McCune-Albright syndrome is a neurocutaneous syndrome manifested by café-au-lait spots and disturbances in bone metabolism. The cause of the hereditary disorder is a genetic mutation in the GNAS1 gene, which encodes a regulator of cAMP. Treatment focuses on the administration of bisphosphonates.
What is McCune-Albright syndrome?
The neurocutaneous syndromes are hereditary disorders whose leading symptoms are neuroectodermal mesenchymal dysplasias. The disease group includes the classic phakomatoses. Apart from these diseases, the group includes a number of syndromes that manifest dermally and simultaneously in the central nervous system. McCune-Albright syndrome is also a neurocutaneous syndrome. This extremely rare disease is symptomatically characterized by café-au-lait spots associated with disturbances in bone metabolism. U.S. pediatrician Donovan James McCune and endocrinologist Fuller Albright first described the condition in the 20th century. In the broadest sense, the Austrian pathologist Carl Sternberg was also among the first to describe the disease. For this reason, the symptom complex is sometimes referred to as McCune-Albright-Sternberg syndrome. Other synonyms include the terms osteitis fibrosa cystica, leontiasis ossea, Weil-Albright syndrome, and osteodystrophia fibrosa.
Causes
The prevalence of McCune-Albright syndrome is reported to be between one to nine patients in 1000000 people. Girls are more commonly affected than boys. A familial clustering has been observed in the cases documented to date. Thus, the syndrome does not seem to occur sporadically. The mode of inheritance is not yet known. The cause of McCune-Albright syndrome is apparently a genetic mutation. In half of all patients a mutation of the GNAS1 gene was found. This gene codes in the DNA for certain polypeptides and is located on chromosome 20 in the gene locus 20q13.2. Among other things, the gene codes for the protein Gs-alpha, which is considered a cAMP-regulating protein. The genetic alteration results in a loss of function of the protein and thus results in a lack of regulation. The alteration is a postzygotic mutation and for this reason can only be found inform a mosaic. The spontaneous mutation of the gene switches on the adenylyl cyclase and consequently increases the cAMP level of the patients. These processes activate control-independent mechanisms of signal transduction. An autonomous regulatory loop emerges.
Symptoms, complaints, and signs
Patients of MAS present with isolated symptoms or symptoms in multiple areas of the skeleton. A limp often presents, accompanied by pain. At times, the condition manifests inform pathologic fractures. In many cases, patients suffer from progressive scoliosis. In women, vaginal bleeding occurs. The mammary glands develop unusually early. In men, testicular enlargements or penile enlargements are sometimes present, resulting in early sexual activity. These symptoms correspond to an endocrinopathy with hyperfunction. Endocrinopathies may also manifest as hyperthyroidism and be associated with increased secretion of growth hormones. In addition to symptoms of Cushing’s syndrome, phosphate loss via the kidneys often occurs. The syndrome manifests in the form of café-au-lait spots usually in the neonatal period. The skull of the patients is often affected by abnormalities. The same can be true for the entire skeleton. Thus, pseudopubertas praecox including acromegaly or short stature is particularly often present. In some cases, affected individuals suffer from progressive visual deterioration and also develop malignancies in the course of the disease.
Diagnosis and course of the disease
The particular extent of McCune-Albright syndrome depends on the proliferation, migration, and survival of the mutant cells. The diagnosis is made by the physician on the basis of clinical presentation. Radiographs are often enough for diagnosis. In case of doubt, biopsies may take place to confirm the diagnosis. When examining and diagnosing patients, specific tests consider each organ that may be involved in MAS. To confirm the diagnosis, no molecular analysis is yet available to detect the GNAS mutation. Nevertheless, genetic counseling is recommended.Neurofibromatoses, osteofibrous dysplasias and non-ossifying fibromas must be excluded in the diagnosis. Idiopathic central pubertas praecox and ovarian neoplasia must also be differentiated. Treatment and prognosis depend on the tissues involved and the severity of involvement.
Complications
McCune-Albright syndrome causes a number of different complaints and symptoms in the patient. In most cases, this syndrome significantly limits the movement of the affected person, causing a limp and other movement problems. Likewise, many women suffer from increased vaginal bleeding due to the syndrome, resulting in pain. It is not uncommon for the patient to experience mood swings and thus a significantly reduced quality of life. The skin of those affected shows brown spots, which have a very negative effect on the aesthetics of the patient. Thus, there is a decreased self-esteem and often a sense of shame. Likewise, children may be teased or bullied due to the symptoms of McCune-Albright syndrome. Furthermore, short stature occurs and those affected suffer from vision problems that can additionally limit everyday life. The individual complaints of McCune-Albright syndrome can be alleviated by various therapies. However, a complete cure does not occur. Furthermore, the affected person is also dependent on a high level of sun protection to protect the skin. Life expectancy is usually not affected by the disease.
When should one go to the doctor?
Abnormalities of the skeletal system or disorders of mobility should be presented to a physician. If there are irregularities in movement patterns, restrictions in joint activity or an inconsistency in locomotion, a doctor is needed. A misaligned or crooked posture, pain during movement or a curved posture of the body are signs of an existing health disorder. An examination is necessary so that a diagnosis and treatment can be made. Women often experience involuntary vaginal bleeding with McCune-Albright syndrome. They should seek medical attention. Additionally, they should take special care to avoid further complications within the planning of possible reproduction. Affected boys and men show enlarged external sexual characteristics when they have the disease. A visit to the doctor is advisable so that the cause can be clarified and no sexual dysfunctions develop. If psychological problems occur due to the visual changes of the testicles and penis, a doctor is also needed. In case of growth disorders, a short stature or any other optical blemish, a doctor should be consulted. Characteristic of McCune-Albright syndrome is a change in the shape of the head. If changes or abnormalities in the general appearance of the skin occur, the affected person needs a doctor. Spotting or other discoloration of the skin should be presented to a physician, as it is an indication of an existing condition.
Treatment and therapy
To date, no causal therapy is available for patients with McCune-Albright syndrome. Thus, the syndrome is still considered an incurable disease. Causal therapy will not be available until gene therapy approaches reach the clinical phase. Treatment is mainly symptomatic and also includes regular supportive controls. Consistent avoidance of UV exposure is recommended as a preventive measure in view of the malignancies that may occur. The same applies to the consistent use of photoprotective agents. In addition to these preventive steps, patients sometimes receive cosmetic care for their hyperpigmentation. Therapy of their fibrous dysplasia aims at stabilization. Conservative drug therapy lends itself to this end. For example, bisphosphonates are frequently used. MAS-associated endocrinopathies may require surgical intervention. The same is true for malignancies. In most cases, patients are also recommended strength exercises to strengthen the muscles in the immediate vicinity of the bones and thus reduce the general risk of fractures. The strength exercises usually take place under physiotherapeutic supervision. Depending on the respective organ involvement, the above treatment steps can be supplemented by organ-specific treatment measures.
Outlook and prognosis
McCune-Albright syndrome has an unfavorable prognosis. The disease is based on a genetic disposition. To date, there is no treatment option that provides a cure for the health disorder. Scientists are not allowed to alter the genetics of humans. This means that no causal treatment can take place. The legal requirements cause doctors to focus on alleviating the existing symptoms in a treatment. Long-term therapy is necessary, since a relapse of the complaints is associated with a termination of the initiated measures. Medications are administered to ensure that sufficient bisphosphonates are available to the organism. In addition, the musculoskeletal system of the affected person is supported with physiotherapeutic measures. Regular check-ups are necessary in order to document changes in the skin’s appearance at an early stage. As soon as abnormalities become apparent, further treatment measures become necessary. If a skin cancer develops, the patient is threatened with premature death. The further development improves if the affected person takes precautionary measures. A sufficient protection against light influences is necessary as well as a self-responsible execution of the physiotherapeutic exercise units. Due to the visual conspicuousness of the disease as well as the impairment of the movement processes, an increased risk of secondary diseases is to be expected with this disorder. Emotional stress in everyday life is so severe for some sufferers that psychological secondary disorders can develop.
Prevention
McCune-Albright syndrome cannot yet be successfully prevented because it is a spontaneous genetic mutation. At most, genetic counseling may be helpful in this context.
Follow-up
Because treatment of McCune-Albright syndrome is relatively complex and lengthy, follow-up care focuses on safe management of the disease. Affected individuals should try to focus on a positive healing process despite the adversity. To build the appropriate mindset, relaxation exercises and meditation can help calm and focus the mind irritated by the rigors of illness. Meditative exercises can have a positive effect on the strong mood swings. If depression or other mental upsets have developed in the affected patient or family, this should be discussed with a psychologist. Therapy can help to restore mental balance and build up a more positive attitude that makes it easier to deal with the disease. In this way, the quality of life can be improved despite the circumstances.
Here’s what you can do yourself
The individual symptoms of McCune-Albright syndrome can often be relieved by those affected themselves. First, however, the syndrome must be medically clarified and treated to rule out a severe course and serious complications. After diagnosis, strict personal hygiene is important to avoid inflammation in the area of the bleeding. Women suffering from vaginal bleeding should talk to their gynecologist. If growth disorders occur, the affected person or their parents should seek therapeutic help. It is also important to avoid UV radiation, as this can aggravate individual symptoms and possibly also cause long-term damage. Light protection products and similar products should also be avoided or used only in consultation with the responsible physician. Accompanying this, a healthy lifestyle with a balanced diet, plenty of exercise and the avoidance of stress is recommended. This and preventive measures can avoid serious consequences in many cases. If the above-mentioned self-help measures do not have any effect or if new symptoms occur, the doctor must be consulted in any case. It is possible that there is another disease besides McCune-Albright syndrome that needs to be clarified and, if necessary, treated.
