McCune-Albright syndrome is a disorder that affects the bones, skin, and several hormone-producing (endocrine) tissues.

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. 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. 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.

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.

Other endocrine problems may also occur in people with McCune-Albright syndrome. 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.

Number of People Affected

MAS is rare, affecting between 1 in every 100,000 to 1 million live births worldwide.

Who is at risk?

Because the genetic change or mutation that causes MAS occurs at random very early in fetal development, MAS is not an inherited disease, meaning parents do not pass it on to their children.

MAS likely occurs equally in males and females.

MAS is a genetic disorder, which means that a change, also called a mutation (pronounced myoo-TEY-shuhn), in a gene causes it. Genes are in the chromosomes of almost all human cells, and they code for each cell’s specialized actions. The mutation that causes MAS leads to errors in the functioning of certain cells.

MAS is not an inherited disease, meaning parents do not pass it on to their child, because the mutation occurs randomly while an embryo is developing.

GNAS Gene Mutation

MAS is caused by a mutation in the GNAS gene. The GNAS gene codes for one part of the G protein, which is short for guanine (pronounced GWAH-neen) nucleotide-binding protein. This protein plays an important role in triggering many other cell processes. One of these processes is to turn off an enzyme (pronounced EN-zahym) called the adenylate cyclase (pronounced uh-DEN-l-it SAHY-kleys) enzyme. The mutated form of the G protein cannot turn this enzyme off, so the constantly active adenylate cyclase enzyme causes excess production of other hormones, resulting in the symptoms of MAS.

Mosaicism

The GNAS mutation happens after an embryo begins to form, and not when the mother’s egg or the father’s sperm is formed. Therefore, not all of the embryo’s cells have the mutation. This is called mosaicism (pronounced moh-ZAY-uh-ciz-uhm). The severity of MAS symptoms depends on the number and location of cells containing the mutated GNAS gene.

MAS is caused by a mutation in the GNAS gene. The mutation leads to errors in the functioning of certain cells.

The GNAS gene codes for one part of the G protein, which is short for guanine (pronounced GWAH-neen) nucleotide-binding protein. This protein plays an important role in triggering many cell processes, including the process that "turns off" an enzyme called the adenylate cyclase (pronounced uh-DEN-uh-lit SAHY-kleys) enzyme. The mutated form of the G protein cannot turn off the enzyme. High levels of active adenylate cyclase cause excess production of other hormones, resulting in the symptoms of MAS.

Not every cell in the body is exactly the same, so some cells may have the GNAS mutation while others do not. This is called mosaicism (pronounced moh-ZAY-uh-siz-uhm). The severity of MAS symptoms depends on the number of cells with the mutated GNAS gene and the location of those cells in the body.

Normal Function

The GNAS gene provides instructions for making one component, the stimulatory alpha subunit, of a protein complex called a guanine nucleotide-binding protein (G protein). Each G protein is composed of three proteins called the alpha, beta, and gamma subunits.

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 G protein made with the subunit produced from the GNAS gene helps stimulate the activity of an enzyme called adenylate cyclase. This enzyme is involved in controlling the production of several hormones that help regulate the activity of endocrine glands such as the thyroid, pituitary gland, ovaries and testes (gonads), and adrenal glands. Adenylate cyclase is also believed to play a key role in signaling pathways that help regulate the development of bone (osteogenesis). In this way, the enzyme helps prevent the body from producing bone tissue in the wrong place (ectopic bone).

Health Conditions Related to Genetic Changes

McCune-Albright syndrome

At least three GNAS gene mutations have been identified in people with McCune-Albright syndrome, a disorder that affects the bones, skin, and several hormone-producing (endocrine) tissues. These mutations result in an abnormal version of the G protein that causes the adenylate cyclase enzyme to be constantly turned on (constitutively activated). Constitutive activation of the adenylate cyclase enzyme leads to over-production of several hormones, resulting in the signs and symptoms of McCune-Albright syndrome.

McCune-Albright syndrome is not inherited. The gene mutation that causes this disorder is described as somatic. Instead of being passed from parent to child, somatic mutations are acquired during a person's lifetime and are present only in certain cells. McCune-Albright syndrome 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.

Primary macronodular adrenal hyperplasia

At least two mutations in the GNAS gene have been identified in people with primary macronodular adrenal hyperplasia (PMAH), a disorder that causes multiple lumps (nodules) to form in the adrenal glands, which are small hormone-producing glands located on top of each kidney. These nodules cause adrenal gland enlargement (hyperplasia) and result in production of higher-than-normal levels of the hormone cortisol. Cortisol normally helps maintain blood glucose levels, protects the body from physical stress, and suppresses inflammation. Increased cortisol levels can lead to weight gain in the face and upper body, fragile skin, bone loss, fatigue, and other health problems, which often occur in people with PMAH.

The GNAS gene mutations that cause PMAH are believed to result in an overactive G protein. Research suggests that the overactive G protein may increase levels of adenylate cyclase, which results in the overproduction of another compound called cyclic AMP (cAMP). An excess of cAMP may trigger abnormal cell growth and lead to the adrenal nodules characteristic of PMAH.

As in McCune-Albright syndrome, the GNAS gene mutations that cause PMAH are somatic mutations that are believed to occur early in embryonic development. Cells with the mutated GNAS gene can be found in both adrenal glands.

Progressive osseous heteroplasia

At least 14 GNAS gene mutations have been identified in people with progressive osseous heteroplasia. People normally inherit one copy of each gene from their mother and one copy from their father. For most genes, both copies are active, or "turned on," in all cells. For a small subset of genes, however, only one of the two gene copies is active. For some of these genes, only the copy inherited from a person's father (the paternal copy) is active, while for other genes, only the copy inherited from a person's mother (the maternal copy) is active. These differences in gene activation based on the gene's parent of origin are caused by a phenomenon called genomic imprinting.

The GNAS gene has a complex genomic imprinting pattern. In some parts of the body the maternal copy of the gene is active, while in others the paternal copy is active. Progressive osseous heteroplasia is caused by certain mutations that affect the paternal copy of the gene. These mutations disrupt the function of the G protein and impair its ability to regulate osteogenesis. Impaired regulation of osteogenesis results in the ectopic production of bony tissue in the skin and muscles seen in progressive osseous heteroplasia.

Cholangiocarcinoma

MedlinePlus Genetics provides information about Cholangiocarcinoma

Other disorders

Mutations in the GNAS gene also cause Albright hereditary osteodystrophy (AHO), which is characterized by short stature, obesity, unusually short fingers and toes (brachydactyly), ectopic development of bony tissue under the skin, and other skeletal abnormalities. When a mutation that causes AHO is inherited from a person's mother, the affected individual will usually have AHO accompanied by a resistance to multiple hormones (a condition called pseudohypoparathyroidism type Ia, or PHPIa). A paternally-inherited mutation can result in AHO without endocrine problems; this form of the condition is called pseudopseudohypoparathyroidism (PPHP).

Somatic mutations in the GNAS gene have been found in tumors of the endocrine glands and in fibrous lesions (dysplasia) that can occur in bones. These mutations are believed to result in an overactive G protein, which triggers abnormal cell growth. Because the cells with mutations are not as widespread in the body as in McCune-Albright syndrome (described above), the abnormal growth is confined to a particular gland or fibrous lesion.

Other Names for This Gene

• ADENYLATE CYCLASE STIMULATORY PROTEIN, ALPHA SUBUNIT
• adenylate cyclase-stimulating G alpha protein
• AHO
• C20orf45
• dJ309F20.1.1
• dJ806M20.3.3
• GNAS1
• GNAS1_HUMAN
• GNASXL
• GPSA
• Gs, ALPHA SUBUNIT
• GSA
• GSP
• guanine nucleotide binding protein (G protein), alpha stimulating activity polypeptide 1
• guanine nucleotide regulatory protein
• MGC33735
• NESP
• NESP55
• NEUROENDOCRINE SECRETORY PROTEIN 55
• PHP1A
• PHP1B
• POH
• SCG6
• secretogranin VI
• SgVI
• STIMULATORY G PROTEIN

Genomic Location

MAS symptoms can vary from mild to severe. They may begin at birth or later in childhood.

Main Symptoms

Many people with MAS have the following symptoms:

• Café-au-lait spots
  Café-au-lait (French for "coffee with milk") spots, which are light-brown birthmarks. The birthmarks:
  • Are sually are present at birth
  • May be hard to see on dark skin
  • Often appear on one side of the body
  • Have jagged edges sometimes referred to as the "coast of Maine"
• Polyostotic fibrous dysplasia
  A person with polyostotic fibrous dysplasia (PFD) has scar-like tissue, or fibrous tissue, in his or her bones. PFD usually occurs on one side of the body in weight-bearing bones, such as leg bones. PFD may cause:
  • Bone pain
  • Cancer of the bone (very rare)
  • Abnormal bone growth
  • Fractures
  • Limping
  • Scoliosis (pronounced skoh-lee-OH-sis), a curvature of the spine
  • Uneven growth, including uneven growth of the face

In addition, bone lesions in the skull may pinch nerves that affect a person’s ability to see and hear.

• Precocious puberty
  Precocious puberty is when sexual and physical changes occur earlier than normal.
  
  Girls with MAS may experience such symptoms as:
  • Early menstrual bleeding, usually before 2 years of age
  • Early breast growth
  • Beginning to grow faster
  Boys with MAS are less likely to experience early puberty. Symptoms in boys include:
  • Faster than normal growth of penis or testicles
  • Premature sexual behavior
  • Early growth of armpit or pubic hair

Additional Symptoms

Additional features of MAS may include (but are not limited to):

• Overproduction of growth hormone from the pituitary gland
• Cushing syndrome, overactivity of the adrenal glands, leading to an increase in stress hormone levels
• Formation of benign (noncancerous) tumors in the testicles, called Sertoli cell hyperplasia and Leydig cell hyperplasia
• Hyperthyroidism (pronounced hahy-per-THAHY-roi-diz-uhm), an overactive thyroid gland
• Loss of phosphate in the urine, leading to low blood phosphorus levels
• Liver disease

A person is diagnosed with MAS if he or she has a combination of any of the following symptoms:

• Café-au-lait (French for "coffee with milk") spots, which are light brown birthmarks
• Polyostotic fibrous dysplasia (PFD), which is a bone irregularity
• Precocious puberty, which is premature development in a child
• Hyperthyroidism, which is an overactive thyroid gland
• Growth hormone excess
• Cushing syndrome, an overactivity of the adrenal glands
• Sertoli cell hyperplasia and Leydig cell hyperplasia, which are tumors in the testicles

A health care provider may use X-rays to examine bones for PFD. He or she may perform ultrasounds to look for an abnormal appearance of the thyroid or testicles. Blood tests may be done to check for abnormal hormone levels. He or she may take a small sample or biopsy of abnormal bone tissue and analyze it to confirm PFD, thereby confirming MAS.

A genetic test is also available to detect the GNAS gene mutation, but it is often not reliable for diagnosing MAS. The diagnosis of MAS is made clinically, based on the presence of characteristic features.

Symptoms and severity of MAS vary, so diagnosis may occur at birth or later in childhood.

Treatment for MAS depends on the extent and the severity of a person’s symptoms. For example, health care providers may recommend medication for endocrine problems, or surgery for bone issues.

• Medications, including agents that block the production of certain hormones, may help address several conditions associated with MAS, including:
  • Cushing syndrome
  • Hyperthyroidism
  • Growth hormone excess
  • Low blood phosphates
  • Precocious puberty
  • Bone pain
• Surgery may help address:
  • Bone deformities or uneven growth
  • Cushing syndrome, by removing adrenal glands
  • Hyperthyroidism, by removing the thyroid gland
  • Hearing and vision problems, such as by relieving pinched nerves

Health care providers may also recommend bisphosphonates (pronounced bihz-fahs-FOH-naytz), or drugs that help prevent bone loss. More research is needed to determine the role of these medications in MAS; at present, they are often recommended to treat pain from the PFD caused by MAS. In addition, strengthening exercises may help build muscle around bones affected by PFD, which can reduce the risk of bone fractures.