17-alpha-hydroxylase deficiency in three siblings: short- and long-term studies.

We have studied a family (12 members) with 3 patients (2 adult females and 1 pubertal-aged genotypic male) affected by congenital adrenal hyperplasia due to 17-alpha-hydroxylase deficiency, all of whom presented as phenotypically female subjects with lack of sexual development and with hypokalemic hypertension. The baseline hormonal pattern revealed low glucocorticoid levels (17-hydroxyprogesterone, plasma and urinary cortisol, cortisol secretion rate), as well as androgen (testosterone and dehydroepiandrosterone sulfate) and estrogen (17-beta-estradiol) levels, since the defect is present at both adrenal and gonadal levels. As a consequence ACTH, LH, and FSH concentrations were high. Otherwise steroids not requiring 17-alpha-hydroxylation, such as deoxycorticosterone, corticosterone and their 18-hydroxylated compounds, were secreted in excess with the exception of aldosterone whose levels were undetectable; baseline plasma renin activity levels were suppressed. Short-term dexamethasone treatment normalized potassium and reduced blood pressure and the abnormal mineralocorticoid levels. During chronic ACTH suppression with low doses of glucocorticoids (8 years), electrolyte disturbances were corrected, blood pressure was normalized in 2 cases but only reduced in the third; plasma renin activity returned to normal range within four years in all the patients, while urinary aldosterone was normalized only after 8 years of therapy and became partially responsive to posture, ACTH, angiotensin II, and furosemide. The other mineralocorticoids were reduced but remained above the normal range. The HLA-genotyping in all the family members revealed that the gene responsible for 17-alpha-hydroxylase deficiency was not linked to the HLA system. Measurement of plasma steroids (deoxycorticosterone, corticosterone, aldosterone) in this family revealed that the heterozygotes were different from the control population only in their ACTH-stimulated corticosterone levels.