Werner syndrome

Definition

Werner syndrome is a very rare, inherited disease that resembles premature aging. Since the gene responsible was discovered in the mid-1990s, Werner syndrome has greatly interested researchers as a possible model for the study of human aging. It is also being extensively studied for insights it may eventually supply into a number of other diseases including cancer , diabetes mellitus, and atherosclerosis.

Description

This syndrome is named for the German physician C. W. Otto Werner (1879-1936). Werner was a medical student in 1903 when he first observed the syndrome in four siblings, all about 30 years of age. The following year, Werner wrote about these observations in his "Inaugural Dissertation."

The clinical signs and symptoms of Werner syndrome start to appear during the teen or early adult years, after which patients appear to age rapidly and have a greater-than-usual chance of developing cancer, cardiovascular disease, or diabetes mellitus. By the time the patient is 30–40 years old, he or she has the look of old age. The most common cause of death is heart attack.

While in many ways the signs and symptoms of Werner syndrome resemble those of premature aging (referred to in adults as progeria), there are also some significant differences. For instance, the tumors commonly seen in Werner syndrome patients are commonly derived from the cells of the mesoderm, a middle layer of the embryo that gives rise to a variety of tissues including cartilage, muscle, bone, kidneys, and connective tissue. In normal aging, tumors are more likely to be derived from the epithelial cells that cover the body's exterior and line most of its hollow structures. Osteoporosis and soft-tissue calcium deposits are found both in Werner syndrome and normal aging, but the distribution of these conditions within the body is different in patients with Werner syndrome. In addition, patients with Werner syndrome do not generally experience symptoms of Alzheimer disease or premature cognitive decline, as do their aging counterparts in the general population.

Researchers are uncertain whether the symptoms of Werner syndrome are really a speeding-up of normal aging, or whether the many similarities are coincidental. There is nonetheless considerable optimism that further research into Werner syndrome may lead to a better understanding of aging, cancer, diabetes, systemic sclerosis, atherosclerosis, cataracts, and other conditions.

Genetic profile

Werner syndrome results from mutation of a single gene. In 1992, the gene responsible (WRN) was mapped to chromosome 8p11-12. In 1996, a research group based in Seattle cloned the WRN gene. It was also discovered that the syndrome resulted from an autosomal recessive mutation that affects a member of a family of enzymes known as helicases that unwind deoxyribonucleic acid (DNA ) and, in some cases, ribonucleic acid (RNA ).

Despite the discovery that Werner syndrome is caused by a genetic defect, researchers are unable to explain exactly how this defect causes the disease. The purpose of helicases in the body is not fully understood, but they are known to unwind DNA, splitting the double-stranded molecules into separate single-stranded molecules. In this way, the enzymes are involved in the repair, recombination, replication, and transcription of DNA. There appear to be many damaged sites in DNA taken from patients with Werner syndrome. It has therefore been suggested that Werner syndrome may be caused by failure in these DNA-related processes, and that the somatic cells of those with Werner syndrome may be particularly prone to mutations.

The WRN gene is not known to bind to DNA damage, but recent research has suggested it might be able to sense the presence of damaged DNA. Since the discovery of the WRN gene, more than 10 mutations have been uncovered. Many of these mutations were in the Japanese population. It has been suggested that the relatively high incidence of Werner syndrome in that country may be related to traditions of marriages between closely related individuals in some areas of Japan.

Researchers are seeking an animal model to allow them to further study Werner syndrome. Specifically, they hoped to create mice with a genetic equivalent of the WRN gene, and to determine whether these mice would age more quickly than normal mice.

Demographics

Because of the limited number of cases, the demographic distribution of Werner syndrome is difficult to determine. Estimates of the number of people affected range from one in 95,000 to one in 1,000,000 people. Unlike progeria, which can be diagnosed at birth or soon after, Werner syndrome is not usually detected prior to adolescence. It is commonly noticed only after patients have failed to undergo the normal growth spurt associated with their teen years. The full range of symptoms is not usually seen until patients reach their 20s or 30s. Werner syndrome is more common in families in which a close biological relationship exists between parents. It occurs equally in both sexes. There is no evidence of a birth-order effect.

Signs and symptoms

The cardinal signs and symptoms of Werner syndrome start to appear after the age of 10. They are:

• Cataracts. These occur in both eyes, and usually develop by age 25 or 30.
• Skin problems including tight, shiny, smooth skin, ulceration, general wasting of the skin and localized wasting of the subcutaneous area underneath it, pigmentary changes, a thickening of the horny outer layer of the skin, and a characteristic bird-like facial appearance, including a beaked or pinched nose and unusually prominent eyes.
• Shortness of stature.
• An affected sibling or a close biological relationship between parents (third cousin or closer).
• Earlier-than-usual graying and/or thinning of scalp hair, usually by age 20.
• Excess amounts of hyaluronic acid (more commonly found in the body's connective tissues and in the fluids of the eyes and joints) in the urine.

Additional signs and symptoms of Werner syndrome include the following:

• Diabetes mellitus. This is usually mild, but can be found in between 44% and 67% of Werner syndrome patients.
• Impaired function of the ovaries or testes, as indicated by small or poorly developed genitalia or reduced fertility.
• Osteoporosis, most commonly in the upper limbs and spine, as well as in the lower limbs, feet, and ankles. In patients with Werner syndrome, osteoporosis is unlikely to be found in the skull or the torso.
• Unusually high bone density in the extremities of the finger and toe bones. This must be established by an x-ray examination.
• Deposits of calcium salts in soft tissues of the body. Common locations are around the Achilles tendon and the tendons of the elbow and the knee.
• Evidence pointing to earlier-than-usual arterial disease, such as a prior heart attack or abnormal electrocardiograms, etc.

• Rare or multiple tumors, or tumors derived from the mesoderm, the middle layer of the embryo. Werner syndrome is not marked by increased occurrence of all forms of tumors, but by selectively higher proportions of certain cancers that are relatively rare.
• Changes to the voice, rendering it squeaky, hoarse, or high-pitched.
• Flat feet.

In addition to the above signs and symptoms used for formal diagnostic purposes, other clinical observations have been reported, including loss of eyelashes and eyebrow hair, nail deformities, as well as the presence of thin limbs with a stocky trunk. A possible link to lung cancer has also been proposed.

In some cases, Werner syndrome can occur in a slower and milder partial form, with only some of the symptoms present.

Diagnosis

A definite diagnosis of Werner syndrome is established by the presence of all of the cardinal signs and symptoms listed above, plus at least two of the additional signs and symptoms.

A probable diagnosis is indicated by the presence of all of the first three cardinal signs, plus any two from the additional list.

A possible diagnosis is suggested by the presence of either cataracts or the skin manifestations, plus any four of the other signs or symptoms.

Werner syndrome may be ruled out if the above signs and symptoms appear prior to adolescence. The exception to this rule is shortness of stature, because patterns of pre-adolescent growth are not sufficiently understood.

Diagnosis may involve x rays to study hormone excretion, skin biopsies, and a blood-sugar test to determine whether diabetes mellitus is present. Werner syndrome can also be diagnosed by mutational analysis of the WRN gene.

Treatment and management

There is no known cure for Werner syndrome, so treatment is related to the specific symptoms present. For example, cataracts can be corrected by surgery and skin ulcers can be treated with grafts.

Prognosis

Because it mimics the human aging process, Werner syndrome significantly reduces life expectancy in most patients. Average life expectancy for a Werner symptom patient is somewhere between 40 and 47 years. The most common causes of death are heart attacks, cerebrovascular accidents, and cancers.

Resources

BOOKS

Thoene, Jess G., ed. Physicians' Guide to Rare Diseases. 2nd ed. Montvale, NJ: Dowden Publishing Company Inc., 1995.

ORGANIZATIONS

International Progeria Registry. IBR Dept. of Human Genetics, 1050 Forest Hill Rd., Staten Island, NY 10314. (718) 494-5333. [email protected].

International Registry of Werner Syndrome. University of Washington Dept. of Pathology, Health Science Bldg K543, Box 357470, Seattle, WA 98195. (206) 543-5088. <http://www.pathology.washington.edu/werner/registry/frame2.html>.

March of Dimes Birth Defects Foundation. 1275 Mamaroneck Ave., White Plains, NY 10605. (888) 663-4637. [email protected]. <http://www.modimes.org>.

David L. Helwig