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

Abstract

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.

Deletion within theCYP17 Gene Together with Insertion of Foreign DNA Is the Cause of Combined Complete 17α-Hydroxylase/17,20-Lyase Deficiency in an Italian Patient

“…More than 125 cases of 17a-hydroxylase/17,20-lyase deficiency syndrome have been reported (7), including cases of combined deficit of both activities (20) as well as isolated deficit of either 17a-hydroxylation (21) or 17,20-lyase activity (22)(23)(24). To date, all of the mutations in the CVP17 gene described have consisted of relatively small changes in the nucleotide sequence (7,(12)(13)(14)(15).…”

“…ACTH, FSH, and LH were increased, whereas renin was suppressed (0.08 ng/ ml • 3 h). The family history revealed that two sisters (DA and DM) displayed the same symptomatology and similar hormonal patterns, although their karyotypes were 46.XX (20).…”

“…The patient, DG, at the time of the study was a 14-yr-old girl, the tenth of 13 offspring and the child of a consanguineous marriage (the D family) (20). The patient was brought to the attention of clinicians because of severe headache and episodes of recent-onset vomiting.…”

Genetics, Ancestry, and Hypertension: Implications for Targeted Antihypertensive Therapies

“…The CYP17A1 (cytochrome P450 enzyme) protein is a key enzyme in the steroidogenic pathway that produces mineralocorticoids and glucocorticoids, and rare Mendelian mutations manifest by congenital adrenal hyperplasia and hypokalemic hypertension [38]. This locus has been identified in GWAS of both European and East Asian individuals [16•, 28•].…”

Genetic Variation inCYP17A1Is Associated with Arterial Stiffness in Diabetic Subjects

“…The CYP17A1 gene encodes a key cytochrome P450 enzyme important for the production of sex hormones, mineralocorticoids, and glucocorticoids. Mutations in CYP17A1 gene typically cause congenital adrenal hyperplasia and hypokalemic hypertension [24]. This gene was shown to be consistently and significantly associated with SBP and DBP in the two large GWA meta-analyses, the Cohorts for Heart and Aging Research in Genome Epidemiology (CHARGE) Consortium [6] and the Global Blood Pressure Genetics (Global BPgen) Consortium [7], and subsequently cross-validated in Korean and Japanese populations [25, 26].…”