Introduction
Congenital adrenal hyperplasia(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.
Cause
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.
(1) 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.
(two) pathogenesis
Adrenal synthesis of 3 steroids:
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.
symptom
Increased ACTH secretion causes 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 appear within 1 to 4 weeks after birthHyponatremiaAdrenal crisis manifestations such as hyperkalemia, hyperreninemia, and hypovolemic shock. 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.
3. Non-classical type, formerly known as delayed-type 21-hydroxylase deficiency, patients have only mild clinical manifestations of excessive androgen. Female patients have normal or mild clitoris hypertrophy at birth and no genital hermaphroditism. Adrenal steroid precursors were only slightly elevated, and 17-hydroxyprogesterone levels were between heterozygous carriers and classic patients. After ACTH1～24 stimulation test (at 60min), 17-hydroxyprogesterone is generally above 10ng/ml. If only the serum level of 17-hydroxyprogesterone is measured, the patient will be missed. Symptoms and signs of mild androgen excess vary widely, and many affected individuals will have no symptoms. The most common symptoms are early appearance of pubic hair in children, or severe cystic acne, hirsutism, polycystic ovary, menstrual thinning or even amenorrhea in young women. Female patients with non-classical 21-hydroxylase deficiency also have reduced fertility, to a lesser extent than classic patients.
Non-classical male patients diagnosed after puberty usually present with acne or infertility. Most of them are diagnosed in home screening without any symptoms. In rare cases, male non-classical 21-hydroxylase deficiency patients present with unilateral testicular enlargement. In boys, it is difficult to clearly define the boundaries between classic masculine patients and non-classical patients. Because 17-hydroxyprogesterone levels are a continuous process of change between mild and severe cases, the clinical manifestations of male androgen excess are not as pronounced as in female patients.
The degree of aldosterone synthesis and sodium balance reduction in patients with non-classical 21-hydroxylase deficiency is not sufficient to cause any clinical manifestations. Similarly, the lack of cortisol secretion under stress conditions does not cause adrenal crisis. At present, there is no report of death due to adrenal insufficiency.
Whether the final height of adults in non-classical 21-hydroxylase deficiency patients is affected is inconclusive.
In women with hyperandrogenism (hirsutism, acne, polycystic ovary syndrome), the prevalence of non-classical 21-hydroxylase deficiency is 1.2% to 14%, much higher than that in normal people. Screening for non-classical 21-hydroxylase deficiency should be noted for these patients.
1. Examination of external genital malformations For the examination of neonates with suspected 21-hydroxylase deficiency, the urethra must be clearly defined and the gonads in the inguinal canal, labia or scrotum should be carefully palpated. The laboratory examination includes at least the basic serum 17-OHP, preferably the ACTH1-24 stimulation test, intravenous injection of ACTH1～24250μg, pre-treatment (ml) and serum 17-OHP 1h after administration. The 17-OHP base value usually exceeds 100 ng/ml. Loss of salt patients can reach up to 220 nmol/L (1000 ng/ml) after ACTH excitation. The level of 17-OHP in patients with simple masculinization is lower, but it partially overlaps with patients with salt loss. Non-classical patients usually require an ACTH stimulation test to diagnose. In newborns, these tests must be postponed until 24 hours after birth. These tests can identify defects in the steroid hormone synthesis process in the adrenal gland. After the examination is completed, the child's vital signs must be monitored to see if there is an adrenal crisis. Although the salt loss crisis rarely occurs within 7 days of birth, many doctors check electrolytes in the first week of neonatal examination to see if there is hyponatremia and hyperkalemia in CAH newborns.
2. Check for rapid karyotype analysis and pelvic and abdominal ultrasound examinations that are helpful for understanding the causes of genital malformations. After the initial inspection, the next inspection is carried out in a targeted manner. Disease data should be analyzed as soon as possible, and family members should be advised on gender and drug/surgical treatment.
3. Further biochemical examination
(1) ACTH1～24 excitement test.
(2) Inspection of salt loss.
(3) Other hormones used to diagnose and monitor 21-hydroxylase deficiency.
diagnosis
Many congenital malformations affecting external genital development resemble adrenal syndrome, including:
(1) severe hypospadias and cryptorchidism;
(2) Non-adrenal female pseudo-hermaphroditism (due to excessive androgen or progesterone medications during pregnancy).
(3) male pseudohermaphroditism,
(4) True hermaphroditism, these children are not ahead of any hormonal abnormalities, bone age and maturity.
In the differential diagnosis:
1. Mainly identified with 11β-hydroxylase deficiency (11β-OHD) 11β hydroxylase (P450c11β) deficiency is the second most common type of CAH, accounting for only 5% to 8%. The incidence rate in the population is 1/10,000.
When the CYP11B1 gene is defective, it causes 11β-OHD-induced CAH, adrenal 11-deoxycortisol (S) cannot be converted to cortisol (F), and deoxycorticosterone (DOC) cannot be converted to corticosterone (S), which ultimately cannot be synthesized. Aldo, resulting in increased blood DOC and S concentrations, DOC is also a strong sodium-sodium hormone, can cause high blood sodium, hypokalemia, hypertension, alkalosis, through feedback, renin-angiotensin is inhibited, so Aldo Reduced synthesis, decreased levels of blood PRA and Aldo. As cortisol synthesis is blocked, symptoms of adrenal insufficiency can occur, ACTH levels increase, and levels of androgen, DHEA, △4-A, testosterone, and urinary 17-KS increase, and high androgen symptoms and characteristics similar to 21-OHD appear.
2. Identification of CAH by various other enzyme deficiency is shown in Table 1.
3. Loss of salt 21-OHD is differentiated from chronic adrenal insufficiency (hypoadrenocorticism, Addison disease). Addison disease has loss of salt, reduction of cortisol, decreased sex hormones, no masculine symptoms, and 17-OHP is normal.
4. Simple masculine CAH and the following diseases
(1) Males should be identified with true precocious puberty: the morphology of the external genitalia is similar, but the latter testicles and penis increase at the same time, close to puberty, 17-KS and testosterone reach puberty level, but 17-OHP is normal, FSH, LH increase .
(2) Female CAH needs to be differentiated from true hermaphroditism. Although the external genitalia can be masculine, the blood levels of 17-KS and testosterone can be normal.
(3) Adrenal male tumors: After birth, male symptoms gradually develop, blood androgen levels can be increased, 17-OHP is normal, and one adrenal mass can be found by B-ultrasound or CT.
5. Female atypical 21-OHD and polycystic ovary syndrome identified the latter occurred in women of childbearing age, with high androgen symptoms and signs, and insulin resistance; B-ultrasound showed multiple ovarian cysts.
complication
Congenital defects in certain adrenal enzymes cause abnormal steroid production. Women cause false hermaphroditism and male genitals are huge. Enzyme deficiency is accompanied by excessive androgen products in the uterus of the fetus, which will develop normally in the female Müllerian catheter structure (ie, ovary, uterus, and vagina), while excess androgen exerts its male in the genitourinary and reproductive nodules. The effect of the vaginal and urethra is connected, and the enlarged clitoris is low and open. The labia are often hypertrophied, and severe cases have hypospadias and cryptorchidism. The adrenal cortex causes varying degrees of cortisol deficiency due to the majority of secreted anabolic male steroids.
As the callus matures early and early, the adult height is significantly lower than normal; there are varying degrees of adrenal insufficiency, such as vomiting, diarrhea, dehydration and severe metabolic acidosis, uncorrectable hyponatremia, high blood Potassium, resulting in decreased blood volume, decreased blood pressure, shock, circulatory failure; poor testicular development, no sperm or oligozoospermia; male patients with true precocious puberty, delayed menarche, delayed menorrhagia or Amenorrhea; causing decline in fertility in men and women.
treatment
Early diagnosis is absolutely necessary. Reasonable treatment is to give glucocorticoids, that is, oral dexamethasone 0.5 ~ 1.5mg corrected loss at 11 o'clock every night, inhibiting ACTH secretion. For patients with severe low-salt syndrome, fludrocortisone helps maintain blood pressure and body weight, which can be 0.05-0.3 mg, depending on the severity of the disease and age.
After development, surgery can be used to separate the vagina from the urethra, and the vaginal opening is in the normal position of the perineum. If the clitoris is often erect, the clitoris can be considered. Careful administration of estrogen or medication after birth can prevent patients with pseudohermaphroditism from maintaining their appearance and improving their mental state.
(a) treatment
Glucocorticoid replacement therapy
(1) General: All patients with classic 21-hydroxylase deficiency and symptomatic non-classical patients are treated with glucocorticoids, which inhibits excessive secretion of CRH and ACTH in the hypothalamus and pituitary, abnormal blood levels. Increased adrenal hormones are reduced. In children, it is recommended to take hydrocortisone (ie cortisol itself) at a dose of 10-20 mg/(m2·d), 2/d or 3/d. These doses exceed the physiological level of cortisol secretion, and the physiological level of cortisol secretion in children and adolescents is approximately 6-7 mg/(m2·d). Although mild elevation of cortisol secretion in neonates is normal [7 to 9 mg/(m2·d)], CAH infants usually give a minimum dose of 6 mg/(m2·d), 3/d. Children with 21-hydroxylase deficiency must be given a super-physiological dose of glucocorticoids, which is sufficient to inhibit adrenal androgens and reduce the possibility of adrenal insufficiency.
HydrocortisoneThe short half-life can reduce the inhibition of growth and the side effects of other hormones. These hormones have a long duration of action and strong potency, such asPrednisone,Dexamethasone. On the other hand, the application of a short-acting glucocorticoid once a day does not effectively control the secretion of hormones in the adrenal cortex.
Cortisone acetate is not the drug of choice for 21-hydroxylase deficiency. The bioavailability of cortisone acetate is 80% of hydrocortisone, and the utility is only 2/3 of hydrocortisone. In addition, since cortisone must be converted to cortisol to exert biological activity, a decrease in 11β-hydroxysteroid dehydrogenase reductase activity further reduces the efficacy.
Older adolescents and adults can use a minimum dose of prednisone (eg, 5 to 7.5 mg/d in 2 divided doses) or dexamethasone (total 0.25 to 0.5 mg, 1/d or 2/d). Signs of iatrogenic Cushing's syndrome, such as rapid weight gain, high blood pressure, purple skin, and reduced bone mass, must be carefully monitored. Male CAH patients remaining in the testicular adrenal gland require a larger dose of dexamethasone to inhibit ACTH.
The therapeutic effect (i.e., inhibition of adrenal hormones) was judged by monitoring the levels of 17-OHP and androstenedione. In female and prepubertal male patients,TestosteroneCan also be used as a useful indicator. Because of the excessive side effects of treatment, the secretion of endogenous corticosteroids should not be completely inhibited. The control range of 17-0HP is preferably 1 to 10 ng/ml, and the testosterone level is equivalent to the same age and sex. The relationship between the time of hormone determination and the time of administration should be fixed. It is best to take blood at 8:00 am of the ACTH physiological peak or at the bottom of the trough before the next dose.
Children must check the X-ray bone age phase every year and carefully monitor the growth line. Despite careful monitoring of the indicators and patient compliance, most retrospective studies have shown that adult final height is lower than the expected height based on parental height and lower than the average height of normal people.
In addition, patients with salt-loss CAH must also receive mineralocorticoid replacement therapy, and some patients can increase salt intake (1 ~ 3g / d) in the diet. Most patients have 0.1 mg/d fluorocorticosterone. Infants and toddlers sometimes need 0.1 to 0.2 mg/time, 2/d. It mainly relies on the determination of blood renin activity to regulate drug dosage and salt intake.
(2) indications for treatment of non-classical patients: patients with non-classical 21-hydroxylase deficiency should receive glucocorticoid therapy if they have symptoms and signs of excessive androgen. Children with precocious puberty are given a small dose of glucocorticoids. Young women with non-classical patients should also be treated with glucocorticoids if they develop hirsutism, menstrual thinning or amenorrhea, and acne. Infertility should also be treated with glucocorticoid replacement because hormonal disorders are a major obstacle to pregnancy and are easy to conceive after treatment. After glucocorticoid treatment inhibits excessive secretion of adrenal androgen, the clinical symptoms of excessive androgen are gradually improved. Treatment with glucocorticoid alone is difficult to relieve hirsutism because the hair follicles that have formed are difficult to eliminate. As an aid, cosmetic treatment of hirsutism can be recommended to these patients. Male non-classical 21-hydroxylase deficiency patients have improved spermatogenic and fertility after receiving glucocorticoid therapy. Non-classical male patients with testicular enlargement should also receive glucocorticoid therapy.
Glucocorticoid therapy may be considered for patients with non-classical 21-hydroxylase deficiency who have been relieved of symptoms, or for non-classical patients who have passed the reproductive age.
(3) Stress dose: In the case of adrenal crisis, the treatment of adrenal crisis uses 0.9% saline to maintain blood volume (at least 20 ml/kg intravenous bolus). After acute expansion, it was maintained intravenously with 0.9% saline and a small amount of dextran at a rate twice the rate of maintenance. In the absence of a definitive diagnosis, blood samples were taken before glucocorticoid treatment to detect androgen, 17-OHP, ACTH and cortisol. Hydrocortisone is preferred for treatment. For intravenous use, hydrocortisone has mineralocorticoid activity. The initial dose is 25mg for newborns, 50mg for children, and 75-100mg for puberty. After the initial loading dose, 50 to 100 mg/(m2·d) must be administered intermittently, divided into 6 times.
The dose of hydrocortisone under stress is 40-100 mg/(m2·d). It can be taken orally, once every 8 hours, or intravenously, every 6 hours. The dosage, the route of administration and the number of administrations are determined according to the stress. Increase the dose of the drug for any febrile illness (until the fever is removed for 24 hours). The dose is 3 to 5 times the usual maintenance dose. Glucocorticoids should be administered parenterally when more severe stress or oral effects are affected. In these cases, a larger dose of 75 mg/(m2·d) is required. The dose of hydrocortisone should also be increased before surgery. The preoperative night was given 3 to 5 times the usual dose, and the hydrocortisone intravenous load was given during the induction of anesthesia before surgery. The dose given at the time of induction was similar to the initial dose used for adrenal crisis: neonatal 25 mg, children 75 mg, puberty and adult 75-100 mg. Stress protection should last for 24 to 72 hours, depending on the type of surgery and recovery. Gradually reduce to the maintenance amount.
Non-classical 21-hydroxylase deficiency patients do not need to be given a stress dose of hydrocortisone during surgery unless iatrogenic cortical dysfunction is previously caused by long-term glucocorticoid therapy.
2. Problems in treatment and progress in treatment Over the past 50 years, with the use of glucocorticoid and mineralocorticoid replacement therapy and LHRH agonists to control LHRH-dependent precocious puberty, the quality of life of patients with CAH has been significantly improved. Despite many advances, treatment programs currently do not allow many CAH children to have normal growth and development. The treatment of adult CAH may have iatrogenic Cushing's syndrome, which does not adequately control hyperandrogenism and infertility. Even if the patient's compliance is very good, these problems are not solved.
In the treatment of 21-hydroxylase deficiency, the application of physiological doses of hydrocortisone can normalize plasma ACTH levels in CAH patients. Exogenous hydrocortisone (2/d or 3/d) does not accurately mimic the close time-dependent relationship between ACTH pulse secretion and cortisol pulse. In addition, CAH patients often have a decreased central sensitivity to glucocorticoid feedback inhibition. Decreased glucocorticoid sensitivity further reduces the central role of glucocorticoid therapy, while peripheral glucocorticoid sensitivity can be maintained, leading to side effects such as growth inhibition.
Even though ACTH secretion can return to normal in CAH patients, androgen synthesis does not return to normal, because the steroid intermediates that flow into the androgen pathway after 21-hydroxylase blockade during adrenal hormone synthesis are more than normal. In order to prevent excessive secretion of endogenous androgen in the adrenal gland in CAH, the rate of cholesterol side chain cleavage must be reduced below normal levels in order to avoid excessive accumulation of 17-hydroxyprogesterone and diversion into the androgen pathway. In order to inhibit the rate of cholesterol side chain cleavage below normal levels by negative feedback, it is necessary to apply a physiological dose of glucocorticoid. Traditional treatments are difficult to maintain a balance between hypercortisolemia and hyperandrogenism. Excessive levels of glucocorticoids, such as obesity, decreased growth rates, or other clinical features of Cushing's syndrome, are common in treated patients. Symptoms and signs of hyperandrogenism include: masculinization in women, precocious puberty in men, and the short height of adults in both women and men. Another complication in children is central precocious puberty, delayed CAH diagnosis, and poor precocious puberty in patients with poor adrenal androgen secretion therapy, which complicates the problem of excessive adrenal androgen secretion.
The height of adults with CAH is often lower than normal, possibly due to hypercortisolemia (iatrogenic), or hyperandrogenemia, which indirectly affects the growth axis through hyperestrogenemia, or both. Retrospective studies have shown that the final height of the treated patients is relatively independent of the level of adrenal androgen control. In theory, patients treated with hydrocortisone closest to the physiological dose have the worst control of adrenal androgen levels and skeletal maturity, and therefore, the final height will decrease due to early bone closure. However, excessive glucocorticoids also inhibit growth. Constantly adjusting the dose and finding the best balance point according to different individuals is the art of medication. A randomized controlled prospective crossover trial showed that patients treated with hydrocortisone 15 mg/(m2·d) were less likely to have skeletal inhibition than patients treated with 25 mg/(m2·d).
Once growth and development is completed, female CAH patients continue to face problems with hirsutism, amenorrhea and infertility. Classical CAH girls are often delayed in menarche, such as ovarian dysfunction in PCOS. Androgen directly impedes follicular maturation or affects the hypothalamic-pituitary-gonadal axis; however, irregular menstruation in CAH girls, non-ovulation and infertility are not always caused by untreated hyperandrogenism. Female CAH adrenal progesterone secretion increased, adrenal-derived estrogen levels increased. Ovarian dysfunction in CAH girls may also be due to abnormalities in the levels of the hypothalamus, pituitary or ovary.
Because of the thorny treatment of CAH patients, there are many problems mentioned above, so we are currently working on some new treatments. The goal of the new treatment program is to achieve normal growth and development in CAH children, and to maximize the quality of life in adult CAH. For example, because estrogen, not androgen is the cause of skeletal maturity and early closure of the epiphysis, reducing estrogen production can prevent or improve short stature to some extent. Some scholars are studying the use of aromatase inhibitors (blocking the conversion of androgens into estrogens) and androgen antagonists (reducing the degree of masculinity) to aid in the treatment of 21-hydroxylase deficiency. These drugs can reduce the amount of glucocorticoids without further masculinization or accelerated bone maturity, and have achieved initial results. Adrenalectomy is another highly controversial treatment. Some experts recommend that women with severe masculinization and loss of salt type (allele genotypes with an enzyme activity of O) undergo adrenalectomy during genital reconstruction surgery (within 1 year of age). This method is based on the fact that women must be treated to suppress the adrenal glands in the later stages of life, and surgical removal of the adrenal glands can cure. Treatment with an alternative dose of hydrocortisone and aldosterone after adrenalectomy is simpler than inhibition of the adrenal gland with glucocorticoids. In addition, elevated precursors in some types of CAH cause sodium retention, making treatment more difficult, especially in adrenal crisis. The objection is that recent studies of cancer patients have shown that some adrenal androgens are beneficial to women. Therefore, it is not entirely beneficial to deprive women of all adrenal androgens due to adrenalectomy, and other treatments should continue to be studied.
The latest treatment for CAH is gene therapy. Some research centers currently test this treatment in animal models.
3. The treatment of all genital malformations prior to external genital reconstruction surgery is to enable the patient to have normal sexual function and fertility. Therefore, 46, XX masculine CAH children are usually raised by women, and 46, XY children are raised by men. The initial surgical procedure is to improve the appearance of the external genitalia in the early stages of life (the clitoris hypertrophy is standard) and to make the genitals more suitable for sexual intercourse later (usually after puberty). Some patients are dissatisfied with the outcome of the procedure, and the proportion of male sexual orientation increases in these patients. Improved surgical procedures are now recommended: one-time complete reconstruction surgery within 1 year of age and avoiding damage to sensitive clitoris tissue (fary plasty). Because the patients undergoing this procedure are still young, the treatment outcomes of these new surgical procedures cannot be fully evaluated.
The current goal of treating patients with CAH is to obtain optimal psychotherapy outcomes while considering fertility. The doctor should provide the patient's family with detailed information on each treatment method and let the family make the final decision. In addition, some scholars suggest that in the neonatal period, it is decided to support the sex but not surgery until the child is too big to determine his or her gender orientation. There is not enough evidence to determine whether this method can cause psychological trauma or less trauma than traditional surgical methods.
(two) prognosis
1. The adrenal crisis is the only threat to life and can occur in untreated salt-loss infants.
2. The effect of growth due to the increase of androgen secretion before treatment, the bones mature early, so that the bones close early, can lead to short stature, non-salt-type male sick children are prone to delay diagnosis, resulting in short stature, excessive corticosteroid use It also often causes short stature.
3. Sexual development and fertility effects caused by sexual development and fertility are mainly caused by inappropriate treatment.
If the symptoms can be properly treated at an early stage, the prognosis is still good, and there may be normal growth and fertility.
prevention
If diagnosed early, it will begin to inhibit ACTH secretion even before surgery to correct severe organ malformations. Then the appearance can be found normally and the development is excellent. Delayed treatment will inevitably lead to growth retardation, such as coronary heart disease, will die early in myocardial infarction. In some female pseudohermaphroditism, menstruation will come after treatment. When the deformity is not serious or after surgery, the patient may become pregnant and give birth.
1. Screening for neonatal CAH mainly refers to the screening diagnosis of neonatal 21-OHD. The purpose is to prevent life-threatening adrenal crisis and the resulting brain injury or death, prevent female children from being wronged by gender due to masculinization of external genitalia, prevent shortness, and psychological development after excessive androgen deficiency. Obstacles, so that children get early diagnosis and treatment before clinical symptoms appear.
The newborn CAH screening method is to take blood from the heel and drop it on a special filter paper for 3 to 5 days after birth. By using various detection methods, such as enzyme-linked immunosorbent assay (ELISA), The 17-OHP concentration in the filter paper is measured by fluorescence immunoassay for early diagnosis. 17-OHP of normal infants can be >90nmol/L after birth, and will fall to normal after 12-24h. The level of 17-OHP has a certain relationship with birth weight. The normal 17-OHP level is below 30nmol/L, the low birth weight (1500～2700g) is 40nmol/L, and the very low body weight (<1500g) is 50nmol/L. Newborns born after the birth of some cardiopulmonary diseases, 17-OHT will also rise, due to the above reasons can lead to increased false positive rate and recall rate. In general screening, 17-OHP>500 nmol/L is typical CAH, and 150-200 nmol/L is found in various types of CAH or false positives. Positive cut points for 17-OHP screening should still be based on laboratory methods and adjusted for long-term observations and lessons learned. Positive cases should be closely followed to confirm the diagnosis by measuring plasma cortisol, testosterone, DHEA, DHA and 17-OHP levels.
2. Prenatal diagnosis and treatment 21 hydroxylase gene analysis should be performed on CAH patients and parents. When the mother is pregnant again, oral dexamethasone 20μg / (m2?d) (generally 1 ~ 1.5mg / d) at 4 to 5 weeks of pregnancy, chorionic membranous (CVS) biopsy at 9 to 11 weeks of pregnancy Chromosome detection, DNA analysis of CYP21B gene, such as the above results suggest that the fetus is male, heterozygous or normal fetus, can be discontinued dexamethasone treatment. Amniocentesis detection indicates that the fetus is likely to be a female homozygous child, then dexamethasone is treated until the birth of the fetus.
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