McCune-Albright syndrome

McCune-Albright syndrome (MAS) 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 MAS. The main skeletal feature is fibrous dysplasia, which ranges in severity and can cause various complications.^[1] Early skeletal symptoms may include limping, pain, or fracture.^[2] 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][2] MAS is not inherited.^[1] MAS 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] Management depends on the symptoms in each person and may include optimizing function related to fractures and deformities; medications; and surgery.^[1]

Signs and symptoms of McCune-Albright syndrome (MAS) relate to the skeleton (bones), the endocrine organs (hormone-producing tissues), and the skin. Symptoms can range from mild to severe.^[4]

Skeletal symptoms may include:

• Fibrous dysplasia - Normal bone is replaced by softer, fibrous tissue.^[4] This may lead to limping, pain, fractures, progressive scoliosis, uneven growth, facial deformity, and loss of mobility.^[1][4][5]

Endocrine symptoms may include:

• Early puberty (also called precocious puberty) - Girls with MAS 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.^[4][5][6] Early-onset menstruation is thought to be due to excess estrogen that may be produced by ovarian cysts.^[5] Precocious puberty in boys with MAS occurs less frequently and later in life when compared to girls, and presents with penile growth and testes enlargement.^[4][5][6]
• Thyroid disease - The thyroid gland may become enlarged (called a goiter) or develop masses called nodules. About half of people with MAS have hyperthyroidism.^[4][5]
• Increased production of growth hormone - The pituitary gland may produce too much growth hormone. This can result in acromegaly.^[4][5]
• Cushing’s syndrome - Rarely, people with MAS 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.^[4][5]
• Testicular abnormalities in males - Testicular abnormalities are seen in the majority of males with MAS (~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 MAS usually have light brown patches of skin. These spots often appear on one side of the body and may be present from birth.^[4][5]

Less common features of MAS 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 MAS include bone, thyroid, testicular, and breast. Precocious puberty and growth hormone excess may contribute to an increased risk of cancer.^[1]

McCune-Albright syndrome (MAS) is estimated to occur in 1 in 100,000 to 1 in 1 million people, making it a very rare disorder.^[7]

McCune-Albright syndrome (MAS) is caused by somatic mutations in the GNAS gene. This gene provides instructions for making part of a protein that influences many cell functions by regulating hormone activity. GNAS mutations that cause MAS result in a protein that causes the enzyme adenylate cyclase to always be "on". This leads to over-production of several hormones, resulting in the signs and symptoms of MAS.^[5][8]

Precocious puberty in McCune-Albright syndrome is gonadotropin-independent. This means that it is not caused by early release of gonadotropins (luteinizing hormone and follicle-stimulating hormone), but, instead, the cause is the early secretion of high levels of sex hormones (male androgens and female estrogens). Precocious puberty caused by this condition is much more common in girls than in boys, resulting from an excess of estrogen produced by cysts in the ovaries.^[5][1]

Other endocrine problems that may also occur in people with McCune-Albright syndrome are hyperthyroidism, acromegaly and Cushing syndrome. The hyperthyroidism in the MAS is caused by an enlarged thyroid gland (goiter) or by thyroid masses called nodules. Acromegaly results from an excess of growth hormone produced by the pituitary gland (a structure at the base of the brain that makes several hormones).  Cushing syndrome results from an excess of the hormone cortisol produced by the adrenal glands.^[5]

McCune-Albright syndrome (MAS) is not inherited. It is caused by a random, somatic mutation in the GNAS gene. Mutations that cause MAS occur very early in development, after an egg is fertilized (conception). These mutations are not present in the egg or sperm of the parents of affected children. Because these mutations are acquired after conception, some of the body's cells have a normal GNAS gene, while other cells have the mutated gene. This phenomenon is called mosaicism.^[5][6]

Because mutations that cause MAS are acquired, a person with MAS does not pass the disorder on to children.