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McCune–Albright syndrome is a complex
genetic disorder A genetic disorder is a health problem caused by one or more abnormalities in the genome. It can be caused by a mutation in a single gene (monogenic) or multiple genes (polygenic) or by a chromosomal abnormality. Although polygenic disorders ...
affecting the bone, skin and endocrine systems. It is a
mosaic A mosaic is a pattern or image made of small regular or irregular pieces of colored stone, glass or ceramic, held in place by plaster/mortar, and covering a surface. Mosaics are often used as floor and wall decoration, and were particularly pop ...
disease arising from
somatic Somatic may refer to: * Somatic (biology), referring to the cells of the body in contrast to the germ line cells ** Somatic cell, a non-gametic cell in a multicellular organism * Somatic nervous system, the portion of the vertebrate nervous sys ...
activating mutations in '' GNAS'', which encodes the alpha-subunit of the Gs
heterotrimeric G protein Heterotrimeric G protein, also sometimes referred to as the ''"large" G proteins'' (as opposed to the subclass of smaller, monomeric small GTPases) are membrane-associated G proteins that form a Heteromer, heterotrimeric complex. The biggest no ...
. It was first described in 1937 by American pediatrician Donovan James McCune and American endocrinologist
Fuller Albright Fuller Albright (January 12, 1900 – December 8, 1969) was an American endocrinologist who made numerous contributions to his field, especially to the area of calcium metabolism. Albright made great strides and contributions to the understanding ...
.


Signs and symptoms

McCune–Albright syndrome is suspected when two or more of the following features are present: *
Fibrous dysplasia Fibrous dysplasia is a disorder where normal bone and marrow is replaced with fibrous tissue, resulting in formation of bone that is weak and prone to expansion. As a result, most complications result from fracture, deformity, functional impairm ...
* Hyperpigmented skin lesions with characteristic features, including jagged "coast of Maine" borders and tendency occur along the midline of the body. These lesions are historically termed
café au lait macule A coffeehouse, coffee shop, or café is an establishment that primarily serves coffee of various types, notably espresso, latte, and cappuccino. Some coffeehouses may serve cold drinks, such as iced coffee and iced tea, as well as other non-caf ...
s, however the term "cafe-au-lait" only describes their appearance on lighter-skinned individuals. * Hyperfunctioning
endocrine disease Endocrine diseases are disorders of the endocrine system. The branch of medicine associated with endocrine disorders is known as endocrinology. Types of disease Broadly speaking, endocrine disorders may be subdivided into three groups: # Endocrin ...
Patients may have one or many of these features, which may occur in any combination. As such, the clinical presentation of patients with McCune Albright syndrome varies greatly depending on the disease features. Various endocrine diseases may present in McCune–Albright syndrome due to increased hormone production. *
Precocious puberty In medicine, precocious puberty is puberty occurring at an unusually early age. In most cases, the process is normal in every aspect except the unusually early age and simply represents a variation of normal development. In a minority of childr ...
: The most common endocrinopathy is precocious puberty, which presents in girls (~85%) with recurrent estrogen-producing cysts leading to episodic breast development, growth acceleration, and vaginal bleeding. Precocious puberty may also occur in boys with McCune–Albright syndrome, but is much less common (~10–15%). In children of both sexes, growth acceleration may lead to tall stature in childhood, however premature bone maturation may lead to early growth plate fusion and short stature in adulthood. * Testicular abnormalities: Testicular abnormalities are seen in a majority (~85%) of boys with McCune–Albright syndrome. These typically present with macro-orchidism. On pathology lesions show Leydig and Sertoli cell hyperplasia. *
Hyperthyroidism Hyperthyroidism is the condition that occurs due to excessive production of thyroid hormones by the thyroid gland. Thyrotoxicosis is the condition that occurs due to excessive thyroid hormone of any cause and therefore includes hyperthyroidism ...
: Hyperthyroidism occurs in approximately one-third of patients with McCune Albright syndrome. Patients have characteristic abnormalities on thyroid ultrasound, and may have a slight increased risk for thyroid cancer. * Growth hormone excess: Excess growth hormone secretion and is found in approximately 10–15% of patients. This may lead to expansion of craniofacial fibrous dysplasia, increasing the risk of vision and hearing loss. *
Cushing's syndrome Cushing's syndrome is a collection of signs and symptoms due to prolonged exposure to glucocorticoids such as cortisol. Signs and symptoms may include high blood pressure, abdominal obesity but with thin arms and legs, reddish stretch marks, ...
: In McCune–Albright syndrome, Cushing's syndrome is a very rare feature that develops only in infancy. * Hypophosphatemia due to increased
fibroblast growth factor 23 Fibroblast growth factor 23 (FGF23) is a protein and member of the fibroblast growth factor (FGF) family which participates in the regulation of phosphate in plasma and vitamin D metabolism. In humans it is encoded by the gene. FGF23 decreases rea ...
production may lead to rickets, osteomalacia, and worsening skeletal outcomes.


Genetics

Genetically, there is a spontaneous
postzygotic mutation A postzygotic mutation (or post-zygotic mutation) is a change in an organism's genome that is acquired during its lifespan, instead of being inherited from its parent(s) through fusion of two haploid gametes. Mutations that occur after the zygote ...
of the
gene In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a ba ...
GNAS, on the long (q) arm of chromosome 20 at position 13.3, which is involved in
G-protein G proteins, also known as guanine nucleotide-binding proteins, are a family of proteins that act as molecular switches inside cells, and are involved in transmitting signals from a variety of stimuli outside a cell to its interior. Their act ...
signaling. This mutation, which occurs only in the
mosaic A mosaic is a pattern or image made of small regular or irregular pieces of colored stone, glass or ceramic, held in place by plaster/mortar, and covering a surface. Mosaics are often used as floor and wall decoration, and were particularly pop ...
state, leads to constitutive receptor signaling and inappropriate production of excess
cAMP Camp may refer to: Outdoor accommodation and recreation * Campsite or campground, a recreational outdoor sleeping and eating site * a temporary settlement for nomads * Camp, a term used in New England, Northern Ontario and New Brunswick to descri ...
. The mutation that causes McCune–Albright syndrome arises very early during embryogenesis. Because all cases of the syndrome are sporadic, it is believed that the mutation would be lethal if it affected all cells in the embryo. Mutant cells can only survive when they are intermixed with normal cells. There are no known risk factors for acquiring McCune–Albright syndrome, and no exposures during pregnancy that are known to either cause or prevent the mutation from occurring. The disease cannot be inherited and occurs equally among all ethnic groups.


Diagnosis

McCune–Albright syndrome has different levels of severity. For example, one child with McCune–Albright syndrome may be entirely healthy, with no outward evidence of bone or endocrine problems, enter puberty at close to the normal age, and have no unusual skin pigmentation. Diagnosis may be made only after decades. In other cases, children are diagnosed in early infancy, show obvious bone disease, and obvious increased endocrine secretions from several glands.


Skeletal abnormalities

All patients with known or suspected McCune–Albright syndrome should undergo a screening evaluation for fibrous dysplasia. Nuclear medicine tests such as technetium-99 scintigraphy are the most sensitive way to detect fibrous dysplasia lesions. CT scan of the skull is the most useful test to evaluate craniofacial fibrous dysplasia. Regular hearing and vision screening is recommended. X-rays are usually sufficient to reveal fibrous dysplasia of the appendicular skeleton, but CT and/or MRI scans can reveal microfractures. Regular screening for
scoliosis Scoliosis is a condition in which a person's spine has a sideways curve. The curve is usually "S"- or "C"-shaped over three dimensions. In some, the degree of curve is stable, while in others, it increases over time. Mild scoliosis does not t ...
should also be undertaken.


Endocrine abnormalities

Patients with known or suspected McCune–Albright syndrome should undergo a screening evaluation for endocrine features.
Precocious puberty In medicine, precocious puberty is puberty occurring at an unusually early age. In most cases, the process is normal in every aspect except the unusually early age and simply represents a variation of normal development. In a minority of childr ...
is typically diagnosed based on clinical presentation. A bone age examination should be performed to evaluation for skeletal maturation. Boys and men should have a screening testicular ultrasound.
Hyperthyroidism Hyperthyroidism is the condition that occurs due to excessive production of thyroid hormones by the thyroid gland. Thyrotoxicosis is the condition that occurs due to excessive thyroid hormone of any cause and therefore includes hyperthyroidism ...
is diagnosed based on blood tests. A screening thyroid ultrasound exam may be performed. Growth hormone excess is diagnosed using blood tests, such as insulin-like growth factor-1 levels. Monitoring growth rates alone is not sufficient to screen for growth hormone excess, because linear growth in children with McCune–Albright syndrome may be affected by skeletal deformities and other endocrinopathies. Hypophosphatemia is diagnosed by blood phosphorus levels. Cushing syndrome is very rare, and is typically diagnosed clinically in infants who present with signs of severe illness.


Treatment

Treatment is dictated by both the tissues affected and the extent to which they are affected.


Skeletal abnormalities

Surgical management of skeletal abnormalities has evolved over the years. Surgical intervention may be necessary for some skeletal abnormalities.
Bisphosphonates Bisphosphonates are a class of drugs that prevent the loss of bone density, used to treat osteoporosis and similar diseases. They are the most commonly prescribed drugs used to treat osteoporosis. They are called bisphosphonates because they ...
are helpful in relieving bone pain, but it is no longer believed that they prevent progression of the disease.
Denosumab Denosumab (trade names Prolia and Xgeva) is a human monoclonal antibody for the treatment of osteoporosis, treatment-induced bone loss, metastases to bone, and giant cell tumor of bone. Denosumab is contraindicated in people with low blood calci ...
has been found successful in reducing bone pain and decreasing tumor growth, however there is limited safety data available in patients with fibrous dysplasia. Muscle strengthening exercises are important for preventing bone fractures; cycling and swimming are recommended in order to reduce the risk of fracture during exercise. Screening and management of endocrinopathies is an important part of managing fibrous dysplasia. For example, untreated growth hormone excess increases the risk of craniofacial fibrous dysplasia expansion and may lead to vision loss. Untreated hyperthyroidism and hypophosphatemia increases the risk of fractures and skeletal deformities.


Endocrine abnormalities

For treatment of precocious puberty, the aromatase inhibitor such as
letrozole Letrozole, sold under the brand name Femara among others, is an aromatase inhibitor medication that is used in the treatment of breast cancer. It was patented in 1986 and approved for medical use in 1996. In 2020, it was the 257th most common ...
is effective at prevent bleeding episodes and preventing short stature. In boys, these should be combined with drugs such as
spironolactone Spironolactone, sold under the brand name Aldactone among others, is a medication that is primarily used to treat fluid build-up due to heart failure, liver scarring, or kidney disease. It is also used in the treatment of high blood pressure ...
and
flutamide Flutamide, sold under the brand name Eulexin among others, is a nonsteroidal antiandrogen (NSAA) which is used primarily to treat prostate cancer. It is also used in the treatment of androgen-dependent conditions like acne, excessive hair grow ...
to treat androgen excess. Periodic ultrasounds of testicular lesions should be performed to screen for cancer. Hyperthyroidism is managed with medications such as
thioamide A thioamide (rarely, thionamide, but also known as thiourylenes) is a functional group with the general structure R–CS–NR′R″, where R, R′, and R″ are organic groups. They are analogous to amides but they exhibit greater multiple bond ch ...
s. However, because hyperthyroidism in McCune–Albright syndrome does not resolve, surgery or radiation are more definitive treatments. Periodic thyroid examination should be performed to screen for thyroid cancer. Oral phosphate and
calcitriol Calcitriol is the active form of vitamin D, normally made in the kidney. It is also known as 1,25-dihydroxycholecalciferol. It is a hormone which binds to and activates the vitamin D receptor in the nucleus of the cell, which then increases the ...
may be given for treatment of hypophosphatemia. For growth hormone excess, treatment with
somatostatin Somatostatin, also known as growth hormone-inhibiting hormone (GHIH) or by several other names, is a peptide hormone that regulates the endocrine system and affects neurotransmission and cell proliferation via interaction with G protein-couple ...
analogues or
pegvisomant Pegvisomant, sold under the brand name Somavert, is a growth hormone receptor antagonist used in the treatment of acromegaly. It is primarily used if the pituitary gland tumor causing the acromegaly cannot be controlled with surgery or radiatio ...
may be effective. Surgery may be an option, but may be complicated by the cranial abnormalities associated with the disorder. Excessive prolactin secretion may also occur; this is treated with dopamine agonists such as
cabergoline Cabergoline, sold under the brand name Dostinex among others, is a dopaminergic medication used in the treatment of high prolactin levels, prolactinomas, Parkinson's disease, and for other indications. It is taken by mouth. Cabergoline is an e ...
. Radiation therapy has been associated with malignant transformation of skull base fibrous dysplasia, and should be avoided in all but the most dire cases.
Cushing syndrome Cushing's syndrome is a collection of signs and symptoms due to prolonged exposure to glucocorticoids such as cortisol. Signs and symptoms may include high blood pressure, abdominal obesity but with thin arms and legs, reddish stretch marks, a ...
is a rare but potentially fatal complication that can occur in the first year of life.
Adrenalectomy Adrenalectomy (Latin root Ad "near/at" + renal "related to the kidneys" + Greek '' ‑ectomy'' “out-cutting”; sometimes written as ADX for the procedure or resulting state) is the surgical removal of one ( unilateral) or both (bilateral) adr ...
is the treatment of choice.
Metyrapone Metyrapone, sold under the brand name Metopirone, is a medication which is used in the diagnosis of adrenal insufficiency and occasionally in the treatment of Cushing's syndrome (hypercortisolism). Medical uses Metyrapone can be used in the di ...
may also be used for treatment.


Epidemiology

McCune–Albright syndrome is estimated to occur at a frequency between 1 person in 100,000 to 1 person in 1,000,000 individuals worldwide.


See also

*
List of cutaneous conditions Many skin conditions affect the human integumentary system—the organ system covering the entire surface of the body and composed of skin, hair, nails, and related muscle and glands. The major function of this system is as a barrier against t ...
*
List of radiographic findings associated with cutaneous conditions Many conditions of or affecting the human integumentary system have associated features that may be found by performing an x-ray or CT scan of the affected person. See also * List of cutaneous conditions * List of contact allergens * List of ...


References


External links


GeneReviews entry
for fibrous dysplasia/McCune–Albright Syndrome {{DEFAULTSORT:McCune-Albright syndrome Genodermatoses Congenital disorders Syndromes