21-hydroxylase deficiency

Definition: Congenital adrenal hyperplasia to 21-hydroxylase deficiency (21-OH CAH), in all its forms, accounts for over 90% of diagnosed cases of congenital adrenal hyperplasia. Though, congenital adrenal hyperplasia in most contexts refers to 21-hydroxylase deficiency.

Its incidence is of 1 per 5,000 to 14,500 births (1 in 60 in the normal population are heterozygotes). It accounts for more than 95% of cases of congenital adrenal hyperplasia, occurring once in 15 000 births. It is especially high in Ashkenazi Jews (1:27 live births).

Block in production of aldosterone and cortisol leads to accumulation of 17-hydroxypregnenolone and its catabolite pregnanetriol, and also high plasma ACTH.

21-hydroxylase deficiency causes virilizing syndrome, cortisol deficiency and variable salt wasting syndrome.

The non-classic 21-hydroxylase deficiency is a very common autosomal recessive disorder (1% incidence in parts of US), with mild cortisol deficiency, excessive adrenal androgens, no salt wasting. It is usually diagnosed by early adulthood.

Synopsis

 early sexual development
 bilateral adrenal hyperplasia
 female pseudohermaphroditism (46,XX DSD) with ambiguous genitalia
 normal uterus and ovaries in the pelvis
 enlargement of adrenal glands with maintained corticomedullary differentiation
 enlarged adrenal gland
 adrenal gland with cerebriform appearance
 elevated 17-hydroxy-progesterone level
 virilization of the external genitalia
 hypospadias
 masculinized females
- virilization
 adrenogenital syndrome
 salt-wasting
 systemic arterial hypertension
 recurrent fever
 hypoglycemia
 accelerated growth
 gynecomastia in adults
 sudden death and apparent SIDS (16010485)
 testicular tumors

• Leydig cell hyperplastic nodules without Reinke crystalloids
• Leydig cell tumor (19367056)

 malignant lymphoma (19367056)

Etiology

 CYP21 gene mutations at 6p21.3 (MIM.201910)

21-Hydroxylase deficiency is inherited as an autosomal recessive trait caused by an abnormal gene on chromosome 6 that encodes for cytochrome P450c21 (i.e., CYP21).

The genetic aberrations responsible for expression of the disease are complicated. This gene exists in tandem with a pseudogene, CYP21P, which
is believed to be non-transcribable as it contains a high number of documented mutations. The clinical manifestation depends upon the absence of the single active gene (CYP21, formerly called CYP21B) that actively expresses the 21-hydroxylase
enzyme, or of the rearrangements, deletions or point mutations transferred from the pseudogene present.

Approximately one-fourth of cases of classic congenital adrenogenital syndrome result from the deleted CYP21 gene. The remainder are due to non-deleted mutant gene sequences that have been transferred from the pseudogene, rendering the active gene non-functional.

If the allele carries a defect encoding for a mild defect, then the child will develop a non-classic form of adrenal hyperplasia, which by defi nition occurs after birth and is never associated with genital ambiguity. This latter syndrome is common, occurring in 1% of all women, and is thought to be a major cause of adult-onset virilism.

Sexual ambiguity

In the congenital form of the adrenogenital syndrome, the extent of virilization depends upon the timing in fetal life when the disease begins.

In females - If the onset begins after week 16 of gestation, the clitoris may be enlarged. If androgen excess occurs earlier, the vagina and urethra may open into a common urogenital sinus.

More marked clitoral enlargement and an opening of the urogenital sinus at the clitoral base may mimic penile hypospadias and suggest an even earlier temporal effect. On occasion, the changes have been of such severity that the female infants have been misdiagnosed as cryptorchid males with or without hypospadias.

In males - Males who have the adrenogenital syndrome show no evidence of genital ambiguity, but may have an enlarged phallus and a hyperpigmented rugated scrotum.

Tumor predisposition

In females, tumor development in genetic females with this condition is rare. In one unusual case, prostatic adenocarcinoma developed with osteoblastic skeletal metastases. Presumably, the initial development of the prostate itself was based on excessive testosterone formation during embryogenesis, which itself was reflective of 21-hydroxylase deficiency. In addition, the patient subsequently developed clear cell carcinoma of the endometrium.

In males, clinically detectable bilateral testicular nodules occasionally develop during childhood or young adulthood and must be distinguished from true Leydig cell tumors.

Usually the cells are composed of interstitial cells larger than Leydig cells, secrete cortisol and respond to treatment with the adrenolytic agent o,p’-DDD (mitotane), indicative that these cells are adrenal or adrenal-like in origin.

Bilaterality and decreasing tumor size after corticosteroid therapy are features indicative that the testicular ‘tumor’ of the adrenogenital syndrome is hyperplastic rather than neoplastic.

Screening examinations with ultrasonography and magnetic resonance imaging have shown that intratesticular masses are far more common than expected, being present in 40% of affected males. Rare cases have also been reported of ovarian tumors associated with severe virilizing symptoms.

The tumors, like those which arise in the testes, are bilateral, and are composed of cells with abundant cytoplasm, cytoplasmic lipochrome pigment, and some nuclear pleomorphism.

Pathophysiology

The defective enzyme P450c21, commonly referred to as 21-hydroxylase (21-OH), is embedded in the smooth endoplasmic reticulum of the cells of the adrenal cortex.

It catalyzes hydroxylation of 17-hydroxyprogesterone to 11-deoxycortisol in the glucocorticoid pathway from pregnenolone to cortisol.

It also catalyzes hydroxylation of progesterone to 11-deoxycorticosterone (DOC) in the mineralocorticoid pathway on its way from pregnenolone to aldosterone.

Deficient activity of this enzyme reduces the efficiency of cortisol synthesis, with consequent elevation of ACTH levels and hyperplasia of the adrenal cortex. ACTH stimulates uptake of cholesterol and synthesis of pregnenolone.

Steroid precursors up to and including progesterone, 17-hydroxypregnenolone, and especially 17-hydroxyprogesterone (17OHP) accumulate in the adrenal cortex and in circulating blood. Blood levels of 17OHP can reach 10-1000 times the normal concentration.

Since 21-hydroxylase activity is not involved in synthesis of androgens, a substantial fraction of the large amounts of 17-hydroxypregnenolone is diverted to synthesis of DHEA, androstenedione, and testosterone beginning in the third month of fetal life in both sexes.

Synthesis of aldosterone is also dependent on 21-hydroxylase activity. Although fetal production is impaired, it causes no prenatal effects, as the placental connection allows maternal blood to "dialyze" the fetus and maintain both electrolyte balance and blood volume.

See also

 congenital adrenal hyperplasia
 female pseudohermaphroditism

References

 Leydig cell tumor and malignant lymphoma in a patient with nonclassical 21-hydroxylase deficiency. Inaba H, Suzuki S, Shigematsu S, Shinomiya K, Ohfusa H, Shimojo Y, Uehara T, Hashizume K. Intern Med. 2009;48(8):601-5. PMID: 19367056 [Free]

 Gozzi TG, Harris NP, McGown IN, Cowley DM, Cotterill AM, Campbell PE, Anderson PK, Warne GL. Autopsy diagnosis of 21-hydroxylase deficiency CAH in a case of apparent SIDS. Pediatr Dev Pathol. 2005 May-Jun;8(3):397-401. PMID: 16010485