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Dermatology > PEDIATRIC DISEASES
Werner Syndrome
Article Last Updated: Apr 23, 2008
AUTHOR AND EDITOR INFORMATION
Section 1 of 11  
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 is a member of the following medical societies: American Academy of Dermatology
Coauthor(s):
Anna Wozniacka, MD, PhD, Adjunct Lecturer, Department of Dermatology, Medical University of Lodz, Poland
Editors: Franklin Flowers, MD, Chief, Division of Dermatology, Professor, Department of Medicine and Otolaryngology, University of Florida College of Medicine; Michael J Wells, MD, Associate Professor, Department of Dermatology, Texas Tech University Health Sciences Center; 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; Glen H Crawford, MD, Assistant Clinical Professor, Department of Dermatology, University of Pennsylvania School of Medicine; Chief, Division of Dermatology, The Pennsylvania Hospital; Dirk M Elston, MD, Director, Department of Dermatology, Geisinger Medical Center
Author and Editor Disclosure
Synonyms and related keywords:
progeria adultorum, progeria of the adult, pangeria, WS, premature aging disorders, Werner's syndrome
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.
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.
Mixed Connective Tissue Disease
Rothmund-Thomson Syndrome
Systemic Sclerosis
Other Problems to be Considered
Acrogeria (Gottron syndrome)
Alzheimer disease (presenile dementia, senile dementia)
Lab Studies
- Perform a thorough clinical and laboratory examination, keeping in mind the patient's increased risk of neoplasms.
- WS has no specific laboratory abnormalities. Any laboratory abnormalities are related to concomitant diseases, especially diabetes mellitus, arteriosclerosis, and hypogonadism, which are often seen in WS.
- One should perform the following:
- Fasting blood glucose test
- Oral glucose tolerance test
- Triiodothyronine, levothyroxine, and thyrotropin tests
- Appropriate vascular studies
- Diabetes mellitus is of the late-onset type.
- One should check the blood glucose level.
- An oral glucose tolerance test should be performed.
- Atherosclerosis should be evaluated with a lipid profile.
- An elevated low-density-lipoprotein cholesterol level and a high triglyceride level associated with a low high-density-lipoprotein cholesterol level are the risk factors for atherosclerotic vascular disease.
- The National Cholesterol Education Program has issued guidelines for the diagnosis and optimal treatment of hyperlipidemia.
- Hypogonadism is usually due to intestinal fibrosis.
- One should check estradiol, progesterone, and luteinizing hormone/follicle-stimulating hormone (LH/FSH) levels in the sera of female patients.
- One should check testosterone and LH/FSH in the sera of male patients.
Histologic Findings
The skin and subcutaneous tissue of the extremities, especially where it is taut on clinical examination, shows epidermal thinning, loss of rete ridges, and dermal fibrosis with or without collagen hyalinization. Pilosebaceous structures are not well formed. Newly synthesized hyalinized collagen tends to replace the subcutaneous fat. No inflammatory infiltrate is usually evident.
Medical Care
Specific treatment does not exist. Only symptomatic treatment of related disturbances is recommended.
Consultations
Consultations are related to the concomitant diseases.
No specific treatment exists.
Complications
- Complications are related to the concomitant diseases and symptoms described above (see Physical).
Prognosis
- The prognosis is unfavorable.
- Death usually occurs when patients are aged 30-50 years.
Medical/Legal Pitfalls
- Making this diagnosis is important because these patients are at increased risk of cataracts, carcinomas of the thyroid and other organs, hematologic malignancies, sarcomas, meningiomas, and cutaneous malignancies.
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Werner Syndrome excerpt Article Last Updated: Apr 23, 2008
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