Supplementary Material for: Liver Disease and Other Comorbidities in Wolcott-Rallison Syndrome: Different Phenotype and Variable Associations in a Large Cohort

<p><b><i>Background:</i></b> Wolcott-Rallison syndrome (WRS) is caused by recessive <i>EIF2AK3</i> mutations and characterized by early-onset diabetes and skeletal dysplasia. Hepatic dysfunction has been reported in 60% of patients. <b><i>Aims:</i></b> To describe a cohort of WRS patients and discuss the pattern and management of their liver disease. <b><i>Methods:</i></b> Detailed phenotyping and direct sequencing of <i>EIF2AK3</i> gene were conducted in all patients. <b><i>Results:</i></b> Twenty-eight genetically confirmed patients (67% male; mean age 4.6 years) were identified. 17 different <i>EIF2AK3</i> mutations were detected, of which 2 were novel. The p.S991N mutation was associated with prolonged survival and p.I650T with delayed onset. All patients presented before 25 months with diabetes with variation in the frequency and severity of 10 other features. Liver disease, first manifested as non-autoimmune hepatitis, was the commonest extra-pancreatic feature identified in 85.7% (24/28). 22/24 had at least one episode of acute hepatic failure which was the cause of death in all deceased patients (13/28). One child was treated by liver transplantation and had no liver disease and better diabetes control for the following 6 years. <b><i>Conclusions:</i></b> Liver disease in WRS is more frequent than previously described and carries high mortality. The first experience with liver transplantation in WRS is encouraging.</p