title: Bioinactive ACTH causing glucocorticoid deficiency.
abstract: BACKGROUND
  A 4-year-old girl and a 4-month-old boy presented with hypoglycemia, normal electrolytes, low cortisol, and high ACTH. A diagnosis of primary adrenal insufficiency was made and initial treatment was with glucocorticoids and mineralocorticoids. The genes known to cause ACTH resistance were normal. Whole exome sequencing revealed that the girl was compound heterozygous for POMC mutations: one previously described null allele and one novel p.R8C mutation in the sequence encoding ACTH and α-MSH. The boy was homozygous for the p.R8C mutation.
  
  
  OBJECTIVE
  The p.R8C ACTH mutant is immunoreactive, but the mutant peptides, ACTH-R8C and α-MSH-R8C, are bioinactive.
  
  
  METHODS
  Methods included whole exome sequencing, Sanger sequencing, peptide synthesis, ACTH immunoradiometric assay, hormone binding, and activation assays in cells expressing melanocortin receptors.
  
  
  RESULTS
  ACTH-R8C was immunoreactive but failed to bind and activate cAMP production in melanocortin-2 receptor (MC2R)-expressing cells, and α-MSH-R8C failed to bind and stimulate cAMP production in MC1R- and MC4R-expressing cells.
  
  
  CONCLUSIONS
  These are the first documented cases of glucocorticoid deficiency due to the secretion of an ACTH molecule that lacks biological bioactivity but conserves immunoreactivity. POMC mutations should thus be considered in patients presenting with apparent ACTH resistance. Our findings also highlight a limitation to immunoassay-based diagnostics and demonstrate the value of genetic analysis. Establishing the molecular etiology of the disorder in our patients allowed cessation of the unnecessary mineralocorticoids. Finally, discovery of this mutation indicates that in humans, the amino acid sequence His(6)Phe(7)Arg(8)Trp(9) is important not only for cAMP activation but also for ACTH binding to MC2R.
authors.affiliation: Endocrinology Service and Research Center, Centre Hospitalier Universitaire Sainte-Justine, Department of Pediatrics, University of Montreal, Montreal H3T 1C5, Canada.
authors.forename: Mark E
authors.initials: ME
authors.lastname: Samuels
authors.forename: Nicole
authors.initials: N
authors.lastname: Gallo-Payet
authors.forename: Sandra
authors.initials: S
authors.lastname: Pinard
authors.forename: Caroline
authors.initials: C
authors.lastname: Hasselmann
authors.forename: Fabien
authors.initials: F
authors.lastname: Magne
authors.forename: Lysanne
authors.initials: L
authors.lastname: Patry
authors.forename: Lucie
authors.initials: L
authors.lastname: Chouinard
authors.forename: Jeremy
authors.initials: J
authors.lastname: Schwartzentruber
authors.forename: Patricia
authors.initials: P
authors.lastname: René
authors.forename: Nicole
authors.initials: N
authors.lastname: Sawyer
authors.forename: Michel
authors.initials: M
authors.lastname: Bouvier
authors.forename: Anissa
authors.initials: A
authors.lastname: Djemli
authors.forename: Edgard
authors.initials: E
authors.lastname: Delvin
authors.forename: Céline
authors.initials: C
authors.lastname: Huot
authors.forename: Dardye
authors.initials: D
authors.lastname: Eugene
authors.forename: Cheri L
authors.initials: CL
authors.lastname: Deal
authors.forename: Guy
authors.initials: G
authors.lastname: Van Vliet
authors.forename: Jacek
authors.initials: J
authors.lastname: Majewski
authors.forename: Johnny
authors.initials: J
authors.lastname: Deladoëy
mesh_terms: D000224:Addison Disease / Q000235:genetics*; D000324:Adrenocorticotropic Hormone / Q000235:genetics*; D002675:Child, Preschool; D005260:Female; D005938:Glucocorticoids / Q000172:deficiency*; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D007003:Hypoglycemia / Q000235:genetics*; D007223:Infant; D008297:Male; D009154:Mutation; D044103:Receptor, Melanocortin, Type 2 / Q000235:genetics; D000521:alpha-MSH / Q000235:genetics
chemical_list: D005938:Glucocorticoids; D044103:Receptor, Melanocortin, Type 2; D000521:alpha-MSH; D000324:Adrenocorticotropic Hormone