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Review Werner's Syndrome: from Clinics to Genetics

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Review Werner's Syndrome: from Clinics to Genetics REVIEW Review Werner's syndrome / M. Goto Werner’s syndrome: From clinics to genetics M. Goto Makoto Goto, MD, PhD, Director of ABSTRACT stage of their life (1-3). In addition to the Department of Rheumatology, Werner’s syndrome (WS), a representa- their early onset of age-related clinical Tokyo Metropolitan Otsuka Hospital, tive progeroid syndrome with chromo- manifestations and short life span, nu- 2-8-1 Minami-Otsuka, Toshima-ku, somal instability caused by the mutation merous in vitro experiments on progeroid Tokyo 170-0005, Japan. of RecQ type DNA/RNA helicase, mani- syndrome cells (showing a diminished E-mail: m.goto-o@ohtsuka- fests skin changes similar to those ob- replicative life span of skin fibroblasts, hospital.toshima.tokyo.jp served in systemic sclerosis (SSc). In ad- accelerated telomere shortening, increas- Clin Exp Rheumatol 2000; 18: 760-766. dition, patients with WS show a variety ed chromosomal instability and decreas- Received on August 3, 2000; accepted of the signs and symptoms of normal age- ed immune function) and on body fluids on August 21, 2000. ing at an early stage of their life; gray (showing increased levels of serum © Copyright CLINICAL AND hair, alopecia, muscle atrophy, osteopor- fibronectin, serum and urinary hyaluro- EXPERIMENTAL RHEUMATOLOGY 2000. osis, cataracts, hypogonadism, diabetes nan, and serum autoantibodies) have mellitus, hyperlipidemia, atherosclero- suggested their striking similarity to nor- Key words: Chromosomal instability, sis, malignancy, brain atrophy, and se- mal ageing. helicase, progeroid syndrome, system- nile dementia. Although no direct evi- Despite the fact that much attention has ic sclerosis, Werner’s syndrome. dence has been presented linking RecQ been paid to these unique syndromes, the type DNA/RNA helicase dysfunction with rarity of the patients and the reduced pro- the occurrence of premature ageing liferative potentials of their cells have symptoms in WS, WS may give us a severely limited their study. Here I will unique model to analyze the skin chan- review the clinical and genetical char- ges and the mechanisms of fibrosis in acteristics of a representative progeroid SSc. syndrome, Werner’s syndrome, and dis- cuss the differences between WS and Introduction autoimmune systemic sclerosis (sclero- Werner’s syndrome (WS; MIM#27770), derma, SSc). characterized by scleroderma and juve- nile cataracts, is an autosomal recessive- Historical background of Werner’s ly-inherited progeroid syndrome. WS syndrome research has been recognized as a representative Otto Werner, a medical student in the natural model of human ageing (1). Ophthalmology Clinic at the Royal Al- Other progeroid syndromes or premature brecht University of Kiel, described four ageing syndromes include Cockayne’s siblings with scleroderma and juvenile syndrome (MIM#21640, autosomal re- cataracts living in a small Alpine valley cessive), ataxia telangiectasia (Louis-Bar as his doctoral thesis in 1904 (4). He syndrome) (MIM#20890, autosomal re- pointed out the possible genetic back- cessive), Rothmund-Thomson syndrome ground of the condition and referred to (MIM#26840, autosomal recessive) and the progeric features of this syndrome. progeria (Hutchinson-Gilford progeria Oppenheimer and Kugel drew attention syndrome) (MIM#17667, autosomal to the disorder and coined the term "Wer- dominant ?), in addition to chromosome ner’s syndrome" (5, 6). 21-trisomy Down’s syndrome. Extensive clinical and epidemiological Patients with these progeroid syndromes studies by Epstein et al. (2) and Goto et manifest relatively uniform signs and al. (3, 7) confirmed the clinical entity of symptoms of a variety of elderly phe- this syndrome and the presence of an nomenon (gray hair, alopecia, cataract, autosomal recessive inheritance. A strik- hoarseness, skin atrophy, hyper- or hypo- ing diminution in the growth potential pigmentation, diabetes mellitus, oste- of cultured skin fibroblasts from patients oporosis, osteoarthritis, hypogonadism, with WS was confirmed by Goldstein et brain atrophy, senile dementia, athero- al. (8) and Martin et al. (9), which sug- sclerosis and malignancy) at an early gested an acceleration of the replicative 760 Werner's syndrome / M. Goto REVIEW lifespan of the cultured skin fibroblasts the age of 35 is generally based on the litus, hypogonadism, thyroid dysfunc- in this unique syndrome. In clinical stud- presence of 4 out of the 5 following cri- tion, hyperuricemia, and hyperlipide- ies Tokunaga et al. (10) and Goto et al. teria (3, 12, 15): consanguinity; a char- mia). In addition, in more than two stud- (11) reported an excessive excretion of acteristic bird-like or a mask-like appear- ies over 100 WS patients were further urinary hyaluronan and named this find- ance and body habitus (short stature with examined for the presence of the WRN ing "hyaluronuria". Hyaluronuria and the a stocky trunk and very thin extremities; mutation (12, 14, 16), hyaluronuria (10, diminished cultured lifespan of skin fi- Cushingoid appearance); premature se- 11, 17), decreased replicative lifespan of broblasts represent the in vitro hallmarks nescence (gray hair, alopecia, cataracts, skin fibroblasts, autoantibodies (18, 19, of WS. hoarseness, osteoporosis, arteriosclero- 20), and decreased natural killer cell ac- The clinical identification of WS as a sis, and malignancy); scleroderma-like tivity (21). genetic disorder transmitted by a single skin changes (atrophic skin, skin sclero- The hierarchical deterioration in the cli- gene prompted us to proceed with a link- sis, skin ulcer, hyperkeratosis, hyper- or nical hallmarks of the patient with WS age analysis (12), followed by the suc- hypopigmentation, subcutaneous calci- is shown in Figure 1. After a relatively cessful cloning of the gene (WRN) in fication, and telangiectasia); and endo- normal infancy, by the age of 18 they 1996 (13, 14). This gene encodes a type crine-metabolic disorders (diabetes mel- have failed to manifest the normal pre- of RecQ DNA/RNA helicase (WRN). An extensive functional characterization of WRN has been conducted since then. Sequential appearance of clinical symtoms in Werner's syndrome Clinical characteristics of Werner’s syndrome Since the first description of WS by Otto Werner in 1904, case reports have accu- mulated, to a total of 1,250 worldwide as of 1997 (3). About 80% of the patients are of Japanese origin, and no Oriental patients other than Japanese have ever been reported in the English literature. About 70% of the patients represent the offspring of marriages between first cou- sins. As patients with WS show a wide vari- ety of clinical manifestations, case re- ports have arrived from virtually all areas of medicine - from neurosurgery (men- ingioma) and psychiatry (schizophrenia) to ophthalmology (cataracts) and derma- tology (skin sclerosis and melanoma). As a consequence, the depth and breadth of the clinical descriptions of the patients has varied depending upon the clinician’s speciality and interest. In addition, in- formation regarding the signs and symp- toms observed in the patients has often been subjective, retrospective, and sub- ject to error (2). However, with recent improvements in clinical laboratory tech- niques, a variety of clinical and labora- tory examinations have become avail- able to detect subtle physiologic changes. This review is mainly based on case re- ports published in Japan ever since WS was first described in 1917. The percent- ages of the respective clinical signs and symptoms should be taken into account as a somewhat rough estimate. Fig. 1. Sequential appearance of the typical clinical symptoms of Werner’s syndrome. The average age ± SE at which each manifestation is observed is indicated. The diagnosis of WS in patients under 761 REVIEW Werner's syndrome / M. Goto Fig. 2. The typical Cushingoid appearance in a 42-year-old male patient with Werner’s syndrome: a stocky trunk with thin extremities. The patient also had testicular atrophy with gynecomastia, and intractable skin ulcers on both heels. He was totally bald and in this picture is shown wearing a wig. He died of renal failure due to atherosclerosis of the renal arteries at the age of 43. pubertal growth spurt. This is followed by failures in 4 major body systems, ap- pearing sequentially as summarized be- low. Among the major clinical signs and symptoms observed in this unique syn- Fig. 3. The "bird-like" or "mask-like" face typical of Werner's syndrome in the same patient shown at drome, the characteristic habitus and sta- different ages, as indicated. He had the typical pinched nose with adhesive ears at age 39. ture, scleroderma, gray hair, osteoporo- sis (22, 23), hyaluronuria (10, 11, 17) and nervous system-based clinical manifes- senescent phenotypes observed in nor- cataracts may be classified as connec- tations (incidence: 50% at age 40.1 ± 9.8 mal ageing and also the skin changes tive tissue system-based manifestations y.o.), respectively. Thereafter, disorders characteristic of SSc. Patients with WS (incidence: 100% at age 27 ± 10.4 y.o.). involving more than one system ensue, are usually recognized by their lack of a Diabetes mellitus, hypogonadism, thy- including atherosclerosis-related disor- teenage growth spurt; short stature (141.5 roid dysfunction, hyperlipidemia (24), ders at age 40, and a variety of malig- ± 21.8 cm) and low body weight (35.7 ± and hyperuricemia (25) may be classi- nancies at an average age of 41 followed 17.9 kg). Basically, all WS patients show fied as endocrine-metabolic
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