eMedicine Specialties > Dermatology > Pediatric Diseases

Albright Syndrome

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

Updated: Dec 11, 2009

Introduction

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).

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

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
  • Platelet dysfunction and increased bleeding tendency have been reported in MAS.18
  • Expansion of the mandible with radiopaque-radiolucent areas with ground-glass radiographic appearance has also been reported in MAS.19
  • Severe arterial hypertension can be a complication of MAS.20

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, as shown in the image below. 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.

  • Large café au lait patches around the should...

    Large café au lait patches around the shoulder in a child with McCune-Albright syndrome.

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    Large café au lait patches around the should...

    Large café au lait patches around the shoulder in a child with McCune-Albright syndrome.

  • 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.21
  • In 2007, Medow et al described polyostotic fibrous dysplasia of the cervical spine as a finding of MAS.22

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.

More on Albright Syndrome

Overview: Albright Syndrome
Differential Diagnoses & Workup: Albright Syndrome
Treatment & Medication: Albright Syndrome
Follow-up: Albright Syndrome
Multimedia: Albright Syndrome
References
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References

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Further Reading

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Keywords

Albright syndrome, McCune-Albright syndrome, Albright's syndrome, café au lait macules, CALMs, cafe au lait macules, cafe-au-lait macules, polyostotic fibrous dysplasia, PFD, endocrine dysfunction, precocious puberty, MAS, PPP

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Contributor Information and Disclosures

Author

Noah S Scheinfeld, MD, JD, FAAD, Assistant Clinical Professor, Department of Dermatology, Columbia University; Consulting Staff, Department of Dermatology, St Luke's Roosevelt Hospital Center, Beth Israel Medical Center, 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

Medical Editor

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.

Pharmacy Editor

Richard P Vinson, MD, Assistant Clinical Professor, Department of Dermatology, Texas Tech University 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.

Managing Editor

Van Perry, MD, Assistant Professor, Department of Medicine, Division of Dermatology, University of Texas Health Science Center
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.

CME Editor

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, Department of Dermatology, Geisinger Medical Center
Dirk M Elston, MD is a member of the following medical societies: American Academy of Dermatology
Disclosure: Nothing to disclose.

 
 
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