Monogenic Forms of Low-Renin Hypertension

Vesna D Garovic; Anthony A Hilliard; Stephen T Turner

Disclosures

Nat Clin Pract Nephrol. 2006;2(11):624-630. 

In This Article

Congenital Adrenal Hyperplasia

The term 'congenital adrenal hyperplasia' (CAH) describes a group of syndromes caused by defects in cortisol biosynthesis. CAH is inherited in an autosomal recessive manner. When 21-hydroxylase (CYP21A2) is deficient—the most common cause of CAH—patients are normotensive.[13] In 11β-hydroxylase (CYP11B1) and 17α-hydroxylase (CYP17) deficiencies, production of deoxycorticosterone (DOC), which has mineralocorticoid activity, is increased, leading to hypertension. Defects in CYP11B1 and CYP17 cause inhibition of cortisol production (Figure 2) with a subsequent reduction in feedback inhibition of ACTH secretion by the anterior pituitary and hypothalamus. Increased ACTH secretion then stimulates production of steroid precursors proximal to the 'blocked' step, leading to excessive levels of DOC.

Figure 2.

Adrenal steroid synthesis. Deficiency in 11β-hydroxylase (CYP11B1) results in accumulation of DOC and consequent hypertension; increased androgen synthesis leads to virilization in girls and precocious puberty in boys (black bar). Deficiency in 17α-hydroxylase (CYP17) also causes DOC accumulation and hypertension; sex hormone synthesis is blocked leading to delayed sexual development in girls and ambiguous genitalia in boys (gray bar). Abbreviation: DOC, deoxycorticosterone.

In both disorders, patients present with hypertension and hypokalemia early in life. Signs of androgen excess distinguish the two disorders; 11β-hydroxylase deficiency causes virilization in girls and precocious puberty in boys, whereas 17α-hydroxylase deficiency results in sex hormone deficiency, primary amenorrhea and delayed sexual development in girls, and ambiguous genitalia in boys. Genetic diagnosis of both conditions relies on testing for mutations that either severely depress or abolish enzyme activity. Both conditions can be effectively treated with exogenous glucocorticoids, which normalize ACTH secretion and ACTH-mediated build-up of cortisol precursors proximal to the enzymatic deficiency, including DOC. Acquired forms of the conditions caused by DOC-producing tumors typically present later in life.

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