title: Liver disease and other comorbidities in Wolcott-Rallison syndrome: different phenotype and variable associations in a large cohort.
abstract: BACKGROUND
  Wolcott-Rallison syndrome (WRS) is caused by recessive EIF2AK3 mutations and characterized by early-onset diabetes and skeletal dysplasia. Hepatic dysfunction has been reported in 60% of patients.
  
  
  OBJECTIVE
  To describe a cohort of WRS patients and discuss the pattern and management of their liver disease.
  
  
  METHODS
  Detailed phenotyping and direct sequencing of EIF2AK3 gene were conducted in all patients.
  
  
  RESULTS
  Twenty-eight genetically confirmed patients (67% male; mean age 4.6 years) were identified. 17 different EIF2AK3 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.
  
  
  CONCLUSIONS
  Liver disease in WRS is more frequent than previously described and carries high mortality. The first experience with liver transplantation in WRS is encouraging.
authors: Paediatric Department, Prince Mohammed bin-Abdulaziz Hospital, Madinah, Saudi Arabia.
authors: Abdelhadi M
authors: AM
authors: Habeb
authors: Asma
authors: A
authors: Deeb
authors: Matthew
authors: M
authors: Johnson
authors: Mohammed
authors: M
authors: Abdullah
authors: Majidah
authors: M
authors: Abdulrasoul
authors: Hussain
authors: H
authors: Al-Awneh
authors: Mohammed S F
authors: MS
authors: Al-Maghamsi
authors: Fathiya
authors: F
authors: Al-Murshedi
authors: Ramlah
authors: R
authors: Al-Saif
authors: Siham
authors: S
authors: Al-Sinani
authors: Dina
authors: D
authors: Ramadan
authors: Hala
authors: H
authors: Tfayli
authors: Sarah E
authors: SE
authors: Flanagan
authors: Sian
authors: S
authors: Ellard
mesh_terms: D002675:Child, Preschool; D015331:Cohort Studies; D015897:Comorbidity; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics / Q000401:mortality / Q000601:surgery; D004838:Epiphyses / Q000002:abnormalities* / Q000601:surgery; D005260:Female; D006505:Hepatitis / Q000235:genetics / Q000401:mortality / Q000601:surgery; D006801:Humans; D017093:Liver Failure / Q000235:genetics / Q000401:mortality / Q000601:surgery; D016031:Liver Transplantation; D008297:Male; D009154:Mutation; D010009:Osteochondrodysplasias / Q000235:genetics / Q000401:mortality / Q000601:surgery; D019892:eIF-2 Kinase / Q000235:genetics*
chemical_list: C460640:EIF2AK3 protein, human; D019892:eIF-2 Kinase