For early diagnosis of young patients with Werner syndrome: Indication for genetic testing

Abstract

Werner syndrome (WS) is an autosomal recessive genetic disorder caused by mutations in the WRN gene, which encodes a RecQ-type DNA helicase. Although this disease is known to show early aging phenotypes, such as gray hair, alopecia, cataracts, skin lesions, diabetes and dyslipidemia, starting shortly after puberty,¹ it is generally diagnosed in patients aged in their 40s, indicating a potential delay in timely assessment and intervention.² In addition, because of the growing awareness of this disease, the patients suspected to have WS at a young age is increasing. Thus, there is an urgent need to diagnose WS at a young age; however, its strategy has not yet been established.

There have been no reports on the clinical symptoms among younger WS patients, despite the fact that the prevalence of each symptom in all age groups has been reported.³ To facilitate early detection and diagnosis, we examined the prevalence for each symptom in patients diagnosed with WS aged between their 10s and 20s. Using PubMed, with results by year as “1965–2024”, article type as “Case Reports”, and AGE as “Child: birth–18 years”, “Young Adult: 19–24 years” and “Adult: 19–44 years”, we searched for “Werner syndrome” and found 454 references.

Then, we applied the Japanese diagnostic criteria for WS 2012,³ because they are the only criteria whose diagnostic accuracy was validated using genetic testing.⁴ Of these, 30 patients aged 10–30 years were diagnosed as WS. Of the 30 patients, 13 tested positive by genetic testing. The remaining 17 were not genetically diagnosed, but were diagnosed as “definite” or “probable” based on clinical symptoms according to the diagnostic criteria.

The mean age at diagnosis was 23.6 years for genetically confirmed cases, and 24.6 years for untested cases, respectively. The prevalence for each symptom in each group and all patients is shown in Table 1. Also the symptoms for each patient are shown in Tables S1 and S2.

In the group with positive genetic testing, cataracts, hair changes, short stature and low bodyweight were the most common symptoms, followed by abnormalities in glucose or lipid metabolism. In the group without genetic testing, cataracts, hair changes, abnormalities in glucose or lipid metabolism, short stature and low bodyweight showed a 100% prevalence. In all 30 patients, cataracts and hair changes were the most common, followed by short stature and low bodyweight, abnormalities in glucose or lipid metabolism, and skin changes. Although the prevalence for hypogonadism was high, the small number of cases made them difficult to compare.

We then compared the data with those of the Japanese WS Registry 2023, in which the average age was 51.0 years (Table 1).⁵ The prevalences of skin changes, soft tissue calcification, bird-like faces and abnormal voices were much lower in young patients with WS. Conversely, the prevalences of dyslipidemia and abnormal glucose tolerance were similar between the young and all-age groups. These results indicate that skin changes, soft tissue calcification, bird-like faces and abnormal voices are not reliable for the diagnosis in patients aged <30 years.

Limitations in this study are the small sample size, variability of symptom evaluation among case reports and the fact that the data for all age groups were mostly Japanese, whereas the data in this study were from various countries.

In conclusion, cataracts, hair changes, short stature and low bodyweight were the most frequent signs in young patients with WS, followed by abnormalities in glucose or lipid metabolism and skin changes. When clinicians encounter a patient with bilateral cataracts and hair changes at a young age, they need to be aware of other signs, such as short stature, low bodyweight, glucose intolerance or dyslipidemia. We advocate that, in addition to bilateral cataracts and progeroid hair changes, the presence of one or more of the following is an indication for genetic diagnosis of WS in patients aged <30 years: (i) short stature or underweight, (ii) abnormal glucose or lipid metabolism, and (iii) skin atrophy or hardening.

This work was supported by AMED JP21jm0210096 (KY), JP22ym0126066 (KY), JP23ek0109622 (KY), JP24ek0109713 (KY), MHLW of Japan JPMH21FC1016 (KY) and NIH 5R01CA210916–07 (OJ).

The authors declare no conflict of interest.

TS, YMaezawa, MS, KY and HKato managed this project. YMaeda, HKato, HKaneko and KA managed the patient record. YK, TT, TO, SM, YT, HN, AT, KW, MT, MK, RK, MM, HK, KI, JO and KY wrote and revised the manuscript. All the authors contributed to the review and approval of the final manuscript.