Wolfram syndrome type 1 in siblings – A case report

Wolfram syndrome (WS) type 1 is a rare, autosomal recessive neurodegenerative disorder caused by mutations in the WFS1 gene. It is characterized by the early onset of insulin-dependent diabetes mellitus (DM) and bilateral optic atrophy (AO), often progressing to include other manifestations such as diabetes insipidus (DI), sensorineural hearing loss, urinary tract abnormalities, and neurological or psychiatric disorders. We report the case of a 14-year-old girl who initially presented at 8 years of age with visual loss, initially suspected to be due to a demyelinating neuropathy and treated with steroids. Four days later, she developed signs and symptoms of DM, leading to a diagnosis of WS type 1. Whole-exome sequencing revealed a homozygous c.1582T>G variant in the WFS1 gene. Despite correction of hyperglycemia, polyuria, polydipsia, and enuresis persisted, and DI was confirmed through desmopressin testing and brain MRI. Genetic analysis by targeted Sanger sequencing revealed both parents to be heterozygous carriers of the mutation. The patient’s younger sibling, examined at age 8, was also homozygous for the mutation and showed features of AO without other manifestations of WS type 1. This report illustrates the diagnostic process, genetic findings, and clinical progression in two siblings affected by WS type 1. Early genetic testing of all family members is essential to enable timely diagnosis, appropriate monitoring, and preventive care.