation (radiotherapy) may be necessary.

In some cases Cushing’s syndrome can resolve on its own. Drugs that suppress the production of cortisol may be used and have been effective even in severe cases. However, Cushing’s syndrome can potentially be a severe complication of McCune Albright syndrome and may not respond to drug therapy and some physicians consider the surgical removal of the adrenal glands (adrenalectomy) the treatment of choice. Individuals who undergo an adrenalectomy will receive hormone replacement therapy.

Individuals with rickets or osteomalacia due to hypophosphatemia may require treatment with oral phosphorous supplementation and calcitriol, an activated vitamin-D metabolite. Whether children who have hypophosphatemia, but do not have signs of rickets require treatment is debated. Some physicians recommend that individuals with markedly low serum phosphate levels should be treated.

McCune Albright syndrome life expectancy

The life expectancy for people with McCune-Albright syndrome varies depending on the symptoms and severity in each affected person. Medical therapies can improve or control endocrine symptoms in most people with McCune-Albright syndrome ¹.

Fibrous dysplasia is progressive throughout childhood and adolescence, and typically plateaus in middle and late adulthood. In some people, small amounts of fibrous dysplasia may cause few or no symptoms. In others, extensive bone disease may cause significant problems including loss of mobility, progressive scoliosis, facial deformity, and loss of vision and/or hearing ¹.

Apart from the small proportion of people with increased surgery-related mortality and those who develop cancer, McCune-Albright syndrome is not associated with a significantly increased risk of death. In general, people with McCune-Albright syndrome have a normal life span ¹⁶.

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