title: P450c17 deficiency caused by compound heterozygosity for two novel mutations presenting as hypotension in early infancy.
abstract: OBJECTIVE
  P450c17 deficiency is an uncommon steroidogenic disorder that typically presents as a sexually infantile adolescent phenotypic female with hypertension and hypokalemia. Although cortisol synthesis is impaired, elevated corticosterone and deoxycorticosterone ordinarily prevent adrenal insufficiency. Thus, diagnosis prior to puberty is rare. We report novel clinical features of an infant with complete P450c17 deficiency due to two novel mutations in CYP17A1.
  
  
  METHODS
  A 10-week-old, 46,XY phenotypic female presented with hypotension, developed hypokalemic hypertension post-resuscitation, then hyperkalemic hyponatremia upon weaning salt supplements. All CYP17A1 exons of the proband and parents were PCR-amplified and sequenced. Cosyntropin, GnRH agonist, and hCG tests were performed.
  
  
  RESULTS
  Sequencing demonstrated compound heterozygosity for two novel CYP17A1 mutations, C327dupT and C362G>A (W121X), both generating premature stop codons in exon 2 and predicting non-functional enzymes. Plasma corticosterone was very elevated, deoxycorticosterone normal, cortisol detectable, and aldosterone low-normal at baseline. Responses to cosyntropin of corticosterone and progesterone were elevated, deoxycorticosterone and aldosterone normal, cortisol subnormal, and 17α-hydroxycorticosteroid intermediates undetectable. GnRH agonist/hCG testing showed no androgenic response.
  
  
  CONCLUSIONS
  This is the first report of P450c17 deficiency presenting in a 46,XY female infant with hypotensive shock, a state exacerbated by the atypical absence of deoxycorticosterone elevation.
authors.affiliation: Section of Adult and Pediatric Endocrinology, Diabetes, and Metabolism, University of Chicago Pritzker School of Medicine, Chicago, Ill., USA.
authors.forename: Brigid
authors.initials: B
authors.lastname: Gregg
authors.forename: Larry K
authors.initials: LK
authors.lastname: Kociolek
authors.forename: Kenan
authors.initials: K
authors.lastname: Qin
authors.forename: Robert L
authors.initials: RL
authors.lastname: Rosenfield
authors.forename: Christine
authors.initials: C
authors.lastname: Yu
mesh_terms: D000312:Adrenal Hyperplasia, Congenital / Q000175:diagnosis / Q000235:genetics* / Q000503:physiopathology*; D019943:Amino Acid Substitution; D018389:Codon, Nonsense; D003937:Diagnosis, Differential; D058490:Disorder of Sex Development, 46,XY / Q000175:diagnosis / Q000235:genetics; D006579:Heterozygote; D020249:Hormone Replacement Therapy; D006801:Humans; D007022:Hypotension / Q000235:genetics*; D007223:Infant; D008297:Male; D009154:Mutation; D012769:Shock / Q000235:genetics; D013254:Steroid 17-alpha-Hydroxylase / Q000235:genetics*
chemical_list: D018389:Codon, Nonsense; C501892:CYP17A1 protein, human; D013254:Steroid 17-alpha-Hydroxylase