title: An atypical case of familial glucocorticoid deficiency without pigmentation caused by coexistent homozygous mutations in MC2R (T152K) and MC1R (R160W).
abstract: BACKGROUND
  Familial glucocorticoid deficiency (FGD) is a rare autosomal recessive disorder characterized by isolated cortisol deficiency. Mutations in the gene encoding the ACTH receptor (MC2R) account for 25% of cases. One significant feature is generalized skin hyperpigmentation, which is thought to be due to elevated ACTH acting on the melanocortin 1 receptor (MC1R).
  
  
  OBJECTIVE
  The aim of the study was to determine the cause of a nonhyperpigmented case of FGD.
  
  
  METHODS
  The patient presented at 4 yr of age with hypoglycemia after prolonged fasting during a respiratory tract infection. She had further hypoglycemic attacks and was diagnosed with isolated glucocorticoid deficiency at 6 yr of age. Her parents were consanguineous, and she had two unaffected sisters. Her physical examination was normal, except that her height and weight were greater than the 97th centile for a sex- and age-matched reference population. Interestingly, she had no hyperpigmentation despite very high ACTH levels.
  
  
  RESULTS
  Nucleotide sequence analysis revealed homozygous mutations c.478C>T in MC1R and c.455C>A in MC2R leading to R160W and T152K changes in the amino acid sequences, respectively. The R160W MC1R change has previously been implicated in a red hair/pale skin phenotype, and MC2R -T152K is trafficking defective. Both parents and two unaffected sisters were heterozygous for the MC1R mutation; additionally, one unaffected sister was heterozygous for the MC2R mutation, and the other was wild-type.
  
  
  CONCLUSIONS
  We report an unusual case of FGD without hyperpigmentation due to coexistent MC1R/MC2R mutations. This case is important because it demonstrates for the first time that the assumption that the action of ACTH on MC1R causes skin hyperpigmentation is correct.
authors.affiliation: Marmara University, Department of Pediatric Endocrinology, 34899 Istanbul, Turkey.
authors.forename: Serap
authors.initials: S
authors.lastname: Turan
authors.forename: Claire
authors.initials: C
authors.lastname: Hughes
authors.forename: Zeynep
authors.initials: Z
authors.lastname: Atay
authors.forename: Tulay
authors.initials: T
authors.lastname: Guran
authors.forename: Belma
authors.initials: B
authors.lastname: Haliloglu
authors.forename: Adrian J L
authors.initials: AJ
authors.lastname: Clark
authors.forename: Abdullah
authors.initials: A
authors.lastname: Bereket
authors.forename: Louise A
authors.initials: LA
authors.lastname: Metherell
mesh_terms: D000309:Adrenal Insufficiency / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D005260:Female; D005938:Glucocorticoids / Q000172:deficiency*; D006801:Humans; D017495:Hyperpigmentation / Q000235:genetics; D009154:Mutation; D044102:Receptor, Melanocortin, Type 1 / Q000235:genetics*; D044103:Receptor, Melanocortin, Type 2 / Q000235:genetics*
chemical_list: D005938:Glucocorticoids; D044102:Receptor, Melanocortin, Type 1; D044103:Receptor, Melanocortin, Type 2