Introduction to congenital adrenal hyperplasia

Introduction Congenital adrenal cortical hyperplasia (CAH) is a group of diseases caused by changes in hormone levels such as cortisol due to congenital defects in one or several enzymes in the adrenocortical hormone biosynthetic enzyme system. Often autosomal recessive inheritance. Clinically, 21-hydroxylase deficiency is the most common, accounting for more than 90%. The incidence rate is about 1/4500 newborns, of which about 75% is salt-loss type, followed by 11β-hydroxylase deficiency. It accounts for 5% to 8%, and its incidence rate is about 1/5000 to 7000 newborns. Other types are rare. The cause of this disease is not clear. Most scholars disagree with the pathogenesis of ACTH-dependent to non-dependent transition. It has been confirmed that AIMAH can be caused by factors other than ACTH. It has been found that abnormal expression of gastric inhibitory peptide (GIP), arginine vasopressin (AVP), and β2-adrenergic receptor in the adrenal gland can cause AIMAH. (I) Causes of the disease Almost all CYP21 mutations are the result of recombination between CYP21 and CYP21P (unequal exchange or conversion). Approximately 20% of the mutant alleles carry deletion mutations. Approximately 75% of the mutant alleles are the result of gene conversion. In 32% of patients with salt loss, there is a large fragment deletion or mutation in one allele, and 56% of point mutations in intron 2 on one allele cause RNA splicing abnormalities. These mutations were confirmed in vitro to completely or almost completely lose 21-hydroxylase activity. In the simple male type, the most common mutant allele (35%) is the substitution mutation of the amino acid codon 172 (Ile becomes Asn), and only retains 2% to 11% of the activity of normal 21-hydroxylase. The most common (39%) mutation in the non-classical type is the mutation of amino acid 281 (Val becomes Leu). There is a high correlation between genotype and phenotype. Therefore, DNA analysis can predict enzyme activity to a certain extent, and then predict clinical manifestations. (B) pathogenesis adrenal synthesis of 3 types of sterols: 1 glucocorticoids (cortisol is the most important one) 2 mineralocorticoids (aldosterone is the most important one) 3 androgen. Cortisol secretion has a circadian rhythm, which is crucial in stress situations; its lack causes adrenal crisis including hypotension and hypoglycemia, which can lead to death if not treated in time. Excessive production of adrenal androgen can lead to intrauterine masculinization. Female babies have genital malformations at birth, and adrenal glands appear prematurely in older males and females. Adrenal and gonad androgen production disorders can lead to male masculinization and lack of puberty development. In CAH, steroid synthase activity decreases to varying degrees, leading to abnormal secretion of glucocorticoids, mineralocorticoids and sex hormones, resulting in varying degrees of clinical manifestations. The degree of decline in enzyme activity and clinical phenotype are determined by the severity of the mutation and the type of mutation. In order to better understand the clinical manifestations of CAH, it is necessary to briefly understand the biochemical and related genes of adrenocortical steroid hormones. 1. The P450SCC gene (CYP11A) is a 20 kb single gene located on the long arm of chromosome 15 (15q23-24). Expressed in all steroid cells. 2.3 β-HSD (3β-hydroxysteroid Dehydrogenase II, 3β-hydroxysteroid dehydrogenase II). This microsomal hydroxysteroid dehydrogenase binds to the membrane and is associated with the smooth endoplasmic reticulum. It catalyzes the conversion of the hydroxyl group of carbon atom 3 to a keto group and the isomerization of a double bond from the B ring (delta5 steroid) to the A ring (delta4 steroid). It acts on four substrates, pregnenolone is converted to progesterone, 17α-hydroxypregnenolone is converted to 17α-hydroxyprogesterone, and dehydroepiandrosterone (DHEA) is converted to androstenedione, androstenedione Turned into testosterone. There are two different isozymes: Type II is active in the adrenal glands and gonads, and Type I is active in other tissues (skin, placenta, breast, etc.). The 3β-HSD gene (HSDβ1 and HSDβ2) has 93% homology and is located on chromosome 1 (1p13.1). 3. P450C17 (17α-hydroxylase/17,20 lyase). P450C17 is a microsomal enzyme that binds to the smooth endoplasmic reticulum. Two different and completely independent reactions are catalyzed: 17α-hydroxylase and 17,20 lyase reaction. By 17α-hydroxylation, the pregnenolone is converted to 17α-hydroxypregnenolone and the progesterone is converted to 17α-hydroxyprogesterone. These two substrates are cleaved by C17 and 20 carbon chains to form dehydroepiandrosterone and androstenedione, respectively. The gene encoding this enzyme is a single gene (CYP17) located on chromosome 10 (10q24.3). When P450C17 is completely deficient (such as globular band), aldosterone can be synthesized, but cortisol and sex hormones cannot be synthesized. If only 17α-hydroxylase activity is present, cortisol can be synthesized, and sex hormones must rely on two activities, 17α-hydroxylase and 17,20 lyase activity. For example, before puberty, the synthesis of adrenal cortisol is normal, but there is no synthesis of sex hormones, indicating 17α-hydroxylase activity but no 17,20 lyase activity. 4. P450C21 (21-hydroxylase). P450C21 is also bound to the smooth endoplasmic reticulum and actually competes with P450C17 for electrons derived from membrane-bound P450 reductase. It converts progesterone and 17α-hydroxyprogesterone into 11-deoxycorticosterone (DOC) and 11-deoxycortisol, respectively. Two CYP21 genes are located on chromosome 6 (6p21.3), in the middle of human leukocyte antigen (HLA), between HLA-B and HLA-DR. The CYP21 gene encodes a biologically active enzyme. The pseudogene is called CYP21P. CYP21P shares more than 93% homology with CYP21, but because of the presence of some deleterious mutations in CYP21P, this gene does not transcribe the mRNA of P450C21. It is precisely because of the high homology between CYP21P and CYP212 genes that gene transfer occurs, which is also a reason for the high incidence of CYP21 gene mutation. 5. P450C11β (C11β-hydroxylase). In the adrenal gland, it is active, mainly involved in the synthesis of cortisol. Located in the mitochondrial inner membrane, the mitochondrial inner membrane converts 11-deoxycortisol to cortisol and 11-deoxycorticosterone to corticosterone. Its coding gene is located on chromosome 8 (8q 21-22). Mutations in the above steroid hormone-encoding genes and hormonal synthesis disorders lead to CAH. Defects in CYP21 and CYP11β cause masculinization in women, while HSD3β2, CYP17 and StAR defects cause androgen synthesis disorders, resulting in male masculinization. Some types of HSD3β2 deficiency can cause mild masculinization in women. The gonads and adrenal glands have the same steroidogenic pathways. Therefore, some clinical manifestations are caused by abnormal steroid synthesis in the gonads, but not by abnormalities of adrenal hormones. In the fetal period, the degradation of the Miao tube structure is due to the presence of non-steroidal substances produced by the testes, the Miao tube inhibitor. Therefore, a fetus without a testicle will have a normal female internal genital anatomy regardless of the level of androgen. Fetuses with normal testes, regardless of the level of androgen, Müller tube structure will not develop. Symptoms ACTH secretion increases, causing bilateral adrenal hyperplasia. The hyperplastic cortex continues to synthesize androgen and hypertensive mineral corticosteroids in large quantities. The lack of 20-22 carbon chain enzymes leads to rare congenital fatty adrenal hyperplasia, often with complete barriers to steroidogenesis. If there is not enough replacement therapy, the baby will die early. The lack of 3β-hydroxysteroid dehydrogenase isomerase leads to the synthesis of progesterone, aldosterone and cortisol, and dehydroepiandrosterone is overproduced. The unusual syndrome is characterized by hypotension, hypoglycemia and male pseudo sex. deformity. Women are uncommon hairy and have varying melanin. Insufficient or lack of 21-hydroxylase can not convert 17-carboxyprogesterone to cortisol, the most common deficiency is two forms: (1) a variety of sodium, aldosterone low or lack; (1) common It is a non-sodium type, hairy, masculine, low blood pressure and pigmentation. 17α-hydroxylase deficiency, most commonly seen in female patients, some to adulthood with low levels of cortisol, ACTH compensatory increase. Primary amenorrhea, sexually naive, few male pseudohermaphroditism. Excessive secretion of salt corticosteroids causes hypertension, mainly due to increased 11-deoxycorticosterone. 11β-hydroxylase deficiency hindered the formation of cortisol and corticosterone, ACTH release was too high, resulting in deep melanin deposition, high blood pressure due to excessive secretion of 11-deoxycorticosterone, no obvious abnormalities. Lack of 18-hydroxysteroid dehydrogenase, rare in skin disease, is caused by the specific block of the last step of aldosterone biosynthesis. Therefore, patients with more loss of urinary sodium, causing dehydration and hypotension. After puberty, masculine manifestations such as hairy and amenorrhea are rarely found, and masculinity occurs by chance in middle age. This acquired abnormality of the adrenal mild enzyme is called benign masculinization of the adrenal cortex. The newborn genital genitalia has severe hypospadias and cryptorchidism. The boy is mostly normal at birth. There are excessive androgen in the fetus in the uterus, so there is obvious abnormality. Untreated patients develop hairy, muscular, amenorrhea, and breast development. The reproductive organs of male patients are unusually large. Excessive androgen inhibits the secretion of gonadotropins, causing testicular atrophy. In extremely rare cases, proliferative adrenal cortical remnants in the testicles increase and harden the testes, and the majority of patients have no semen after puberty. Due to adrenal hyperplasia, the height of the patient is soaring at 3 to 8 years old, which is much higher than that of children of the same age. About 9 to 10 years old, excessive androgen causes early fusion of the epiphysis, which causes the growth to terminate, and the patient is shorter after adulthood. Both men and women have provocative behaviors and increased sexual desires, and social problems and disciplinary problems are particularly prominent in some boys. According to the severity of clinical manifestations, there are three types: salt wasting and simple virilization. These two types are called classic21-hydro-xylase deficiency and non-classical (non-classic). Classic). The three types of 21-hydroxylase deficiency are artificial divisions of the same disease continuum, reflecting the general rule of varying degrees of 21-hydroxylase deficiency. 1. Loss of salt type is the most serious type of clinical manifestation. In addition to the masculine manifestations caused by excessive androgen, there is a clear loss of salt performance. It accounts for 3/4 of the classic patients. In the case of salt-loss patients, due to the complete lack of 21-hydroxylase activity, the 21-hydroxylation process of progesterone is severely impaired, resulting in insufficient aldosterone secretion. Lack of aldosterone causes loss of sodium in the kidneys, colon and sweat glands. Insufficient cortisol secretion caused by 21-hydroxylase deficiency aggravates the effects of aldosterone deficiency. Simultaneous defects of mineralocorticoid and glucocorticoid are more likely to cause shock and severe hyponatremia. In addition, the accumulated steroid precursors directly antagonize the mineralocorticoid receptor, aggravating the performance of mineralocorticoid deficiency, especially in patients who have not received treatment. Progesterone is known to have a clear anti-mineralocorticoid effect. There is no evidence that 17-hydroxyprogesterone has a direct or indirect anti-mineralocorticoid effect. The clinical manifestations of salt loss can be some unspecific symptoms such as poor appetite, vomiting, lethargy, and slow weight gain. Severe patients usually present with adrenal crisis such as hyponatremia, hyperkalemia, hyperreninemia and hypovolemic shock within 1 to 4 weeks after birth. If the correct and timely diagnosis and treatment cannot be obtained, the adrenal crisis will lead to the death of the patient. The problem of male salt-loss infants is particularly serious because they do not have external genital malformations in female infants. The doctors were not alert to the diagnosis of CAH before dehydration and shock occurred in these patients. With age, the sodium balance ability of CAH patients with severe salt loss in infants and young children will be improved, and aldosterone synthesis will be more effective. Loss-of-salt patients with the same genetic mutations show different degrees of salt loss, and there is no satisfactory explanation for this. Both genetic and non-genetic factors may play a role. Patients with salt-loss CAH have both clinical manifestations of androgen excess. At the time of birth, the female genitalia has hermaphroditism such as urogenital sinus, labia scrotum, labia fusion, clitoris hypertrophy, penile urethra, or male external genitalia such as perineal hypospadias, painful penile erection and cryptorchidism. Female masculinity was quantitatively assessed using a 5-level Prader grading method. Male and female CAH patients grow too fast, leading to early maturity, pubic hair prematurely, sweat glands secrete body odor, and the boy's penis increases without the testicles increasing. The girl's clitoris is progressively enlarged. During puberty, the patient develops muscles, snoring, acne, hirsutism and ovarian dysfunction such as amenorrhea and menstrual thinning. Due to the early closure of the callus, the final height of male and female patients is generally lower than the average height of their peers. Fertility in women who have lost salt is affected, and few reports of pregnancy. Male patients also have reduced fertility due to small testicles and spermatogenic disorders. 2. Compared with the lack of salt, the clinical manifestations of other androgen excess are almost the same except for the lack of severe salt loss. It accounts for 1/4 of the classic patients. Read more...