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The McCune-Albright syndrome is named for the two physicians who described
it over 50 years ago. They reported a group of children, most of them girls,
with an unusual pattern of associated abnormalities: bone disease,
with fractures, asymmetry and deformity of the legs, arms, and skull; endocrine
disease, including early puberty with menstrual bleeding, development
of breasts and pubic hair and an increased rate of growth; and skin
changes, with areas of increased pigment distributed in an asymmetric
and irregular pattern. Today, the term "McCune-Albright syndrome"
is used to describe patients who have some or all of these bone, endocrine,
and skin abnormalities. In the years since it was first identified, however,
researchers have studied many additional patients, and have learned that
the condition has a broad spectrum of severity. Sometimes, children are
diagnosed in early infancy with obvious bone disease and markedly increased
endocrine secretions from several glands; a very few of these severely
affected children have died. At the opposite end of the spectrum, many
children are entirely healthy, and have little or no outward evidence of
bone or endocrine involvement. They may enter puberty close to the normal
age, and have no unusual skin pigment at all. Because of this marked variability
among patients, the components of this complicated syndrome are described
When the signs of puberty (development of breasts, testes, pubic and
underarm hair, body odor, menstrual bleeding, and increased growth rate)
appear before the age of 8 years in a girl or 9 1/2 years in a boy, it
is termed "precocious puberty." In the most common form of precocious
puberty, there is early activation of the regions in the brain which control
the maturation of the gonads (ovaries in a girl and testes in a boy). One
brain center, the hypothalamus, secretes a substance called gonadotropin-releasing-hormone
or "GnRH." This acts, in turn, on another part of the brain,
the pituitary gland, to cause increased secretion of hormones called "gonadotropins"
(LH and FSH) that travel through the bloodstream, and act on the ovaries
or testes to stimulate secretion of estrogen or testosterone. Endocrinologists
determine if a child with precocious puberty has early activation of the
hypothalamus and pituitary by measuring the levels of LH and FSH in the
blood after an injection of a synthetic preparation of GnRH.
After studying many girls with McCune-Albright syndrome, however, researchers
have learned that most do not appear to have early activation of the hypothalamus
and pituitary, because the levels of LH and FSH are usually low, or similar
to those of prepubertal children. The precocious puberty in McCune-Albright
girls is caused by estrogens which are secreted into the bloodstream by
ovarian cysts, which enlarge, and then decrease in size over periods of
weeks to days. The cysts can be visualized and measured by ultrasonography,
in which sound waves are used to outline the dimensions of the ovaries.
The cysts may become quite big, occasionally over 50 cc in volume (about
the size of a golf ball). Frequently, menstrual bleeding and breast enlargement
accompany the growth of a cyst. In fact, menstrual bleeding under 2 years
of age has been the first symptom of McCune-Albright syndrome in 85 percent
of patients. Although ovarian cysts and irregular menstrual bleeding may
continue into adolescence and adulthood, many adult women with McCune-Albright
syndrome are fertile, and can bear normal children.
The precocious puberty in McCune-Albright syndrome has been difficult
to treat. After surgical removal of the cyst or of the entire affected
ovary, cysts usually recur in the remaining ovary. A progesterone-like
hormone called Provera can be given to suppress the menstrual bleeding,
but does not appear to slow the rapid rates of growth and bone development,
and may have unwanted effects on adrenal functioning. The synthetic forms
of GnRH (Deslorelin, Histerelin, and Lupron) which suppress LH and FSH,
and are used to treat the common, gonadotropin-dependent form of precocious
puberty, are not effective in most girls with McCune-Albright syndrome.
An investigational form of treatment, using oral medications which block
estrogen synthesis, (testolactone and fadrozole) is now being tested in
girls with McCune-Albright syndrome, and has been beneficial in many patients.
Almost 50 percent of patients with McCune-Albright syndrome have thyroid
gland abnormalities; these include generalized enlargement called goiter,
and irregular masses called nodules and cysts. Some patients have subtle
structural changes detected only by ultrasonography. Pituitary thyroid-stimulating-hormone
(TSH) levels are low in these patients, and thyroid hormone levels may
be normal or elevated. Therapy with drugs which block thyroid hormone synthesis
(Propylthiouracil or Methimazole), can be given if thyroid hormone levels
are excessively high.
Excessive secretion of pituitary growth hormone has been seen in a few
patients with McCune-Albright syndrome. Most of these have been diagnosed
as young adults, when they developed the coarsening of facial features,
enlargement of hands and feet, and arthritis characteristic of the condition
termed "acromegaly." Therapy has included surgical removal of
the area of the pituitary which is secreting the hormone, and use of new,
synthetic analogs of the hormone somatostatin, which suppress growth hormone
Although rare, adrenal enlargement and excessive secretion of the adrenal
hormone cortisol is seen in McCune-Albright syndrome. This may cause obesity
of the face and trunk, weight gain, skin fragility and cessation of growth
in childhood. These symptoms are called "Cushing's syndrome."
Treatment is removal of the affected adrenal glands, or use of drugs which
block cortisol synthesis.
Some children with McCune-Albright syndrome have very low levels of
phosphorus in their blood due to excessive losses of phosphate in their
urine. This may cause bone changes associated with rickets, and may be
treated with oral phosphates and supplemental vitamin D.
Disease-Polyostotic Fibrous Dysplasia
The term "polyostotic fibrous dysplasia" means "abnormal
fibrous tissue growth in many bones." However, the severity of bone
disease in McCune-Albright syndrome is quite variable. In affected areas,
normal bone is replaced by irregular masses of fibroblast cells. When this
occurs in weight-bearing bones, such as the femur (upper leg bone), limping,
deformity, and fractures may occur. In many children, the arms and/or legs
are of unequal length, even in the absence of actual fracture. Regions
of fibrous dysplasia are also very common in the bones that form the skull
and upper jaw. If these areas begin to expand, skull and facial asymmetry
Polyostotic fibrous dysplasia can often be seen in a plain X-ray picture
of the skeleton. A more sensitive method of finding lesions is a bone scan,
in which a small amount of radioactivity (an isotope of technetium) is
injected into a vein, taken up by the abnormal tissues, and detected by
Some children may be minimally affected, with no asymmetry, deformity
or fracture, and lesions detected only by a bone scan. In a few children,
lesions are found only in the base of the skull. By repeating bone scans
at intervals of 1 to 2 years, it has been shown that the bone disease in
some children may become more extensive over time. Unfortunately, severe
bone disease can have permanent effects upon physical appearance and mobility.
There is no known hormonal or medical treatment effective in controlling
progressive polyostotic fibrous dysplasia. Surgical procedures to correct
fracture and deformity include grafting, pinning, and casting. Skull and
jaw changes are often corrected surgically, with great improvement in appearance.
Treatment and therapy for this bone disease is usually the most difficult
aspect of caring for a child who has severe polyostotic fibrous dysplasia.
The irregular, flat areas of increased skin pigment in McCune-Albright
syndrome are called "cafe-au-lait" spots because, in children
with light complexions, they are the color of coffee with milk. In dark
skinned individuals, these spots may be difficult to see. Most children
have the pigment from birth, and it almost never becomes more extensive.
The pattern of the pigment distribution is unique, often starting or ending
abruptly at the midline on the abdomen in front or at the spine in back.
Some children have no cafe-au-lait pigment at all; in a few, it is confined
to small areas, such as the nape of the neck or crease of the buttocks.
There are seldom any medical problems associated with the areas of cafe-au-lait
pigment. Some adolescent children may want to use makeup to obscure areas
of dark pigment on the face.
So far, researchers have not found a cure for the bone and endocrine
disease in McCune-Albright syndrome. It cannot yet be diagnosed before
birth and there is no way to accurately predict how severe the disease
may become in an affected child. There are no reported cases of any parent
being affected, and the children of women with McCune-Albright syndrome
are normal. All races appear to be affected equally. Thus, we are not yet
certain of the genetic origin of the defect. It is believed, however, that
it may be the result of a mutation occurring early in the development of
Recently, researchers have discovered abnormal mutations in DNA obtained
from the affected ovaries, adrenals, and liver of several patients with
McCune-Albright syndrome. The DNA contained the genetic code for one component,
called a "G" protein, of a signaling system which is present
in many cells, and which is known to be involved in endocrine cell growth
and secretion. The presence of this mutation could result in uncontrolled
cell function or hormone secretion. This research is continuing, and it
may soon enable us to plan better methods of treatment for patients with
the McCune-Albright syndrome.
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