A Novel Variant in the WRN Gene Detected in a Case of Early-Onset Severe Insulin Resistance Displaying Some but Not All Hallmarks of Progeroid Werner Syndrome

OBJECTIVE Determining the cause of severe insulin resistance and early-onset diabetes in the case of a young woman in which a wide range of differential diagnoses did not apply. RESEARCH DESIGN AND METHODS Diagnostic workup including medical history, physical examination, specialist consultations, imaging methods, laboratory assessment, and genetic testing carried out by next-generation panel sequencing. RESULTS After ruling out several differential diagnoses, genetic testing revealed a previously unknown homozygous variant within the canonical splice site of intron 4 in the WRN gene classified as pathogenic. Thus, although not all cardinal clinical criteria according to existing guidelines had been met, the phenotype of our patient was attributed to Werner syndrome (WS), an autosomal-recessive inherited progeroid syndrome. CONCLUSIONS WS, although rare, must be considered as a differential diagnosis in cases of severe insulin resistance. Moreover, recognized clinical criteria of WS may not lead to diagnosis in all cases.