McCune–Albright syndrome

Overview

McCune–Albright syndrome (MAS) is a rare, complex genetic disorder that affects the bones, skin, and endocrine (hormonal) system. It is characterized by a classic triad of symptoms: fibrous dysplasia of bone (abnormal fibrous tissue growth in place of normal bone), café-au-lait skin pigmentation, and precocious puberty or other endocrine abnormalities. MAS can affect both males and females, but the endocrine manifestations are more common and often more severe in females.

The severity and combination of symptoms vary widely from person to person, depending on which tissues are affected. The syndrome was first described in the 1930s by Donovan McCune and Fuller Albright. While there is no cure, many of the symptoms can be managed effectively with medical treatment and monitoring.

Causes

McCune–Albright syndrome is caused by a post-zygotic, somatic activating mutation in the GNAS gene, which encodes the alpha subunit of the stimulatory G protein (Gsα). This mutation leads to overproduction of cyclic AMP (cAMP) in affected cells, disrupting normal cell signaling and resulting in abnormal growth and hormonal activity.

Because the mutation occurs after fertilization, it is not inherited and is instead mosaic, meaning only some cells in the body carry the mutation. The earlier in embryonic development the mutation occurs, the more tissues may be involved and the more severe the clinical presentation.

Symptoms

Symptoms of McCune–Albright syndrome can vary depending on which tissues are affected. The classic triad of features includes:

• Fibrous dysplasia of bone:

  • Weak, deformed bones due to replacement of normal bone with fibrous tissue

  • Fractures, bone pain, and deformities (e.g., scoliosis, bowing of limbs)

  • Commonly affects the skull, pelvis, femur, and ribs

• Café-au-lait macules:

  • Flat, pigmented skin lesions with irregular (“coast of Maine”) borders

  • Typically present at or shortly after birth

  • Often follow a segmental pattern on one side of the body

• Endocrine abnormalities:

  • Precocious puberty: Early onset of menstruation or breast development in girls, and testicular enlargement in boys (less common)

  • Hyperthyroidism: Overactive thyroid leading to weight loss, rapid heartbeat, and anxiety

  • Growth hormone excess: May result in gigantism or acromegaly

  • Cushing’s syndrome: In rare cases, due to overproduction of cortisol by adrenal glands

  • Phosphate-wasting and hypophosphatemia: Leading to rickets or osteomalacia

Other less common manifestations may include liver, cardiac, and gastrointestinal involvement, depending on the extent of tissue mosaicism.

Diagnosis

Diagnosis of McCune–Albright syndrome is based on clinical evaluation, imaging, and genetic testing. It can often be diagnosed in early childhood based on the presence of two or more of the classic triad features. Diagnostic steps include:

• Clinical examination: Evaluation of skin lesions, growth patterns, and signs of early puberty or other hormonal disorders.

• Imaging studies:

  • X-rays or bone scans to detect fibrous dysplasia

  • CT or MRI of the skull, spine, or long bones for structural evaluation

• Endocrine testing:

  • Hormone panels (estradiol, testosterone, LH, FSH, TSH, cortisol, growth hormone, etc.) to detect overactive endocrine glands

  • Bone density and serum phosphate levels

• Genetic testing:

  • Detection of GNAS mutations in affected tissue (often not present in blood due to mosaicism)

Because the mutation is somatic and mosaic, multiple tissue samples may be needed for definitive genetic confirmation.

Treatment

There is no cure for McCune–Albright syndrome, so treatment is aimed at managing symptoms and preventing complications. A multidisciplinary approach involving endocrinologists, orthopedic surgeons, dermatologists, and other specialists is often required. Common treatment strategies include:

• Bone involvement:

  • Pain management and orthopedic surgeries to stabilize fractures or correct deformities

  • Bisphosphonates (e.g., pamidronate or alendronate) to reduce bone pain and turnover

• Endocrine abnormalities:

  • Precocious puberty: Medications such as aromatase inhibitors or GnRH analogs to delay puberty progression

  • Hyperthyroidism: Treated with antithyroid medications, radioactive iodine, or surgery

  • Growth hormone excess: Somatostatin analogs or surgical removal of pituitary adenomas

  • Cushing’s syndrome: Often managed with adrenalectomy if cortisol excess is severe

• Skin pigmentation: No treatment usually needed, though cosmetic options are available

• Psychological support: Counseling and support for children and families dealing with the chronic and visible aspects of the syndrome

Regular monitoring is essential to detect and manage emerging complications.

Prognosis

The prognosis for individuals with McCune–Albright syndrome varies widely based on the severity and extent of the symptoms. With appropriate treatment and monitoring, many people with MAS can lead relatively normal lives. Key factors influencing prognosis include:

• The number and severity of endocrine abnormalities

• Extent and location of bone involvement

• Response to treatment, especially for hormonal imbalances and bone pain

• Early diagnosis and ongoing multidisciplinary care

Life expectancy is generally normal unless there are severe complications such as uncontrolled endocrine disorders or fractures involving critical bones. Regular follow-up with specialists helps manage the disease proactively and prevent long-term disability.