Introduction: Autosomal recessive mutations in the Wolfram syndrome type 1 gene are responsible for the classical Wolfram syndrome (OMIM_ 222300), also known by the acronym "DIDMOAD" (diabetes insipidus, diabetes mellitus (DM), optic atrophy and deafness). The gene encodes wolframin, a membrane glycoprotein, which helps to regulate the calcium homeostasis in the endoplasmic reticulum of many different tissues, including the pancreatic β-cells and the neuroendocrine cells. Typically, Wolfram syndrome is characterized by early-onset, non-autoimmune DM, usually without significant ketoacidosis at first presentation. The associated symptoms, like optic atrophy, diabetes insipidus, sensoneuronal deafness, urinary tract abnormalities, neurologic degeneration and endocrine dysfunction manifest with inconstant severity and prevalence as well as variable age of onset, often delaying the precise diagnosis.
Objectives: We report the case of a 16-year-old boy who presented with insulin-dependent DM without ketoacidosis at the age of 5 years and developed multiple neuro-endocrine dysfunctions over the following decade.
Results: Since diagnosis, the DM was difficult to control (hemoglobin A1c levels between 8.1-9.7%) despite high-doses of insulin were used (1.7 IU/kg/day). Family history was positive for type 2 DM. During follow-up, the patient showed severe, progressive reduction of visual acuity, short stature and delayed puberty, with poor response to a 6 months course of low-dose testosterone stimulation at age 15 years. Wolfram syndrome was suspected after he presented with neurological signs including progressive sensomotor axonal polyneuropathy, dizziness, and nocturia and polyuria with voiding difficulties associated with an increased bladder capacity at the age of 16 years. Laboratory investigations and thirst test revealed the diagnosis of a diabetes insipidus centralis. Desmopressin supplementation was started successfully decreasing urine output and improving voiding difficulties. Renal function, hepatic function, thyroid function, audiologic examination and magnetic resonance imaging of the brain were normal. Furthermore, no optic atrophy or diabetic retinopathy were observed. Genetic testing of the wolframin gene is pending. Interestingly, repeat antibody testing for type 1 DM revealed positivity for anti-insulin-antibodies.
Conclusions: This case report highlights the need of careful clinical vigilance for atypical features in children having (non-autoimmune) DM. Not only typical monogenic forms should be considered, but also mitochondrial causes such as Wolfram syndrome, which require specific genetic workup and have important consequences on clinical monitoring and outcome. Furthermore, the diagnosis of Wolfram syndrome may have therapeutic implications for such patients as with DM associated with endoplasmic reticulum stressmediated β-cell loss, GLP-1 receptor agonists may improve metabolic control.
19 - 21 Sep 2019
European Society for Paediatric Endocrinology