title: Homozygous nonsense and frameshift mutations of the ACTH  receptor in children with familial glucocorticoid deficiency  (FGD) are not associated with long-term mineralocorticoid  deficiency.
abstract: OBJECTIVE
  Familial glucocorticoid deficiency (FGD) is a rare autosomal recessive disease characterized by isolated glucocorticoid deficiency with preserved mineralocorticoid secretion. Mutations in the ACTH receptor (MC2R) account for approximately 25% of all FGD cases, but since these are usually missense mutations, a degree of receptor function is frequently retained. A recent report, however, suggested that disturbances in the renin-aldosterone axis were seen in some patients with potentially more severe MC2R mutations. Furthermore, MC2R knock out mice have overt aldosterone deficiency and hyperkalaemia despite preservation of a normal zona glomerulosa. We wished to determine whether a group of patients with severe nonsense mutations of the MC2R exhibited evidence of mineralocorticoid deficiency, thereby challenging the conventional diagnostic feature of FGD which might result in diagnostic misclassification.
  
  
  METHODS
  Clinical review of patients with nonsense MC2R mutations.
  
  
  METHODS
  Between 1993 and 2008, 164 patients with FGD were screened for mutations in the MC2R. Totally 42 patients (34 families) were found to have mutations in the MC2R. Of these, 6 patients (4 families) were found to have homozygous nonsense or frameshift mutations.
  
  
  RESULTS
  Mild disturbances in the renin-angiotensin-aldosterone axis were noted in four out of six patients, ranging from slightly elevated plasma renin levels to low aldosterone levels, although frank mineralocorticoid deficiency or electrolyte disturbance were not found. No patient required fludrocortisone replacement.
  
  
  CONCLUSIONS
  Severe nonsense and frameshift MC2R mutations are not associated with clinically significant mineralocorticoid deficiency and are thus unlikely to require long-term mineralocorticoid replacement.
authors.affiliation: Centre for Endocrinology, William Harvey Research Institute, St. Bartholomew's and The Royal London School of Medicine and Dentistry, London, UK.
authors.forename: Li F
authors.initials: LF
authors.lastname: Chan
authors.forename: Louise A
authors.initials: LA
authors.lastname: Metherell
authors.forename: Heiko
authors.initials: H
authors.lastname: Krude
authors.forename: Colin
authors.initials: C
authors.lastname: Ball
authors.forename: Stephen M P
authors.initials: SM
authors.lastname: O'Riordan
authors.forename: Colm
authors.initials: C
authors.lastname: Costigan
authors.forename: Sally A
authors.initials: SA
authors.lastname: Lynch
authors.forename: Martin O
authors.initials: MO
authors.lastname: Savage
authors.forename: Paolo
authors.initials: P
authors.lastname: Cavarzere
authors.forename: Adrian J L
authors.initials: AJ
authors.lastname: Clark
mesh_terms: D000293:Adolescent; D000307:Adrenal Gland Diseases / Q000235:genetics* / Q000378:metabolism / Q000628:therapy; D002648:Child; D002675:Child, Preschool; D018389:Codon, Nonsense; D005260:Female; D016368:Frameshift Mutation; D005938:Glucocorticoids / Q000172:deficiency*; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D008901:Mineralocorticoids / Q000172:deficiency*; D010375:Pedigree; D018043:Receptors, Corticotropin / Q000235:genetics* / Q000378:metabolism; D012189:Retrospective Studies
chemical_list: D018389:Codon, Nonsense; D005938:Glucocorticoids; D008901:Mineralocorticoids; D018043:Receptors, Corticotropin