title: A novel entity of clinically isolated adrenal insufficiency caused by a partially inactivating mutation of the gene encoding for P450 side chain cleavage enzyme (CYP11A1).
abstract: BACKGROUND
  Cytochrome P450 side-chain cleavage enzyme (CYP11A1) facilitates the first and rate-limiting step of steroidogenesis. Only nine patients with CYP11A1 deficiency have been described. All patients presented with adrenal insufficiency (AI) and disorder of sex development in 46,XY individuals.
  
  
  OBJECTIVE
  Our objective was to define the pathogenic consequences of a novel CYP11A1 mutation (p.R451W) found in two brothers with isolated adrenal insufficiency.
  
  
  METHODS
  The two brothers (46,XY) presented with AI and normal male genital development. The older boy first presented with signs and symptoms suggestive of AI at the age of 2.8 yr but was only diagnosed at the age of 4.1 yr during an adrenal crisis. The younger brother was diagnosed with AI at the age of 2.5 yr while being clinically asymptomatic. Both boys had entirely normal appearance of their external genitalia.
  
  
  RESULTS
  The novel p.R451W mutation and five published missense CYP11A1 mutations were characterized employing two in vitro approaches using the natural substrate cholesterol and the intermediate 22R-hydroxycholesterol, respectively. Pregnenolone generation was measured by highly specific liquid chromatography tandem mass spectrometry. p.R451W had 30% of wild-type activity consistent with the clinical phenotype in our patients. Two previously published mutations (p.L222P and p.A359V) had 2- to 3-fold higher in vitro activities than originally reported, correlating better with the associated phenotypes.
  
  
  CONCLUSIONS
  We provide the first evidence that partial CYP11A1 deficiency has to be considered as a differential diagnosis in clinically isolated adrenal insufficiency. Our assays demonstrate a tighter genotype-phenotype correlation in CYP11A1 deficiency than previous in vitro studies.
authors: Centre for Endocrinology, Diabetes, and Metabolism, School of Clinical and Experimental Medicine, University of Birmingham, Institute of Biomedical Research, Wolfson Drive, Birmingham B15 2TT, United Kingdom.
authors: Silvia
authors: S
authors: Parajes
authors: Clemens
authors: C
authors: Kamrath
authors: Ian T
authors: IT
authors: Rose
authors: Angela E
authors: AE
authors: Taylor
authors: Christiaan F
authors: CF
authors: Mooij
authors: Vivek
authors: V
authors: Dhir
authors: Joachim
authors: J
authors: Grötzinger
authors: Wiebke
authors: W
authors: Arlt
authors: Nils
authors: N
authors: Krone
mesh_terms: D000309:Adrenal Insufficiency / Q000235:genetics*; D002675:Child, Preschool; D002786:Cholesterol Side-Chain Cleavage Enzyme / Q000235:genetics*; D005838:Genotype; D006801:Humans; D008297:Male; D020125:Mutation, Missense; D010641:Phenotype
chemical_list: D002786:Cholesterol Side-Chain Cleavage Enzyme