Liver disease and other comorbidities in Wolcott-Rallison syndrome: Different phenotype and variable associations in a large cohort

Habeb, Abdelhadi M.; Deeb, Asma Al; Johnson, Matthew B.; Abdullah, Mohamed Ahmed; Abdulrasoul, Majedah M.; Al-Awneh, Hussain; Al-Maghamsi, Mohammad S.F.; Al-Murshedi, Fathiya M.; al-Saif, Ramlah; Al-Sinani, Siham; Ramadan, Dina G.; Tfayli, Hala M.; Flanagan, Sarah E.; Ellard, Sian

doi:https://doi.org/10.1159/000369804

Liver disease and other comorbidities in Wolcott-Rallison syndrome: Different phenotype and variable associations in a large cohort

Date

2015

Authors

Habeb, Abdelhadi M.

Deeb, Asma Al

Johnson, Matthew B.

Abdullah, Mohamed Ahmed

Abdulrasoul, Majedah M.

Al-Awneh, Hussain

Al-Maghamsi, Mohammad S.F.

Al-Murshedi, Fathiya M.

al-Saif, Ramlah

Al-Sinani, Siham

Publisher

S. Karger AG

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. Aims: 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. © 2015 S. Karger AG, Basel.

Keywords

Childhood diabetes, Eif2ak3 mutations, Hepatitis, Liver transplantation, Skeletal dysplasia, Child, preschool, Cohort studies, Comorbidity, Diabetes mellitus, type 1, Eif-2 kinase, Epiphyses, Female, Humans, Liver failure, Male, Mutation, Osteochondrodysplasias, Aminotransferase, Hemoglobin a1c, Insulin, Eif2ak3 protein, human, Protein kinase r, Acute liver failure, Adolescent, Article, Autosomal recessive disorder, Bile duct disease, Bone dysplasia, Cause of death, Child, Clinical article, Cohort analysis, Consanguineous marriage, Conservative treatment, Diabetes control, Disease duration, Disease severity, Eif2ak3 gene, Follow up, Gene, Gene mutation, Gene sequence, Genetic analysis, Genetic association, Genetic screening, Genotype, Genotype phenotype correlation, Growth rate, Hepatomegaly, Human, Human tissue, Infant, Insulin dependent diabetes mellitus, Insulin treatment, Jaundice, Kidney dysfunction, Liver disease, Liver fibrosis, Liver function, Mortality, Non autoimmune hepatitis, Onset age, Phenotype, Priority journal, Wolcott rallison syndrome, Abnormalities, Clinical trial, Epiphysis, Genetics, Multicenter study, Preschool child