title: Severe loss-of-function mutations in the adrenocorticotropin receptor (ACTHR, MC2R) can be found in patients diagnosed with salt-losing adrenal hypoplasia.
abstract: OBJECTIVE
  Familial glucocorticoid deficiency type I (FGD1) is a rare form of primary adrenal insufficiency resulting from recessive mutations in the ACTH receptor (MC2R, MC2R). Individuals with this condition typically present in infancy or childhood with signs and symptoms of cortisol insufficiency, but disturbances in the renin-angiotensin system, aldosterone synthesis or sodium homeostasis are not a well-documented association of FGD1. As ACTH stimulation has been shown to stimulate aldosterone release in normal controls, and other causes of hyponatraemia can occur in children with cortisol deficiency, we investigated whether MC2R changes might be identified in children with primary adrenal failure who were being treated for mineralocorticoid insufficiency.
  
  
  METHODS
  Mutational analysis of MC2R by direct sequencing.
  
  
  METHODS
  Children (n = 22) who had been diagnosed with salt-losing forms of adrenal hypoplasia (19 isolated cases, 3 familial), and who were negative for mutations in DAX1 (NR0B1) and SF1 (NR5A1).
  
  
  RESULTS
  MC2R mutations were found in three individuals or kindred (I: homozygous S74I; II: novel compound heterozygous R146H/560delT; III: novel homozygous 579-581delTGT). These changes represent severely disruptive loss-of-function mutations in this G-protein coupled receptor, including the first reported homozygous frameshift mutation. The apparent disturbances in sodium homeostasis were mild, manifest at times of stress (e.g. infection, salt-restriction, heat), and likely resolved with time.
  
  
  CONCLUSIONS
  MC2R mutations should be considered in children who have primary adrenal failure with apparent mild disturbances in renin-sodium homeostasis. These children may have been misdiagnosed as having salt-losing adrenal hypoplasia. Making this diagnosis has important implications for treatment, counselling and long-term prognosis.
authors.affiliation: UCL Institute of Child Health & Department of Medicine, University College London, London, UK.
authors.forename: Lin
authors.initials: L
authors.lastname: Lin
authors.forename: Peter C
authors.initials: PC
authors.lastname: Hindmarsh
authors.forename: Louise A
authors.initials: LA
authors.lastname: Metherell
authors.forename: Mahmoud
authors.initials: M
authors.lastname: Alzyoud
authors.forename: Maryam
authors.initials: M
authors.lastname: Al-Ali
authors.forename: Caroline E
authors.initials: CE
authors.lastname: Brain
authors.forename: Adrian J L
authors.initials: AJ
authors.lastname: Clark
authors.forename: Mehul T
authors.initials: MT
authors.lastname: Dattani
authors.forename: John C
authors.initials: JC
authors.lastname: Achermann
mesh_terms: D000309:Adrenal Insufficiency / Q000097:blood / Q000235:genetics*; D000324:Adrenocorticotropic Hormone; D000450:Aldosterone / Q000097:blood; D004252:DNA Mutational Analysis; D005260:Female; D016368:Frameshift Mutation; D017353:Gene Deletion; D005938:Glucocorticoids; D006720:Homozygote; D006801:Humans; D006854:Hydrocortisone / Q000097:blood; D007010:Hyponatremia / Q000097:blood / Q000235:genetics; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D009154:Mutation; D044103:Receptor, Melanocortin, Type 2 / Q000235:genetics*; D012083:Renin / Q000097:blood
chemical_list: D005938:Glucocorticoids; D044103:Receptor, Melanocortin, Type 2; D000450:Aldosterone; D000324:Adrenocorticotropic Hormone; D012083:Renin; D006854:Hydrocortisone