title: Delayed diagnosis of adrenal insufficiency in a patient with severe penoscrotal hypospadias due to two novel P450 side-change cleavage enzyme (CYP11A1) mutations (p.R360W; p.R405X).
abstract: BACKGROUND
  Cytochrome P450 side-chain cleavage enzyme (CYP11A1) catalyses the first and rate-limiting step of steroidogenesis, the conversion of cholesterol to pregnenolone. CYP11A1 deficiency is commonly associated with adrenal insufficiency, and in 46,XY individuals, with variable degrees of disorder of sex development (DSD).
  
  
  METHODS
  The patient was born with hyperpigmentation, micropenis, penoscrotal hypospadias, and mild cryptorchidism. Biochemical and hormonal findings were normal except for low testosterone and low-borderline cortisol. However, no short synacthen test was undertaken. Development was unremarkable apart from an episode labeled as sepsis with documented hyperkalemia and elevated C-reactive protein at age 15 days. Diagnosis of 46,XY DSD was made at age 2.5 months. Progression of hyperpigmentation prompted further investigations and the diagnosis of adrenal insufficiency was established at 2 years with raised ACTH, normal renin activity, and failure of cortisol to respond to short synacthen test. Genetic analyses were performed. The novel CYP11A1 mutations were characterized in vitro and in silico.
  
  
  RESULTS
  The patient was compound heterozygous for two novel CYP11A1 mutations, p.R360W and p.R405X. p.R360W retained 30-40% of wild-type activity. In silico analyses confirmed these findings and indicated that p.R405X is severe.
  
  
  CONCLUSIONS
  This study demonstrates the pathogenicity of two novel CYP11A1 mutations found in a patient with delayed diagnosis of CYP11A1 deficiency. Patients with partial deficiencies of steroidogenic enzymes are at risk to be misdiagnosed if adrenal function is not assessed. The adrenocortical function should be routinely assessed in all patients with DSD including severe hypospadias of unknown origin to prevent life-threatening adrenal crises.
authors.affiliation: School of Clinical and Experimental Medicine, Institute of Biomedical Research, Centre for Endocrinology, Diabetes and Metabolism, University of Birmingham, Wolfson Drive, Birmingham B15 2TT, UK.
authors.forename: Silvia
authors.initials: S
authors.lastname: Parajes
authors.forename: Angel O K
authors.initials: AO
authors.lastname: Chan
authors.forename: W M
authors.initials: WM
authors.lastname: But
authors.forename: Ian T
authors.initials: IT
authors.lastname: Rose
authors.forename: Angela E
authors.initials: AE
authors.lastname: Taylor
authors.forename: Vivek
authors.initials: V
authors.lastname: Dhir
authors.forename: Wiebke
authors.initials: W
authors.lastname: Arlt
authors.forename: Nils
authors.initials: N
authors.lastname: Krone
mesh_terms: D000309:Adrenal Insufficiency / Q000175:diagnosis* / Q000235:genetics*; D002675:Child, Preschool; D002786:Cholesterol Side-Chain Cleavage Enzyme / Q000235:genetics*; D057210:Delayed Diagnosis; D006801:Humans; D008297:Male; D009154:Mutation
chemical_list: D002786:Cholesterol Side-Chain Cleavage Enzyme