McCune-Albright Syndrome
Introduction
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 separately below.
Endocrine
Abnormalities
Precocious
Puberty
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.
Thyroid
Function
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.
Growth
Hormone
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 secretion.
Other
Endocrine Abnormalities
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.
Bone 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
may result.
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 a scanner.
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.
Skin
Abnormalities
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.
Recent
Research
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 the embryo.
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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