The range of severity of McCune-Albright syndrome is broad: some children are diagnosed in early infancy with obvious anomalies of bone and increased hormone production by one or more of the endocrine glands; others show no evidence of bone, skin or endocrine malfunction in childhood and may enter puberty at an appropriate age. The degree of severity of individual symptoms may also vary greatly. Therefore, it is important to note that affected individuals may not have all of the symptoms discussed below and that every individual case is unique. Parents should talk to their child’s physician and medical team about their specific case, associated symptoms and overall prognosis.
The parts of the body most commonly affected by MAS are the bone, skin and endocrine system.
BONE Polyostotic fibrous dysplasia is a distinctive finding in affected individuals. Fibrous dysplasia refers to bone that is replaced by abnormal scar-like (fibrous) connective tissue. This abnormal fibrous tissue weakens the bone, making it abnormally fragile and prone to fracture. Fracture may be the presenting symptom in some cases. Pain may occur in the affected areas. Polyostotic refers to cases in which multiple skeletal sites are affected, but in some cases only one skeletal site is affected (monostotic fibrous dysplasia). Fibrous dysplasia often predominates on one side of the body (unilateral).
Specific symptoms associated with polyostotic fibrous dysplasia depend upon the specific bones involved. Any part of the skeleton can potentially be affected, but the long bones of the arms and legs, the bones of the face and skull (craniofacial area), and the ribs are most often affected. Polyostotic fibrous dysplasia often presents as a painless swellings on the ribs. Fibrous dysplasia affecting the spine can cause abnormal curvature of the spine (scoliosis), which is often progressive. When the long bones of the legs are affected, this can lead to frequent fractures due to weight bearing when walking or standing. Additionally, the long bones can eventually become bowed. In children, their legs may not be of equal length (limb length discrepancy). Eventually, this can affect a person’s ability to walk, causing an abnormal gait (e.g. walking with a limp).
Some affected individual develop polyostotic fibrous dysplasia of the craniofacial region, which can cause a variety of symptoms depending on the type and specific location of the lesions(s). Such symptoms can include pain, nasal congestion, misaligned or displaced teeth, uneven jaws, and facial asymmetry, in which one side of the face does not match the other side. Polyostotic fibrous dysplasia in the craniofacial region can alter the Facial features resulting in an abnormally Prominent forehead (frontal bossing), bulging eyes (proptosis), and difference in the vertical positions of the eyes so that the eyes are uneven (vertical dystopia). The degree of facial abnormality can vary greatly from one person to another. The shape of the skull may be altered in certain cases.
Fibrous dysplasia lesions can potentially cause a variety of neurological symptoms as areas of abnormal tissue development can compress nearby nerves. Specific symptoms are related to the specific nerves involved. For example, vision loss or hearing impairment can occur because of compression of optic and auditory nerves in the skull. However, vision loss and hearing impairment only occur in rare instances.
SKIN Some individuals with MAS have Abnormal skin coloring (pigmentation) known as café-au-lait spots. Café-au-lait spots are abnormal patches of light-brown skin that have irregularly-shaped, jagged borders. They may be present at birth or shortly thereafter (neonatal period) and may become more pronounced with age. Individual lesions often abruptly stop at the midline of the body, which is the imaginary line that divides the body into right and left halves. The lesions can be of varying size and often affect only one side of the body. Some individuals do not develop café-au-lait spots.
ENDOCRINE DYSFUNCTION The endocrine system is the system of glands that regulate the body’s rate of growth, its sexual development, and certain other metabolic functions. Individuals with MAS often experience an abnormally early onset of puberty (gonadotropin independent precocious puberty). A sequence of events occurs during which a child develops adult secondary sexual characteristics beginning at an unexpectedly early age. In MAS, this occurs because glands that secrete sex hormones are inappropriately active abnormally early in life.
In females, there may be vaginal bleeding or early development of breast tissue. Onset can be within the first few months of life or later during childhood around 6 or 7 years of age. Some females may have frequent episodes of vaginal bleeding, while others may only have a few sporadic episodes. Precocious puberty is often associated with the development of benign ovarian cysts. Precocious puberty may result in an advanced bone age, which could potentially limit growth potential and final adult height.
Precocious puberty is more common in females than males with more than 50% of females experiencing precocious puberty. In males, there may be enlargement of the penis and one or both testicles. The scrotum may thicken and gain wrinkles (rugae). Males may also grow pubic hair, hair under the armpits, and body odor.
Children with precocious puberty are often tall and have an increased growth velocity while they are still growing. Individuals end up short because they finish growing earlier than other people.
Other endocrine disorders may occur in individuals with MAS including those affecting the thyroid, the pituitary, and adrenal glands.
The thyroid is a butterfly-shaped gland at the base of the neck. Involvement of the thyroid may range from no obvious clinical symptoms to enlargement of the thyroid (goiter) and overproduction of thyroid hormone (hyperthyroidism). Hyperthyroidism can cause anxiety, fatigue, prominence of the eyes, sweating, heart palpitations, unintended weight loss, and heat intolerance. Osteoporosis may be caused by or worsened by hyperthyroidism. In some cases, hyperthyroidism cannot be controlled by medication.
The pituitary gland is a small gland located near the base of the skull that stores several hormones including growth hormone and releases them into the bloodstream as needed by the body. Some individuals with MAS experience excessive levels of growth hormone. Growth hormone has several functions in the body such as affecting growth and muscle mass. Increased growth velocity is the most common sign of growth hormone excess, however, in individuals with precocious puberty this may be masked (because precocious puberty has already increased the growth spurt). Growth hormone excess can lead to an abnormally large head (macrocephaly) and can potentially cause vision problems. Some individuals with MAS develop a disorder known as acromegaly, which is due to growth hormone excess after the growth plates have fused. The development of acromegaly can be associated with fibrous dysplasia affecting the skull base. (For more information on this disorder, choose “acromegaly” as your search term in the Rare Disease Database.)
The adrenal glands are located above the kidneys near the lower back and produce several hormones including cortisol. Cortisol is a glucocorticoid, a class of steroid hormone that is important in regulating metabolism of glucose and modulating stress. Individuals with MAS may have elevated levels of cortisol and can development a disorder known as Cushing syndrome. Symptoms can include upper body obesity, a round face, thin purple streaks (striae) that occur on the skin, increased fat around the neck, and thin, slender arms and legs. Children with Cushing syndrome are typically obese with slowed growth rates. (For more information on this disorder, choose “Cushing” as your search term in the Rare Disease Database.)
Some individuals with MAS develop elevated levels of phosphate in the blood (hypophosphatemia) because the kidneys cannot properly reabsorb phosphate. This occurs because fibrous dysplasia tissue produces a protein known as fibroblast growth factor 23 (FGF23). The amount of FGF23 correlates to the inability of the kidneys to metabolize phosphate (renal phosphate wasting). Therefore, individuals with significant fibrous dysplasia are more likely to develop hypophosphatemia. Hypophosphatemia can cause severe rickets or osteomalacia. Rickets is a childhood bone disease with characteristic bowing deformity of the legs and can contribute to short stature. Individuals with hypophosphatemia generally experience their first fracture at a younger age than individuals with MAS who do not have hypophosphatemia. Individuals with hypophosphatemia also develop more fractures and bone pain. In adults, hypophosphatemia can cause osteomalacia, a softening of the bones.
ADDITIONAL FINDINGS Less common symptoms sometimes associated with MAS include gastroesophageal reflux, gastrointestinal polyps, Inflammation of the pancreas (pancreatitis), and several abnormalities of the heart (cardiac abnormalities). Such abnormalities include a faster than normal heart rate (tachycardia), high output heart failure, and aortic root dilatation.
Although the term tumor may be used to describe fibrous dysplasia lesions, these growths are benign (non-cancerous). Only in extremely rare cases, likely less than 1% of patients, have these lesions become cancerous (malignant transformation). These malignant tumors (osteosarcomas) developed in individuals who had been radiated for bone pain; a treatment option that has been abandoned.
Individuals may also be at an increased risk of developing breast cancer or tumors of the liver, bile duct or pancreas. Some reports suggest that this increased risk is more likely in individuals with growth hormone excess. Thyroid cancer and testicular cancer have also been reported in individuals with MAS in extremely rare instances.