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. 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.

En bloc multiorgan transplant (liver, pancreas, and kidney) for acute liver and renal failure in a patient with wolcott‐rallison syndrome

“…The clinical severity and course of WRS is very variable. 3 Neurodevelopmentally, our patient was attending school (third grade), academically performing well, had her bone dysplasias corrected, and was participating in physical activities expected of a third grader. We thought it was appropriate to move forward with transplantation candidacy with our patient because it was felt that the patient would experience significant benefits over burdens, even if not every potential benefit would be realized.…”

“…[2][3][4] Diabetic ketoacidosis is the usual presenting condition. [2][3][4] In consanguineous families, WRS is the most frequent cause of permanent neonatal diabetes mellitus. 2 Our patient presented at an early age with symptoms; however, the diagnosis was not made until later in life, when other characteristic findings developed.…”

“…Over time, WRS can affect a wide amalgam of organ systems, causing liver failure, neutropenia associated with recurrent infections, kidney failure, and/or hypothyroidism (euthyroid sick syndrome). [2][3][4] In the past 15 years or so, more cases of WRS have been reported in the literature, so we now know more about its clinical spectrum, pathophysiology, and genetics. [1][2][3][4] Mutations to the gene that encodes for EIF2AK3 (also called protein kinase RNA-like endoplasmic reticulum kinase [PERK]) are known to cause WRS.…”

“…[2][3][4] In the past 15 years or so, more cases of WRS have been reported in the literature, so we now know more about its clinical spectrum, pathophysiology, and genetics. [1][2][3][4] Mutations to the gene that encodes for EIF2AK3 (also called protein kinase RNA-like endoplasmic reticulum kinase [PERK]) are known to cause WRS. [1][2][3] A transmembrane protein, PERK, is responsible for multiple protective cellular mechanisms, including folding of proteins and cellular response to stress.…”

“…[1][2][3][4] Mutations to the gene that encodes for EIF2AK3 (also called protein kinase RNA-like endoplasmic reticulum kinase [PERK]) are known to cause WRS. [1][2][3] A transmembrane protein, PERK, is responsible for multiple protective cellular mechanisms, including folding of proteins and cellular response to stress. The PERK mutation deregulates multiple systems, affecting overall cell integrity when misfolded proteins accumulate.…”