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McCune-Albright syndrome
This syndrome is characterised by a combination of fibrous dysplasia (bone abnormalities), distinctive skin pigmentation (café-au-lait spots), and various hormonal problems. It typically affects individuals from early childhood and can lead to a range of health challenges.
Overview
McCune-Albright syndrome (MAS) is a rare genetic disorder that typically presents with a triad of symptoms: fibrous dysplasia of bone, café-au-lait skin spots, and hyperfunctioning endocrinopathies (hormonal imbalances). These features can vary in severity and presentation among affected individuals [PMID:33671214]. The condition is not inherited from parents in the typical sense; instead, it arises from a spontaneous genetic change that occurs very early in development.
Because the genetic change happens after conception, not all cells in the body are affected, leading to a 'mosaic' pattern of involvement. This means some tissues may have the genetic alteration, while others do not, which accounts for the wide range of symptoms observed. MAS affects both males and females equally and its exact prevalence is not well established, but it is considered a very rare condition [PMID:31535451].
Symptoms & clinical features
The symptoms of McCune-Albright syndrome are diverse and depend on which body tissues are affected by the genetic change. Fibrous dysplasia involves normal bone tissue being replaced by abnormal, fibrous tissue, making bones weaker and more prone to fractures. This can occur in one or multiple bones and may lead to bone pain, deformities, and limping [PMID:33671214].
Café-au-lait spots are light brown patches on the skin, often with irregular borders, which are typically present from birth or early childhood. Endocrine problems are also common and can include precocious puberty (early onset of puberty), hyperthyroidism (overactive thyroid), Cushing's syndrome (excess cortisol), and acromegaly (excess growth hormone). The specific hormonal issues can significantly influence an individual's growth and development.
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Affected organs
McCune-Albright syndrome primarily affects the skeletal system, leading to fibrous dysplasia in bones throughout the body, including the skull, face, pelvis, and long bones of the limbs. The skin is also affected, presenting with characteristic café-au-lait macules. Furthermore, various endocrine glands can be involved, such as the pituitary gland, thyroid gland, adrenal glands, and ovaries or testes, leading to hormonal imbalances.
Risks & severity
The severity of McCune-Albright syndrome varies significantly between individuals, ranging from mild forms with few symptoms to severe cases with extensive bone involvement and multiple endocrine issues. The age of onset for symptoms can also vary, though many features, such as café-au-lait spots and some endocrine problems like precocious puberty, often appear in early childhood. Fibrous dysplasia can worsen over time, potentially leading to significant skeletal deformities and fractures.
While most individuals with MAS live a normal lifespan, complications can arise from severe fibrous dysplasia or uncontrolled hormonal imbalances. There is a small risk of malignant transformation (cancer) within areas of fibrous dysplasia, particularly in very extensive cases, though this is rare. Regular monitoring and appropriate management are important for addressing potential complications and improving quality of life.
Genetic causes
McCune-Albright syndrome is caused by a specific genetic change (pathogenic variant) in the GNAS gene. This gene provides instructions for making a protein called Gs alpha subunit, which plays a crucial role in cell signalling, particularly in response to various hormones [PMID:31535451].
The GNAS gene variant found in MAS results in a continuously active Gs alpha protein. This constant activation inappropriately stimulates cell growth and hormone production in affected cells. Because the genetic change occurs during early foetal development, not all cells contain the variant, leading to the mosaic pattern of the condition. The variant is not typically inherited from a parent but arises spontaneously (de novo) very early after conception.
- GNAS GNAS complex locus
Inheritance pattern
McCune-Albright syndrome is considered an autosomal dominant condition, but it is almost always caused by a spontaneous genetic change that happens in a person's body cells very early in development. This means the genetic variant is not usually present in the sperm or egg cells of the parents, and therefore, it is rarely passed down from one generation to the next.
Because the genetic change is somatic (happens after conception) rather than germline (present in sperm or egg), affected individuals have a very low chance of passing the condition on to their children. For family members, the risk is typically not increased compared to the general population. Genetic counselling can provide specific information and support for families concerned about inheritance patterns.
Each child has a 50% chance of inheriting the pathogenic variant, regardless of sex.
Diagnosis & testing
Diagnosis of McCune-Albright syndrome often begins with clinical suspicion based on the presence of characteristic symptoms like fibrous dysplasia, café-au-lait spots, and signs of endocrine overactivity. Imaging studies, such as X-rays, CT scans, or MRI, are used to evaluate the extent of fibrous dysplasia in the bones.
Confirmation of MAS is typically achieved through genetic testing, which looks for the specific pathogenic variant in the GNAS gene. Because the condition is mosaic, genetic testing might involve sampling affected tissue, such as a bone biopsy from a fibrous dysplasia lesion, or specialised blood tests. Referral to a clinical genetics service via an NHS Genomic Medicine Centre is appropriate for individuals where MAS is suspected. The relevant NHS R-codes for genetic testing for MAS would typically fall under rare disease testing pathways, as directed by a specialist.
Management & lifestyle
Management of McCune-Albright syndrome is individualised and focuses on addressing the specific symptoms and complications present. This multidisciplinary approach often involves specialists such as endocrinologists, orthopaedic surgeons, dermatologists, and clinical geneticists. Regular monitoring for the progression of fibrous dysplasia and for the development of new endocrine problems is crucial.
Bone health management may include pain relief, physical therapy, and surgical interventions for fractures or significant deformities. Medications, such as bisphosphonates, may be used to help manage bone pain and reduce fracture risk in some cases. Endocrine issues are treated symptomatically; for example, precocious puberty may be managed with hormone-blocking medications, and hyperthyroidism with anti-thyroid drugs or other interventions. There is no cure for MAS, so management aims to control symptoms and improve quality of life within the NHS care pathway framework.
UK care pathway
In the UK, individuals suspected of having McCune-Albright syndrome would typically be referred by their GP or another specialist to a regional NHS Genomic Medicine Centre or a specialist paediatric or adult endocrine clinic. Clinical geneticists and genetic counsellors play a vital role in confirming the diagnosis, explaining the condition, and providing support to individuals and families.
Genetic testing for McCune-Albright syndrome is available through the NHS Genomic Medicine Service, often utilising the Rare and Inherited Disease testing directory (e.g., R146 Fibrous Dysplasia / McCune-Albright Syndrome). A clinical genetics team can guide the appropriate testing strategy and interpret results.
Frequently asked questions
Is McCune-Albright syndrome inherited?
McCune-Albright syndrome is almost never inherited from a parent. It results from a spontaneous genetic change in the GNAS gene that happens very early in development, after conception. This means it is typically not passed down through families.
What are the main signs of McCune-Albright syndrome?
The main signs are fibrous dysplasia (abnormal bone growth), distinctive light brown skin patches called café-au-lait spots, and problems with hormone-producing glands, such as early puberty or an overactive thyroid. The severity of these signs can vary widely.
Can McCune-Albright syndrome be cured?
There is currently no cure for McCune-Albright syndrome. Treatment focuses on managing the symptoms and preventing complications. This often involves a team of specialists to address bone issues, hormonal imbalances, and other health challenges.
How is McCune-Albright syndrome diagnosed?
Diagnosis typically involves a review of clinical symptoms, imaging scans of bones to look for fibrous dysplasia, and genetic testing for the specific change in the GNAS gene. Your doctor may refer you to a clinical genetics service for confirmation.
What kind of doctors treat McCune-Albright syndrome?
Management of McCune-Albright syndrome usually involves a team of specialists. This may include endocrinologists for hormone issues, orthopaedic surgeons for bone problems, dermatologists for skin concerns, and clinical geneticists for overall coordination and genetic counselling.
References
- Nicolaides NC, Kontou M, Vasilakis IA. McCune-Albright Syndrome: A Case Report and Review of Literature. International journal of molecular sciences. 2023. PMID: 37239810
- Spencer T, Pan KS, Collins MT. The Clinical Spectrum of McCune-Albright Syndrome and Its Management. Hormone research in paediatrics. 2019. PMID: 31865341
- Javaid MK, Boyce A, Appelman-Dijkstra N. Best practice management guidelines for fibrous dysplasia/McCune-Albright syndrome: a consensus statement from the FD/MAS international consortium. Orphanet journal of rare diseases. 2019. PMID: 31196103
- Szymczuk V, Taylor J, Boyce AM. Craniofacial Fibrous Dysplasia: Clinical and Therapeutic Implications. Current osteoporosis reports. 2023. PMID: 36849642
- Holbrook L, Brady R. McCune-Albright Syndrome. 2023. PMID: 30725777
- Sarathi V, Melkunte Shanthaiah D. McCune-Albright Syndrome. The New England journal of medicine. 2024. PMID: 39504523
- Jibbe N, Jibbe A, Rajpara A. McCune Albright Syndrome. Kansas journal of medicine. 2020. PMID: 32190188
- Robinson C, Collins MT, Boyce AM. Fibrous Dysplasia/McCune-Albright Syndrome: Clinical and Translational Perspectives. Current osteoporosis reports. 2016. PMID: 27492469