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I.R.F. / Aging news / Diseases / 04061101

Werner's Syndrome
Posted on: June 11, 2004

Werner's syndrome was initially described by Werner in 1904, when he reported 4 cases of brothers and sisters with symptoms and signs including juvenile cataract, pachyderma-like alteration of the extremities, small stature, premature ageing of the face, juvenile grey hair, and genital hypoplasia. In 1934, Werner's syndrome was described by Oppenheimer and KugeP as an independent disease, with additional endocrine abnormalities, such as osteoporosis and hyperglycaemia. To the best of the authors' knowledge, about 1300 cases reported around the world from 1916 to 2002, including about 1000 Japanese patients. Japan is an area of extremely high incidence of Werner's syndrome. Scientists were able to locate 411 Japanese cases in the literature from 1916 to 2002. Cases were most frequently reported in the fields of dermatology and ophthalmology but infrequently in the field of orthopaedics, with only 45 Japanese cases reported.
Werner's syndrome is regarded as a representative model disease of early senility in human beings. This syndrome rarely appears before puberty, but thereafter is evident in signs such as a 'bird-like' face or generalised signs of senility (grey hair, alopecia, cataracts, and skin atrophy with refractory skin ulceration). It is also evident in diseases generally caused by ageing, such as arteriosclerotic diseases (myocardial infarction, cerebral infarction), diabetes mellitus with hyperinsulinaemia, hyperlipaemia, hyperuricaemia, and osteoporosis from the age of 30 years. In many cases the patient dies of malignant tumours or arteriosclerotic diseases, at an average age of 46 years. Irwin and Ward identified a total of 17 features associated with Werner's syndrome (Table 1).

Table 1. Characteristic features of Werner's syndrome. Diagnostic criteria by Irwin and Ward.

Characteristic habitus and stature
Short stature (from adolescence)
Slender extremities witk stocky trunk
Beak-shaped nose
Premature senility
Premature grey hair
Premature baldness
Atropic skin
Weak and high-pitched voice
Arteriosclerosis
Juvenile cataracts
Scleroderma-like changes
Atrophic skin and subcutaneous tissues
Circumscribed hyperkeratosis
Ulcers over the malleoli of the ankles, Achilles tendon, heels and toes
Other manifestations
Tendency to diabetes mellitus
Hypogonadism
Osteoporosis
Localised calcification
Tendency to occur in siblings

The most problematic complications of Werner's syndrome are arteriosclerosis and malignant tumours. The frequency of malignant tumours reported ranges from 5.6% to 25%. In Japanese cases, this figure is 20.7% (85 of 411 reported cases). Of the 411 Japanese cases, 25 patients (6.1%) died of malignant tumours (Table 2); which is considerably higher than that of the Japanese general population (0.3%). Moreover, this is the most common cause of death in Werner's syndrome in Japan. For the general population, epithelial cancer has an incidence rate 10 times that of mesenchymal sarcoma, but among patients with Werner's syndrome the incidence is approximately equal. An increased incidence of thyroid cancer, malignant melanoma, and osteosarcoma and soft tissue sarcoma is evident. Benign tumours were found in a total of 37 Japanese patients, including 18 patients with mesenchymal. However, there were no reports in the literature of synovial sarcoma. Although synovial sarcoma was often reported in other sites. All 85 reported cases with malignant tumour were investigated, and the age of onset of malignant tumour and Werner's syndrome clearly described. To the best of the authors' knowledge, the first manifestations of malignant tumour and Werner's syndrome among Japanese patients were at 41.4 and 24.7 years, respectively. Generally, the earlier manifestation of Werner's syndrome was more clearly demonstrated. As investigators suggested, it is therefore important to recognise Werner's syndrome at an early stage to facilitate identification of subsequent malignant tumours.

Table 2. Causes of death in Werner's syndrome

Cause of death Number
Malignant tumor 25
Cardiac failure, myocardial infarction 8
Pneumonia 3
Respiratory failure 3
Disseminted intravascular coagulation 2
Hepatic failure 2
Renal failure 2
Cerebrovascular disorder 2
Total 47

Immunological abnormalities, such as a decrease in natural killer cell activities or a decrease in T-cell subpopulations, have been associated with malignant tumour development, as well as DNA abnormalties. It is presumed that cellular life span is decreased after telomeres are shortened due to DNA herited abnormalties, and these phenomena promote chromosome instability, providing a platform for accelerated manifestation of malignant tumours in general.
With respect to refractory ulceration, 189 (46.0%) of the 411 reported Japanese cases had associated refractory ulceration, while 13 (3.2%) had osteomyelitis, with the most common site the extremities. A total of 156 (82.5%) of the 189 cases of refractory ulceration and 10 (76.9%) of the 13 cases with osteomyelitis affected the periphery of the lower extremities. The causes of refractory ulceration may include disorders of the vasculature, such as arteriosclerotic changes in the blood vessels and decreases in local blood flow, extrinsic stimulation of the atrophic skin that has decreased ability to support the tissue, and complications of generalised metabolic disorders such as diabetes mellitus. 59 (31.2%) of 189 Japanese patients with ulcer received only conservative treatment, and 57 patients of those refractory to conservative treatment received combined surgical treatment. Surgical treatment, other than amputation of a lower limb, was performed in 37 patients but the results were poor for 16 (43.2%) patients. 37 (19.6%) subsequently underwent amputation of a lower limb.
The mechanism of action of hyperbaric oxygen therapy for ulceration involves resolution of local hypoxia due to physically elevated solubility of oxygen and promotion of the formation of fresh granulation tissue. Scientists consider hyperbaric oxygen therapy useful, based on their experience. However they could not find any other reports of hyperbaric oxygen therapy applied to refractory ulceration associated with Werner's syndrome in the literature between 1916 and 2002. Other representative orthopaedic complications include ectopic calcification and joint contracture, which tend to occur in the periphery of the extremities. Calcification of the Achilles tendon and contracture/deformity of the toes, including hallux valgus, is common (Table 3).

Table 3. Orthopaedic complications and sites in reported Japanese cases

Site Number
Ectopic calcification, 154 patients (37.5%)
Achilles tendon 71
Triceps tendon 15
Quadriceps tendon 6
Heel, foot sole 7
Patellar logament 7
Finger 6
Ankle 6
Toe 4
Others 17
Unknown 15
Articular contracture, deformity, 99 patients (24.0%)
Toe 24
Ankle joint 21
Hallux valgus 19
Finger 15
Knee joint 6
Wrist joint 5
Elbow joint 1
Others 8

In terms of pathogenesis, several theories have been proposed including embryological defects in the germ layer becoming evident at puberty, polyglandular dysfunction of endocrine functions (e.g. parathyroid dysfunction and pituitary dysfunction), and abnormal metabolism in connective tissue. Pathological and biochemical studies point to abnormal metabolism in connective tissue as the most likely explanatory theory because abnormal mucopolysaccharides and fibroblasts are found in patients with Werner's syndrome. The genes associated with Werner's syndrome were isolated and identified using the positional cloning method in 1996.

The WRN gene was identified in 1996, and was subsequently shown to act both as a DNA helicase and as an exonuclease. Since then, cancer researchers and those that study DNA metabolism have collaborated to further characterize WS and the function of the WRN gene. The more scientists understand about the WRN gene, the more they realize that WS is not merely involved in accelerated aging. WS certainly does not represent premature aging, in a sense that the characteristic aging phenotypes seen in WS are considerably different from those observed in normal elders. WS is now being more correctly recognized as a condition in which the lack of WRN protein (WRNp) results in an overall decline in the normal physiological functions of various organs, including those most frequently used to estimate the chronological age, such as skin and hair.
Since the identification of the WRN gene five years ago, various in vitro biochemical studies of WRNp have answered many of our initial questions regarding the helicase and exonuclease functions of this enzyme. Considerably more time will be required to answer the more difficult questions concerning the in vivo functions of WRN at the organism and cellular levels. The lack of mouse models of WS that mimic the human disorder currently limits our ability to carry out such studies.
Following the initial biochemical characterization of the helicase and exonuclease activities of WRNp, the identification of WRN-interacting proteins has led to a variety of studies exploring various ways in which WRNp may be involved in DNA metabolism. These include DNA repair at the site of stalled replication. WRN may also have a special role in transcription by RNA polymerases I and II, as well as in homologous recombination. Cell biological studies raise an interesting question regarding the role of WRN in telomere maintenance. If WRN is capable of all these functions, how do cells regulate the functions of WRN at any given time? How is the switching of these roles mediated? How are the relationships with other RecQ helicases regulated? Since symptoms of WS are relatively mild (not lethal), WRN may have evolved for the "fine tuning" of these various DNA metabolisms. If this hypothesis is true, what are the driving forces for the origin of WRN? At the animal level, how is WRN involved in the progression of "normal" aging phenotypes? Scientists look forward to learning the answers to these and other important questions during the coming decades.

Source 1: A report of two cases of Werner's syndrome and review of the literature. K Yamamoto, A Imakiire, N Miyagawa, T Kasahara. Journal of Orthopaedic Surgery. Hong Kong: Dec 2003. Vol. 11, Iss. 2; pg. 224-234.
Source 2: Werner Syndrome. Lishan Chen and Junko Oshima. Journal of Biomedicine and Biotechnology, 2:2 (2002) 46-54.
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