McCune-Albright syndrome
(Redirected from Polyostotic fibrous dysplasia)
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Dushka Riaz, MD
Overview
McCune-Albright syndrome is a rare genetic disorder caused by an activating mutation of the GNAS gene resulting in various phenotypic presentations. McCune-Albright syndrome typically presents with the triad of fibrous dysplasia, precocious puberty and café au lait spots in both genders. Other manifestations include acromegaly, Cushing’s syndrome and thyroid hyperplasia or toxic nodular goiters.
Historical Perspective
- McCune-Albright syndrome was first discovered by physicians Donovan McCune and Fuller Albright in 1937. [1]
Classification
There is no established system for the classification of McCune-Albright syndrome.
Pathophysiology
- The pathogenesis of McCune-Albright syndrome is characterized by increased cAMP signaling in bone, skin and endocrine tissues. In bone, osteoblasts differentiation results in fibrous dysplasia. In the skin, there is stimulation of melanin production resulting in café au lait macules with irregular borders. In endocrine tissues, increased cAMP results in increased production of hormones depending on which tissue is affected including the gonads, thyroid, parathyroid, pituitary and adrenal glands. [2]
- The GNAS gene mutation has been associated with the development of McCune-Albright syndrome, involving the cAMP pathway-associated G-protein, Gsα. [3]
Causes
McCune-Albright syndrome is caused by a missense mutation of the GNAS gene alpha subunit which becomes constitutively activated. This increases intracellular cAMP which activates downstream hormones resulting in multiple tissue types being affected and mosaicism presented in its patients. [2]
Differentiating McCune-Albright syndrome from other Diseases
McCune-Albright syndrome must be differentiated from Neurofibromatosis, isolated fibrous dysplasia and other causes of precocious puberty.
- Neurofibromatosis and McCune-Albright syndrome both have café au lait macules. However, neurofibromatosis macules have smooth borders with McCune-Albright being irregular. [4]
- Neurfibromatosis would also have the additional sign of neurofibromas,[2] optic gliomas, iris hamartomas, and axillary freckling.[5]
- The absence of endocrinopathies and café au lait macules would differentiate MAS from isolated fibrous dysplasia.[2]
Epidemiology and Demographics
Prevalence
- The prevalence of McCune-Albright syndrome is between 1:100,000 and 1:1,000,000 making it very rare. [6]
Age
- McCune-Albright syndrome is more commonly observed among infants and young children. [6]
Gender
- Girls are more commonly affected with McCune-Albright syndrome than boys. [6]
Race
- There is no racial predilection for McCune-Albright syndrome. [6]
Risk Factors
There are no risk factors for McCune-Albright syndrome.
Natural History, Complications and Prognosis
- Early clinical features include café-au-lait macules often at birth. [7]
- If left untreated, patients may progress to develop decreased adult stature as a result of precocious puberty.
- Common complications of McCune-Albright syndrome include rickets because of phosphate wasting and fractures at fibrous dysplastic sites. [2]
Diagnosis
Diagnostic Criteria
- The diagnosis of McCune-Albright syndrome is a clinical diagnosis. [2]
- Though there are genetic tests available for the GNAS gene mutation with new PCR techniques for those who show clinical signs of the syndrome. [8]
- Patients who present with monostotic fibrous dysplasia are required to have evidence of the pathogenic GNAS gene by molecular testing. [3]
Symptoms
- Symptoms of McCune-Albright syndrome include the following:
- Precocious puberty being the most common presentation. [9]
- Fibrous dysplasia leading to pathologic fractures or pain [2] because of fibrous tissue replacing the normal bone.
- This can be either monostotic (involving one bone) or polyostotic (involving multiple bones). [3]
- This presents in adolescent years affecting males more than females. [11]
- Café au lait spots with “coast of Maine” irregular borders. [12] are often the first presenting sign [3] and may increase over time. [13]
- Possible hyperthyroidism, Cushing syndrome, acromegaly or prolactin secretion due to increased thyroid, cortisol, growth hormone or prolactin secretion respectively depending on which tissues are affected. [2]
- Phosphate wasting with or without hypophosphatemia mediated by Fibroblast growth factor 23 (FGF23). [3]
- Possible hepatitis, cholestasis and cardiac arrhythmias. [4]
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Physical Examination
- Patients with McCune-Albright syndrome usually present with bone pain or limping.
- Physical examination may be remarkable for:[7]
- Facial asymmetry due to craniofacial fibrous dysplasia.
- Hearing impairment or visual disturbances due to craniofacial fibrous dysplasia.
- Café au lait macules.
- Goiter due to hyperthyroidism.
- Macrocephaly due to excess growth hormone.
- Vaginal bleeding in females due to ovarian cysts.
- Pubic and or axillary hair and penile enlargement in males.
- Growth acceleration in both genders.
- Cushingoid features due to hypercortisolism.
Laboratory Findings
- Girls will have raised estradiol levels indicating an activated hypothalamic-pituitary axis.
- Other laboratory findings consistent with the diagnosis of McCune-Albright syndrome are elevated growth hormone which can be deduced by an oral glucose tolerance test, serum GH and prolactin measurements.
- Evaluation of hyperthyroidism by measuring TSH, free and bound thyroxine and T3. [2]
Electrocardiogram
There are no ECG findings associated with McCune-Albright syndrome.
X-ray
The fibrous dysplasia of bone is present at multiple sites (polyostotic) and xrays would give a ground glass appearance. [8]
Echocardiography or Ultrasound
US in boys may be helpful in the diagnosis of McCune-Albright syndrome. Findings on an US suggestive of McCune-Albright syndrome include testicular ultrasounds to detect hormonally active tumors.[2]
CT scan
CT scan may be helpful in the diagnosis of McCune-Albright syndrome. Findings on CT scan suggestive of/diagnostic of McCune-Albright syndrome include fibroblastic lesions. It is helpful to identify these early in children to prevent permanent deformities. [2]
MRI
There are no MRI findings associated with McCune-Albright syndrome.
Other Imaging Findings
There are no other imaging findings associated with McCune-Albright syndrome.
Other Diagnostic Studies
- McCune Albright may be diagnosed using total body bone scintigraphy to identify the fibrous dysplastic lesions. This should then be followed up with radiographs and CT to clearly determine the extent of the lesions.
- It is helpful to perform baseline ophthalmic and audiologic testing for those patients whose fibrous dysplastic lesions involve the craniofacial area. [3]
Treatment
Medical Therapy
- The treatment for McCune Albright syndrome includes:
- Precocious puberty- treatment is aimed to prevent bone age advancement. [3]
- For girls- Letrozole (aromatase inhibitor) and or tamoxifen (estrogen receptor modulator). [8]
- For boys- treatment options are not well established.
- Fibrous dysplasia – treatment is aimed to minimize pain and fractures:
- Bisphosphonates such as zoledronic acid and pamidronate [3] have been used for fibrous dysplasia pain. [8]
- Endocrinopathies:
- Thyroid disease – Methimazole is effective though surgery is preferred.
- Increased growth hormone:
- Octreotride which acts as a somatostatin analog and should be monitored for signs and symptoms of gallbladder disease.
- Pegvisomant which is a growth hormone receptor antagonist and should be monitored for hepatotoxicity.
- Hypercortisolism - metyparone is effective.
- FGF23-mediated phosphate wasting with oral phosphorus and calcitriol. [3]
- Café-au-lait macules:
- There is no effective treatment [14]
- Precocious puberty- treatment is aimed to prevent bone age advancement. [3]
Surgery
- Surgery should be used in extreme caution for female patients with ovarian cysts because of the high risk of recurrence and resultant decrease in ovarian reserve.
- Patients with hyperthyroidism are preferred to have a thyroidectomy with total gland resection. [3]
Prevention
- Once diagnosed, patients with McCune-Albright syndrome are followed-up with:
- Females – early breast cancer screening.
- Males – testicular lesions by physical examination and US. [3]
- Both genders – signs of precocious puberty, growth hormone excess or growth acceleration (IGF-1 levels), monitoring thyroid function (TSH, free T4, and T3), routine radiographs for fibrous dysplasia lesions particularly to check for scoliosis, serum phosphorous to monitor for development of hypophosphatemia [3] and annual vision and hearing testing to monitor fibrotic lesions affecting these areas. [2]
- Parents should be counseled that McCune-Albright syndrome is not inherited. [3]
- There is an increased risk for malignancies. [15]
- Patients should also be advised to avoid contact sports and optic nerve decompressions. [3]
References
- ↑ Manring MM, Calhoun JH (2011). "Biographical sketch: Fuller Albright, MD 1900-1969". Clin Orthop Relat Res. 469 (8): 2092–5. doi:10.1007/s11999-011-1831-0. PMC 3126964. PMID 21384213.
- ↑ 2.00 2.01 2.02 2.03 2.04 2.05 2.06 2.07 2.08 2.09 2.10 2.11 "StatPearls". 2020. PMID 30725777.
- ↑ 3.00 3.01 3.02 3.03 3.04 3.05 3.06 3.07 3.08 3.09 3.10 3.11 3.12 3.13 Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJH, Stephens K; et al. (1993). "GeneReviews®". PMID 25719192.
- ↑ 4.0 4.1 Javaid MK, Boyce A, Appelman-Dijkstra N, Ong J, Defabianis P, Offiah A; et al. (2019). "Best practice management guidelines for fibrous dysplasia/McCune-Albright syndrome: a consensus statement from the FD/MAS international consortium". Orphanet J Rare Dis. 14 (1): 139. doi:10.1186/s13023-019-1102-9. PMC 6567644 Check
|pmc=value (help). PMID 31196103. - ↑ DeBella K, Szudek J, Friedman JM (2000). "Use of the national institutes of health criteria for diagnosis of neurofibromatosis 1 in children". Pediatrics. 105 (3 Pt 1): 608–14. doi:10.1542/peds.105.3.608. PMID 10699117.
- ↑ 6.0 6.1 6.2 6.3 Lumbroso S, Paris F, Sultan C, European Collaborative Study (2004). "Activating Gsalpha mutations: analysis of 113 patients with signs of McCune-Albright syndrome--a European Collaborative Study". J Clin Endocrinol Metab. 89 (5): 2107–13. doi:10.1210/jc.2003-031225. PMID 15126527.
- ↑ 7.0 7.1 Spencer T, Pan KS, Collins MT, Boyce AM (2019). "The Clinical Spectrum of McCune-Albright Syndrome and Its Management". Horm Res Paediatr. 92 (6): 347–356. doi:10.1159/000504802. PMC 7302983 Check
|pmc=value (help). PMID 31865341. - ↑ 8.0 8.1 8.2 8.3 8.4 Pratt VM, McLeod HL, Rubinstein WS, Scott SA, Dean LC, Kattman BL; et al. (2012). "Medical Genetics Summaries". PMID 28520344.
- ↑ de Sanctis C, Lala R, Matarazzo P, Balsamo A, Bergamaschi R, Cappa M; et al. (1999). "McCune-Albright syndrome: a longitudinal clinical study of 32 patients". J Pediatr Endocrinol Metab. 12 (6): 817–26. doi:10.1515/jpem.1999.12.6.817. PMID 10614538.
- ↑ Frisch LS, Copeland KC, Boepple PA (1992). "Recurrent ovarian cysts in childhood: diagnosis of McCune-Albright syndrome by bone scan". Pediatrics. 90 (1 Pt 1): 102–4. PMID 1614755.
- ↑ Biermann JS (2002). "Common benign lesions of bone in children and adolescents". J Pediatr Orthop. 22 (2): 268–73. PMID 11856945.
- ↑ Pichard DC, Boyce AM, Collins MT, Cowen EW (2014). "Oral pigmentation in McCune-Albright syndrome". JAMA Dermatol. 150 (7): 760–3. doi:10.1001/jamadermatol.2014.184. PMC 4933654. PMID 24671640.
- ↑ Nabhan ZM, West KW, Eugster EA (2007). "Oophorectomy in McCune-Albright syndrome: a case of mistaken identity". J Pediatr Surg. 42 (9): 1578–83. doi:10.1016/j.jpedsurg.2007.04.021. PMID 17848252.
- ↑ Ozawa T, Tateishi C, Shirakawa M, Murakami E, Ishii M, Harada T (2011). "Long-term follow-up of a case of cheek hyperpigmentation associated with McCune-Albright syndrome treated with Q-switched ruby laser". Dermatol Surg. 37 (2): 263–6. doi:10.1111/j.1524-4725.2010.01864.x. PMID 21272121.
- ↑ Chanson P, Salenave S, Orcel P (2007). "McCune-Albright syndrome in adulthood". Pediatr Endocrinol Rev. 4 Suppl 4: 453–62. PMID 17982395.