Children with Werner syndrome often appear unusually thin and, during late childhood, have an unusually slow growth rate. In addition, there is absence of the growth spurt typically seen during adolescence. Affected individuals typically reach their final height by approximately 13 years of age. However, adult height may be reached as early as at age 10 or as late as at age 18. Weight is also unusually low, even relative to short stature.
Before age 20, most individuals with Werner syndrome develop early graying and whitening of the scalp hair (canities). By about 25 years of age, affected individuals may experience premature loss of scalp hair (alopecia) as well as loss of the eyebrows and eyelashes. In addition, hair under the arms (axillary hair), in the pubic area, and on the trunk may be unusually sparse or absent. According to reports in the medical literature, the hair loss seen in those with Werner syndrome may occur secondary to impaired functioning of the ovaries in females or the testes in males (hypogonadism), an endocrine condition associated with deficient growth and sexual development. Both males and females with Werner syndrome may be affected by hypogonadism. As a result, affected males usually have an unusually small penis and small testes. Some females with the disorder may fail to develop secondary sexual characteristics (e.g., appearance of axillary and pubic hair, breast development, menstruation) and have poorly developed genitals. In other affected females, menstruation may be spare and irregular. Due to hypogonadism, most of those with the disorder may be infertile. However, there have been reports in the literature confirming that some affected males and females have reproduced.
In addition to premature graying and hair loss, individuals with Werner syndrome are affected by other progressive degenerative changes, including gradual loss of the layer of fat beneath the skin (subcutaneous adipose tissue); severe wasting (atrophy) of muscles within the hands, legs, and feet; and premature, generalized loss of bone density (osteoporosis), a condition that may cause or contribute to repeated fractures following minor trauma. Dental abnormalities may also be present, including abnormal development and premature loss of teeth. In approximately one third of individuals with Werner syndrome, there is also an abnormal accumulation of calcium salts (calcification) in and associated hardening of soft tissues (e.g., ligaments, tendons), particularly those of the elbows, knees, and ankles. In addition, due to progressive atrophy of the vocal cords, most individuals with the disorder develop an abnormally high-pitched voice. In other cases, the voice may be squeaky or unusually hoarse.
By approximately 25 years of age, individuals with Werner syndrome also develop progressive skin changes, particularly affecting the facial area, the upper arms and hands, and the lower legs and feet (distal extremities). For example, there is skin wasting (atrophy) over areas in which there is depletion of fatty (adipose), connective, and muscle tissue, resulting in the appearance of unusually shiny, “waxy,” smooth, or hardened (“scleroderma-like”) skin patches that may adhere to underlying tissues. Affected areas may be prone to developing open sores (ulcers) due to decreased supply of oxygenated blood to tissues (ischemia). The ulcers may be chronic and slow healing. Deep ulcerations around Achilles tendons and, less frequently, at elbows, are highly characteristic to Werner syndrome.
Many individuals with Werner syndrome also have additional skin abnormalities. Skin of the arms and legs may develop abnormally increased coloration (hyperpigmentation), decreased coloration (hypopigmentation), or abnormal widening of certain small underlying blood vessels, causing associated redness (telangiectasias). In addition, skin of the palms, of the soles, and overlying certain prominent joints, such as the elbows and knees, may become unusually thickened (hyperkeratosis) and tend to develop ulcers due to destruction of surface tissues.
Due to atrophic changes of the skin and underlying tissues in the facial area, affected individuals may have a distinctive, “pinched” facial appearance including unusually prominent eyes; stiff ears that have lost their elasticity; and a thin, beaked or pinched nose. Premature graying and loss of hair contribute to the characteristic appearance. According to reports in the medical literature, in most individuals with Werner syndrome, the appearance of premature aging is apparent by approximately age 30 to 40.
Werner syndrome is also typically characterized by the premature onset of senile cataracts, a condition in which there is loss of transparency of the lenses of the eyes. In individuals with Werner syndrome, cataracts typically affect both eyes (bilateral) and have an abrupt onset within the third or fourth decade of life. (Senile cataracts typically develop in individuals over age 50.) In some cases, other abnormalities of the eyes may also be present, such as an accumulation of calcium deposits within the transparent region in the front of the eyes (corneal calcification), inflammation of the middle and innermost layers of the eyes (chorioretinitis), degeneration of the nerve cells (rods and cones) of the retina that respond to light (retinitis pigmentosa), and/or progressive degeneration of the central region of the retina (senile macular degeneration). The degree of associated visual impairment depends upon the severity and/or combination of eye abnormalities present.
Approximately 70 percent of affected individuals have develop non-insulin-dependent (or type II) diabetes mellitus at the time of diagnosis. Non-insulin-dependent diabetes mellitus is a metabolic disorder characterized by resistance to the effects of the hormone insulin and abnormal insulin secretion by the pancreas, resulting in increased levels of the simple sugar glucose in the blood. (Insulin regulates glucose levels in the blood by promoting the movement of glucose into cells for energy production.) This form of diabetes usually develops in normal individuals of approximately 50 to 60 years. However, in those with Werner syndrome, the condition may become apparent by about age 35. Affected individuals may have no apparent symptoms (asymptomatic) at diagnosis or experience increased urination (polyuria), excessive thirst (polydipsia), increased hunger (polyphagia), and/or other characteristic symptoms. In addition, those with this form of diabetes may be susceptible to diabetic coma due to severely reduced levels of fluid within cells (hyperosmolar nonketotic coma). According to reports in the medical literature, although non-insulin-dependent diabetes mellitus may be associated with certain long-term complications, such as nerve damage (neuropathy), impaired kidney function (nephropathy), and damage to blood vessels within the retina (diabetic retinopathy), such complications have not been reported in affected individuals with Werner syndrome.
Werner syndrome is also characterized by severe, progressive, often widespread thickening and loss of elasticity of artery walls (arteriosclerosis). In some affected arteries, there may be abnormal accumulations of calcium deposits within the middle coat (tunica media) of the arteries and progressive destruction and replacement of the arteries’ muscle and elastic fibers with fibrous tissue (Monckeberg’s arteriosclerosis). Arteries affected by this form of arteriosclerosis may include those that transport oxygen-rich blood to heart muscle (coronary arteries) or certain arteries of the legs (peripheral vascular disease). Arteriosclerosis of peripheral blood vessels may cause or aggravate skin wasting (atrophy) and ulceration In addition, abnormal calcium deposits may accumulate within certain heart valves, such as the valve situated where the body’s major artery (aorta) arises from the lower left chamber of the heart (aortic valve) and the valve located between the left upper and lower heart chambers (mitral valve). Progressive arteriosclerosis may lead to episodes of chest pain due to deficient oxygen supply to heart muscle (anginal attacks); progressive inability of the heart to effectively pump blood to the lungs and the rest of the body (heart failure); localized loss of heart muscle caused by interruption of its blood supply (myocardial infarction or heart attack); and/or other potentially life-threatening complications.
People with Werner syndrome also have an increased predisposition to cancers. The most common neoplasms in Werner syndrome are carcinomas of thyroid, followed by cancers of the pigment-producing cells in skin and mucosa (malignant melanoma), cancer of the protective membranes surrounding the brain and the spinal cord (meningioma), tumors that arise within the soft tissues and bones (sarcomas and osteosarcoma), soft tissue sarcomas, primary bone tumors and leukemia/myelodysplasia.
Due to progressive arteriosclerosis, malignancies, and/or other associated abnormalities, many individuals with Werner syndrome may experience life-threatening complications by approximately the fourth or fifth decade of life.