McCune Albright Syndrome

McCune Albright Syndrome

National Organization for Rare Disorders, Inc.

Important

It is possible that the main title of the report McCune Albright Syndrome is not the name you expected. Please check the synonyms listing to find the alternate name(s) and disorder subdivision(s) covered by this report.

Synonyms

  • MAS
  • Albright Syndrome
  • Osteitis Fibrosa Disseminata
  • Polyostotic, Fibrous Dysplasia
  • PFD
  • Precocious Puberty with Polyostotic Fibrosis and Abnormal Pigmentation
  • POFD

Disorder Subdivisions

  • None

General Discussion

McCune-Albright Syndrome (MAS) is a rare multisystem disorder characterized by (1) replacement of normal bone tissue with areas of abnormal fibrous growth (fibrous dysplasia); (2) patches of abnormal skin pigmentation (i.e., areas of light-brown skin [cafe-au-lait spots] with jagged borders); abnormalities in the glands that regulate the body's rate of growth, its sexual development, and certain other metabolic functions (multiple endocrine dysfunction). Depending on the number and location of the skeletal abnormalities, mobility may be impaired, as well as vision and/or hearing and the individual may experience substantial pain. Malfunctioning endocrine glands can result in the development of secondary sexual characteristics at an age younger than normal (precocious puberty).



McCune-Albright Syndrome is the result of a genetic change (mutation) that occurs randomly, for no apparent reason (sporadic). In individuals with the disorder, this sporadic genetic mutation is present in only some of the body's cells (mosaic pattern). The symptoms and physical characteristics associated with the disorder vary greatly from case to case, depending upon the specific body cells and tissues that are affected by the genetic mutation. This mutation occurs after fertilization (postzygotic somatic mutation). It is not inherited from the parents.



The range of severity of the disorder is very broad: some children are diagnosed in early infancy with obvious anomalies of bone and increased hormone production by one or more of the endocrine glands; others show no evidence of bone, skin or endocrine malfunction in childhood and may enter puberty at an appropriate age.

Symptoms

McCune-Albright Syndrome (MAS), a rare multisystem disorder, is primarily characterized by displacement of normal bone tissue with areas of fibrous growth (fibrous dysplasia) in more than one bone (polyostotic) of the body; large areas of dark pigmentation with irregular borders (i.e., "Coast of Maine" cafe-au-lait spots); and/or multiple abnormalities of endocrine function, including the early development of secondary sexual characteristics (precocious puberty). The range and severity of symptoms and physical characteristics associated with McCune-Albright Syndrome vary greatly among affected individuals according to the specific body cells and tissues that are affected by the sporadic genetic mutation.



BONE

In individuals with McCune-Albright Syndrome, the bones of the arms, legs, ribs, skull, and/or face are most frequently affected, although any bone may be involved. Bones with fibrous lesions are weaker than normal and may bend or bow under what might ordinarily be a normal load to bear. The bones on opposite sides of the body (e.g., bones within the arms or legs, cheekbones, etc.) may develop unevenly (asymmetrically) with clear consequences. Affected individuals may experience bone pain and frequent bone fractures in affected areas. In addition, fibrous dysplasia that affects bones of the facial area and skull may result in changes in facial appearance and, because the bones may impinge on the nerves, may cause vision and/or hearing loss.



If children with McCune-Albright Syndrome experience premature onset of secondary sexual characteristics (precocious puberty), they may grow more rapidly than normal, leading to tall stature during childhood. However, such growth may stop prematurely, and affected individuals may not achieve normal adult height (short stature).



In addition, in some affected children, the tiny tubes in the kidney (renal tubules) that normally reabsorb salt, water, and several essential substances (e.g., glucose, amino acids, calcium, phosphorus) may fail to properly reabsorb phosphorus, a chemical element essential for calcium metabolism. As a result, inadequate amounts of phosphorus are incorporated into the bones as they grow, leading to unusually thin and bowed bones (Hypophosphatemic Rickets). (For more information on this disorder, choose "Rickets" as your search term in the Rare Disease Database.)



SKIN

Most people with McCune-Albright Syndrome have patchy areas of irregular dark pigmentation (cafe-au-lait spots) on the skin. These large, light brown areas, which may appear anywhere on the skin, tend to have irregular, jagged borders, giving them a "Coast of Maine" contour in contrast to the more regular "Coast of California" borders typically associated with the cafe-au-lait spots in Neurofibromatosis Type 1. (For more information on Neurofibromatosis Type 1, see the Related Disorders section below.)



The pattern of skin pigmentation is unique to each affected person. In some, it may not be noticeable or may be confined to a very small area in the back of the neck or the crease of the buttocks. The patch often starts or stops at the midline of the stomach in front or at the spine in back.



ENDOCRINE ABNORMALITIES

Many individuals with McCune-Albright Syndrome may also demonstrate abnormalities of certain hormone-producing glands that help to regulate the rate of growth, sexual development, and certain metabolic functions (multiple endocrine dysfunction).



Reproduction/Gonads

Many children, often, but not always, female, with McCune-Albright Syndrome may begin puberty earlier than would be expected (precocious puberty). This occurs more often among females than among males. In the extreme, puberty may begin as early as three months of age. The associated characteristics include the early onset of menstrual periods and premature breast development (breast budding). However, it may be years before the breasts fully develop and before underarm (axilliary) hair growth occurs. In some cases, females with McCune-Albright Syndrome may develop benign cysts in one or both ovaries. However, the medical literature does not describe malignant ovarian tumors as part of the McCune-Albright Syndrome.



Although precocious puberty is more common in females with McCune-Albright Syndrome, it may also affect some males. Males with MAS may present with accelerated growth, body odor, acne, and/or early genital development (e.g., early, sudden increase in the growth and development of the penis, testes, and scrotum).



Precocious puberty in male or female children with MAS is the result of estrogen (a steroid) secreted by the benign cysts that are often associated with the syndrome. The path of development of precocious puberty usually involves other endocrine glands (hypothalamus and pituitary) but these two powerful, regulatory glands are not involved in this aspect of MAS.



Pituitary

The pituitary, a small gland at the base of brain, produces several hormones and releases them directly into the bloodstream. One such hormone is growth hormone (GH), which stimulates normal growth and development. Some individuals with McCune-Albright Syndrome, usually young adults, may tend to develop pituitary tumors that secrete excessive amounts of growth hormone, potentially leading to the rare condition, acromegaly or gigantism. Acromegaly is characterized by progressive enlargement of the soft tissues and bones of the face, hands, and feet. If the condition develops before young adulthood, when fusion of bones is completed, affected individuals will continue to grow, resulting in gigantism. (For more information on acromegaly or gigantism, please see the Related Disorders section below.)



Adrenals

The adrenals, a pair of small endocrine glands located above the kidneys, secrete several hormones (e.g., cortisol, androgens) directly into the bloodstream. In some individuals with McCune-Albright Syndrome, there may be excessive secretion of cortisol hormone from the adrenal glands that may lead to symptoms of Cushing Syndrome. (For more information on this condition, please see the Related Disorders section of this report.)



Thyroid

The thyroid gland, which lies in front of the neck, also secretes certain hormones (e.g., thyroxine and triiodothyronine) that, when associated with MAS, may be present in greater than normal concentrations. Almost 50 percent of patients with MAS have thyroid gland abnormalities that may lead to goiter or hyperthyroidism. (For more information on hyperthyroidism, please see the Related Disorders section of this report.)

Causes

Clinical studies suggest that McCune-Albright Syndrome (MAS) occurs randomly, for no apparent reason (sporadic) due to changes (mutations) affecting a particular gene (see below). Because this genetic mutation occurs after fertilization (postzygotic somatic cell mutation), the disorder is not inherited from the parents and the mutation is present in only some of the body's cells (mosaic pattern). There is no definitive evidence in the medical literature that McCune-Albright Syndrome runs in families.



The gene thought to be responsible for McCune-Albright Syndrome has been located on the long arm of chromosome 20 (20q13.2). This GNAS1 (Guanine Nucleotide-Binding Protein, Alpha-Stimulating Polypeptide) gene is responsible for a critical step in transmitting the signal from some hormones to certain cells' nuclei. Chromosomes are found in the nucleus of all body cells. They carry the genetic characteristics of each individual. Pairs of human chromosomes are numbered from 1 through 22, with an unequal 23rd pair of X and Y chromosomes for males, and two X chromosomes for females. Each chromosome has a short arm designated as "p" and a long arm identified by the letter "q". Chromosomes are further sub-divided into bands that are numbered.



Because the genetic mutation is not present in all of the body's cells (postzygotic somatic cell mutation mosaicism), the symptoms of McCune-Albright Syndrome are variable. In almost all cases, the mutation developed some time after a normal sperm from the father fertilized a normal egg from the mother (zygote). If the genetic mutation occurred early in the embryo's development, a greater number and variety of tissues would be affected.



In many individuals with McCune-Albright Syndrome, premature gonadal functioning occurs due to the presence of the GNAS1 mutation in the gonads (i.e., ovaries in females, testes in males), rather than stimulation by pituitary hormones (gonadotropins). In addition, excessive production of cortisol from the adrenal glands and/or overproduction of thyroid hormones by the thyroid gland result from the presence of the GNAS1 mutation in these glands, rather than pituitary gland activity. The medical literature has also reported that, in individuals who exhibit only Acromegaly (isolated Acromegaly), approximately 40 percent of growth hormone-secreting pituitary tumors have the same genetic mutation that has been identified in cases of McCune-Albright Syndrome. This suggests that the GH-secreting pituitary tumors in individuals with McCune-Albright Syndrome may result from the same mutation that is responsible for the syndrome as a whole.



More recently, researchers have discovered abnormal mutations in the DNA obtained from the affected ovaries, adrenals, and livers of patients with MAS. This DNA contained the genetic code for the so-called G protein, which is one component of a signaling system, present in many cells and known to be involved in endocrine cell growth and secretion. It is suspected that the presence of this mutation might result in uncontrolled cell function or hormone secretion. Some clinician-researchers believe that further research into the function and structure of G protein may yield improved strategies for the development of improved therapies.

Affected Populations

McCune-Albright Syndrome is a rare disorder that affects females more often than males by a ratio of about 3:2. Hundreds of cases of McCune-Albright Syndrome have been reported in the medical literature since the disorder was first described in the mid-1940s.



McCune-Albright Syndrome may be apparent at birth based upon the presence and recognition of the characteristic skin pigmentations (cafe-au-lait spots). However, in many cases, the disorder may not become apparent until late infancy or childhood when precocious puberty develops or when bone deformities become obvious.

Standard Therapies

Diagnosis

The diagnosis of McCune-Albright Syndrome (MAS) may be suspected at birth based upon identification of the characteristic skin pigmentations (cafe-au-lait spots). However, in many cases, the disorder may not be suspected until late infancy or childhood when precocious puberty develops or when bone deformities become obvious. A diagnosis of McCune-Albright Syndrome may be confirmed based upon characteristic physical findings (i.e., association of characteristic skin, bone, and endocrine abnormalities), a detailed patient history, thorough clinical evaluation, and specialized tests including x-ray studies and blood tests. A complete body survey should be performed for the characteristic cafe-au-lait spots, and x-ray studies should be combined with bone scans to evaluate the presence and extent of fibrous dysplasia. Blood tests may reveal elevated hormone levels (e.g., estrogen, testosterone, cortisol, thyroid hormone, growth hormone, prolactin, somatomedin C) and evidence of abnormally increased bone activity (elevated alkaline phosphatase).



Treatment

The treatment of McCune-Albright Syndrome is symptomatic and supportive. In some cases, physicians may attempt to delay puberty with medications that affect hormone production. There are several drugs for precocious puberty that may be helpful for males or females with McCune-Albright Syndrome (such as testolactone, which may be an effective treatment for precious puberty in some females with MAS) . In individuals with McCune-Albright Syndrome who also exhibit acromegaly or gigantism, surgical removal of the pituitary tumor should be considered, although fibrous dysplasia at the base of the skull may make this difficult. Radiation therapy for pituitary, thyroid, or bone lesions carries potential risks including malignant changes in nearby bone lesions. In some severe cases, surgical removal of the thyroid gland (thyroidectomy) may become necessary to control the excessive production of thyroid hormones (persistent hyperthyroidism).



Fibrous dysplasia is usually treated conservatively. The choice of treatment is generally made based upon age, severity of symptoms, and the size and location of bone lesions. In some cases, MAS may be managed with a variety of orthopedic procedures including the use of casts and/or the surgical removal of portions of bone (osteotomy). However, surgery may be contemplated only when certain indications (e.g., progressive deformity, non-union of fractures, or unrelenting chronic pain) are present. Individuals with skull involvement should be monitored frequently for hearing and visual acuity.



In some affected females who develop large, benign ovarian cysts, such cysts may be treated by surgical removal of the ovary in some cases. However, the condition usually recurs in the opposite ovary and surgical removal is now rarely performed.



Although the GNAS1 genetic mutation has been found in breast tissue in individuals with McCune-Albright Syndrome, it is not known whether such mutation affects the incidence of breast cancer in such individuals. Thus, as a precaution, regular breast examinations are recommended.



Genetic counseling is indicated for individuals with McCune-Albright Syndrome and their families.

Investigational Therapies

Patients are being recruited for six clinical trials involving MAS at the National Institute of Dental and Craniofacial Research (NIDCR) of the National Institutes of Health (NIH). These studies are:



1) Effects of the Aromatase Inhibitor Letrozole on Pubertal Progression and Indices of Bone Turnover in Girls with Precocious Puberty and the McCune-Albright Syndrome



This study is testing the safety and effectiveness of letrozole in treating precocious puberty in girls with MAS. Study ID Numbers: 000183; 00-D-0183



2) A Randomized, Placebo-Controlled Trial of Alendronate in the Treatment of Polyostotic Fibrous Dysplasia and the McCune-Albright Syndrome



This study is designed to test the effectiveness of alendronate in treating the bone abnormality in these two diseases. Study ID Numbers: 980146; 98-D-0146



3) Studies on Tissues from Patients with Fibrous Dysplasia of Bone/McCune Albright Syndrome and Other Disorders of Calcified Tissues



This project is designed to help determine how a gene mutation causes the abnormal bone in fibrous dysplasia. The bone abnormalities in fibrous dysplasia can occur in a single bone (monostotic fibrous dysplasia), multiple bones (polyostotic fibrous dysplasia), or in McCune-Albright Syndrome in which there are associated glandular disturbances. Study ID Numbers: 970055; 97-D-0055



4) Screening and Natural History of Patients with Polyostotic Fibrous Dysplasia and McCune-Albright Syndrome



This study has two purposes: to study how the disease progresses over time (its natural history), and to screen patients for participation in one of NIH's treatment studies for these diseases. Study ID Numbers: 980145; 98-D-0145



5) A Study of the Effects of Pegvisomant on Growth Hormone Excess in McCune-Albright Syndrome



This study focuses on the effects of pegvisomant, a synthetic drug that prevents growth hormone from binding, in its normal way, to receptors on a cell. Study ID Numbers: 010197; 01-D-0197



Evaluation and Treatment to Improve Bone Quality and Prevent Fractures by the Percutaneous Replacement of Diseased Tissue in Polyostotic Fibrous Dysplasia and McCune-Albright Syndrome



This study is designed to evaluate the effectiveness of a new bone injection technique for treating patients with polyostotic fibrous dysplasia or McCune-Albright Syndrome. The new treatment is intended to reduce the risk of fracture, minimize deformities and improve overall function in these patients. Study ID Numbers: 990003; 99-D-0003



For additional information on the six clinical trials listed above, contact:



Contact and ID Information

National Institute of Dental and Craniofacial Research (NIDCR)

9000 Rockville Pike

Bethesda, MD 20892

Patient Recruitment and Public Liaison Office

Tel: 1-800-411-1222

e-mail: prpl@mail.cc.nih.gov



Information about these trials may also be obtained by contacting:



Michael Collins, M.D.

NIH/National Institute of Dental and Craniofacial Research (NIDCR)

31 Center Dr MSC 2290

Building 31 Rm 2C35

Bethesda, MD 20892-2290

Tel: (301) 496-1913

http://csdb.nidcr.nih.gov/csdb/



Clinical trials are also underway at the National Institutes of Health (NIH) to study the use of aromatase inhibitors, such as testolactone, for the treatment of precocious puberty and short stature in females and males with McCune-Albright Syndrome. More studies are needed to determine the long-term safety and effectiveness of this treatment of McCune-Albright Syndrome. For more information, contact:



Penelope P. Feuillan, M.D.

or Michael Collins, M.D.

NIH/National Institute of Child Health and Human Development

10 Center Drive

Building 10 Room 10N262

Bethesda, MD 20892

Tel: (301) 496-4686

Fax: (301) 402-0574

E-mail: pfeuil@helix.nih.gov



Investigators in the Reproductive Endocrine Unit at Massachusetts General Hospital are studying the reproductive function in adolescent and adult females with McCune-Albright Syndrome. Interested individuals will be sent a questionnaire. For more information on this study, contact:



Paul Boepple, M.D.

Reproductive Endocrine Unit

Bartlett Hall Extension, 5th Floor

Massachusetts General Hospital

Fruit St.

Boston, MA 02114

Tel: (617) 726-8433

Fax: (617) 726-5357



Pamidronate has been used for treatment of fibrous dysplasia in uncontrolled human trials. In addition, transplantation of normal bone to areas of dysplastic bone (cortical bone grafting with autografts of bone marrow stroma) in individuals with MAS is of potential benefit and is being evaluated in Israel. (During such transplants, normal bone derived from an individual with MAS is taken from bone shaft that also contains supporting tissue [stroma] from the bone marrow and is transplanted to areas of abnormal bone in the same individual.) More research is needed to determine the long-term safety and effectiveness of such treatments in individuals with McCune-Albright Syndrome. For more information on current studies, contact:



Pierre J. Meunier, M.D.

Institut National de la Sante et la Recherche Medicale (INSERM)

Unite 403, Pavilion F

Edouard Herriot Hospital

69437, Lyon France



Shlomo Weintroub, M.D.

Orthopedic Pediatric Society Multi-center Study

Dana Children's Hospital, Tel-Aviv Medical Center

6 Weitzmann St

64239 Tel-Aviv, Israel

(972) 3 697-4261

(972) 3 697-4542 (fax)



Uri A. Libermann, M.D.

Metabolic Diseases

Beilinson Medical Center

49100 Petah-Tikva, Israel

(972) 3 972-6681

(972) 3 972-9685 (fax)



Molecular and clinical studies including biphosphonate treatment are currently being conducted for fibrous dysplasia. More research is needed to determine the long-term safety and effectiveness of biphosphonate treatment for fibrous dysplasia in individuals with McCune-Albright Syndrome. Physicians who are interested in obtaining additional information concerning such research may contact:



Professor Francis H. Glorieux

Genetics Unit, Shriners Hospital for Children

1529 Cedar Avenue

Montreal, Quebec H3G 1A6

Canada

Telephone: 1 514 842 7685

Telefax: 1 514 842 5581

e-mail: glorieux@shriners.mcgill.ca



Laboratory studies on the cell biology of McCune-Albright Syndrome are being conducted at the National Institutes of Health (NIH) and elsewhere. Physicians and surgeons who are interested in making surgical bone specimens available for research should contact:



Pamela G. Robey, Ph.D.

NIH/NIDR

Bldg. 30, Rm. 106

9000 Rockville Pike

Bethesda, MD 20817

(301) 496-4563

(301) 402-0824 (fax)



Andrew Shenker, M.D., Ph.D.

Children's Memorial Hospital, Box 225

2300 Children's Plaza

Chicago, IL 60614

e-mail: ashenker@nwu.edu

(312) 880-8297

(312) 880-4568 (fax)



Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.



For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:



Tollfree: (800) 411-1222

TTY: (866) 411-1010

Email: prpl@cc.nih.gov



For information about clinical trials sponsored by private sources, contact:

www.centerwatch.com

References

TEXTBOOKS

Wilson JD, Foster DW, eds. Textbook Of Endocrinology, 8th ed. W.B. Saunders Co., Philadelphia; PA: 1992;1200-03, 1510.



Bennett JC, Plum F, eds. Cecil Textbook Of Medicine, 20th Ed. W.B. Saunders Co. Philadelphia; PA: 1996;1347.



Jones KL, ed. Smith's Recognizable Patterns Of Human Malformation, 5th Ed. W. B. Saunders Co. Philadelphia; PA:1997;510.



REVIEW ARTICLES

Lania A, Mantovani G, Spada A. G Protein mutations in endocrine diseases. Eur J Endocrinol. 2001;145:543-59.



Marie PJ. Cellular and molecular basis of fibrous dysplasia. Histol Histopathol. 2001;16:981-88.



Spiegel AM. G protein defects in signal transduction. Horm Res. 2000;53 Suppl 3:17-22.



Feuillan P, Merke D, Leschek EW, et al. Use of aromatase inhibitors in precocious puberty. Endocr Relat Cancer. 1999;6:303-06.



Levine MA. Clinical Implications of genetic defects in G proteins: oncogenic mutations in G alpha s as the molecular basis for the McCune-Albright syndrome. Arch Med Res. 1999;30:522-31.



De Sanctis C, Lala R, Matarazzo P, et al. McCune-Albright syndrome: a longitudinal clinical study of 32 patients. J Pediatr Endocrinol Metab. 1999;12:817-26.



Cohen MM Jr, Howell RE. Etiology of fibrous dysplasia and McCune-Albright syndrome. Int J Oral Maxillofac Surg. 1999;28:366-71.



Olsen BR. A rare disorder, yes; an unimportant one, never. J Clin Invest. 1998;101:1545-46.



FOR NON-PROFESSIONALS

Feuillan PP. McCune-Albright Syndrome. The Magic Foundation, nd:3pp



No Author Listed. McCune-Albright Syndrome. The National Institute of Child Health & Human Development. Last Modified; 06/19/2001:3pp.



FROM THE INTERNET

McKusick VA. Ed. Online Mendelian Inheritance In Man (OMIM). Johns Hopkins University, Baltimore; MD: Entry No: 174800; Last Edit Date 8/17/2001.

Resources

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Fibrous Dysplasia Foundation, Inc.

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Tel: (202)547-3288

Fax: (202)546-2854

Email: info@fibrousdysplasia.org

Internet: http://www.fibrousdysplasia.org



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