Variable phenotype in five patients with Wolcott-Rallison syndrome due to the same EIF2AK3 (c.1259delA) mutation

Wolcott-Rallison syndrome (WRS) is a rare condition characterized by permanent neonatal diabetes (PND), skeletal dysplasia, and recurrent hepatitis. Other features, including central hypothyroidism, have been reported. We compared the phenotype of five patients from two families with WRS caused by the same EIF2AK3 mutation who have been followed up since diagnosis. Direct sequencing of the EIF2AK3 gene identified a homozygous frameshift mutation (c.1259delA) in all patients that has been reported only in these families. All patients presented with PND and four experienced recurrent hepatitis. A 3.5-year-old girl has isolated PND, whereas her younger sister has typical WRS features. Two children developed skeletal abnormalities and two had transient central hypothyroidism. Other reported features of WRS were not detected. The EIF2AK3 c.1259delA mutation results in a variable phenotype, ranging from isolated PND to typical WRS. Thyroid dysfunction in WRS is a transient phenomenon reflecting euthyroid sickness.