Close
New

Medscape is available in 5 Language Editions – Choose your Edition here.

 

Werner Syndrome

  • Author: Camila K Janniger, MD; Chief Editor: Dirk M Elston, MD  more...
 
Updated: Jun 13, 2016
 

Background

Otto Werner originally defined Werner syndrome (WS) in 1904 on the basis of sclerodermalike, thin, tight skin and bilateral cataracts. WS is also known as progeria adultorum, progeria of the adult, and pangeria. WS is the most common of the premature aging disorders. Progeria can also refer to Hutchinson-Gilford syndrome, which is described as a lamin A gene defect and has onset early in life. The term progeria is derived from a Greek term meaning "before old age." See the images below.

Werner syndrome. Werner syndrome.
Werner syndrome. Werner syndrome.

The aging process involves increasing errors in the mitotic machinery of dividing cells in the postreproductive stage of life; therefore, WS serves as a model for studying the aging process in vivo and in vitro.[1] However, many organs in patients with WS prematurely undergo changes that are usually associated with aging. No mental retardation is observed.

WS is a premature aging disorder that may serve as a model of normal human aging.[2] In vivo aging is linked with accelerated aging of fibroblasts in culture, possibly due to the genomic instability, a hallmark of WS. Genome instability activates stress kinases, implying that kinase inhibitors may form the basis of antiaging therapies for individuals with WS.

Next

Pathophysiology

Werner syndrome (WS) is an autosomal recessive disorder that affects connective tissue throughout the body. This segmental progeroid syndrome is caused by null mutations at the WRN locus,[3] which codes for a member of the RecQ family of DNA helicases. Enzymes in this group unwind double helix RNA and DNA. The protein is likely to be involved in the response to DNA damage during replication, as well as in the replication and transcription processes. The disease is connected with excessive synthesis of collagen types I and III, which is dependent on elevated messenger RNA (mRNA) levels.

Skin fibroblasts in WS patients demonstrate characteristics of cells in conditions of stress with slow growth rates, an elongated cell cycle, and an altered morphology that suggests stress-induced premature senescence transduced in part by the p38α MAP kinase signaling pathway. This p38 involvement has been documented in WS cells.[4]

More than 70 disease-causing mutations have been described, the majority being stop codon mutations, splice mutations, or small ins/del-producing truncations of the protein and/or non-sense–mediated decay of mutant mRNA.[5] Two novel WRN mutations were described in patients of South Asian ancestry.[6] Another patient had a homozygous novel 1bp-deletion in exon 19 of WRN, 2426/27delG, causing frameshift and protein truncation R809SfsX2.[7]

The collagenase level is also increased several times. However, a child may have characteristics of WS but with no identifiable mutation in the WRN gene. Such cases are classified as atypical WS.[8] A paper from 2010 reported 18 new mutations, including 2 genomic rearrangements, a deep intronic mutation resulting in a novel exon, a splice consensus mutation leading to utilization of the nearby splice site, and 2 rare missense mutations.[9]

WS have been classified is a member of the RecQ family of DNA helicases implicated in the resolution of DNA structures leading to the stall of replication forks.[10] Fragile sites may be DNA regions particularly sensitive to replicative stress. Evidence was recently presented of a crucial role for a helicase in protecting cells against chromosome breakage at normally occurring replication fork-stalling sites.

Human progeroid syndromes are linked with mutations in single genes accelerating some, but not all, features of normal aging.[11] Most are associated with defects in genome maintenance.

LMNA (lamin A/C) gene mutation has been described with atypical Werner syndrome, with the severe metabolic complications, the extent of the lipodystrophy being linked with A133L mutation in the LMNA gene.[12, 13]

Previous
Next

Epidemiology

Frequency

United States

WS is a rare disorder. The estimated incidence is 1 case in 1 million individuals.

International

WS is more common in Japan and Sardinia than in other regions.[14] About 1000 cases are reported in the world; more than 800 of these cases are in Japan.

Race

No racial predilection is reported.

Sex

Both sexes are affected equally.

Age

The onset of WS might occur in individuals in their mid teens, or it may be delayed until an individual is as old as 30 years. The average age of patients at the time of diagnosis is 37 years.

Previous
Next

Prognosis

The prognosis is unfavorable. The mean survival for patients with WS is 46 years. Death usually occurs when patients are aged 30-50 years because of atherosclerosis or malignant tumors. Adroit medical management may enhance life expectancy; one patient was described who survived until dying of acute heart failure at age 68 years.[15]

Previous
 
 
Contributor Information and Disclosures
Author

Camila K Janniger, MD Clinical Professor of Dermatology, Clinical Associate Professor of Pediatrics, Chief of Pediatric Dermatology, Rutgers New Jersey Medical School

Camila K Janniger, MD is a member of the following medical societies: American Academy of Dermatology

Disclosure: Nothing to disclose.

Coauthor(s)

Anna Wozniacka, MD, PhD Professor, Department of Dermatology, Medical University of Lodz, Poland

Anna Wozniacka, MD, PhD is a member of the following medical societies: European Academy of Dermatology and Venereology, Polish Dermatological Society

Disclosure: Nothing to disclose.

Specialty Editor Board

Michael J Wells, MD, FAAD Associate Professor, Department of Dermatology, Texas Tech University Health Sciences Center, Paul L Foster School of Medicine

Michael J Wells, MD, FAAD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, American Medical Association, Texas Medical Association

Disclosure: Nothing to disclose.

Robert A Schwartz, MD, MPH Professor and Head of Dermatology, Professor of Pathology, Pediatrics, Medicine, and Preventive Medicine and Community Health, Rutgers New Jersey Medical School; Visiting Professor, Rutgers University School of Public Affairs and Administration

Robert A Schwartz, MD, MPH is a member of the following medical societies: Alpha Omega Alpha, New York Academy of Medicine, American Academy of Dermatology, American College of Physicians, Sigma Xi

Disclosure: Nothing to disclose.

Chief Editor

Dirk M Elston, MD Professor and Chairman, Department of Dermatology and Dermatologic Surgery, Medical University of South Carolina College of Medicine

Dirk M Elston, MD is a member of the following medical societies: American Academy of Dermatology

Disclosure: Nothing to disclose.

Additional Contributors

Franklin Flowers, MD Department of Dermatology, Professor Emeritus Affiliate Associate Professor of Pathology, University of Florida College of Medicine

Franklin Flowers, MD is a member of the following medical societies: American College of Mohs Surgery

Disclosure: Nothing to disclose.

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. [Medline].

  2. Davis T, Wyllie FS, Rokicki MJ, Bagley MC, Kipling D. The role of cellular senescence in Werner syndrome: toward therapeutic intervention in human premature aging. Ann N Y Acad Sci. 2007 Apr. 1100:455-69. [Medline].

  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. [Medline].

  4. Davis T, Brook AJ, Rokicki MJ, Bagley MC, Kipling D. Evaluating the Role of p38 MAPK in the Accelerated Cell Senescence of Werner Syndrome Fibroblasts. Pharmaceuticals (Basel). 2016 Apr 28. 9 (2):[Medline].

  5. Hisama FM, Kubisch C, Martin GM, Oshima J. Clinical utility gene card for: Werner syndrome. Eur J Hum Genet. 2012 Jan 18. [Medline].

  6. Saha B, Lessel D, Nampoothiri S, Rao AS, Hisama FM, Peter D, et al. Ethnic-Specific WRN Mutations in South Asian Werner Syndrome Patients: Potential Founder Effect in Patients with Indian or Pakistani Ancestry. Mol Genet Genomic Med. 2013 May 1. 1(1):7-14. [Medline]. [Full Text].

  7. Mansur AT, Elçioglu NH, Demirci GT. Werner syndrome: clinical evaluation of two cases and a novel mutation. Genet Couns. 2014. 25(2):119-27. [Medline].

  8. Barrios Sanjuanelo A, Munoz Otero C. [Atypical Werner syndrome: Atypical progeroid syndrome: A case report.]. An Pediatr (Barc). 2010 May 7. [Medline].

  9. Friedrich K, Lee L, Leistritz DF, et al. WRN mutations in Werner syndrome patients: genomic rearrangements, unusual intronic mutations and ethnic-specific alterations. Hum Genet. 2010 May 5. [Medline].

  10. 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].

  11. Kyng KJ, Bohr VA. Gene expression and DNA repair in progeroid syndromes and human aging. Ageing Res Rev. 2005 Nov. 4(4):579-602. [Medline].

  12. Doh YJ, Kim HK, Jung ED, Choi SH, Kim JG, Kim BW, et al. Novel LMNA gene mutation in a patient with Atypical Werner's Syndrome. Korean J Intern Med. 2009 Mar. 24(1):68-72. [Medline].

  13. McKenna T, Sola Carvajal A, Eriksson M. Skin Disease in Laminopathy-Associated Premature Aging. J Invest Dermatol. 2015 Jul 29. [Medline].

  14. 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. [Medline].

  15. Kawai T, Nozato Y, Kamide K, Onishi M, Yamamoto-Hanasaki H, Tatara Y, et al. Case report of a long-surviving Werner syndrome patient with severe aortic valve stenosis. Geriatr Gerontol Int. 2012 Jan. 12(1):174-5. [Medline].

  16. Takada-Watanabe A, Yokote K, Takemoto M, Fujimoto M, Irisuna H, Honjo S, et al. A case of Werner syndrome without metabolic abnormality: implications for the early pathophysiology. Geriatr Gerontol Int. 2012 Jan. 12(1):140-6. [Medline].

  17. Lauper JM, Krause A, Vaughan TL, Monnat RJ Jr. Spectrum and risk of neoplasia in Werner syndrome: a systematic review. PLoS One. 2013. 8(4):e59709. [Medline]. [Full Text].

  18. Mitamura Y, Azuma S, Matsumoto D, Takada-Watanabe A, Takemoto M, Yokote K, et al. Case of sarcomatoid carcinoma occurring in a patient with Werner syndrome. J Dermatol. 2016 Apr 14. [Medline].

  19. 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. [Medline].

  20. Solek-Pastuszka J, Zagrodnik-Ulan E, Plonka T, et al. Pregnancy complicated by Werner syndrome. Acta Obstet Gynecol Scand. 2011 Feb. 90(2):201-2. [Medline].

  21. Wang Z, Xu Y, Tang J, Ma H, Qin J, Lu C, et al. A polymorphism in Werner syndrome gene is associated with breast cancer susceptibility in Chinese women. Breast Cancer Res Treat. 2009 Feb 10. [Medline].

  22. Oshitari T, Kitahashi M, Mizuno S, Baba T, Kubota-Taniai M, Takemoto M, et al. Werner syndrome with refractory cystoid macular edema and immunohistochemical analysis of WRN proteins in human retinas. BMC Ophthalmol. 2014 Mar 12. 14:31. [Medline]. [Full Text].

 
Previous
Next
 
Werner syndrome.
Werner syndrome.
 
 
 
All material on this website is protected by copyright, Copyright © 1994-2016 by WebMD LLC. This website also contains material copyrighted by 3rd parties.