Definition

McCune-Albright syndrome is a condition that affects the bones, skin, and various hormone-producing tissues (the endocrine system). This disorder has an incidence rate of approximately 1 in every 100,000 to 1 in every 1,000,000 individuals worldwide.

Causes

McCune-Albright syndrome arises due to mutations in the GNAS gene. The protein encoded by the GNAS gene plays a role in stimulating the enzyme adenylate cyclase. In this syndrome, mutations in the GNAS gene lead to the persistent production of G protein, resulting in the continuous activation of adenylate cyclase.

This ongoing activation of adenylate cyclase results in the overproduction of several hormones, which leads to abnormal bone development and other clinical manifestations of McCune-Albright syndrome.

Risk Factor

McCune-Albright syndrome can occur in both boys and girls, with an equal distribution among affected individuals. The syndrome is not inherited but results from a random mutation in the GNAS gene that arises during early development. This mutation is sporadic and unpredictable. The genetic mutation occurs shortly after conception/fertilization due to errors during cellular division and replication.

The severity and characteristics of McCune-Albright syndrome are influenced by the number and distribution of cells that carry the mutated GNAS gene.

Symptoms

Individuals with McCune-Albright syndrome develop abnormal regions of scar-like (fibrous) tissue in their bones, a condition known as polyostotic fibrous dysplasia. The term "polyostotic" refers to the occurrence of these abnormalities in multiple bones, often affecting only one side of the body. The replacement of normal bone with fibrous tissue can result in fractures, uneven bone growth, and bone deformities. If this abnormality involves the skull or jaw bones, it can lead to asymmetrical facial growth.

Asymmetry may also affect long bones. When this occurs in the leg bones, it disrupts normal bone growth, leading to uneven leg length and causing a limp. Scoliosis, or abnormal spinal curvature, may also develop. Although the risk of these bone abnormalities progressing to cancer exists, it is seen in less than 1% of individuals with McCune-Albright syndrome.

In addition to bone abnormalities, affected individuals typically have light brown skin patches known as café-au-lait spots, which are present from birth and have irregular borders. As with bone abnormalities, these spots in McCune-Albright syndrome may appear on only one side of the body.

Girls with McCune-Albright syndrome may experience precocious puberty, with some children exhibiting menstrual bleeding as early as age 2. This early menstruation is driven by an excess of estrogen, a female sex hormone, which is produced by a cyst in one of the ovaries. Although less common, boys with McCune-Albright syndrome may also experience early puberty.

Other endocrine disorders can arise in people with McCune-Albright syndrome. The thyroid gland, located at the base of the neck, may enlarge (a condition known as goiter) or develop nodules. Approximately 50% of those with thyroid involvement produce excess thyroid hormone (hyperthyroidism), which can cause symptoms such as a rapid heartbeat, high blood pressure, weight loss, tremors, and sweating.

The pituitary gland, located at the base of the brain, is responsible for producing several hormones. In some cases, it may produce excessive amounts of growth hormone, leading to a condition known as acromegaly, which is marked by enlarged hands, feet, and distinctive facial features. Overproduction of growth hormone can also increase the occurrence of fibrous dysplasia, especially in the bones of the skull. Although rare, individuals with McCune-Albright syndrome may develop Cushing's syndrome, a condition caused by the overproduction of cortisol by the adrenal glands, which are situated above each kidney. Cushing's syndrome results in weight gain in the face and upper body, delayed growth in children, fragile skin, fatigue, and other health issues. In McCune-Albright syndrome, Cushing's syndrome typically manifests before the age of 2.

In addition to endocrine-related complications, McCune-Albright syndrome can lead to other organ and system issues, including benign growths in the digestive tract, called polyps, and other abnormalities.

Diagnosis

The diagnosis of McCune-Albright syndrome may be considered at birth due to the presence of characteristic café-au-lait spots. However, the disorder is often not diagnosed until later in childhood, when puberty begins or bone deformities become noticeable.

Physicians will evaluate the child for physical signs of the disorder, such as endocrine irregularities, café-au-lait spots, and fibrous dysplasia.

Diagnostic tests for McCune-Albright syndrome may include:

• Blood tests to assess endocrine function
• Genetic testing to detect mutations in the GNAS gene, often using a biopsy of skin or other tissue
• Imaging tests, such as X-rays, to evaluate bone growth

Management

Treatment for McCune-Albright syndrome is individualized, as there is no cure for the condition. The goal of therapy is to manage symptoms. Treatment options may include:

• Medications such as bisphosphonates to reduce the risk of fractures and manage abnormal bone growth
• Hormone therapies, such as aromatase inhibitors, to manage precocious puberty
• Antithyroid medications to treat hyperthyroidism
• Physical and occupational therapy to address movement difficulties
• Surgical interventions to correct abnormalities caused by fibrous dysplasia

Complications

Potential complications of McCune-Albright syndrome may include:

• Brittle bones (osteoporosis)
• Repeated bone fractures
• Vision or hearing impairments due to abnormal skull bone development
• Adrenal gland tumors
• Osteitis fibrosa cystica (soft bones that may form cysts)
• Mobility issues or disability caused by asymmetric or abnormal bone growth

In rare cases, excessive growth (gigantism) may occur due to hormonal imbalances, often affecting the face, hands, and feet.

Growth disorders are also possible; some children may be shorter than their peers due to early closure of growth plates caused by precocious puberty. Early diagnosis and treatment, however, may help prevent premature puberty-related changes. It is important to monitor your child’s development and growth milestones to ensure they are progressing as expected.

There is also a small risk of cancer associated with McCune-Albright syndrome. Women with the condition may have a higher likelihood of developing breast cancer at a younger age than the general population, making it essential to discuss screening options with a healthcare provider.

Prevention

McCune-Albright syndrome is caused by a genetic mutation, which means it cannot be prevented. If you are considering pregnancy, it may be helpful to speak with your healthcare provider about genetic testing to assess the risk of having a child with a genetic disorder.

When to See a Doctor?

You should consult a healthcare provider if your child exhibits any symptoms of McCune-Albright syndrome, including:

• Anxiety, hyperactivity, mood swings, difficulty sleeping (potential signs of hyperthyroidism)
• Bone deformities or irregularities in bone shape
• Difficulty walking
• Early onset of menstruation
• Severe bone pain

If you suspect your child has sustained a fracture, characterized by pain, swelling, difficulty moving or bearing weight, or bruising, it is essential to seek medical attention immediately.

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