Wolfram syndrome

The estimated prevalence is 1/550,000. Regional estimates have ranged from 1/54,478 in Sicily to 1/1,351,000 in Italy, reflecting cohort and ascertainment differences.

Wolfram syndrome is mainly inherited in an autosomal recessive manner; dominant pathogenic variants in WFS1 have rarely been reported (Wolfram-like syndrome). The parents of an affected individual are typically asymptomatic carriers who each carry one pathogenic WFS1 variant; the recurrence risk for siblings is 25%. Carrier testing for at-risk relatives requires prior identification of the familial pathogenic variants. Prenatal molecular testing is technically possible once the familial pathogenic variants have been identified.

The diagnosis of Wolfram syndrome is established by molecular genetic identification of biallelic pathogenic variants in WFS1. Brain MRI may show an absent or diminished posterior pituitary bright spot, T1-/T2-weighted pontine signal abnormalities, optic nerve atrophy, white-matter T2 hyperintensities, and cerebellar atrophy; audiometry typically reveals a high-frequency sensorineural pattern. These findings support clinical suspicion but do not establish the diagnosis.

Main differential diagnoses include:

• Wolfram-like syndrome: only hearing impairment and diabetes, or hearing loss, optic atrophy and congenital cataracts
• Wolfram syndrome type 2: similar diabetes mellitus and optic atrophy, distinguished by peptic ulcers and defective platelet aggregation; CISD2
• : insulin-resistant diabetes, cone-rod dystrophy with early progressive vision loss, sensorineural hearing loss and early obesity; ALMS1
• Thiamine-responsive megaloblastic anaemia syndrome: non-type-1 diabetes, sensorineural hearing loss, optic atrophy and megaloblastic anaemia; SLC19A2

• Establishing the diagnosis: Molecular genetic identification of the underlying pathogenic variants confirms the clinical diagnosis at the genetic level.
• Specific and individualised surveillance and clinical management: Confirmation of the genetic diagnosis enables specific, individualised surveillance of disease manifestations and forms the prerequisite for targeted medical care, to be planned by the treating physicians in consultation with the affected individual.
• Family member testing: Identification of the familial pathogenic variants enables targeted testing of at-risk relatives for clinical and reproductive decisions.

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