title: From diarrhea to obesity in prohormone convertase 1/3 deficiency: age-dependent clinical, pathologic, and enteroendocrine characteristics.
abstract: OBJECTIVE
  The aim of this report is to delineate the clinical, pathologic, and enteroendocrine (EE) features of prohormone convertase 1/3 (PC1/3) deficiency in children.
  
  
  BACKGROUND
  Prohormone convertases play a pivotal role in the activation of biologically inactive hormones. Congenital defects in the EE axis, such as PC1/3 deficiency, have been rarely reported and their pathophysiological mechanisms are largely unknown.
  
  
  METHODS
  EE function and pathology was evaluated in 4 males (1, 2, 7, and 10 y old) from 2 families with PC1/3 deficiency at a university children's hospital. Clinical course, pathology analysis including immunohistochemistry for PC1/3, PC2, and glucagon-like peptide 1 (GLP-1) and electron microscopy, as well as EE function tests (GLP-1, GLP-2, oral glucose tolerance test) were performed.
  
  
  RESULTS
  All (n=4) suffered from congenital severe diarrhea associated with malabsorption. The diarrhea improved during the first year of life and hyperphagia with excessive weight gain (BMI>97th percentile) became the predominant phenotype at an older age. Analysis of the enteroendocrine axis revealed high proinsulin levels (57 to 1116 pmol/L) in all patients, low serum GLP-2 levels, and impaired insulin and GLP-1 secretion after an oral glucose tolerance test at a young age, with improvement in 1 older child tested. Electron microscopy showed normal ultrastructure of enterocytes and EE cells. Immunohistochemistry revealed normal expression of chromogranin A, a marker of EE cells but markedly reduced immunostaining for PC1/3 and PC2 in all patients.
  
  
  CONCLUSIONS
  PC1/3 deficiency is associated with an age dependent, variable clinical phenotype caused by severe abnormalities in intestinal and EE functions. Serum level of proinsulin can be used as an effective screening tool.
authors.affiliation: Divisions of *Gastroenterology, Hepatology and Nutrition †Pathology §Endocrinology, The Hospital for Sick Children ‡Department of Physiology, Faculty of Medicine, University of Toronto, Toronto, ON ∥Alberta Children's Hospital Intestinal Rehabilitation Program, Alberta Children's Hospital and University of Calgary, Calgary, AB, Canada ¶Department of Pediatrics, Mattel Children's Hospital, David Geffen School of Medicine at the University of California, Los Angeles, CA.
authors.forename: Robert H J
authors.initials: RH
authors.lastname: Bandsma
authors.forename: Christiane
authors.initials: C
authors.lastname: Sokollik
authors.forename: Rose
authors.initials: R
authors.lastname: Chami
authors.forename: Ernest
authors.initials: E
authors.lastname: Cutz
authors.forename: Patricia L
authors.initials: PL
authors.lastname: Brubaker
authors.forename: Jill K
authors.initials: JK
authors.lastname: Hamilton
authors.forename: Kusiel
authors.initials: K
authors.lastname: Perlman
authors.forename: Stanley
authors.initials: S
authors.lastname: Zlotkin
authors.forename: David L
authors.initials: DL
authors.lastname: Sigalet
authors.forename: Philip M
authors.initials: PM
authors.lastname: Sherman
authors.forename: Martin G
authors.initials: MG
authors.lastname: Martin
authors.forename: Yaron
authors.initials: Y
authors.lastname: Avitzur
mesh_terms: D000367:Age Factors; D002648:Child; D002675:Child, Preschool; D003967:Diarrhea / Q000453:epidemiology / Q000209:etiology*; D004700:Endocrine System Diseases / Q000503:physiopathology*; D019858:Enteroendocrine Cells / Q000378:metabolism*; D052216:Glucagon-Like Peptide 1 / Q000378:metabolism*; D053767:Glucagon-Like Peptide 2 / Q000097:blood; D005951:Glucose Tolerance Test; D006776:Hospitals, Pediatric; D006801:Humans; D007150:Immunohistochemistry; D007223:Infant; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D008297:Male; D008854:Microscopy, Electron; D009765:Obesity / Q000503:physiopathology*; D045664:Proprotein Convertase 1 / Q000172:deficiency*; D045706:Proprotein Convertase 2 / Q000378:metabolism; D012189:Retrospective Studies; D012720:Severity of Illness Index
chemical_list: D053767:Glucagon-Like Peptide 2; D007328:Insulin; D052216:Glucagon-Like Peptide 1; D045664:Proprotein Convertase 1; D045706:Proprotein Convertase 2