Adrenogenital syndrome is a group of autosomally recessively inherited violations of the synthesis of corticosteroids. More than 90% of all cases of adrenogenital syndrome are caused by deficiency of 21-hydroxylase. What provokes / Causes of Adrenogenital Syndrome:
The 21-hydroxylase enzyme gene is located on the short arm of chromosome 6. There are two genes, the active gene CYP21-B, encoding 21-hydroxylase, and the inactive pseudogen CYP21-A. These genes are largely homologous. The presence of a homologous DNA sequence alongside the coding gene often leads to mismatching in meiosis and, as a consequence, to gene conversion (movement of the active gene fragment to a pseudogen) or to the deletion of a part of the sense gene. In both cases, the function of the active gene is disrupted. On chromosome 6, next to the CYP21 genes, there are HLA genes that are inherited codominantly, so that all homozygotic siblings will have an identical HLA-haplotype.
Pathogenesis (what happens?) During adrenogenital syndrome: The pathogenetic essence of adrenogenital syndrome is the inhibition of the production of some corticosteroids with simultaneous increase in the production of others due to a deficiency of one or another enzyme that provides one of the stages of steroidogenesis. As a result of the deficiency of P450c21, the process of 17-hydroxyprogesterone transition 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. Deficiency of cortisol stimulates the production of ACTH, the effect of which on the adrenal cortex leads to its hyperplasia and stimulation of the synthesis of corticosteroids, steroidogenesis shifts toward synthesis of an excess of androgens. Hyperandrogenia develops in the adrenal genesis. The clinical phenotype is determined by the degree of activity of the mutated CYP21-B gene. With its complete loss, a salt variant of the syndrome develops, in which synthesis of glucocorticoids and mineralocorticoids is disrupted. With moderate activity of the enzyme retained, mineralocorticoid insufficiency does not develop due to the fact that the physiological requirement for aldosterone is about 200 times lower than in cortisol. There are 3 variants of deficiency of 21-hydroxylase:
The prevalence of adrenogenital syndrome varies considerably among different nationalities. Among the representatives of the European race, the prevalence of classical variants (salt and simple) of the deficiency of 21-hydroxylase is approximately 1 per 14,000 newborns. Significantly higher this figure for Jews (nonclassical form of deficiency of 21-hydroxylase - up to 19% of Jews in Ashkenazi). Among the Alaskan Eskimos, the prevalence of classical forms of 21-hydroxylase deficiency is 1 in 282 newborns.
Soltering form of deficiency of 21-hydroxylase
Excess androgen, beginning with the early stages of fetal development, in neonatal girls causes inter-sexual structure of the external genitalia (female pseudohermaphroditism). The severity of the changes varies from simple clitoral hypertrophy to complete masculinization of the genitals: the penis-like clitoris with the extensiveness of the urethral opening on its head. The structure of the internal genitalia in fetuses with a female genotype with adrenogenital syndrome is always normal. In boys, penis enlargement and hyperpigmentation of the scrotum are noted. In the absence of treatment in the postnatal period, a rapid progression of virilization occurs. Bone growth zones are quickly closed, as a result of which, as a rule, adulthood is observed in adult patients. In girls, in the absence of treatment, primary amenorrhea is associated with the suppression of the pituitary-ovarian system by 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. Develops characteristic for adrenal insufficiency electrolyte changes and dehydration. These symptoms in most cases manifest between the 2 nd and 3 rd week after the birth of the child. One of the manifestations of glycocorticoid deficiency is progressive hyperpigmentation.
A simple viril form of 21-hydroxylase deficiency develops as a result of moderate deficiency of the enzyme, while soltering syndrome (adrenal insufficiency) does not develop. But a pronounced excess of androgens, beginning with the intrauterine period, causes the above described manifestations of virilization.
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 a purposeful examination of oligomenorrhea (50% of patients), infertility, hirsutism (82%), acne (25%). In some cases, there are practically no clinical manifestations and a decline in fertility.
The main marker of deficiency of 21-hydroxylase is a high level of the precursor of cortisol - 17-hydroxyprogesterone (17-OHPg). Normally, it does not exceed 5 nmol / l. The level of 17-OHPg more than 15 nmol / l confirms the deficiency of 21-hydroxylase. In most patients with classical forms of adrenogenital syndrome, the level of 17-OHPg exceeds 45 nmol / l.
In addition, a deficiency of 21-hydroxylase is characterized by an increase in the level of dehydroepiandrosterone (DHEA-S) and androstenedione. For salt-losing form, a typical increase in plasma renin level, reflecting aldosterone deficiency and dehydration. At classical forms along with it the level of ACTH is raised.
In classical forms, children are given tablet hydrocortisone in a daily dose of 15-20 mg / m2 body surface or prednisolone 5 mg / m2. The dose is divided into 2 doses: 1/3 Dose in the morning, 2/3 doses per night for maximum suppression of ACTH pituitary. When salt form is additionally necessary, the appointment of fludrocortisone (50-200 μg / day). With severe concomitant diseases and surgical interventions, the dose of glucocorticoids should be increased. With the late diagnosis of the viral form of adrenogenital syndrome of streets with a genetically female sex, surgical interventions for the plasty of the external genitalia may be necessary. Postpubertal (nonclassical) form of adrenogenital syndrome due to deficiency of 21-hydroxylase requires therapy only in the presence of pronounced cosmetic problems (hirsutism, acne) or with a decrease in fertility.
In classical forms fully depends on the timeliness of the diagnosis (prevents the development of severe disorders in the structure of the external genitalia in girls) and the quality of the replacement therapy, as well as the timeliness of plastic surgery on the external genitalia. The persisting hyperandrogenism or, conversely, an overdose of corticosteroids, contributes to the fact that the majority of patients remain of small stature, which along with possible cosmetic defects (masking of the figure in women) disrupts psychosocial adaptation. With adequate treatment in women with classic forms of adrenogenital syndrome (including salt loss), it is possible to attack and normal gestation.