What is Adrenogenital Syndrome?
Adrenogenital syndrome is a group of autosomal recessively inherited disorders of corticosteroid synthesis. More than 90% of all cases of adrenogenital syndrome are due to a 21-hydroxylase deficiency.
Causes of Adrenogenital Syndrome
The 21-hydroxylase enzyme gene is located on the short arm of chromosome 6. There are two genes – the active CYP21-B gene, which encodes a 21-hydroxylase, and the inactive pseudogen CYP21-A. These genes are largely homologous. The presence of a homologous DNA sequence close to the coding gene often leads to mating disorders in meiosis and, as a result, to gene conversion (movement of a fragment of the active gene to a pseudogen), or to deletion of part of the sense gene. In both cases, the function of the active gene is disrupted. On chromosome 6, next to the CYP21 genes are the HLA genes that are inherited codominantly, as a result of which all homozygous sibs will have an identical HLA haplotype.
Pathogenesis During Adrenogenital Syndrome
The pathogenetic essence of adrenal syndrome is the inhibition of the production of some corticosteroids while simultaneously increasing the production of others due to the deficiency of an enzyme that provides one of the stages of steroidogenesis. As a result of P450c21 deficiency, the transition of 17-hydroxyprogesterone to 11-deoxycortisol and progesterone to deoxycorticosterone is disrupted.
Thus, depending on the severity of the enzyme deficiency, a deficiency of cortisol and aldosterone develops. Cortisol deficiency stimulates the production of ACTH, whose effect on the adrenal cortex leads to its hyperplasia and stimulation of the synthesis of corticosteroids – steroidogenesis shifts towards the synthesis of excess androgens. Hyperandrogenism of adrenal genesis develops. The clinical phenotype is determined by the degree of activity of the mutated CYP21-B gene. With its complete loss, a salt-losing version of the syndrome develops, in which the synthesis of glucocorticoids and mineralocorticoids is impaired. When the moderate activity of the enzyme is preserved, mineralocorticoid insufficiency does not develop due to the fact that the physiological need for aldosterone is approximately 200 times lower than in cortisol. There are 3 variants of 21-hydroxylase deficiency:
- deficiency of 21-hydroxylase with a salt-losing syndrome;
- simple viril form (incomplete deficiency of 21-hydroxylase);
- non-classical form (post pubertal).
The prevalence of adrenogenital syndrome varies considerably among different nationalities. Among the representatives of the European race, the prevalence of the classical variants (solitary and simple) of 21-hydroxylase deficiency is about 1 in 14,000 babies. This figure is significantly higher among Jews (non-classical form of 21-hydroxylase deficiency – up to 19% of Ashkenazi Jews). Among the Alaskan Eskimos, the prevalence of the classic forms of 21-hydroxylase deficiency is 1 in 282 newborns.
Symptoms of Adrenogenital Syndrome
Solterary form of 21-hydroxylase deficiency
- The excess of androgens, starting from the early stages of fetal development, in newborn girls causes the intersexual structure of the external genitalia (female pseudohermaphroditism). The severity of changes varies from simple clitoral hypertrophy to complete masculinization of the genitalia: a penis-like clitoris with an extension of the urethral opening on its head. The structure of the internal genitalia in fetuses with a female genotype is always normal in adrenogenital syndrome. Boys show an increase in penis size and hyperpigmentation of the scrotum. In the absence of treatment in the postnatal period, there is a rapid progression of virilization. The zones of bone growth quickly close, as a result of which, in adult patients, short stature is observed. In girls with no treatment, primary amenorrhea is associated with the suppression of the pituitary-ovarian system with an excess of androgens.
- Adrenal insufficiency (deficiency of aldosterone and cortisol) is manifested by such symptoms as sluggish sucking, vomiting, dehydration, metabolic acidosis, increasing adynamia. Electrolyte changes and dehydration characteristic of adrenal insufficiency are developing. These symptoms in most cases manifest between the 2nd and 3rd week after childbirth. One of the manifestations of glkzhokortikoidov deficiency is progressive hyperpigmentation.
The simple viril form of 21-hydroxylase deficiency develops due to a moderate deficiency of the enzyme, and the salt-losing syndrome (adrenal insufficiency) does not develop. But a pronounced excess of androgens, starting from the prenatal period, determines the manifestations of virilization described above.
Non-classical (post-pubertal) form of 21-hydroxylase deficiency
Prenatal virilization of the external genitalia and signs of adrenal insufficiency are absent. The clinical picture varies considerably. Most often, this form of the syndrome is diagnosed in women of reproductive age with targeted examination for oligomenorrhea (50% of patients), infertility, hirsutism (82%), acne (25%). In some cases, any clinical manifestations and fertility decline are practically absent.
Diagnosis of Adrenogenital Syndrome
The main marker for 21-hydroxylase deficiency is a high level of cortisol precursor – 17-hydroxyprogesterone (17-OHPg). Normally, it does not exceed 5 nmol / l. A 17-OHPg level of more than 15 nmol / L confirms a 21-hydroxylase deficiency. In most patients with classic forms of adrenogenital syndrome, the level of 17-OHPg exceeds 45 nmol / l.
In addition, an increase in the level of dehydroepiandrosterone (DHEA-S) and androstenedione is characteristic of a 21-hydroxylase deficiency. An increase in plasma renin level is typical for the salt-losing form, which reflects aldosterone deficiency and dehydration. In classical forms, along with this, the level of ACTH is increased.
Treatment of Adrenogenital Syndrome
In classical forms, children are prescribed hydrocortisone tablets at a daily dose of 15-20 mg / m2 of body surface or prednisone 5 mg / m2. The dose is divided into 2 doses: 1/3 of the dose in the morning, 2/3 of the dose at night for maximum suppression of ACTH production by the pituitary gland. In the case of the salt-losing form, the addition of fludrocortisone (50–200 µg / day) is additionally necessary. In case of severe concomitant diseases and surgical interventions, the dose of glucocorticoids should be increased. In case of late diagnosis of the viril form of adrenogenital syndrome of the streets with genetically female sex, surgical interventions may be necessary for plastics of the external genitalia. Post-pubertal (non-classical) form of adrenogenital syndrome due to 21-hydroxylase deficiency requires therapy only in the presence of pronounced cosmetic problems (hirsutism, acne) or while reducing fertility.
Forecast
In classical forms, it fully depends on the timeliness of diagnosis (prevents the development of pronounced violations of the structure of the external genitalia in girls) and the quality of replacement therapy, as well as the timeliness of plastic surgery on the external genitalia. Continuing hyperandrogenism, or, conversely, overdose with corticosteroids, contributes to the fact that the majority of patients remain of small stature, which, along with possible cosmetic defects (mask line shape in women), violates psychosocial adaptation. With adequate treatment in women with classic forms of adrenogenital syndrome (including the salt-losing one), the onset and normal gestation of pregnancy are possible.