McCune Albright syndrome

Synonyms

7

Overview

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 often appear on only one side of the body.

Girls with McCune-Albright syndrome usually reach puberty early. These girls usually have menstrual bleeding by age two, many years before secondary sex characteristics such as breast enlargement and pubic hair are evident. 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." Rarely, affected individuals develop Cushing's syndrome, an excess of the hormone cortisol produced by the adrenal glands, which are small glands located on top of each kidney. Cushing's syndrome causes weight gain in the face and upper body, slowed growth in children, fragile skin, fatigue, and other health problems.

Symptoms

People with McCune Albright syndrome (MAS) may have symptoms related to bones, the endocrine system, and/or skin. The symptoms can range from mild to severe.

Bone symptoms may include:

  • Polyostotic fibrous dysplasia: This is when normal bone is replaced by softer, fibrous tissue. Polyostotic means the abnormal areas 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 it occurs in skull and jaw it can result in uneven growth of the face. This may also occur in the long bones; uneven growth of leg bones may cause limping
  • Abnormal curvature of the spine (scoliosis)
  • Cancer: Bone lesions may become cancerous, but this happens in less than 1% of people with MAS

Endocrine symptoms may include:

  • Early puberty: Girls with MAS usually reach puberty early. They often have menstrual bleeding by age 2 (as early as 4-6 months in some), many years before characteristics such as breast enlargement and pubic hair growth are evident. 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 MAS may also experience early puberty.
  • Enlarged thyroid gland: The thyroid gland may become enlarged (a condition called a goiter) or develop masses called nodules. About half 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.
  • Increased production of growth hormone: The pituitary gland may produce too much growth hormone. This can result in acromegaly, a condition characterized by large hands and feet, arthritis, and distinctive facial features that are often described as "coarse."
  • Cushing's syndrome: Rarely, individuals with MAS produce too much of the hormone cortisol in the adrenal glands. Cushing's syndrome causes weight gain in the face and upper body, slowed growth in children, fragile skin, fatigue, and other health problems.

Skin symptoms may include:

  • Cafe-au-lait spots: Individuals with MAS usually have light brown patches of skin called cafe-au-lait spots. Like the bone lesions, these spots often appear on only one side of the body. Most children have these spots from birth and the spots rarely grow. There are usually not any medical problems caused by these skin changes.

Additional findings:

Less common symptoms sometimes associated with MAS include gastroesophageal reflux, gastrointestinal polyps, inflammation of the pancreas (pancreatitis), and several abnormalities of the heart (cardiac abnormalities). Such abnormalities include a faster than normal heart rate (tachycardia), high output heart failure, and aortic root dilatation.

Although the term tumor may be used to describe fibrous dysplasia lesions, these growths are benign (non-cancerous). Only in extremely rare cases, likely less than 1% of cases, have these lesions become cancerous (malignant transformation). These malignant tumors (osteosarcomas) developed in individuals who had been radiated for bone pain; a treatment option that has been abandoned.

Individuals may also be at an increased risk of developing breast cancer. Some reports suggest that this increased risk is more likely in individuals with growth hormone excess. Thyroid cancer and testicular cancer have also been reported in individuals with MAS in extremely rare instances.



Causes

McCune Albright syndrome (MAS) is caused by a change (mutation) in the GNAS gene. This gene provides instructions for making part of a protein that ultimately influences many cell functions by regulating hormone activity. GNAS gene mutations that cause MAS result in a protein that causes the enzyme adenylate cyclase to be constantly turned on. This, in turn, leads to over-production of several hormones, resulting in the signs and symptoms of MAS. 

McCune Albright syndrome (MAS) is not inherited. It is caused by a random change (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. This mutation is not passed on to any of the affected individual's children.

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.

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 FD 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 FD and may be necessary to distinguish a FD 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 MAS. 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 MAS, 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 MAS, and so this test is not frequently used in clinical diagnosis.

Prognosis

The long-term outlook (prognosis) for people with McCune Albright syndrome (MAS) varies depending on the nature and severity of features in each affected person. In general, people with MAS have a normal life span. The condition is typically not associated with a significantly increased mortality rate, except for the small portion of affected people with increased perioperative mortality (death related to surgery) and those who develop cancers. Several authors have reported unexplained death in severely affected people (presumably due to arrhythmias), but two long-term follow-up studies have shown no increased risk of premature death.

Treatment

Although there is no cure for McCune Albright syndrome (MAS), drug treatments may help some of the endocrine symptoms, and surgery can help repair some of the bone problems. Generally, treatment depends on what tissues are affected as well as the severity.

Surgery may be needed to manage complications associated with fibrous dysplasia, such as progressive visual disturbance, severe pain, and severe disfigurement. Surgery may also be needed to manage associated endocrine abnormalities and/or cancers. Bisphosphonates are frequently used to treat fibrous dysplasia. Strengthening exercises are recommended to help maintain musculature around the bones and minimize the risk of fracture. Treatment of all endocrine symptoms, whether by hormone inhibitors or surgery, is commonly required.