McCune-Albright Syndrome

What is McCune-Albright Syndrome?

McCune-Albright syndrome is a uncommon genetic condition. It was originally identified by a combination of symptoms: polyostotic fibrous dysplasia (a bone disease where areas of bone become weak), early puberty, and café-au-lait spots (light brown skin marks). Today, we know that several hormonal disorders are connected to the syndrome. They include hyperthyroidism (overactive thyroid), acromegaly (a condition where the body produces too much growth hormone), phosphate wasting (where the body loses too much phosphate), and Cushing’s syndrome (high levels of cortisol hormone).

The varied mix of symptoms comes from a specific change in the GNAS gene, present in many tissues in the body. This mutation doesn’t affect everyone the same way because it doesn’t happen in all the cells, but just in some (this is known as a ‘somatic’ mutation).

What Causes McCune-Albright Syndrome?

McCune-Albright syndrome is caused by a spontaneous mutation in a specific gene, known as GNAS, while the baby is still developing in the womb. This gene makes a protein that is a part of a larger signaling complex found in various tissue types, such as bone, skin, and hormone-producing tissues.

The mutation doesn’t happen everywhere in the body but is distributed in a patchwork or “mosaic” pattern. The signs and symptoms of McCune-Albright depend on when the mutation happens as the baby is developing. The mutation in the GNAS gene leads to a constantly active protein part, which subsequently increases the levels of a molecule called cAMP inside the cells. This then affects the functions of various hormones in the body.

Risk Factors and Frequency for McCune-Albright Syndrome

McCune-Albright syndrome is a rare condition. It’s estimated that this condition affects between 1 in 100,000 to 1 in 1,000,000 people.

Signs and Symptoms of McCune-Albright Syndrome

McCune-Albright syndrome is a condition that can show up in different ways. It often presents as early signs of puberty or issues linked to fibrous dysplasia.

Girls might experience early periods and breast growth.
Boys may show signs like an increase in testicle size, the growth of pubic and underarm hair, and stronger body odor.
Café-au-lait spots, which are light brown skin discolorations, might be noticed. Usually, these spots are found along the midline of the body and have irregular ‘coast of Maine’ jagged edges.
Fibrous dysplasia often causes bone problems. It can lead to a fracture from mild injury or can cause pain. Lesions on the skull and facial bones can also happen, resulting in painless facial asymmetry. Imaging of the bones may reveal a certain pattern, where the hard outer layer of the bone is thin, and the inner bone has a ‘ground glass’ appearance.
Finally, different glands in the body may not function correctly. Overactive thyroid gland is common. Growth hormone and prolactin levels might also be high, leading to growth changes and menstrual irregularities. In rare cases, a condition called Cushing syndrome might present in newborns, usually temporarily affecting the adrenal glands.

Testing for McCune-Albright Syndrome

McCune-Albright syndrome is a condition that is primarily diagnosed based on the patient’s symptoms and physical examination. There is a genetic test available for a specific mutation in the GNAS gene, which is associated with this syndrome. However, due to the nature of the syndrome, this test may sometimes give a negative result even if the person has the condition. Moreover, getting a positive result from this test doesn’t really change the treatment approach a lot.

The diagnosis process may also involve taking X-rays or conducting a CT scan to identify and understand the extent of bone abnormalities, which are a common feature of this syndrome. CT scans of the skull specifically can help spot any abnormalities in the facial and pituitary (a small gland at the base of the brain) structures. Regular vision and hearing tests also play a role in surveillance of the disease as the conditions can affect these systems. A bone scan may be advised to assess any endocrine-related (hormonal) problems affecting bone development.

Early puberty is often a part of McCune-Albright syndrome, it can be due to early activation of the ovaries or testicles. This can be evaluated through blood tests that measure levels of sex hormones like estradiol and testosterone. Boys may need an ultrasound of the testes to check for hormone-releasing tumors. High levels of estradiol in girls could trigger a hormonal chain reaction, which may require assessment for early onset of puberty. This could include a GnRH stimulation test and blood tests to measure levels of hormones that control the reproductive system such as luteinizing hormone and follicle-stimulating hormone.

If there are signs of excessive growth hormone, tests might be done, such as an oral glucose tolerance test and measuring levels of growth hormone and prolactin in the blood. High levels of thyroid hormones can be checked through measuring levels of hormones like thyroid-stimulating hormone (TSH), thyroxine, and T3. An ultrasound scan may also be done regularly to monitor any changes and abnormalities. In addition, doctors will keep track of kidney function and serum phosphate levels as part of ongoing monitoring of the patient’s health.

Treatment Options for McCune-Albright Syndrome

Gonadotropin-independent precocious puberty, a condition where children’s bodies begin changing into that of an adult’s too soon, can be treated with drugs called aromatase inhibitors and tamoxifen in girls. If it progresses into central precocious puberty, we can use medications called gonadotropin-releasing hormone analogs to slow down the progression.

Hyperthyroidism, a condition where your thyroid gland produces too much thyroid hormone, is usually first treated with antithyroid medications and a procedure called radioablation. Overproduction of the growth hormone is treated with drugs called somatostatin or direct Growth Hormone (GH) receptor antagonists. If there’s too much prolactin hormone in the blood (hyperprolactinemia), bromocriptine can be used. If a patient has growths called adenomas on the pituitary gland, surgery to remove these growths is an option. There’s a debate around treating hypophosphatemia (low phosphate levels in the blood) with oral supplements, but these should be given in cases of rickets, which is a disorder causing soft and weak bones in children.

Currently, there are no specific rules for deciding when surgery becomes necessary for fibrous dysplastic lesions (abnormal growth or changes in the fibrous tissue). As a general guideline, surgical treatment may be considered if there’s worsening pain, stress fracture, deformity, or loss of function. The benefits of preventative surgery are uncertain. High-dose bisphosphonate therapy, a medication used to slow bone loss, has shown mixed results and is used primarily for pain relief. Operating on cranial-facial lesions, which are abnormal tissues in the head and face, might be necessary if there’s a likelihood of losing sight or hearing.

Both Neurofibromatosis and McCune-Albright syndrome can show up with spots on the skin called café-au-lait macules, which resemble the color of coffee with milk. The ones linked with neurofibromatosis usually have smooth edges, whereas the spots in McCune-Albright syndrome may appear irregular or jagged and usually appear along the midpoint of the body. Besides, neurofibromatosis is typically associated with growths on nerve tissues, known as neurofibromas, a feature not seen in McCune-Albright syndrome.

Fibrous dysplasia, characterized by bone areas where normal bone is replaced with fibrous bone tissue, often occurs as an isolated abnormality involving one or multiple bone lesions. In some cases, these lesions might result from the same genetic mutation (GNAS) that causes McCune-Albright syndrome. However, if the patient does not exhibit skin spots or endocrine system disorders, then a diagnosis of isolated fibrous dysplasia, a condition specifically related to bone issues, is more likely.

Evidence of unusually early onset of puberty, also known as precocious puberty, could be attributed to several causes. These might be related to problems in the brain (central) or outside the brain (peripheral), and the exact cause is often unknown in girls. Possible causes can also include hormone-producing tumours or a condition called congenital adrenal hyperplasia. Whenever a patient presents early puberty symptoms, a thorough examination of the entire skeleton should be performed. This is necessary to ensure they do not have McCune-Albright syndrome, which can cause such symptoms.

What to expect with McCune-Albright Syndrome

Predicting the long-term outcome can be difficult because this disease varies greatly in severity. Younger patients who have high levels of phosphates in their urine and bone lesions in many parts of their body have a higher risk of experiencing significant bone pain and fractures.

The main objective in treating early onset of puberty is to ensure the child can grow to their full potential adult height. If left untreated, the parts of the child’s bones that enable growth might stop growing too early, resulting in short stature.

Though it’s rare, fibrous dysplastic lesions, which are abnormal bone tissues, could turn malignant or cancerous. There has also been reports indicating an increased risk of breast cancer.

Possible Complications When Diagnosed with McCune-Albright Syndrome

If a condition known as precocious puberty (where a child’s body begins changing into that of an adult at an age earlier than is typical) is left untreated, it may result in shorter adult height.

Durig Complications:

Pain at sites of fibrous dysplastic lesions
Fractures at sites of fibrous dysplastic lesions
Increased risk of developing rickets due to phosphate wasting
Decreased adult stature due to untreated precocious puberty

Preventing McCune-Albright Syndrome

If you or your child has McCune-Albright syndrome, it’s important to know this condition happened due to a random change in genes that was not inherited, meaning it can’t be passed down to your children. This disease often affects the body’s hormone levels and bone growth, so it’s crucial to have regular medical check-ups. These check-ups will include tracking hormone levels and checking on the maturity of the bones to ensure the body is functioning as it should.

Frequently asked questions

McCune-Albright Syndrome is an uncommon genetic condition characterized by a combination of symptoms including polyostotic fibrous dysplasia, early puberty, and café-au-lait spots. It is also associated with several hormonal disorders such as hyperthyroidism, acromegaly, phosphate wasting, and Cushing's syndrome. The syndrome is caused by a specific change in the GNAS gene, which occurs in some cells but not all.

McCune-Albright syndrome is estimated to affect between 1 in 100,000 to 1 in 1,000,000 people.

Signs and symptoms of McCune-Albright Syndrome include: - Early signs of puberty in girls, such as early periods and breast growth. - Signs in boys, including an increase in testicle size, the growth of pubic and underarm hair, and stronger body odor. - Presence of café-au-lait spots, which are light brown skin discolorations. These spots are typically found along the midline of the body and have irregular 'coast of Maine' jagged edges. - Bone problems caused by fibrous dysplasia, which can lead to fractures from mild injury and cause pain. Lesions on the skull and facial bones can also occur, resulting in painless facial asymmetry. Imaging of the bones may reveal a certain pattern, where the hard outer layer of the bone is thin, and the inner bone has a 'ground glass' appearance. - Dysfunction of different glands in the body, such as an overactive thyroid gland. High levels of growth hormone and prolactin can also occur, leading to growth changes and menstrual irregularities. In rare cases, newborns may temporarily experience a condition called Cushing syndrome, which affects the adrenal glands.

McCune-Albright syndrome is caused by a spontaneous mutation in a specific gene, known as GNAS, while the baby is still developing in the womb.

The doctor needs to rule out the following conditions when diagnosing McCune-Albright Syndrome: 1. Neurofibromatosis: This condition can also present with café-au-lait macules on the skin, but it is typically associated with growths on nerve tissues called neurofibromas, which are not seen in McCune-Albright Syndrome. 2. Isolated fibrous dysplasia: Fibrous dysplasia can occur as an isolated abnormality involving one or multiple bone lesions. If the patient does not exhibit skin spots or endocrine system disorders, a diagnosis of isolated fibrous dysplasia, a condition specifically related to bone issues, is more likely. 3. Precocious puberty due to other causes: Early onset of puberty can be attributed to several causes, including problems in the brain or outside the brain, hormone-producing tumors, or congenital adrenal hyperplasia. A thorough examination of the entire skeleton should be performed to rule out McCune-Albright Syndrome as the cause of early puberty symptoms.

The types of tests that may be needed for McCune-Albright Syndrome include: - Genetic test for the specific mutation in the GNAS gene associated with the syndrome (although a negative result does not rule out the condition) - X-rays or CT scans to identify and understand bone abnormalities, particularly in the skull - Regular vision and hearing tests to monitor any effects on these systems - Blood tests to measure levels of sex hormones, such as estradiol and testosterone, to evaluate early puberty - Ultrasound of the testes in boys to check for hormone-releasing tumors - GnRH stimulation test and blood tests to measure levels of hormones that control the reproductive system in girls - Oral glucose tolerance test and blood tests to measure levels of growth hormone and prolactin for excessive growth hormone - Blood tests to measure levels of thyroid hormones, such as TSH, thyroxine, and T3, for hyperthyroidism - Ultrasound scans to monitor any changes and abnormalities - Monitoring of kidney function and serum phosphate levels - Gonadotropin inhibitors and tamoxifen for gonadotropin-independent precocious puberty - Gonadotropin-releasing hormone analogs for central precocious puberty - Antithyroid medications and radioablation for hyperthyroidism - Somatostatin or direct GH receptor antagonists for overproduction of growth hormone - Bromocriptine for hyperprolactinemia - Surgery to remove adenomas on the pituitary gland if present - Surgery for fibrous dysplastic lesions if there are worsening pain, stress fracture, deformity, or loss of function - High-dose bisphosphonate therapy for pain relief in fibrous dysplastic lesions - Surgery on cranial-facial lesions if there is a risk of losing sight or hearing.

McCune-Albright Syndrome, a condition characterized by fibrous dysplastic lesions, can be treated with surgical intervention if there is worsening pain, stress fracture, deformity, or loss of function. However, the benefits of preventative surgery are uncertain. High-dose bisphosphonate therapy may also be used primarily for pain relief in treating this syndrome.

There are a few potential complications associated with fibrous dysplastic lesions, namely discomfort and potential fractures. Additionally, due to the loss of phosphate, there's a heightened risk of developing a bone-weakening disease called rickets. If precocious puberty, a symptom of McCune-Albright Syndrome, is left untreated, it may result in shorter adult height.

The prognosis for McCune-Albright Syndrome varies greatly in severity and can be difficult to predict. However, younger patients with high levels of phosphates in their urine and bone lesions in many parts of their body have a higher risk of experiencing significant bone pain and fractures. Additionally, there is a rare possibility of fibrous dysplastic lesions turning malignant or cancerous, and there have been reports indicating an increased risk of breast cancer.

An endocrinologist.

Genetic Disorders Precociuos Puberty