Werner's syndrome: what is it, symptoms, treatment, prognosis

What is Werner's Syndrome?

Werner's syndrome (or adult progeria) Is a rare progressive disease characterized by the appearance of unusually accelerated aging (Progeria). Although the disorder is usually recognized by the third or fourth decade of life, certain characteristics are present from adolescence to early adulthood.

People with Werner's syndrome have a slow growth rate, and growth stops at puberty. As a result, patients are short in stature and low in weight compared to their height. By the age of 25, patients with this condition usually experience early graying (graying) and premature hair loss on the scalp (alopecia). As the disease progresses, additional abnormalities include loss of a layer of fat under the skin (subcutaneous adipose tissue); severe wasting (atrophy) of muscle tissue in certain areas of the body; and degenerative changes in the skin, especially in the face, forearms and hands, and legs and feet (distal extremities). Due to degenerative changes affecting the facial area, people with Werner's syndrome may have unusually bulging eyes, a beak-shaped or pinched nose, and / or other characteristic facial anomalies.

Werner's syndrome can also be characterized by the development of a characteristic high-pitched voice; ocular abnormalities, including premature clouding of the lens of the eye (bilateral senile cataract); and some endocrine defects such as ovarian dysfunction in women or testicular dysfunction in men (hypogonadism) or abnormal production insulin hormonepancreas and insulin resistance (non-insulin dependent diabetes mellitus / type 2 diabetes). In addition, patients with Werner's syndrome may develop progressive thickening and loss of elasticity of the arterial walls (arteriosclerosis). Affected blood vessels usually include arteries that transport oxygen-rich (oxygenated) blood to the heart muscle (coronary arteries). Some people may also be susceptible to developing certain benign or malignant tumors. Progressive arteriosclerosis, malignant neoplasms and / or related disorders can lead to potentially life-threatening complications by about the fourth or fifth decade life. Werner's syndrome is inherited in an autosomal recessive manner.

Signs and symptoms

Children with Werner syndrome often appear unusually thin and have an unusually slow growth rate in late childhood. In addition, there is no growth spurt commonly seen in adolescence. Patients reach their final height by about 13 years of age. However, adult growth can be achieved as early as age 10 or as early as age 18. The weight is also unusually small, even when compared to the short stature.

Before the age of 20, most people with Werner syndrome experience early graying and discoloration of hair on the scalp. By about age 25, people may experience premature loss of scalp hair (alopecia), as well as loss of eyebrows and eyelashes. In addition, hair in the armpits (hair in the armpits), pubic area, and trunk may be unusually sparse or absent. According to reports in the medical literature, hair loss seen in patients with Werner's syndrome may be secondary to ovarian dysfunction in women or testes in men (hypogonadism), an endocrine state associated with insufficient growth and sexual development. Both men and women with Werner syndrome can suffer from hypogonadism. As a result, affected men usually have an unusually small penis and small testicles. Some women with this condition may not develop secondary sexual characteristics (for example, the appearance of hair in the armpits and on the pubis, breast development, menstruation) and poorly developed genital organs. In other sick women, menstruation may be scanty and irregular. Most people with this condition can be infertile due to hypogonadism. However, there have been reports in the literature confirming that some sick men and women reproduced.

In addition to premature graying and hair loss, people with Werner syndrome are prone to other progressive degenerative changes, including

• gradual loss of the layer of fat under the skin;
• severe wasting (atrophy) of the muscles of the arms, legs and feet;
• premature total loss of bone density (osteoporosis), a condition that can cause or contribute to re-fracture after minor trauma.

Dental abnormalities may also be present, including abnormal development and premature tooth loss. About one third of patients with Werner syndrome also have an abnormal accumulation of calcium salts (calcification) and associated hardening of soft tissues (eg, ligaments, tendons), especially elbows, knees and ankles. In addition, due to progressive atrophy of the vocal cords, most patients with this disease develop a high-pitched voice. In other cases, the voice may be raspy or unusually hoarse.

By about the age of 25, patients with Werner's syndrome also develop progressive skin changes, especially in the area of ​​the face, forearms and hands, as well as the legs and feet (distal limbs). For example, there is a loss (atrophy) of the skin in areas with depleting adipose, connective and muscle tissue, which results in unusually shiny, smooth, or hardened areas of skin that can adhere to the underlying tissues. Open ulcers may develop in the affected area due to a decrease in the supply of oxygenated blood to the tissues (ischemia). Ulcers can be chronic and slow to heal. Deep ulcers around the Achilles tendon and, less commonly, on the elbows, are very characteristic of Werner's syndrome.

Many people with Werner's syndrome also have additional skin abnormalities. The skin of the hands and feet may have hyperpigmentation or hypopigmentation and / or abnormal enlargement certain small underlying blood vessels, causing corresponding redness (telangiectasia). In addition, the skin on the palms, soles, and over some prominent joints, such as the elbows and knees, can become unusually thickened (hyperkeratosis) and tend to develop ulcers due to destruction of superficial fabrics.

Due to atrophic changes in the skin and underlying tissues in the facial area, patients may have a characteristic "pinched" appearance of the face, including:

• unusually protruding eyes;
• hard ears that have lost their elasticity;
• thin beak-shaped and flattened nose.

Premature graying and hair loss give a distinctive look. According to reports in the medical literature, the majority of patients with Werner syndrome develop premature aging around the age of 30 to 40 years.

Werner's syndrome is also usually characterized by the premature onset of senile cataracts, a condition in which there is a loss of transparency of the lenses of the eyes. In people with Werner's syndrome, cataracts usually affect both eyes (bilateral) and suddenly occur during the third or fourth decade of life. (Senile cataracts usually develop in people over 50.) In some cases, there may be other abnormalities in the eye, such as a buildup of calcium deposits in the clear area in front of the eyes. (corneal calcification), inflammation of the middle and inner layers of the eyes (chorioretinitis), degeneration of nerve cells (rods and cones) of the retina, responsive to light (retinitis pigmentosa), and / or progressive degeneration of the central region of the retina (senile macular degeneration / age-related macular degeneration). The degree of associated visual impairment depends on the severity and / or combination of the eye abnormalities present.

Approximately 70 percent of those affected have developed non-insulin dependent (or type 2) diabetes. Non-insulin dependent diabetes mellitus is a metabolic disorder characterized by resistance to the action insulin hormone and abnormal insulin secretion pancreas, which leads to an increase in the level of simple sugar (glucose) in the blood. (Insulin regulates the level blood glucose, promoting the movement of glucose into cells for energy.) This form of diabetes usually develops in healthy people between the ages of 50 and 60. However, in patients with Werner's syndrome, the condition can manifest itself by about 35 years of age. Patients may not have overt symptoms at the time of diagnosis, or they may have increased frequency of urination (polyuria), excessive thirst (polydipsia), increased hunger (polyphagia) and / or other characteristic symptoms. In addition, people with this form of diabetes may be predisposed to diabetic coma due to dramatically reduced fluid levels in their cells (hyperosmolar diabetic coma). According to reports in the medical literature, although insulin-dependent diabetes mellitus may be associated with certain long-term complications such as nerve damage (diabetic neuropathy), impaired renal function (diabetic nephropathy) and damage to retinal blood vessels (diabetic retinopathy), no such complications were reported in patients with Werner's syndrome.

Werner syndrome is also characterized by severe, progressive, often widespread thickening and loss of elasticity in the walls of the arteries (arteriosclerosis). Some affected arteries may have abnormal accumulations of calcium deposits in the middle lining of the arteries and progressive destruction and replacement of muscle and elastic fibers of the arteries with fibrous tissue (arteriosclerosis Menckeberg). Arteries affected by this form of arteriosclerosis may include those that transport oxygen-rich blood to the heart muscle (coronary arteries) or certain arteries in the legs (peripheral disease vessels). Arteriosclerosis of peripheral blood vessels can cause or worsen skin wasting (atrophy) and ulceration (ulceration). In addition, abnormal calcium deposits can build up in certain heart valves, such as the valve located where the main artery is body (aorta) exits from the lower left chamber of the heart (aortic valve), and a valve located between the left upper and lower chambers of the heart (mitral valve). Progressive arteriosclerosis can lead to:

• episodes of chest pain due to insufficient oxygen supply to the heart muscle (attacks angina pectoris);
• progressive inability of the heart to efficiently pump blood to the lungs and the rest of the body (heart failure);
• localized loss of the heart muscle caused by a violation of its blood supply (myocardial infarction or heart attack);
• and / or other potentially life-threatening complications.

Patients with Werner's syndrome also have an increased predisposition to cancer. The most common neoplasms in Werner syndrome are thyroid cancerfollowed by cancer of the pigment-producing cells of the skin and mucous membranes (malignant melanoma), cancer of the protective membranes surrounding the brain and spinal cord (meningioma), tumors arising inside soft tissues and bones (sarcomas and osteosarcomas), sarcomas of soft tissues, primary bone tumors, and leukemia / myelodysplasia.

Due to the progressive atherosclerosis, malignant neoplasms and / or other related disorders, many patients with Werner syndrome can experience life-threatening complications by about the fourth or fifth decade of life.

Causes

Werner's syndrome is transmitted in an autosomal recessive manner. Human traits, including classic genetic diseases, are the product of the interaction of two genes, one from the father and the other from the mother.

Recessive genetic disorders occur when a person inherits an abnormal gene from each parent. If a person receives one normal gene and one abnormal gene for a disease, they will be a carrier of the disease, but usually asymptomatic. The risk for both carrier parents of passing on the abnormal gene and therefore having a sick child is 25% with each pregnancy. The risk of having a carrier child, like a parent, is 50% with every pregnancy. The probability that a child will receive normal genes from both parents is 25%. The risk is the same for men and women.

The parents of some people with Werner's syndrome were close in blood (blood relatives). In these cases, if both parents carry the same disease gene, there is a higher than usually, the risk that their children may inherit two disease genes necessary for development diseases.

Werner's syndrome is caused by abnormal (pathological) changes (mutations) in a gene WRN. More than 80 different gene mutations have been identified in people with this disease WRN.

WRN the gene encodes a protein called helicase, suggesting that impaired DNA metabolism is involved in the premature aging seen in people with this disease. Metabolism refers to the chemical processes that take place in the tissues of the body. DNA or deoxyribonucleic acid carries the genetic code in cells, has a spiral ladder structure and is made up of chains of specific chemical groups. DNA "helicase" proteins are thought to promote DNA "unwinding" during certain cellular actions, such as repair damaged DNA and the division of identical chromosomes (chromosomal segregation) into two "daughter cells" during division and reproduction cells. Researchers suggest that Werner's syndrome occurs due to the complete loss of function of the helicase protein encoded by WRN gene. The specific function of the helicase protein in preventing premature aging remains unclear.

However, in laboratory (in vitro) studies of skin cell samples (cultured human fibroblasts), researchers have demonstrated that human cells without disease can multiply about 60 times ("doubling the population"), while fibroblasts with Werner's syndrome can reproduce only about 20 once. Based on these results, some researchers have suggested that WRN is essentially a "counting gene" that regulates the total number of times that human cells can divide and reproduce. Such researchers suggest that gene mutations WRN can lead to premature inhibition of DNA replication (synthesis) and early cellular senescence - events that usually occur later in normal aging human cells.

Researchers have also observed a high incidence of chromosomal abnormalities (such as accidental translocations) in cultured skin cells (fibroblasts) and cultured leukocytes (lymphocytes) obtained from certain cell lines (clones) in people with the syndrome Werner. Such findings (sometimes called "multi-translocation mosaicism") suggest that "chromosome breakage" may be a characteristic or play a role in the disease process. However, the specific implications of such discoveries remain unknown and further research is required.

Affected populations

Werner's syndrome is a rare disease that affects men and women equally. Since the disorder was first described in the medical literature in 1904 (O. Werner), more than 800 cases have been reported. The incidence of the disorder is estimated to be between 1 and 20 per million people. Although certain associated features are present during childhood, puberty, and young age, the disorder is most often diagnosed in the third or fourth decade of life.

Symptomatic disorders

Symptoms of the following disorders may be similar to those of Werner's syndrome. Comparisons can be useful for differential diagnosis:

• Progeria (Hutchinson-Guildford syndrome or premature aging syndrome) is a very rare childhood disease characterized by premature aging, short stature and characteristic facial features. The primary symptoms of the disorder are related to the aging process. Children with Hutchinson-Guildford syndrome age very quickly and suffer from older age disorders at a young age. By about age 10, most children with Premature Aging Syndrome reach the height of the average 3-year-old child. Arthritis is common and affects bone joints during childhood and adolescence.
• Gottron syndrome (acrogeria) is a mild hereditary form of premature aging (progeria), characterized by abnormally small arms and legs with thin and delicate skin. From infancy, children with the disorder appear to be older than their actual age. The skin on the arms and legs is unusually thin and looks like parchment. The hands and feet remain abnormally small into adulthood.
• De Barcy Syndrome - a rare disease transmitted by an autosomal recessive genetic trait. Major characteristics include degeneration of the elastic tissue of the skin (elastolysis), involuntary movement of the arms and legs (athetosis), clouding of the cornea of ​​the eyes, large protruding ears, and loss of muscle tone. Other symptoms may include unusual flexibility in small joints, a protruding forehead, and / or short stature. Loss of skin elasticity leads to aging and wrinkling.
• Mulwichill-Smith Syndrome - an extremely rare hereditary disease associated with premature aging. It is characterized by short stature, small head (microcephaly), aging of the face, loss of fatty layers under the skin, multiple age spots on the skin (nevi), hearing loss and / or impaired immune system. This disease can occur during childhood or adolescence. Mulwichill-Smith syndrome is described in only four people in the medical literature.
• Storm Syndrome - an extremely rare hereditary disease associated with premature aging and heart disease. Other symptoms during adolescence can include loss of eyebrows and eyelashes, and thinning and graying of hair on the scalp. The skin on the hands and face becomes tight, wrinkled. Some people also experience pain and joint dysfunction.
• Combined growth factor defect (Werner's syndrome due to a combined deficiency of growth factors) is an extremely rare hereditary disease. The symptoms of this disorder are similar to those of Werner's syndrome and include loss of fat layers on the arms and legs, a beak-like nose, a small jaw, and / or a narrow mouth. Other symptoms may include joint dysfunction, flat feet, and thin tight skin.
• Rothmund-Thomson syndrome - an inherited skin disorder characterized by abnormal redness of the skin caused by blockage of small blood vessels (capillaries). Most people with Rothmund-Thomson syndrome have short stature, loss of muscle mass, and red skin. Some people are abnormally sensitive to light (photosensitivity) and may develop cataracts during adolescence. Other symptoms may include underdeveloped teeth and nails, unusually small hands and feet, deformed or missing thumbs and / or sparse and premature gray hair, or baldness.

Diagnostics

In some cases, Werner's syndrome can be recognized clinically as early as about 15 years of age on the basis of careful clinical assessment, characteristic physical findings (eg, no growth spurt during puberty, short stature, low weight) and careful consideration of the patient's history and families. However, the disease often cannot be recognized or confirmed until the third or fourth decade of life after certain characteristic symptoms have been noted and signs (eg, premature graying and hair loss, characteristic voice, loss of subcutaneous tissue, muscle atrophy, skin changes, bilateral senile cataracts, and etc.).

Specialized imaging studies and laboratory tests may be performed to detect, confirm, or characterize certain anomalies potentially associated with disease. For example, eye specialists (ophthalmologists) can regularly monitor patients for the development of cataracts using certain measures, such as using a special instrument that allows you to visualize the inside of the eyes (ophthalmoscope). When cataracts are found, an illuminated microscope (slit lamp) can be used to examine the internal structures of the anterior parts of the eyes, which allows ophthalmologists to determine the specific location and degree of cataracts.

Additional testing may include monitoring blood sugar levels to ensure rapid detecting diabetes mellitus, bone scans and blood tests for osteoporosis and / or others research. In addition, careful cardiac examinations and ongoing monitoring (e.g., clinical examinations, X-rays studies, specialized cardiac examinations) to assess associated cardiovascular abnormalities and determine appropriate treatment diseases. Individuals with Werner syndrome should also be monitored regularly as needed to ensure prompt detection and appropriate treatment. certain malignant neoplasms or benign tumors that may arise in connection with the disease (for example, osteosarcoma, meningioma).

In some cases, specialized laboratory tests can be performed on cultured cells skin (fibroblasts) of sick patients, showing abnormally reduced replication of fibroblast syndrome Werner. Evaluation of the chromosomal composition (karyotype) in the nuclei of cultured fibroblasts and some leukocytes (lymphocytes) can reveal a high frequency of certain chromosomal rearrangements (mosaicism of heterogeneous translocations). In addition, according to several researchers, urine tests can reveal elevated levels of hyaluronic acid, a complex carbohydrate that is present in the spaces between certain cells (intercellular spaces) in certain connective tissues. The implications of this discovery are not understood.

Confirmation of the clinical diagnosis of Werner's syndrome can be achieved by molecular examination of the gene WRN. Molecular gene sequencing WRN to identify mutations that cause disease, as well as biochemical research to quantify the amount of protein WRNproduced by cells is available on a clinical basis.

Standard treatments

Treatment for Werner's syndrome focuses on the specific symptoms that each person experiences. Treatment of the disorder may require a coordinated effort by a team of specialists who may require systematic and comprehensive planning of the victim's treatment. These professionals may include therapists; doctors who diagnose and treat diseases of the skeleton, muscles, joints and other related tissues (orthopedists); doctors who diagnose and treat pathologies of the heart and its major blood vessels; ophthalmologists (ophthalmologists); doctors involved in the diagnosis and treatment of endocrine system disorders (endocrinologists); and / or other healthcare professionals.

Specific treatments for patients with Werner's syndrome are symptomatic and supportive. According to reports in the medical literature, diabetesis usually mild and can often be treated with dietary changes and intake appropriate medications by mouth to lower elevated blood sugar (glucose) levels (oral hypoglycemic drugs).

In patients with cataracts, treatment may include surgical removal of the clouded lens and implantation of a replacement lens (intraocular lens) or prescription of corrective glasses or contact lenses. Some doctors report that patients with Werner syndrome may have a significantly increased risk of separation layers of the surgical wound (wound dehiscence) and / or other complications (for example, endothelial decompensation cornea). Therefore, these doctors recommend taking special precautions during such surgical procedures. procedures (for example, making small surgical incisions, avoiding topical or systemic cortisone).

In patients with Werner's syndrome, measures for the treatment of arteriosclerosis and associated cardiovascular anomalies are symptomatic and supportive. For example, in patients with attacks of chest pain due to insufficient oxygen supply to the heart muscle (attacks angina) treatment may include the use of certain medications that can help minimize or control such symptoms.

If benign or malignant tumors develop in connection with Werner's syndrome, appropriate treatment measures may vary depending on the specific type of tumor present; benign or malignant tumor; type, stage and / or degree of the disease; and / or other factors. Depending on such factors, treatments may include surgery, the use of certain anticancer drugs (chemotherapy), radiation therapy, and / or other measures.

Genetic counseling is recommended for patients with Werner's syndrome and their families.

Forecast

The prognosis is unfavorable. The average life expectancy of patients with Werner's syndrome is 46 years. Death usually occurs between the ages of 30-50 due to atherosclerosis or malignant tumors. Skillful medical administration of a patient can increase his life span; One patient was described who lived to age 68 and died of acute heart failure.