ﺑﺎﺯﮔﺸﺖ ﺑﻪ ﺻﻔﺤﻪ ﻗﺒﻠﯽ
خرید پکیج
تعداد آیتم قابل مشاهده باقیمانده : 3 مورد
نسخه الکترونیک
medimedia.ir

Werner syndrome

Werner syndrome
Literature review current through: Jan 2024.
This topic last updated: Oct 27, 2023.

INTRODUCTION — Werner syndrome (WS; MIM #277700), also known as adult progeria, is a rare, autosomal recessive, progeroid (premature aging-like) syndrome caused by loss-of-function variants of the WRN gene on chromosome 8p12 [1,2]. WS is characterized by short stature and signs of premature aging in young or middle-aged adults, including early graying and loss of hair, bilateral cataracts, and scleroderma-like skin changes (picture 1). These changes are accompanied by an elevated risk of clinically important, age-associated diseases, including cardiovascular disease, diabetes mellitus, and osteoporosis. Moreover, patients with WS have an elevated risk of several different types of cancer.

This topic will discuss the genetics, pathogenesis, diagnosis, and management of WS. Atypical WS and several other rare, progeroid syndromes will also be briefly discussed here [2]. Hutchinson-Gilford progeria syndrome (HGPS) is discussed separately. (See "Hutchinson-Gilford progeria syndrome".)

EPIDEMIOLOGY — Individuals with Werner syndrome (WS) have been reported worldwide. Males and females are diagnosed in equal numbers. The estimated incidence ranges from <1 per 100,000 births to 1 per 10,000. Geographic case and family clusters of WS often reflect local founder pathogenic variants of WRN and have been reported in Japan, Sardinia, India, and Pakistan [3].

In a study of 9019 individuals from the combined Exome Sequencing Project/1000 Genomes Project datasets designed to capture genetic variation in geographic and ancestrally diverse populations, the pathogenic WRN allele carrier frequency was estimated to be approximately 2 percent [4]. Carriers were virtually all heterozygotes, with the exception of four putative homozygous individuals [4]. This high population prevalence of known pathogenic WRN variants, despite the apparent rarity of WS, supports the hypothesis that WS is clinically under-recognized and underdiagnosed.

PATHOPHYSIOLOGY

Inheritance and molecular genetics — Werner syndrome (WS) is an autosomal recessive disorder caused by pathogenic loss-of-function variants of the WRN gene on chromosome 8p12. Positional cloning and analysis revealed that WRN is a 145 kb gene consisting of 35 exons that encode a 1432 amino acid protein with ATPase, 3'-5' helicase, and 3'-5' exonuclease activities [5]. Presence of the deeply conserved helicase domain led to identification of WRN as one of five human RECQ helicase genes. Loss of function of two other human RECQ helicases, BLM and RECQL4, have been linked, respectively, to two other cancer predisposition syndromes: Bloom syndrome and Rothmund-Thomson syndrome [6]. (See "Bloom syndrome".)

The human WRN gene displays abundant genetic variation. Nearly 2300 sequence variants in or within 75 base pairs of a WRN coding exon were identified in 125,748 exome sequences and 15,708 whole genome sequences from unrelated individuals [7]. The most common pathogenic WRN variant is a nonsense mutation in exon 8 (c.1105C>T, rs17847577, p.R369*), which accounts for approximately 20 percent of pathogenic alleles, with a frequency of 1.8 to 3.0 per 10,000 in The Genome Aggregation Database (gnomAD) [7,8]. One Japanese pathogenic variant (c.3139-1G>C, leading to an exon 26 skip) accounts for approximately 70 percent of the mutant alleles identified in patients with WS in Japan, where the aggregate carrier frequency for pathogenic variants is estimated to be 1 in 167 [5,9,10]. Other common pathogenic variants include c.2089-3024A>G (which alters splicing with the inclusion of a new exon between exons 18 and 19) in Sardinian patients with WS, with a reported frequency of approximately 1 in 120 [11]; c.561A>G (which alters exon 6 splicing) in patients with WS of Indian/Pakistani ancestry; and c.3460-2A>G (leading to exon 30 skipping) identified in patients with WS of Turkish ancestry [3,12].

Functions of the WRN protein — WRN gene and protein expression are ubiquitous, though the tissue and cell type-specific expression during development or adult lifespan is not known [1,6].

The WRN helicase belongs to a DEAH-box-containing RecQ family of helicases. It is involved in the repair of potentially deleterious deoxyribonucleic acid (DNA) structures, such as branched intermediates formed during DNA replication, recombination, and transcription, and sequence-dependent structures, such as G-quadruplex DNA and the telomere "caps" that protect chromosome ends [1,13,14]. These DNA structures may disrupt DNA metabolism and trigger cell cycle arrest or death if not appropriately handled during cell replication and division.

WRN is unique among the human RECQ helicase proteins in possessing a 3'-5' exonuclease activity in addition to ATPase and helicase activities. Other WRN protein domains include a C-terminal nuclear localization signal (NLS) and RECQ conserved/consensus (RQC) and helicase, RNaseD, C-terminal conserved region (HRDC) domains, which play roles in substrate DNA binding and WRN recruitment to DNA double-strand breaks, respectively. The WRN protein also possesses single-strand DNA annealing activity.

Virtually all of the clinically ascertained WRN variants mentioned above confer a common biochemical phenotype: loss of the WRN protein together with helicase, ATPase, and exonuclease activities [15]. Experimental data and the absence of clinically ascertained variants that selectively eliminate a single WRN catalytic activity indicate that WS pathogenesis requires the loss of all WRN-associated catalytic activities from patient cells [16]. This idea is reinforced by an analysis of individuals homozygous for a WRN missense variant, p.R834C, that largely abolishes WRN helicase activity, preserves WRN-associated catalytic activity, but does not confer a WS clinical phenotype [17,18].

WRN helicase and cancer — Patients with WS have an increased risk of developing several specific types of cancer (table 1). Only a few of the neoplasms arising in patients with WS have been molecularly characterized, and therefore, it is not known whether they have unique or defining genomic features [19].

The loss of WRN function in the presence of a mismatch repair (MMR) deficiency confers a strong cell-lethal phenotype. This observation is of high conceptual and practical interest. It predicts that patients with WS are protected against cancers associated with MMR deficiency, such as colorectal cancer [20-23], and has generated considerable interest in developing small molecule inhibitors of WRN catalytic activities as a novel way to treat MMR-deficient cancers in the general population [24,25]. MMR-deficient cancers include subsets of common adult epithelial malignancies, such as colorectal, gastric, and endometrial carcinomas [26].

CLINICAL FEATURES — The clinical phenotype of Werner syndrome (WS) is often first expressed and clinically discernable in adolescence or early adulthood. This is in contrast with nearly all other progeroid syndromes that have strongly penetrant phenotypes in infancy or early childhood (see "Hutchinson-Gilford progeria syndrome"). The delayed initial appearance and continued clinical progression spanning over several decades can be readily appreciated in pairs of photos taken of patients with WS when they were teenagers, then later in their 40s or 50s (picture 1) [1,27-31].

Clinical signs that develop in virtually all patients with WS and referred to as cardinal signs of WS include:

Short stature – Short stature, due to lack of a growth spurt during adolescence, is often the first sign of WS.

Cataracts – Most patients develop bilateral cataracts by the second or third decade of life. The cataracts are predominantly posterior cortical and subcapsular, with less frequent vacuolization and small, punctate opacities in other parts of the lens. This type of cataract, often referred to as "juvenile," is distinct from the nuclear opacities commonly observed in the "senile" cataracts occurring in older individuals without WS.

Graying and loss of hair – Early graying and hair loss are, together with short stature, among the earliest and most consistent findings in patients with WS. They start in the second decade of life and first affect the scalp and eyebrows. The loss of hair pigmentation is progressive and may eventually be complete. Similar changes occur in body hair but usually start later and may not be as extensive as those observed in the scalp and eyebrows.

Scleroderma-like skin changes – Scleroderma-like skin changes are often first noted in the face and extremities and lead to a progressive sharpening of facial features, with many patients eventually developing a "pinched," "beaked," or "bird-like" appearance. Lower extremities, especially the feet, are often affected with foot deformation and flattening, ulceration of non-pressure-bearing portions of the foot and ankles (picture 2), and a characteristic calcification of soft tissue and tendons (image 1) [32-34]. Indolent foot and ankle ulcers are highly characteristic of WS and a significant source of morbidity.

Skin biopsies reveal epidermal atrophy extending into the skin appendages (hair follicles, sweat glands, and sebaceous glands), in conjunction with focal hyperkeratosis and basal hypermelanosis. Dermal, subcutaneous connective tissue atrophy is common, often in conjunction with dermal fibrosis and atrophy of underlying adipose, connective, and muscle tissue [28,32]. This constellation of changes gives skin a "tight and shiny" appearance, with loss of normal elasticity.

High-pitched, hoarse voice – A thin, high-pitched voice is characteristic and results from proliferative and atrophic, laryngeal changes.

Other prominent clinical features – These include:

Atherosclerosis and its cardiovascular and cerebral vascular sequelae

Osteoporosis, which is typically most severe in the distal phalanges of the extremities

Diabetes mellitus

Hypogonadism and declining fertility affecting males and females

Age-associated, neurodegenerative diseases, such as Alzheimer disease and Parkinson disease, do not appear to be more prevalent among patients with WS, including those who live into their sixth or seventh decade.

CLINICAL COURSE — One aspect of Werner syndrome (WS) not well appreciated from the list of diagnostic findings (table 2) is the progressive nature of WS. Full expression with the eventual appearance of the canonical features of WS may appear only two or three decades after an initial diagnosis in the second decade of life. A sense of this progressive expression of findings is readily apparent from pairs of patient photos taken in early adulthood and later in midlife (picture 1).

This phenotypic progression of WS can be usefully described as three overlapping phases:

The first phase is the absence of an adolescent growth spurt, followed over the subsequent decade by the appearance of graying and loss of hair and development of skin changes and cataracts. Indeed, prior to puberty, many patients with WS display no signs characteristic of WS.

A second phase, often first seen late in the third decade, includes skin ulceration, hypogonadism, and infertility together with further progression of primary changes. Both females and males with WS have been reported as having biologic children, although generally at younger ages.

A third phase includes a rapidly rising risk of age-associated diseases, such as atherosclerosis, osteoporosis, diabetes mellitus, and cancer. These complications develop earlier or are more severe in patients with WS than in age- and sex-matched control individuals. Deep, chronic ulcerations of the medial or lateral malleolus or the Achilles tendon, ubiquitous in patients of Japanese ancestry and frequently noted in individuals of other ancestries with WS, are a major source of morbidity in many patients [33,34].

RISK OF CANCER — Patients with Werner syndrome (WS) are at increased risk of developing cancer, and cancer remains a leading cause of premature morbidity and death among individuals with WS. A systematic review of published cases of WS that included 139 patients from Japan and 50 patients of diverse ethnicities and locations reported between 1939 and 2011 found that six types of cancer (thyroid epithelial neoplasms, melanoma, meningiomas, soft tissue sarcomas, leukemia and preleukemic conditions, and primary bone neoplasms) represented two-thirds of all cancers reported in WS (table 1) [35].

In Japanese patients, the cancer standardized incidence ratio (SIR) relative to the general population ranged from 8.9 for thyroid neoplasms (95% CI 4.9-15.0) to 53.5 for melanoma (95% CI 24.5-101.6). No good model exists to explain why or how the incidence of these specific neoplasms is elevated in patients with WS. Diabetes mellitus, a common feature of WS, may confer a higher general risk of cancer; however, this hypothesis is disputed [36,37].

The development of cancer at an early age, at unusual sites (eg, osteosarcoma of the patella), or with less common histopathologic subtypes (eg, follicular, as opposed to the more common papillary, thyroid carcinoma) may raise an initial suspicion of WS. These atypical or unusual clinical presentations are a feature of many other cancer predisposition syndromes.

Melanomas in WS are, in most cases, acral lentiginous melanomas and mucosal involving the nasal or esophageal mucosa [35,38]. The elevated risk of acral lentiginous melanoma in Japanese patients with WS suggests a potential role for population-specific risk modifiers.

Multiple neoplasms are remarkably common in WS. Up to five different primary neoplasms have been reported in individual patients, and nearly one-quarter of patients have two or more histologically distinct types of cancer [35].

Knowledge of the histopathologic spectrum of neoplasia in WS and the potential for unusual presentations or features can guide cancer surveillance in individuals with WS. (See 'Prevention of complications' below.)

DIAGNOSIS — The adult onset and slow development of clinical signs and symptoms make the clinical diagnosis of Werner syndrome (WS) challenging. The definitive diagnosis is often delayed, especially in young adults who may show only a few findings. This diagnostic "lag" is often accentuated in the absence of a family history [2,39].

Clinical suspicion – A diagnostic suspicion of WS is often driven by considering the clinical findings in light of patient age (see 'Clinical features' above). Although the family history is usually negative, the presence of affected siblings or parental consanguinity should increase suspicion of WS. Patient ancestry is also important to note, as many patients with WS with Japan, Syria, Sardinia, and Turkey as countries of residence and/or ancestry carry common pathogenic founder alleles of WRN. Parental consanguinity increases the risk of rare, recessive conditions in general and, more specifically, increases the likelihood of identity by descent at the WRN locus.

Diagnostic criteria – Key clinical or "cardinal" findings are eventually observed in nearly all patients with WS and have been used to develop clinical diagnostic criteria for WS. Two sets of diagnostic criteria for WS, which combine cardinal and additional findings to establish a clinical diagnosis, have been developed by the International Registry of Werner Syndrome and the Japanese Werner Syndrome Registry (table 2) [2,40].

Cardinal signs of WS include:

Premature graying and/or thinning of scalp hair

Bilateral cataract

Scleroderma-like skin changes, intractable lower leg skin ulcers

Soft tissue calcification (most often Achilles tendon)

Bird-like face

High-pitched voice

Genetic testing – The identification of causative pathogenic variants in both copies of WRN can be used to confirm the diagnosis.

DIFFERENTIAL DIAGNOSIS — The most likely clinical syndromes that may be mistaken for Werner syndrome (WS) include atypical WS, MDPL (mandibular hypoplasia, deafness, progeroid features, and lipodystrophy) syndrome, mandibuloacral dysplasia, and Hutchinson-Gilford progeria syndrome (HGPS).

Atypical Werner syndrome — Patients with atypical WS may resemble patients with classical WS, but the age of onset is often earlier, and clinical progression may be more rapid. Approximately 15 percent of patients have heterozygous, pathogenic, missense variants in LMNA, the gene encoding lamin A [27,41].

MDPL syndrome — MDPL (mandibular hypoplasia, deafness, progeroid features, and lipodystrophy) syndrome (MIM #615381) is an autosomal dominant disorder characterized by progeroid features, lipodystrophy, and sensorineural hearing loss with characteristic facial features. In contrast with WS, it is not associated with ocular cataracts or elevated risk of neoplasia. MDPL syndrome is caused by de novo, heterozygous, pathogenic variants in the POLD1 subunit of one of the major human replicative DNA polymerases [42,43].

Mandibuloacral dysplasia — Mandibuloacral dysplasia with type A lipodystrophy (MADA; MIM #248370) is a progeroid syndrome characterized by short stature; loss of fat in the extremities but accumulation of fat in the neck and trunk; thin, hyperpigmented skin; partial alopecia; prominent eyes; a convex nasal ridge; tooth loss, micrognathia, and retrognathia; and short fingers. MADA is caused by biallelic, pathogenic variants in LMNA [44].

Mandibuloacral dysplasia with type B lipodystrophy (MADB; MIM #608612) is associated with a generalized loss of subcutaneous fat and insulin resistance. MADB has been attributed to biallelic, pathogenic variants in the zinc metalloproteinase gene ZMPSTE24 [45].

Hutchinson-Gilford progeria syndrome — Hutchinson-Gilford progeria syndrome (HGPS; MIM #176670), also known as "progeria of childhood," is a multisystem disorder with accelerated aging in the first few years of life after a profound failure to thrive during the first year. Characteristic facies, partial alopecia progressing to total alopecia, loss of subcutaneous fat, progressive joint contractures, bone changes, and abnormal tightness and/or small, soft outpouchings of the skin over the abdomen and upper thighs usually become apparent from the second year of life. Motor and mental development is normal. Individuals with HGPS develop severe atherosclerosis, with cardiac or cerebrovascular disease beginning as early as age six. The average lifespan of individuals with HGPS is approximately 15 years, and death usually occurs as a result of cardiovascular complications [46]. Classic HGPS is caused by the single nucleotide substitution c.1824C>T in the lamin A/C gene LMNA. Nearly all well-documented patients with HGPS carry this de novo, autosomal dominant, pathogenic variant [47]. (See "Hutchinson-Gilford progeria syndrome".)

Other hereditary and acquired syndromes — Several syndromes share features with WS, though they can be distinguished from WS by age of onset.

Flynn-Aird syndrome – Flynn-Aird syndrome is a neuroectodermal syndrome presenting with cataracts, skin atrophy and ulceration, and neurologic abnormalities [48].

Branchio-oculo-facial syndrome – Branchio-oculo-facial syndrome (BOFS; MIM #113620) is a rare, autosomal dominant disorder characterized by premature graying of the hair in adults in conjunction with strabismus, coloboma and microphthalmia, and variable dysmorphic facial features. BOFS is caused by pathogenic variants in TFAP2A, encoding the AP-2-alpha transcription factor [49].

SHORT syndrome – Features of SHORT (short stature, hyperextensibility, hernia, ocular depression, Rieger anomaly, and teething delay; MIM #269880) syndrome may include progeria-like facies, lipodystrophy, type 2 diabetes mellitus, cataracts, and glaucoma. Pathogenic variants in the PIK3R1 gene have been identified as causal variants for this autosomal dominant disorder [50]. (See "Lipodystrophic syndromes", section on 'Other syndromes with a component of lipodystrophy'.)

Early-onset type 2 diabetes – Early-onset type 2 diabetes mellitus with secondary cardiovascular and cutaneous complications may suggest WS, but it should be easily distinguished based on other clinical features and patient history. (See "Epidemiology, presentation, and diagnosis of type 2 diabetes mellitus in children and adolescents".)

Myotonic dystrophy type 1 or 2 – Myotonic dystrophy type 1 (MIM #160900) and myotonic dystrophy type 2 (MIM #602668) should be considered in young individuals with adult-type cataracts as well as in adults with muscle wasting. However, the cataracts in WS are most often posterior subcapsular, and other features of myotonic dystrophies (eg, myotonia or cardiac conduction abnormalities) are quite different from WS, although they may appear first in adulthood. (See "Myotonic dystrophy: Etiology, clinical features, and diagnosis".)

Scleroderma, mixed connective tissue disorders, and lipodystrophy – These conditions may have skin changes, including distal atrophy and skin ulcerations, that could be mistaken for WS. (See "Clinical manifestations and diagnosis of systemic sclerosis (scleroderma) in adults" and "Mixed connective tissue disease" and "Lipodystrophic syndromes".)

Other cancer-prone syndromes — Clinical features of neoplasia in WS (early age of onset, unusual histopathologic type or subtype, atypical anatomical locations) are often observed in other cancer predisposition syndromes [51]. Cancer predisposition syndromes that can be distinguished from WS by clinical findings and molecular diagnostic test data include:

Rothmund-Thomson syndrome and Bloom syndrome – These two other RECQ helicase deficiency syndromes are caused by pathogenic variants in the RECQL4 and BLM genes, respectively [52]. They can be distinguished from WS on the basis of age of onset, differing clinical findings, and genetic test results. Rothmund-Thomson syndrome is characterized by poikiloderma, short stature, skeletal and dental abnormalities, juvenile cataracts, and an increased risk for cancer, especially osteosarcoma and skin cancers. Bloom syndrome is characterized by short stature, characteristic facies, and often a sun-sensitive facial "butterfly" skin rash. (See "Bloom syndrome".)

Li-Fraumeni syndrome – Li-Fraumeni syndrome is caused by germline, pathogenic variants in the TP53 tumor suppressor gene and is linked to an elevated risk of several cancers, including nonepithelial cancers similar to those observed in WS. Other prominent features of WS, such as cataracts, are not part of Li-Fraumeni syndrome. (See "Li-Fraumeni syndrome".)

MANAGEMENT — There is no specific or effective therapy for Werner syndrome (WS). Because of the multisystem nature of WS, patients should be managed in medical centers with expertise in rare, complex diseases and ready access to multiple specialty consultation, including medical genetics, ophthalmology, cardiology, dermatology, and oncology.

Patients with WS are responsive to common therapeutic interventions, such as pharmacologic management of hypertension, diabetes mellitus, and lipid metabolic abnormalities; surgical removal of cataracts; and screening for cancer or other acquired diseases. Effective screening and management of these associated diseases, together with aggressive treatment of foot, ankle, and elbow ulcers, have the potential to substantially extend longevity and the quality of life for many patients [33,34,53].

Guidelines based on expert opinion for the management of diabetes mellitus, hyperlipidemia, skin ulceration, tendon calcification, infection control, and sarcopenia associated with WS have been published [33,34,54-58].

Baseline evaluation — Once a diagnosis of WS is established, a baseline assessment should be performed to collect biometric and clinical laboratory data. This will also be an opportunity to initiate screening to identify or exclude common associated disease, including diabetes mellitus or impaired glucose tolerance; hyperlipidemia; hypertension; osteoporosis; skin changes, especially at locations prone to ulceration; and neoplasia. A family history should be taken to assess whether other relatives may be affected and to identify likely heterozygous carriers of a pathogenic WRN variant. In a patient with a diagnosis of WS, the initial evaluation to establish the extent of disease and make a management plan includes:

Physical examination for signs and symptoms of cardiovascular disease, cerebrovascular disease, or cancer types that are common and/or occur at elevated risk in WS (eg, thyroid nodules).

Total body skin examination, focused on early detection of foot and ankle ulceration, nail bed and foot sole acral lentiginous melanomas, and soft tissue calcification.

Type 2 diabetes mellitus screening, including determinations of fasting glucose level, hemoglobin A1C level, and/or an oral glucose tolerance test. (See "Screening for type 2 diabetes mellitus".)

Lipid panel profiling.

Ophthalmologic examination, including slit lamp examination for cataract detection. Vision can be restored by cataract removal, although the risk of cystic macular edema as a postsurgical complication may be higher in patients with WS [59].

Dual-energy x-ray absorptiometry scan to evaluate for osteopenia.

Subfertility or infertility can be assessed in females by inquiring about menstrual cycles and measurement of follicle-stimulating hormone (FSH) and luteinizing hormone (LH), and in males by semen analysis. Males and females with WS who plan to have children benefit from referral to a reproductive endocrinology infertility specialist to discuss fertility preservation and reproductive options.

Imaging studies where clinically appropriate (eg, cranial magnetic resonance imaging if there are persistent or especially recent-onset seizures, focal neurologic signs such as weakness or a visual field defect, or symptoms such as diplopia or headache that may signal the presence of meningioma or atherosclerotic cerebrovascular disease).

Prevention of complications — The initial clinical evaluation is often the best opportunity to discuss with patients and family members/caregivers the clinical course of WS, practical management and screening issues, and the importance of continued monitoring to identify treatable, potentially life-threatening complications, such as neoplasia or cardiovascular disease. This should include a discussion of primary and secondary prevention measures, including:

Risk assessment and primary prevention of atherosclerotic cardiovascular disease (see "Atherosclerotic cardiovascular disease risk assessment for primary prevention in adults: Our approach" and "Cardiovascular disease risk assessment for primary prevention: Risk calculators" and "Overview of primary prevention of cardiovascular disease")

Smoking avoidance or cessation (see "Overview of smoking cessation management in adults")

Regular exercise to maintain weight, counter sarcopenia, and aid in the control of diabetes mellitus, hyperlipidemia, and hypertension

Use of protective clothing and sunscreen to prevent skin cancer (see "Cutaneous squamous cell carcinoma: Primary and secondary prevention" and "Primary prevention of melanoma" and "Selection of sunscreen and sun-protective measures")

Careful, continuous skin care to avoid, detect, and aggressively treat skin ulcers (see "Overview of treatment of chronic wounds")

Prevention of falls resulting in fractures (eg, adding grab bars in the shower, wearing shoes with good traction, eliminating tripping hazards, providing adequate lighting) (see "Falls: Prevention in community-dwelling older persons")

Screening/surveillance for the most common cancers associated with WS (eg, osteosarcomas, melanoma, and thyroid carcinoma), as well as for other types of cancer that have been reported in patients with WS, though not at apparent elevated rates (table 1) (see 'Cancer surveillance' below)

Clinical management — The clinical management of patients with WS involves addressing immediate concerns (eg, planning surgery for ocular cataracts) and providing appropriate treatment for common complications of WS, such as diabetes mellitus, hypertension, dyslipidemia, osteoporosis, skin ulcerations, soft tissue calcification, and cancer [33,34,54-58,60-62]. A detailed discussion of treatments for these conditions is beyond the scope of this review but can be found elsewhere in UpToDate.

Diabetes mellitus – Diabetes associated with WS is characterized by marked insulin resistance [55]. Oral agents, such as thiazolidinediones and metformin, have been used with benefit for glycemic control. (See "Thiazolidinediones in the treatment of type 2 diabetes mellitus" and "Initial management of hyperglycemia in adults with type 2 diabetes mellitus".)

Dyslipidemia – Most patients with WS have hypertriglyceridemia and/or elevated levels of low-density lipoprotein (LDL) cholesterol and low levels of high-density lipoprotein (HDL) cholesterol. Statin treatment has been successfully used in patients with WS to achieve target values of lipid levels [63]. (See "Low-density lipoprotein cholesterol-lowering therapy in the primary prevention of cardiovascular disease" and "Statins: Actions, side effects, and administration".)

Osteoporosis – Bisphosphonates have been widely used for the treatment of osteoporosis in WS [56]. (See "Bisphosphonate therapy for the treatment of osteoporosis".)

Skin ulcers – Chronic skin ulcers of the lower legs and feet in patients with WS are an important source of morbidity and are difficult to treat. Management may involve surgical debridement and curettage, use of topical preparations and special dressings, control of infection and pain, dermis matrix substitutes, and negative pressure wound therapy [33,34]. (See "Overview of treatment of chronic wounds" and "Skin substitutes" and "Negative pressure wound therapy".)

Fertility issues — The initial or subsequent follow-up visits provide an opportunity to discuss fertility issues as well as counsel family members regarding their WRN carrier status and disease risk. Males and females with WS are fertile, with variable, apparently rapid loss of fertility over time. This issue was initially quantified in 125 patients with WS, who had a net fertility of 0.4 children per patient (or 1.1 children per known married patient) [28]. Nineteen females included in this series reported at least 53 pregnancies, with 10 giving birth to 30 children who survived the perinatal period. The other 23 known pregnancies ended either in abortions, stillbirths, premature deliveries, or deaths at delivery.

Reduced fertility in patients with WS may reflect a combination of hypogonadism, reduced sperm viability and counts, and inability to conceive or carry pregnancies to live births. Preterm deliveries have been reported and attributed to cervical incompetence [64], and preeclampsia has been noted as an obstetric complication.

Cancer surveillance — Many different histologic types of cancer have been identified in patients with WS [35]. Among these, a small subset of "elevated risk" cancer types account for two-thirds of cancer reports in patients with WS (table 1). In descending frequency, these elevated risk cancer types are thyroid epithelial neoplasms, melanoma, meningiomas, soft tissue sarcomas, leukemia and preleukemic conditions, and osteosarcoma (table 1).

Annual screening for thyroid cancer by ultrasound is recommended, given the elevated risk in individuals with WS [65], as well as annual total body skin examination for the early detection of melanoma, with attention to the nasal mucosa, nail beds, palms, and soles.

Genetic counseling — Genetic counseling may be useful for many patients with WS to clarify the nature and inheritance of WS; explain molecular diagnosis testing results and options; and discuss practical issues, such as the probability of reproductive success and associated risks. Parents and offspring of patients with WS are obligate heterozygote carriers of one WRN pathogenic, variant allele, though they do not appear to be at elevated risk of developing clinical findings of WS or associated disorders. Siblings of affected patients have a 25 percent likelihood of being affected themselves, a 50 percent chance of carrying a single WRN pathogenic allele, and a 25 percent chance of being both unaffected and not a carrier [2]. Referral to a genetics professional is recommended for family members who are or at risk to be heterozygous carriers, so that they can be counseled regarding carrier testing for their partners and reproductive options.

Investigational therapies — Several pharmacologic agents have been investigated in vitro or in animal models for their potential to delay the onset or progression of WS signs and symptoms. Examples include vitamin C [66-69], p38 mitogen-activated protein kinase (MAPK) inhibitors [70-73], nicotinamide in the form of nicotinamide adenine dinucleotide (NAD+) [74], and the mammalian (mechanistic) target of rapamycin (mTOR) inhibitors sirolimus and everolimus [75].

Among pathogenic WRN variants, very few appear to be good candidates for mutation-specific therapies, such as exon skipping or stop codon readthrough [4]. One cell line from a patient with WS with a newly reported WRN stop codon variant (c.3767C>G) re-expressed modest levels of full-length WRN protein after being treated with aminoglycosides and ataluren to promote stop codon readthrough [76]. Approximately two-thirds of pathogenic WRN variants are single base substitutions and, therefore, may be good candidates for in vivo base editing or other types of corrective genome engineering.

PROGNOSIS — Active clinical management to detect, treat, or prevent common clinical problems that contribute to morbidity and early mortality in many patients with Werner syndrome (WS) allows them to lead longer and productive lives. The median age of death is approximately 54 years [53,77]. Cancer and myocardial infarction have been the main causes of death [53]. However, a retrospective study from 2011 to 2020 of Japanese patients with WS reported a mean age at death of 59 years, a four- to seven-year increase in life span [78]. Epithelial and nonepithelial malignancies remained the leading causes of death, followed by infection, with no reported deaths from cardiovascular diseases.

ONLINE RESOURCES — Online information on Werner syndrome (WS) can be found at:

International Registry of Werner Syndrome

WRN Locus-Specific Mutational Database

National Organization for Rare Disorders (NORD)

SUMMARY AND RECOMMENDATIONS

Epidemiology and pathogenesis – Werner syndrome (WS) is a rare, autosomal recessive disorder caused by biallelic, pathogenic variants in the WRN gene encoding a RECQ helicase protein involved in DNA replication, recombination, and repair. The incidence is 1 per 10,000 to <1 per 100,000 births and is highest in Japan, Sardinia, India, and Pakistan due to the presence of common local pathogenic founder variants. (See 'Epidemiology' above and 'Pathophysiology' above.)

Clinical features – WS is characterized by short stature and the appearance in adolescence or early adulthood of premature graying and loss of hair; progressive sharpening of facial features, with "beaked" or "bird-like" appearance (picture 1); bilateral cataracts; high-pitched voice; scleroderma-like skin changes with ulcerations of feet and ankles (picture 2); and a characteristic calcification of soft tissue and tendons (image 1). Patients with WS have earlier onset of clinically important, age-related diseases, including atherosclerosis, diabetes mellitus, osteoporosis, and some cancers (table 1). (See 'Clinical features' above and 'Risk of cancer' above.)

Diagnosis – The diagnosis of WS is based on characteristic clinical features that together are diagnostic, though they may be difficult to assess or absent in young individuals. Cardinal signs of WS include (table 2):

Premature graying and/or thinning of scalp hair

Bilateral cataract

Scleroderma-like skin changes, intractable lower leg skin ulcers

Soft tissue calcification (Achilles tendon)

Bird-like face

High-pitched voice

The identification of causative pathogenic variants in both copies of the WRN gene by molecular genetic testing confirms the diagnosis. (See 'Diagnosis' above.)

Management – There is no specific or effective therapy for WS. Because of the multisystem nature of WS, patients should be managed in medical centers with expertise in rare, complex diseases and ready access to multiple specialty consultation. Pharmacologic management of hypertension, diabetes mellitus, and lipid metabolic abnormalities; surgical removal of cataracts; aggressive treatment of skin ulcers; and screening for cancer or other acquired diseases are the mainstays of management. (See 'Management' above.)

  1. Oshima J, Sidorova JM, Monnat RJ Jr. Werner syndrome: Clinical features, pathogenesis and potential therapeutic interventions. Ageing Res Rev 2017; 33:105.
  2. Oshima J, Martin GM, Hisama FM. Werner syndrome. In: GeneReviews, Adam MP, Ardinger HH, Pagon RA, et al (Eds), University of Washington, Seattle, 1993.
  3. Saha B, Lessel D, Nampoothiri S, et al. Ethnic-Specific WRN Mutations in South Asian Werner Syndrome Patients: Potential Founder Effect in Patients with Indian or Pakistani Ancestry. Mol Genet Genomic Med 2013; 1:7.
  4. Fu W, Ligabue A, Rogers KJ, et al. Human RECQ Helicase Pathogenic Variants, Population Variation and "Missing" Diseases. Hum Mutat 2017; 38:193.
  5. Yu CE, Oshima J, Fu YH, et al. Positional cloning of the Werner's syndrome gene. Science 1996; 272:258.
  6. Croteau DL, Popuri V, Opresko PL, Bohr VA. Human RecQ helicases in DNA repair, recombination, and replication. Annu Rev Biochem 2014; 83:519.
  7. Karczewski KJ, Francioli LC, Tiao G, et al. The mutational constraint spectrum quantified from variation in 141,456 humans. Nature 2020; 581:434.
  8. Lek M, Karczewski KJ, Minikel EV, et al. Analysis of protein-coding genetic variation in 60,706 humans. Nature 2016; 536:285.
  9. Schellenberg GD, Miki T, Yu CE, Nakura J. Werner syndrome. In: Online Metabolic and Molecular Basis of Inherited Disease, Valle D, Beaudet AL, Vogelstein B, et al (Eds), McGraw-Hill, 2019.
  10. Satoh M, Imai M, Sugimoto M, et al. Prevalence of Werner's syndrome heterozygotes in Japan. Lancet 1999; 353:1766.
  11. Masala MV, Scapaticci S, Olivieri C, et al. Epidemiology and clinical aspects of Werner's syndrome in North Sardinia: description of a cluster. Eur J Dermatol 2007; 17:213.
  12. Friedrich K, Lee L, Leistritz DF, et al. WRN mutations in Werner syndrome patients: genomic rearrangements, unusual intronic mutations and ethnic-specific alterations. Hum Genet 2010; 128:103.
  13. Yokote K, Chanprasert S, Lee L, et al. WRN Mutation Update: Mutation Spectrum, Patient Registries, and Translational Prospects. Hum Mutat 2017; 38:7.
  14. Tang W, Robles AI, Beyer RP, et al. The Werner syndrome RECQ helicase targets G4 DNA in human cells to modulate transcription. Hum Mol Genet 2016; 25:2060.
  15. Moser MJ, Kamath-Loeb AS, Jacob JE, et al. WRN helicase expression in Werner syndrome cell lines. Nucleic Acids Res 2000; 28:648.
  16. Swanson C, Saintigny Y, Emond MJ, Monnat RJ Jr. The Werner syndrome protein has separable recombination and survival functions. DNA Repair (Amst) 2004; 3:475.
  17. Kamath-Loeb AS, Welcsh P, Waite M, et al. The enzymatic activities of the Werner syndrome protein are disabled by the amino acid polymorphism R834C. J Biol Chem 2004; 279:55499.
  18. Kamath-Loeb AS, Zavala-van Rankin DG, Flores-Morales J, et al. Homozygosity for the WRN Helicase-Inactivating Variant, R834C, does not confer a Werner syndrome clinical phenotype. Sci Rep 2017; 7:44081.
  19. Tokita M, Kennedy SR, Risques RA, et al. Werner syndrome through the lens of tissue and tumour genomics. Sci Rep 2016; 6:32038.
  20. Chan EM, Shibue T, McFarland JM, et al. WRN helicase is a synthetic lethal target in microsatellite unstable cancers. Nature 2019; 568:551.
  21. Lieb S, Blaha-Ostermann S, Kamper E, et al. Werner syndrome helicase is a selective vulnerability of microsatellite instability-high tumor cells. Elife 2019; 8.
  22. Kategaya L, Perumal SK, Hager JH, Belmont LD. Werner Syndrome Helicase Is Required for the Survival of Cancer Cells with Microsatellite Instability. iScience 2019; 13:488.
  23. van Wietmarschen N, Sridharan S, Nathan WJ, et al. Repeat expansions confer WRN dependence in microsatellite-unstable cancers. Nature 2020; 586:292.
  24. Sommers JA, Kulikowicz T, Croteau DL, et al. A high-throughput screen to identify novel small molecule inhibitors of the Werner Syndrome Helicase-Nuclease (WRN). PLoS One 2019; 14:e0210525.
  25. Aggarwal M, Sommers JA, Shoemaker RH, Brosh RM Jr. Inhibition of helicase activity by a small molecule impairs Werner syndrome helicase (WRN) function in the cellular response to DNA damage or replication stress. Proc Natl Acad Sci U S A 2011; 108:1525.
  26. Picco G, Cattaneo CM, van Vliet EJ, et al. Werner Helicase Is a Synthetic-Lethal Vulnerability in Mismatch Repair-Deficient Colorectal Cancer Refractory to Targeted Therapies, Chemotherapy, and Immunotherapy. Cancer Discov 2021; 11:1923.
  27. Oshima J, Hisama FM. Search and insights into novel genetic alterations leading to classical and atypical Werner syndrome. Gerontology 2014; 60:239.
  28. Epstein CJ, Martin GM, Schultz AL, Motulsky AG. Werner's syndrome a review of its symptomatology, natural history, pathologic features, genetics and relationship to the natural aging process. Medicine (Baltimore) 1966; 45:177.
  29. Goto M. Clinical characteristics of Werner syndrome and other premature aging syndromes: pattern of aging in progeroid syndromes. Gann Monograph Cancer Res 2001; 49:27.
  30. Tollefsbol TO, Cohen HJ. Werner's syndrome: an underdiagnosed disorder resembling premature aging. Age 1984; 7:75.
  31. Goto M. Werner's syndrome: from clinics to genetics. Clin Exp Rheumatol 2000; 18:760.
  32. Hatamochi A. Dermatological features and collagen metabolism in Werner syndrome. In: Premature Gray Hair to Helicase-Werner Syndrome: Implications for Aging and Cancer, 1st ed, Goto M, Miller RW (Eds), Karger Publishers, 2001. p.51.
  33. Kubota Y, Takemoto M, Taniguchi T, et al. Management guideline for Werner syndrome 2020. 6. Skin ulcers associated with Werner syndrome: Prevention and non-surgical and surgical treatment. Geriatr Gerontol Int 2021; 21:153.
  34. Motegi SI, Takemoto M, Taniguchi T, et al. Management guideline for Werner syndrome 2020. 7. Skin ulcer associated with Werner syndrome: Dermatological treatment. Geriatr Gerontol Int 2021; 21:160.
  35. Lauper JM, Krause A, Vaughan TL, Monnat RJ Jr. Spectrum and risk of neoplasia in Werner syndrome: a systematic review. PLoS One 2013; 8:e59709.
  36. Onishi S, Takemoto M, Ishikawa T, et al. Japanese diabetic patients with Werner syndrome exhibit high incidence of cancer. Acta Diabetol 2012; 49 Suppl 1:S259.
  37. Lauper JM, Monnat RJ Jr. Diabetes mellitus and cancer in Werner syndrome. Acta Diabetol 2014; 51:159.
  38. Kadowaki Y, Kodama S, Moriyama M, Suzuki M. The Relationship between Werner Syndrome and Sinonasal Malignant Melanoma: Two Sibling Cases of Werner Syndrome with Malignant Melanoma. Case Rep Otolaryngol 2017; 2017:9361612.
  39. Koshizaka M, Maezawa Y, Maeda Y, et al. Time gap between the onset and diagnosis in Werner syndrome: a nationwide survey and the 2020 registry in Japan. Aging (Albany NY) 2020; 12:24940.
  40. Takemoto M, Mori S, Kuzuya M, et al. Diagnostic criteria for Werner syndrome based on Japanese nationwide epidemiological survey. Geriatr Gerontol Int 2013; 13:475.
  41. Chen L, Lee L, Kudlow BA, et al. LMNA mutations in atypical Werner's syndrome. Lancet 2003; 362:440.
  42. Weedon MN, Ellard S, Prindle MJ, et al. An in-frame deletion at the polymerase active site of POLD1 causes a multisystem disorder with lipodystrophy. Nat Genet 2013; 45:947.
  43. Lessel D, Hisama FM, Szakszon K, et al. POLD1 Germline Mutations in Patients Initially Diagnosed with Werner Syndrome. Hum Mutat 2015; 36:1070.
  44. Garavelli L, D'Apice MR, Rivieri F, et al. Mandibuloacral dysplasia type A in childhood. Am J Med Genet A 2009; 149A:2258.
  45. Barrowman J, Hamblet C, Kane MS, Michaelis S. Requirements for efficient proteolytic cleavage of prelamin A by ZMPSTE24. PLoS One 2012; 7:e32120.
  46. Gordon LB, Brown WT, Collins FS. Hutchinson-Gilford progeria syndrome. In: GeneReviews, Adam MP, Ardinger HH, Pagon RA, et al (Eds), University of Washington, Seattle, 1993.
  47. Eriksson M, Brown WT, Gordon LB, et al. Recurrent de novo point mutations in lamin A cause Hutchinson-Gilford progeria syndrome. Nature 2003; 423:293.
  48. Flynn P, Aird RB. A neuroectodermal syndrome of dominant inheritance. J Neurol Sci 1965; 2:161.
  49. Milunsky JM, Maher TA, Zhao G, et al. TFAP2A mutations result in branchio-oculo-facial syndrome. Am J Hum Genet 2008; 82:1171.
  50. Avila M, Dyment DA, Sagen JV, et al. Clinical reappraisal of SHORT syndrome with PIK3R1 mutations: toward recommendation for molecular testing and management. Clin Genet 2016; 89:501.
  51. Carbone M, Arron ST, Beutler B, et al. Tumour predisposition and cancer syndromes as models to study gene-environment interactions. Nat Rev Cancer 2020; 20:533.
  52. Oshima J, Kato H, Maezawa Y, Yokote K. RECQ helicase disease and related progeroid syndromes: RECQ2018 meeting. Mech Ageing Dev 2018; 173:80.
  53. Goto M, Ishikawa Y, Sugimoto M, Furuichi Y. Werner syndrome: a changing pattern of clinical manifestations in Japan (1917~2008). Biosci Trends 2013; 7:13.
  54. Kuzuya M, Takemoto M, Kubota Y, et al. Management guideline for Werner syndrome 2020. 2. Sarcopenia associated with Werner syndrome. Geriatr Gerontol Int 2021; 21:139.
  55. Takemoto M, Kubota Y, Taniguchi T, et al. Management guideline for Werner syndrome 2020. 3. Diabetes associated with Werner syndrome. Geriatr Gerontol Int 2021; 21:142.
  56. Mori S, Takemoto M, Kubota Y, et al. Management guideline for Werner syndrome 2020. 4. Osteoporosis associated with Werner syndrome. Geriatr Gerontol Int 2021; 21:146.
  57. Taniguchi T, Takemoto M, Kubota Y, et al. Management guideline for Werner syndrome 2020. 5. Infection associated with Werner syndrome. Geriatr Gerontol Int 2021; 21:150.
  58. Taniguchi A, Tanaka Y, Takemoto M, et al. Management guideline for Werner syndrome 2020 8. Calcification in tendons associated with Werner syndrome. Geriatr Gerontol Int 2021; 21:163.
  59. Lyons C, Gallagher D, McSwiney T, et al. The ophthalmic diagnosis and management of four siblings with Werner syndrome. Int Ophthalmol 2019; 39:1371.
  60. Yeong EK, Yang CC. Chronic leg ulcers in Werner's syndrome. Br J Plast Surg 2004; 57:86.
  61. Matucci-Cerinic M, Denton CP, Furst DE, et al. Bosentan treatment of digital ulcers related to systemic sclerosis: results from the RAPIDS-2 randomised, double-blind, placebo-controlled trial. Ann Rheum Dis 2011; 70:32.
  62. Noda S, Asano Y, Masuda S, et al. Bosentan: a novel therapy for leg ulcers in Werner syndrome. J Am Acad Dermatol 2011; 65:e54.
  63. Tsukamoto K, Takemoto M, Kubota Y, et al. Management guideline for Werner syndrome 2020 1. Dyslipidemia and fatty liver associated with Werner syndrome. Geriatr Gerontol Int 2021; 21:133.
  64. Sołek-Pastuszka J, Zagrodnik-Ułan E, Płonka T, et al. Pregnancy complicated by Werner syndrome. Acta Obstet Gynecol Scand 2011; 90:201.
  65. Walsh MF, Chang VY, Kohlmann WK, et al. Recommendations for Childhood Cancer Screening and Surveillance in DNA Repair Disorders. Clin Cancer Res 2017; 23:e23.
  66. Aumailley L, Lebel M. The Impact of Vitamin C on Different System Models of Werner Syndrome. Antioxid Redox Signal 2021; 34:856.
  67. Aumailley L, Roux-Dalvai F, Kelly I, et al. Vitamin C alters the amount of specific endoplasmic reticulum associated proteins involved in lipid metabolism in the liver of mice synthesizing a nonfunctional Werner syndrome (Wrn) mutant protein. PLoS One 2018; 13:e0193170.
  68. Aumailley L, Dubois MJ, Brennan TA, et al. Serum vitamin C levels modulate the lifespan and endoplasmic reticulum stress response pathways in mice synthesizing a nonfunctional mutant WRN protein. FASEB J 2018; 32:3623.
  69. Massip L, Garand C, Paquet ER, et al. Vitamin C restores healthy aging in a mouse model for Werner syndrome. FASEB J 2010; 24:158.
  70. Freund A, Patil CK, Campisi J. p38MAPK is a novel DNA damage response-independent regulator of the senescence-associated secretory phenotype. EMBO J 2011; 30:1536.
  71. Davis T, Brook AJ, Rokicki MJ, et al. Evaluating the Role of p38 MAPK in the Accelerated Cell Senescence of Werner Syndrome Fibroblasts. Pharmaceuticals (Basel) 2016; 9.
  72. Davis T, Rokicki MJ, Bagley MC, Kipling D. The effect of small-molecule inhibition of MAPKAPK2 on cell ageing phenotypes of fibroblasts from human Werner syndrome. Chem Cent J 2013; 7:18.
  73. Davis T, Baird DM, Haughton MF, et al. Prevention of accelerated cell aging in Werner syndrome using a p38 mitogen-activated protein kinase inhibitor. J Gerontol A Biol Sci Med Sci 2005; 60:1386.
  74. Fang EF, Hou Y, Lautrup S, et al. NAD+ augmentation restores mitophagy and limits accelerated aging in Werner syndrome. Nat Commun 2019; 10:5284.
  75. Saha B, Cypro A, Martin GM, Oshima J. Rapamycin decreases DNA damage accumulation and enhances cell growth of WRN-deficient human fibroblasts. Aging Cell 2014; 13:573.
  76. Agrelo R, Sutz MA, Setien F, et al. A novel Werner Syndrome mutation: pharmacological treatment by read-through of nonsense mutations and epigenetic therapies. Epigenetics 2015; 10:329.
  77. Huang S, Lee L, Hanson NB, et al. The spectrum of WRN mutations in Werner syndrome patients. Hum Mutat 2006; 27:558.
  78. Kato H, Koshizaka M, Kaneko H, et al. Lifetime extension and the recent cause of death in Werner syndrome: a retrospective study from 2011 to 2020. Orphanet J Rare Dis 2022; 17:226.
Topic 106742 Version 2.0

References

آیا می خواهید مدیلیب را به صفحه اصلی خود اضافه کنید؟