Continuing Education Activity
Werner syndrome, also known as adult progeria, is a rare autosomal recessive condition that begins in late adolescence or early adulthood and leads to early aging. It presents with characteristic physical and metabolic abnormalities that result in severe complications more commonly seen in the elderly, including diabetes, hypertension, osteoporosis, myocardial infarction, stroke, and cancer. This activity describes the evaluation and management of patients with Werner syndrome and highlights the interprofessional team's role in improving care for affected patients.
Objectives:
Determine how to counsel a patient with Werner syndrome.
Apply the evaluation of Werner syndrome.
Identify treatment options for Werner syndrome.
Communicate the importance of collaboration and coordination amongst the interprofessional team in optimizing the care of patients with Werner syndrome.
Access free multiple choice questions on this topic.
Introduction
Werner syndrome (WS) is 1 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 seen in the elderly population.[1][2][3][4]
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 the body cannot repair these abnormalities in Werner syndrome. This results in the accumulation of genetic instabilities, manifesting as a premature aging phenotype in the affected individual. 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.[5][6]
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 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 in 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 also maintains 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 skeletal muscle loss is unknown but postulated due to a defect in the mesenchymal stem cells in patients with Werner syndrome. The stem cells are thought to have 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 hair loss, and hypogonadism. The loss of subcutaneous fat and dermal atrophy produce a scleroderma-like appearance. They typically have a bird-like face with short stature, high-pitched voice, dental abnormalities, decreased 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 impaired mobility and suffer from osteoporosis of the distal limb bones, more so than the 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 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.[7][8][5][9]
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 study in the appropriate clinical scenario to thoroughly evaluate for underlying disorders, infections, or tumors. DEXA scans should also be performed regularly to evaluate and monitor osteoporosis.
Treatment / Management
Treatment of Werner syndrome is aimed at symptomatic relief and control of secondary organ dysfunction. Treatment of atherosclerosis, hypertension, diabetes, and other diseases is achieved through standard conventional monitoring and medical therapy, but the disorder continues 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 foot 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.
Complications
Complications are tied to the symptoms derived from affected systems as described above. Werner syndrome patients have an elevated risk of developing cancer, particularly skin and thyroid cancers. These patients typically have shorter than average life spans, with cancer and myocardial infarction being the most common causes of death.
Consultations
Management of Werner syndrome patients should include an interdisciplinary approach based on the patient's 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 like the National Organization for Rare Disorders.
Enhancing Healthcare Team Outcomes
Werner syndrome is a very rare genetic disorder, and it is unlikely that most clinicians ever see such a case. However, because the disorder involves rapid aging of the entire body, these individuals need to be seen by an interprofessional team that includes a social worker, therapist, cardiologist, dermatologist, endocrinologist, orthopedic surgeon, ophthalmologist, oncologist, and rheumatologist. The key is to improve the quality of life and provide supportive care. There is no cure for Werner syndrome, and most people affected by the disorder are dead by the fifth decade of life. Thus, it is important not to offer radical surgeries and procedures because this usually leads to more harm than good.[10]
References
- 1.
Sarbacher CA, Halper JT. Connective Tissue and Age-Related Diseases.
Subcell Biochem. 2019;91:281-310. [
PubMed: 30888657]
- 2.
Isaev NK, Stelmashook EV, Genrikhs EE. Neurogenesis and brain aging.
Rev Neurosci. 2019 Jul 26;30(6):573-580. [
PubMed: 30763272]
- 3.
Kuk MU, Kim JW, Lee YS, Cho KA, Park JT, Park SC. Alleviation of Senescence via ATM Inhibition in Accelerated Aging Models.
Mol Cells. 2019 Mar 31;42(3):210-217. [
PMC free article: PMC6449716] [
PubMed: 30726661]
- 4.
Sargolzaeiaval F, Zhang J, Schleit J, Lessel D, Kubisch C, Precioso DR, Sillence D, Hisama FM, Dorschner M, Martin GM, Oshima J. CTC1 mutations in a Brazilian family with progeroid features and recurrent bone fractures.
Mol Genet Genomic Med. 2018 Nov;6(6):1148-1156. [
PMC free article: PMC6305643] [
PubMed: 30393977]
- 5.
Geng L, Liu Z, Zhang W, Li W, Wu Z, Wang W, Ren R, Su Y, Wang P, Sun L, Ju Z, Chan P, Song M, Qu J, Liu GH. Chemical screen identifies a geroprotective role of quercetin in premature aging.
Protein Cell. 2019 Jun;10(6):417-435. [
PMC free article: PMC6538594] [
PubMed: 30069858]
- 6.
Oshima J, Kato H, Maezawa Y, Yokote K. RECQ helicase disease and related progeroid syndromes: RECQ2018 meeting.
Mech Ageing Dev. 2018 Jul;173:80-83. [
PMC free article: PMC6217841] [
PubMed: 29752965]
- 7.
Isaev NK, Genrikhs EE, Oborina MV, Stelmashook EV. Accelerated aging and aging process in the brain.
Rev Neurosci. 2018 Mar 28;29(3):233-240. [
PubMed: 29150992]
- 8.
Kusumesh R, Sinha BP, Ambastha A, Thakur SK. Management of cataract in Werner syndrome.
Indian J Ophthalmol. 2018 Sep;66(9):1337-1339. [
PMC free article: PMC6113835] [
PubMed: 30127165]
- 9.
Compagnucci C, Bertini E. The Potential of iPSCs for the Treatment of Premature Aging Disorders.
Int J Mol Sci. 2017 Nov 07;18(11) [
PMC free article: PMC5713319] [
PubMed: 29112121]
- 10.
Domínguez-Gerpe L, Araújo-Vilar D. Prematurely aged children: molecular alterations leading to Hutchinson-Gilford progeria and Werner syndromes.
Curr Aging Sci. 2008 Dec;1(3):202-12. [
PubMed: 20021393]
Disclosure: Christine Sickles declares no relevant financial relationships with ineligible companies.
Disclosure: Gary Gross declares no relevant financial relationships with ineligible companies.
