McCune-Albright Syndrome

The McCune-Albright syndrome consists of at least 2 features of the triad of polyostotic fibrous dysplasia, cafe au lait skin pigmentation and autonomous endocrine hyperfunction, including precocious puberty, thyrotoxicosis, pituitary gigantism and Cushing's syndrome.¹ It is usually caused by mosaicism for a mutation in the GNAS1 (Gs alpha) gene. A mutation in the GNAS1 gene occurs post-zygotically in a somatic cell. All cells descended from the mutated cell can manifest features of McCune-Albright syndrome.² The syndrome was first described by Fuller Albright and Donovan McCune in 1937.

• McCune-Albright syndrome is a rare disease with estimated prevalence between 1/100,000 and 1/1,000,000.³
• Gonadotropin-independent precocious puberty is far more common in affected girls than in boys. Other manifestations of McCune-Albright syndrome probably occur equally in both sexes.
• Sporadic and therefore very rarely associated with transmission from generation to generation.

• May be diagnosed at birth (presence of cafe au lait spots), early childhood (in cases with severe polyostotic fibrous dysplasia) or by adolescence (development of precocious puberty). Onset most often occurs in early childhood.
• The clinical presentation is highly variable, depending on which of the various potential components of the syndrome predominate.
• Marked polyostotic fibrous dysplasia:
  • May involve a single or multiple skeletal sites.
  • Bony involvement is often unilateral. Presentation may be abnormal gait, visible bony deformities, bone pain or joint stiffness with pain (most often due to secondary osteoarthrosis). The disease may be clinically silent and discovered on routine x-rays or occasionally it presents with a pathological fracture.
  • Virtually any bone in the body may be affected, but especially the femur, tibia, ribs, facial bones and small bones of the hands and feet.
  • Multiple pathological fractures are prominent in childhood.
  • As a result of the combination of precocious puberty, recurrent fractures, and hypophosphataemic rickets, the majority of patients are short in stature, unless there is co-existing excess growth hormone.
  • Scoliosis is common and may be progressive.³
  • In mild cases, the onset of symptoms is delayed and may include more subtle features, e.g. mild facial asymmetry, dysmorphism and mild unequal limb length.
  • Patients with myxomas often present with a history of palpable masses in the limbs, anterior abdominal wall, and/or back. These may be painful.⁴
• Endocrine abnormalities:
  • In addition to precocious puberty (vaginal bleeding or spotting and development of breast tissue in girls, testicular and penile enlargement and precocious sexual behaviour in boys), other hyperfunctioning endocrinopathies may be involved including hyperthyroidism, growth hormone excess, Cushing syndrome.
  • Precocious puberty affects more than 50% of females and presents as premature thelarche or menarche as early as 2-3 years old. Also occurs in male patients but is less common.
  • Other associated endocrinopathies include goitres (with or without hyperthyroidism), diabetes mellitus, acromegaly, Cushing's syndrome, hyperprolactinaemia, thyroid nodules (rarely thyroid cancer) and renal phosphate wasting.^3,5
• Cafe au lait spots:
  • Are absent in 10-20% of patients and can be detected in as many as 10% of healthy individuals.
  • May be difficult to diagnose in very young patients but tend to become more prominent with age.
  • Common areas include the nape of the neck and nasal clefts.
  • They often terminate abruptly at the midline and are most common on the side most affected by bony involvement.
  • Are fairly prominent and have irregular edges. These cafe au lait spots are larger and less numerous than the smooth-edged lesions found in patients with neurofibromatosis.

Differential diagnoses include neurofibromatosis, osteofibrous dysplasia, non-ossifying fibromas, idiopathic central precocious puberty, and ovarian neoplasm.³ The differential diagnosis will depend on the presentation and include:

• Ossifying fibromas of the bone.
• Predominant multiple bony fractures and deformity may be mistaken for a milder form of osteogenesis imperfecta.
• Other causes of cafe au lait pigmentation, e.g. neurofibromatosis and healthy individuals.
• Other causes of endocrine hyperfunction, particularly precocious puberty.

The diagnosis of McCune-Albright syndrome is usually established on clinical grounds.³

• Sexual precocity: LH, FSH (both baseline and in response to stimulation by gonadotropin-releasing hormone) are below normal limits. Oestrogen levels are elevated and androgen levels are normal in female patients. Males who are affected have elevated serum-free and total testosterone levels.
• Blood and urinary chemistries show evidence of excessive bone turnover. Serum alkaline phosphatase levels are elevated. Serum calcium may be normal or slightly reduced depending on the extent of coexisting osteomalacia.
• The associated rickets or osteomalacia is usually hypophosphataemic and hyperphosphaturic.
• Plain bone x-rays typically show multiple patchy areas of bony lysis and sclerosis.
• Formal bone-age estimations may be higher in patients with sexual precocity.
• Ultrasound: to evaluate patients with evidence of soft-tissue swellings; may show ovarian cysts, thyroid nodules.
• MRI scans may be useful to define the extent of bony disease as well as in the assessment of associated endocrine lesions, e.g. pituitary adenoma.
• Radionuclide bone scans: helpful to define the extent of disease activity of polyostotic fibrous dysplasia.
• Bone biopsy may be necessary to rule out malignancy in a patient with a rapidly expanding lesion.
• Enlarging thyroid nodules or hypofunctioning solitary thyroid nodules will require a fine-needle aspiration biopsy.

• Will depend on the individual presentation and associated endocrine abnormalities.
• Management is multidisciplinary and will include orthopaedics, endocrinology as well as physiotherapy.
• Severely affected patients and their families are likely to need a great deal of support.
• Genetic testing is possible if not routinely available but genetic counseling should be offered.³

Bone disease

• The bony disease is very difficult to treat and no specific treatments are available.
• Activity: should maintain regular physical activity, but this is often difficult with associated generalised polyostotic fibrous dysplasia. May need to avoid various contact sports and games, and any other activity associated with risk of fracture.
• Bisphosphonates are often used.³ Some preliminary data suggest that bisphosphonates may have beneficial effects on the bone disease, including reducing bone pain, reducing frequency of pathological fractures, and slowing the evolution of the bone disease.⁶
• Orthopaedic surgical care for multiple bony fractures and deformities.

Precocious puberty

• Management for precocious puberty: in patients with McCune-Albright syndrome, it is gonadotrophin-independent and so continuous GnRH therapy does not have a role.
• For female patients, testolactone, a competitive aromatase inhibitor, is used to block oestrogen effects. Testolactone has been shown to be an effective treatment of precocious puberty in the McCune-Albright syndrome.⁷
• Oestrogen receptor antagonists, such as tamoxifen, may have a therapeutic role but have not yet been systematically investigated.⁸
• Other alternative treatment options include medroxyprogesterone acetate, which is particularly useful for controlling menstrual bleeding. No definitive clinical trials have determined the efficacy of this medication.
• Precocious puberty in males with antiandrogen and antioestrogens. This often consists of a combination of spironolactone and testolactone. Alternative antiandrogens, such as ketoconazole may also be used.

• Complications of fractures include secondary osteomyelitis, compressive neuropathy, Volkmann contractures, sympathetic algodystrophy, myositis, ligamentous ossifications and pseudoarthrosis.
• The most serious complication of polyostotic fibrous dysplasia is osteosarcoma, which most often follows irradiation to affected bones. It is very uncommon with an overall incidence rate of 1% in patients with polyostotic fibrous dysplasia. Most often involves the bones of the face and femur.⁹
• Skull involvement may cause compression neuropathies of the optic nerve, vestibulocochlear nerve or the cranial nerves located at the base of the skull.
• A minority of patients have significant risk for perioperative sudden death. This is presumed to be secondary to either cardiomyopathy or arrhythmia.
• Females may have a greater risk for breast cancer, probably due to their prolonged exposure to elevated oestrogen levels.
• Hypophosphataemic rickets may further worsen the bone disease associated with polyostotic fibrous dysplasia.¹⁰

• Apart from the small subgroup of patients that have increased perioperative mortality and those who develop malignancies, McCune-Albright Syndrome is not associated with a significantly increased mortality risk.
• Deformities associated with polyostotic fibrous dysplasia result in variable degrees of morbidity, ranging from mild to very severe.
• Sudden cardiac death has been reported in a few severely affected patients.⁹