Congenital adrenal hyperplasia in children

　　The normal synthesis of adrenal cortical hormones is converted from cholesterol to cortisol, aldosterone, sex hormones, and others under the action of various enzymes. Patients with this disease have a lack of enzymes at different sites in the process of synthesizing the above hormones, resulting in reduced synthesis of cortisol and corticosterone, leading to increased secretion of adrenocorticotropic hormone by the anterior pituitary gland. Due to different enzyme defects, symptoms such as hyponatremia and hypertension may be accompanied.

　　Congenital adrenal hyperplasia not only severely affects the daily life of patients but also, if left untreated for a long time, can lead to other diseases. The main complications include the following.

　　1. Adrenal crisis: Adrenal crisis can occur in infants with salt-losing congenital adrenal hyperplasia who have not been treated. The child shows varying degrees of adrenal cortex insufficiency, such as vomiting, diarrhea, dehydration, severe metabolic acidosis, difficult-to-correct hyponatremia, hyperkalemia, leading to decreased blood volume, decreased blood pressure, shock, and circulatory failure.

　　2. Impact on growth: Due to increased androgen secretion and rapid growth before treatment, bone maturation is accelerated, leading to early closure of epiphyses, which can result in short stature. Non-salt-losing male children are prone to delayed diagnosis and short stature. Excessive use of corticosteroids can also cause short stature.

　　3. Impact on sexual development and fertility: The main reasons for the impact on sexual development and fertility are improper treatment. Patients have poor testicular development, lack of sperm or few sperm. Male patients have true precocious puberty; female patients have delayed menarche, secondary oligomenorrhea, or amenorrhea. Fertility is reduced.

　　This disease is more common in girls, with a ratio of male to female of about 1:4. Deficiency in any enzyme (except 3β-hydroxysteroid dehydrogenase) can lead to excessive adrenal androgen secretion and common symptoms.

　　Common congenital adrenal hyperplasia is caused by defects in 21-hydroxylase (CYP21), 11β-hydroxylase (CYP11B1), 3β-steroid dehydrogenase (3β-HSD), 17α-hydroxylase (CYP17), and other enzymes, as follows:

　　One, 21-hydroxylase deficiency (ZD-OHD)

　　According to the degree of enzyme activity deficiency and the resulting different clinical manifestations, it can be divided into three types: typical simple masculinization, salt-losing type, and atypical type.

　　1, Simple masculinization type: Boys may show同性性早熟. There are no symptoms at birth, and signs of precocious puberty appear after 6 months. The signs are more obvious after 4-5 years old. The external genitalia are significantly enlarged, the scrotum is enlarged, but the size of the testes is proportional to age. Pubic hair, axillary hair, beard, acne, Adam's apple, low voice, and muscular development may appear early. The bone maturation accelerates, so the bone age exceeds the age, so the height is abnormally high at the beginning of the disease, but finally becomes short. The intelligence development of the patient is normal. Female patients may show different degrees of male pattern signs at birth, such as clitoral hypertrophy, varying degrees of labial fusion, similar to male hypospadias, large labia resembling the scrotum of boys, but without testes. Although the external genitalia have hermaphroditism, the internal genitalia are still female, with ovaries, fallopian tubes, and uterus. Pubic hair and axillary hair may appear after 2-3 years. In adolescence, female sexual characteristics are lacking, without breast development and menstruation.

　　2, Salt-losing type: Patients may have symptoms such as refusal to eat, vomiting, diarrhea, no weight gain or weight loss, dehydration, low blood sodium, high blood potassium, metabolic acidosis, and so on shortly after birth. If not treated in time, death may occur due to circulatory failure. Female patients may have hermaphroditism at birth.

　　3, Atypical type: The clinical manifestations are various and the onset age is different. Patients may show male pattern symptoms during childhood or adolescence. Boys may have pubic hair, precocious puberty, accelerated growth, and advanced bone age; female patients may have delayed menarche, primary amenorrhea, hirsutism, and infertility, etc.

　　Two, 11β-hydroxylase deficiency

　　Patients may show male pattern symptoms similar to those of 21-hydroxylase deficiency, but to a lesser extent, with hypertension and sodium retention. Most patients have moderate hypertension, which can be reduced after the administration of glucocorticoids and rise again after discontinuation of medication.

　　Three, 3β-hydroxysteroid dehydrogenase deficiency

　　When this enzyme is deficient, the synthesis of aldosterone, cortisol, and testosterone is all inhibited. Boys may appear pseudohermaphroditism, such as poor penis development and hypospadias. Girls may show mild masculinization at birth. Due to the low secretion of aldosterone, salt loss and dehydration symptoms occur in the neonatal period, and the condition is relatively severe.

　　Four, 17-hydroxylase deficiency

　　Due to the inhibition of cortisol and sex hormone synthesis, the secretion of 11-deoxycorticosterone increases, leading to clinical manifestations of hypokalemia alkalosis and hypertension. Due to the lack of sex hormones, girls may have幼稚型sex characteristics, primary amenorrhea, and other symptoms. Boys may show feminization of external genitalia, breast development, but with testes in the child.

　　Congenital adrenal hyperplasia severely affects the daily life and physical and mental health of children, so it is particularly important to prevent this disease. The main preventive measures are the following two aspects:

　　1. Newborn screening

　　Newborn screening mainly refers to the screening and diagnosis of newborns with 21-hydroxylase deficiency. The purpose is to prevent life-threatening adrenal crisis and the resulting brain damage or death, prevent gender misjudgment in female patients due to virilization of the external genitalia, prevent the growth disorders caused by excessive androgens in the future, and enable early diagnosis and treatment before the appearance of clinical symptoms.

　　2. Prenatal diagnosis and treatment

　　Genetic analysis of the 21-hydroxylase gene should be performed for children with congenital adrenal hyperplasia and their parents. When the mother is pregnant again, oral dexamethasone 20μg/(m2·d) (usually 1-1.5mg/d) should be taken from 4 to 5 weeks of gestation. At 9 to 11 weeks of gestation, chorionic villus sampling (CVS) is performed for chromosomal testing and genetic analysis. If the above results suggest that the fetus is male, a heterozygote, or a normal fetus, the treatment with dexamethasone can be interrupted. If amniocentesis suggests that the fetus is female, with a high possibility of being a homozygote or a fetus with the disease, dexamethasone treatment should continue until the fetus is born.

　　In addition to the obvious clinical manifestations, the diagnosis of congenital adrenal hyperplasia in children also relies on the results of chemical tests. The main examination methods are as follows:

　　Firstly, biochemical tests

　　1. Determination of urine 17-hydroxysteroids (17-OHCS), 17-ketosteroids (17-KS), and pregnenolone. Among them, 17-KS is an important indicator reflecting the secretion of androgens by the adrenal cortex. The 17-KS in patients with adrenal cortical hyperplasia is significantly increased.

　　2. Determination of blood 17-hydroxypregnenolone (17-OHP), renin-angiotensinogen (PRA), aldosterone (Aldo), dehydroepiandrosterone (DHEA), deoxycorticosterone (DOC), and testosterone (T). The elevated baseline value of 17-OHP is a specific indicator of 21-hydroxylase deficiency.

　　3. Blood electrolyte measurement. Salt-losing type may have low sodium and high magnesium血症.

　　Secondly, other examinations

　　1. Chromosome examination. When there is severe malformation of the external genitalia, chromosome karyotype analysis can be performed to distinguish gender.

　　2. X-ray examination. Take an anteroposterior radiograph of the left wrist's radial styloid process to determine bone age. The patient's bone age exceeds their age.

　　3. Ultrasound or CT examination. It can be found that both adrenal glands are enlarged.

　　For children with congenital adrenal hyperplasia, it is first necessary to limit the intake of water and salt-containing foods. The diet should be light, with an emphasis on vegetables and fruits, and eating more bananas and other potassium-rich foods. In addition, patients should avoid eating too much sugary foods, greasy foods, and drinking alcohol.

　　Congenital adrenal hyperplasia in children severely affects the child's life, so it should be treated promptly once diagnosed. The main treatment methods are as follows:

　　First, Glucocorticoids

　　Once diagnosed, the child should be given corticosteroids immediately, such as hydrocortisone HC or cortisone acetate treatment. Especially for newborns, the initial treatment dose should be large enough to inhibit ACTH secretion. Female patients require lifelong corticosteroid replacement therapy; male patients with simple virilization type can discontinue treatment when they reach adulthood and achieve their final height. Salt-losing patients, regardless of gender, should receive lifelong treatment. Concurrent administration of mineralocorticoids such as 9α-FHC during corticosteroid treatment can significantly improve the salt-losing state and is beneficial to improve other clinical symptoms and signs, reduce the dose of corticosteroids, and avoid causing Cushingoid appearance and growth disorders.

　　Second, Treatment for Acute Adrenal Cortex Insufficiency

　　1, Correct Dehydration: For mild to moderate dehydration, 5% to 10% glucose physiological saline 20 to 40ml/kg should be administered intravenously in the first 2 hours.

　　2, Correct Hyponatremia: For children with mild hyponatremia, those under 2 years of age can take NaCl 0.1-0.2g/kg orally; those over 2 years of age can obtain salt from food and do not need to take additional salt.

　　3, Correct Severe Hyperkalemia: Glucose 0.5g/kg plus insulin 0.3U/kg intravenous infusion.

　　Third, Surgical Management

　　Female patients have only a slight enlargement of the clitoris after birth, which is covered by the normal development of the vulva and does not require surgery. If the clitoris is enlarged and affects gender identification, then the clitoral plastic surgery should be performed as early as possible within 2 years. Some children have varying degrees of fusion of the labia and narrow vaginal orifice, so it is often necessary to perform vaginal shaping and expansion surgery after puberty, before marriage.

　　Fourth, Sex Hormones

　　For patients with 20,22 carbon chain enzyme deficiency, 3β-hydroxysteroid dehydrogenase deficiency, and 17α-hydroxylase deficiency, relevant sex hormones should be supplemented until puberty.

　　Fifth, Adjuvant Treatment

　　Due to rapid growth, patients often have osteomalacia and should supplement calcium and vitamin D. During infection, hormones should be increased and active control of infection should be carried out to prevent spread.

　　Sixth, Prenatal Treatment

　　For patients with 21-hydroxylase deficiency, the pregnant mother should take dexamethasone 0.5mg orally, 2-3 times a day, from 3 to 10 weeks of pregnancy, with a maximum dose of 20μgkg·d, which can prevent female infants from having vulvar deformities.