Background: The side chain cleavage enzyme (CYP11A1) catalyzes the conversion of cholesterol to pregnenolone, the first rate-limiting step of steroidogenesis. CYP11A1 mutations are associate with primary adrenal insufficiency (PAI) and, in 46,XY patients, Disorders of Sex Development (DSD). A total of 35 patients (27 families) are reported including 15 intermediate forms with delayed onset of PAI, variable degrees of DSD or normal male phenotype.
Objective and hypotheses: To report 15 patients (13 families) with 15 CYP11A1 mutations (10 new) and variable clinical presentations
Method: CYP11A1 gene was analyzed by Sanger sequencing or massive parallel sequencing (MPS).
Results: Nine patients with a severe classic form (neonatal PAI and female phenotype in seven 46,XY patients) were homozygous or heterozygous composite for 10 mutations: p.Gly94Asp, p.Pro104Leu, p.Gly138Arg, p.Ala277Ser, p.Asp329Gly, p.Arg396Gly, p.Arg465Gln, p.Arg465Trp, p.Leu170Valfs*30 (all unpublished) and p.Arg120*. Five patients with an intermediate form (delayed onset of PAI and variable degree of DSD in 46,XY patients) had the mutations: p.Arg120Gln, p.Ala269Val (11% residual activity), p.Glu314Lys and a new one: p.Gly454Asp. One 46,XY patient with complete normal male genital development had a mutation reported in similar cases: p.Arg451Trp (32% residual activity). Functional studies are underway but in silico studies predict good phenotype genotype correlation.
Conclusion: The incidence of CYP11A1 mutations (33%) is higher in our cohort of patient with first step of steroidogenesis deficiency (STAR and CYP11A1 gene) than in global population. We report novel mutations with genotype phenotype correlation in these patients with varying clinical presentations, including one 46,XY patient without DSD. Is it due to a residual activity of the enzyme or to a tissue specific defect? Intermediate forms are rare but at risk to be misdiagnosed because the phenotype overlaps with other causes of PAI. This emphasizes the utility of MPS allowing the study of many causative genes all at once.
10 - 12 Sep 2016
European Society for Paediatric Endocrinology