Background: Wolcott-Rallison syndrome (WRS) is a rare autosomal recessive disorder characterized by the association of permanent neonatal or early-infancy insulin-dependent diabetes, multiple bone dysplasia, hepatic dysfunction, and growth retardation. All clinical manifestations result from gene mutations encoding pancreatic endoplasmic reticulum eIF2 α kinase (PERK), an endoplasmic reticulum transmembrane protein that plays a role in the unfolded protein response. Histological and ultrastructural lesions of bone and pancreas have been described in animal models and WRS patients. However, histological and ultrastructural findings of other organs, especially of the liver, are lacking.
Methods: Autopsy specimens from two pediatric patients with WRS were analyzed. An immunohistochemical study was performed on the pancreas. An ultrastructural study was realized from samples of liver, pancreas, kidney, and myocardium. Our findings were compared with those of the literature and correlated with the molecular data.
Results: Hepatocytes and pancreatic exocrine cells exhibited very peculiar features of necrosis suggestive of secondary changes because of endoplasmic reticulum overload. Steatosis occurred in renal tubular cells, hepatocytes, and myocardial fibers. Abnormal mitochondria were noted in renal and myocardial fibers. Pancreas islets were characterized by a marked reduction in the number of insulin-secreting β cells.
Conclusions: The histological and ultrastructural features that occur in WRS are directly or indirectly linked to endoplasmic reticulum (ER) dysfunction and can explain the peculiar phenotype of this syndrome.
Keywords: Wolcott-Rallison syndrome; diabetes mellitus permanent neonatal; endoplasmic reticulum; liver steatosis; pathology.
© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.