Physical Examination

Perform a thorough clinical and laboratory examination, keeping in mind the patient's increased risk of neoplasms.

Characteristic clinical features of the disease

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.

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.

Nailfold capillary abnormalities resembling those seen in scleroderma have been described.^[25]

Graying of the hair, loss of hair, and nail dystrophy usually are observed.

A high-pitched voice is characteristic.

Soft tissue calcification, including tendon calcification, is an important finding, with Achilles tendon calcification suggested for inclusion as a diagnostic criterion for Werner syndrome.^[26]

Related diseases

Rapidly progressing cataracts typically occur when patients are aged 20-40 years. Cataracts are usually posterior and subcapsular.

Disturbances in the parathyroid glands are the main cause of osteoporosis.

It is also associated with diabetes mellitus.

Related neoplasias are as follows:

Hematologic malignancies (leukemia and preleukemic conditions of the bone marrow^[27])
Carcinomas of the thyroid^[27]and other organs
Sarcomas (soft tissue^[27])^[28]
Meningiomas^[27]
Cutaneous malignancies, including malignant melanoma^[27]
Possible evolution of ankle and heel ulcers into squamous cell carcinomas
Hyperthyreosis
Pituitary dysfunction
Vascular changes (arteriosclerotic type)
Hypogonadism or agonadism and premature menopause
Primary bone neoplasms^[27]

Complications

Complications of Werner syndrome (WS) are related to the concomitant diseases and symptoms described above (see Physical Examination). Pregnancy complicated by the presence of Werner syndrome has been reported.^[29]

The variant genotype of WRN Leu1074Phe has been associated with a 1.36-fold significantly increased risk of breast cancer in Chinese women, particularly pronounced in those carrying Phe/Phe genotype and having an earlier age at menarche, to produce a 3.58-fold increased risk of breast cancer.^[30]

Patients with WS may develop severe cystoid macular edema after laser therapy.^[31]The trauma of cataract surgery may be the main stimulus for the development of cystoid macular edema, which is difficult to manage in WS patients.^[32]

Differential Diagnoses

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Lautrup S, Caponio D, Cheung HH, Piccoli C, Stevnsner T, Chan WY, et al. Studying Werner syndrome to elucidate mechanisms and therapeutics of human aging and age-related diseases. Biogerontology. 2019 Jan 21. [QxMD MEDLINE Link].
Nehlin JO, Skovgaard GL, Bohr VA. The Werner syndrome. A model for the study of human aging. Ann N Y Acad Sci. 2000 Jun. 908:167-79. [QxMD MEDLINE Link].
Davis T, Wyllie FS, Rokicki MJ, Bagley MC, Kipling D. The role of cellular senescence in Werner syndrome: toward therapeutic intervention in human premature aging. Ann N Y Acad Sci. 2007 Apr. 1100:455-69. [QxMD MEDLINE Link].
Kawai T, Nozato Y, Kamide K, Onishi M, Yamamoto-Hanasaki H, Tatara Y, et al. Case report of a long-surviving Werner syndrome patient with severe aortic valve stenosis. Geriatr Gerontol Int. 2012 Jan. 12(1):174-5. [QxMD MEDLINE Link].
Hisama FM, Kubisch C, Martin GM, Oshima J. Clinical utility gene card for: Werner syndrome. Eur J Hum Genet. 2012 Jan 18. [QxMD MEDLINE Link].
Takada-Watanabe A, Yokote K, Takemoto M, Fujimoto M, Irisuna H, Honjo S, et al. A case of Werner syndrome without metabolic abnormality: implications for the early pathophysiology. Geriatr Gerontol Int. 2012 Jan. 12(1):140-6. [QxMD MEDLINE Link].
Lohynská R, Pechačová Z, Mazaná E, et al. Radiotherapy and radiosensitivity syndromes in DNA repair gene mutations. Klin Onkol. 2022 Spring. 35 (2):119-127. [QxMD MEDLINE Link].
Massip L, Garand C, Paquet ER, et al. Vitamin C restores healthy aging in a mouse model for Werner syndrome. FASEB J. 2010 Jan. 24(1):158-72. [QxMD MEDLINE Link].
DuBose AJ, Lichtenstein ST, Petrash NM, Erdos MR, Gordon LB, Collins FS. Everolimus rescues multiple cellular defects in laminopathy-patient fibroblasts. Proc Natl Acad Sci U S A. 2018 Apr 17. 115 (16):4206-4211. [QxMD MEDLINE Link].
Zhao N, Hao F, Qu T, Zuo YG, Wang BX. A novel mutation of the WRN gene in a Chinese patient with Werner syndrome. Clin Exp Dermatol. 2008 May. 33(3):278-81. [QxMD MEDLINE Link].
Matsumoto N, Ohta Y, Deguchi K, Kishida M, Sato K, Shang J, et al. Characteristic Clinical Features of Werner Syndrome with a Novel Compound Heterozygous WRN Mutation c.1720+1G>A Plus c.3139-1G>C. Intern Med. 2019 Apr 1. 58 (7):1033-1036. [QxMD MEDLINE Link].
Miller DE, Lee L, Galey M, et al. Targeted long-read sequencing identifies missing pathogenic variants in unsolved Werner syndrome cases. J Med Genet. 2022 May 9. [QxMD MEDLINE Link].
Davis T, Brook AJ, Rokicki MJ, Bagley MC, Kipling D. Evaluating the Role of p38 MAPK in the Accelerated Cell Senescence of Werner Syndrome Fibroblasts. Pharmaceuticals (Basel). 2016 Apr 28. 9 (2):[QxMD MEDLINE Link].
Saha B, Lessel D, Nampoothiri S, Rao AS, Hisama FM, Peter D, 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 May 1. 1(1):7-14. [QxMD MEDLINE Link]. [Full Text].
Mansur AT, Elçioglu NH, Demirci GT. Werner syndrome: clinical evaluation of two cases and a novel mutation. Genet Couns. 2014. 25(2):119-27. [QxMD MEDLINE Link].
Barrios Sanjuanelo A, Munoz Otero C. [Atypical Werner syndrome: Atypical progeroid syndrome: A case report.]. An Pediatr (Barc). 2010 May 7. [QxMD MEDLINE Link].
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 May 5. [QxMD MEDLINE Link].
Pirzio LM, Pichierri P, Bignami M, Franchitto A. Werner syndrome helicase activity is essential in maintaining fragile site stability. J Cell Biol. 2008 Jan 28. 180(2):305-14. [QxMD MEDLINE Link].
Kyng KJ, Bohr VA. Gene expression and DNA repair in progeroid syndromes and human aging. Ageing Res Rev. 2005 Nov. 4(4):579-602. [QxMD MEDLINE Link].
Doh YJ, Kim HK, Jung ED, Choi SH, Kim JG, Kim BW, et al. Novel LMNA gene mutation in a patient with Atypical Werner's Syndrome. Korean J Intern Med. 2009 Mar. 24(1):68-72. [QxMD MEDLINE Link].
McKenna T, Sola Carvajal A, Eriksson M. Skin Disease in Laminopathy-Associated Premature Aging. J Invest Dermatol. 2015 Jul 29. [QxMD MEDLINE Link].
Goto M, Ishikawa Y, Sugimoto M, Furuichi Y. Werner syndrome: a changing pattern of clinical manifestations in Japan (1917~2008). Biosci Trends. 2013 Feb. 7(1):13-22. [QxMD MEDLINE Link].
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 Dec 29. 12 (24):24940-24956. [QxMD MEDLINE Link].
Ingegnoli F, Crotti C. Nailfold scleroderma-like capillary abnormalities in Werner syndrome (adult progeria). Vasc Med. 2017 Jun. 22 (3):246-247. [QxMD MEDLINE Link].
Taniguchi A, Tanaka Y, Takemoto M, Kubota Y, Taniguchi T, Motegi SI, et al. Management guideline for Werner syndrome 2020 8. Calcification in tendons associated with Werner syndrome. Geriatr Gerontol Int. 2021 Feb. 21 (2):163-165. [QxMD MEDLINE Link].
Lauper JM, Krause A, Vaughan TL, Monnat RJ Jr. Spectrum and risk of neoplasia in Werner syndrome: a systematic review. PLoS One. 2013. 8(4):e59709. [QxMD MEDLINE Link]. [Full Text].
Mitamura Y, Azuma S, Matsumoto D, Takada-Watanabe A, Takemoto M, Yokote K, et al. Case of sarcomatoid carcinoma occurring in a patient with Werner syndrome. J Dermatol. 2016 Apr 14. [QxMD MEDLINE Link].
Solek-Pastuszka J, Zagrodnik-Ulan E, Plonka T, et al. Pregnancy complicated by Werner syndrome. Acta Obstet Gynecol Scand. 2011 Feb. 90(2):201-2. [QxMD MEDLINE Link].
Wang Z, Xu Y, Tang J, Ma H, Qin J, Lu C, et al. A polymorphism in Werner syndrome gene is associated with breast cancer susceptibility in Chinese women. Breast Cancer Res Treat. 2009 Feb 10. [QxMD MEDLINE Link].
Oshitari T, Kitahashi M, Mizuno S, Baba T, Kubota-Taniai M, Takemoto M, et al. Werner syndrome with refractory cystoid macular edema and immunohistochemical analysis of WRN proteins in human retinas. BMC Ophthalmol. 2014 Mar 12. 14:31. [QxMD MEDLINE Link]. [Full Text].
Lyons C, Gallagher D, McSwiney T, McElnea E, Kinsella F. The ophthalmic diagnosis and management of four siblings with Werner syndrome. Int Ophthalmol. 2018 Apr 28. [QxMD MEDLINE Link].