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Werner Syndrome

WS

Werner Syndrome is a rare genetic disorder associated with premature aging. Symptoms generally manifest during the third decade of life and consist of several pathologies, typically observed in much older people. Severe atherosclerosis and cancer are two of these symptoms and the most common causes of death.


Presentation

WS is generally diagnosed clinically; it is a progeria syndrome, characterized by premature aging and patients affected by this disease appear years older than they really are. They exhibit illnesses typically seen in much older patients.

Patients often experience an uncomplicated childhood. They may be thin, but due to the absence of other symptoms they are not diagnosed with WE. Growth retardation in puberty may be the first real symptom of WS, no growth spurt can be observed and patients typically stay rather small [7]. When entering their twenties, people affected by WS typically develop graying, thinning hair and skin diseases. Characteristic skin disorders are sclerosis, age spots, ulcerations, hyperkeratosis and subcutaneous atrophy and mainly affect face and distal limbs. Because atrophy also affects the vocal cords, voice changes are frequent in WS patients. They often have a very high-pitched voice, almost squeaky voice. It has also been reported that WS patients have a hoarse voice. Dental problems are frequent and premature loss of teeth can often be observed. Patients may furthermore show bilateral cataracts, which develop rapidly, and diabetes mellitus type 2 [8]. The latter affects approximately half of all WS patients. Hypogonadism may be detected, too. General symptoms of aging such as muscle atrophy and osteoporosis may also be observed; the osteoporosis may even cause susceptibility to traumas and provoke pathological fractures. In about a third of all patients calcifications may be found in ligaments and tendons, which will then feel hardened. Elbows, knees and ankles are often affected. Neurologic symptoms may also be associated with WS and affect approximately every third patient. Paresthesias have been reported, sensations of prickling, itching or even burning. Some reflexes may be slowed down or absent.

Neoplastic conditions and severe, progressive atherosclerosis frequently develop and are the most common cause of death in WS patients. While most people affected by WS develop melanomas and sarcomas, meningiomas may be detected in a smaller share of patients. Atherosclerosis developed by WS patients is often widespread and associated with a considerable loss of arterial elasticity.

Short Stature
  • Clinical findings include: senile appearance, short stature, grey hair, alopecia, bird-like face, scleroderma-like skin changes, skin ulcers, voice abnormalities, cataracts, osteoporosis, type 2 diabetes mellitus, ischemic heart disease and hypogonadism[ncbi.nlm.nih.gov]
  • WS presents between the ages of 20 and 30 with major symptoms of early onset bilateral cataracts, thinning and graying of the hair, short stature and skin changes (ankle ulceration, hyperkeratosis, tight skin, age spots, ''bird-like'' facies and subcutaneous[orpha.net]
  • Werner syndrome is a rare autosomal recessive disorder characterized by clinical signs of premature aging, short stature, scleroderma-like skin changes, endocrine abnormalities, cataracts, and an increased incidence of malignancies.[ncbi.nlm.nih.gov]
  • His characteristic medical history and physical findings, i.e. bilateral cataracts, short stature, baldness, diabetes mellitus, high-pitched voice, and multiple malignancies, met the clinical criteria for possible Werner syndrome, a genetic premature[ncbi.nlm.nih.gov]
  • The habitus is characteristic, with short stature, stocky trunk and slender extremities. WS frequency has been roughly estimated to be 1: 100,000 in Japan and 1: 1,000,000-1: 10,000,000 outside of Japan.[ncbi.nlm.nih.gov]
Juvenile Cataract
  • The patient had a high-pitched voice, hoarseness, a characteristic bird-like facial appearance with a beak-shaped nose, canities and juvenile cataracts.[ncbi.nlm.nih.gov]
  • Showing graying and loss of hair, skin atrophy, and juvenile cataract, he was diagnosed with Werner syndrome type 4 by molecular analysis. His serum adiponectin concentration was low.[ncbi.nlm.nih.gov]
  • She displayed typical features of Werner syndrome including juvenile cataract, short stature and low weight, a bird-like face, a hoarse voice, and dry, atrophic, pigmented skin.[ncbi.nlm.nih.gov]
  • It is characterized by the graying and loss of hair, juvenile cataracts, sclerosis and ulceration of skin, insulin-resistant diabetes mellitus, dyslipidemia, abdominal adiposity, osteoporosis, atherosclerosis, and malignant neoplasm.[ncbi.nlm.nih.gov]
  • Examination disclosed juvenile cataracts, scleroderma-like skin changes, hair loss, deficiency of adipose tissue, and sensory neuropathy of the lower limbs (right panel).[nejm.org]
Pleural Effusion
  • Computed tomography (CT) revealed a poorly demarcated homogeneous mass (diameter, 4 cm) in the S1 2 lung area; no pleural effusion was observed. CT-guided percutaneous needle biopsy revealed the presence of an adenocarcinoma.[ncbi.nlm.nih.gov]
Hematemesis
  • We report a patient who presented with hematemesis due to cirrhosis of liver and was subsequently diagnosed with Werner syndrome. Further genetic analysis showed a novel mutation in the WRN gene which has not previously been reported.[ncbi.nlm.nih.gov]
Normal Stature
  • In contrast to the usual appearance of WS, the G574R patient has normal stature. Thus the short stature normally associated with WS may not be due to helicase deficiency.[ncbi.nlm.nih.gov]
Beaked Nose
  • Grating hair, scanty eyebrows, a pinched or beaked nose, protuberant eyes and the absence of eyelashes contribute to the presenile appearance. Either sex may be affected. Inheritance is autosomal recessive. Tendency to occur in brother and sister.[whonamedit.com]
  • Characteristic features include short stature, premature graying, early baldness, wizened face, beaked nose, cataracts, skin changes reminiscent of those in scleroderma, deposits of calcium beneath the skin, premature arteriosclerosis, and a tendency[medicinenet.com]
  • In their 30’s, signs that may develop include cataracts or clouding of the eye’s lens, type 2 diabetes, skin ulcers, a beaked nose, cancers, and osteoporosis, meaning decrease in bone mineral density.[cancer.net]
  • nose and cancers of non-epithelial cell origin Neoplastic risk Malignancy is found in approximately 10% of WRN patients Excess of soft-tissue sarcomas, osteosarcomas, myeloid disorders and benign meningiomas.[atlasgeneticsoncology.org]
  • Mandibuloacral dysplasia presents very similarly to WS but its characteristic facial features (beaked nose, small recessed chin) and absence of bilateral cataracts differentiates it from WS.[dermatologyadvisor.com]

Workup

Diagnosis of WS requires a thorough clinical and laboratory examination. While blood screenings do not reveal specific alterations, they allow detection of comorbidities such as diabetes mellitus and atherosclerosis. Thus, fasting blood glucose and oral glucose tolerance tests are generally indicated as well as a blood screening to measure serum concentrations of indicators for vascular diseases, which can best be evaluated in a lipid profile. Typically, low levels of high-density lipoprotein (HDL) are accompanied by high levels of low-densitiy lipoprotein (LDL) and triglycerides. If signs of severe atherosclerosis are found, cardiac function tests should be carried out afterwards. In order to clarify the causes of possible hypogonadism, sex hormones estradiol and progesterone or testosterone should be checked as well as levels of luteinizing hormone (LH) and follicle-stimulating hormone (FSH). Hypogonadism is, however, usually caused by intestinal fibrosis. An examination of the thyroid function (triiodothyronine, thyroxine and thyrotropin) may reveal possible causes for other comorbidities.

Because WS patients are susceptible to cancer, the clinical examination should also focus on detecting possible neoplasms. Diagnostic imaging can be of great help to achieve this and may at the same time reveal signs of osteoporosis and pathologic fractures.

Due to the fact that WS patients frequently develop bilateral cataracts, an ophthalmologic examination should be carried out, not only to support a possible diagnosis of WS but also to intervene as early as possible.

WS may be clinically confirmed, if all major symptoms, i.e. small body size, greying and thinning hair, skin problems, bilateral cataracts, and two additional ones, e.g., diabetes mellitus and osteoporosis, are present in young to middle-aged adults.

Even though the results of clinical and laboratory examinations may sometimes give strong reason to suspect WS, genetic testing by PCR and RT-PCR may be the method of choice to confirm it [7]. However, it should be noted that not all cases of WS produce positive results in the corresponding genetic test. 

Erythroblast
  • Thus, immunohistochemical detection of WRN in erythroblasts from bone marrow paraffin sections could be useful in screening of WS cases and worthy of further molecular confirmation.[ncbi.nlm.nih.gov]
Neurofibrillary Tangle
  • In addition, there were marked lipofuscin deposition and corpora amylacea, but no neurofibrillary tangles or plaques.[ncbi.nlm.nih.gov]
Pleural Effusion
  • Computed tomography (CT) revealed a poorly demarcated homogeneous mass (diameter, 4 cm) in the S1 2 lung area; no pleural effusion was observed. CT-guided percutaneous needle biopsy revealed the presence of an adenocarcinoma.[ncbi.nlm.nih.gov]

Treatment

Since WS is a genetic disorder, there is no causal treatment. Up until now, it is not possible to restore the function of the defective helicase. Treatment is therefore limited to symptomatic therapy. The disease itself is not curable and the effort to alleviate the symptoms is be a continous one. WS patients require repeated examinations and a very close monitoring by an interdisciplinary team of physicians in order to allow treatment of comorbidities as early as possible.

Generally, WS patients do not exhibit severe diabetes mellitus and this comorbidity may be treated with dietary adaptions and oral medication. Skin diseases require adequate treatment that depends on the specific nature of the disorder. If at all possible, skin ulcerations should be prevented. If cataracts are detected during the ophthalmologic examination, an ophthalmologist may recommend surgery to replace the clouded lens with an artificial substitute. Surgery may also be the treatment of choice if the patient develops malignant tumors. Other options are chemotherapy, radiation or any combination of those. An oncologist should be consulted. Of note, it has been reported that wound healing is delayed in WS patients [9]. Whereas surgery may be mandatory in some cases, special care should be taken to keep incisions small and avoid the use of steroids as much as possible. Cardiovascular complications of WS should be treated with the appropiate drugs. It has been proposed that WS patients may benefit from vitamin C supplementation [10].

Furthermore, the patient should be advised to choose a healthy lifestyle, avoid smoking and any food rich in fat. Regular exercise is strongly recommended. The patient, as well as his or her family, may also benefit from psychological counseling. 

Prognosis

The prognosis is unfavorable and patients usually die aged 30 to 50 years.

DNA instability causes patients affected by WS to exhibit predisposition for cancers, particularly melanomas and sarcomas. Malignant tumors are a common cause of death in WS patients. They may also develop severe atherosclerosis and die from myocardial infarction.

Etiology

WS is a genetic disorder, caused by different mutations of a gene on chromosome 8 (p12-11.2). Almost 100 different mutations have been detected so far. WS is inherited with an autosomal recessive pattern.

The mutated gene encodes a helicase, an enzyme whose principal function is DNA repair. A defective helicase thus implies persisting DNA damage and genome instability. To date, the precise relation between a defective helicase and premature aging is not fully understood.

Of note, about 10% of all WS cases are characterized as atypical Werner Syndrome because they do not present the characteristic mutation.

Epidemiology

WS is a very rare disease. Incidence has been estimated to be around 1 in 1,000,000 individuals, with more frequent occurence in Japan and Sardinia [2]. About 80% of all known cases are located in Japan. According to current knowledge, men and women are affected equally.

The disease generally manifests at the age of 30 to 40 years, but some symptoms are usually detectable in young adulthood, puberty and even childhood.

Sex distribution
Age distribution

Pathophysiology

WS is a genetic disorder that is inherited with an autosomal recessive mechanism. Different mutations may lead to a non-functional DNA helicase of the RecQ family [3]. Helicases unwind double-stranded nucleic acids, allow replication and are involved in transcription and repair processes. It has been proposed that replication forks do not translocate normally in WS patients [4]. This may leave the affected DNA regions sensitive to replication errors and eventually lead to chromosome instability.

Humans have five RecQ helicases. The helicase affected in WS seems to be particularly important for genome maintenance in connective tissue, so the symptoms of WS are strongly related to defective synthesis of connective tissue components. People suffering from WS show excessive synthesis of collagen types I and III that are, in turn, caused by augmented gene expression and transcription.

WS is also called adult progeria and is part of a bigger group of human progeroid syndromes, all of which are genetic diseases. They are generally characterized by accelerated aging and are in most cases linked to impaired DNA repair and genome maintenance [5].

The atypical Werner syndrome has been associated with mutations affecting the LMNA gene, which encodes for lamin A and lamin C, components of the nuclear lamina. It is accompanied by severe metabolic disturbances and lipodystrophy [6].

Prevention

Because WS is a very rare disease, genetic testing for RecQ helicase mutations are not part of any standard test and no direct prevention is possible. Action can only be taken as soon as WS is diagnosed.

WS is inherited with an autosomal recessive trait. Due to the severity of the disease, the family of the WS patient should receive genetic counseling and possibly take reproductive decisions accordingly.

In case the WS patient has children, they necessarily carry the defective gene. However, they most probably also carry a functional gene that they received from the other parent. Their offspring are thus unlikely to develop WS. The probability for receiving a second defective gene grows when both parents share consanguinity.

A family history of WS should prompt genetic testing before the decision to have children is made.

Summary

Otto Werner, a German physician, first described the Werner Syndrome (WS) in 1904. It is also called adult progeria and it is the disease most commonly associated with premature aging.

It is caused by a mutation in a gene encoding a helicase, an enzyme involved in DNA replication, transcription and repair. This mutation is inherited with an autosomal recessive pattern. It renders the DNA more susceptible to breaking and thus provokes genome instability. However, no direct link between these facts and premature aging has been established as of yet. Nevertheless, WS serves as a model for in vitro and in vivo studying of aging [1].

Patients suffering from WS show retarded growth in puberty, but otherwise manifest symptoms in the third and fourth decade of their lives. The main symptoms are small body size, greying and thinning hair, skin problems and bilateral cataracts. Comorbidities frequently seen in older people are often detectable in WS patients, e.g. diabetes mellitus type 2, osteoporosis, atherosclerosis and cancer.

There is no causal therapy. Close monitoring may help to detect any comorbidities early and provide adequate supportive treatment. Life expectancy is 40 to 50 years and WS patients often die from myocardial infarction, resulting from severe and widespread atherosclerosis, or malignancies such as melanomas and sarcomas.

Patient Information

WS is a genetic disease that causes premature aging. While during puberty the most noticeable symptom is hindered growth, more severe signs of WS develop during the third and fourth decade of life. They are conditions and diseases usually attributed to much older people, e.g. greying and thinning hair, skin problems, cataracts, diabetes mellitus, osteoporosis, atherosclerosis and cancer. People affected by WS appear much older than they really are. The disease is not curable, only symptomatic treatment can be given.

References

Article

  1. Nehlin JO, Skovgaard GL, Bohr VA. The Werner syndrome. A model for the study of human aging. Ann N Y Acad Sci. 2000 Jun. 908:167-79.
  2. Goto M, Ishikawa Y, Sugimoto M, Furuichi Y. Werner syndrome: a changing pattern of clinical manifestations in Japan (1917~2008). Biosci Trends. 2013 Feb. 7(1):13-22.
  3. Zhao N, Hao F, Qu T, Zuo YG, Wang BX. A novel mutation of the WRN gene in a Chinese patient with Werner syndrome. Clin Exp Dermatol. 2008 May. 33(3):278-81.
  4. Pirzio LM, Pichierri P, Bignami M, Franchitto A. Werner syndrome helicase activity is essential in maintaining fragile site stability. J Cell Biol. 2008 Jan 28. 180(2):305-14. [Medline].
  5. Kyng KJ, Bohr VA. Gene expression and DNA repair in progeroid syndromes and human aging. Ageing Res Rev. 2005 Nov. 4(4):579-602.
  6. Doh YJ, Kim HK, Jung ED, et al. Novel LMNA gene mutation in a patient with Atypical Werner's Syndrome. Korean J Intern Med. 2009 Mar. 24(1):68-72.
  7. Hisama FM, Kubisch C, Martin GM, Oshima J. Clinical utility gene card for: Werner syndrome. Eur J Hum Genet. 2012 Jan 18.
  8. Takada-Watanabe A, Yokote K, Takemoto M, et al. A case of Werner syndrome without metabolic abnormality: implications for the early pathophysiology. Geriatr Gerontol Int. 2012 Jan. 12(1):140-6.
  9. Noda S, Asano Y, Masuda S, et al. Bosentan: a novel therapy for leg ulcers in Werner syndrome. J Am Acad Dermatol. 2011;65(2):e54-55.
  10. Massip L, Garand C, Paquet ER, et al. Vitamin C restores healthy aging in a mouse model for Werner syndrome. FASEB J. 2010 Jan. 24(1):158-72.

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Last updated: 2019-07-11 21:54