AUTHOR AND EDITOR INFORMATION

Section 1 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

INTRODUCTION

Section 2 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Background

In 1937, McCune-Albright syndrome (MAS) was described as the triad of café au lait macules (CALMs), polyostotic fibrous dysplasia (PFD), and endocrine dysfunction with precocious puberty. Mutations of Gs-alpha residues involved in the GTPase reaction that result in constitutive activation are present in persons with MAS.¹

The mutation leads to aberrant Gs protein alpha-subunit coupling 7-transmembrane-domain receptors to adenylate cyclase, resulting in constitutive adenylate cyclase activation and cAMP overproduction.² The long-term effect of these mutations is based on a population of mutated multipotent postnatal skeletal stem cells (mesenchymal stem cells). These stem cells underlie the formation of abnormal bone and a fibrotic marrow in fibrous dysplasia.³

MAS is related to Albright hereditary osteodystrophy (AHO), and heterozygous inactivating Gs-alpha mutations result in AHO.¹ Gs-alpha is imprinted in a tissue-specific fashion. It is primarily expressed from the maternal allele in the renal proximal tubules, the thyroid, the pituitary, and the ovaries.¹ Maternally inherited mutations result in AHO plus parathyroid hormone, thyrotropin, and gonadotropin resistance (pseudohypoparathyroidism type 1A). On the other hand, paternally inherited mutations result in AHO alone.¹

Other eMedicine articles include McCune-Albright Syndrome (endocrinology focus) and McCune-Albright Syndrome (pediatric focus). A Medscape CME course that may be of interest is Genetics of Adrenal Tumors Associated With Cushing's Syndrome: A New Classification for Bilateral Adrenocortical Hyperplasias.

Pathophysiology

Girls with MAS have gonadotropin-independent precocious puberty related to estrogen secretion from ovarian cysts. The most widely accepted hypothesis is that a spontaneous mutation in early embryogenesis leads to a mosaic pattern of autonomously functioning clones of cells in the affected child's organs (eg, ovarian cysts). The proposed mutation is in the GNAS1 gene coding for the signal-transducing guanine nucleotide-binding protein G-alpha subunit (protein Gs). This membrane-bound protein has a role in regulating the adenylate cyclase system.
 
In normal hormone-sensitive cells, such as endocrine cells, the Gs protein transmits messages from hormone receptors to intracellular targets. A stimulatory hormone (eg, thyrotropin) binds to a receptor on the cell surface coupled to the Gs protein, activating the Gs protein and stimulating cellular adenylate cyclase to produce elevated levels of cyclic adenosine monophosphate, which, in turn, stimulates hormone production and cell proliferation in targeted endocrine cells (eg, thyroxine production).

In several patients with MAS, investigators have found a substitution for arginine-201 with cystine or histidine in the alpha subunit of protein G, causing a gain of function with the protein in the activated state and constitutive activation of adenylyl cyclase in the absence of any stimulatory hormone. This mutation has been found in cells from ovarian cysts, CALMs, and PFD bony lesions in patients with MAS. Such a mutation in the germline is thought to be lethal; therefore, only the mosaic phenotype is observed.

Researchers have isolated activating mutations of GNAS1 in pituitary adenomas, thyroid adenomas, ovarian cysts, monostotic bone dysplasia, and the adrenal glands.⁴ GNAS1 gene abnormality in pseudohypoparathyroidism I-a has also been noted.⁵

Frequency

United States

The frequency is unknown.

International

From 1966-1995, 158 cases have been documented in the literature.

Mortality/Morbidity

Although 2 long-term follow-up studies have shown no increased risk of premature death, several authors have noted unexplained sudden death in patients with a severe phenotype. Patients may have multiple endocrine, cardiac, GI, central nervous system, hematopoietic, and hepatic manifestations, all of which can contribute to significant morbidity.

One study of 16 girls and 10 boys with MAS and found that (1) MAS occurs slightly more frequently in girls than in boys, (2) peripheral precocious puberty (PPP) in MAS occurs significantly more frequently and at a younger age in girls than in boys, (3) PPP in boys with MAS correlates with bilateral testicular enlargement, (4) monolateral macroorchidism can occur, and (5) testicular microlithiasis might function as another marker for MAS in males.⁶

Sex

A male-to-female ratio of 1:2 has been reported. The fact that girls develop precocious puberty far more frequently than boys (9:1 female-to-male ratio) probably explains why this autosomal mutation is recognized more frequently in girls than in boys.

Age

MAS manifests in childhood, with the mean onset of precocious puberty (the usual presenting sign) at 4.9 years (range 0.3-9 y).

CLINICAL

Section 3 of 11  

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• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

History

Patients with MAS can present with a variety of bone, skin, and endocrine pathology.

• Premature pubertal changes occur, including premature pubarche (the beginning of growth of pubic hair), thelarche (the beginning of breast development), and menarche. Average age is 4.9 years, with a female predominance.
• Pathologic fractures and bone pain occur at sites of PFD.
• CALMs are often noted at birth.
• A wide variety of endocrine symptoms are noted, including metabolic acidosis and abnormal electrolyte, insulin, and/or glucose levels.
• Patients do not have a family history of MAS.
• Developmental abnormalities and associated problems may include failure to thrive, developmental delay, microcephaly, and neonatal jaundice.
• Pregnant women with MAS have accelerated bone turnover with potential complications involving the bone.⁷
• A persistence of autonomous ovarian hyperfunction may occur in females with MAS during adolescence and early adult age.⁸
• Hepatobiliary dysfunction and cardiac disease are likely important risk factors for early death in patients with MAS.⁹
• Albright hereditary osteodystrophy, a syndrome distinct from MAS, is associated with pseudohypoparathyroidism.¹⁰
• A 52-year-old man has been described as having a limited form of MAS. He had PFD, acromegaly resulting from a pituitary tumor, and subclinical hyperthyroidism resulting from a toxic multinodular goiter. He did not have a history of sexual precocity, nor did he have CALMs on his skin.¹¹
• Leet et al¹² at the US National Institutes of Health report that in children with PFD, loss of a normal femoral neck-shaft angle and the lower extremity disease burden cause the maximum impact on functional activity based on the Pediatric Outcomes Data Collection Instrument tool.
• Fibrous dysplasia protuberans is a type of benign fibroosseous exophytic mass originating in the intramedullary cavity of an adjacent bone, and this was reported as an exudative pleural effusion in a 49-year-old man with MAS.¹³
• MAS reportedly is associated with acromegaly and bipolar affective disorder.¹⁴
• Restrictive lung disease and cor pulmonale secondary to polyostotic fibrous dysplasia has been reported in MAS patients.¹⁵
• Bhat et al¹⁶ noted hyperthyroidism associated with MAS.
• Sudden infant death syndrome and activating GNAS1 gene mutations are described in association with MAS.¹⁷

Physical

• Hyperpigmented patches, which roughly follow the lines of Blaschko, are located most commonly on the buttocks and lumbosacral back. The patches are large, are few in number, and have irregular borders resembling the coast of the US state of Maine (see Media File 1). This is in contrast to the CALMs of neurofibromatosis, which have a smooth border resembling the coast of the US state of California. The CALMs are usually on the same side of the body as the skeletal lesions and respect the midline. They may be bilateral.
• Signs of sexual precocity (98% of cases) include pubarche, menarche, and thelarche. Precocious puberty is found much more commonly in girls than in boys (9:1 female-to-male ratio).
• The following are other signs of endocrine dysfunction:
• • Thyroid storm (particularly during general anesthesia), tachyarrhythmia, and fever
  • Cushingoid habitus
  • Acromegaly
  • Hirsutism
  • Galactorrhea
• Skeletal deformities include recurrent fractures, limb bowing, and length discrepancies.
• Testis enlargement (macroorchidism) occurs in males with MAS. It is usually bilateral and occurs against a context of sexual precocity. However, the enlargement is not always bilateral. A 4.6-year-old boy with unilateral macroorchidism without sexual precocity or other MAS pathology has been described.¹⁸
• In 2007, Medow et al described polyostotic fibrous dysplasia of the cervical spine as a finding of MAS.¹⁹

Causes

MAS is caused by a sporadic, early postzygotic somatic mutation in the GNAS1 gene at locus 20q13.1-13.2, coding for G protein subunit, Gs-alpha.

DIFFERENTIALS

Section 4 of 11  

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• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Other Problems to be Considered

Café au lait macules

Neurofibromatosis type I or II
Tuberous sclerosis
Bloom syndrome
Ataxia-telangiectasia
Russell-Silver syndrome
Fanconi anemia

Precocious puberty

Ovarian/testicular tumors
Adrenal tumors
Congenital adrenal hyperplasia
Exogenous estrogens/androgens
Organic brain disease/tumors

WORKUP

Section 5 of 11  

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• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Lab Studies

• A highly sensitive polymerase chain reaction test can find activating mutations of the GNAS1 gene in peripheral blood cells of patients with MAS or isolated fibrous dysplasia.²⁰
• Full endocrine studies should be performed.
• • Testicular/ovarian hyperfunction is the most common abnormality. Testosterone or estradiol levels are elevated. Gonadotropin levels are usually reduced or normal.
  • Hyperthyroidism is common (33%), with elevated thyroxine, but low or normal thyrotropin levels.
  • Growth hormone (GH), prolactin, and, rarely, luteinizing hormone or follicle-stimulating hormone, levels may be elevated. The GH excess among patients with MAS has been noted to be as high as 21%. The basis of GH hypersecretion in MAS remains incompletely understood, but it appears to have a different basis from acromegaly/gigantism in non-MAS patients.²¹
  • Elevated cortisol levels are not suppressed by dexamethasone.
  • Hypophosphatemia with hyperphosphaturia is noted.
• Arterial blood gas determination can be performed to evaluate for acidosis, if suspected.
• A complete metabolic profile can be performed to screen for hyperbilirubinemia, elevated liver enzyme levels, and electrolyte abnormalities.
• Amylase and lipase levels can be measured to evaluate for pancreatitis, if suspected.
• To surmount the variations in mutations of GNAS1 analysis for MAS, sensitive and specific molecular methods are needed and must be performed on affected tissues and from easily accessible tissues. This was shown to be particularly true for atypical and monosymptomatic forms of MAS.²²

Imaging Studies

• Plain radiography
• • For PFD, lytic lesions are seen in the affected bones, with scalloped borders in the cortex and a central ground-glass pattern. The femur and pelvis are involved most commonly (see Media File 2).
  • Sclerosis of the basilar or temporal skull is seen, with possible involvement of the ossicles or impingement on the temporal nerve.
  • Evidence of past or current pathologic fractures is seen.
  • Findings of hypophosphatemic rickets may be present.
  • Osteosarcoma is rare (2%) and is found most often in patients who have received radiation treatment to affected bone lesions.
• CT scanning
• • The skull may show pituitary adenoma.
  • The pathologic bone findings of MAS can be solitary (monostotic) or multiple (polyostotic). The bones most frequently affected in MAS are the femur, tibia, ribs, and facial skeleton. A specific change involving the fibula is pseudocystic areas, and ground glass–like areas occur in the femur. The specific change involving the fibula is referred to as the shepherd's crook deformation; it is due to the weight put on a less resistant bone, and the occurrence of many secondary cortical microfractures is not uncommon.
• MRI and bone scintigraphy: MRI helps define bone pathology in persons with MAS. Bone scintigraphy with technetium Tc 99m is necessary to monitor disease progression.²³
• Ultrasound
• • The thyroid may show nodules.
  • The ovaries may show cysts.

Other Tests

• Electrocardiogram can be performed to evaluate for arrhythmia, if suspected.

Procedures

• Endoscopy can be performed to evaluate for GI polyposis, if suspected.

Histologic Findings

Skin biopsy of CALMs reveals hyperpigmentation of the epidermis, with a normal number of melanocytes. While some specimens show giant melanosomes, this is by no means diagnostic. Giant melanosomes can also be found in CALMs of patients with neurofibromatosis and in healthy patients.

The bone histology of MAS has been reassessed in view of the pathological effect of the genetic lesions on mutated skeletal stem cells. MAS is a disease of excess abnormal and imperfect bone formation, a fact which helps elucidate its mechanisms.²⁴

TREATMENT

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Medical Care

Medical treatment is only partially effective and transsphenoidal surgery remains difficult secondary to massive thickening of the skull base. Radiotherapy is contraindicated because of the possibility of sarcomatous transformation.²¹ Their puberty does not generally respond to gonadotropic-releasing hormone agonists, and short-acting aromatase inhibitors have had limited effectiveness. Bromocriptine, cabergoline, and octreotide or a combination of these has demonstrated inconsistent results; pegvisomant, a GH receptor antagonist, is a possibility, although it has not yet been used as a treatment for MAS with GH pathology.²¹

• Diagnosis and treatment require a high index of suspicion in any patient with characteristic CALMs and endocrine dysfunction or pathologic fractures.
• Address symptomatic hyperthyroidism with supportive care such as oral or intravenous iodine, antithyroid agents, propranolol, and dexamethasone.
• Address metabolic acidosis by correcting the underlying endocrine disorder and providing supportive care.
• One study found that long-term bisphosphonate treatment had beneficial effects on the bone health of patients with MAS; the fracture rate and bone pain were reduced and radiological evidence of long bone pathology resolution was observed.²⁵ However, another report described that bisphosphonate treatment of PFD in children with MAS did not arrest progressive bone pathology.²⁶
• Despite disappointing results in other trials, one study indicated gonadotropin-releasing hormone analogue therapy for children has had some success in girls with MAS.²⁷
• The third-generation aromatase inhibitor letrozole has had some success.²⁸

Surgical Care

Ovarian cysts occur frequently in females with PPP with MAS.²⁹ Surgery remains an option for the evaluation and treatment of cysts.

• Laparoscopy minimizes surgical aggression and allows for the acquisition of tissue biopsy specimens for molecular analysis. Additionally, hyperestrogenism can be arrested with the excision of hyperactive ovarian tissue. In girls younger than 3 years, laparoscopy can be performed using the transumbilical laparoscopic ovarian cystectomy approach. In older females, traditional techniques are used.
• The need for excision of hyperfunctional endocrine tissue is directed by the severity of the patient's endocrine imbalance and the efficacy of medical treatment.
• En bloc resection and free metatarsal transfer have been used to treat fibrous dysplasia of the fourth metacarpal associated with MAS.³⁰

Consultations

• Endocrinologist consultation is indicated because patients may have multiple endocrine defects, which may require careful orchestration of treatment.
• Orthopedist consultation is indicated for pathologic fractures.

MEDICATION

Section 7 of 11  

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A variety of medications may be required to correct various endocrine and metabolic derangements. Some of these include medroxyprogesterone acetate, testolactone, bromocriptine, propylthiouracil, ergocalciferol, and calcitonin. A qualified endocrinologist should conduct therapy.

Feuillan et al³¹ reported on a pilot study of letrozole treatment for precocious puberty in girls with the MAS. Bisphosphonate therapy may have a role in the treatment of fibrous dysplasia.³² Somatostatin analogs are useful in some, but not all, cases. The GH receptor antagonist pegvisomant can be useful in normalizing insulinlike growth factor-I levels.²

Drug Category: Hormones

Given to correct endocrine disorders associated with sexual precocity manifestations (98% of cases), such as pubarche, menarche, and thelarche.

Drug Name	Testolactone (Teslac)
Description	Synthetic peripheral aromatase inhibitor that blocks production of estradiol and estrone from testosterone and androstenedione.
Adult Dose	250 mg PO qid; adjust to effect
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity; males with breast cancer
Interactions	Need to monitor INR closely in patients taking warfarin and possibly adjust dose
Pregnancy	C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions	Monitor liver function; edema may develop in patients with congestive heart failure, liver, or renal insufficiency; may worsen hypertension; may exacerbate epilepsy and migraine

Drug Category: Ergot alkaloids

Some agents have dopaminergic properties that inhibit prolactin secretion.

Drug Category: Antithyroid agents

Used in the palliative treatment of hyperthyroidism.

Drug Category: Metabolic agents

Agents (eg, vitamin D) are indicated to correct deficiencies leading to hypoparathyroidism. Agents (eg, calcitonin) are indicated to treat hypercalcemia and prevent bone loss.

Drug Name	Calcitonin (Miacalcin, Osteocalcin)
Description	Lowers elevated serum calcium level in patients with primary hyperparathyroidism. Expect a higher response when serum calcium levels are high. Onset of action is approximately 2 h following injection and activity lasts for 6-8 h. May lower calcium levels for 5-8 d by approximately 9% if given q12h. IM route is preferred at multiple injection sites with dose >2 mL.
Adult Dose	4 IU/kg IM/SC q12h Increase dose to 8 IU/kg q12h if response not satisfactory after 1-2 d and 8 IU/kg q6h if response remains unsatisfactory >2 d
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity
Interactions	None reported
Pregnancy	C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions	Hypocalcemia may occur; examine urine sediment during prolonged therapy

FOLLOW-UP

Section 8 of 11  

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Further Outpatient Care

• Endocrinology follow-up care is lifelong.
• Ablation of hyperfunctional endocrine tissue should be arranged early.
• Patients with MAS have an increased incidence of breast cancer and osteosarcoma, and they require lifelong follow-up screening.

Prognosis

• With control of severe metabolic/endocrine abnormalities, patients achieve normal height and fertility.
• In general, patients achieve a normal life span. Sudden cardiac death has been reported in a few severely affected patients.

Patient Education

• MAS is not hereditary, and offspring of affected patients are not at an increased risk.

MISCELLANEOUS

Section 9 of 11  

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Medical/Legal Pitfalls

• Consider MAS in any patient with a metabolic/endocrine disorder and CALMs.
• Expand screening laboratory tests to cover multiple possible endocrine disorders.

MULTIMEDIA

Section 10 of 11  

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• Differentials
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• Follow-up
• Miscellaneous
• Multimedia
• References

Media file 1:  Large café au lait patches around the shoulder in a child with McCune-Albright syndrome.
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Media type:  Photo

Media file 2:  Lucency characteristic of polyostotic fibrous dysplasia in a patient with McCune-Albright syndrome.
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Media type:  X-RAY

REFERENCES

Section 11 of 11

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39. Riminucci M, Fisher LW, Shenker A, Spiegel AM, Bianco P, Gehron Robey P. Fibrous dysplasia of bone in the McCune-Albright syndrome: abnormalities in bone formation. Am J Pathol. Dec 1997;151(6):1587-600. [Medline].
40. Ringel MD, Schwindinger WF, Levine MA. Clinical implications of genetic defects in G proteins. The molecular basis of McCune-Albright syndrome and Albright hereditary osteodystrophy. Medicine (Baltimore). Jul 1996;75(4):171-84. [Medline].
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Article Last Updated: Mar 13, 2008