Home > D. Systemic pathology > Genetic and developmental anomalies > Genetic metabolic diseases > 11-hydroxylase deficiency

11-hydroxylase deficiency

Tuesday 26 May 2009

Digital case

- HPC:400 : para-ovarian Leydig cell tumor in 11beta-hydroxylase deficiency

Definition: 11β-Hydroxylase deficient congenital adrenal hyperplasia (11β-OH CAH) is an uncommon form of congenital adrenal hyperplasia resulting from a defect in the gene for the enzyme which mediates the final step of cortisol synthesis in the adrenal.

11-beta hydroxylase deficiency is the second most common form (5%) of congenital adenal hyperplasia. Its incidence is of 1 per 100,000 live births.

It is associated with increased androgens and deoxycorticosterone. It causes virilization and hypertension

11β-OH CAH results in hypertension due to excessive mineralocorticoid effects. It also causes excessive androgen production both before and after birth and can virilize a genetically female fetus or a child of either sex.

11β-OH CAH resembles 21-hydroxylase deficient CAH in its androgenic manifestations: partial virilization and ambiguous genitalia of genetically female infants, childhood virilization of both sexes, and rarer cases of virilization or infertility of adolescent and adult women.

The mineralocorticoid effect differs: hypertension is usually the clinical clue that a patient has 11- rather than 21-hydroxylase CAH.

Diagnosis of 11β-OH CAH is usually confirmed by demonstration of marked elevations of 11-deoxycortisol and 11-deoxycorticosterone (DOC), the substrates of 11β-hydroxylase.

Management is similar to that of 21-hydroxylase deficient CAH except that mineralocorticoids need not be replaced.

Pathophysiology

11β-OH CAH is autosomal recessive.The enzyme which mediates 11β-hydroxylase activity is now known as P450c11β since it is one of the cytochrome P450 oxidase enzymes located in the inner mitochondrial membrane of cells of the adrenal cortex. It is coded by a gene at 8q21-22.

Like the other forms of CAH, a number of different defective alleles for the gene have been identified, producing varying degrees of impaired 11β-hydroxylase activity.

Also like the other forms of CAH, 11β-OH CAH is inherited as an autosomal recessive disease.

11β-Hydroxylase mediates the final step of the glucocorticoid pathway, producing cortisol from 11-deoxycortisol. It also catalyzes the conversion of 11-deoxycorticosterone (DOC) to corticosterone in the mineralocorticoid pathway.

- Mineralocorticoid effects

Mineralocorticoid manifestations of severe 11β-hydroxylase deficient CAH can be biphasic, changing from deficiency (salt-wasting) in early infancy to excess (hypertension) in childhood and adult life.

Salt-wasting in early infancy does not occur in most cases of 11β-OH CAH but can occur because of impaired production of aldosterone aggravated by inefficiency of salt conservation in early infancy.

When it occurs it resembles the salt-wasting of severe 21-hydroxylase deficient CAH: poor weight gain and vomiting in the first weeks of life progress and culminate in life-threatening dehydration, hyponatremia, hyperkalemia, and metabolic acidosis in the first month.

Despite the inefficient production of aldosterone, the more characteristic mineralocorticoid effect of 11β-OH CAH is hypertension.

Progressive adrenal hyperplasia due to persistent elevation of ACTH results in extreme overproduction of 11-deoxycorticosterone (DOC) by mid-childhood.

DOC is a weak mineralocorticoid, but usually reaches high enough levels in this disease to cause effects of mineralocorticoid excess: salt retention, volume expansion, and hypertension.

- Sex steroid effects

Because 11β-hydroxylase activity is not necessary in the production of sex steroids (androgens and estrogens), the hyperplastic adrenal cortex produces excessive amounts of DHEA, androstenedione, and especially testosterone.

These androgens produce effects that are similar to those of 21-hydroxylase deficient CAH.

In the severe forms, XX fetuses (genetically female) can be markedly virilized, with ambiguous genitalia that look more male than female, though internal female organs, including ovaries and uterus develop normally.

XY fetuses (genetic males) typically show no signs of excess androgens.

In milder mutations, androgen effects in both sexes appear in mid-childhood as early pubic hair, overgrowth, and accelerated bone age.

Although "nonclassic" forms causing hirsutism and menstrual irregularities and appropriate steroid elevations have been reported, most have not had verifiable mutations and mild 11β-hydroxylase deficient CAH is currently considered a very rare cause of hirsutism and infertility.

All of the issues related to virilization, neonatal assignment, advantages and disadvantages of genital surgery, childhood and adult virilization, gender identity and sexual orientation are similar to those of 21-hydroxylase deficiency.

Tumors and hyperplasias

The association between testicular tumors/nodules and congenital adrenal hyperplasia (CAH) has been reported.

- testicular nodules or tumors
- bilateral testicular enlargement (#9165472#)
- testicular adrenal rest hyperplasia (testicular adrenal remnant hyperplasia) (#12602540#)

- Leydig cell tumor

  • unilateral or bilateral testicular Leydig cell tumor (#21259051#, #20704142#)
  • unilateral or bilateral ovarian Leydig cell tumor (#1825720#)

- ovarian steroid cell tumor (NOS) (#10905393#)

See also

- congenital adrenal hyperplasia (CAH)