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.

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.

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.

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.^[4] Two novel WRNmutations were described in patients of South Asian ancestry.^[5] Another patient had a homozygous novel 1bp-deletion in exon 19 of WRN, 2426/27delG, causing frameshift and protein truncation R809SfsX2.^[6]

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.^[7] 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.^[8]

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.^[9] 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.^[10] 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.^{[11, 12]}

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.^[13] 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.

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.

In general, this is an adult-onset disorder, with the earliest sign the lack of a growth spurt during adolescence.^[4] A prematurely aged appearance with gray hair and sclerodermatous cutaneous changes begins in the 20-30s in association with cataracts, diabetes mellitus, atherosclerosis, cancers, and osteoporosis.

Metabolic abnormalities, including insulin resistance, may not be a pivotal part at disease onset.^[14]

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 is as follows:

• 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 findings are as follows:

• 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, as follows:

• 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, as follows:

• Hematologic malignancies (leukemia and preleukemic conditions of the bone marrow ^[15] )
• Carcinomas of the thyroid ^[15] and other organs
• Sarcomas (soft tissue ^[15] )
• Meningiomas ^[15]
• Cutaneous malignancies, including malignant melanoma ^[15]
• 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
• Primary bone neoplasms ^[15]

WS is a genetic disorder. See Pathophysiology.

Differential Diagnoses

• Dermatologic Manifestations of Mixed Connective Tissue Disease

• Rothmund-Thomson Syndrome

• Systemic Sclerosis