Pediatric McCune-Albright Syndrome Workup

  • Author: Bruce A Boston, MD; Chief Editor: Stephen Kemp, MD, PhD   more...
 
Updated: Apr 23, 2010
 

Laboratory Studies

The following laboratory studies may be indicated in patients with suspected McCune-Albright syndrome:

  • Serum estradiol, follicle-stimulating hormone (FSH), leuteinizing hormone (LH) levels: Precocious puberty in McCune-Albright syndrome is gonadotropin independent. Therefore, the finding of elevated estradiol levels and suppressed or undetectable gonadotropins is diagnostic of gonadotropin-independent puberty. However, estrogen secretion is frequently episodic in McCune-Albright syndrome; thus, multiple assays over time may be necessary to demonstrate an elevation in estradiol levels.
  • Factrel stimulation testing: Random gonadotropin levels in early puberty are often equal to prepubertal levels as LH and FSH secretion is pulsatile. Additionally, significant pulses may only occur at night in early puberty. A luteinizing hormone-releasing hormone (LH-RH) stimulation test (Factrel at 100 mg intravenously [IV]) can help to differentiate between central gonadotropin-dependent and gonadotropin-independent precocious puberty. 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 McCune-Albright syndrome.
  • Multichemistry panel, including liver function tests: Individuals with McCune-Albright syndrome may have elevated liver enzymes or hyperbilirubinemia. Even after normalization of cortisol or thyroxine levels, these elevations can persist, suggesting the presence of the alpha subunit of G protein (Gsa)–activating mutations in the liver. Furthermore, hypophosphatemia may result from increased urinary phosphate excretion. Therefore, individuals with McCune-Albright syndrome should have a complete multichemistry panel performed that includes calcium, phosphorus, and liver function tests.
  • Thyroid function testing: Elevated thyroxine levels and suppressed thyroid-stimulating hormone (TSH) levels are consistent with hyperthyroidism.
  • Thyroid-stimulating antibodies: Because hyperthyroidism associated with McCune-Albright syndrome 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.
  • Serum adrenocorticotropic hormone (ACTH) levels: The glucocorticoid secretion in infantile Cushing syndrome is ACTH independent. Therefore, ACTH levels are generally suppressed despite elevated cortisol levels.
  • Dexamethasone suppression test: Cortisol levels are normally suppressed by overnight administration of dexamethasone (0.050 mg/kg; not to exceed 1 mg). Elevated 8:00 am cortisol levels are suggestive of Cushing syndrome but do not distinguish between ACTH-dependent and ACTH-independent excess cortisol production.
  • Urine collection assayed for free cortisol: Twenty-four–hour urinary free cortisol is the most sensitive measure of cortisol production rate and is more accurate in determining Cushing syndrome than random cortisol levels. Normal values for 24-hour urine free cortisol vary with the size of the patient and should be adjusted for body surface area in order to compare with published adult normal ranges (ie, 10-84 mcg /1.7 m2/d). Elevated 24-hour urine free cortisol levels are suggestive of 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/d) and high-dose (8 mg/1.7 m2/d) dexamethasone suppression tests can help to distinguish ACTH-dependent Cushing syndrome from pituitary and ectopic sources and confirm the ACTH-independent nature of excessive cortisol secretion in McCune-Albright syndrome.
    • Because recommended treatment of ACTH-independent Cushing syndrome is bilateral adrenalectomy, this test should be performed before surgery.
    • 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 collecting baseline measurements, 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 but suppression with high dose is suggestive of ACTH-dependent Cushing syndrome. Lack of suppression with high dose dexamethasone is suggestive of either ectopic ACTH production or ACTH-independent Cushing syndrome.
    • Diagnosis of ACTH-independent Cushing syndrome consistent with McCune-Albright syndrome is confirmed in this situation if ACTH levels are also suppressed.
  • Serum growth hormone (GH) and insulinlike growth factor-1 (IGF-1) levels: Individuals with somatotroph adenomas due to Gsa activating mutations have detectable elevations of either GH and/or IGF-1 in the serum.
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Imaging Studies

The following imaging studies may be indicated:

  • Pelvic ultrasonography: Ultrasonographic examination of the pelvis is helpful in identifying ovarian cysts. Typically, ovarian size in McCune-Albright syndrome is not uniform. 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 to detect or rule out ovarian tumors or the presence of vaginal tumors or foreign bodies as a cause of isolated vaginal bleeding.
  • Bone scanning: Asymptomatic sites of fibrous dysplasia can be detected with bone scanning. Positive sites on bone can then be confirmed as fibrous dysplasia by means of radiography. Finding these sites when gonadotropin-independent precocious puberty is also present can confirm the diagnosis of McCune-Albright syndrome.
  • Skeletal survey: Polyostotic fibrous dysplasia 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 scan.
  • Abdominal CT scanning: Abdominal CT scanning 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 McCune-Albright syndrome. Unilateral enlargement is more consistent with an adrenal adenoma or adrenocorticocarcinoma.
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Histologic Findings

Specific histologic findings include the following:

  • Ovary: Examination of the ovary in McCune-Albright syndrome generally reveals large unilateral ovarian cysts. These cysts are follicular in nature.
  • Café au lait spots: Café au lait spots in McCune-Albright syndrome are large, melanotic macules. Except for hyperpigmentation of the basal layer, no abnormal pathology is seen. Number and size of the melanocytes are normal.
  • Fibrous dysplasia: Examination of these lesions reveals an abundance of fibroblastlike cells with minimal extracellular matrix. Osteoblasts in the areas of fibrous dysplasia tend to lay down bone matrix rich in antiadhesion proteins, such as versican and osteonectin, rather than proadhesion molecules, such as osteopontin and bone sialoprotein. The lamellar trabeculae have been extensively resorbed and entrapped within dysplastic bone, giving the appearance of woven bone. Islands of cartilage may exist within the woven bone. The excess of preosteogenic cells is thought to be predominantly preosteoblasts that mature into abnormal osteoblasts.
  • Thyroid nodules: Findings in the thyroid gland in individuals with hyperthyroidism secondary to McCune-Albright syndrome can range from a single adenoma to a goiter. The histological appearance has been reported to range from multinodular hyperplasia to colloid goiter. Single nodules have the appearance of follicular adenomas.
  • Adrenal hyperplasia: Cushing syndrome in McCune-Albright syndrome 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 Gsa mutation. The surrounding normal tissue does not contain the activating mutation, thus supporting the mosaic nature of this genetic disorder. Adrenal hyperplasia with nodular elements in an adAdrenal hyperplasia with nodular elements in an adrenal gland isolated from an infant with infantile Cushing syndrome. DNA isolated from nodular tissue was determined to have the activating Gs alpha mutation, whereas DNA isolated from surrounding tissue did not contain the mutation.
  • Somatotroph adenoma: 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 immunostaining. Although they are technically not malignant, somatotroph adenomas may be locally invasive into the surrounding bony architecture and vasculature.
  • Liver: The histology of the liver in individuals with elevated liver enzymes can range from 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.
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Contributor Information and Disclosures
Author

Bruce A Boston, MD  Chief, Division of Pediatric Endocrinology, Director, Pediatric Endocrine Training Program, Associate Professor, Department of Pediatrics, Division of Pediatric Endocrinology, Oregon Health Sciences University and Doernbecher Children's Hospital

Bruce A Boston, MD is a member of the following medical societies: Alpha Omega Alpha, American Diabetes Association, Endocrine Society, and Pediatric Endocrine Society

Disclosure: Nothing to disclose.

Coauthor(s)

Marcie K Drury Brown, MD  Fellow in Pediatric Endocrinology, Department of Pediatrics, Oregon Health and Science University

Marcie K Drury Brown, MD is a member of the following medical societies: American Academy of Pediatrics, American Medical Association, and Oregon Medical Association

Disclosure: Nothing to disclose.

Specialty Editor Board

Arlan L Rosenbloom, MD  Adjunct Distinguished Service Professor Emeritus of Pediatrics, University of Florida; Fellow of the American Academy of Pediatrics; Fellow of the American College of Epidemiology

Arlan L Rosenbloom, MD is a member of the following medical societies: American Academy of Pediatrics, American College of Epidemiology, American Pediatric Society, Endocrine Society, Florida Pediatric Society, Pediatric Endocrine Society, and Society for Pediatric Research

Disclosure: Nothing to disclose.

Mary L Windle, PharmD  Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Nothing to disclose.

George P Chrousos, MD, FAAP, MACP, MACE, FRCP(London)  Professor and Chair, First Department of Pediatrics, Athens University Medical School, Aghia Sophia Children's Hospital, Greece; UNESCO Chair on Adolescent Health Care, University of Athens, Athens, Greece

George P Chrousos, MD, FAAP, MACP, MACE, FRCP(London) is a member of the following medical societies: American Academy of Pediatrics, American College of Endocrinology, American College of Physicians, American Pediatric Society, American Society for Clinical Investigation, Association of American Physicians, Endocrine Society, Pediatric Endocrine Society, and Society for Pediatric Research

Disclosure: Nothing to disclose.

Merrily P M Poth, MD  Professor, Department of Pediatrics and Neuroscience, Uniformed Services University of the Health Sciences

Merrily P M Poth, MD is a member of the following medical societies: American Academy of Pediatrics, Endocrine Society, and Pediatric Endocrine Society

Disclosure: Nothing to disclose.

Chief Editor

Stephen Kemp, MD, PhD  Professor, Department of Pediatrics, Section of Pediatric Endocrinology, University of Arkansas College of Medicine and Arkansas Children's Hospital

Stephen Kemp, MD, PhD is a member of the following medical societies: American Academy of Pediatrics, American Association of Clinical Endocrinologists, American Pediatric Society, Endocrine Society, Phi Beta Kappa, Southern Medical Association, and Southern Society for Pediatric Research

Disclosure: Nothing to disclose.

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Café au lait pigmentation in a case of McCune-Albright syndrome. Lesion does not cross the midline, which is typical of the pigmented lesions in this syndrome.
Adrenal hyperplasia with nodular elements in an adrenal gland isolated from an infant with infantile Cushing syndrome. DNA isolated from nodular tissue was determined to have the activating Gs alpha mutation, whereas DNA isolated from surrounding tissue did not contain the mutation.
The G protein cycle begins with ligand binding to a 7 transmembrane G protein coupled receptor. The ligand receptor complex stimulates an exchange of guanosine triphosphate (GTP) for guanosine diphosphate (GDP) on the alpha subunit of the stimulatory G protein. This activates the alpha subunit, which subsequently stimulates adenylyl cyclase to increase the production of cyclic adenosine monophosphate (cAMP). The alpha subunit contains intrinsic GTPase activity, which cleaves a phosphate group from GTP, converting it to GDP, and thus inactivates the alpha subunit. The inactivated alpha subunit is now ready to be reactivated by the ligand receptor complex.
Mutations in McCune-Albright syndrome inactivate the intrinsic GTPase activity, thus preventing the inactivation of the Gs alpha subunit. Once activated, the mutated Gs alpha subunit is able to continuously stimulate adenylyl cyclase, even in the absence of ligand binding to the receptor. The result is an elevation of intracellular cyclic adenosine monophosphate (cAMP) and continual stimulation of downstream cAMP signaling cascades.
 
 
 
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