ESPE Abstracts (2015) 84 P-2-300

Non-Immune Diabetes Mellitus and Neurodegeneration: Two Distinct Cases of Wolfram Syndrome

Annelies Lemaya, Margje Sinnemac, Marieke den Brinkera, Hilde Dotremonta, Annick Francea, Raoul Roomana & Saartje Straetemansa,b


aDivision of Paediatric Endocrinology, Department of Paediatrics, University Hospital Antwerp, Antwerp, Belgium; bDivision of Paediatric Endocrinology, Department of Paediatrics, University Hospital Maastricht, Maastricht, The Netherlands; cDivision of Genetics, Department of Paediatrics, University Hospital Maastricht, Maastricht, The Netherlands


Background: Wolfram syndrome features diabetes insipidus, diabetes mellitus, optic nerve atrophy, and deafness (DIDMOAD). Especially the neurological degeneration usually leads to a very poor prognosis. We present two cases of Wolfram syndrome, an autosomal dominant and an autosomal recessive type, caused by heterozygous mutations in the WFS1 gene.

Case report: Case 1: a 13-year-old girl with a history of progressive sensorineuronal hearing loss and optic nerve atrophy presented with growth failure. GH deficiency was diagnosed and accordingly treated. Non-immune diabetes mellitus developed after the initiation of GH therapy, eventually leading to the diagnosis of Wolfram syndrome. Wolfram syndrome was confirmed by a pathogenic heterozygous mutation in the WFS1 gene: c.2051C>T(p.Ala684Val) variant in exon 8. Our patient responded well to GH therapy, reaching normal adult height. After discontinuation of GH treatment our patient remained fully insulin dependent. Case 2: a 13-year-old boy presented with bilateral loss of vision (50%) and diplopia since 4 months. Optic nerve atrophy was diagnosed. Hyperglycemia was observed during work-up and non-immune diabetes mellitus was revealed. In retrospect, the boy experienced polydipsia and polyuria since 2 years. Treatment with continuous subcutaneous insulin was started. The diagnosis of Wolfram syndrome was confirmed by two heterozygous mutations in the WFS1 gene: c.631+2T>G(r.spl?) and c.1511C>G(p.(Pro504Arg).

Conclusion: The clinical picture of Wolfram syndrome is highly variable. The combination of insulin-dependent non-immune diabetes mellitus and bilateral progressive optic nerve atrophy are the main diagnostic criteria. However, in our first patient diabetes mellitus only appeared after the occurrence of neurodegenerative disease and pituitary dysfunction, delaying the diagnosis of Wolfram syndrome. In the second patient vision loss was the main presenting symptom with hyperglycemia as an incidental finding. Therefore, the diagnosis of Wolfram syndrome should also be considered in patients without diabetes mellitus who have evidence of neurodegenerative disease.

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