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An Atypical Presentation of Werner Syndrome in a patient with a novel likely pathogenic variant in WRN: A Case Report

Clinical Genetics and Therapeutics
  • Primary Categories:
    • Clinical-Adult
  • Secondary Categories:
    • Clinical-Adult & Pediatric
Introduction
Werner syndrome (WS) is a premature aging syndrome resulting from biallelic variants in the WRN gene, a gene which functions as a DNA helicase, important for maintaining genomic integrity. Cardinal findings on physical examination (present in 91% of patients with molecularly confirmed diagnosis) include:

  1. Ocular cataracts, bilateral

  2. Premature graying/thinning of scalp hair

  3. Dermatologic pathology which are described as "scleroderma like"

  4. Short stature with early puberty


Additional features of WS include thin limbs, pinched facial features, osteoporosis, voice changes, hypogonadism, type II diabetes mellitus, soft tissue calcification, neoplasms, skin ulcers, and atherosclerosis. The first sign of WS is typically the lack of growth spurt in early teenage years. Other characteristic features typically present in an affected individual’s 20’s and 30’s.

Case Presentation
We report a 36-year-old male referred for medical genetics evaluation to evaluate for WS. His history was notable for poor growth early in life and he was evaluated by a pediatric endocrinologist but no diagnosis was made. As a child, he and his parents noted an aged appearance to his hands, with a possible diagnosis of scleroderma made later to explain these findings. He reached his adult height of 5’3” (predicted mid-parental heigh calculated to be 5’11”) around 12 years of age.   At 36 years of age, he was diagnosed with a right frontal lobe meningioma. An eye exam at this time was negative for cataracts. Shortly thereafter, his rheumatology team referred him to medical genetics for evaluation to rule out WS.  

Diagnostic Workup
Upon evaluation, the patient's phenotype included several features of WS including his short stature in the setting of early puberty, scleroderma-like skin changes, and thinned scalp hair (although this was difficult to assess given recent radiation therapy for his meningioma). Additional features included hyperlipidemia, high-pitched voice, soft tissue calcifications, and neoplasm (meningioma). The patient was offered two testing options: WRN-specific gene analysis or exome sequencing, to include WRN and other alternative diagnoses, given the patient only met 2 of 4 cardinal criteria for WS. Given insurance coverage for both options, he elected to pursue exome sequencing. Testing confirmed the patient to be homozygous for a novel variant, c.1829+5G>A p.?, in the WRN gene. The performing lab classifies this variant as likely pathogenic, following ACMG variant classification guidelines.

Treatment and Management
Management and surveillance recommendations were made for the patient in line with current published guidelines.

Outcome and Follow-Up
The patient continues to follow with his comprehensive care team. He was diagnosed with bilateral posterior subcapsular polar senile cataracts at 37 years old.

 

Discussion
The WRN variant, c.1829+5G>A p.?, is an intronic variant that directly or indirectly alters the +5 splice site. Splice predictors support this variant has a deleterious effect which is a known mechanism of disease for WS. This patient met 2 out of 4 cardinal criteria for WS at the time of diagnosis. Current literature supports all four cardinal features of WS are present in 91% of individuals with a molecular diagnosis. Features of WS in prepubescence (such as short stature and skin findings in our patient’s case) have not been reported to date with similar WRN variants.

Conclusion
This case highlights features of WS may present at unexpected times and evaluation of non-cardinal features of WS may lead to a WS diagnosis. This patient’s diagnostic journey, including his growth differences and skin findings in prepubescence, his meningioma diagnosis prompting evaluation for WS, and his presentation of 2 out of 4 cardinal features at time of diagnosis, deviate from the typical diagnostic journey reported in the literature for WS.  This case underscores the challenges of counseling patients with WS as our understanding of the variability of WS continues to broaden.

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