Albright Syndrome 

  • Author: Noah S Scheinfeld, MD, JD, FAAD; Chief Editor: Dirk M Elston, MD   more...
 
Updated: Sep 21, 2011
 

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 and McCune-Albright Syndrome (pediatric focus).

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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]

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Epidemiology

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).

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Contributor Information and Disclosures
Author

Noah S Scheinfeld, MD, JD, FAAD  Assistant Clinical Professor, Department of Dermatology, Columbia University College of Physicians and Surgeons; Consulting Staff, Department of Dermatology, St Luke's Roosevelt Hospital Center, Beth Israel Medical Center, and New York Eye and Ear Infirmary; Private Practice

Noah S Scheinfeld, MD, JD, FAAD is a member of the following medical societies: American Academy of Dermatology

Disclosure: Optigenex Consulting fee Independent contractor

Specialty Editor Board

Eleanor E Sahn, MD  Director, Division of Pediatric Dermatology, Associate Professor, Departments of Dermatology and Pediatrics, Medical University of South Carolina

Eleanor E Sahn, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, and Southern Medical Association

Disclosure: Nothing to disclose.

Richard P Vinson, MD  Assistant Clinical Professor, Department of Dermatology, Texas Tech University Health Sciences Center, Paul L Foster School of Medicine; Consulting Staff, Mountain View Dermatology, PA

Richard P Vinson, MD is a member of the following medical societies: American Academy of Dermatology, Association of Military Dermatologists, Texas Dermatological Society, and Texas Medical Association

Disclosure: Nothing to disclose.

Van Perry, MD  Assistant Professor, Department of Medicine, Division of Dermatology, University of Texas School of Medicine at San Antonio

Van Perry, MD is a member of the following medical societies: American Academy of Dermatology and American Society for Laser Medicine and Surgery

Disclosure: Nothing to disclose.

Catherine M Quirk, MD  Clinical Assistant Professor, Department of Dermatology, University of Pennsylvania

Catherine M Quirk, MD is a member of the following medical societies: Alpha Omega Alpha and American Academy of Dermatology

Disclosure: Nothing to disclose.

Chief Editor

Dirk M Elston, MD  Director, Ackerman Academy of Dermatopathology, New York

Dirk M Elston, MD is a member of the following medical societies: American Academy of Dermatology

Disclosure: Nothing to disclose.

Additional Contributors

The authors and editors of eMedicine gratefully acknowledge the contributions of previous author, D. Stanton Whittaker Jr, MD, to the development and writing of this article.

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Large café au lait patches around the shoulder in a child with McCune-Albright syndrome.
Lucency characteristic of polyostotic fibrous dysplasia in a patient with McCune-Albright syndrome.
 
 
 
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