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Werner Syndrome
Werner syndrome

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.

Entire Body System

  • Short Stature

    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]

    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]

    short stature (E45) pituitary short stature (E23.0) progeria (E34.8) renal short stature (N25.0) Russell-Silver syndrome (Q87.19) short-limbed stature with immunodeficiency (D82.2) short stature in specific dysmorphic syndromes - code to syndrome - see [icd10data.com]

    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]

  • Asymptomatic

    At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being neither affected nor a carrier. [ncbi.nlm.nih.gov]

    Neuroradiological studies of neurologically asymptomatic cases of Werner syndrome are lacking. CASE REPORT A 48-year-old male patient who had been diagnosed with Werner syndrome visited our hospital complaining of a mild headache. [ghrnet.org]

    The patient remained asymptomatic since then. Discussion Background Herlyn-Werner-Wunderlich syndrome (HWWS) is characterised by uterus didelphys, obstructed hemivagina and ipsilateral renal agenesis. [eurorad.org]

  • Juvenile Cataract

    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]

    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]

  • Fatigue

    We ask about general symptoms (anxious mood, depressed mood, fatigue, pain, and stress) regardless of condition. Last updated: April 27, 2020 [patientslikeme.com]

    […] increased length along an axis of the globe, myopia, corneal flatness, strabismus, exotropia, and esotropia.[11] Cardiovascular system[edit] The most serious signs and symptoms associated with Marfan syndrome involve the cardiovascular system: undue fatigue [en.wikipedia.org]

Respiratoric

  • High Pitched Voice

    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]

    voice, and flat feet. [ommbid.mhmedical.com]

Gastrointestinal

  • Failure to Thrive

    […] to thrive, facial dysmoprhism, palmoplantar keratoderma and late-onset ichthyosis. [informatics.jax.org]

    She was seen as a child by paediatricians for failure to thrive. She suffered from irregular periods throughout puberty and had cataracts removed from both eyes whilst in her early 20s, at which age she also developed alopecia and grey hair. [academic.oup.com]

    Signs and symptoms include failure to thrive, limited growth, alopecia, wrinkled skin, small face, development of atherosclerosis, and heart disease. There is no cure for this condition. [icd10data.com]

    Newborns with HGPS usually appear normal, but profound failure to thrive occurs during the first year. [ncbi.nlm.nih.gov]

  • Polydipsia

    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. [rarediseases.org]

Cardiovascular

  • Heart Disease

    The disease, Werner's syndrome, causes young people who would be otherwise healthy to suffer from such aging-related conditions as osteoporosis, heart disease, cataracts, wrinkled skin and grey hair. [fightaging.org]

    Systemic Implications and Complications Patients with WS are at an increased risk of developing many of the disease entities seen in the elderly at a premature age such as Type II diabetes mellitus, atherosclerosis, heart disease, osteoporosis, cataracts [dermatologyadvisor.com]

    People affected by Werner syndrome usually do not live past their late forties or early fifties, often dying from the results of cancer or heart disease. Causes WS is a genetic disorder. [checkorphan.org]

    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]

Musculoskeletal

  • Osteoporosis

    Given that patients with this disease exhibit osteoporosis, the present study aimed to determine whether the WRN gene contributes to the etiology of osteoporosis. [ncbi.nlm.nih.gov]

    a rare genetic disorder with onset during adolescence or early adulthood that is characterized by cessation of growth at puberty and by premature and accelerated aging with associated abnormalities (as muscle wasting, cataracts, osteoporosis, and hypogonadism [merriam-webster.com]

    Osteoporosis. Management Early recognition of the syndrome is helpful, as screening for malignancies and associated diseases such as diabetes may then be performed on a regular basis. [patient.info]

  • Muscular Atrophy

    Synonyms of Werdnig-Hoffmann Disease infantile spinal muscular atrophy SMA 1 SMA, infantile acute form spinal muscular atrophy type 1 Werdnig-Hoffman paralysis General Discussion The spinal muscular atrophies (SMAs), are characterized by degeneration [rarediseases.org]

    An autosomal recessive disorder that causes premature aging in adults, characterized by sclerodermal skin changes, cataracts, subcutaneous calcification, muscular atrophy, a tendency to diabetes mellitus, aged appearance of the face, baldness, and a high [connects.catalyst.harvard.edu]

    Its physical characteristics may include short stature (common from childhood on) and other features usually developing during adulthood: wrinkled skin, baldness, cataracts, muscular atrophy and a tendency to diabetes mellitus, among others. [ncbi.nlm.nih.gov]

    Definición: An autosomal recessive disorder that causes premature aging in adults, characterized by sclerodermal skin changes, cataracts, subcutaneous calcification, muscular atrophy, a tendency to diabetes mellitus, aged appearance of the face, baldness [hon.ch]

    atrophy, a tendency to diabetes mellitus, aged appearance of the face, baldness, and a high incidence of neoplastic disease Werner syndrome (ws) is an inherited disease characterized by an early onset of atherosclerosis, osteoporosis, diabetes mellitus [icd9data.com]

Eyes

  • Visual Impairment

    The degree of associated visual impairment depends upon the severity and/or combination of eye abnormalities present. [rarediseases.org]

  • Blurred Vision

    Nearsightedness (myopia), and blurred vision are common due to connective tissue defects in the eye. [12] Farsightedness can also result particularly if the lens is highly subluxated. [en.wikipedia.org]

Skin

  • Alopecia

    Although our APS/AWS patient had overlapping features with Werner syndrome (WS), such as high-pitched voice, scleroderma, lipoatrophy and atherosclerosis, several cardinal features of WS, including short stature, premature graying/alopecia, cataract, [ncbi.nlm.nih.gov]

    She suffered from irregular periods throughout puberty and had cataracts removed from both eyes whilst in her early 20s, at which age she also developed alopecia and grey hair. [academic.oup.com]

    The characteristic features of the disease include growth retardation, short stature, alopecia, scleroderma, atrophic skin with ulcerations, infertility, cataracts, premature arteriolosclerosis, diabetes, osteoporosis, and increased risk of malignancies [escholarship.org]

    Otto Werner A hereditary multisystem disorder characterized by premature aging, dwarfism, premature graying of the hair (canities|), alopecia, scleroderma like skin changes, trophic leg ulcers, cataracts, hypogonadism, diabetes mellitus, calcification [whonamedit.com]

  • Skin Atrophy

    The patient was prematurely old, had skin atrophy, characteristic posterior subcapsular cataracts and prepubertal primary hypogonadism. [ncbi.nlm.nih.gov]

    He is prematurely old, has diabetes mellitus of adult onset, skin atrophy, poliosis, and characteristic posterior subcapsular cataracts. [jamanetwork.com]

    Clinical description Atypical WS shows accelerated aging characterized by short stature, thinning/graying of hair, a ''bird-like'' facial appearance, skin atrophy, lipodystrophy, myopathy along with other age-related disorders such as osteoporosis and [orpha.net]

  • Hyperpigmentation

    Generalized hypotrichosis, scattered ephelid-like macules, sclerotic fingers, calcinosis cutis on ears, hyperpigmentation on elbows were the other alterations of skin. Skeletal survey revealed osteoporosis. [ncbi.nlm.nih.gov]

    Premature senescence: bird-like appearance, alopecia/gray hair, hoarseness, diffuse arteriosclerosis, juvenile bilateral cataracts, osteoporosis 3 Scleroderma-like skin changes; atrophic skin and muscle, hyperkeratosis, telangiectasis, ulcer, calcification, hyperpigmentation [ghrnet.org]

    Contractures of hands and feet with mottled hyperpigmentation were present with 20 nail dystrophy. On examination of eyes, unilateral central lens opacity in left eye was seen. [longdom.org]

    Sclerodermoid and poikilodermatous hyperpigmentation changes are seen throughout the body, with the former being responsible for the mask-like faces or bird-like nose phenotype. [dermatologyadvisor.com]

    If scarring or fusion is present this will not recover, and it is common to see post-inflammatory hyperpigmentation. Warn the patient that the ointment may sting at first but to persevere as there is no alternative. [nps.org.au]

  • Sweating

    The reduced sebaceous and sweat secretion may be the cause of skin dehydration. [dovepress.com]

    Negative reactions to receiving vitamin B-1 may vary, and can include alcohol withdrawal symptoms such as insomnia, sweating, or mood swings. You may also experience hallucinations, confusion, or agitation. [healthline.com]

    Patients should also be routinely followed for systemic signs of malignancy such as weight loss, night sweats, etc. [dermatologyadvisor.com]

    Cold-Induced Sweating Syndrome Including Crisponi Syndrome Angelika F Hahn and Helge Boman. Initial Posting: March 3, 2011; Last Update: March 17, 2016. [ncbi.nlm.nih.gov]

  • Eruptions

    The patients presented unique clinical features for Werner syndrome such as chilblain-like eruption in infancy and glaucoma caused by uveitis. Cell culture studies revealed cellular abnormalities compatible with Werner syndrome. [ncbi.nlm.nih.gov]

Psychiatrical

  • Fear

    The main object of this work is to articulate and overcome conflicting attitudes, to find better ways of dealing with ethically ambiguous situations, to detect and explain fears, misgivings, and prejudices, and, finally, to integrate genetic information [psychologyinrussia.com]

Face, Head & Neck

  • Beaked Nose

    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]

    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]

    Signs and symptoms of this progressive disorder include a distinctive appearance: Slowed growth, with below-average height and weight Narrowed face, small lower jaw, thin lips and beaked nose Head disproportionately large for the face Prominent eyes and [mayoclinic.org]

    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]

    In their 30s, signs that may develop include cataracts or clouding of the eye’s lens, type 2 diabetes, skin ulcers, a beaked nose, and osteoporosis, meaning a decrease in bone mineral density. [cancer.net]

  • Narrow Face

    face Decreased breadth of face Decreased width of face [ more ] 0000275 Pulmonary artery stenosis Narrowing of lung artery 0004415 Rocker bottom foot Rocker bottom feet Rocker-bottom feet Rockerbottom feet [ more ] 0001838 Skeletal muscle atrophy Muscle [rarediseases.info.nih.gov]

Neurologic

  • Stroke

    Children with progeria usually die of heart attacks or strokes. Progeria doesn't affect a child's intelligence or brain development. A child with the condition isn't any more likely to get infections than other kids, either. [webmd.com]

    Heart problems or strokes are the eventual cause of death in most children with progeria. The average life expectancy for a child with progeria is about 13 years. Some with the disease may die younger and others may live longer, even up to 20 years. [mayoclinic.org]

    However, in the present study, there were no apparent deaths from atherosclerotic diseases such as myocardial infarction or stroke. [ojrd.biomedcentral.com]

    It presents with characteristic physical and metabolic abnormalities that result in severe age-associated complications, such as diabetes, hypertension, osteoporosis, myocardial infarction, stroke, and cancer that are normally be seen in the elderly population [statpearls.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. 

Serum

  • Hypercholesterolemia

    Identification by whole-genome resequencing of gene defect responsible for severe hypercholesterolemia. Hum. Mol. Genet. 19, 4313–4318. Pubmed Abstract | Pubmed Full Text Sirmaci, A., Walsh, T., Akay, H., Spiliopoulos, M., Sakalar, Y. l. r. m. [frontiersin.org]

    Familial Hypercholesterolemia Emily Youngblom, Mitchel Pariani, and Joshua W Knowles. Initial Posting: January 2, 2014; Last Update: December 8, 2016. Familial Hyperinsulinism David Gillis. [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.

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

  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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