Progeria (Werner Syndrome)

Article Author:
Christine Sickles
Article Editor:
Gary Gross
Updated:
10/27/2018 12:32:04 PM
PubMed Link:
Progeria (Werner Syndrome)

Introduction

Werner syndrome (WS) is one of the premature aging syndromes named progeria. Otto Werner first described it in 1904. It is a rare autosomal recessive condition that begins in late adolescence or early adulthood. 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.

Etiology

Werner syndrome is an inherited disorder that results in the loss of function in the DNA protective repair mechanisms. Genetic instabilities are a normal feature of aging, but in Werner syndrome, the body cannot repair these abnormalities. This results in the accumulation of genetic instabilities, which manifests as a premature aging phenotype in the affected individual. The premature aging only affects certain types of tissue. Premature neurocognitive deficits are not typically seen in Werner syndrome patients, making an argument against the classification of an overall accelerated aging syndrome, but more a segmental aging syndrome.

Epidemiology

Werner syndrome is estimated to occur in 1 out of 100,000 live births worldwide. It has a high prevalence in Japan, where the frequency has been reported to be as high as 1 in 20,000 to 40,000 live births. The prevalence in the United States has been reported as 1 in 200,000 live births.

Pathophysiology

Werner syndrome is caused by a truncating mutation in the WRN gene due to the production of a stop codon from a nonsense or frameshift mutation. The WRN gene encodes a 142 amino acid protein that is part of the Rec Q DNA helicase family. Its function is to unwind the 2 DNA strands and act as an exonuclease. The WRN gene plays a role in maintaining proper DNA replication and repair through base excision repair, non-homologous end joining and homologous recombination. It is also involved in maintaining telomere stability, which is pivotal for genomic stability. Telomeres are a marker for aging and act by counting the number of cell divisions.

It is postulated that epigenetic changes to histones can contribute to the pathogenesis of Werner syndrome, but there is not enough data to support this theory.

The mechanism behind the loss of skeletal muscle is unknown but postulated to be due to a defect in the mesenchymal stem cells in patients with Werner syndrome. The stems cells are thought to be of a senescent phenotype in Werner syndrome, rendering a low capacity for regenerative potential.

Toxicokinetics

Caution should be exercised with Werner syndrome patients and chemotherapy treatments. They are at an increased risk of chemotoxicity due to their impaired ability in DNA repair mechanisms.

History and Physical

Werner syndrome patients appear unaffected at birth and develop normally until the adolescent period or second decade of life when they start to exhibit signs and symptoms of accelerated aging. Patients develop skin ulcers, cataracts, graying or even loss of their hair, and hypogonadism. The loss of subcutaneous fat and dermal atrophy produces a scleroderma-like appearance. They typically have a bird-like face with short stature, high pitched voice, dental abnormalities, decrease in body weight and body mass index (BMI).

Patients also experience a rapid loss of muscle mass, most notably in the limbs with sparing of the trunk. They also have a decrease in their grip strength and skeletal muscle index, reaching the level of sarcopenia before the age of 40. They have impairment of their mobility and suffer from osteoporosis of the distal limb bones more so than vertebral column. Soft tissue calcifications can occur, most commonly in the Achilles tendon. Pes planus, hallux valgus and flexion contractures can occur in the feet with subsequent development of ulceration, osteitis, and osteomyelitis.

Metabolic abnormalities also occur including the development of type 2 diabetes mellitus and an increase in the visceral fat accumulation.

Cardiovascular abnormalities develop as well, which can include atherosclerosis, mitral regurgitation, and aortic stenosis.

WS patients are at an increased risk of tumor formation with up to 10% of patients developing a malignancy. However, the types of tumors that develop are unusual compared to the aging population. Up to 50% of the malignancies reported are soft tissue sarcomas, such as schwannoma, rhabdomyosarcoma, malignant fibrous histiocytoma, leiomyosarcoma, and osteosarcoma of the upper extremities. Patients have also been reported to develop meningiomas, malignant melanoma, and thyroid carcinomas.

Evaluation

Genetic testing through nuclear sequencing by reverse transcription polymerase chain reaction (PCR) with western blot protein analysis can confirm the diagnosis of Werner syndrome. Prenatal testing with amniocentesis and chorionic villus sampling is now done in patients at high risk for having infants with this disorder.

Patients diagnosed with Werner syndrome should undergo regular screening tests for hyperlipidemia, breast and colorectal cancer, diabetes, and thyroid abnormalities. Given the number of musculoskeletal abnormalities and high prevalence of soft tissue sarcomas in Werner syndrome patients, clinicians should perform an x-ray, CT, or MRI studies in the appropriate clinical scenario to evaluate for underlying disorders, infections or tumors thoroughly. DEXA scans should also be performed on a regular basis to evaluate and monitor osteoporosis.

Treatment / Management

Treatment of Werner syndrome is aimed at symptomatic relief and control of the secondary organ dysfunction. Treatment of atherosclerosis, hypertension, diabetes, and other diseases is achieved through standard conventional monitoring and medical therapy, but the disorder will continue to progress. It has been reported that bosentan, which is an endothelin receptor antagonist, can be used to treat severe cutaneous ulcers. Sodium etidronate can help improve symptomatic calcifications in the soft tissue. Orthotics can be used to manage complications with feet deformities. Cataracts should be managed surgically. Sarcopenia can be treated with diets rich in branched amino acids, exercise, vitamin D supplementation, and hormone therapy, although this is controversial given the increased risk of malignancy.

Differential Diagnosis

Differential diagnosis includes systemic sclerosis, dermatomyositis, and other premature aging syndromes. These include Hutchinson-Gilford Progeria syndrome, Bloom syndrome, Cockayne syndrome, ataxia telangiectasia, xeroderma pigmentosum, and Wiedemann-Rauten-Strauch syndrome. 

Staging

If a Werner syndrome patient develops a malignancy, they should be referred to the appropriate specialist for the staging of the tumor.

Prognosis

Werner syndrome patients typically live into the fifth decade of life. Patients usually die of malignancy or cardiovascular disease.

Consultations

Management of Werner syndrome patients should include an interdisciplinary approach based on the secondary complications. This may include endocrinology, dietetics, cardiology, geriatrics, ophthalmology, infectious disease, oncology, and orthopedic surgery.

Deterrence and Patient Education

Clinicians should refer patients and their families to a genetic counselor for further information regarding the condition. They should also be encouraged to join a support group, such as National Organization for Rare Disorders.