Adrenal 21-hydroxylase deficiency

Congenital enzymatic defects in the adrenal biosynthetic pathways lead to diminished cortisol and aldosterone production and release. In these conditions, corticotrophin secretion is increased, and adrenal hyperplasia occurs, accompanied by enhanced secretion of steroid intermediates, especially adrenal androgens. More than 90% of cases of congenital adrenal hyperplasia are due to 21-hydroxylase deficiency, which is cre-afed by mufafions in fhe CYP21 gene encoding fhe en-... 

In patients suspected of congenital adrenal hyperplasia, to identify 21-hydroxylase deficiency, 11- hydroxylase deficiency, and 3l3-hydroxy-A5 steroid dehydrogenase deficiency, based on the steroids that accumulate in response to ACTH administration (see Figure 39-1 and Chapter 39)... 

Merke DP et al Future directions in the study and management of congenital adrenal hyperplasia due to 21-hydroxylase deficiency. Ann Intern Med 2002 136 320. [PMID 11848730]... 

Joannou GE (1981) Identification of 15/5-hydroxylated C21 Steroids in the neo-natal period the role of 3a,15/),17a-trihydroxy-5/ -pregnan-20-one in the perinatal diagnosis of congenital adrenal hyperplasia (CAH) due to a 21-hydroxylase deficiency. J Steroid Biochem 14 901-912... 

ACTH stimulation may distinguish three forms of "late-onset" (nonclassic) congenital adrenal hyperplasia from states of ovarian hyperandrogenism, all of which may be associated with hirsutism. In patients with deficiency of 21-hydroxylase, ACTH stimulation results in an incremental rise in plasma 17-hydroxyprogesterone, the substrate for the deficient enzyme. Patients with 11-hydroxylase deficiency manifest a rise in 11-deoxycortisol, while those with 3B-hydroxy-5 5 steroid dehydrogenase deficiency show an increase of 17-hydroxypregnenolone in response to ACTH stimulation. 

Congenital Adrenal Hyperplasia P450c21 Steroid Hydroxylase Deficiency... 

David M, Forest MG Prenatal treatment of congenital adrenal hyperplasia resulting from 21-hydroxylase deficiency. J Pediatr 105 799-803, 1984. 

Mercado AB, Wilson RC, Cheng KC, et al. Prenatal treatment and diagnosis of congenital adrenal hyperplasia owing to steroid 21-hydroxylase deficiency. / Clin Endocrinol Metab 80 2014-... 

Bilateral adrenal hyperplasia Secondary hyperaldosteronism Hyperreninemic hyperaldosteronism (hypertension) Congenital adrenal hyperplasia (due to adrenal enzyme deficiencies in cortisol production [11 3- or 17a-hydroxylase])... 

Interpretation Serum cortisol values more than 20ixg/dL exclude primary adrenal insufficiency. Glucocorticoid withdrawal would be required before assessing secondary or tertiary adrenal insufficiency in such cases. Little or no increase in cortisol secretion is seen in primary adrenal failure even over-successive days. A progressive staircase rise is seen over 2 to 3 days in adrenal insufficiency caused by pituitary or hypothalamic disease or steroid concentration suppression. Little or no response is also seen in congenital adrenal hyperplasia (CAH) caused by 21- and 17-hydroxylase deficiencies. 

A deficiency of ll -hydroxylase is the second most common form of CAH, with an incidence of 1 per 100,000 births, and is associated with manifestations of virilization, elevated concentrations of plasma androstenedione and DHEA-S, and hypertension. The mineralocorticoid-induced hypertension is caused by an elevation of DOC 11-deoxycortisol concentrations are markedly raised in subjects with this enzyme defect,The major distinguishing characteristic of this disorder from 21-hydroxylase deficiency, besides the elevated plasma concentrations of 11-deoxycortisol, is hypertension elicited by the salt retention caused by increased concentrations of DOC, A deficiency of 3 -hydroxysteroid dehydrogenase-isomerase has been reported and leads to an elevation in the ratio of 17a-hydroxypregnenolone to that of 17a-hydroxyprogesterone and to an increased ratio of DHEA to androstenedione. In severe forms of this rare disorder, female infants have pseudohermaphroditism, and male infants present with incomplete masculinization. Patients with this disorder usually present in early infancy with complete adrenal insufficiency including salt wasting. A late-onset form has also been reported in patients with premature pubarche with hirsutism, acne, and menstrual irregularities. The... 

In practice the measurement of serum or plasma 11-deoxycortisol (compound S) is used to document an Up-hydroxylase deficiency or as part of the metyrapone stimulation test. Because metyrapone inhibits the lip-hydroxylase enzyme, a fortyfold to eightyfold increase in plasma 11-deoxycortisol is observed in patients with normal pituitary-adrenal reserve. Consequently, immunoassay methods for 11-deoxycortisol in metyrapone test specimens need not be higlily sensitive. In these patients, a corresponding drop in serum cortisol is observed. A failure to demonstrate an increase in 11-deoxycortisol to at least 4 U,g/dL suggests either an inadequate pituitary ACTH reserve or primary adrenal failure. 

Chrousos GP, Loriaux DL, Mann D, Cutler GB. Late-onset 21-hydroxylase deficiency is an allelic variant of congenital adrenal hyperplasia characterized by attenuated clinical expression and different HLA haplo-type associations. Horm Res 1982 16 193-200. 

XO gonadal and X dysgenesis and variants XX gonadal dysgenesis Turner s syndrome Testicular feminization syndrome 17-Hydroxylase deficiency of the ovaries and adrenal glands... 

Classical congenital hyperplasia 21-Hydroxylase deficiency 11-Hydroxylase deficiency 3P-Hydroxysteroid dehydrogenase deficiency Adult or attenuated adrenal hyperplasia Androgen-producing adrenal tumors... 

Azziz R, Hincapie LA, Knochenhauer ES, Dewailly D, Fox L, Boots LR. Screening for 21-hydroxylase-deficient nonclassic adrenal hyperplasia among hyperandrogenic women A prospective study. Fertil Steril 1999 72 915-25. 

Hughes lA. Congenital adrenal hyperplasia 21-hydroxylase deficiency in the newborn and during infancy. Semin Reprod Med 2002 20 229-42. 

Biosynthesis of steroid hormones from cholesterol. The different pathways occur to varying extent in adrenals, gonads, and placenta. The systematic names for cytochrome P-450 enzymes, namely CYP followed by a number, are given in parentheses. CYPI1B2 and CYP17 possess multiple enzyme activities. [Reproduced with permission from P. C. White and P. W. Speiser, Congenital adrenal hyperplasia due to 21-hydroxylase deficiency. Endocrine Reviews 21,245 (2000).]... 

P. C. White and P. W. Speiser Congenital adrenal hyperlpasia due to 21-hydroxylase deficiency. Endocrine Reviews 21, 245 (2000). 

Hypoaldosteronism is rare and usually is associated with low renin status, diabetes, complete heart block, or severe postural hypotension, or it may occur postoperatively following tumor removal. Hypoaldosteronism may be part of a larger adrenal insufficiency or be the only defect the patient has. In nonselective hypoaldosteronism, the etiology of the low aldosterone is most likely generalized adrenocortical insufficiency (see Addison s disease). In selective hypoaldosteronism, the etiology is usually a specific defect in the stimulation of adrenal aldosterone secretion (21-hydroxylase deficiency being most common) or a defect in peripheral aldosterone action (decreased aldosterone receptors). 

Because many enzyme systems are needed to complete the complex cholesterol-to-cortisol pathway, enzyme deficiencies may lead to disruptions of the normal cascade of events (see Fig. 74—2). This group of enzyme disorders is known as congenital adrenal hyperplasia, mainly because of the resultant chronic adrenal gland stimulation that occurs following enzyme deficiency. The most frequent is steroid 21-hydroxylase deficiency, accounting for more than 90% of cases. Any enzyme deficiency is capable of affecting any one or all three of the steroid pathways. Therefore treatment should be focused on replacement of the deficient hormone, as well as cessation of the chronic stimulation causing the hyperplasia. In Table 74—8, six of the most common enzyme deficiencies are briefly outlined. 

Evidence that the A steroids are of adrenal origin has been supplied by Reynolds (R2), who showed that the urinary excretions of 16a-OH-DHA and 16-oxo-androstenediol were 0.3-1.4 mg/24 hours in a newborn female with the C-21 hydroxylase deficiency type of congenital adrenal hyperplasia. These fell to undetectable amounts with dexamethasone suppression therapy. A very low excretion of three 3y8-hydroxy-A steroids was found by the authors in the case of a baby shown subsequently at autopsy to have little adrenal tissue (see Section 11). Further circumstantial evidence is given when abnormalities are considered in Section 11 and also the effect of corticotropin in Section 12. 

Steroid 21-hydroxylase deficiency is the most common cause of congenital adrenal... 

Portrat, S., P. Mulatero, K.M. Curnow, J.L. Chaussain, Y. Morel, and L. Pascoe (2001). Deletion hybrid genes, due to unequal crossing over between CYPllBl (113-hydroxylase) and CYP11B2 (aldosterone synthase) cause steroid 113-hydroxylase deficiency and congenital adrenal hyperplasia. J. Clin. Endocrinol. Metab. 86, 3197-3201. 

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