Գլխավոր Հիվանդություններ Congenital adrenal hyperplasia

Congenital adrenal hyperplasia (CAH) are any of several autosomal recessive diseases resulting from mutations of genes for enzymes mediating the biochemical steps of production of mineralocorticoids, glucocorticoids or sex steroids from cholesterol by the adrenal glands (steroidogenesis). Most of these conditions involve excessive or deficient production of sex steroids and can alter development of primary or secondary sex characteristics in some affected infants, children, or adults. Signs and symptoms The symptoms of CAH vary depending upon the form of CAH and the sex of the patient. Symptoms can include: Due to inadequate mineralocorticoids: vomiting due to salt-wasting leading to dehydration and death Due to excess androgens:

functional and average sized penis in cases involving extreme virilization (but no sperm) ambiguous genitalia, in some females, such that it can be initially difficult to identify external genitalia as male or female. early pubic hair and rapid growth in childhood precocious puberty or failure of puberty to occur (sexual infantilism: absent or delayed puberty) excessive facial hair, virilization, and/or menstrual irregularity in adolescence infertility due to anovulation clitoromegaly, enlarged clitoris and shallow vagina Due to insufficient androgens and estrogens: Undervirilization in XY males, which can result in apparently female external genitalia In females, hypogonadism can cause sexual infantilism or abnormal pubertal development, infertility, and other reproductive system abnormalities Genetics Each form of CAH is associated with a specific defective gene. The most common type (95% of cases) involves the gene for 21-hydroxylase, which is found on 6p21.3 as part of the HLA complex. 21-hydroxylase deficiency results from a unique mutation with two highly homologous near-copies in series consisting of an active gene (CYP21A) and an inactive pseudogene (CYP21P). Mutant alleles result from recombination between the active and pseudo genes (gene conversion). Penetrance Further variability is introduced by the degree of enzyme inefficiency produced by the specific alleles each patient has. Some alleles result in more severe degrees of enzyme inefficiency. In general, severe degrees of inefficiency produce changes in the fetus and problems in prenatal or perinatal life. Milder degrees of inefficiency are usually associated with excessive or deficient sex hormone effects in childhood or adolescence, while the mildest forms of CAH interfere with ovulation and fertility in adults. Diagnosis Clinical evaluation Female infants with classic CAH have ambiguous genitalia due to exposure to high concentrations of androgens in utero. CAH due to 21-hydroxylase deficiency is the most common cause of ambiguous genitalia in genotypically normal female infants (46XX). Less severely affected females may present with early pubarche. Young women may present with symptoms of polycystic ovarian syndrome (oligomenorrhea, polycystic ovaries, hirsutism). Males with classic CAH generally have no signs of CAH at birth. Some may present with hyperpigmentation, due to co-secretion with melanocyte-stimulating hormone (MSH), and possible penile enlargement. Age of diagnosis of males with CAH varies and depends on the severity of aldosterone deficiency. Boys with salt-wasting disease present early with symptoms of hyponatremia and hypovolemia. Boys with non-salt-wasting disease present later with signs of virilization. In rarer forms of CAH, males are under-masculinized and females generally have no signs or symptoms at birth. Laboratory studies Genetic analysis can be helpful to confirm a diagnosis of CAH but it is not necessary if classic clinical and laboratory findings are present. In classic 21-hydroxylase deficiency, laboratory studies will show: hypoglycemia (due to hypocortisolism) hyponatremia (due to hypoaldosteronism) hyperkalemia (due to hypoaldosteronism) elevated 17-hydroxyprogesterone Classic 21-hydroxylase deficiency typically causes 17-hydroxyprogesterone blood levels >242 nmol/L. (For comparison, a full-term infant at three days of age should have <3 nmol/L. Many neonatal screening programs have specific reference ranges by weight and gestational age because high levels may be seen in premature infants without CAH.) Salt-wasting patients tend to have higher 17-hydroxyprogesterone levels than non-salt-wasting patients. In mild cases, 17-hydroxyprogesterone may not be elevated in a particular random blood sample, but it will rise during a corticotropin stimulation test. Classification Cortisol is an adrenal steroid hormone that is required for normal endocrine function. Production begins in the second month of fetal life. Poor cortisol production is a hallmark of most forms of CAH. Inefficient cortisol production results in rising levels of ACTH, because cortisol feeds back to inhibit ACTH production, so loss of cortisol results in increased ACTH. This increased ACTH stimulation induces overgrowth (hyperplasia) and overactivity of the steroid-producing cells of the adrenal cortex. The defects causing adrenal hyperplasia are congenital (i.e. present at birth). Cortisol deficiency in CAH is usually partial, and not the most serious problem for an affected person. Synthesis of cortisol shares steps with synthesis of mineralocorticoids such as aldosterone, androgens such as testosterone, and estrogens such as estradiol. The resulting excessive or deficient production of these three classes of hormones produce the most important problems for people with CAH. Specific enzyme inefficiencies are associated with characteristic patterns of over- or underproduction of mineralocorticoids or sex steroids.

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