A novel homozygous mutation in CYP11A1 gene is associated with late-onset adrenal insufficiency and hypospadias in a 46,XY patient.

CONTEXT: The first and the rate-limiting step in the biosynthesis of hormones in all steroidogenic tissues, conversion of cholesterol to pregnenolone, is catalyzed by the cholesterol side-change cleavage cytochrome P450 (P450scc) encoded by a single gene, CYP11A1. To date, mutations in CYP11A1 gene have been reported in six patients, all of whom presented with adrenal insufficiency within the first 4 yr of life and severely underandrogenized external genitalia (Prader stages 1-2).

OBJECTIVE: Our aim was to characterize in vitro and in vivo effects of a novel homozygous CYP11A1 gene mutation identified in a patient with an unusual presentation of P450scc deficiency.

METHODS AND PATIENTS: A 46,XY patient presented with mid-shaft hypospadias and cryptorchidism at birth and signs of adrenal failure at 9 yr. Mutational analysis of CYP11A1 gene was performed by PCR, followed by direct sequencing. P450scc activity was determined by measuring concentration of pregnenolone synthesized from cholesterol in the medium after a transient transfection of HEK293 cells with P450scc, adrenodoxin, adrenodoxin reductase, and steroidogenic acute regulatory protein expression plasmids.

RESULTS: The sequencing of CYP11A1 gene in the proband revealed a novel homozygous L222P mutation, whereas both parents were heterozygous carriers for this mutation. In vitro P450scc activity of L222P mutant was approximately 7% compared with the wild type.

CONCLUSIONS: This case represents the mildest phenotype of P450scc deficiency to be described. The phenotypic presentation was consistent with the partial reduction of P450scc activity of L222P mutant.