McCune-Albright Syndrome Workup

Updated: May 18, 2023
  • Author: Ranjodh Singh Gill, MD, FACP, CCD; Chief Editor: George T Griffing, MD  more...
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Approach Considerations

A comprehensive approach consisting of a detailed history, a physical examination, and a battery of tests is required in the diagnostic workup of MAS. Full endocrine studies should be performed. Testicular or ovarian hyperfunction is the most common abnormality. Testosterone and/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 (PRL), and, rarely, luteinizing hormone (LH) or follicle-stimulating hormone (FSH) levels may be elevated. Elevated cortisol levels are not suppressed by dexamethasone. Hypophosphatemia with hyperphosphaturia is noted.

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 is particularly true for atypical and monosymptomatic forms of MAS. [37]

Diagnostic imaging modalities that may be considered include plain radiography, ultrasonography, computed tomography (CT), magnetic resonance imaging (MRI), and radionuclide bone scanning.


Laboratory Studies

Gonadotropin and sex hormone levels

In patients with sexual precocity, baseline gonadotropin (ie, LH and FSH) and gonadotropin levels stimulated by gonadotropin-releasing hormone (GnRH) are below normal limits. In females who are affected, estrogen levels are elevated above the age-adjusted expected level. Similarly, males who are affected have elevated serum free and total testosterone levels. Androgen levels in female patients remain within normal limits.

Precocious puberty in MAS is gonadotropin-independent. Therefore, the finding of elevated estradiol levels and suppressed or undetectable gonadotropin levels is diagnostic of gonadotropin-independent puberty. However, estrogen secretion is frequently episodic in MAS; thus, multiple assays over time may be necessary to demonstrate an elevation in estradiol levels.

Because secretion of LH and FSH is pulsatile, random gonadotropin levels in early puberty are often equal to prepubertal levels. Additionally, significant pulses may only occur at night in early puberty. An LH-releasing hormone (LH-RH) stimulation test (gonadorelin hydrochloride 100 mg intravenously [IV]) can help to differentiate between central gonadotropin-dependent and gonadotropin-independent precocious puberty.

In this test, serum is sampled for LH and FSH at 0 minutes, 15 minutes, 30 minutes, 45 minutes, and 60 minutes after administration of LH-RH. Suppressed or undetectable levels of LH and FSH after administration of LH-RH are consistent with MAS.

Blood and urinary chemistries

Individuals with MAS may have elevated liver enzymes or hyperbilirubinemia. Even after normalization of cortisol or thyroxine levels, these elevations can persist, suggesting the presence of G protein alpha subunit (Gs alpha)–activating (GNAS1) mutations in the liver. Furthermore, hypophosphatemia may result from increased urinary phosphate excretion. Therefore, a complete multichemistry panel should be performed that includes calcium, phosphorus, and liver function tests.

Blood and urinary chemistries show evidence of excessive bone turnover and elevated indicators for bone formation and resorption (eg, urinary N-telopeptide, pyridinolines, deoxypyridinolines). Serum alkaline phosphatase levels (total and bone-specific fractions), osteocalcin, and serum cyclic adenosine monophosphate (cAMP) [38] levels are elevated.

Urinary excretion of hydroxyproline, N-telopeptides, pyridinium X-links, and cAMP is elevated. Depending on the extent of coexisting osteomalacia, serum calcium may be normal or slightly reduced. Typically, the rickets or osteomalacia associated with MAS is hypophosphatemic and hyperphosphaturic.

Thyroid testing

Elevated thyroxine levels and suppressed thyroid-stimulating hormone (TSH) levels are consistent with hyperthyroidism. Because hyperthyroidism associated with MAS is not immune-mediated, levels of antithyroid antibodies, particularly thyroid-stimulating immunoglobulins (TSIs), are generally undetectable. Detection of these antibodies would be consistent with a diagnosis of Graves disease.

Adrenocorticotropic hormone levels

The glucocorticoid secretion in infantile Cushing syndrome is independent of adrenocorticotropic hormone (ACTH). Therefore, serum ACTH levels are generally suppressed despite elevated cortisol levels.

Dexamethasone suppression testing

Normally, cortisol levels are suppressed by overnight administration of dexamethasone (0.050 mg/kg; not to exceed 1 mg). Elevated cortisol levels at 8:00 AM suggest Cushing syndrome but do not distinguish between ACTH-dependent and ACTH-independent excess cortisol production.

Low-dose/high-dose dexamethasone suppression test

Low-dose (2 mg/1.7 m2/day)/high-dose (8 mg/1.7 m2/day) dexamethasone suppression testing can help distinguish ACTH-dependent Cushing syndrome from pituitary and ectopic sources and confirm the ACTH-independent nature of excessive cortisol secretion in MAS. Because the recommended treatment of ACTH-independent Cushing syndrome is bilateral adrenalectomy, such testing should be performed preoperatively.

Low-dose/high-dose dexamethasone suppression tests in infants are performed in a hospital setting. A Foley catheter is placed, and urine is collected in 24-hour increments for free cortisol determinations. ACTH and cortisol levels are obtained at 8:00 AM each day. After baseline measurements are collected, low-dose dexamethasone is administered for 2 days, followed by high dose dexamethasone for 2 days.

Lack of suppression of cortisol production with low-dose dexamethasone but suppression with high-dose dexamethasone suggests ACTH-dependent Cushing syndrome. Lack of suppression with high-dose dexamethasone suggests either ectopic ACTH production or ACTH-independent Cushing syndrome. Diagnosis of ACTH-independent Cushing syndrome consistent with MAS is confirmed in this situation if ACTH levels are also suppressed.

Urine collection assayed for free cortisol

A 24-hour urinary free cortisol (UFC) is the most sensitive measure of the cortisol production rate and is more accurate in determining Cushing syndrome than random cortisol levels are. Normal values for 24-hour urinary free cortisol vary with the size of the patient and should be adjusted for body surface area to allow comparison with published adult normal ranges (ie, 10-84 µg/1.7 m2/day). Elevated 24-hour urine free cortisol levels suggest Cushing syndrome but do not distinguish between ACTH-dependent and ACTH-independent excess cortisol production.

Serum growth hormone and insulinlike growth factor 1 levels

Individuals with somatotroph adenomas due to GNAS1 mutations have detectable elevations of GH, insulinlike growth factor 1 (IGF-1), or both in serum.

Polymerase chain reaction assay

A highly sensitive polymerase chain reaction (PCR) assay is capable of detecting activating mutations of the GNAS1 gene in peripheral blood cells of patients with MAS or isolated fibrous dysplasia (FD). [39] Using next-generation sequencing (NGS), millions of PCR amplicons can be analyzed in an independent fashion, and this can be expected to quantitatively detect low-abundance GNAS. NGS is able to detect somatic activating GNAS mutations sensitively and quantitatively and from peripheral blood. Now the peptide nucleic acid/NGS method appears most likely the most sensitive method to detect low-abundance mutated GNAS. [40]


Plain Radiography

In MAS, plain bone radiographs typically show multiple patchy areas of bony lysis (see the first image below) and sclerosis. The findings are consistent with bone dystrophy (ie, areas of hypertrophy and geodes bounded by fine sclerotic rims). Mixed radiopaque and radiolucent areas with thin or hypertrophic cortices are present (see the second image below).

Fibrous dysplasia of a long bone characterized by Fibrous dysplasia of a long bone characterized by focal bony expansion, patchy areas of sclerosis, and bony cyst formation in McCune-Albright syndrome.
Lucency characteristic of polyostotic fibrous dysp Lucency characteristic of polyostotic fibrous dysplasia in patient with McCune-Albright syndrome.

In general, monostotic FD (MFD) is more common than polyostotic FD (PFD); however, MFD is not associated with other findings that are typical of MAS. PFD can be detected by means of a skeletal survey. Total radiation exposure can be decreased if the skeletal survey is preceded by a bone scan. The laboratory can reduce the number of radiographs needed by focusing only on positive sites indicated by bone scanning.

Virtually any bone in the body may be affected. Commonly affected bones include the femur, tibia, ribs, and facial bones. Involvement of the small bones of the hands and feet accounts for 50% of cases. Long-bone lesions are more frequent in the metaphyseal and diaphyseal regions. The individual lesions may be trabeculated, with thin cortices and ground-glass appearance. Formal bone-age estimations may be higher in patients with sexual precocity.

Sclerosis of the basilar or temporal skull is seen (see the image below), 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.

Plain skull radiograph in a typical McCune-Albrigh Plain skull radiograph in a typical McCune-Albright syndrome case shows marked macrocrania, frontal bossing, and markedly thickened bony table in patchy areas, particularly at base of skull and occiput. Skull also shows hair-on-end appearance, which needs to be differentiated from similar radiologic appearances in Paget disease or poorly controlled hemoglobinopathy (eg, beta-thalassemia, sickle cell disease).


Ultrasonography may be a useful diagnostic adjunct for evaluating patients with historical or physical evidence of soft-tissue swelling. Myxomas in the context of MS can be seen as sharply defined hypoechoic masses with a few central, fluid-filled cavities. However, an abdominal ultrasonogram that reveals multiple hypoechoic cystic lesions within the uterus and upper vaginal vault is characteristic of embryonal rhabdomyosarcoma.

Ultrasonographic examination of the pelvis is helpful in identifying ovarian cysts. Typically, ovarian size is not uniform in MAS: Cysts tend to be larger in one ovary. Often, cysts are unilateral, whereas cysts in central precocious puberty are small and bilateral. Furthermore, ultrasonography can help detect or rule out ovarian tumors or the presence of vaginal tumors or foreign bodies as a cause of isolated vaginal bleeding.

An uncomplicated ovarian cyst in a 3-year-old girl with MAS and precocious puberty mimicking an ectopic pregnancy is referred to as the daughter-cyst sign with ultrasound. [41]


CT and MRI

CT of the skull (see the image below) may show pituitary adenoma. Pathologic bone findings may be solitary (MFD) or multiple (PFD). The bones most frequently affected in MAS are the femur, tibia, ribs, and facial skeleton. A specific change involving the fibula is the presence of pseudocystic areas. This change 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. Ground glass–like areas occur in the femur.

Base of the skull computed tomography scan showing Base of the skull computed tomography scan showing extensive fibrous dysplasia in McCune-Albright syndrome. Note the asymmetrical affectation, with near-total obliteration of various neural foramina at the base of the skull. This degree of fibrous dysplasia can result in multiple cranial nerve compression neuropathies, of which blindness and deafness (from involvement of cranial nerves II and VIII) are among the most disabling.

Abdominal CT can help evaluate infantile Cushing syndrome. Bilateral enlargement of the adrenal glands is consistent with the adrenal hyperplasia seen in infantile Cushing syndrome secondary to MAS. Unilateral enlargement is more consistent with an adrenal adenoma or adrenocortical carcinoma.

In the setting of myxomas, MRI identifies hypointense or isointense areas on T1-weighted imaging with gadolinium enhancement or on T2-weighted imaging. Like bone scanning, MRI may be useful for defining the extent of bony disease. [42]


Other Studies

Asymptomatic sites of FD can be detected with radionuclide (technetium-99m [99m Tc]–labeled methylene diphosphonate) bone scans. On bone scanning, PFD appears as areas of increased activity. This is helpful in defining the extent of disease activity after the diagnosis is made. [43, 44] Finding these sites when gonadotropin-independent precocious puberty is also present can confirm the diagnosis of MAS. The poor specificity of increased patchy bone activity on bone scans precludes their use for screening or exact diagnosis.

Arterial blood gas determination can be performed to evaluate for acidosis, if suspected. Electrocardiography (ECG) can be performed to evaluate for arrhythmia, if suspected. Endoscopy can be performed to evaluate for gastrointestinal (GI) polyposis, if suspected.



Bone biopsy may be necessary to rule out malignancy in a patient with a rapidly expanding lesion. It can be used clinically to aid in the diagnosis of osteomalacia and has been used for research purposes in an academic setting. Similarly, a rapidly expanding myxoma may call for muscle or soft-tissue biopsy. Enlarging thyroid nodules or hypofunctioning solitary thyroid nodules warrant a fine-needle aspiration (FNA) biopsy to establish a definitive diagnosis and—important—to exclude thyroid cancer.


Histologic Findings

The café-au-lait spots seen in MAS are large, melanotic macules (café-au-lait macules [CALMs]). Except for hyperpigmentation of the basal layer, no abnormal pathology is apparent. The melanocytes are normal in both number and size. Some specimens show giant melanosomes, but this finding is by no means diagnostic. Giant melanosomes can also be found in CALMs of patients with neurofibromatosis (NF) and in healthy patients.

That MAS is a disease of excess abnormal and imperfect bone formation helps elucidate its mechanisms. [45] The bone affected by PFD has areas of fibrous metaplasia within flat and tubular bones. The basic anomaly in FD lesions is a progressively expanding fibrous lesion of bone-forming mesenchyme. The lesions typically expand concentrically from the medullary cavity outwards (ie, toward the cortex). The bony lesions are well defined, though invariably, they are not encapsulated.

The bony lesions are rich in spindle-shaped fibroblasts, with a swirled appearance within the marrow space and erratically arranged “tongues” of woven bone. Islands of cartilaginous tissue also may be interspersed within the lesions. Some parts of the affected bones may have cystic lesions lined by multinucleated giant cells, akin to osteitis fibrosa cystica (of severe hyperparathyroidism) but with a paucity of osteoblasts.

Thyroid findings in individuals with hyperthyroidism secondary to MAS can range from a single adenoma to a goiter. The histologic appearance has been reported to range from multinodular hyperplasia to colloid goiter. Single nodules have the appearance of follicular adenomas.

Cushing syndrome in MAS is associated with bilateral nonpigmented adrenocortical hyperplasia with nodular elements (see the image below). Multiple micronodules can be found in the adrenal cortex surrounded by normal tissue. Only the nodules contain DNA coding for the activating Gs alpha mutation; the surrounding normal tissue does not contain the activating mutation, a finding that supports the mosaic nature of this genetic disorder.

Somatotroph adenomas take on the character of typical pituitary adenomas. Somatotroph tumors lack true capsules, with the margins of the adenoma containing normal cells interspersed with adenomatous cells. These adenomatous cells can be confirmed as somatotrophs by means of immunostaining. Although technically not malignant, somatotroph adenomas may be locally invasive into the surrounding bony architecture and vasculature.

Liver histology in individuals with elevated hepatic enzymes can range from the presence of normal hepatocytes with some fatty infiltration to focal nodular hyperplasia with bridging fibrosis and chronic cholestasis. Detailed study of liver biopsy specimens has detected mild biliary abnormalities in many of the specimens, with extramedullary hematopoiesis in a few.

Examination of the ovary in MAS generally reveals large unilateral ovarian cysts, which are follicular in nature.