eMedicine Specialties > Dermatology > Pediatric Diseases

Werner Syndrome

Author: Camila K Janniger, MD, Clinical Professor of Dermatology, Clinical Associate Professor of Pediatrics, Chief of Pediatric Dermatology, New Jersey Medical School
Coauthor(s): Anna Wozniacka, MD, PhD, Adjunct Lecturer, Department of Dermatology, Medical University of Lodz, Poland
Contributor Information and Disclosures

Updated: Apr 23, 2008

Introduction

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 Hutchinson-Gilford Progeria for more information.

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.

Pathophysiology

WS is an autosomal recessive disorder that affects connective tissue throughout the body. This entity is caused by a mutation at the WS gene (WRN) locus,3 which belongs to the family of RecQ helicases. WS is caused by a helicase defect. 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. The collagenase level is also increased several times.

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.4 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.5 Most are associated with defects in genome maintenance.

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. About 1000 cases are reported in the world; more than 800 of these cases are in Japan.

Mortality/Morbidity

  • 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.

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.

Clinical

History

In young adults, mutation in the WS gene is believed to be associated with clinical symptoms typically found in elderly individuals.

  • The most important feature of WS is healthy development in the patient's first decade of life.
  • Adult progeria is usually diagnosed on the basis of characteristic clinical features and typical concomitant diseases.
  • The hallmark of this syndrome is a striking disproportion between the patient's real age and the patient's appearance.

Physical

Perform a thorough clinical and laboratory examination, keeping in mind the patient's increased risk of neoplasms.
  • Characteristic clinical features of the disease
    • General appearance
      • Short stature, usually less than 1.60 m, is observed.
      • Thin skin is present on the acral surfaces.
      • Muscle atrophy is noted.
      • The skull is relatively large, with a disproportionate lower part of the face.
    • Skin
      • Wrinkling and aging of the face occurs.
      • A sclerodermalike appearance with nose and lip atrophy is typical.
      • The nose is pinched, and the cheeks are sunken because of fat loss, which causes the birdlike facial appearance.
      • Loss of subcutaneous fat complicated with ulceration can be observed on the shins and feet.
      • In most patients, calluses, hyperkeratosis, and ulcerations on the soles are present mainly over bony prominences.
  • Graying of the hair, loss of hair, and nail dystrophy usually are observed.
  • A high-pitched voice is characteristic.
  • Related diseases
    • Cataracts
      • Rapidly progressing cataracts typically occur when patients are aged 20-40 years.
      • Cataracts are usually posterior and subcapsular.
    • Osteoporosis: Disturbances in the parathyroid glands are the main cause of osteoporosis.
    • Diabetes mellitus
    • Neoplasia
      • Carcinomas of the thyroid and other organs
      • Hematologic malignancies
      • Sarcomas
      • Meningiomas
      • Cutaneous malignancies, including malignant melanoma
      • Possible evolution of ankle and heel ulcers into squamous cell carcinomas
    • Hyperthyreosis
    • Pituitary dysfunction
    • Vascular changes (arteriosclerotic type)
    • Hypogonadism or agonadism and premature menopause
    • Soft tissue calcification

Causes

WS is a genetic disorder. See Pathophysiology.

More on Werner Syndrome

Overview: Werner Syndrome
Differential Diagnoses & Workup: Werner Syndrome
Treatment & Medication: Werner Syndrome
Follow-up: Werner Syndrome
Multimedia: Werner Syndrome
References
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References

  1. Nehlin JO, Skovgaard GL, Bohr VA. The Werner syndrome. A model for the study of human aging. Ann N Y Acad Sci. Jun 2000;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. Apr 2007;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. May 2008;33(3):278-81. [Medline].

  4. Pirzio LM, Pichierri P, Bignami M, Franchitto A. Werner syndrome helicase activity is essential in maintaining fragile site stability. J Cell Biol. Jan 28 2008;180(2):305-14. [Medline].

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

  6. Ariyoshi K, Suzuki K, Goto M, Watanabe M, Kodama S. Increased Chromosome Instability and Accumulation of DNA Double-strand Breaks in Werner Syndrome Cells. J Radiat Res (Tokyo). May 2007;48(3):219-31. [Medline].

  7. Barak Y, Sirota P, Kimhi R, Slor H. Werner's syndrome (adult progeria): an affected mother and son presenting with resistant psychosis. Compr Psychiatry. Nov-Dec 2001;42(6):508-10. [Medline].

  8. Bohr VA, Souza Pinto N, Nyaga SG, Dianov G, Kraemer K, Seidman MM, et al. DNA repair and mutagenesis in Werner syndrome. Environ Mol Mutagen. 2001;38(2-3):227-34. [Medline].

  9. Brosh RM Jr, Bohr VA. Roles of the Werner syndrome protein in pathways required for maintenance of genome stability. Exp Gerontol. Apr 2002;37(4):491-506. [Medline].

  10. Fossel M. Human aging and progeria. J Pediatr Endocrinol Metab. 2000;13 Suppl 6:1477-81. [Medline].

  11. Harrigan JA, Wilson DM, Prasad R, Opresko PL, Beck G, May A, et al. The Werner syndrome protein operates in base excision repair and cooperates with DNA polymerase beta. Nucleic Acids Res. Jan 30 2006;34(2):745-54. [Medline].

  12. Hrabko RP, Milgrom H, Schwartz RA. Werner's syndrome with associated malignant neoplasms. Arch Dermatol. Feb 1982;118(2):106-8. [Medline].

  13. Ishikawa Y, Miller RW, Machinami R, Sugano H, Goto M. Atypical osteosarcomas in Werner Syndrome (adult progeria). Jpn J Cancer Res. Dec 2000;91(12):1345-9. [Medline].

  14. Machwe A, Xiao L, Orren DK. Length-dependent degradation of single-stranded 3' ends by the Werner syndrome protein (WRN): implications for spatial orientation and coordinated 3' to 5' movement of its ATPase/helicase and exonuclease domains. BMC Mol Biol. 2006;7:6. [Medline].

  15. Navarro CL, Cau P, Levy N. Molecular bases of progeroid syndromes. Hum Mol Genet. Oct 15 2006;15 Spec No 2:R151-61. [Medline].

  16. Opresko PL, Laine JP, Brosh RM Jr, Seidman MM, Bohr VA. Coordinate action of the helicase and 3' to 5' exonuclease of Werner syndrome protein. J Biol Chem. Nov 30 2001;276(48):44677-87. [Medline].

  17. Oshima J. The Werner syndrome protein: an update. Bioessays. Oct 2000;22(10):894-901. [Medline].

  18. Shibuya H, Kato A, Kai N, Fujiwara S, Goto M. A case of Werner syndrome with three primary lesions of malignant melanoma. J Dermatol. Sep 2005;32(9):737-44. [Medline].

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Further Reading

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Keywords

progeria adultorum, progeria of the adult, pangeria, WS, premature aging disorders, Werner's syndrome

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Contributor Information and Disclosures

Author

Camila K Janniger, MD, Clinical Professor of Dermatology, Clinical Associate Professor of Pediatrics, Chief of Pediatric Dermatology, 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, Adjunct Lecturer, 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
Disclosure: Nothing to disclose.

Medical Editor

Franklin Flowers, MD, Chief, Division of Dermatology, Professor, Department of Medicine and Otolaryngology, University of Florida College of Medicine
Franklin Flowers, MD is a member of the following medical societies: American College of Mohs Micrographic Surgery and Cutaneous Oncology
Disclosure: Nothing to disclose.

Pharmacy Editor

Michael J Wells, MD, Associate Professor, Department of Dermatology, Texas Tech University Health Sciences Center
Michael J Wells, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, American Medical Association, and Texas Medical Association
Disclosure: Nothing to disclose.

Managing Editor

Robert A Schwartz, MD, MPH, Professor and Head of Dermatology, Professor of Medicine, Professor of Pediatrics, Professor of Pathology, Professor of Preventive Medicine and Community Health, UMDNJ-New Jersey Medical School
Robert A Schwartz, MD, MPH is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, American College of Physicians, and Sigma Xi
Disclosure: Nothing to disclose.

CME Editor

Glen H Crawford, MD, Assistant Clinical Professor, Department of Dermatology, University of Pennsylvania School of Medicine; Chief, Division of Dermatology, The Pennsylvania Hospital
Glen H Crawford, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, American Medical Association, Phi Beta Kappa, and Society of USAF Flight Surgeons
Disclosure: Nothing to disclose.

Chief Editor

Dirk M Elston, MD, Director, Department of Dermatology, Geisinger Medical Center
Dirk M Elston, MD is a member of the following medical societies: American Academy of Dermatology
Disclosure: Nothing to disclose.

 
 
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