Congenital adrenal hyperplasia in children

Introduction to congenital adrenal hyperplasia in children Congenitaladrenal 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, due to decreased cortisol levels, negative feedback inhibition of pituitary release of ACTH is weakened, resulting in excessive secretion of ACTH, adrenal hyperplasia and excessive secretion of hormones and precursors synthesized before the enzyme. Its clinical manifestations and biochemical changes depend on the type and extent of defective enzymes, which can be manifested as changes in sugar, mineralocorticoid and sex hormone levels and corresponding symptoms, signs and biochemical changes such as fetal genital dysplasia, sodium balance disorders, blood pressure changes and Growth retardation, etc. According to the type of defective enzyme, it can be divided into five categories: 12l-hydroxylase (CYP21) deficiency, and is divided into typical sub-salt type, masculine type and atypical type. 211-hydroxylase (CYP11) deficiency can be further divided into type I and type II. 33-hydroxysteroid dehydrogenase (3-HSD) deficiency. 417-hydroxylase (CYP17) deficiency, with or without 17,20-crackase (17,20LD) deficiency. 5 cholesterol carbon chain enzyme deficiency. Clinically, 21-hydroxylase deficiency is the most common, accounting for more than 90%, and its incidence is about 1/4500 newborns, of which about 75% are salt-loss type, followed by -hydroxyl deficiency, accounting for about 5% to 8%, the incidence rate is about 1 / 5000 ~ 7000 newborns, other types are rare. basic knowledge The proportion of illness: 0.001% Susceptible people: children Mode of infection: non-infectious Complications: diarrhea, dehydration, metabolic acidosis, shock, precocious puberty, amenorrhea

The cause of congenital adrenal hyperplasia in children

Body factors (95%):

Almost all CYP21 mutations are the result of recombination between CYP21 and CYP21P (unequal exchange or transformation), about 20% of the mutant alleles carry deletion mutations, and about 75% of the mutant alleles are the result of gene conversion, 32% Loss-of-salt patients have large fragment deletions or transition mutations in one allele, and 56% of point mutations in intron 2 on one allele cause RNA splicing abnormalities, which were confirmed in vitro to make 21-hydroxyl The enzyme activity is completely or almost completely lost. In the simple male type, the most common mutant allele (35%) is the substitution mutation of the 172th amino acid codon (Ile becomes Asn), and only the normal 21-hydroxylation is retained. The enzyme is 2% to 11% active, and the most common (39%) mutation in the non-classical type is the mutation of amino acid No. 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.

Genetic factors (5%):

The gonads and adrenal glands have the same steroidogenic pathway. Therefore, part of the clinical manifestations are caused by abnormal steroid synthesis in the gonads, but not caused by abnormal adrenal hormones. In the fetal period, the degeneration of the Miao tube structure is due to the presence of non-steroidal substances produced by the testes. - Miao's tube inhibitor, therefore, the fetus without the testis will have normal female genital anatomy regardless of the level of androgen, and the normal testicular fetus, regardless of the level of androgen, the Müller tube structure will not develop .

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 of causes adrenal crisis including hypotension and hypoglycemia, if not treated in time will lead to death, excessive adrenal androgen production will lead to intrauterine masculinity, female babies born with genital malformations, at a slightly older age male Adrenal gland is premature in women and women. Adrenal and gonadal androgenetic disorders can lead to male masculinization and lack of puberty. In CAH, steroid synthase activity decreases to varying degrees, leading to glucocorticoids, mineralocorticoids and sex hormones. Abnormal secretion, resulting in varying degrees of clinical manifestations, and 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 adrenal corticosteroids. The biochemical and related genes of hormones.

1. The P450SCC gene (CYP11A) is a 20 kb single gene located on the long arm of chromosome 15 (15q23-24) and expressed in all steroid cells.

2.3-HSD (3-hydroxysteroid dehydrogenase II, 3-hydroxysteroid dehydrogenase II), this microsomal hydroxysteroid dehydrogenase binds to the membrane and is associated with the smooth endoplasmic reticulum, which catalyzes the hydroxyl group of carbon atom 3. The group is converted into a keto group and a double bond from the B ring (delta5 steroid) to the A ring (delta4 steroid) isomerization, which acts on four substrates, the pregnenolone is converted to progesterone, 17-hydroxypregnenolone Conversion to 17-hydroxyprogesterone, dehydroepiandrosterone (DHEA) converted to androstenedione, androstenedione converted to testosterone, with two different isoenzymes: type II active in adrenal and gonads, type I It is active in other tissues (skin, placenta, breast, etc.), and the 3-HSD genes (HSD1 and HSD2) have 93% homology, all located on chromosome 1 (1p13.1).

3. P450C17 (17-hydroxylase/17,20 lyase), a microsomal enzyme that binds to the smooth endoplasmic reticulum and catalyzes two distinct and completely independent reactions: 17-hydroxylase and 17 , 20 lyase reaction, through 17-hydroxylation, pregnenolone is converted to 17-hydroxypregnenolone, progesterone is converted to 17-hydroxyprogesterone, these two substrates are generated by C17, 20 carbon chain cleavage Dehydroepiandrosterone and androstenedione, the gene encoding this gene 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 17-hydroxylase activity is present, cortisol can be synthesized, and sex hormones must rely on two activities, 17-hydroxylase and 17,20 lyase activity, for example, prepubertal, normal synthesis of adrenal cortisol, but no sex hormone synthesis, indicating 17-hydroxylase activity but no 17,20 lyase activity.

4. P450C21 (21-hydroxylase), P450C21 is also bound to the smooth endoplasmic reticulum, which actually competes with P450C17 for electrons derived from membrane-bound P450 reductase, which converts progesterone and 17-hydroxyprogesterone into 11-, respectively. Deoxycorticosterone (DOC) and 11-deoxycortisol, 2 CYP21 genes located on chromosome 6 (6p21.3), in the middle of human leukocyte antigen (HLA), between HLA-B and HLA-DR, CYP21 The gene encodes a biologically active enzyme. The pseudogene is called CYP21P. CYP21P has more than 93% homology with CYP21. However, because of the harmful mutations in CYP21P, this gene does not transcribe P450C21 mRNA, just because of CYP21P and CYP212 genes. There is a high degree of homology that allows gene transfer to occur, which is one reason for the high incidence of CYP21 gene mutations.

5. P450C11 (C11-hydroxylase), active in the adrenal gland, mainly involved in the synthesis of cortisol, located in the mitochondrial inner membrane, the mitochondrial inner membrane transforms 11-deoxycortisol into cortisol and 11-deoxycorticosteroid The ketone is converted to corticosterone, and its coding gene is located on chromosome 8 (8q 21-22).

Mutations in the above-mentioned steroid hormone-encoding genes, hormonal synthesis disorders can lead to masculinization of CAH, CYP21 and CYP11 defects, and HSD32, CYP17 and StAR defects can cause androgen synthesis disorders, resulting in male masculinization, some HSD32 defects Types can cause mild masculinity in women.

Congenital adrenal hyperplasia prevention in children

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, and prevent female genitalia due to external genital masculinization Caused by gender error, prevention of short stature, psychological, physiological development and other obstacles caused by excessive androgen, 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), Fluorescence immunoassay and other determination of 17-OHP concentration in the filter paper for early diagnosis, normal infants after birth 17-OHP can be >90nmol / L, 12 ~ 24h after the decline to normal, 17-OHP level and birth weight have a certain relationship, The normal 17-OHP level is below 30nmol/L, the low birth weight (15002700g) is 40nmol/L, and the very low body weight (<1500g) is 50nmol/L. 17-OHT will also rise in the disease, due to the above reasons can lead to increased false positive rate and recall rate, generally 17-OHP> 500nmol / L for typical CAH, 150 ~ 200nmol / L can be seen in various types of CAH Or false positives, the positive cut point of 17-OHP screening should still be based on each laboratory method, and adjusted through long-term observation and experience, positive cases should be closely followed, by measuring plasma cortisol, testosterone, DHEA, DHA And 17-OHP levels to confirm the diagnosis.

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 20g/(m2·d) is given at 4 to 5 weeks of pregnancy. Generally 1 ~ 1.5mg / d), at 9 ~ 11 weeks of pregnancy, chorionic (CVS) biopsy for chromosome detection, DNA for CYP21B gene analysis, such as the above results suggest that the fetus is male, heterozygous or normal fetus, can be interrupted Dexamethasone treatment, amniotic fluid test indicates that the fetus is likely to be a female homozygous child, then dexamethasone treatment until the birth of the fetus.

Congenital adrenal hyperplasia complications in children Complications diarrhea dehydration metabolic acidosis shock precocious amenorrhea

As the epiphysis matures early and closes 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, hyperkalemia, decreased blood volume, decreased blood pressure, shock, and circulatory failure. Testicular development is poor, no sperm or less sperm. Male patients with true precocious puberty, female patients with delayed menarche, secondary menorrhagia or amenorrhea. Caused the decline in fertility of men and women.

Pediatric congenital adrenal hyperplasia symptoms common symptoms clitoris hypertrophy androgen excess labia fusion hyperkalemia precocious diarrhea amphoteric malformation dehydration metabolic acidosis blood pressure drop

Due to the lack of P450c21, 21OHD is divided into three types: typical salt-loss type and simple masculine type and atypical (late type or light type).

1. Clinical manifestations of typical 21-OHD

(1) Simple male type: P450c21 partial deficiency, accounting for 25% of 21-OHD patients, blood Aldo and cortisol (F) synthesis partially blocked, in the case of increased feedback ACTH secretion, still able to maintain Aldo, F close Normal or lower than normal, there is no obvious salt loss symptoms in the clinic. The main clinical manifestations are the symptoms and signs of androgen increase. The external genitalia seems normal at birth, and a few have mild penis enlargement and scrotal pigmentation. These children grow older, often after 2 years of age, there are obvious signs of excessive androgen, and the penis is thick, but because the increase of androgen is not caused by the increase of gonadotropin secretion, the testicles do not increase, which is true. Sexual precocity is completely different, the latter with testicular development, women can be expressed as clitoris hypertrophy, with or without labial fusion, severely inserted into the scrotum, the clitoris hypertrophy like the penis, the urethra under the hypertrophy of the clitoris (like the urethra Cracked, looks like male external genitalia but failed to touch the testicles, and the internal genitalia is still female, regardless of male and female 21-OHD, due to abnormal increase in androgen, generally can be obvious in 4 to 7 years old Now there are beards, pubic hair, mane, and some even develop pubic hair in infancy. In addition, body odor, baldness, hemorrhoids, etc., due to increased ACTH, there are varying degrees of pigmentation in the skin wrinkles, due to increased androgen, children The early growth of height increased, surpassing the same age, normal children of the same sex, strong body, like "Little Hercules", and later with the early maturity of the skeleton, early closure, resulting in the final adult height is significantly lower than normal.

(2) Loss of salt type: P450c21 is completely lacking, accounting for about 75% of the total number of patients with 21-OHD. In addition to a series of clinical manifestations of simple masculine type, it can also cause symptoms of salt loss due to severe lack of Aldo. Loss of salt symptoms 1 to 4 weeks after birth, and due to cortisol synthesis disorders, often have varying degrees of adrenal insufficiency, such as vomiting, diarrhea, dehydration and severe metabolic acidosis, difficult to correct Low blood sodium, hyperkalemia, if not diagnosed and treated, resulting in decreased blood volume, blood pressure, shock, circulatory failure, with age, generally after 4 years of age, the body's tolerance to salt loss Increased, salt loss gradually improved.

Because the salt-loss type is more likely to attract attention than the masculine CAH, and can get earlier treatment, Wyk JJV and other surveys found that the final height of the lost salt type adult is (156.8 ± 6.6) cm, and the final height of the simple male type ( 153.3 ± 5.4) cm; about 1/3 of CAH's final adult height is lower than the normal 3rd percentile of normal height or significantly lower than the maternal, pithalal-gonadal axis (hypothalamus-pituitary-gonads axis) maturation inhibition, resulting in Poor testicular development and azoospermia or oligozoospermia in adulthood. There are a few male patients with true precocious puberty.

2. Atypical (late or light) 21-OHD This type of P450c21 activity is 20% to 50% of normal people, and about 1/3 of this type in CAH, more common in Caucasian women, these patients are not born after birth Clinical symptoms, normal genitalia, with age, mostly in childhood or adulthood, gradually appearing signs of increased androgen, hairy, delayed menarche, secondary menorrhagia or amenorrhea, boys appear beard early, Pubic hair, acne, and sperm reduction can lead to fertility disorders, so atypical 21-OHD is a cause of decreased fertility in women and men, secondary amenorrhea or decreased menstruation in women, and all women with polycystic ovary syndrome It is best to have a CAH screening diagnosis for people with fertility disorders.

Examination of congenital adrenal hyperplasia in children

1. ACTH124 excitatory test: For patients with classic 21-hydroxylase deficiency, according to clinical manifestations and basic 17-OHP, it is generally possible to confirm the diagnosis. If the serum 17-OHP basic value does not provide sufficient diagnostic basis, it is necessary. Perform ACTH1~24 excitatory test. Generally, the 17-OHP level above 10ng/ml at 60min should consider the diagnosis of non-classical 21 hydroxylase deficiency. Each laboratory should carry heterozygous according to 21 hydroxylase deficiency. And normal people determine their own diagnostic criteria.

For newborns, if CAH is suspected based on hereditary genital hermaphroditism, the ACTH1-24 stimulation test must be postponed until 24 hours after birth. If the specimen is taken immediately after birth, there will be a higher false positive rate and false negative rate.

The ACTH1-24 stimulation test also helps in the differential diagnosis. 17-OHP is also elevated in other enzyme-deficient CAH patients, such as 11-hydroxylase deficiency or 3-hydroxysteroid dehydrogenase deficiency, in order to identify each The best way to detect enzyme defects is to detect 17-OHP, DOC, cortisol and 11-deoxycortisol, 17-hydroxypregnenolone, DHEA and androstenedione at 0, 60 min. If it is a young baby, blood collection If the amount is a problem, blood can be taken only at 60 minutes. The ratio of precursor to product is especially useful for identifying various enzyme defects. If the diagnosis is still unclear, the patient should be treated experimentally and then partially reduced in glucocorticoids. Check again after the amount or complete termination.

2. Loss of salt test: PRA (plasma renin activity) increased, especially the increase in the ratio of PRA to 24h urinary aldosterone marks aldosterone synthesis disorder, ACTH, high levels of 17-0HP and progesterone in circulating blood, but aldosterone These indicators will also increase in patients with normal levels, so that the biochemical performance of a simple masculine patient who is not well controlled will be confused with the loss of salt type. Mineralocorticoid therapy can inhibit adrenal gland in these patients and help to distinguish between the two. Ideally, plasma and urinary aldosterone levels should be correlated with PRA and sodium balance, which can help to accurately determine the clinical type. When analyzing the significance of renin levels, it is important to note that newborns have higher normal values than older children. .

3. Other hormones used to diagnose and monitor 21-hydroxylase deficiency: Other biochemical diagnostic tests are available, but few are widely available. 21-deoxycortisol can detect more than 90% of CAH carriers. , levels of androgen metabolites (3-androstane glycol glucuronide) are elevated in patients with non-classical 21-hydroxylase deficiency, highly correlated with androstenedione and testosterone levels, 17-OHP in urine The main metabolite gestational triol can also be used for the diagnosis of 21-hydroxylase deficiency. In addition, urinary glycerol glucuronide can be used to monitor the therapeutic effect and over-treatment, as an alternative to enzyme-linked immunosorbent assay or RIA. Urinary steroid metabolites can be detected by GS/MS method, which can simultaneously detect CAH and other steroid metabolic disease related indicators.

4. Sex chromosome examination: female nuclear chromatin is positive, male is negative, female chromosome counting sex chromosome is XX, male is XY, can determine its true gender.

5. B-mode ultrasonography: Congenital adrenal hyperplasia female pseudo- and hermaphroditism genital normal, B-ultrasound and intubation X-ray angiography can show uterus and fallopian tubes, B-ultrasound, CT, MRI can help identify adrenal hyperplasia or tumor Congenital hyperplasia is equal to the bilateral adrenal glands, and the tumors are mostly unilateral isolated masses, which may have calcification, and liquefaction cavities may form due to hemorrhage and necrosis.

6. Others: Adrenal hyperplasia, pseudo-hermaphroditism, urethroscopic examination of urogenital sinus, visible vaginal opening in the cervix, if the family has 21-hydroxylase deficiency, polymerase chain reaction (PCR), Amniotic cell HLA typing and DNA were analyzed.

Diagnosis and diagnosis of congenital adrenal hyperplasia in children

diagnosis

1. Check the external genital malformation: For the newborns suspected of 21-hydroxylase deficiency, the urethra must be clearly defined, and the gonads in the inguinal canal, labia or scrotum should be carefully palpated. Laboratory tests include at least the basic serum 17- OHP, it is best to carry out ACTH124 excitatory test, intravenous ACTH124250g, pre-treatment (ml) and serum 17-OHP 1h after administration, 17-OHP basic value usually exceeds 100ng/ml, salt-losing patients are excited at ACTH After the maximum of 220nmol / L (1000ng / ml), the level of 17-OHP in the simple masculine patients is lower, but partially overlap with the patients with salt loss, non-classic patients usually need ACTH stimulation test to diagnose, in neonates, 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 test 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 tested electrolytes during the first week of neonatal examination to see if there were hyponatremia and hyperkalemia in CAH newborns.

2. The examination helps to understand the causes of genital malformation: rapid karyotype analysis and pelvic, abdominal ultrasound examination, after the initial examination, the next step is targeted, the disease data should be analyzed as soon as possible, and the family should be provided with certain gender and Advice on medication/surgical treatment.

3. Further biochemical examination

(1) ACTH124 excitement test.

(2) Inspection of salt loss.

(3) Other hormones used to diagnose and monitor 21-hydroxylase deficiency.

Differential diagnosis

1. Mainly differentiated from 11-hydroxylase deficiency (11-OHD) 11-hydroxylase (P450c11) deficiency is the second most common type of CAH, accounting for only 5% to 8%, and its incidence rate is 1/1 in the population. Million.

When the CYP11B1 gene is defective, it causes 11-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 Decreased synthesis, decreased levels of blood PRA and Aldo, due to obstruction of cortisol synthesis, symptoms of adrenal insufficiency, increased levels of ACTH, androgen DHEA, 4-A, testosterone, urinary 17-KS levels increased, similar to 21 Hyperandrogen symptoms and characteristics of -OHD.

2. The lack of other various enzymes leads to the identification of CAH.

3. Loss of salt 21-OHD is differentiated from chronic adrenal insufficiency (hypoadrenocorticism, Addison disease). Addison disease has lost salt, cortisol is reduced, sex hormones are reduced, 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 testicular 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.

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