Congenital adrenal hyperplasia caused by what?Almost all CYP21 and CYP21 mutations are the result of recombination between CYP21P (unequal exchange or conversion). About 20% of mutant alleles carry deletions. About 75% of the mutant allele is the result of gene conversion. 32% of patients the loss of salt on a large deletion allele or conversion mutation, 56% in one allele has a point mutation in intron 2 causes abnormal RNA splice. In in vitro experiments confirm that these mutations 21 - hydroxylase activity completely or almost completely lost. In simple virilizing, the most common mutant allele (35%) of 172 amino acid substitution mutation in codon exists (Ile into Asn), we have only the normal 21 - hydroxylase 2% to 11% of the activity. The most common type of non-classical (39%) of 281 amino acid mutation is the first mutation (Val into Leu).
Between genotype and phenotype in a high degree of correlation exists, therefore, DNA analysis can be predicted to some extent, activity, and then speculated that the clinical manifestations.Synthesis of 3 types of adrenal steroids: glucocorticoids (cortisol is the most important one); mineralocorticoid (aldosterone is the most important one); androgen. Circadian rhythm of cortisol secretion, is essential in stress situations; it will cause a lack of adrenal crisis include low blood pressure and low blood sugar, if not timely medical treatment lead to death. Adrenal androgen excess generated will lead to intrauterine m
asculine, female infants born with genital hermaphroditism in males and females are slightly larger than the age of the early occurrence of early adrenal gland. Adrenal and gonadal androgen build barriers will lead to masculine men, lack of pubertal development. In CAH, the steroidogenic enzyme activity decreased to varying degrees, resulting in glucocorticoid, mineralocorticoid and sex hormone secretion anomalies, which have varying degrees of clinical manifestations. The decline in activity level and clinical phenotype in turn, the severity of mutation and mutation type. To better understand the clinical manifestations of CAH, it is necessary to understand summary of adrenal steroid hormones and related biochemical genetic situation.
1.P450SCC gene (CYP11A) is 20kb of the single gene, located in the long arm of chromosome 15 (15q23 ~ 24). In all steroid cells.
2.3 -HSD (3 -hydroxysteroid Dehydrogenase , 3 -hydroxysteroid dehydrogenase ). The microsomal hydroxysteroid dehydrogenase with the membrane, and smooth endoplasmic reticulum related. It catalyzes the carbon atoms 3 hydroxyl groups into carbonyl and double bond from the B ring (delta5 steroids) to the A ring (delta4 steroids) heterogeneous. It acts on four kinds of substrates, pregnenolone into progesterone, 17 -hydroxy pregnenolone into 17 -hydroxy progesterone, dehydroepiandrosterone (DHEA) into androstenedione, androstenedione into testosterone. There are 2 different isozymes: -type activity in the adrenal glands and gonads are, -type in other tissues (skin, placenta, breast, etc.) in activity. 3 -HSD gene (HSD 1 and HSD 2) and 93% homology, are located on chromosome 1 (1p13.1).
3.P450C17 (17 -hydroxylase / 17,20 lyase). P450C17 is a microsomal enzyme, combined with the smooth endoplasmic reticulum. Catalyst 2 different and completely independent of the reaction: 17 -hydroxylase and 17,20 lyase reaction. By 17 -hydroxylation, pregnenolone into 17 -hydroxy pregnenolone, progesterone into 17 -hydroxy progesterone. After these 2 substrates C17, 20 carbon chain cleavage were generated DHEA and androstenedione. The gene encoding this enzyme is a single gene (CYP17), located on chromosome 10 (10q24.3).
P450C17 complete lack of time (such as spherical zone), aldosterone can be synthesized, but not cortisol and sex hormone synthesis. If there is only 17 -hydroxylase activity, cortisol can be synthesized, and must rely on two kinds of sex hormone activity of the 17 -hydroxylase and 17,20 lyase. For example, before puberty, the normal adrenal synthesis of cortisol, but not the synthesis of sex hormones that are 17 -hydroxylase activity but not 17,20 lyase.
4.P450C21 (21 - hydroxylase). P450C21 is combined with the smooth endoplasmic online, the actual competition with the P450C17 P450 reductase from the membrane-bound electron. It makes progesterone and 17 -hydroxy progesterone, respectively, into 11 - deoxy-cortical steroid ketones (DOC) and 11 - deoxy cortisol. 2 CYP21 gene located on chromosome 6 (6p21.3), in the human leukocyte antigen (HLA) in the middle, in the HLA-B and HLA-DR between. CYP21 gene encodes a biological activity of the enzyme. Pseudogene called CYP21P. CYP21P and CYP21 have more than 93% homology, but because CYP21P some deleterious mutations, the gene is not transcribed P450C21 the mRNA. Because there CYP21P and CYP212 genes highly homologous to gene conversion to occur, and this is the high incidence of CYP21 gene mutations in one of the reasons.
5.P450C11 (C11 -hydroxylase). Bundle with the activity in the adrenal gland, mainly related to cortisol synthesis. Located in the inner membrane of mitochondria, the mitochondrial membrane so that 11 - deoxy-cortisol into cortisol and 11 - deoxy ketone into cortical steroid corticosterone. The gene encoding it is located on chromosome 8 (8q 21 ~ 22).
The steroid hormone coding gene mutation, hormone synthesis and obstacles can cause CAH. CYP21 and CYP11 defects can cause women masculine, and HSD3 2, CYP17, and StAR deficiencies can cause disorders of androgen synthesis, leading to lack of male masculinity. HSD3 2 some types of defects can cause mild masculine women.
Gonadal and adrenal steroidogenesis in the same way, therefore, part of the clinical presentation is due to abnormal gonadal steroid synthesis caused an exception rather than the cause of adrenal hormones. In the fetal period, the degradation of Tony''s management structure is produced due to the non-steroidal testicular material - seedlings venturi inhibitor. Therefore, no fetal testicular testosterone levels regardless of how the inside will have normal female genital anatomy. A normal fetal testis, regardless of the level of testosterone, Mullerian structures are not developed.Congenital adrenal hyperplasia which performance and how to diagnose?
Due to lack P450c21 different levels, 21OHD into the typical loss of salt type and simple virilizing and atypical (delayed or light) three.
1. The typical clinical manifestations of 21-OHD
(1) simple virilizing: P450c21 partial lack of accounting for the total number of 21-OHD were 25%. Aldo and blood cortisol (F) blocked the synthesis of, the feedback of ACTH secretion in the case, and can still maintain Aldo, F close to normal levels or below normal. No obvious clinical symptoms of salt loss, the main clinical manifestations of androgen symptoms and signs of increased. Like normal external genitalia at birth, a few slight increase penis and scrotum pigmentation. These children increases with age, usually after 2 years of age clear signs of androgen excess, thick penis, but not testosterone increases the increase in gonadotropin secretion, so there is no increase testosterone, which is true precocious puberty completely different, which is significantly associated with testicular development. Women can be expressed as clitoral hypertrophy, labial fusion with or without serious cases, like the scrotum completely fused labia, clitoris hypertrophy like the penis, urethral opening in the hypertrophy of the clitoris under (like hypospadias), like male external appearance genital but failed to reach the testicles, but still within the genitals of women. Both men and women 21-OHD, the abnormal increase of androgens, usually 4 to 7 years old can be a marked beard, pubic hair, armpit hair, some even in infancy there pubic hair development. Also, there body odor, baldness, acne and so on. Because ACTH increased in the skin folds of varying degrees of pigmentation. Because male hormones increase, children with early height growth accelerated over the same age, same sex normal children, physically strong, like "Little Hercules", after epiphyseal maturation in advance as early as closed, leading to the final adult height was significantly lower than normal.
(2) loss of salt type: P450c21 complete lack of accounting for the total number of 21-OHD were about 75%. In addition to the clinical appear simple virilizing a series of clinical manifestations, it can also result in a loss due to serious lack of Aldo symptoms of salt. Often 1 to 4 weeks after birth, loss of salt and symptoms appear, and because cortisol synthesis accompanied by disorder, often with varying degrees of adrenal insufficiency performance, such as vomiting, diarrhea, dehydration and severe metabolic acidosis, it is difficult to correct hyponatremia, hyperkalemia, if not timely diagnosis and treatment have resulted in lower blood volume, blood pressure, shock, circulatory failure. Increases with age, usually in the 4 years of age, the body''s tolerance for loss of salt increased, the phenomenon of loss of salt and gradually improved.
Type due to loss of salt more than the simple virilizing CAH attention, and can be treated earlier, Wyk JJV, etc. The survey found that loss of salt, the final height of adult-type persons (156.8 6.6) cm, simple virilizing those final height ( 153.3 5.4) cm; about 1 / 3 CAH who were below the normal final adult height of 3 standard height percentile or lower than its parent. Pituitary - gonadal axis (hypothalamus-pituitary-gonads axis) of mature inhibition, leading to poor and adult testicular development troubles sperm no sperm or less; accompanied by a small number of male patients with precocious puberty.
2. Atypical (delayed or light) 21-OHD activity in the normal type of the P450c21 20% to 50%. This type of CAH in about 1 / 3. More common in white women. These patients had no clinical symptoms after birth, normal external genitalia, increases with age, mostly in childhood or adulthood, gradually emerging signs of increased androgen. Hairy, delayed menarche, secondary amenorrhea or less after a month. The boy appeared earlier beard, pubic hair, acne, decreased sperm can cause fertility barriers. Thus atypical 21-OHD is caused by reduced fertility of men and women a reason, women with secondary amenorrhea or decreased menstrual flow, for women with polycystic ovary syndrome, impaired fertility and all the best to do the screening for CAH diagnosis.
1. Check the external genital malformations of the suspected 21 - hydroxylase deficiency in the newborn examination must clear the urethra, paying careful palpation of the inguinal canal, labia or scrotum in the gonads. Laboratory tests include at least the basis of serum 17-OHP, the best to ACTH1 ~ 24 stimulation test, intravenous ACTH1 ~ 24250 g, measured before treatment (ml) and 1h after treatment of serum 17-OHP. 17-OHP values are generally based on more than 100ng/ml. Loss of salt-type patients after ACTH excited up to 220nmol / L (1000ng/ml). Simple virilizing patients with lower levels of 17-OHP, but the loss of salt and some overlap of patients. Patients usually require non-classical ACTH stimulation test to diagnose. In newborns, these checks must be postponed to a later birth 24h. These checks can clear in adrenal steroid synthesis defects. Once complete, the importance of monitoring children''s vital signs to see if there is adrenal crisis. Despite the loss of rare salt crisis within 7 days of birth, many doctors in the neonatal detection of electrolytes 1 week, to see whether there is CAH neonatal hyponatremia and hyperkalemia.
2. Check the help to understand the reasons for genital hermaphroditism rapid karyotype analysis and pelvic and abdominal ultrasound. After the initial inspection and carry out further checks. Analysis of disease data as soon as possible, to the families on the determination of sex and drug / surgical treatment recommendations.(1) ACTH1 ~ 24 stimulation test.
(2) loss of salt in the examination.
(3) for the diagnosis and monitoring of 21 - hydroxylase deficiency of other hormones.Congenital adrenal hyperplasia should do what check?
1.ACTH1 ~ 24 stimulation test for the classic 21 - hydroxylase deficiency patients, based on clinical manifestations and basic 17-OHP, generally confirm the diagnosis. The underlying value of serum 17-OHP can not provide sufficient diagnostic evidence, it is necessary to ACTH1 ~ 24 stimulation test. Generally speaking, 60min, 17-OHP levels above 10ng/ml consider non-classical 21 hydroxylase deficiency diagnosis. Each laboratory should be under the 21-hydroxylase deficiency and normal heterozygous carriers determine their own diagnostic criteria.
For newborns. If the under genital hermaphroditism suspected CAH, ACTH1 ~ 24 stimulation test must be delayed until 24h after birth. If the samples taken immediately after birth will have a higher rate of false positive and false negative rates.
ACTH1 ~ 24 stimulation test is also useful in differential diagnosis. Defects in other enzymes in CAH patients also increased 17-OHP, such as 11 -hydroxylase deficiency, or 3 -hydroxysteroid dehydrogenase deficiency. In order to identify defects in a variety of enzymes, the best detection method is 0,60 min 17-OHP, DOC, cortisol and 11 - deoxy-cortisol and 17 - hydroxy pregnenolone, DHEA and androstenedione. If the young infant, blood volume is a problem, you can only 60min, blood. Precursors and the ratio of the identification of the product particularly useful for a variety of enzyme deficiencies. If the diagnosis is still not clear, patients should be on the experimental treatment, then some reduction in the glucocorticoid re-examination or complete termination.
2. Loss of salt Check the PRA (plasma renin activity) rises, in particular the ratio of PRA and aldosterone increased 24h urinary aldosterone synthesis obstacle marks. Circulating blood in the ACTH ,17-0HP and progesterone levels high, but patients with normal aldosterone levels also increased in these indicators, so there is no good biological control performance of simple virilizing patients with loss of salt and type of confusion. Mineralocorticoid therapy for these patients adrenal suppression, contribute to the identification of the two. Ideally, plasma and urinary aldosterone levels should be associated with the PRA and sodium balance, thus helping to determine the accuracy of clinical types. In analyzing the significance of renin levels, higher than the normal newborn should be noted that older children.
3. For the diagnosis and monitoring of the 21 - hydroxylase deficiency of other hormones and biochemical diagnostic tests for a number of other considerations, but rarely extensively. 21 - deoxy cortisol can detect more than 90% of the CAH carriers. Androgen metabolites (3 -diol glucuronide male alkyl) levels in non-classic 21 - hydroxylase deficiency in patients with elevated testosterone and androstenedione levels and a high degree of correlation. 17-OHP in urine the main metabolite of glycerol can also be used for pregnant 21 - hydroxylase deficiency diagnosis. In addition, pregnancy estriol glucuronide in urine can be used to monitor treatment effects and whether the treatment of excessive. ELISA or RIA as a substitute method of steroid metabolites in urine by GS / MS method for detection, this method can make the CAH steroid metabolic diseases and other related indicators at the same time to be detected.
1. Of the nuclear chromatin chromosome positive women, compared to negative male and female sex chromosome to chromosome counting XX, males XY, to determine their true gender.
2.B-mode ultrasound examination of congenital adrenal hyperplasia in female pseudohermaphroditism normal genitals, B ultrasound and X-ray contrast by intubation can display the uterus and fallopian tubes. B-, CT, MRI may help differentiate adrenal hyperplasia or tumor, congenital adrenal hyperplasia and other bilateral increases, while the tumors were unilateral solitary mass, may have calcification, hemorrhage and necrosis may be due to the formation of liquid cavity.
3. Other female pseudohermaphroditism adrenal hyperplasia who, with urinary tract endoscopy urogenital sinus, vaginal opening in the cervix can be seen, if the family of 21 - hydroxylase deficiency, can be used polymerase chain reaction (PCR), HLA typing of amniotic cells and DNA analysis.Congenital adrenal hyperplasia and the diseases easily confused?1. Mainly 11 -hydroxylase deficiency (11 -OHD) Identification of 11 -hydroxylase (P450c11 ) deficiency is the second common type of CAH, accounting for only 5% to 8%. The incidence in the populati / 1 million.
When the CYP11B1 gene defects, the result caused by 11 -OHD CAH, the adrenal 11 - deoxy-cortisol (S) can not be transformed into cortisol (F), deoxy corticosterone (DOC) can not be transformed into corticosterone (S), the end can not be synthesized Aldo, resulting in increased blood concentration of DOC and S, DOC is also a strong sodium retention hormones, can cause hypernatremia, hypokalemia, hypertension, alkalosis, through feedback, the renin - angiotensin inhibited, the Aldo synthesis decreased, blood PRA and Aldo levels. Because cortisol synthesis blocked, there may be to reduce the symptoms of adrenal function, ACTH levels increase, the male hormone that DHEA, 4-A, testosterone, increased levels of urinary 17-KS, a similar 21-OHD of symptoms and characteristics of androgen.
2. Other enzyme deficiency led to the identification of CAH in Table 3. Loss of salt-type 21-OHD and chronic adrenal insufficiency (hypoadrenocorticism, Addison disease) identification, Addison disease beneath salt, reducing cortisol, sex hormones decrease, no masculine symptoms, and 17-OHP to normal.
4. Simple virilizing CAH and the identification of the following diseases
(1) males with precocious puberty should identify: genital morphology similar to the testes and penis while the latter increases, close to puberty ,17-KS and the level of testosterone of puberty, but normal 17-OHP, FSH, LH increased .
(2) Women with this type of CAH need to distinguish true hermaphroditism, although the external genitalia can be masculine, but the latter 17-KS serum androgen and testosterone levels can be normal.
(3) of adrenal tumors in male: male after the birth of the progressive development of symptoms, serum androgen levels increased ,17-OHP may be normal, B ultrasound or CT can be found in the side of the adrenal mass.
5. Women atypical 21-OHD with polycystic ovary syndrome, which occurred in the identification of women of childbearing age, with symptoms and signs of hyperandrogenism, and insulin resistance in; B showed multiple ovarian cysts over.Congenital adrenal hyperplasia can be complicated by the diseases?
As early epiphyseal maturation, early closure, resulting in adult height was significantly lower than normal; there are different levels of performance adrenocortical insufficiency, such as vomiting, diarrhea, dehydration and severe metabolic acidosis, it is difficult to correct the low sodium, high blood Potassium disorders, resulting in lower blood volume, blood pressure, shock, circulatory failure; poor testicular development, sperm no sperm or less; male patients associated with precocious puberty, women with delayed menarche, secondary or hypomenorrhea amenorrhea; induced fall in fertility between men and women.Congenital adrenal hyperplasia should be how to prevent?
1. Newborns mainly refers to the newborn screening for CAH 21-OHD in the screening and diagnosis. Purpose is to prevent life-threatening adrenal crisis and the resulting brain damage or death, prevention of female genital virilization in children caused by the sex determination of the error, caused by the prevention of androgen excess after the short stature, mental, physical development, etc. barriers, so that before the appearance of clinical symptoms in children with early treatment.
CAH newborn screening is a baby born every 3 to 5 days after birth, in the heel blood, dripping on special filter paper, by using various detection methods, such as enzyme-linked immunosorbent assay (ELISA), Determination of fluorescence immunoassay and other film filter paper blood 17-OHP concentrations for early diagnosis. Normal 17-OHP after birth can 90nmol / L, 12 ~ 24h to normal after. 17-OHP levels and there is a certain relationship between birth weight and normal full-term children 17-OHP levels in 30nmol / L the following, low birth weight (1500 ~ 2700g) for 40nmol / L, very low birth weight (<1500g) was 50nmol / L after birth the newborn, such as consolidation of some cardiovascular diseases will rise 17-OHT, for these reasons can lead to false-positive rate and recall rate increased. When the general screening 17- 500nmol / L is a typical CAH, 150 ~ 200nmol / L can be found in all types of CAH or false positive. 17-OHP cut-off point of screening positive should the development of the various laboratory methods, and through observation and lessons learned to be adjusted. Positive cases require close follow-up, by measuring plasma cortisol, testosterone, DHEA, DHA, and 17-OHP levels in order to confirm the diagnosis.
2. Prenatal diagnosis and treatment of CAH patients first, and parents who should be 21-hydroxylase gene analysis. When the mother was pregnant again at 4 to 5 weeks of pregnancy, oral dexamethasone 20 g / (m2 Â· d) (generally 1 ~ 1.5mg / d), 9 to 11 weeks gestation, the chorion (CVS) biopsy done chromosome detection, DNA analysis of the CYP21B gene, such as the above results suggest that the fetus is male, heterozygous and normal fetuses, dexamethasone treatment can be interrupted. Prompt detection of fetal amniotic fluid of women homozygous for the possibility of children is large, then dexamethasone to fetal birth date.Congenital adrenal hyperplasia should be treated?1. Glucocorticoid P450c21 deficiency upon diagnosis of CAH patients, should immediately be given corticosteroids, such as hydrocortisone (HC) or cortisone acetate treatment. Especially in newborns, the start of treatment dose should be larger enough to suppress ACTH secretion. Children are generally oral dose of 10 ~ 20mg / (m2 Â· d), slightly larger than the physiological requirements, the total general points 2 to 3 times, as early as 1 / 2, afternoon and evening of the 1 / 4. CAH patients generally require higher doses of glucocorticoids to suppress ACTH and androgen levels, in order to achieve better therapeutic effect, the adrenal cortex to maintain a low response state, the control is not ideal for a period of time are required to give a high dose of HC [20 ~ 25mg / (m2 Â· d)] in order to achieve an appropriate degree of adrenal atrophy, later given the dose to maintain close physical needs. Glucocorticoid dose rate should still be based on height, bone maturation ,17-OHP, androstenedione, testosterone, cortisol and other indicators of a comprehensive analysis to adjust. If the patient has entered to adulthood (> 16 years), the epiphysis is closed at this time can be given at bedtime a 0.25 ~ 0.5mg of dexamethasone to suppress ACTH secretion in the next morning. Under stress, glucocorticoid dose should be increased to 2 to 3 times the original dose to avoid adrenal insufficiency crisis.
Female patients need lifelong glucocorticoid replacement therapy; simple virilizing CAH in the male patients into adulthood, has reached final height, it can interrupt treatment. But when the stress level should be appropriate to add some according to the severity of glucocorticoid; loss of salt-type persons, both men and women should be life-long treatment. For those associated with precocious puberty, while to the LHRH-a treatment, the dose 4 g / (m2 Â· d).
Glucocorticoid treatment in the same time give mineralocorticoid hormones (such as 9 -FHC), can significantly improve the state of loss of salt and other help to improve the clinical symptoms and signs, to reduce corticosteroid dose, avoid face and growth retardation Cushing. Salt loss in neonates and infants of poor tolerance, larger doses of 9 -FHC 0.15 ~ 0.3mg / d, sometimes added to the diet every day to be 1 ~ 2g salt; small dose of children age 0.05 ~ 0.15mg / d.
2. Acute adrenal failure treatment
(1) to correct dehydration: mild to moderate dehydration, intravenous infusion in the first 2h in 5% to 10% glucose saline 20 ~ 40ml/kg.
(2) to correct hyponatremia: complement sodium (mmol / L) = (135 a measured value) 0.6 body weight, 8 ~ 12h to give the early half of the total, more than half the amount into the amount of maintenance supplies; available 9 -FHC 0.05 ~ 0.1mg / d orally; for mild hyponatremia, "2 years old can be taken orally NaCl 0.1 ~ 0.2g/kg,> 2-year-old from the food intake of salt, do not need additional salt.
(3) to correct severe hyperkalemia: 0.5g/kg of glucose plus insulin 0.3U/kg by intravenous infusion.
(4) added HC 100 ~ 200mg / (m2 Â· d) or a cortisone acetate 125 ~ 250mg / (m2 Â· d), 3 times orally, 1 week after the reduction, reduced to 3 to 4 weeks after the maintenance dose.
3. Surgical treatment of different 21-OHD levels, resulting in female patients with different degrees of external genitalia virilization, the light just after the birth of a little clitoral hypertrophy, with the normal development of the vulva was covered, without surgery; such as clitoral hypertrophy has affected to sex determination, then as soon as possible within the 2-year-old clitoris plastic surgery. Some children also have different degrees of fusion of the labia, vaginal stenosis, it often takes in after puberty, if necessary, shaping the premarital vaginal dilation.1. Adrenal crisis is life, the only threat, can occur at the loss of salt-type untreated infants.
2. The growth of androgen treatment due to increased secretion of excessive growth, bone maturation in advance, so early epiphyseal closure, the body can lead to short, non-volatile salt sportsman Erzhi delayed diagnosis of sick children easily dwarf the body, excessive use of corticosteroids also a common cause of short stature.
3. Sexual development and reproduction of sexual development and reproductive effects caused mainly caused by inappropriate treatment.
Symptoms if the appropriate treatment early, the prognosis is still good, can have normal growth and fertility.