Identification of steroid biosynthetic defects in genotype-proven heterozygous individuals for 17alpha-hydroxylase/17,20- lyase deficiency. Clinical endocrinology [Clin Endocrinol (Oxf)] Journal article

Summary
Objective: P450c17 deficiency (17alpha-hydroxylase/17,20-lyase deficiency, 17OHD) is a rare form of congenital adrenal hyperplasia caused by CYP17A1 gene mutations. The D487_F489 deletion in exon 8 and Y329fs in exon 6 are relatively frequent mutations of the CYP17A1 gene in China that completely abolish the enzyme activity of P450c17. However, little is known about steroid biosynthetic functions in carriers with these mutations in a single allele of the CYP17A1 gene, who are assumed to have 50% P450c17 activity. We investigated adrenal steroidogenic function in genotype-proven heterozygotes carrying such mutations in the CYP17A1 gene in vivo. Patients and design: Eight patients and fourteen family members from five families with 17OHD were recruited. The mutations of the CYP17A1 gene in these individuals were screened by sequencing. The hormonal response to cosyntropin was evaluated in the 14 genotype-proven carriers and 45 age- and gender-matched normal controls.
Results: Fourteen carriers of the CYP17A1 mutation-7 with the D487_F489 deletion, 6 with Y329fs and 1 with H373L-were identified from the 5 families with 17OHD. Compared to normal controls, carriers showed lower basal and cosyntropin-stimulated cortisol levels but higher cosyntropin-stimulated corticosterone levels. The ratios of corticosterone to cortisol in the genotype-proven heterozygotes were higher than those of the normal controls at the baseline and after cosyntropin stimulation. Similarly, the progesterone levels and the ratios of progesterone to 17-hydroxyprogesterone in the male heterozygotes were also higher than those of the normal controls, both before and after cosyntropin stimulation.
Conclusion: Genotype-proven carriers of the CYP17A1 mutation who lack apparent clinical symptoms exhibit decreased adrenal 17alpha-hydroxylase activity and altered adrenal gland reserve for steroid biosynthesis.

Clinical endocrinology [Clin Endocrinol (Oxf)]