McCune-Albright Syndrome

McCune-Albright syndrome is a mosaic disorder from post-zygotic activating GNAS variants (R201), causing polyostotic fibrous dysplasia, café-au-lait skin macules and autonomous endocrine hyperfunction.

It is rare, with an estimated prevalence of 1 in 100,000 to 1,000,000, and is sporadic, since germline transmission is not viable. Features depend on which tissues carry the variant.

The classic triad is fibrous dysplasia, café-au-lait macules and gonadotrophin independent precocious puberty. Other endocrine features are hyperthyroidism, growth hormone excess, neonatal Cushing syndrome and FGF23-mediated phosphate wasting.

Pathophysiology.

Activating GNAS variants cause constitutive Gs alpha signalling and raised cyclic AMP in affected tissues. In bone, osteoprogenitor cells make abnormal fibro osseous tissue; in the ovary, follicular cysts produce oestradiol autonomously.

Raised FGF23 from dysplastic bone can cause hypophosphataemia.

• Café-au-lait macules with irregular borders ("coast of Maine") that do not cross the midline.
• Fibrous dysplasia: bone pain, deformity, pathological fracture, facial asymmetry, visual or hearing loss from skull base involvement.
• Girls: recurrent vaginal bleeding and breast development in infancy. Boys: testicular enlargement and precocious puberty (rarer).
• Hyperthyroidism, acromegaly or gigantism, Cushing syndrome in infants, and hypophosphataemic osteomalacia.

Red flags.

• Optic neuropathy, hearing loss or proptosis.
• Pathological fracture, rapidly growing bone lesion (malignant change is rare) or severe hypophosphataemia.

• Clinical diagnosis from two of the three components. GNAS testing of affected tissue by sensitive methods (blood is often negative).
• Skeletal survey and bone scan (technetium) to map lesions. CT of the skull base if cranial involvement.
• Precocious puberty: oestradiol, LH and FSH (suppressed LH), pelvic ultrasound with ovarian cysts. Boys: testosterone, testicular ultrasound.
• Thyroid function, IGF-1 and growth hormone suppression, cortisol tests, and phosphate, calcium, parathyroid hormone, alkaline phosphatase and FGF23.

Differential diagnosis.

• Central precocious puberty (LH raised, pituitary response to gonadotrophin releasing hormone).
• Neurofibromatosis type 1, and other causes of café-au-lait macules.
• Isolated monostotic fibrous dysplasia, hyperparathyroidism and Paget disease.
• Mazabraud syndrome (fibrous dysplasia with intramuscular myxomas) and Carney complex.

• Precocious puberty in girls: letrozole 2.5 mg daily (or anastrozole 1 mg daily), tamoxifen 20 mg daily, or fulvestrant 4 mg/kg intramuscularly monthly (maximum 250 mg). If central puberty develops later, add a gonadotrophin releasing hormone analogue. Boys: letrozole 2.5 mg daily with bicalutamide 12.5 to 50 mg daily.
• Hyperthyroidism: carbimazole 15 to 40 mg daily with propranolol 10 to 40 mg three to four times daily, then definitive treatment by total thyroidectomy because remission is rare.
• Growth hormone excess: surgery where possible, long acting octreotide 20 mg every 4 weeks or lanreotide 90 to 120 mg every 4 weeks, with pegvisomant 10 mg daily after a loading dose. Neonatal Cushing syndrome: metyrapone 250 mg three times daily and bilateral adrenalectomy for refractory disease.
• Hypophosphataemia: elemental phosphorus 1 to 3 g daily in 3 to 5 divided doses with calcitriol 0.5 to 1.5 micrograms daily (children 20 to 40 mg/kg and 20 to 30 nanograms/kg daily); correct vitamin D deficiency.
• Bone: calcium and vitamin D; intravenous bisphosphonate (pamidronate 0.5 to 1 mg/kg infusion every 3 to 6 months) for bone pain, with limited evidence for fracture prevention. Orthopaedic surgery for fracture or deformity (internal fixation, not curettage and grafting). Avoid growth hormone treatment. Optic canal decompression is not done prophylactically.
• Denosumab can cause rebound hypercalcaemia and is used cautiously.

Special groups. Pregnancy: fibrous dysplasia can worsen with raised oestrogen, so monitor the skeleton and thyroid. Children: paediatric endocrine, orthopaedic and ophthalmology review.

Monitoring. Growth, pubertal progress, thyroid function, IGF-1, phosphate and alkaline phosphatase every 6 to 12 months. Skull base imaging and visual assessment as indicated.

Referral and escalation. Endocrinology with orthopaedics, ophthalmology and ENT; paediatric endocrinology for children; urgent review for visual loss.