Abstract
BackgroundWolcott-Rallison syndrome (WRS) is characterized by permanent early-onset diabetes, skeletal dysplasia and several additional features, e.g. recurrent liver failure. This is the first multicentre approach that focuses on diabetes management in WRS. We searched the German/Austrian Diabetes-Patienten-Verlaufsdokumentation (DPV) registry and studied anthropometric characteristics, diabetes treatment, glycaemic control and occurrence of severe hypoglycaemia (SH) and diabetic ketoacidosis (DKA) in 11 patients with WRS. Furthermore, all local treatment centres were personally contacted to retrieve additional information on genetic characteristics, migration background and rate of consanguinity.ResultsData were analysed at diabetes onset and after a median follow-up period of 3 (1.5–9.0) years (time from diagnosis to latest follow-up). Median age at diabetes onset was 0.2 (0.1–0.3) years, while onset was delayed in one patient (aged 16 months). Seventy percent of patients manifested with DKA. At follow-up, 90% of patients were on insulin pump therapy requiring 0.7 [0.5–1.0] IU of insulin/kg/d. More than two third of patients had HbA1c level ≥ 8%, 40% experienced at least one episode of SH in the course of the disease. Three patients died at 0.6, 5 and 9 years of age, respectively. To the best of our knowledge three patients carried novel mutations in EIF2AK3.ConclusionInsulin requirements of individuals with WRS registered in DPV appear to be comparable to those of preschool children with well-controlled type 1 diabetes, while glycaemic control tends to be worse and episodes of SH tend to be more common. The majority of individuals with WRS in the DPV registry does not reach glycaemic target for HbA1c as defined for preschool children (< 7.5%). International multicentre studies are required to further improve our knowledge on the care of children with WRS.
Highlights
Wolcott-Rallison syndrome (WRS) is characterized by permanent early-onset diabetes, skeletal dysplasia and several additional features, e.g. recurrent liver failure
Wolcott-Rallison syndrome (WRS) is a rare autosomal recessive disorder caused by loss-of-function mutations in the eukaryotic translation initiation factor 2α kinase 3 (EIF2AK3) gene encoding pancreatic PKR-like endoplasmic reticulum kinase (PERK) that phosphorylates the alpha subunit of the eukaryotic translation-initiation factor 2 [1]
This study further revealed that less than one third of individuals with WRS in the DPV registry reached glycaemic targets for haemoglobin A1c (HbA1c) as defined by the International Society for Pediatric and Adolescent Diabetes (ISPAD) and the American Diabetes Association (ADA) for preschool children (HbA1c < 7.5%; n = 3) [24, 29]
Summary
Wolcott-Rallison syndrome (WRS) is characterized by permanent early-onset diabetes, skeletal dysplasia and several additional features, e.g. recurrent liver failure. This is the first multicentre approach that focuses on diabetes management in WRS. Several additional features have been described, whose presence and severity vary between patients These may be present upon diagnosis or develop later during the course of the disease and include recurrent episodes of hepatic failure (in up to 85% of patients [3]), impaired renal function, exocrine pancreatic insufficiency, osteopenia, growth retardation, anaemia, neutropenia associated with recurrent infections, hypothyroidism during stress conditions (referred to as the euthyroid sick syndrome) and developmental delay [4, 5]. Given the extensive phenotypic variability, it has been proposed to consider WRS in any infant with permanent early-onset diabetes mellitus born from consanguineous parents or originating from isolated populations or countries in which inbreeding is frequent [4]
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