McCune Albright syndrome

2008-05-01   Margaret Zacharin  

The Royal Childrens Hospital, Parkville, Victoria 3052, Australia

Identity

Name

McCune Albright syndrome

Note

McCune Albright syndrome is characterized by the triad of polyostotic fibrous dysplasia, pigmentary skin lesions and endocrinopathy.

Inheritance

MAS is not inherited. It is a sporadic genetic disorder, caused by a mutation in the GNAS gene encoding the alpha subunit of the stimulatory G protein (GSalpha), cyclic AMP protein kinase dependent cellular signaling pathway involving G protein coupled receptors. An arginine or occasionally serine, leucine or glycine to histidine transposition at residue 201 attenuates GTpase activity. This results in constitutive activation of adenylyl cyclase.
 , The somatic mutation occurs in early embryogenesis, resulting in widespread tissue distribution of abnormalities. The post zygotic mutation is responsible for the mosaic pattern of tissue distribution and the extreme variability of clinical changes, varying from multi system disease to almost unrecognized disorders with single organ involvement.
 , Increased adenylate cyclase activity in bone from clinical fibrous dysplastic lesions is caused by expression of Cfos proto-oncogene in bone. Recent identification of increased fibroblast growth factor ( FGF23 ) activity in fibrous dysplastic lesions has linked the bony abnormalities to a recognized marker of bone metabolism.

Omim

174800

Mesh

D005359

Orphanet

562 McCune-Albright syndrome

Umls

C0242292

Clinics

Phenotype and clinics

The phenotype of MAS is extremely varied, ranging from multisystem disease, to minimal single organs being affected.

  • Fibrous dysplasia is the characteristic lesion seen in MAS, the bone lesion being of marrow stromal cells of osteogenic lineage, with increasing cyclic AMP up regulating osteogenic cells to osteoblasts within the fibrous dysplastic cells, compared to normal woven bone. Cartilaginous islands with woven bone and immature mesenchymal cells are found in the lesions, with resultant increased bone fragility in affected areas. Lesions may be polyostotic, panostotic or monostotic, with increased risk for long bone fractures, shepherds crook deformity of proximal long bones and spinal compression fractures. Osteomalacia complicates 50% of fibrous dysplasia bone lesions, due to increased FGF23 activity resulting in phosphaturia.

  • Café au lait marks with a coast of Maine appearance follow a dermatomal distribution along the lines of Blaschko. The activating GSalpha mutation in skin involves tyrosinase gene activation in affected melanocytes. Similar pigmentation is seen in oral mucosa.

    Endocrinopathies
    The endocrine events most commonly seen are gonadotrophin independent precocious puberty, thyrotoxicosis and Cushing syndrome.

  • Gonadotrophin independent precocious puberty in girls is seen in at least 30%, presenting with premature thelarche. Progress is often intermittent and characterized by suppressed gonadotrophins and elevated oestrogen levels, confirming the ovarian source of the disorder. Ovarian cysts are commonly seen. Continuous oestrogen production may result in long term continuing menstrual abnormalities and infertility.
  • Male precocious puberty is less common, seen in 15%. Macro-orchidism without precocity is more common and may be unilateral or bilateral, often with excess Sertoli cell hyperactivity. Testicular microlithiasis is present in 62% compared with a normal population microlithiasis rate of 5%.
  • Thyroid disease has been described in association with nodular and diffuse goitres, single toxic adenoma and hyperthyroidism with T3 toxicosis, with an overall prevalence of 30%. Thyroid cancer has only rarely been described. Clinical difficulty in detection of hyperthyroidism in the presence of a hyperdynamic circulation due to polyostotic fibrous dysplasia is significant, with biochemical evaluation prior to surgery suggested to reduce the risk of thyroid storm.
  • Acromegaly is reported in up to 21% of affected patients, the pattern of disease varying from the common isolated form and often being co-secretory without adenoma formation. GS alpha mutations in these lesions have been demonstrated on the maternal allele.
  • Cushing syndrome Macro nodular adrenocortical hyperplasia is the typical feature, with various outcomes reported, from spontaneous resolution to a severe neonatal presentation.
  • Upper gastrointestinal polyps are now identified in association with MAS, with the typical hamartomatous appearance similar to Peutz Jegher syndrome polyps. These may be in association with oral melanotic pigmentation or independent of pigmentary changes. Overlap in clinical features between disorders associated with multiple endocrine disease such as Carney complex and Peutz Jegher syndrome is evident.
  • Phosphaturia with associated hypophosphataemia may require oral phosphate and calcitriol. No outcome data has been reported. Surgical removal of FD lesions has been observed to decrease phosphate wasting.

    • Neoplastic risk

  • Café au lait skin lesions are benign
  • Fibrous dysplastic lesions can undergo malignant sarcomatous transformation, most commonly in cranio-facial bones. Other rare sarcomas include angiosarcoma, liposclerosing myxoma and chondrosarcoma. Of those patients who have developed sarcoma within FD lesions, 46% had received prior radiation treatment in the affected field (for acromegaly).NB Increased sensitivity of FD lesions to metaplasia after radiation has cause for concern for treatment planning strategies
  • Thyroid cancer has only rarely been reported.
  • Testicular Sertoli and Leydig cell tumours have both been described, but are rare.
  • Ovarian hyperfunction is associated with ovarian cysts but are benign. Long term excess oestrogen secretion might increase the risk for breast cancer, particularly in the presence of growth hormone excess.
  • Growth hormone excess with acromegaly is benign but care is required with treatment planning strategies in view of excess radiation risk in an area affected with fibrous dysplasia.

    • Treatment

  • Fibrous dysplasia can be treated with bisphosphonates. These drugs are well tolerated and reduce bone pain and bone turnover. Overall impact on the course of the disease is unclear, with minimal reduction in long term fracture risk and variable reports of possible reduction in lesional size in adults. Bisphosphonate use in children has not been shown to arrest uncontrolled expansion of dysplastic lesions in long bones or to change histomorphology in treated children or adolescents. Dental extractions and restorations do not exacerbate FD lesions. Surgical interventions using a combined approach, involving medullary rodding and bisphosphonate have been shown to improve surgical outcomes.Optic canal decompression in fibrous dysplasia of the sphenoid should be confined to surgical intervention for uncontrolled compression of visual or other nerve pathways.
  • Precocious puberty in girls. Treatment is complex with escape from effect of aromatase inhibitors. Selective oestrogen receptor modulators have been reported to be effective but with similar escape phenomena. Secondary activation of the hypothalamic pituitary ovarian axis in response to persistent oestrogen exposure may require addition of GRNH analogue. Surgery for removal of a cystic ovary or laparoscopic cystectomy has been occasionally effective. Oophorectomy is not recommended as fertility is potentially normal.
  • Precocious puberty in boys. Aromatase inhibitors or androgen blockade have been utilized with variable outcome. GNRH analogues may be required for secondary activation of the hypothalamic pituitary axis.
  • Acromegaly. Management is difficult due to lack of a discrete lesion, limited access due to sphenoid wing fibrous dysplasia and radiation risk to dysplastic areas. Somatostatin and dopamine agonists have been used with variable outcomes.

    • Prognosis

    Morbidity is most commonly related to complications of polyostotic fibrous dysplasia and the need for orthopaedic intervention. Multiple lower limb fractures and bilateral hip shepherds crook deformity frequently result in limited locomotion in adulthood, for severely affected individuals. Endocrinopathies are amenable to intervention, but management strategies are limited by effectiveness of medical interventions and radiation related risk. Excess mortality risk is related to malignancy risk and occasionally to high output cardiac failure or cardiomyopathy.

    Genes involved and Proteins

    Alias

    gsp oncogene

    Note

    Mutations of gsp are readily identified in lesional tissue from affected individuals with enhanced detection by multiple rounds of nested PCR and by including a peptide nucleic acid (PNA) in the PCR to block amplification of wild type GNAS targets.
    Peripheral Blood gsp detection is similarly enhanced, using PNA clamping.
    Protein expression: The GNAS locus is under complex imprinting control. GNAS encodes GS alpha expressed from maternal and paternal alleles in most tissues, with preferential expression of the maternal allele in kidney, thyroid and pituitary somatotrophs. Transcripts upstream from Exon 1 are expressed only from the paternal allele.
    Other transcripts 38kb upstream from exon 1 encode 2 proteins, XLalphas and ALEX and a transcript 52kb upstream of exon 1, encode distinct proteins that may affect signal transduction. The latter is expressed exclusively from the maternal allele, encoding a neurosecretory protein, NESP55.
    Gsalpha expression from the maternal allele will result in pathophysiological abnormality in tissues where that allele is expressed, but paternally expressed GNAS alleles may also result in endocrine dysfunction. Imprinting suppressing expression of paternal GNAS allele in some patients may result in a more severe phenotype.
    Mutations occurring later in embryogenesis are likely to give rise to fewer mutant cells and a milder phenotype.

    Article Bibliography

    Pubmed IDLast YearTitleAuthors
    129732832003Dental characteristics of fibrous dysplasia and McCune-Albright syndrome.Akintoye SO et al
    106461212000Mutations of the GNAS1 gene, stromal cell dysfunction, and osteomalacic changes in non-McCune-Albright fibrous dysplasia of bone.Bianco P et al
    80773781994Activating mutation in the stimulatory guanine nucleotide-binding protein in an infant with Cushing's syndrome and nodular adrenal hyperplasia.Boston BA et al
    52541981969Polyostotic fibrous dysplasia with oral melanotic pigmentation.Bowerman JE et al
    77397081995Increased expression of the c-fos proto-oncogene in bone from patients with fibrous dysplasia.Candeliere GA et al
    110904072000Testicular microlithiasis: prevalence and tumor risk in a population referred for scrotal sonography.Cast JE et al
    109257512000Fibrous dysplasia of bone.Chapurlat RD et al
    129703182003Thyroid carcinoma in the McCune-Albright syndrome: contributory role of activating Gs alpha mutations.Collins MT et al
    112976172001Macroorchidism due to autonomous hyperfunction of Sertoli cells and G(s)alpha gene mutation: an unusual expression of McCune-Albright syndrome in a prepubertal boy.Coutant R et al
    1713611975Cushing syndrome, sexual precocity, and polyostotic fibrous dysplasia (Albright syndrome) in infancy.Danon M et al
    9485431976Hypophosphataemic osteomalacia in fibrous dysplasia.Dent CE et al
    83706861993Long-term testolactone therapy for precocious puberty in girls with the McCune-Albright syndrome.Feuillan PP et al
    64272611984Absence of pubertal gonadotropin secretion in girls with McCune-Albright syndrome.Foster CM et al
    127279682003Cushing's syndrome secondary to adrenocorticotropin-independent macronodular adrenocortical hyperplasia due to activating mutations of GNAS1 gene.Fragoso MC et al
    134524091957Oral melanotic pigmentation in polyostotic fibrous dysplasia, Albright's syndrome.GORLIN RJ et al
    97075961998The human GNAS1 gene is imprinted and encodes distinct paternally and biallelically expressed G proteins.Hayward BE et al
    153274992004Ductal carcinoma in situ in a 27-year-old woman with McCune-Albright syndrome.Huston TL et al
    9329061976McCune-Albright syndrome associated with a functioning pituitary chromophobe adenoma.Joishy SK et al
    108444131999Activating mutation of GS alpha in McCune-Albright syndrome causes skin pigmentation by tyrosinase gene activation on affected melanocytes.Kim IS et al
    103561551999Cushing's syndrome caused by nodular adrenal hyperplasia in children with McCune-Albright syndrome.Kirk JM et al
    24926361989Treatment of familial male precocious puberty with spironolactone and testolactone.Laue L et al
    113978632001Dynamics of ovarian function in an adult woman with McCune--Albright syndrome.Laven JS et al
    15145601992The development of thyroid storm in a child with McCune-Albright syndrome after orthopedic surgery.Lawless ST et al
    124441812002Normal vision despite narrowing of the optic canal in fibrous dysplasia.Lee JS et al
    150058442004Fracture incidence in polyostotic fibrous dysplasia and the McCune-Albright syndrome.Leet AI et al
    84214791993Case records of the Massachusetts General Hospital. Weekly clinicopathological exercises. Case 7-1993. A six-year-old boy with multiple bone lesions, repeated fractures, and sexual precocity.
    167896242006McCune-Albright syndrome: persistence of autonomous ovarian hyperfunction during adolescence and early adult age.Matarazzo P et al
    146528232003Activating Gs alpha mutation at the Arg201 codon in liposclerosing myxofibrous tumor.Matsuba A et al
    166314712006Low prevalence of Gs alpha mutations in śomatotroph adenomas of children and adolescents.Metzler M et al
    79379801994Oncogenic potential of guanine nucleotide stimulatory factor alpha subunit in thyroid glands of transgenic mice.Michiels FM et al
    183979872008The aromatase inhibitor anastrozole is ineffective in the treatment of precocious puberty in girls with McCune-Albright syndrome.Mieszczak J et al
    116967072001The prevalence of testicular microlithiasis in an asymptomatic population of men 18 to 35 years old.Peterson AC et al
    145574242003Effect of pamidronate treatment in children with polyostotic fibrous dysplasia of bone.Plotkin H et al
    148913261951Sexual precocity in females; report of two cases, with arrest of precocity in the McCune-Albright syndrome after removal of a cystic ovary.PRAY LG et al
    118364492002An R201H activating mutation of the GNAS1 (Gsalpha) gene in a corticotroph pituitary adenoma.Riminucci M et al
    86999581996Clinical implications of genetic defects in G proteins. The molecular basis of McCune-Albright syndrome and Albright hereditary osteodystrophy.Ringel MD et al
    15946251992Identification of a mutation in the gene encoding the alpha subunit of the stimulatory G protein of adenylyl cyclase in McCune-Albright syndrome.Schwindinger WF et al
    80773561994An activating Gs alpha mutation is present in fibrous dysplasia of bone in the McCune-Albright syndrome.Shenker A et al
    167896252006Clinical presentation of McCune-Albright syndrome in males.Wasniewska M et al
    19444691991Activating mutations of the stimulatory G protein in the McCune-Albright syndrome.Weinstein LS et al
    39173011985Puberty without gonadotropins. A unique mechanism of sexual development.Wierman ME et al
    86908001996Increased IL-6-production by cells isolated from the fibrous bone dysplasia tissues in patients with McCune-Albright syndrome.Yamamoto T et al
    17553131991A case of neonatal McCune-Albright syndrome with Cushing syndrome and hyperthyroidism.Yoshimoto M et al