title: Microscopic and ultrastructural features in Wolcott-Rallison syndrome, a permanent neonatal diabetes mellitus: about two autopsy cases.
abstract: 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.
authors.affiliation: Department of Pathology, Children and Mother's Hospital, Groupement Hospitalier Est, CHU de Lyon-Bron, France.
authors.forename: Sophie
authors.initials: S
authors.lastname: Collardeau-Frachon
authors.affiliation: Department of Pathology, Children and Mother's Hospital, Groupement Hospitalier Est, CHU de Lyon-Bron, France.
authors.forename: Alexandre
authors.initials: A
authors.lastname: Vasiljevic
authors.affiliation: Department of Pathology, Children and Mother's Hospital, Groupement Hospitalier Est, CHU de Lyon-Bron, France.
authors.forename: Anne
authors.initials: A
authors.lastname: Jouvet
authors.affiliation: Department of Pathology, Children and Mother's Hospital, Groupement Hospitalier Est, CHU de Lyon-Bron, France.
authors.forename: Raymonde
authors.initials: R
authors.lastname: Bouvier
authors.affiliation: Medical Faculty Paris 7, Inserm UMR-S958, Paris, France.
authors.forename: Valérie
authors.initials: V
authors.lastname: Senée
authors.affiliation: Department of Endocrinology, Children and Mother's Hospital, Groupement Hospitalier Est, CHU de Lyon-Bron, France.
authors.forename: Marc
authors.initials: M
authors.lastname: Nicolino
mesh_terms: D001344:Autopsy; D003241:Consanguinity; D057210:Delayed Diagnosis; D003922:Diabetes Mellitus, Type 1 / Q000175:diagnosis / Q000235:genetics / Q000473:pathology* / Q000503:physiopathology; D004721:Endoplasmic Reticulum / Q000378:metabolism / Q000473:pathology* / Q000648:ultrastructure; D004838:Epiphyses / Q000002:abnormalities* / Q000473:pathology / Q000503:physiopathology; D005192:Family Health; D006321:Heart / Q000503:physiopathology; D006801:Humans; D007223:Infant; D007668:Kidney / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology / Q000648:ultrastructure; D008099:Liver / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology / Q000648:ultrastructure; D017114:Liver Failure, Acute / Q000209:etiology; D008297:Male; D009154:Mutation; D009206:Myocardium / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D010009:Osteochondrodysplasias / Q000175:diagnosis / Q000235:genetics / Q000473:pathology* / Q000503:physiopathology; D010179:Pancreas / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology / Q000648:ultrastructure; D019892:eIF-2 Kinase / Q000235:genetics
chemical_list: C460640:EIF2AK3 protein, human; D019892:eIF-2 Kinase
keywords: Wolcott-Rallison syndrome; diabetes mellitus permanent neonatal; endoplasmic reticulum; liver steatosis; pathology