Врожденная гиперплазия надпочечников: генетика, формы и клинические проявления.

Congenital adrenal hyperplasia (CAH) is a group of autosomal recessive disorders characterized by impaired cortisol synthesis. It results from the deficiency of one of the five enzymes required for the synthesis of cortisol in the adrenal cortex. Most of these disorders involve excessive or deficient production of hormones such as glucocorticoids, mineralocorticoids, or sex steroids, It is one of the most common autosomal recessive disorders in humans.

CAH can occur in various forms. The clinical presentation of each form is different and depends to a large extent on the underlying enzyme defect, its precursor retention, and deficient products. Classical forms appear in infancy, and nonclassical forms appear in late childhood. The presentation in patients with classic CAH can be further subdivided into three forms: salt wasting, simple virilizing, and non classic (NC) depending on whether mineralocorticoid deficiency presents or absents, respectively. This subtyping is often not clinically meaningful, though, because all patients lose salt to some degree, and clinical presentations may overlap.

CAH results 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). Each form of CAH is associated with a specific defective gene. The most common type (95% of cases) Mutant alleles result from recombination between the active and pseudogenes (gene conversion). About 5% of cases of CAH are due to defects in the gene encoding 11β hydroxylase and consequent 11β hydroxylase deficiency. Other, more rare forms of CAH are caused by mutations in genes, including HSD3B2 (3β hydroxysteroid dehydrogenase 2), CYP17A1 (17α hydroxylase/17,20 lyase), CYP11A1 (P450scc; cholesterol side chain cleavage enzyme), STAR (steroidogenic acute regulatory protein; StAR), CYB5A (cytochrome b5), and CYPOR (cytochrome P450 oxidoreductase; POR).

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.

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, 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. and females generally have no signs or symptoms at birth.

Cortisol is an adrenal steroid hormone 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. Since the 1960s, most endocrinologists have referred to the forms of CAH by the traditional names in the left column, which generally correspond to the deficient enzyme activity. As exact structures and genes for the enzymes were identified in the 1980s, most of the enzymes were found to be cytochrome P450 oxidases and were renamed to reflect this. In some cases, more than one enzyme was found to participate in a reaction, and in other cases, a single enzyme mediated in more than one reaction. Variation in different tissues and mammalian species also was found. In all its forms, congenital adrenal hyperplasia due to 21 hydroxylase deficiency accounts for about 95% of diagnosed cases of CAH. CAH screening had the lowest positive predictive value (111 true positive cases among 20,647 abnormal screening results in a 2 year period, or 0.53%, compared with 6.36% for biotinidase deficiency, 1.84% for congenital hypo thyroidism, 0.56% for classic galactosemia, and 2.9% for phenylketonuria). According to this estimate, 200 unaffected newborns required clinical and laboratory follow up for every true case of CAH. In 2020, Wael AbdAlmageed from USC Information Sciences Institute and Mimi Kim from USC Keck School Of Medicine led a joint study in which they used deep learning technology to analyze the facial morphology and features of CAH patients compared to control. In this cross sectional study of 102 patients with CAH and 144 control participants, deep learning methods achieved a mean area under the receiver operating characteristic curve of 92% for predicting CAH from facial images. Facial features distinguished patients with CAH from controls, and analyses of facial regions found that the nose and upper face were most contributory. The findings suggest that facial morphologic features, as analyzed by deep neural network techniques, can be used as a phenotypic biomarker to predict CAH.

Since the clinical manifestations of each form of CAH are unique and depend to a large extent on the underlying enzyme defects, their precursor retention and defective products, the therapeutic goal of CAH is to replenish insufficient adrenal hormones and suppress excess of precursors. Treatment can be monitored by measuring androstenedione and 17α hydroxyprogesterone levels in blood or saliva

An Italian anatomist, Luigi De Crecchio (1832 1894) provided the earliest known description of a case of probable CAH. I propose in this narrative that it is sometimes extremely difficult and even impossible to determine sex during life. In one of the anatomical theaters of the hospital , there arrived toward the end of January a cadaver which in life was the body of a certain Joseph Marzo The general physiognomy was decidedly male in all respects. There were no feminine curves to the body. There was a heavy beard. There was some delicacy of structure with muscles that were not very well developed The distribution of pubic hair was typical of the male. Perhaps the lower extremities were somewhat delicate, resembling the female, and were covered with hair The penis was curved posteriorly and measured 6 cm, or with stretching, 10 cm. The corona was 3 cm long and 8 cm in circumference. There was an ample prepuce. There was a first grade hypospadias There were two folds of skin coming from the top of the penis and encircling it on either side. These were somewhat loose and resembled labia majora. De Crecchio then described the internal organs, which included a normal vagina, uterus, fallopian tubes, and ovaries. It was of the greatest importance to determine the habits, tendencies, passions, and general character of this individual I was determined to get as complete a story as possible, determined to get at the base of the facts and to avoid undue exaggeration which was rampant in the conversation of many of the people present at the time of the dissection. He interviewed many people and satisfied himself that Joseph Marzo "conducted himself within the sexual area exclusively as a male", even to the point of contracting the "French disease" on two occasions. The cause of death was another in a series of episodes of vomiting and diarrhea. This account was translated by Alfred Bongiovanni from De Crecchio ("Sopra un caso di apparenzi virili in una donna. Morgagni 7:154–188, 1865) in 1963 for an article in The New England Journal of Medicine.